Clinical trial NCT04723394
Conditions: COVID-19
Keywords: Treatment of COVID-19
Sponsor: AstraZeneca
Start date: 2021-01-28; Completion date: 2022-10-19
Enrollment: 910 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase III study will assess whether AZD7442 (a combination of 2 mAbs) can safely treat outpatient adults with COVID-19 and prevent either severe COVID-19 or death.

Detailed description:
A novel coronavirus, SARS-CoV-2, first emerged in China in November 2019 causing cases of atypical pneumonia. As of 6 October 2020, the virus has spread to all corners of the globe, with over 35 million confirmed cases reported and more than one million associated deaths according to the WHO. The COVID-19 pandemic is causing major disruption to global healthcare systems with significant socioeconomic impacts. Effective interventions to prevent or treat COVID-19 remain few in number and clinical experience is limited.

There is an urgent need to rapidly evaluate treatments in the non-hospitalized setting to prevent progression and reduce serious complications of COVID-19, as well as its transmission.

As a response to the ongoing pandemic, AstraZeneca is developing mAbs to the SARS-CoV-2 spike 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 treat or prevent COVID-19. There are currently one ongoing Phase I study and two ongoing Phase III studies with AZD7442, in addition to this treatment study.

Enrollment of up to approximately 1700 participants is planned.

Arms: arm 1: Up to approximately 1700 participants will be randomized in a 1:1 ratio. Arm 1 (n=up to approximately 850) will receive a single dose (× 2 IM injections) of 600 mg of AZD7442. arm 2: Up to approximately 1700 participants will be randomized in a 1:1 ratio. Arm 2 (n=up to approximately 850) will receive saline placebo.
Interventions: intervention 1: AZD7442 intervention 2: Placebo
Intervention descriptions: intervention 1: Single dose (× 2 separate IM injections) of 600 mg of AZD7442 or saline placebo on Day 1. intervention 2: Single dose (× 2 separate IM injections) of 600 mg of AZD7442 or saline placebo on Day 1.

Protocol documents:
SAP_007.pdf: 
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STATISTICAL ANALYSIS PLAN 
Study Code 
D8851C00001 
Edition Number 
5.0 
Date 
20-Sep-2021 
 
 
 
 
 
 
 
 
A Phase III Randomized, Double-blind, Placebo-controlled, 
Multicenter Study to Determine the Safety and Efficacy of 
AZD7442 for the Treatment of COVID-19 in Non-hospitalized 
Adults 
 


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TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................. 2 
LIST OF ABBREVIATIONS ............................................................................................. 5 
AMENDMENT HISTORY .............................................................................................. 7 
1 
INTRODUCTION ....................................................................................... 16 
1.1 
Objectives and Endpoints ............................................................................. 16 
1.2 
Study Design ................................................................................................ 19 
1.3 
Sample Size .................................................................................................. 20 
2 
CHANGES TO PROTOCOL PLANNED ANALYSES .............................. 20 
3 
DATA ANALYSIS CONSIDERATIONS .................................................. 20 
3.1 
Timing of Analyses ....................................................................................... 20 
3.2 
Analysis Populations ..................................................................................... 21 
3.3 
General Considerations ................................................................................. 22 
3.3.1 
Statistical Hypothesis ................................................................................... 22 
3.3.2 
General Study Level Definitions .................................................................. 22 
3.3.3 
23 
3.3.4 
Handling of Unscheduled Visits, Retest, and Early Discontinuation ........... 28 
3.3.5 
 28 
3.3.6 
Handling of Important Protocol Deviations in Study Analysis .................... 28 
4 
STATISTICAL ANALYSIS ......................................................................... 29 
4.1 
Study Population ........................................................................................... 29 
4.1.1 
Participant Disposition and Completion Status ............................................ 29 
4.1.1.1 
Definitions and Derivations ......................................................................... 29 
4.1.1.2 
Presentation .................................................................................................. 29 
4.1.2 
Analysis Sets ................................................................................................ 30 
4.1.2.1 
Definitions and Derivations ......................................................................... 30 
4.1.2.2 
Presentation .................................................................................................. 30 
4.1.3 
Important Protocol Deviations ...................................................................... 30 
4.1.3.1 
Definitions and Derivations ......................................................................... 30 
4.1.3.2 
Presentation .................................................................................................. 30 
4.1.4 
Demographics .............................................................................................. 30 
4.1.4.1 
Definitions and Derivations ......................................................................... 30 
4.1.4.2 
Presentation .................................................................................................. 31 
4.1.5 
Baseline Characteristics ............................................................................... 31 
4.1.5.1 
Definitions and Derivations ......................................................................... 31 
4.1.5.2 
Presentation .................................................................................................. 31 
4.1.6 
Disease Characteristics ................................................................................. 31 
4.1.6.1 
Definitions and Derivations ......................................................................... 31 
4.1.6.2 
Presentation .................................................................................................. 32 
4.1.7 
Medical History and Concomitant Disease .................................................. 32 
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LIST OF ABBREVIATIONS 
 
Abbreviation or 
Specialized 
Term 
 
Definition 
ADA 
Anti-drug-antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AUC 
Area under the serum concentration-time curve 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus 2019 
CRF 
Case report form 
CSP 
Clinical study protocol 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal membrane oxygenation 
FAS 
Full Analysis Set 
GMFR 
Geometric mean fold rises 
GMT 
Geometric mean titer 
gSD 
Geometric standard deviation 
ICU 
Intensive care unit 
IM 
Intramuscular 
IMP 
Investigational medicinal product 
IP 
Investigational product 
IPD 
Important Protocol Deviations 
IV 
Intravenous 
LOCF 
Last observation carried forward 
mAbs 
monoclonal antibodies 
nAb 
Neutralizing antibodies 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetics 
RNA 
Ribonucleic acid 
RR 
Relative Risk or Risk Ratio 
RRR 
Relative Risk Reduction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 


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SARS-CoV-2 
Severe Acute Respiratory Syndrome-Coronavirus 2 
SpO2 
Oxygen saturation 
WHO 
World Health Organization 


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AMENDMENT HISTORY 


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CATEGORY 
Change refers to: 
Date 
Description of change 
In line with CSP? 
Rationale 
N/A 
26 Feb 2021 
Initial approved SAP 
Yes, version 3.0 
N/A 
 
Section 3.1 
 
08 Mar 2021 
 
Removed references to CSR 
 
Yes, version 3.0 
To eliminate confusion with 
regards to timing of CSR 
output development. 
 
 
Section 4.2.1.7 
 
 
08 Mar 2021 
Added exploratory subgroup 
analysis for primary 
endpoint, to evaluate 
efficacy in an alternatively 
defined High Risk subgroup 
 
 
Not a protocol defined 
subgroup. 
To explore an alternatively 
defined subgroup that aligns 
with analyses conducted for 
previously approved 
emergency use 
authorizations. 
 
 
Section 3.3.2 
 
 
18 Mar 2021 
Specified that if there is 
missing data for Risk Factors 
for Progression in EDC, then 
IRT reported stratifications 
will be used. 
 
 
Yes, version 6.0 
 
To avoid missing data for 
stratification variables. 
 
 
 
Section 4.2.1.7 
 
 
 
18 Mar 2021 
 
Specified that an assessment 
of interaction cannot be 
conducted for the Standard 
of Care subgroup. 
 
 
 
Yes, version 6.0 
To make clear that an 
assessment of interaction 
cannot be conducted on 
Standard of Care because 
participants may be 
included in more than one 
category. 


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Section 4.2.3.2 
 
 
 
 
 
26 Mar 2021 
Specified: For Time to Usual 
health, if a participant has 
not returned to usual health 
by Day 29, time will be 
calculated as Date of Day 29 
visit – date of dosing + 1. If 
the fever has not subsided by 
Day 29, then the time for the 
patients will be calculated as 
Date of Day 29 – Fever start 
date + 1. 
 
 
 
 
 
Yes, version 6.0 
 
 
 
To clarify how to derive 
follow-up time for events 
that do not occur by Day 29, 
to support the Wilcoxon 
analyses. 
 
Section 1.2 
 
26 Mar 2021 
Updated to be consistent 
with Protocol v5.0. See 
protocol for description and 
justification. 
 
Yes, version 6.0 
Updated to be consistent 
with Protocol v5.0 and US 
specific amendment 1 that 
includes adolescents. 
 
Section 1.3 
26 Mar 2021 
Updated to be consistent 
with Protocol v5.0. See 
protocol for description and 
justification. 
 
Yes, version 6.0 
Updated to be consistent 
with Protocol v5.0 
 
Section 3.1 
26 Mar 2021 
Updated to be consistent 
with Protocol v5.0. See 
protocol for description and 
justification. 
 
Yes, version 6.0 
Updated to be consistent 
with Protocol v5.0 
 
Section 3.3.1 
26 Mar 2021 
Updated to be consistent 
with Protocol v5.0. See 
protocol for description and 
justification. 
 
Yes, version 6.0 
Updated to be consistent 
with Protocol v5.0 
 
Section 3.3.5 
26 Mar 2021 
Updated to be consistent 
with Protocol v5.0. See 
protocol for description and 
justification. 
 
Yes, version 6.0 
Updated to be consistent 
with Protocol v5.0 


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Section 4.2.1 
26 Mar 2021 
Updated to be consistent 
with Protocol v5.0. See 
protocol for description and 
justification. 
 
Yes, version 6.0 
Updated to be consistent 
with Protocol v5.0 
 
Section 4.2. 
26 Mar 2021 
Updated to be consistent 
with Protocol v5.0. See 
protocol for description and 
justification. 
 
Yes, version 6.0 
Updated to be consistent 
with Protocol v5.0 
 
Section 5 
26 Mar 2021 
Updated to be consistent 
with Protocol v5.0. See 
protocol for description and 
justification. 
 
Yes, version 6.0 
Updated to be consistent 
with Protocol v5.0 
 
 
 
 
 
Section 4.2.1.6 
07 Apr 2021 
Added KM summary 
statistics to be summarized. 
Specified that duration of 
follow-up for will be 
summarized. Specified Efron 
method for ties in Cox 
analysis will be used. 
 
 
 
 
 
Yes, version 6.0 
KM summary estimates 
were added to provide more 
context for time to event 
analysis.
 
 
 Efron 
method was specified to 
describe how ties should be 
handled. 
Section 4.1.10 (4.1.10.1 and 
4.1.10.2) 
07 Apr 2021 
Added section for Duration 
of On-study and safety 
follow up to be summarized 
 
Yes, version 6.0 
 
 
Section 4.1.1.2 
07 Apr 2021 
Added summary for 
discontinuation by age group 
Yes, version 6.0 
 
 
Section 4.2.2.7, Section 4.2.3.6 
15 Apr 2021 
Added in subgroup analyses 
by serostatus at baseline 
Yes, version 6.0 
Added per request of 
clinical science team. 
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Section 1.1 
19 Apr 2021 
Update footnote to refer to 
CSP for definition of 
hospitalization. Also include 
Type of Hospitalization as an 
endpoint. 
 
 
Yes, version 6.0 
Updated to be in line with 
CSP. 
 
 
Section 4.2.4 
19 Apr 2021 
Updated to specify summary 
of hospitalization through 
Day 29 in addition to Day 
169. Also included a 
summary by Type of 
Hospitalization. 
 
 
Yes, version 6.0 
Updated to show 
hospitalizations related to 
the primary and key 
secondary endpoints 
separately. 
 
Section 4.1.4.1 
21 Apr 2021 
Update region in 
Demographics section to 
include Latin America and 
Asia. 
 
Yes, version 6.0 
Updated per request of 
clinical. 
 
Section 4.2.3.3 
21 Apr 2021 
Specify handling of partial or 
missing date for respiratory 
failure 
 
Yes, version 6.0 
Updated to ensure follow-up 
time can be calculated for 
analysis. 
 
Section 1 
16 July 2021 
Updated to be consistent 
with Protocol v7.0. See 
protocol for description and 
justification. 
 
Yes, version 7.0 
Updated to be in line with 
CSP v7.0. 
 
Figure 1. 
16 July 2021 
Updated to be consistent 
with Protocol v7.0. See 
protocol for description and 
justification. 
 
Yes, version 7.0 
Updated to be in line with 
CSP v7.0. 
 
Section 1.3 
16 July 2021 
Updated to be consistent 
with Protocol v7.0. See 
protocol for description and 
justification. 
 
Yes, version 7.0 
Updated to be in line with 
CSP v7.0. 


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Section 3.1 
16 July 2021 
Updated to be consistent 
with Protocol v7.0. See 
protocol for description and 
justification. 
 
Yes, version 7.0 
Updated to be in line with 
CSP v7.0. 
 
Section 3.2 
16 July 2021 
Updated to be consistent 
with Protocol v7.0. See 
protocol for description and 
justification. 
 
Yes, version 7.0 
Updated to be in line with 
CSP v7.0. 
 
 
 
 
Section 3.3.2 
16 July 2021 
Added clarification on using 
Smoking History eCRF page 
to support High Risk 
derivation 
 
 
 
 
Yes, version 7.0 
Updated to provide clarity 
to programming team, and 
to account for potential 
missing data on symptom 
eCRF page
 
 
 
 
Section 3.3.5 
16 July 2021 
Updated to be consistent 
with Protocol v7.0. See 
protocol for description and 
justification. 
 
Yes, version 7.0 
Updated to be in line with 
CSP v7.0. 
Sections 4.1.1.2 and 4.1.4.1 
16 July 2021 
Removed <18 years category 
Yes, version 7.0 
Adolescents are no longer 
being enrolled into study 
 
Sections 4.1.4.2, 4.1.6.2, 4.1.7.2, 
4.1.8.2, 4.1.10.2 
16 July 2021 
Added mFAS as a repeat 
table 
 
Yes, version 7.0 
Included repeat tables in 
mFAS to report baseline 
characteristics in primary 
analysis population 
 
Section 4.1.5.1 
16 July 2021 
Added BMI as a categorical 
variable, and smoking 
history. 
 
Yes, version 7.0 
Left out inadvertently in 
previous SAP version 
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Section 4.2 
16 July 2021 
Updated to be consistent 
with Protocol v7.0. See 
protocol for description and 
justification. 
 
Yes, version 7.0 
Updated to be in line with 
CSP v7.0. 
 
Section 4.2.1.2 
16 July 2021 
Updated to be consistent 
with Protocol v7.0. See 
protocol for description and 
justification. 
 
Yes, version 7.0 
Updated to be in line with 
CSP v7.0. 
 
Section 4.2.1.5 
16 July 2021 
Updated to be consistent 
with Protocol v7.0. See 
protocol for description and 
justification. 
 
Yes, version 7.0 
Updated to be in line with 
CSP v7.0. 
 
 
Section 4.2.1.6 
16 July 2021 
Updated to include non- 
responder sensitivity 
analysis, and updated 
multiple imputation method 
to be consistent with CMH 
method 
 
 
Yes, version 7.0 
Non-responder analysis was 
left out inadvertently in 
previous version. 
 
 
 
 
Section 4.2.1.8 
16 July 2021 
Update to CMH. Removed 
subgroup for Vitamin D 
based on normal range. 
Remove exploratory analysis 
for alternatively defined 
High Risk population. 
 
 
 
 
Yes, version 7.0 
Normal range for Vitamin D 
does not exist in data. 
 
 
 
 
 
 
 
Section 4.2.2 
16 July 2021 
Updated to be consistent 
with Protocol v7.0. See 
protocol for description and 
justification. 
 
Yes, version 7.0 
Updated to be in line with 
CSP v7.0. 
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Section 4.2.3 
16 July 2021 
Updated to specify relevant 
analyses will be conducted in 
mFAS, instead of FAS. 
 
Yes, version 7.0 
Updated analysis set to be 
aligned with primary 
analysis population. 
 
Section 4.2.3.4 
16 July 2021 
Updated to specify CMH 
will be used for binary 
endpoint 
 
Yes, version 7.0 
Updated to align with 
primary analysis method 
Section 4.2.3.6 
16 July 2021 
Updated to specify CMH 
will be used 
Yes, version 7.0 
Updated to align with 
primary analysis method 
 
 
Section 4.2.4.1 
16 July 2021 
Updated to clarify the 
reporting the 
hospitalizations, and 
duration of hospitalizations. 
Updated to specify use of 
mFAS. 
 
 
Yes, version 7.0 
Updated to provide clarity 
on how to identify and 
report unique hospitalization 
events. 
 
Section 4.5.4.2 
16 July 2021 
Updated to clarify patients 
will be summarized by their 
worst observed value 
 
Yes, version 7.0 
Updated to clarify patients 
will be summarized by their 
worst observed value 
 
Section 3.3.3 
25 August 2021 
Updated to include visit 
window definition for all 
visit-based assessments 
 
Yes, version 7.0 
Updated to include visit 
window definition for all 
visit-based assessments 
 
Section 4.2 
25 August 2021 
Table 11. was updated to be 
consistent with text. The 
second and third estimands 
were incorrect. 
 
Yes, version 7.0 
Table 11. was updated to be 
consistent with text. The 
second and third estimands 
were incorrect. 
 
Section 4.5 
31 August 2021 
Indicate that Safety outputs 
will be repeated in High Risk 
patients 
 
Yes, version 7.0 
Safety outputs will be 
repeated in High Risk 
patients 
 
Section 4.2.2.7 
17 September 
2021 
Removed text specifying that 
an interaction p-value will be 
presented 
 
Yes, version 7.0 
Text should’ve been 
removed in previous SAP 
amendment. 


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Section 4.2.3.1 
17 September 
2021 
Updated to specify analysis 
duration will start at date of 
dosing. And updated to 
indicate analysis will only be 
for participants with 
documented fever at 
baseline. 
 
 
 
Yes, version 7.0 
Analysis updated to be 
aligned with logic used for 
time to return to usual 
health. Additionally, to 
clarify participant 
population analysis should 
occur in. 
 
Section 4.2.3.2 
17 September 
2021 
Updated to include 
imputation of half the LLOQ 
for viral load analysis 
 
Yes, version 7.0 
Confirmed with translation 
science, and updated to 
support programming 
derivations. 
 
Section 4.5.5 
17 September 
2021 
Updated to specify highest 
baseline ECG value would 
be used for shift table 
 
Yes, version 7.0 
Clarification for 
programming activities. 








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1.2 
Study Design 
This is a Phase III, randomized, double-blind, placebo-controlled study assessing the safety 
and efficacy of a single 600 mg IM dose of AZD7442 compared to placebo for the 
treatment of COVID-19. 
Participants will be outpatient adults  18 years) with a documented positive SARS-CoV-2 
molecular test (antigen or nucleic acid) from a sample coOOHFWHGGD\VSULRUWRVWXG\
entry DQGZLWKGD\VRIV\PSWRPVRI&29,'-19 at study entry, plus the presence of 
select symptoms within 24 hours prior to Day 1. 
At least 60% of participants will meet the protocol definition of being at high risk of 
progression to severe COVID-19, which is defined in Protocol Section 4.1. 
Randomization will be stratified (using centralized blocked randomization) by: 
 
x Time from symptom onset GD\V versus > 5 days) 
x High risk versus low risk of progression to severe COVID-19 
 
Up to approximately 1700 participants will be randomized in a 1:1 ratio to receive a single 
IM dose of 600 mg of AZD7442 (n = up to approximately 850) or placebo (n = up to 
approximately 850) on Day 1. The first 20 participants to be dosed (approximately 10 
allocated to the AZD7442 group and 10 allocated to placebo) will form a sentinel group. 
After the entire sentinel group has been dosed, further enrollment will pause until the 
sentinel group’s safety data through Day 8 has been reviewed by the DSMB (Data Safety 
Monitoring Board) in order to provide a recommendation to the AstraZeneca Unblinded 
Review Committee to continue or to halt dosing of additional participants. For DSMB, see 
Protocol Section 9.6. 
Participants will be enrolled into one of 2 independent cohorts: 
x &RKRUWQ§ZKLFKZLOOLQFOXGHWKHVHQWLQHOJURXSZLOOXQGHUJRPRUH
intensive testing to characterize their virological and immunological status, and to 
correlate that status with clinical outcomes. 
x Cohort 2 (n up to § 1400) will be followed for clinical outcomes. 
After administration of the dose of study intervention on Day 1, participants will undergo 
28 days of intensive follow-up, followed by limited follow-up through Day 457. See 
Figure 1. 


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Figure 1. Study Design
1.3
Sample Size
Up to approximately 1700 participants will be randomized in a 1:1 ratio to receive a single 
,0PJGRVHRI$='QXSWR§RUSODFHERQXSWR§RQ'D\ 1. 
This is an event-driven study with a primary analysis initiated 30 days after approximately 
43 primary endpoints have been confirmed in the primary analysis population. The study 
has at least 
 to detect a relative reduction of 
 in the incidence of severe 
COVID-19/death between the study groups (AZD7442 vs placebo), using the following 
assumptions:
x
2
CHANGES TO PROTOCOL PLANNED ANALYSES
There is no change of planned analyses.
3
DATA ANALYSIS CONSIDERATIONS
3.1
Timing of Analyses
The primary analysis will be initiated 30 days after 43 primary endpoint events have been 
confirmed in the primary analysis population. The number of events may be higher if the 
event accrual rate is different than expected at this time. All data during this 30 day 
interval, including additional primary endpoint events, will be evaluated. A Day 169 
analysis (Key Secondary Analysis and safety) will be conducted when all participants have 
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been followed through Day 169. A final analysis will be conducted when all participants 
have completed the study. 
3.2 
Analysis Populations 
Table 2 
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 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. 
Modified full analysis set 
$OOSDUWLFLSDQWVLQWKHIXOODQDO\VLVVHWZKRUHFHLYHG,03GD\VIURP
symptom onset and were not hospitalized at baseline  Day 1) for isolation 
purpose. 
Early Intervention Analysis Set 
All participants in the modified full analysis set who received IMP  5 days 
from symptom onset. 
Seronegative Analysis Set 
All participants in the modified full analysis set who were seronegative at 
baseline. 
Safety analysis set 
The safety analysis set consists of all participants who have received 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. 
PK analysis set 
Dosed participants for whom an adequate (measurable drug concentration) PK 
profile has been obtained. 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. 
Virology analysis set 
The Virology analysis set consists of all participants in Cohort 1, who 
undergo more intensive virologic and immunologic assessments. 
Participants will be analyzed according to their received treatment. 
ADA evaluable analysis set 
The ADA evaluable analysis set contains all participants in the Safety 
analysis set who have a non-missing baseline AZD7442 ADA result and 
at least one non-missing post-baseline AZD7442 ADA result. This 
analysis set is not defined in the CSP but is required for analysis. 
 
 
 
 
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3.3 
General Considerations 
Categorical variables will be summarized using frequency and percentages, where the 
denominator for calculation is the underlying analysis set population, unless otherwise 
stated. A row denoted as “Missing” will be included in the count tabulations where 
necessary to account for missing values. Summaries will be provided by treatment and 
visit when applicable. 
Continuous variables will be summarized with descriptive statistics of number of 
participants with available data (N), mean, standard deviation (SD), median, the first 
quartile (Q1), third quartile (Q3), minimum and maximum. Summaries will be provided by 
treatment 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. 
3.3.1 
Statistical Hypothesis 
The primary efficacy endpoint is a binary response whereby a participant is classified as 
either having severe COVID-19 symptoms or death from any cause, or not. Efficacy will be 
FDOFXODWHGDVWKHUHODWLYHULVNUHGXFWLRQ555GHILQHGDVí5HODWLYH5LVNThe null 
hypothesis is the RRR of severe COVID-19 or death from any cause through Day 29 in 
participants on AZD7442 compared with those on placebo is equal to zero. The alternative 
hypothesis is that the RRR is not equal to zero. 
The primary efficacy endpoint will be formally assessed at timepoints as described in 
Section 3.1. The type I error rate will be controlled by a 2-sided alpha = 0.05. The primary 
estimand, supportive estimands, and key secondary endpoints will be tested at an alpha 
level of 5%. The methodology used to conserve alpha is detailed in Section 3.3.5. 
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. 
3.3.2 
General Study Level Definitions 
In general, baseline is defined as the last non-missing measurement taken prior to dose of 
IMP. If the last non-missing measurement is taken at time of the dose of IMP, this 
measurement will be considered baseline, with the exception of adverse events (AEs) and 
medications commencing on the date and time of the dose of IMP, these assessments will 
be considered post-baseline. 


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Change from baseline will be calculated as (post-baseline visit – baseline visit). Percent 
change from baseline will be calculated as (change from baseline/baseline*100). 
For any presentation for or by strata, or for any analysis requiring the adjustment of strata 
as covariates, variables will be derived from the eCRF data captured in the RAVE EDC. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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x Participants who are identified as developing an issue worthy of study withdrawal, 
but are not withdrawn 
x Participants who experience an investigational product deviation 
x Participants who receive concomitant use of disallowed medications 
x Participants who experience deviations related to planned study procedures 
x Other important deviations that may impact safety or violate study 
Suspension/Termination rule per CSP Section 7.4. 
 
4 
STATISTICAL ANALYSIS 
This section provides information on definitions, derivation and analysis/data presentation 
per domain. 
4.1 
Study Population 
The study population domain covers participant disposition, analysis sets, protocol 
deviations, demographics, baseline characteristics medical history, prior and concomitant 
medication and study drug compliance. 
4.1.1 
Participant Disposition and Completion Status 
4.1.1.1 
Definitions and Derivations 
Treatment groups are reported based on randomized treatment. The All Participant 
Analysis Set (PAS) as defined in Section 3.2 is used for reporting disposition and screening 
failures. 
4.1.1.2 
Presentation 
Numbers and percentages will be presented by treatment and total for the following. Note: 
Percentages are based on total randomized participants. 
x Randomized participants 
x Participants randomized but not dosed 
x Participants ongoing in study (for primary analysis only) 
x Participant who completed the study 
x Participant who discontinued early from study 
o Reason for discontinuing early from study 
x Participants 18 to 64 years who discontinued early from study 
o Reason for discontinuing early from study 


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x Participants >= 65 years who discontinued early from study 
o Reason for discontinuing early from study 
4.1.2 
Analysis Sets 
4.1.2.1 
Definitions and Derivations 
Analysis sets are defined in Section 3.2. 
4.1.2.2 
Presentation 
Number of participants will be reported by treatment for Full Analysis Set (FAS), modified 
Full Analysis Set (mFAS), Early Intervention Analysis Set (EIAS), Seronegative Analysis 
Set (SNAS), Safety Analysis Set, PK Analysis Set, Virology Analysis Set, ADA evaluable 
analysis set, and nAB evaluable analysis set. For each analysis set, number of participants 
excluded and number for each reason will be reported by treatment. 
4.1.3 
Important Protocol Deviations 
4.1.3.1 
Definitions and Derivations 
IPDs will be identified by the study team in a blinded fashion before database lock. 
4.1.3.2 
Presentation 
Number and percentage of participants with IPDs will be provided by treatment group and 
total for each category of protocol deviations. The summary will be based on the FAS. 
4.1.4 
Demographics 
4.1.4.1 
Definitions and Derivations 
Demographics are categorized as follows: 
x Age group: 
o  18 to < 65 \HDUV 65 to < 75 years,  to <80 years and years. 
o < 65 years vs  65 years 
x Sex: Male, Female 
x Ethnicity: Hispanic or Latino, Not Hispanic or Latino 
x Race: American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islanders, White 
x Region: US, Europe, Latin America, Asia, Other 


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The summary of demographics characteristics will be provided for the FAS and mFAS. If 
there are major differences between the FAS and the Safety Analysis Set, the summaries 
will be repeated and presented by actual treatment for the Safety Analysis Set. 
Demographics will be summarized by treatment group and total using descriptive statistics 
for age and number and percentage of participants for age group, sex, race, ethnicity, and 
region. 
4.1.5 
Baseline Characteristics 
4.1.5.1 
Definitions and Derivations 
Baseline characteristics include the following: 
x Weight (kg) 
x Height (cm) 
x Body Mass Index (BMI) (kg/m2) = weight (kg)/ [height (m)2] as a continuous 
variable 
x BMI as a categorical variable (<25, 25 - <30, 30 - <35,  
x Time from Symptom Onset as a continuous variable 
x Time from Symptom Onset GD\V > 5 days) 
x Risk Group (High, Low) 
x Smoking History (Current, Former, Never) 
4.1.5.2 
Presentation 
Baseline characteristics will be summarized with demographics. 
4.1.6 
Disease Characteristics 
4.1.6.1 
Definitions and Derivations 
Disease characteristics include the following: 
x COVID-19 co-morbidities (at least one co-morbidity, no co-morbidity) 
Note: Comorbidity = Risk factors in CRF: SARS-CoV-2 Progression risk to 
COVID-19, excluding the risk factor “Person aged >=65 year”. 
x Serum for SARS-CoV-2 Serology (Positive, Negative) 
x Nicotine Use (Current, Former, Never) 
x WHO Clinical Progression Scale score (ordinal 2 – 3 based on inclusion criteria) 


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Disease characteristics will be summarized by treatment group and total using descriptive 
statistics for continuous variables and number and percentage of participants for categorical 
variables. 
Summary of disease characteristics will be provided for the FAS and mFAS. If there are 
major differences between the FAS and the Safety Analysis Set, the summaries will be 
repeated and presented by actual treatment for the Safety Analysis Set. 
 
COVID-19 co-morbidities for adult and pediatric participants will be summarized 
separately. 
 
4.1.7 
Medical History and Concomitant Disease 
4.1.7.1 
Definitions and Derivations 
Medical history and concomitant disease will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) 23.1 or higher. 
Medical history is defined as any medical condition/disease that started and stopped before 
the first dose of IMP. Concomitant diseases are defined as any medical condition/disease 
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. 
4.1.7.2 
Presentation 
Medical history and concomitant disease will be summarized by System Organ Class 
(SOC) and Preferred Term (PT) by treatment and total based on the FAS and mFAS. 
A participant having more than one condition/disease within the same SOC or PT will be 
counted only once for that SOC or PT. 
4.1.8 
Prior and Concomitant Medications 
4.1.8.1 
Definitions and Derivations 
All medications will be coded using the World Health Organization (WHO) Drug Global 
dictionary, version B3 March 2020, or a more recent version. 
A medication will be regarded as prior if it was stopped prior to the dose of IMP. A 
medication will be regarded as concomitant if the start date is on or after the date of dose of 
IMP, or if it started on or prior to the dose of IMP and ongoing after the dose of IMP. 
The handling of partial/missing dates is detailed in Appendix 1. 


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Prior and concomitant medications will be summarized by Anatomical Therapeutic Class 
(ATC) level 2 and preferred drug name by treatment and total based on the FAS and 
mFAS. 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. 
4.1.9 
Study Drug Compliance 
4.1.9.1 
Definitions and Derivations 
Compliance will not be calculated since participants will receive a single dose (2 IM 
injections) within clinic. 
4.1.9.2 
Presentation 
Not applicable. 
4.1.10 
Duration of On-Study and Safety Follow-up 
4.1.10.1 
Definitions and Derivations 
On-study follow-up will be calculated as Time = max(Date of Last Safety 
Assessment/Study Discontinuation/Death/Study Completion) – Date of dosing + 1. 
Safety follow-up will be calculated as Time = Date of Last Safety Assessment – Date of 
dosing + 1. 
4.1.10.2 
Presentation 
Duration of on-study and safety follow-up time will be summarized using descriptive 
statistics: n, mean, SD, Q1, median, Q3, min, and max, which will be presented for both the 
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4.2.1 
Primary Efficacy Endpoint 
All analyses for the primary efficacy endpoint will be based on mFAS. 
4.2.1.1 
Definition 
The primary efficacy endpoint is a composite of either severe COVID-19 or death from any 
cause through Day 29. 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 (see Protocol Appendix F). 
4.2.1.2 
Derivations 
Binary response 
The primary efficacy endpoint is a binary response, for which participants who have either 
severe COVID-19 or death from any cause through Day 29 will be coded as “Yes” (Event), 
otherwise “No” (Non-event) or “Missing” depending on the analysis method being used. 
Missing data 
For the primary analyses using the Cochran-Mantel-Haenszel (CMH) method, participants 
who withdraw from the study or are lost to follow-up prior to Day 29 for the primary 
endpoint will be considered as missing and will be excluded from the primary efficacy 
analyses. See Section 4.2.1.3 for handling of missing data. 
 
 
 
 
 
 
 
Follow-up time 
Follow-up time or the time-to-event (T) will be the response in the supplementary time-to- 
event analyses (Section 4.2.1.6). Calculation of T and definition of censoring are as 
follows: 
x For participants who have an event on or before the primary assessment timepoint: 
T = Date of event – Date of dosing + 1 
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x For participants who do not have an event on or before the primary assessment 
timepoint: 
T = 29 days 
The participants will be censored at Day 29 for the supplementary analysis. 
x For participants who discontinue or are lost to follow-up prior to Day 29, they will 
be censored at the last known status before Day 29. The follow-up time will be 
calculated as follows: 
T = Date of last known status before Day 29 – Date of dosing + 1 
 
 
4.2.1.3 
Handling of Dropouts and Missing Data 
This section is regarding missing response data as defined in Section 4.2.1.2 
For the primary analysis of the primary endpoint, missing data will not be imputed and will 
be treated as missing. For the sensitivity analysis, missing data will be imputed as 
indicated in Section 4.2.1.6. For the supplementary analysis, missing data will be included 
and censored at the date of last known status. 
4.2.1.4 
Primary Estimand Analysis of Primary Efficacy Endpoint 
For the binary endpoint described in Section 4.2.1.2, the CMH method will be used to 
investigate treatment effect stratified by the 2 stratification factors as described in Sections 
1.2 and 3.3.2. If the test results in a warning due to sparse data in a specific stratum, then a 
stratification factor will be dropped. 
The efficacy will be estimated by the common relative risk, or risk ratio (RR) from the 
&0+PHWKRG7KHUHODWLYHULVNUHGXFWLRQ555 [í55UHSUHVHQWVWKHSHUFHQW
reduction in incidence of severe COVID-19 or death from any cause in the AZD7442 group 
relative to the placebo group. 
The CMH method will be implemented by using the SAS PROC FREQ procedure using the 
CMH option. The null hypothesis will be rejected by a General Association p-value <0.05. 
The 2-sided 95% CI will be presented. The Breslow-Day test p-value will be presented to 
evaluate homogeneity of the RRR across strata. 
If the CMH test continues to produce a warning due to sparse data after dropping a 
stratification factor as specified above, the Chi-squared method will be used to perform the 
primary analysis. The RRR, the 95% CI, and p-value will be reported. This analysis will be 
performed without any imputation of missing data. 


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x 
 
 
4.2.1.7 
Supplementary Analyses of the Primary Efficacy Estimand 
For the supplementary analysis, the response is time-to-event, which is defined in Section 
4.2.1.2. 
Kaplan-Meier analyses, including median survival time and survival probability estimates 
for Day 29, will be summarized, and curves for time to severe COVID-19 or death from 
any cause during the first 28 days of follow-up will be generated for each randomized 
group. The duration of follow-up for the primary endpoint will be summarized using the 
reverse Kaplan-Meier method. 
A stratified Log-Rank test with the two stratification factors will be conducted to assess the 
difference between the curves. A Cox-Proportional Hazards model will be performed to 
obtain the hazard ratio and the 95% CI. The Cox model will include terms of treatment and 
the two stratification factors. The Efron method will be used to handle ties. 
Additionally, the absolute risk reduction of AZD7442 with respect to placebo in preventing 
severe COVID-19 or death from any cause at Day 29, will be presented, along with the 2- 
sided 95% CI using the stratified Miettinen and Nurminen's score method (Miettinen and 
Nurminen 1985). 
4.2.1.8 
Subgroup Analyses 

 
 
 
 
 
 
 
 
 
 
 
Subgroups are listed and categorized as below: 
x Age: 18 - <65 YV 65; < 75 YV 75; < 80 YV80 
x Sex: Male vs Female 
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x Race: American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islanders, White 
x Ethnicity: Hispanic vs Not Hispanic 
x Region: US, Europe, Other 
x Time from Symptom Onset: 
- 
 5 days vs >5 days 
- 
GD\V vs >3 days 
- 
Quartile: 25%, 50%, 75% 
x Risk Group: High vs Low 
x COVID-19 co-morbidities: at least one co-morbidity vs. no co-morbidity 
x Baseline Vitamin D 
- 
< 30 ng/mL vs  30 ng/ml 
x Baseline Zinc: < 100 ug/dl vs  100 ug/dl 
x Standard of Care: Antiviral Therapy, Antiviral Therapy, not active against COVID, 
Immune-Based Therapy, Corticosteroids, Adjunctive Therapy, Antibiotic, Other , 
None 
(Note: The clinical team will review concomitant medications given to treat disease 
under study, and will classify each to one of the above categories prior to database 
lock.) 
Participants may be assigned to multiple Standard of Care categories, therefore, an 
assessment for interaction will not be conducted for this subgroup. 
x Baseline Serum for SARS-CoV-2 Serology: Positive vs Negative 
x Depending on the availability of data, efficacy by virus variant strain may be 
explored. 
 
 
4.2.2 
Key Secondary Efficacy Endpoint 
All analyses for the key secondary efficacy endpoint will be based on mFAS. 
4.2.2.1 
Definition 
The key secondary endpoint is a composite of either death from any cause or 
hospitalization for COVID-19 complications or sequelae during the 168-day post-dose 
period (Day 1 to Day 169). 


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4.2.2.2 
Derivations 
Binary response 
The key secondary endpoint is a binary response, for which participants who have either 
death from any cause or hospitalization for COVID-19 complications or sequelae during 
the 168-day post-dose period will be coded as “Yes” (Event), otherwise “No” (Non-event) 
or “Missing” depending on the analysis method being used. 
Missing data 
For the analysis using the Cochran-Mantel-Haenszel (CMH) method, participants who 
withdraw from the study or are lost to follow-up prior to Day 169 for the key secondary 
endpoint will be considered as missing and will be excluded from the key secondary 
efficacy analyses. See Section 4.2.2.3 for handling of missing data. 
 
 
 
 
 
 
Follow-up time 
Follow-up time or time-to-event (T) will be the response in the supplementary analysis 
(Section 4.2.2.6). Calculation of T and definition of censoring are as follows: 
x For participants who have an event on or before Day 169: 
T = Date of event – Date of dosing + 1 
x For participants who do not have an event on or before Day 169: 
T = 169 days 
The participants will be censored at Day 169 for the supplementary analysis. 
x For participants who discontinue or are lost to follow-up, they will be censored at 
the last known status before date of dosing + 168. The follow-up time will be 
calculated as follows: 
T = Date of last known status before Day 169 – Date of dosing + 1. 
 
Date of last known status will be either the date of study discontinuation visit or the 
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last assessment before Date of dosing + 168 for the key secondary endpoint, for 
those who are lost to follow-up. 
4.2.2.3 
Handling of Dropouts and Missing Data 
This section is regarding missing response data as defined in Section 4.2.2.2. 
For the analysis of the key secondary endpoint, missing data will not be imputed and will 
be treated as missing. No assumptions will be made about data not collected after 
discontinuation. For the supplementary analysis missing data will be included and 
censored at the date of last known status. 
4.2.2.4 
Analysis of the Key Secondary Efficacy Endpoint 
Being consistent with the primary analysis of primary endpoint, CMH test will be used. 
The RRR and its 95% CI will be calculated at Day 169. The same methods will be used as 
described for the analysis of the primary endpoint. 
To control for multiplicity of the primary estimand, supportive estimands, and key 
secondary endpoint, see Section 3.3.5 for a hierarchical approach. If the significance of the 
primary efficacy estimands and supportive estimands is not achieved, then the p-value for 
testing the key secondary efficacy endpoint will be considered nominal. 
Similar to that in Section 4.2.1.4, a Chi-square test will be used instead of the CMH if it 
fails. 
 
 
 
 
 
4.2.2.6 
Supplementary Analyses of the Key Secondary Efficacy Endpoint 
For the supplementary analyses, the response will be time-to-event through Day 169, which 
is defined in Section 4.2.2.2. 
Similar to the supplementary analyses of the primary endpoint (Section 4.2.1.6), Kaplan- 
Meier summaries and curves will be reported. A stratified Log-Rank test will be conducted 
to assess the difference between the curves. The Cox-Proportional Hazards model will be 
used to obtain hazard ratios and their respective 95% CIs. The absolute risk reduction will 
be calculated similarly as for the primary efficacy endpoint. Sensitivity analyses related to 
unblinding for vaccination apply. 
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4.2.2.7 
Subgroup Analysis 
A subgroup analysis of the Key Secondary efficacy endpoint will be conducted using 
serostatus (positive/negative) at baseline. No other subgroups will be evaluated for the Key 
Secondary endpoint. No forest plot will be presented. 
 
 
4.2.3 
Other Secondary Endpoint 
Analysis for time to undetectable of SARS-CoV-2 RNA from nasal swabs will be based on 
virology analysis set. 
All other analyses will be based on mFAS. 
4.2.3.1 
Definition 
Endpoints with binary outcome: 
x The incidence of participants with respiratory failure, through Day 29, defined as a 
requirement for mechanical ventilation, ECMO, non-invasive ventilation, or high 
flow cannula oxygen delivery. 
Participants will be coded as “Yes” if there is respiratory failure through Day 29; 
otherwise, “No”. 
x The incidence of participants with progression, through Day 29, of one or more 
COVID-19-associated symptoms to worse status (increasing in severity scale by 
1) than recorded in the participant-reported symptom diary entry prior to start of 
AZD7442 or placebo. 
Participants will be coded as “Yes” if there is progression through Day 29; 
otherwise, “No”. Participants with severity score of 4 on every scale at baseline 
will be excluded. 
Endpoints with time-to-event outcome: 
x Time to undetectable of SARS-CoV-2 RNA from nasal swabs through Day 29. 
x Time to return to usual (pre-COVID-19) health through Day 29. 
Endpoints with continuous outcome: 
x Change from baseline in COVID-19 symptom severity assessments (SARS-CoV-2 
Daily Symptoms Questionnaire) based on symptom severity scores over time during 
the 28-day period. 
Each symptom is scored from 0 to 4: Shortness of Breath Severity, Difficulty Breath 
Severity, Chills Severity, Cough Severity, Fatigue Severity, Muscle Aches Severity, 
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Severity, Sore Throat Severity, Congestion Severity, Runny Nose Severity, Nausea 
Severity, Vomiting Severity, Diarrhea Severity. 
x Change from baseline of SARS-CoV-2 RNA from nasal swabs through Day 29. 
x Duration of fever from date of dosing through Day 29 defined as the last day in the 
participant-reported symptom diary on which a temperature greater than 37.8°C was 
recorded or a potentially antipyretic drug, such as acetaminophen or ibuprofen, was 
taken. This analysis will be conducted on participants who have a documented fever 
at baseline. 
The following endpoints are detailed in Section 4.4. 
x Serum concentration and PK parameters. 
x Incidence of ADA to AZD7442 in serum over time. 
4.2.3.2 
Derivations 
Follow-up time: For endpoints with binary or time-to-event outcome, follow-up time will 
be derived similarly to those for the primary endpoint (Section 4.2.1.2). 
For time to return to usual health, if a participant has not returned to usual health by Day 
29, time will be imputed as Day 29. 
For duration of fever, if the fever has not subsided by Day 29, time will be imputed as Day 
29. 
For analyses of SARS-CoV-2 RNA, “Not Detected” results will be imputed with a value 
half of the LLOQ. Values measured as above the upper limit of quantification (ULOQ) will 
be imputed at the ULOQ value. 
The time-weighted average change in log10 SARS-CoV-2 RNA from baseline (Day 1) to 
Day 6 and 29 is defined as: 
 
where Yi is the change from baseline in log10 SARS-CoV-2 RNA at Visit i, t is the time at 
the specified timepoint (the actual study day), a is the baseline assessment at Day 1, and b 
is the last assessment at or prior to Day 6 and 29, respectively. Sensitivity analysis will be 
performed for this derived endpoint – see Section 4.2.3.5. 
4.2.3.3 
Handling of Dropouts and Missing Data 
Absence of data following participants’ withdrawal/lost to follow-up prior to cut-off time of 
analysis will be treated as missing. 


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For the endpoints with binary outcome, missing data will not be imputed. For the endpoints 
with time-to-event outcome, missing data will be included and censored at the date of last 
known status. 
For continuous endpoints with change from baseline to Day 6 or Day 29, missing Day 6 or 
Day 29 data will be imputed using last-observation-carried-forward (LOCF) method for 
ANCOVA. There will be no imputation for the Mixed Model for Repeated Measures 
(MMRM). 
For respiratory failure, the following imputation rules will be used for missing or partial 
dates, if mechanical ventilation, non-invasive ventilation, ECMO, or high flow nasal 
cannula is indicated as being given to a participant” 
x If ‘Day” is missing AND the “Month” is after the Month in which the Day 29 visit 
occurs, then the participant will be censored as not having Respiratory Failure at the 
date of the Day 29 visit. 
x Otherwise, impute partial or missing date as Day 1 visit date. 
4.2.3.4 
Analysis of Other Endpoints 
All CIs and p-values will be considered nominal for analysis of other endpoints. Unless 
otherwise noted, the mFAS will be used. 
Endpoints with binary outcome will be analyzed using CMH model as in the primary 
efficacy analysis in Section 4.2.1.4. 
Endpoints with time-to-event outcome will be analyzed using only Kaplan-Meier 
analysis, which is described in Section 4.2.1.6. 
Note: For time to undetectable of SARS-CoV-2 RNA from nasal swabs, an analysis will be 
conducted in the virology analysis set. 
Endpoints with continuous outcome: 
For SARS-CoV-2 RNA, the observed and change from baseline values at each visit, will 
be summarized using descriptive statistics on the original and log10 scale. 
For Cohort 1 (Virology Analysis Set), log10 change from baseline to all post-baseline values 
will be analyzed using an MMRM, which will include log10 baseline value, the 2 
stratification factors, treatment, visit, and treatment by visit interaction in the model. The 
LS Mean, standard error and 95% CI will be reported at each visit by treatment. The LS 
Mean difference, it’s 95% CI, and p-value, will be reported for each visit. 
For the MMRM, an unstructured (UN) correlation matrix will be used to model within 
subject autocorrelation [repeated statement within SAS]. If this model fails to converge, 
simpler correlation structures will be considered, e.g. AR(1), CS. 
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For all participants pooled, i.e., combined Cohort 1 and Cohort 2 (modified Full Analysis 
Set), treatment groups will be compared with respect to log10 change from baseline to Day 
6, and change from baseline to Day 29, using an Analysis of Covariance (ANCOVA) 
model. Log10 baseline, treatment, and the 2 stratification factors will be included in the 
model. LS mean and 95% CI by treatment will be reported. Missing values at Day 6 and 
Day 29 will be imputed using LOCF as indicated in Section 4.2.3.3. 
The analyses above (both the Cohort 1 and Pooled analyses), including figures, will be 
repeated based on viral load at baseline. The analyses will be repeated for participants with 
baseline viral load: >104 copies/ml, >105 copies/ml, >106 copies/ml, and >107 copies/ml. 
For each COVID-19 symptom severity assessment during the 28-day period, the 
observed and change from baseline values at each visit, will be summarized using 
descriptive statistics. 
To assess treatment difference over time, change from baseline to all post-baseline values 
will be analyzed using an MMRM analysis, which will include baseline severity score, the 
2 stratification factors, treatment, visit, and treatment by visit interaction in the model. 
This analysis is similar to that of SARS-CoV-2 RNA as shown above, which has more 
details. 
For each symptom, shift tables will be used to show the proportion of participants shifting 
from baseline severity score to maximum post-baseline severity score, and baseline 
severity score to last recorded post-baseline severity score, through Day 29. 
 
Additionally, for each symptom, the proportion of participants who experience a reduction 
in severity >= 1 from baseline to worst post-baseline value, will be tabulated. 
 
A tornado plot for each symptom, by treatment, will be produced to describe the presence 
of each symptom and proportions of severity scores, by visit. 
For time to return to usual health through Day 29 and duration of fever, descriptive 
statistics by treatment will be provided. Treatment groups will be compared using a 2-sided 
Wilcoxon Rank Sum test at an alpha level of 5%. The Hodges-Lehmann estimate and its 
95% CI for the location shift between the AZD7442 and placebo groups will be reported. 
 
 
 
 
 
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4.2.3.6 
Subgroup Analyses 
A subgroup analysis by serostatus (positive/negative) at baseline will be conducted on the 
following previously described secondary endpoint: Incidence of Respiratory Failure, 
Incidence of Symptom Progression, Time to Return to Usual Health, and SARS-CoV-2 
RNA viral load. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.3 
Pharmacodynamic Endpoint 
Not Applicable. 
4.4 
Pharmacokinetics and ADA Endpoints 
4.4.1 
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 
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PK analysis may be performed by the Sponsor and reported in a separate report. The 
analysis is not covered in this SAP. 
4.4.2 
Immunogenicity 
4.4.2.1 
The Incidence of ADA to AZD7442 In Serum 
4.4.2.1.1 
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 results 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. 
x ADA positive at any visit (at baseline and/or post-baseline). The percentage of these 
participants in a population is known as ADA prevalence. 
x Treatment-induced ADA positive (positive post-baseline and not detected at 
baseline). 
x Treatment-boosted ADA positive (baseline ADA titer that was boosted by -fold 
following drug administration). 
x Treatment-emergent ADA positive (either treatment-induced ADA positive or 
treatment-boosted ADA positive). The percentage of these participants in a 
population is known as ADA incidence. 
x ADA positive post-baseline and positive at baseline. 
x ADA positive at baseline and not detected post-baseline. 
x Treatment-emergent ADA (TE-ADA) persistently positive, defined as treatment- 
emergent 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. 
x Treatment-emergent ADA (TE-ADA) transiently positive, defined as treatment- 
emergent ADA positive participants having at least one post-baseline ADA positive 
measurement and not fulfilling the conditions for TE-ADA persistently positive. 




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missing will be reported as No Sample (NS) in the listings. Serum concentrations that are 
NQ, NR, or NS will be handled as follows for the provision of descriptive statistics: 
x Any values reported as NR or NS will be excluded from the summary tables and 
corresponding figures. 
x 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. 
x 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. 
x 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. 
x The number of values below LLOQ (n < LLOQ) will be reported for each time 
point together with the total number of collected values (n). 
Three observations > LLOQ are required as a minimum for a serum concentration or PK 
parameter (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 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. 
7LWHUYDOXHVRISRVLWLYH$'$VDPSOHVUHSRUWHGDV/2'DUHLPSXWHGDV/2'LQWKH
calculation of summary statistics on ADA titer. 
 
 
 
4.5 
Safety Analyses 
The domain safety covers exposure, adverse events, clinical laboratory, vital signs, and 
ECG. 
Tables are provided for the Safety Analysis Set; listings are provided for All participants or 
the Safety Analysis Set depending on the availability of data. Safety tables will be repeated 
in the High Risk population. 
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4.5.1 
Exposure 
4.5.1.1 
Definitions and Derivations 
Due to the simplicity of dosing for this study, exposure is summarized in the participant 
disposition table. 
4.5.1.2 
Presentation 
Not applicable. 
4.5.2 
Adverse Events 
4.5.2.1 
Definitions and Derivations 
All Adverse events (AEs) will be coded using the MedDRA dictionary, version 23.1 or 
higher. 
The safety of AZD7442 will assessed by: 
x Incidence of AEs through end of study 
x Incidence of Serious Adverse Events (SAEs) through end of study 
x Incidence of adverse events of special interest (AESIs) through end of study 
 
AEs and SAEs 
AEs will be recorded from the time of IMP administration throughout the study up to and 
including the last visit. Serious adverse events (SAEs) are those events recorded as 
“Serious” on the AE page of the eCRF. SAEs will be recorded from the time of signing the 
informed consent form. The definition of AEs and SAEs can be found in Protocol 
Appendix B. 
Listings of AEs and SAEs will be provided. SAEs prior to the dose of IMP and AEs 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 SAE prior to the 
dose of IMP. Otherwise, it will be considered as SAE post dose of IMP. 
AESIs 
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. AESIs for AZD7442 include the following: 
x Anaphylaxis and other serious hypersensitivity reactions, including immune 
complex disease 
x Injection site reactions 


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Deaths 
If any participants die during the study as recorded on the “Death Details” page of the 
eCRF, 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 Safety 
Analysis Set. 
Severity 
Summary of AEs and SAEs post the dose of IMP will be broken down further by maximum 
severity and relationship to study intervention. Severity will be classified as mild, 
moderate, severe, life-threatening or disabling, and death by using grading for AEs. 
Severity for AEs will be collected on “Adverse Events” form of eCRF. Should a participant 
experience multiple events within a system organ class (SOC) or preferred term (PT), only 
the participant’s worst severity grade will be counted for that SOC or PT. 
Relationship to IMP 
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. 
Exposure adjusted rate 
Exposure adjusted rate is calculated as number of participants with AEs in categories 
divided by total participant-year exposure to investigational study intervention. Participant 
years is determined by summing the total number of follow-up days of each participant, and 
then dividing by 365.25. The exposure period is calculated from time of dose to end of 
study. 
4.5.2.2 
Presentation 
AEs will be presented for actual treatment for the Safety Analysis Set in categories as 
below. Intensity and causality will be presented for the different categories. 
x AEs 
x SAEs 
x SAEs with outcome death 
x AEs leading to IMP discontinuation 
x AEs leading to study discontinuation 
x AESIs 
Summaries will include the number and percentage of participants reporting at least one 
event, number of events, and exposure adjusted rates, where appropriate. 


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An overview table of AEs will be presented for actual treatment, including the number and 
percentage of participants for each category. 
Moreover, each category will be presented by SOC and PT. Should a participant 
experience multiple events within a category, the participant will be counted only once for 
that category. 
AEs that occur after unblinding due to vaccination will be presented and tabulated 
separately. 
4.5.3 
Clinical Laboratory, Blood Sample and Urinalysis 
4.5.3.1 
Definitions and Derivations 
Hematology, serum clinical chemistry, coagulation, and urinalysis will be performed as per 
the schedule of events (refer to Protocol Sections 1.3 and 8.2.4 for schedule and lists of 
parameters). A urine pregnancy test will be performed at screening and per the schedule of 
events (refer to protocol, Section 1.3). If urine tests positive or indeterminate, a serum test 
will be performed for confirmation. 
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 (ULQ), 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. 
Quantitative laboratory parameters will be compared with the relevant central laboratory 
normal ranges in SI units and categorized as: 
x Low: Below the lower limit of the laboratory normal range. 
x Normal: Within the laboratory normal range (upper and lower limit included). 
x High: Above the upper limit of the laboratory normal range. 
Quantitative laboratory parameters with available CTCAE toxicity grades will be 
categorized as follows where higher grades representing a more severe toxicity (refer to 
Appendix 2 for each parameter toxicity grade criteria): 
x Grade 1 (i.e., mild); 
x Grade 2 (i.e., moderate); 
x Grade 3 (i.e., severe); 
x Grade 4 (i.e., life-threatening); 
x 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 


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grading system will be categorized as ‘No Event’ for the purpose of the shift from baseline 
summaries. 
4.5.3.2 
Presentations 
The following summaries will be provided by actual treatment group for laboratory 
parameters: 
x Observed and change from baseline in Standard International (SI) units by visit (for 
quantitative parameters). 
x Number and percentage of participants in each laboratory parameter category by 
visit (for categorical parameters). 
x Maximum post-baseline ALT/AST observed value categorized as < 3 x upper limit 
of normal 8/1WR[8/1WR[8/1RU8/1E\PD[LPXP
post-baseline total bilirubin (TBL) observed value categorized as < 2 x ULN or  2 
x ULN. 
x Scatter plots of the maximum post-baseline observed value in ALT value by the 
maximum post-baseline observed value in TBL value, both expressed as multiple of 
ULN. 
x Scatter plots of the maximum post-baseline observed value in AST value by the 
maximum post-baseline observed value in TBL value, both expressed as multiple of 
ULN. 
x A listing of participants with at least one observed value in ALT value  3 x ULN, 
$67YDOXH[8/1RU7%/YDOXH[8/1ZLOOEHSURYLGHG 
x 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 
4.5.3.1). 
x 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 4.5.3.1). 
x Listing of participants with at least one abnormal laboratory observed value outside 
the normal range criteria (refer to Section 4.5.3.1). 
4.5.4 
Vital Signs 
4.5.4.1 
Definitions and Derivations 
Vital signs will be performed at time points specified in Protocol Section 1.3, including the 
following parameters: 


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x Systolic blood pressure (SBP) (mmHg) 
x Diastolic blood pressure (DBP) (mmHg) 
x Pulse rate (beats per minute [bpm]) 
x Body temperature (C) 
x Respiratory rate (breaths/min) 
x Oxygen saturation (%) 
4.5.4.2 
Presentations 
For severity grades of abnormal Vital Signs refer to Appendix 3. 
The following summaries will be provided by actual treatment group for each vital sign 
parameter: 
x Observed and change from baseline by visit 
x Number and percentages of participants with at least one abnormal post-baseline 
observed value (refer to Appendix 3) 
o Participants will be summarized by the worst severity observed. 
4.5.5 
Electrocardiogram 
4.5.5.1 
Definitions and Derivations 
The following ECG parameters will be measured for this study as per the schedule of 
events (see Protocol Section 1.3): 
x PR interval (msec) 
x QRS duration (msec) 
x QT interval (msec) 
x QTcB interval (msec) 
x QTcF interval (msec) 
x RR interval (msec) 
x ECG maximum heart rate (beats/min) 
x ECG mean heart rate (beats/min) 
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 highest of 
the 3 measurements collected at baseline and the highest among all post-baseline 
measurements will be used for the shift from baseline summaries. Should one or two of the 


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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. 
Markedly abnormal quantitative ECG parameters will be identified in accordance with the 
following predefined markedly abnormal criteria: 
x Observed values for QTc, QTcF, and QTcB intervals will be classified as: 
o > 450 but  480 msec 
o > 480 but  500 msec 
o > 500 msec 
x Change from baseline for QTc, QTcF, and QTcB intervals will be classified as: 
o  30 to 60 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. 
4.5.5.2 
Presentations 
The following summaries will be provided by actual treatment group for each ECG 
parameter: 
x Observed and change from baseline by visit (for quantitative parameters) 
x Number and percentages of participants with at least one markedly abnormal post- 
baseline observed value/change from baseline (for quantitative parameters; refer to 
Section 4.5.5.1) 
x Listing of participants with at least one markedly abnormal observed value/change 
from baseline 
x Shift from baseline in overall ECG interpretation to the worst post-baseline 
assessment 
x Listing of participants with at least one abnormal overall ECG interpretation, 
including the finding(s) for each participant 
All individual measurements will be listed. 
4.5.6 
Other Safety Assessments 
4.5.6.1 
Definitions and Derivations 
Not applicable. 


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4.5.6.2 
Presentations 
Not applicable. 
 
5 
INTERIM ANALYSIS 
No interim analysis will be conducted. 


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6 
REFERENCES 
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. 
Wilson, E.B., Hilferty, M.M. The distribution of chi-squared. Proceedings of the National 
Academy of Sciences, Washington; 1931, 684-688. 
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 2. CTCAE Toxicity Grade, Version 5.0 
 
 
 
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 - 
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 
 - 
< 75 x 10E9/L 
 - 
< 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 


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CTCAE Term 
Laboratory Test 
No Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
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 
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 – 
 mmol/L 
n/a 
> 1.23 – 
 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 


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CTCAE Term 
Laboratory Test 
No Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Creatinine increased 
Creatinine (μmol/L) 
 ULN 
> ULN – 
 x ULN 
> 1.5 – 
 3.0 x ULN 
or 
> 1.5 –  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; 
[
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 
Alanine transaminase 
(ALT) increased 
ALT (U/L) 
 ULN if 
baseline 
normal; 
[
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 


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CTCAE Term 
Laboratory Test 
No Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Aspartate transaminase 
(AST) increased 
AST (U/L) 
 ULN if 
baseline 
normal; 
[
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; 
[
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 – 
 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; 
EDVHOLQHLI
on 
anticoagulant 
> 1.2 –  if 
not on 
anticoagulant; 
> baseline - 
 1.5 x baseline 
if on 
anticoagulant 
> 1.5 –  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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Statistical Analysis Plan - 2.0 
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AstraZeneca 
 
 
 
Appendix 3. Clinical Abnormalities: Vital Signs 
 
 
 
 
Vital Signs 
Vital Signs Grade 
Mild 
(Grade 1) 
Moderate 
(Grade 2) 
Severe 
(Grade 3) 
Potentially Life 
Threatening 
(Grade 4) 
 
Fever ႏ ႔ 
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 
 
ER = emergency room; Hg = mercury. 

Prot_006.pdf: 
Clinical Study Protocol - 7.0 
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CONFIDENTIAL AND PROPRIETARY1 of 115 
 
 
Clinical Study Protocol  
 
Study Intervention 
AZD7442 
 
Study Code 
D8851C00001  
 
Version 
7.0 
 
Date 
30 June 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Phase III Randomized, Double-blind, Placebo-controlled, 
Multicenter Study to Determine the Safety and Efficacy of 
AZD7442 for the Treatment of COVID-19 in Non-hospitalized 
Adults 
 
Sponsor Name: 
AstraZeneca AB 
Legal Registered Address: 
151, 85 Södertälje, Sweden 
Regulatory Agency Identifier Number(s): 
EudraCT Number: 2020-005315-44 
 
IND 150712 
 
 
 
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. 
 
 


Clinical Study Protocol - 7.0 
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Protocol Number: D8851C00001 
Amendment Number: Amendment 6 
Study Intervention: AZD7442, a combination product of 2 monoclonal antibodies 
(AZD8895 and AZD1061) 
Study Phase: Phase III 
Short Title: Phase III Double-blind, Placebo-controlled Study of AZD7442 for Treatment of 
COVID-19 in Outpatient Adults 
Acronym: TACKLE (Treating acute COVID-19 condition with a long half-life engineered 
antibody) 
Study Physician Name and Contact Information will be provided separately 
International Co-ordinating Investigator: Prof Hugh Montgomery, University College 
London, UK 




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CONFIDENTIAL AND PROPRIETARY4 of 115 
 
EDVHOLQH'D\ for isolation purposes. 
Early intervention analysis 
set 
All participants in the modified full analysis set who 
UHFHLYHG,03GD\VIURPV\PSWRPonset. 
Seronegative analysis set 
All participants in the modified full analysis set who were 
seronegative at baseline. 
 
Synopsis, Sections 1.2 (Schema), 4.1 (Study Design), 9.1 (Statistical Hypotheses), 9.4.1 
(General Considerations): The number of primary endpoint events required for the 
primary analysis has been reduced from 52 to 43 and this will be sufficient to provide 90% 
power for the primary analysis. The data cut-off for the primary analysis will be 30 days 
after approximately 43 primary endpoint events have been confirmed in the primary 
analysis population. Enrollment will stop when approximately 43 primary events have been 
confirmed in the primary analysis population. 
Synopsis, Section 9.2 (Sample Size Determination): Statistical power has been reduced 
from 95% to 90%, resulting in the number of events required for the primary analysis being 
reduced from 52 to 43. 
Section 9.3 (Populations for Analysis): Analysis populations have been defined to 
accommodate the clarification of the primary endpoint population and the inclusion of 
additional supportive estimands. 
Section 9.4.1 (General Considerations): The data cut off has been changed to reflect the 
change in sample size from 52 to 43 primary endpoint events in the primary analysis 
population.  
Section 9.4.2.1 (Primary Endpoint): Primary analysis method has been changed from 
Poisson regression model to CMH method. Additional supportive estimands have been 
included in the multiple testing hierarchy. 
Section 9.4.2.2 (Secondary Endpoint): Analysis population for secondary endpoint has 
been changed in line with the clarification of the primary analysis population. 
Section 9.4.5 (Methods for Multiple Testing Control): Additional supportive estimands 
have been included in the multiple testing hierarchy. 
Section 9.4.6 (Sensitivity Analyses): Clarification has been added to the analysis method in 
line with the change to the primary analysis method. 


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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 ................................................................................... 10 
1.1 
Synopsis ................................................................................................................ 10 
1.2 
Schema .................................................................................................................. 15 
1.3 
Schedule of Activities ........................................................................................... 16 
2 
INTRODUCTION ................................................................................................ 25 
2.1 
Study Rationale ..................................................................................................... 25 
2.2 
Background ........................................................................................................... 26 
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 ...................................................................... 27 
4 
STUDY DESIGN ................................................................................................. 30 
4.1 
Overall Design ...................................................................................................... 30 
4.2 
 32 
4.3 
 34 
4.4 
End of Study Definition ........................................................................................ 35 
5 
STUDY POPULATION ....................................................................................... 35 
5.1 
Inclusion Criteria .................................................................................................. 35 
5.2 
Exclusion Criteria ................................................................................................. 38 
5.3 
Lifestyle Considerations ....................................................................................... 40 
5.4 
Screen Failures ..................................................................................................... 40 
6 
STUDY INTERVENTION .................................................................................. 40 
6.1 
Investigational Medicinal Products Administered ............................................... 40 
6.1.1 
Investigational Medicinal Products ...................................................................... 40 
6.2 
Preparation/Handling/Storage/Accountability ...................................................... 41 
6.2.1 
Dose Preparation and Administration Instructions ............................................... 42 
6.3 
Measures to Minimize Bias: Randomization and Blinding .................................. 42 
6.3.1 
Randomization ...................................................................................................... 42 
6.3.2 
Blinding ................................................................................................................ 42 
6.3.3 
Procedures for Unblinding .................................................................................... 43 
6.4 
Investigational Medicinal Product Compliance ................................................... 43 
6.5 
Concomitant Therapy ........................................................................................... 43 
6.5.1 
COVID-19 Vaccination ........................................................................................ 45 
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6.6 
Dose Modification ................................................................................................ 46 
6.7 
Intervention After the End of the Study ............................................................... 46 
7 
DISCONTINUATION OF IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ............................................................ 47 
7.1 
Discontinuation of Investigational Medicinal Product ......................................... 47 
7.2 
Participant Withdrawal from the Study ................................................................ 47 
7.3 
Lost to Follow-up ................................................................................................. 47 
7.4 
Study Suspension/Early Termination ................................................................... 48 
8 
STUDY ASSESSMENTS AND PROCEDURES ............................................... 49 
8.1 
Efficacy Assessments ........................................................................................... 49 
8.1.1 
Clinical Assessments ............................................................................................ 49 
8.1.2 
Collect/Update Secondary Contacts ..................................................................... 50 
8.1.3 
Survival Status Check ........................................................................................... 50 
8.1.4 
Participant-reported Symptom Diary .................................................................... 50 
8.1.5 
Return to Usual Health ......................................................................................... 52 
8.1.6 
 52 
8.1.7 
Virologic Studies .................................................................................................. 52 
8.2 
Safety Assessments ............................................................................................... 52 
8.2.1 
Physical Examinations .......................................................................................... 52 
8.2.2 
Vital Signs ............................................................................................................ 53 
8.2.3 
Electrocardiograms ............................................................................................... 53 
8.2.4 
Clinical Safety Laboratory Assessments .............................................................. 53 
8.2.4.1 
Females Only ........................................................................................................ 55 
8.2.5 
Injection Site Inspection ....................................................................................... 55 
8.2.5.1 
Monitoring After IMP Administration .................................................................. 55 
8.3 
Adverse Events and Serious Adverse Events ....................................................... 56 
8.3.1 
Time Period and Frequency for Collecting AE and SAE Information ................. 56 
8.3.2 
Follow-up of AEs and SAEs ................................................................................ 56 
8.3.3 
Causality Collection ............................................................................................. 58 
8.3.4 
Adverse Events of Special Interest ....................................................................... 58 
8.3.5 
Adverse Events Based on Signs and Symptoms .................................................. 59 
8.3.6 
Adverse Events Based on Examinations and Tests .............................................. 59 
8.3.7 
Hy’s Law .............................................................................................................. 59 
8.3.8 
Disease Under Study ............................................................................................ 60 
8.3.9 
Reporting of Serious Adverse Events ................................................................... 60 
8.3.10 
Pregnancy ............................................................................................................. 61 
8.3.10.1 
Maternal Exposure ................................................................................................ 61 
8.3.10.2 
Paternal Exposure ................................................................................................. 62 
8.3.11 
Medication Error ................................................................................................... 62 
8.4 
Overdose ............................................................................................................... 62 
8.5 
Human Biological Samples .................................................................................. 63 
8.5.1 
Pharmacokinetics Assessments ............................................................................ 63 
8.5.1.1 
Determination of Drug Concentration .................................................................. 64 
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LIST OF TABLES 
Table 1 
Schedule of Activities for Cohort 1 ............................................................ 16 
Table 2 
Schedule of Activities for Cohort 2 ............................................................ 21 
Table 3 
Objectives and Endpoints ............................................................................ 27 
Table 4 
 41 
Table 5 
Summary of Permitted, Prohibited, or Restricted Medications .................. 44 
Table 6 
Injection Site Inspection on Day 1 .............................................................. 55 
Table 7 
Populations for Analysis ............................................................................. 67 
 
LIST OF APPENDICES 
Appendix A 
Regulatory, Ethical, and Study Oversight Considerations .......................... 76 
Appendix B 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................... 82 
Appendix C 
Handling of Human Biological Samples ..................................................... 87 
Appendix D 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law .............................................................................. 89 
Appendix E 
Abbreviations .............................................................................................. 95 
Appendix F 
WHO Clinical Progression Scale for COVID-19 ....................................... 98 
Appendix G 
Participant-reported Symptom Diary .......................................................... 99 
Appendix H 
Hospitalization Definition ......................................................................... 105 
Appendix I 
Amendment History .................................................................................. 106 
 
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ADA Anti-drug-antibody; AE Adverse event; AESI Adverse event of special interest; AUC Area under the 
plasma concentration-time curve; COVID-19, Coronavirus disease 2019; ECMO Extracorporeal membrane 
oxygenation; IM Intramuscular; IMP Investigational medicinal product; PK Pharmacokinetic; RNA Ribonucleic 
acid; SAE Serious adverse event; SARS-CoV-2 Severe acute respiratory syndrome-coronavirus-2; SpO2 Oxygen 
saturation; WHO World Health Organization. 
 
 
Overall Design 
This is a Phase III, randomized, double-blind, placebo-controlled, multicountry, multicenter 
study assessing the safety and efficacy of a single 600 mg dose of AZD7442 compared to 
placebo for the treatment of COVID-19. AZD7442 is a combination product of 2 monoclonal 
antibodies (AZD8895 and AZD1061), administered as 2 separate IM injections of 300 mg 
each. All participants will receive background local standard of care therapy (according to 
participating institution/hospital) regardless of the study treatment group to which they are 
randomized. Approximately 130 to 140 sites will participate in this study. 
3DUWLFLSDQWVZLOOEHRXWSDWLHQWDGXOWV\HDUVZLWKDGRFXPHQWHGSRVLWLYH6$56-CoV-2 
PROHFXODUWHVWDQWLJHQRUQXFOHLFDFLGIURPDVDPSOHFROOHFWHGGD\VSULRUWRVWXG\HQWU\
DQGZLWKGD\s of symptoms of COVID-19 at study entry (‘Day 1’ symptom count starts 
from the first day of symptoms), plus the presence of select symptoms within 24 hours prior to 
Day 1. 
At least 60% of participants will meet the protocol definition of being at high-risk of 
progression to severe COVID-19 as defined by any of the following: 
x 
Persons aged 65 years and older at randomization 
x 
Persons aged < 65 years and having at least one of the following conditions: 
 
Cancer 
 
Chronic lung disease or moderate to severe asthma 
 
Obesity (BMI > 30; may be based on self-report of recent height and weight 
measurement) 
 
Hypertension 
 
Cardiovascular disease (including history of stroke) 
 
Diabetes 
 
Chronic kidney disease 
 
Chronic liver disease 
 
Immunocompromised state from solid organ transplant, blood or bone marrow 
transplant, immune deficiencies, HIV, use of corticosteroids, or use of other 
immunosuppressive medicines 
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 
Sickle cell disease 
 
Smoking (current or former) 
 
Randomization will be stratified (using centralized blocked randomization) by: 
1 
7LPHIURPV\PSWRPRQVHW 5 days versus > 5 days) 
2 
High-risk versus low-risk of progression to severe COVID-19 (high-risk is defined above) 
 
The enrollment of low-risk participants has stopped. 
Up to approximately 1700 participants will be randomized in a 1:1 ratio to receive a single IM 
dose of 600 mg of AZD7442 (n = up to approximately 850) or placebo (n = up to 
approximately 850) on Day 1. The first 20 participants to be dosed (approximately 
10 allocated to the AZD7442 group and 10 allocated to placebo) will form a sentinel group. 
After the entire sentinel group has been dosed, further enrollment will pause until the sentinel 
group’s safety data through Day 8 has been reviewed by the DSMB in order to provide a 
recommendation to continue or to halt dosing of additional participants. 
Participants will be enrolled into one of 2 independent cohorts: 
x 
Cohort 1 (n = approximately 300), which will include the sentinel group, will undergo 
more intensive testing to characterize their virological and immunological status, and to 
correlate that status with clinical outcomes. 
x 
Cohort 2 (n = up to approximately 1400) will be followed for clinical outcomes. 
 
Following screening, and no more than 7 days (‘Day 1’ symptom count starts from the first 
day of symptoms) from self-reported onset of COVID-19-related symptoms or measured 
fever, participants will receive a single dose of IMP. The dose will be administered as 2 
separate IM injections (one for AZD8895 and one for AZD1061; the 2 compounds will not be 
co-administered) in the gluteal region. In Cohort 1, the first 20 participants dosed (ie, the 
sentinel group) will undergo safety monitoring for 4 hours post IMP administration before 
further participants are dosed. At each site, there will be an interval of 24 hours after dosing of 
the first participant in the sentinel group before the next participant can be dosed. The next 80 
participants (21 to 100) will then undergo safety monitoring for 2 hours post IMP 
administration. If hypersensitivity reactions are observed in the first 100 participants, 
subsequent participants will continue to be monitored for 2 hours post IMP administration, 
otherwise the minimum safety monitoring time will be 1 hour. In addition, the sentinel group 
will be contacted daily (in-person or by telephone) for the first 4 days after IMP 
administration. The study will be temporarily suspended if the criteria listed in Section 7.4 are 
met. All sites will have access to emergency kits for treatment of severe anaphylactic 


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reactions/shock and to medical staff trained in using these emergency kits.  
After administration of the dose of study intervention on Day 1, participants will undergo 
28 days of intensive follow-up, followed by limited follow-up through Day 457.  
Disclosure Statement: This is a parallel-group treatment study with 2 arms that are 
double-blind.  
Number of Participants: CRM 7 Enrollment of up to approximately 1700 participants is 
planned, contingent upon safety. At least 60% of participants will meet the protocol definition 
of being at high-risk of progression to severe COVID-19. Enrollment will stop when 
approximately 43 primary endpoint events have been confirmed in the primary analysis 
population. 
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”, unless otherwise 
specified by the protocol.  
Intervention Groups and Duration: Participants will be randomized in a 1:1 ratio to receive 
a single 600 mg dose of AZD7442 or placebo. Investigational medicinal product will be 
administered on Day 1, and participants will be monitored for up to 15 months after IMP 
administration. 
Data Safety Monitoring Board: Yes 
Statistical Methods 
Primary Endpoint: The primary efficacy endpoint is a composite of either severe COVID-19 
or death from any cause through Day 29. 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 (Appendix F). 
Sample Size: Up to approximately 1700 participants will be randomized in a 1:1 ratio to 
receive a single 600 mg IM dose of AZD7442 (n = up to approximately 850) or placebo (n = 
up to approximately 850) on Day 1. 
The study has 
 to detect a RRR of 
 in the incidence of severe COVID-19/death 
in the AZD7442 group compared to the placebo group, 
 
.  
All participants will remain in the study for up to 456 days following the administration of 
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IMP. The primary analysis will be conducted 30 days after approximately 43 primary endpoint 
events have been confirmed in the primary analysis population. A Day 169 analysis will be 
conducted when all participants have been followed through Day 169. A final analysis will be 
conducted when all participants have completed the study (ie, all participants have completed 
Day 457 visit, see Figure 1).
The study will be completely double-blind until the primary analysis (ie, blind for participants, 
Investigators/site staff, and Sponsor/designated clinical research organization). The site 
personnel, participants, and the study team members who participate in the advice or decisions 
involving study conduct or day-to-day interactions with the site, will remain blinded until the 
end of the study (ie, all participants have completed Day 457 visit) to ensure the trial integrity 
is maintained.
1.2
Schema
Figure 1 
Study Design
An independent DSMB will monitor safety throughout, including the safety data through Day 8 from the 
participants in the sentinel group. 
Primary analysis will be conducted 30 days after approximately 43 events have been confirmed in the primary 
analysis population. 
DSMB Data Safety Monitoring Board; IM Intramuscular


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1.3 
Schedule of Activities 
The SoA for Cohort 1 is in Table 1 and the SoA for Cohort 2 is in Table 2. 
Table 1 
Schedule of Activities for Cohort 1 
Procedure 
Screening 
 
Day -1 or 
Day 1 
Treatment and Follow-up Period 
Early 
Discontinuation 
Visit 
Details 
in 
Section 
of CSP 
Day 
1 
Day 
3 
Day 
6 
Day
8 
Day 
15 
Day 
29 
Day 
85 
Day 
169 
Day 
366 
Day 457 
Before 
Day 29 
After 
Day 
29 
Window (days) 
 
NA 
± 1 
± 1 
± 1 
± 2 
± 4 
± 7 
± 7 
± 7 
± 7 
 
 
 
P = In-Person Visit 
H = Home Visit 
R = Remote Visit 
P 
P 
P/Ha 
P/Ha 
R 
P/Ha 
P 
P 
P 
P 
P/R 
P 
P 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assignment SID number 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Documentation of SARS-CoV-2 
infection  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Respiratory sample for rapid 
SARS-CoV-2 
Xb 
 
 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 Symptom screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
5.1 
Medical/medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Risk categorization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
4.1 
Smoking status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessments 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
8.1.1 
Complete physical examinationd 
X 
 
 
 
 
 
 
 
 
X 
 
X 
X 
8.2.1 
Targeted physical examination 
 
X 
Xc 
Xc 
 
Xc 
X 
X 
X 
 
 
 
 
8.2.1 
Vital signs 
X 
Xe 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
8.2.2 
Triplicate 12-lead ECG 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
X 
8.2.3 


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Table 1 
Schedule of Activities for Cohort 1 
Procedure 
Screening 
 
Day -1 or 
Day 1 
Treatment and Follow-up Period 
Early 
Discontinuation 
Visit 
Details 
in 
Section 
of CSP 
Day 
1 
Day 
3 
Day 
6 
Day
8 
Day 
15 
Day 
29 
Day 
85 
Day 
169 
Day 
366 
Day 457 
Before 
Day 29 
After 
Day 
29 
Window (days) 
 
NA 
± 1 
± 1 
± 1 
± 2 
± 4 
± 7 
± 7 
± 7 
± 7 
 
 
 
P = In-Person Visit 
H = Home Visit 
R = Remote Visit 
P 
P 
P/Ha 
P/Ha 
R 
P/Ha 
P 
P 
P 
P 
P/R 
P 
P 
 
Hematology 
 
Xf,g 
Xg 
Xg 
 
Xg 
Xg 
 
X 
X 
 
Xg 
X 
8.2.4 
Serum chemistry panel 
 
Xf 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
8.2.4 
Serum sample for vitamin Do 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
8.5.2.5 
Serum sample for zinco 
 
Xf 
 
 
 
 
 
 
 
 
 
 
 
8.5.2.5 
Urinalysis 
 
Xf 
 
X 
 
X 
X 
 
X 
X 
 
X 
X 
8.2.4 
Pregnancy testingi 
Xf,h 
Xf,h 
 
X 
 
 
X 
X 
X 
X 
 
X 
X 
8.2.4.1 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
6.5 
Collect/update secondary contacts 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
8.1.2 
Verify eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
5.1, 5.2 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
6.3.1 
Survival status check 
 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
8.1.3 
Participant-reported symptom diaryj 
 
Daily through Day 29 
 
 
 
 
 
 
8.1.4 
Participant-reported symptom 
reminderk 
 
Daily through Day 29 
 
 
 
 
 
 
8.1.4 
Staff review of participant-reported 
symptom diary 
 
 
X 
X 
 
X 
X 
 
 
 
 
X 
 
8.1.4 
Retrieval of participant-reported 
symptom diary  
 
 
 
 
 
 
Xl 
 
 
 
 
X 
 
8.1.4 


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Table 1 
Schedule of Activities for Cohort 1 
Procedure 
Screening 
 
Day -1 or 
Day 1 
Treatment and Follow-up Period 
Early 
Discontinuation 
Visit 
Details 
in 
Section 
of CSP 
Day 
1 
Day 
3 
Day 
6 
Day
8 
Day 
15 
Day 
29 
Day 
85 
Day 
169 
Day 
366 
Day 457 
Before 
Day 29 
After 
Day 
29 
Window (days) 
 
NA 
± 1 
± 1 
± 1 
± 2 
± 4 
± 7 
± 7 
± 7 
± 7 
 
 
 
P = In-Person Visit 
H = Home Visit 
R = Remote Visit 
P 
P 
P/Ha 
P/Ha 
R 
P/Ha 
P 
P 
P 
P 
P/R 
P 
P 
 
Return to usual (pre-COVID-19) 
health 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
X 
8.1.5 
Household infection report 
 
X 
 
 
 
 
X 
X 
X 
 
 
X 
X 
8.1.6 
Study staff-collected mid-turbinate 
nasal swab for SARS-CoV-2 RT-
PCR and sequencingm 
 
Xf 
X 
X 
 
X 
X 
  
 
 
 
X 
 
8.1.7 
 
Serum for SARS-CoV-2 serology 
 
Xn 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
X 
8.5.2.2 
 
 
Serum for AZD7442 
pharmacokinetics 
 
Xn 
X 
X 
 
X 
X 
X 
X 
X 
X 
[optional] 
X 
X 
8.5.1 
Serum for AZD7442 anti-drug 
antibodies 
 
Xf 
 
 
 
 
X 
X 
X 
X 
X 
[optional] 
X 
 
8.5.2.1 
 
 
 
 
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Table 1 
Schedule of Activities for Cohort 1 
Procedure 
Screening 
 
Day -1 or 
Day 1 
Treatment and Follow-up Period 
Early 
Discontinuation 
Visit 
Details 
in 
Section 
of CSP 
Day 
1 
Day 
3 
Day 
6 
Day
8 
Day 
15 
Day 
29 
Day 
85 
Day 
169 
Day 
366 
Day 457 
Before 
Day 29 
After 
Day 
29 
Window (days) 
 
NA 
± 1 
± 1 
± 1 
± 2 
± 4 
± 7 
± 7 
± 7 
± 7 
 
 
 
P = In-Person Visit 
H = Home Visit 
R = Remote Visit 
P 
P 
P/Ha 
P/Ha 
R 
P/Ha 
P 
P 
P 
P 
P/R 
P 
P 
 
 
 
IMP administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
6 
Check injection sites 
 
Xp 
X 
Xq 
 
  
 
 
 
 
 
 
 
8.2.5 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xs 
X 
X 
8.3 
SAEs and AESIs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xs 
X 
X 
8.3 
8.3.4 
Telephone contact for safety 
monitoringr 
 
Daily 
 
 
 
 
 
 
 
 
 
 
8.2.5.1 
a 
Visits noted P/H can be performed either in-person at clinical site or at home depending on the participant’s clinical status, availability of safe transfer to sites (eg, to avoid 
risk of infection spread), and local guidelines for travel restrictions/social distancing. For home visits, a nurse or HCP trained on study procedures will visit the participant at 
home; nasal swabs, blood collection (where at-home collection is possible), and inspection of injection sites will be performed by the nurse or HCP. Nurse or HCP will 
ensure shipment of specimens collected and reporting of AEs to study sites. 
b 
Perform if no documentation of SARS-CoV-2 infection available; tested locally. 
c 
Assessment will be performed only for participants attending in-person visits, or if a nurse or HCP visiting the participant at home is properly trained for these assessments. 
d 
Height is recorded only at the screening visit. 
e 
Perform pre-dose and 15 minutes (± 5 minutes) after both injections are complete. 
f 
Perform pre-dose on Day 1. 
g 
Hematology panel includes coagulation markers. 
h 
Urine pregnancy test (local laboratory) at screening. Perform another urine test (local laboratory) on Day 1 if screening urine test was performed on Day -1. Single serum 
(central laboratory) must be performed on Day 1. Sample urine test must return negative result before dosing.  
i 
Urine pregnancy test (local laboratory). 
j 
Participants will report COVID-19-related symptoms daily in an electronic device, starting pre-dose and post-dose on Day 1. 
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k 
Participant will be reminded every day through Day 29 to complete their diary. This reminder will be received through the electronic device. 
l 
If Day 29 visit is conducted earlier in ± 4 day window, participant should retain symptom diary in order to complete required daily entries through Study Day 29. 
m 
Mid-turbinate nasal swab is tested centrally. Sequencing applies to nasal swabs collected through Day 15. 
n 
Pre-dose sample and post-dose sample (ie, samples obtained prior to and upon completion of IMP administered via IM injections on Day 1). 
o 
Serum vitamin D, serum zinc, 
 dependent on availability of laboratory kits. 
p 
Perform 30 minutes (± 10 minutes) after the IMP has been administered and just prior to release from the study site or departure of the study staff.  
q 
If evidence of injection site reaction persists at the Day 6 visit, the injection site will be rechecked at each visit until no evidence of an active reaction remains. 
r 
The first 20 participants dosed (ie, the sentinel group) will undergo safety monitoring for 4 hours post IMP administration before further participants are dosed. At each site, 
there will be an interval of 24 hours after dosing of the first participant in the sentinel group before the next participant can be dosed. The next 80 participants (21 to 100) will 
then undergo safety monitoring for 2 hours post IMP administration. If hypersensitivity reactions are observed in the first 100 participants, subsequent participants will 
continue to be monitored for 2 hours post IMP administration, otherwise the minimum safety monitoring time will be 1 hour. In addition, the sentinel group will be contacted 
daily (in-person or by telephone) for the first 4 days after IMP administration. Contact will be made by telephone on days when there is not an in-person visit. 
s 
At Day 457 AE/SAE/AESI assessment will be made by telephone only.  
Note: Remote (denoted by R) visit: either a phone call, or a web-based virtual assessment.  
Note: Day 6 and Day 8 assessments must be performed on different days.  
AESI Adverse events of special interest; COVID-19 Coronavirus disease 2019; CSP Clinical Study Protocol; ECG Electrocardiogram; HCP Healthcare personnel; IM 
Intramuscular; IMP Investigational medicinal product; NA Not applicable; Nab Neutralizing antibody; NP Nasopharyngeal; 
 RNA 
Ribonucleic acid; RT-PCR Reverse transcription polymerase chain reaction; SAE Serious adverse event; SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2; SID 
Subject identification number. 
 
 
 
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Table 2 
Schedule of Activities for Cohort 2 
Procedure 
Screening 
 
Day -1 or 
Day 1 
Treatment and Follow-up Period 
Early 
Discontinuation 
Visit 
Details 
in 
Section 
of CSP 
Day 
1 
Day 
6 
Day 
8  
Day 
29 
Day 
85 
Day 
169 
Day 
366 
Day 457 
Before 
Day 29 
After 
Day 
29 
Window (days) 
 
NA 
± 1 
± 1 
± 4 
± 7 
± 7 
± 7 
± 7 
 
 
 
P = In-Person Visit 
H = Home Visit 
R = Remote Visit 
P 
P 
P/Ha 
R 
P 
P 
P 
P 
P/R 
P 
P 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Assignment SID number 
X 
 
 
 
 
 
 
 
 
 
 
 
Documentation of SARS-CoV-2 infection  
X 
 
 
 
 
 
 
 
 
 
 
 
Respiratory sample for rapid SARS-CoV-2 
Xb 
 
 
 
 
 
 
 
 
 
 
 
COVID-19 Symptom screen 
X 
 
 
 
 
 
 
 
 
 
 
5.1 
Medical/medication history 
X 
 
 
 
 
 
 
 
 
 
 
 
Risk categorization 
X 
 
 
 
 
 
 
 
 
 
 
4.1 
Smoking statust 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessments 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
8.1.1 
Complete physical examinationd 
X 
 
 
 
 
 
 
X 
 
X 
X 
8.2.1 
Targeted physical examination 
 
X 
Xc 
 
X 
X 
X 
 
 
 
 
8.2.1 
Vital signs 
X 
Xe 
X 
 
X 
X 
X 
X 
 
X 
X 
8.2.2 
Triplicate 12-lead ECG 
X 
 
 
 
X 
 
 
X 
 
X 
X 
8.2.3 
Hematology 
 
Xf,g 
Xg 
 
Xg 
 
X 
X 
 
Xg 
X 
8.2.4 
Serum chemistry panel 
 
Xf 
X 
 
X 
 
X 
X 
 
X 
X 
8.2.4 
Serum sample for vitamin Dh 
 
Xf 
 
 
 
 
 
 
 
 
 
8.5.2.5 
Serum sample for zinch 
 
Xf 
 
 
 
 
 
 
 
 
 
8.5.2.5 
Urinalysis 
 
Xf 
X 
 
X 
 
X 
X 
 
X 
X 
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Table 2 
Schedule of Activities for Cohort 2 
Procedure 
Screening 
 
Day -1 or 
Day 1 
Treatment and Follow-up Period 
Early 
Discontinuation 
Visit 
Details 
in 
Section 
of CSP 
Day 
1 
Day 
6 
Day 
8  
Day 
29 
Day 
85 
Day 
169 
Day 
366 
Day 457 
Before 
Day 29 
After 
Day 
29 
Window (days) 
 
NA 
± 1 
± 1 
± 4 
± 7 
± 7 
± 7 
± 7 
 
 
 
P = In-Person Visit 
H = Home Visit 
R = Remote Visit 
P 
P 
P/Ha 
R 
P 
P 
P 
P 
P/R 
P 
P 
 
Pregnancy testingj 
Xf,i 
Xf,i 
X 
 
X 
X 
X 
X 
 
X 
X 
8.2.4.1 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
6.5 
Collect/update secondary contacts 
 
X 
X 
X 
X 
 
 
 
 
 
 
8.1.2 
Verify eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
5.1, 5.2 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
6.3.1 
Survival status check 
 
 
X 
 
X 
X 
X 
X 
 
X 
X 
8.1.3 
Participant-reported symptom diaryk 
 
Daily through Day 29 
 
 
 
 
 
 
8.1.4 
Participant-reported symptom reminderl 
 
Daily through Day 29 
 
 
 
 
 
 
8.1.4 
Staff review of participant-reported 
symptom diary 
 
 
X 
 
X 
 
 
 
 
X 
 
8.1.4 
Retrieval of participant-reported symptom 
diary  
 
 
 
 
Xm 
 
 
 
 
X 
 
8.1.4 
Return to usual (pre-COVID-19) health 
 
 
X 
X 
X 
X 
X 
 
 
X 
X 
8.1.5 
 
Study staff-collected mid-turbinate nasal 
swab for SARS-CoV-2 RT-PCR and 
sequencingn 
 
Xf 
X 
 
X 
  
 
 
 
X 
 
8.1.7 
 
Serum for SARS-CoV-2 serology 
 
Xo 
X 
 
X 
X 
X 
X 
 
X 
X 
8.5.2.2 
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Table 2 
Schedule of Activities for Cohort 2 
Procedure 
Screening 
 
Day -1 or 
Day 1 
Treatment and Follow-up Period 
Early 
Discontinuation 
Visit 
Details 
in 
Section 
of CSP 
Day 
1 
Day 
6 
Day 
8  
Day 
29 
Day 
85 
Day 
169 
Day 
366 
Day 457 
Before 
Day 29 
After 
Day 
29 
Window (days) 
 
NA 
± 1 
± 1 
± 4 
± 7 
± 7 
± 7 
± 7 
 
 
 
P = In-Person Visit 
H = Home Visit 
R = Remote Visit 
P 
P 
P/Ha 
R 
P 
P 
P 
P 
P/R 
P 
P 
 
 
Serum for AZD7442 pharmacokinetics 
 
Xo 
X 
 
X 
X 
X 
X 
X 
[optional] 
X 
X 
8.5.1 
Serum for AZD7442 anti-drug antibodies 
 
Xf 
 
 
X 
X 
X 
X 
X 
[optional] 
X 
 
8.5.2.1 
 
IMP administration 
 
Xp 
 
 
 
 
 
 
 
 
 
6 
Check injection sites 
 
Xq 
Xr 
 
 
 
 
 
 
 
 
8.2.5 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
Xs 
X 
X 
8.3 
SAEs and AESIs 
X 
X 
X 
X 
X 
X 
X 
X 
Xs 
X 
X 
8.3 
8.3.4 
a 
Visits noted P/H can be performed either in-person at clinical site or at home depending on the participant’s clinical status, availability of safe transfer to sites (eg, to avoid 
risk of infection spread), and local guidelines for travel restrictions/social distancing. For home visits, a nurse or HCP trained on study procedures will visit the participant at 
home; nasal swabs, blood collection (where at-home collection is possible), and inspection of injection sites will be performed by the nurse or HCP. Nurse or HCP will 
ensure shipment of specimens collected and reporting of AEs to study sites. 
b 
Perform if no documentation of SARS-CoV-2 infection available; tested locally. 
c 
Assessment will be performed only for participants attending in-person visits, or if a nurse or HCP visiting the participant at home is properly trained for these assessments. 
d 
Height is recorded only at the screening visit. 
e 
Perform pre-dose and 15 minutes (± 5 minutes) after both injections are complete. 
f 
Perform pre-dose on Day 1. 
g 
Hematology panel includes coagulation markers. 
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h 
Serum vitamin D and serum zinc, dependent on availability of laboratory kits. 
i 
Urine pregnancy test (local laboratory) at screening. Perform another urine test (local laboratory) on Day 1 if screening urine test was performed on Day -1. Single serum 
(central laboratory) must be performed on Day 1. Sample urine test must return negative result before dosing.  
j 
Urine pregnancy test (local laboratory). 
k 
Participants will report COVID-19-related symptoms daily in an electronic device, starting pre-dose and post-dose on Day 1. 
l 
Participant will be reminded every day through Day 29 to complete their diary. This reminder will be received through the electronic device. 
m 
If Day 29 visit is conducted earlier in ± 4 day window, participant should retain symptom diary in order to complete required daily entries through Study Day 29. 
n 
Mid-turbinate nasal swab is tested centrally. Sequencing applies to nasal swabs collected through Day 15. 
o 
Pre-dose sample and post-dose sample (ie, samples obtained prior to and upon completion of IMP administered via IM injections on Day 1). 
p 
After the sentinel group is dosed, the next 80 participants dosed (21 to 100) will undergo safety monitoring for 2 hours post IMP administration. If hypersensitivity reactions 
are observed in the first 100 dosed participants, subsequent participants will continue to be monitored for 2 hours post IMP administration, otherwise the minimum safety 
monitoring time will be 1 hour. 
q 
Perform 30 minutes (± 10 minutes) after the IMP has been administered and just prior to release from the study site or departure of the study staff. 
r 
If evidence of injection site reaction persists at the Day 6 visit, the injection site will be rechecked at each visit until no evidence of an active reaction remains. 
s 
At Day 457 AE/SAE/AESI assessment will be made by telephone only. 
t 
Current or former smoking status to be captured. 
Note: Remote (denoted by R) visit: either a phone call, or a web-based virtual assessment.  
Note: Day 6 and Day 8 assessments must be performed on different days.  
AESI Adverse events of special interest; COVID-19 Coronavirus disease 2019; CSP Clinical Study Protocol; ECG Electrocardiogram; HCP Healthcare personnel; IM 
Intramuscular; IMP Investigational medicinal product; NA Not applicable; Nab Neutralizing antibody; NP Nasopharyngeal; RNA Ribonucleic acid; RT-PCR Reverse transcription 
polymerase chain reaction; SAE Serious adverse event; SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2; SID Subject identification number. 
 
 


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2 
INTRODUCTION 
A novel coronavirus, SARS-CoV-2, first emerged in China in November 2019 causing cases 
of atypical pneumonia. As of 6 October 2020, the virus has spread to all corners of the globe, 
with over 35 million confirmed cases reported and more than one million associated deaths 
(Tamhane et al 2018 and WHO 2020). The COVID-19 pandemic is causing major disruption 
to global healthcare systems with significant socioeconomic impacts.  
Effective interventions to prevent or treat COVID-19 remain few in number and clinical 
experience is limited.  
As a response to the ongoing pandemic, AstraZeneca is developing mAbs to the SARS-CoV-2 
spike 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.  
AZD7442, a combination of 2 of these mAbs (AZD8895 and AZD1061), is being evaluated 
for administration to treat or prevent COVID-19. There is currently one ongoing Phase I study 
with AZD7442 (study D8850C00001) and 2 ongoing Phase III prophylaxis studies (a 
pre-exposure prophylaxis of COVID-19 study D8850C00002, and a post-exposure 
prophylaxis of COVID-19 study D8850C00003), in addition to this treatment study. 
Further details about AZD7442 are provided throughout this section and in the AZD7442 IB. 
2.1 
Study Rationale 
There is an urgent need to rapidly evaluate treatments in the non-hospitalized setting, to 
prevent disease progression, and reduce serious complications of COVID-19 and 
transmission. AZD7442 is a combination of 2 mAbs, with non-overlapping epitopes directed 
against RBD of the SARS-CoV-2 spike protein for neutralization of the virus. The use of 
2 mAbs provides redundancy in case of virus mutation and escape. AZD8895 and AZD1061 
mAbs have been engineered with triple amino acid substitutions M252Y/S254T/T256E (YTE) 
in the Fc region to prolong the half-life, which is expected to provide protection from 
COVID-19 for a duration of at least 5 months. In addition, the triple amino acid substitutions 
L234F/L235E/P331S I in the Fc region were engineered for both AZD8895 and AZD1061 to 
abrogate Fc mediated effector function, which is expected to reduce theoretical risk of 
antibody-dependent enhancement. The purpose of this Phase III study is to determine if 
AZD7442 can safely treat COVID-19 symptoms and prevent either severe COVID-19 or 
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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 
S glycoprotein, envelope, membrane, and nucleocapsid proteins. Envelope, membrane, and 
nucleocapsid proteins are mainly responsible for virion assembly while the S protein is 
involved in receptor binding, mediating virus entry into host cells during coronavirus 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. 
Summaries of nonclinical pharmacology, PK, drug metabolism, and toxicology of AZD7442 
are 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. 
 
 
 
 
 
AZD7442 is a combination of 2 human mAbs, with non-overlapping epitopes directed against 
RBD of the SARS-CoV-2 spike protein for neutralization of the virus. Neither mAb has any 
human target. There are no potential risks based on mechanism of action. 
Potential risks are associated with the administration of any immunoglobulin, including 
polyclonal immunoglobulin preparations and mAbs. 
The important potential risks associated with the administration of immunoglobulin, include, 
but are not limited to, anaphylaxis and other serious hypersensitivity reactions, including 
immune complex disease.  
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x 
Persons aged < 65 years and having at least one of the following conditions: 
 
Cancer 
 
Chronic lung disease or moderate to severe asthma 
 
Overweight (defined as a body mass index (BMI) > 25 kg/m2 but < 30 kg/m2) or 
REHVLW\%0,NJP2); may be based on self-report of recent height and weight 
measurement) 
 
Hypertension 
 
Cardiovascular disease (including history of stroke) 
 
Diabetes 
 
Chronic kidney disease 
 
Chronic liver disease 
 
Immunocompromised state from solid organ transplant, blood or bone marrow 
transplant, immune deficiencies, HIV, use of corticosteroids, or use of other 
immunosuppressive medicines 
 
Sickle cell disease 
 
Smoking (current or former) 
 
Randomization will be stratified (using centralized blocked randomization) by: 
1 
7LPHIURPV\PSWRPRQVHWGD\VYHUVXV!GD\V 
2 
High-risk versus low-risk of progression to severe COVID-19 (high-risk is defined above) 
 
The enrollment of low-risk participants has stopped. 
Up to approximately 1700 participants will be randomized in a 1:1 ratio to receive a single IM 
dose of 600 mg of AZD7442 (n = up to approximately 850) or placebo (n = up to 
approximately 850) on Day 1. The first 20 participants to be dosed at selected sites will form a 
sentinel group. To ensure balanced size of the two treatment groups in the sentinel group, 
randomization of these sentinel participants will be in a 1:1 ratio without stratification. After 
the entire sentinel group has been dosed, further enrollment will pause until the sentinel 
group’s safety data through Day 8 has been reviewed by the DSMB in order to provide a 
recommendation to continue or to halt dosing of additional participants. 
Participants will be enrolled into one of 2 independent cohorts: 
x 
Cohort 1 (n = approximately 300), which will include the sentinel group, will undergo 
more intensive testing to characterize their virological and immunological status, and to 
correlate that status with clinical outcomes.  


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x 
Cohort 2 (n = up to approximatley1400) will be followed for clinical outcomes.  
 
Following screening, and no more than 7 days from self-reported onset of COVID-19-related 
symptoms or measured fever, participants will be randomized on Day 1 and receive a single 
dose of IMP. The dose will be administered as 2 separate IM injections (one for AZD8895 and 
one for AZD1061; the 2 compounds will not be co-administered) in the gluteal region. In 
Cohort 1, the first 20 participants dosed (ie, the sentinel group) will undergo safety monitoring 
for 4 hours post IMP administration before further participants are dosed. At each site, there 
will be an interval of 24 hours after dosing of the first participant in the sentinel group before 
the next participant can be dosed. The next 80 participants (21 to 100) will then undergo 
safety monitoring for 2 hours post IMP administration. If hypersensitivity reactions are 
observed in the first 100 participants, subsequent participants will continue to be monitored 
for 2 hours post IMP administration, otherwise the minimum safety monitoring time will be 
1 hour. In addition, the sentinel group will be contacted daily (in-person or by telephone) for 
the first 4 days after IMP administration. The study will be temporarily suspended if the 
criteria listed in Section 7.4 are met. All sites will have access to emergency kits for treatment 
of severe anaphylactic reactions/shock and to medical staff trained in using these emergency 
kits.  
After administration of the dose of study intervention on Day 1, participants will undergo 
28 days of intensive follow-up, followed by limited follow-up through visit Day 457. 
An independent DSMB will monitor safety throughout, including the safety data through 
Day 8 from the participants in the sentinel group. The primary analysis for efficacy will be 
conducted by the Sponsor or its delegates 30 days after approximately 43 primary endpoint 
events have been confirmed in the primary analysis population. Enrollment will stop when 
approximately 43 primary events have been confirmed in the primary analysis population. A 
Day 169 analysis (additional efficacy and safety) will be conducted when all participants have 
been followed through Day 169. A final analysis will be conducted when all participants have 
completed the study. See Section 9.6 for further details. 
 
 
 
 
 
 
 
 
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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 stages of 
the study, including the last scheduled procedure shown in the SoA (Table 1 for Cohort 1 and 
Table 2 for Cohort 2). 
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 inclusive at the time of signing the informed 
consent. 
Type of Participant and Disease Characteristics 
2 
Participant who has a documented laboratory-confirmed SARS-CoV-2 infection, as 
determined by a molecular test (antigen or nucleic acid) from any respiratory tract 
VSHFLPHQHJRURSKDU\QJHDO13RUQDVDOVZDERUVDOLYDFROOHFWHGGD\VSULRUWR
Day 1. 
3 
WHO Clinical Progression Scale score > 1 and < 4. 
4 
Participant must be dosed with IMP no more than 7 days from self-reported onset of 
COVID-19-related symptoms (mild to moderate COVID) or measured fever, defined as 
the self-reported date of first reported sign/symptom from the following list: 
 
Subjective fever or feeling feverish 
 
Cough 
 
Shortness of breath or difficulty breathing at rest or with activity 
 
Sore throat 
 
Body pain or muscle pain/aches 
 
Fatigue 
 
Headache 
 
Chills 
 
Nasal obstruction or congestion 


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 
Nasal discharge 
 
New loss of taste or smell 
 
Nausea or vomiting 
 
Diarrhea 
 
Documented temperature > 37.8°C/100°F 
 
New onset confusion (only for participants  60 years old) 
 
$SSHWLWHORVVRUGHFUHDVHGIRRGLQWDNHRQO\IRUSDUWLFLSDQWV\HDUVROG 
 
Increased supplemental oxygen requirement (only for participants on baseline 
supplemental oxygen) 
5 
One or more of the following signs/symptoms must be present within 24 hours prior to 
Day 1: 
 
Cough 
 
Sore throat 
 
Shortness of breath or difficulty breathing at rest or with activity 
 
Body pain or muscle pain/aches 
 
Fatigue 
 
Headache 
 
Chills 
 
Nasal obstruction or congestion 
 
Nasal discharge 
 
Nausea or vomiting 
 
Diarrhea 
 
New loss of taste or smell 
6 
2[\JHQDWLRQVDWXUDWLRQRIREWDLQHGDWUHVWE\VWXG\VWDIIZLWKLQKRXUVSULRUWR
Day 1, unless the potential participant regularly receives chronic supplementary oxygen 
for an underlying lung condition. 
Participation in another COVID-19 treatment trial 
7 
Agrees not to participate in another clinical trial for the treatment of COVID-19 or 
SARS-CoV-2 during the study period until reaching hospitalization or 28 days post-entry, 
whichever is earliest. 


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Reproduction 
8 
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 90 days following administration of 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 amenorrheic 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 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatment and follicle-stimulating hormone levels in the postmenopausal range. 
o 
:RPHQ\HDUVROGZRXOGEHFRQVLGHUHGSRVWPHQRSDXVDOLIWKH\KDYHEHHQ
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatment. 
 
Women 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 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 pregnancy test result at Visit 1 and during the study as in the SoA (Table 1 
for Cohort 1 and Table 2 for Cohort 2). 
 
Examples of highly effective birth control methods are listed below. 
x 
Intrauterine device  
x 
Intrauterine hormone-releasing system (IUS)  
x 
Bilateral tubal occlusion 


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x 
Vasectomized partner (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). 
x 
Sexual abstinence (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). 
x 
Combined (estrogen- and progestogen-containing hormonal contraception) 
 
Oral (combined pill) 
 
Injectable 
 
Transdermal (patch) 
x 
Progestogen-only hormonal contraception 
 
Oral 
 
Injectable 
 
Implantable 
 
Informed Consent 
9 
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.  
10 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 or current hospitalization for COVID-19 [see also Appendix H for further 
guidance on the definition of hospitalization]. 
2 
Current need for hospitalization or immediate medical attention in a clinic or emergency 
room service in the clinical opinion of the site investigator [see also Appendix H for 
further guidance on the definition of hospitalization]. 
3 
Previous hypersensitivity, infusion-related reaction, or severe adverse reaction following 
administration of a mAb. 


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4 
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 administration immediately 
after enrollment 
5 
Current requirement for mechanical ventilation or anticipated impending need for 
mechanical ventilation. 
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 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. 
8 
Known allergy/sensitivity or any hypersensitivity to components of the IMP or placebo. 
9 
Any co-morbidity requiring surgery within 7 days prior to study entry, or that is 
considered life-threatening in the opinion of the site investigator within 30 days prior to 
study entry. 
Prior/Concomitant Therapy 
10 Use of any prohibited medication listed in Section 6.5 within 30 days or 5 half-lives, 
whichever is longer, prior to study entry. 
11 Receipt of convalescent COVID-19 plasma treatment at any time prior to study entry. 
12 Receipt of systemic steroids (eg, prednisone, dexamethasone) or inhaled steroids within 
30 days prior to study entry unless a stable dose used for a chronic condition. 
Prior/Concurrent Clinical Study Experience 
13 Receipt of any IMP in the preceding 90 days or 5 half-lives, whichever is longer, or 
expected receipt of IMP during the period of study follow-up, or concurrent participation 
in another interventional study. 
Other Exclusions 
14 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements. 
15 Previous randomization in the present study.  
16 For women only, currently pregnant (confirmed with positive pregnancy test) or breast 
feeding. 
17 Blood drawn in excess of a total of 450 mL (1 unit) for any reason within 30 days prior to 
randomization. 
18 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.  


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19 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 
1 
Participants must follow the contraception requirements outlined in Section 5.1. 
2 
Restrictions relating to concomitant medications are described in Section 6.5. 
 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently 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 
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 
re-screened if the eligibility criterion that resulted in screen failure has changed in a manner 
that meets eligibility. Only a single re-screening is allowed in the study. Re-screened 
participants should be assigned the same participant number as for the initial screening. 
Individuals who are re-screened 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. 
6.1 
Investigational Medicinal Products Administered 
6.1.1 
Investigational Medicinal Products 
Participants will be randomized in a 1:1 ratio to receive one single 600 mg dose of AZD7442 
(administered as a 3 mL IM injection containing 300 mg AZD8895 and a 3 mL IM injection 
containing 300 mg AZD1061) or saline placebo (administered as 2 separate 3 mL IM 
injections) (Table 4). Investigational medicinal product will be administered on Day 1, and 
participants will be monitored for 456 days after IMP administration. 


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IMP Investigational medicinal product; IM Intramuscular; w/v Weight/volume. 
 
6.2 
Preparation/Handling/Storage/Accountability 
1 
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. 
2 
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 labeled 
storage conditions, with access limited to the investigator and authorized site staff. 
3 
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). 
 
CCI
CCI


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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. 
AZD7442 (AZD8895 and AZD1061) or placebo should be administered intramuscularly with 
one 3.0 mL injection in each gluteal region. The 2 drug products, 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. Refer to Handling Instructions for detailed dose preparation and 
administration information. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
6.3.1 
Randomization 
All participants will be centrally assigned to 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 stratified (using centralized blocked randomization) 
by: 
1 
7LPHIURPV\PSWRPRQVHW 5 days versus > 5 days) 
2 
High-risk versus low-risk of progression to severe COVID-19 (high-risk is defined in 
Section 4.1) 
The enrollment of low-risk participants is stopped. 
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. 
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 study 
intervention 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 randomization code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment 
randomization, or in the instance a participant wishes to be considered for a SARS-CoV-2 
vaccine. The investigator documents and reports the action to the Sponsor, without revealing 


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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’ IMP assignment is warranted. Participant safety 
must always be the first consideration in making such a determination. If a participant’s IMP 
assignment is unblinded, the Sponsor must be notified within 24 hours after breaking the 
blind. 
6.4 
Investigational Medicinal Product Compliance 
Dosing will take place under the guidance of study personnel. The date (and time, if 
applicable) of dose administered in the clinic will be recorded in the source documents and 
recorded in the eCRF. If a problem occurs during dosing, such as needle break, no re-dosing is 
permitted. 
6.5 
Concomitant Therapy 
Permitted, prohibited, and restricted medications are summarized in Table 5. 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded, along with: 
x 
Reason for use 
x 
Dates of administration, including start and end dates 
x 
Dosage information, including dose and frequency 
 
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy. 


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Table 5 
Summary of Permitted, Prohibited, or Restricted Medications 
Use Category 
Type of Medication/treatment 
Timeline/instructions 
Permitted 
Routine vaccinesa 
Licensed influenza vaccines are permitted at any time. 
All other routine vaccines are permitted beginning 
> 30 days after IMP dose  
Allergen immunotherapy  
Allowed if participant has been receiving stable 
desensitization therapy for allergies for at least 30 days 
prior to Day 1 and there is no anticipated change during 
the treatment period. Allergen immunotherapy should not 
be administered on the same day as IMP. 
Non-prescription treatments for allergies such as 
antihistamines, decongestants, and nasal steroids are 
permitted. 
Commercial biologics, 
prednisone, 
immunosuppressive 
medications (eg, azathioprine, 
tacrolimus, cyclosporine, 
methotrexate, 
hydroxychloroquine, or 
cytotoxic chemotherapy) 
Allowed, provided the participant is stable on 
maintenance dose (at steady state) prior to Day 1 and up 
to Day 29, OR  
Allowed if participant is hospitalized for treatment of 
COVID-19 
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.  
Prohibited 
• 
Investigational products 
indicated for the treatment 
or prevention of 
SARS-CoV-2 or 
COVID-19 
• 
Hydroxychloroquine 
• 
Chloroquine 
• 
Ivermectin 
• 
HIV protease inhibitors 
 
• 
Note: For participants who become hospitalized 
with COVID-19, receipt of approved/licensed 
treatment options are permitted and they should be 
treated according to local standard of care, including 
investigational agents under emergency use 
authorization or equivalent regulations. 
• 
Use of hydroxychloroquine is acceptable if used 
chronically for autoimmune disease, and the dose is 
stable prior to Day 1 and up to Day 29. 
• 
Use of chloroquine if used to treat a parasitic 
infection 
• 
Use of ivermectin is acceptable if used to treat a 
parasitic infection 
• 
HIV protease inhibitors are acceptable if used 
chronically for HIV infection, and the dose is stable 
prior to Day 1 and up to Day 29. 


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Table 5 
Summary of Permitted, Prohibited, or Restricted Medications 
Use Category 
Type of Medication/treatment 
Timeline/instructions 
• 
COVID-19 vaccinea 
• 
It is expected that most participants in this trial 
would have a protective infection-induced immune 
response. At this time, we have no reason to believe 
that the protection afforded by natural infection is 
less frequent or less robust than the protection 
provided by any vaccine and hence may not be 
required during acute illness.  
• 
If participants request vaccination, the procedures 
described below apply. 
Restricted 
Contraceptive methods 
See Section 5.1 
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. 
Ova/Sperm donation 
See Sections 8.3.10.1 and 8.3.10.2 
a 
The potential impact of AZD7442 on COVID-19 vaccines is not known and has not been studied. See 
Section 6.5.1 for instructions on COVID vaccinations. 
COVID-19 Coronavirus disease 2019; HIV Human immunodeficiency virus; IMP Investigational medicinal 
product; SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2. 
 
6.5.1 
COVID-19 Vaccination 
Participants who have received COVID-19 vaccination prior to study entry will be excluded 
from this study.  
During the study, when participants become eligible for access to a SARS-CoV-2 vaccine, it is 
appropriate that they can discuss with the investigator and others after Day 30 so as to make 
an informed choice. The following considerations apply: 
x 
Participants should not receive vaccination with an anti-SARS-CoV-2 vaccine during 
their acute illness. 
 
Participants in this study will have active COVID-19 at the time of enrollment 
Administration of vaccines during acute infectious illness is generally discouraged as 
a matter of standard clinical practice. Even with an effective vaccine, potentially 
protective immunological responses should take approximately 2 weeks to begin to 
appear. No clinical data, nor good immunological rationale, exist to suggest that 
vaccination with an anti-SARS-CoV-2 vaccine will have a beneficial effect on acute 
COVID-19. 
x 
Participants in this study are unlikely to receive any benefit from vaccination with an 
anti-SARS-CoV-2 vaccine after recovery from COVID-19. 
 
There is no evidence that shows that participants will benefit from vaccination with 
an anti-SARS-CoV-2 vaccine after recovery from their acute COVID-19. 


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 
After recovery from COVID-19, most participants in this trial would have a 
protective infection-induced immune response. 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. 
x 
Participants may wish to be vaccinated. If so, they may be unblinded as to their 
randomized investigational treatment in this study as per study unblinding procedure 
(Section 6.3.3), counselled, and referred outside the study for possible vaccination. 
 
Despite the lack of evidence or a rationale that participants in this study are likely to 
benefit from receiving a SARS-CoV-2 vaccine, some may wish to be vaccinated. In 
such situations, after recovery from their COVID-19, and appropriate counselling, 
such participants can be unblinded as to their randomized investigational treatment in 
this study. With that information, they can be further counselled: 
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, 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 (9 to 12 months) before 
receiving an anti-SARS-CoV-2 vaccine. For AZD7442, 9 to 12 months will 
represent 3 or 4 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. 
o 
After such counselling, the decision to receive the vaccine should be left to the 
participants and his or her personal physician. 
 
Participants who have been unblinded in order to receive vaccination can and should remain 
in the study after being unblinded. 
6.6 
Dose Modification 
The IMP will be administered as described in Section 6.1.1. Dose modification is not 
permitted unless in case of discontinuation of IMP, as per investigator’s clinical judgment. Re-
administration of dose (re-challenge) 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). 


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7 
DISCONTINUATION OF IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of Investigational Medicinal Product 
Participants will receive a single dose of 600 mg AZD7442 (administered as a single IM 
injection containing 300 mg AZD8895 and a single IM injection containing 300 mg 
AZD1061) or saline placebo. 
It may be necessary for a participant to temporarily interrupt their injection of IMP. If the 
injection of IMP is not resumed (ie, it is discontinued), the participant should remain in the 
study to be evaluated.  
Note that discontinuation of IMP is NOT the same thing as a withdrawal from the study. 
7.2 
Participant Withdrawal from the Study 
x 
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. 
x 
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). 
x 
At the time of withdrawal from the study, if possible, an Early Discontinuation visit 
should be conducted, as shown in the SoA (Table 1 for Cohort 1 and Table 2 for 
Cohort 2). See the 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. 
x 
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. 
x 
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 


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study visit: 
x 
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
x 
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. 
x 
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
x 
Site personnel, or an independent third party, will attempt to collect the survival status of 
the participant within legal and ethical boundaries for all participants randomized, 
including those who did not get the IMP. Public sources may be searched for survival 
status information. If survival 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 survival status information. 
 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A. 
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: 
x 
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. 
x 
If one or more participants experience a grade 4 hypersensitivity reaction or 
hypersensitivity reaction classified as an SAE. 
x 
If 2 or more participants, within the first 100 participants, experience a grade 3 or higher 
hypersensitivity reaction. 
x 
If 2 or more participants, within the first 100 participants, experience a grade 3 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). 


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8 
STUDY ASSESSMENTS AND PROCEDURES 
x 
Study procedures and their timing are summarized in the SoA (Table 1 for Cohort 1 and 
Table 2 for Cohort 2). Protocol waivers or exemptions are not allowed. 
x 
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
IMP. 
x 
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
x 
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. 
x 
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 have met the protocol-specified criteria and were 
performed within the timeframe defined in the SoA. 
x 
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 300 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
 
8.1 
Efficacy Assessments 
8.1.1 
Clinical Assessments 
Supplemental oxygen use will be recorded at each in-person visit. 
At study entry, if peripheral oxygen saturation is < 92% on usual supplemental oxygen 
requirements, the participant should be referred for emergency department evaluation and 
should not initiate IMP. 
During follow-up in-person visits (after Day 1) through Day 29, peripheral oxygenation 
saturation measures < 96% should be reviewed by an investigator and referral for medical 
attention made at the discretion of the investigator. 
The participant should be assessed for severe COVID-19, 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 score of 5 or higher in the 
WHO Clinical Progression Scale in Appendix F. 


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8.1.2 
Collect/Update Secondary Contacts 
Sites will capture contact information for at least 2 individuals that the site can contact if the 
participant cannot be reached (eg, spouse, friend, neighbor). Sites will also request healthcare 
provider contact information and hospital(s) that the participant is likely to go to if they get 
sick. 
Contact information for secondary contacts or healthcare provider will not be recorded on any 
eCRF. 
On Day 1 only, sites will record the participant’s home address in site records (it will not be 
reported on an eCRF). 
8.1.3 
Survival Status Check 
If a participant cannot be reached after 2 attempts 24 hours apart, then their listed secondary 
contact person(s) or healthcare provider will be contacted for a check of the participant’s 
survival status. 
8.1.4 
Participant-reported Symptom Diary 
During the first 28 days, participants will be asked to report their COVID-19 symptoms and 
temperature in provisioned devices provided to each participant to enable assessments every 
24 hours at home.  
On Day 1, participants will be trained by the site staff on how to complete the diary. It is 
important that the participant responds to questions without being influenced by anyone else. 
Day 1 assessments must be completed before administering IMP. Participants will be asked to 
complete subsequent entries in the diary each evening on Day 1 through 29 (the entry on 
Day 29 may be completed with the site staff during the Day 29 visit, if the visit occurs on 
Day 29 versus another day in the Day 29 visit window). 
The diary will ask participants to report on the following: 
x 
Temperature 
x 
Shortness of breath 
x 
Difficulty breathing 
x 
Chills 
x 
Cough 
x 
Fatigue 
x 
Muscle aches 
x 
Body aches 


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x 
Headache 
x 
Loss of taste 
x 
Loss of smell 
x 
Sore throat 
x 
Congestion 
x 
Runny nose 
x 
Nausea 
x 
Vomiting 
x 
Diarrhea 
 
Symptom severity scoring will be based on the participant’s self-assessment. Participants 
should use the same self-determined approach to severity scoring each day. 
Only participants  60 years of age will be asked to report on the following: 
x 
Have you felt as if you can’t think clearly? 
x 
Have you experienced any loss or decrease in appetite? 
x 
Do you take supplemental oxygen? 
x 
If yes, have you needed to increase your supplemental oxygen intake? 
 
The participant-reported symptom diary is in Appendix G. 
In the event an electronic device is not available when the participant is randomized, there will 
be a paper diary alternative with detailed instructions for participants and site staff. 
Diary Reminder and Staff Review of Diary 
Participant will be reminded every day through Day 29 to complete their diary. This reminder 
will be received through the electronic device. 
The diary will be reviewed by study staff in person with each participant according to the SoA 
(Table 1 for Cohort 1 and Table 2 for Cohort 2). If an appropriate electronic system is 
available, the participant’s diary entries will automatically be captured in the eCRF. If such a 
system is not available, the participant’s answers on the diary will be transcribed into the 
eCRF. 
Participants who report worsening symptoms from any cause during the study may be referred 
to their healthcare provider or closest emergency room. Such instances will be recorded at the 
time of the notification, and during follow-up to assess study endpoints, ie, hospitalization or 
death. 


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Situations in which a COVID-19 sign or symptom should be reported as an AE are described 
in Section 8.3.8. 
8.1.5 
Return to Usual Health 
If the participant returns to usual (pre-COVID-19) health at any time through Day 169, the 
date will be recorded per the SoA (Table 1 for Cohort 1 and Table 2 for Cohort 2). 
 
 
 
 
 
 
At subsequent visits per the SoA (Table 1 for Cohort 1 and Table 2 for Cohort 2), participants 
will be asked if any new household members have been diagnosed with SARS-CoV-2 
infection, and the response recorded on the eCRF. 
8.1.7 
Virologic Studies 
Mid-turbinate nasal swabs and plasma will be collected for qualitative and quantitative 
SARS-CoV-2 RNA assessment. 
 
Mid-turbinate Nasal Swabs 
Mid-turbinate nasal swabs will be taken at in-person visits per the SoA and will be analyzed 
centrally by an authorized or approved RT-PCR assay (Table 1 for Cohort 1 and Table 2 for 
Cohort 2). The Day 1 swab should be collected prior to the dose of IMP. 
 
 
 
8.2 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1 for Cohort 1 
and Table 2 for Cohort 2). 
8.2.1 
Physical Examinations 
A complete physical examination will be performed at screening, followed by a targeted or 
complete physical examination at subsequent visits per the SoA in Table 1 for Cohort 1 and 
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Table 2 for Cohort 2. 
x 
A complete physical examination will include, but not be limited to, assessment of height 
(screening only), 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. 
x 
A targeted physical examination will include areas suggested by the medical history. 
When there are no new complaints or findings this should be documented. Each clinically 
significant abnormal finding following randomization should be reported per Section 8.3 
(AE/SAE reporting). 
 
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 pulse rate, pulse oximetry, blood pressure, and body temperature will be 
performed at time points specified in the SoA (Table 1 for Cohort 1 and Table 2 for Cohort 2). 
The participant should be resting prior to the collection of vital signs. 
Situations in which vital sign results should be reported as AEs are described in Section 8.3.6. 
8.2.3 
Electrocardiograms 
A triplicate 12-lead ECG will be performed at time points specified in the SoA (Table 1 for 
Cohort 1 and Table 2 for Cohort 2). 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 (Table 1 for Cohort 1 and Table 2 for 


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Cohort 2). 
Additional safety samples may be collected, if clinically indicated, at the discretion of the 
investigator. The date and time of collection and results (values, units, and reference ranges) 
will be recorded on the appropriate eCRF. 
The clinical chemistry, hematology, and urinalysis will be performed at a central laboratory. 
Instructions for the collection and handling of the samples will be provided in the 
study-specific Laboratory Manual. If, due to COVID-19 restrictions, samples cannot be sent to 
the central laboratory the safety laboratory assessments may be performed at a local laboratory 
possessing current standard certification for its jurisdiction.  
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 
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) 


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Coagulation 
International normalized ratio (INR) 
Prothrombin time (PT) 
Activated partial thrombin time (aPTT) 
 
NB. In case a participant shows an AST or $/7 3 × ULN together ZLWK7%/ 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. 
TBL Total bilirubin; ULN Upper limit of normal. 
 
8.2.4.1 
Females Only 
Pregnancy test (women of childbearing potential only) 
Serum human beta chorionic gonadotrophin 
(screening, at central laboratory) 
Urine human beta chorionic gonadotrophin 
(locally) 
Pregnancy test (suspected postmenopausal women < 50 years only) 
Follicle-stimulating hormone (FSH) (using serum at screening, at central laboratory) 
 
8.2.5 
Injection Site Inspection 
An inspection of the injection sites should be performed on Day 1 (as according to Table 6), 
and at subsequent in-person visits up to and including Day 6 (see SoA in Table 1 for Cohort 1 
and Table 2 for Cohort 2). If evidence of injection site reaction persists at Day 6 visit, the 
injection site will be rechecked at each visit until no evidence of an active reaction remains. 
Table 6 
Injection Site Inspection on Day 1 
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. 
In Cohort 1, the first 20 participants dosed (ie, the sentinel group) will undergo safety 


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monitoring for 4 hours post IMP administration before dosing further participants. At each 
site, there will be an interval of 24 hours after dosing of the first participant in the sentinel 
group before the next participant can be dosed. The next 80 participants (21 to 100) 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 at least 
1 hour post IMP administration. Should hypersensitivity reactions be observed in the first 
100 participants, all participants will be monitored for safety monitoring for 2 hours post IMP 
administration.  
For the first 4 days after IMP administration, the sentinel group will be contacted daily 
(in-person or by telephone) 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 
Non-serious AEs 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 the ICF throughout the study, up to and 
including the last visit. 
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. 


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Adverse event variables 
The following variables will be collected for each AE; 
x 
AE (verbatim) 
x 
The date and time when the AE started and stopped 
x 
Severity grade/maximum severity  
x 
Whether the AE is serious or not 
x 
Investigator causality rating against the IMP(s) (yes or no) 
x 
Action taken with regard to IMP 
x 
If the AE caused participant’s withdrawal from study (yes or no) 
x 
Outcome 
 
In addition, the following variables will be collected for SAEs: 
x 
Date AE met criteria for SAE 
x 
Date investigator became aware of SAE 
x 
AE is serious due to 
x 
Date of hospitalization 
x 
Date of discharge 
x 
Probable cause of death 
x 
Date of death 
x 
Autopsy performed 
x 
Causality assessment in relation to study procedure(s) 
x 
Causality assessment to other medication 
 
The following severity ratings will be used: 
x 
Grade 1: An event of mild intensity that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
x 
Grade 2: An event of moderate intensity that is usually alleviated with additional, specific 
therapeutic intervention. The event interferes with usual activities of daily living, causing 
discomfort, but poses no significant or permanent risk of harm to the participant. 
x 
Grade 3: A severe event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the clinical status of the 
participant. 


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x 
Grade 4: An event, and/or its immediate sequelae, that is associated with an imminent risk 
of death. 
x 
Grade 5: Death as result of an event. 
 
It is important to distinguish between serious and severe AEs: 
x 
Severity is a measure of intensity, whereas seriousness is defined by the criteria in 
Appendix B 2. 
x 
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 an 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 Table 1 for 
Cohort 1 and Table 2 for Cohort 2). 
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: 
x 
Anaphylaxis and other serious hypersensitivity reactions, including immune complex 
disease 
x 
Injection site reactions 
 


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8.3.5 
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. 
See Section 8.3.8 for the reporting of COVID-19-related symptoms. 
8.3.6 Adverse Events Based on Examinations and Tests 
The results from the protocol-mandated laboratory tests 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 fulfil 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 is not limited to, consideration as to 
whether treatment or non-planned visits were required or other action was taken with the IMP, 
eg, dose adjustment or drug interruption).  
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study. 
8.3.7 Hy’s Law 
Cases where a participant shows elevations in liver biochemistry may require further 
HYDOXDWLRQDQGRFFXUUHQFHVRI$67RU$/7 3 × 8/1WRJHWKHUZLWK7%/ 2 × ULN and 
confirmed as a HL case should be reported as a SAE.  
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IMP, can be found to explain the combination of increases (eg, elevated ALP indicating 
cholestasis, viral hepatitis, or another drug) should be evaluated. The elevation in 


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transaminases must precede or be coincident with (ie, on the same day) the elevation in TBL, 
but there is no specified timeframe within which the elevations in transaminases and TBL 
must occur. 
Please refer to Appendix D for further instruction on cases of increases in liver biochemistry 
and evaluation of HL. 
8.3.8 Disease Under Study 
AZD7442 treatment studies will take a consistent approach to the handling of symptoms 
related to COVID-19, the disease under study. 
COVID-19 symptoms or signs, such as fever, cough, shortness of breath/difficulty breathing, 
sore throat, body/muscle pain, fatigue, headache, chills, nasal obstruction or congestion, nasal 
discharge, new loss of taste or smell, nausea, vomiting, diarrhea, new onset confusion (only 
for participants \HDUVROGDSSHWLWHORVVRUGHFUHDVHIRRGLQWDNHRQO\IRUSDUWLFLSDQWV
 60 years old), increased supplemental oxygen requirement (only for participants on baseline 
supplemental oxygen) will be recorded as AEs when any of the following occur: 
x 
The sign or symptom is serious according to the definition in Appendix B 2. 
x 
The participant discontinues the study due to the sign or symptom. 
x 
In the investigator’s judgment, the sign or symptom is not considered COVID-19 related. 
 
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. 


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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. 
The SAE must also be entered into the EDC system when it is available again. 
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: 
x 
If the pregnancy is discovered before the study participant has received any IMP. 
 
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. 


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Ova Donation 
Female participants should not donate ova for the duration of the study and for at least 365 
days after the IMP dose.  
8.3.10.2 
Paternal Exposure  
Male participants should refrain from fathering a child during the study and for 365 days 
following the administration of IMP. 
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. 
Sperm Donation 
Male participants should not donate sperm for the duration of the study and for at least 365 
days after the IMP dose. 
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 1 (Initial Fatal/Life-Threatening or follow-up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.9) and within 30 days for all other 
medication errors. 
The definition of a Medication Error can be found in Appendix B 4.  
8.4 
Overdose 
For this study, any dose of AZD7442 > 600 mg (ie, AZD8895 > 300 mg or 
AZD1061 > 300 mg) will be considered an overdose. 
AstraZeneca does not recommend a specific treatment for an overdose. Symptoms of overdose 
should be treated as per clinical judgment. 


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x 
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 
x 
An overdose without associated symptoms is only reported on the Overdose eCRF 
module 
 
If an overdose on an AstraZeneca study intervention occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 
or 5 calendar days for overdoses associated with an SAE (see Section 8.3.9) and within 
30 days for all other overdoses. 
8.5 
Human Biological Samples 
Instructions for the collection and handling of biological samples will be provided in the 
study-specific Laboratory Manual. Samples should be stored in a secure storage space with 
adequate measures to protect confidentiality. For further details on Handling of Human 
Biological Samples, see Appendix C. 
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated.  
x 
Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
consented for future analyses.  
 
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. 
x 
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 
x 
Serum samples will be collected for measurement of serum concentrations of AZD7442 
(AZD8895 and AZD1061), as specified in the SoA (Table 1 for Cohort 1 and Table 2 for 
Cohort 2). 


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x 
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.  
x 
Serum samples will be used to analyze 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. 
x 
Samples will be collected, labeled, stored, and shipped, as detailed in the Laboratory 
Manual. 
 
8.5.1.1 
Determination of Drug Concentration 
Samples for determination of drug concentration in serum will be assayed 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. 
 
 
 
 
 
8.5.2.1 
Anti-drug Antibody 
Blood samples for determination of ADA in serum will be assayed using an appropriately 
validated bioanalytical method. Full details of the methods used will be described in a separate 
report. Samples will be collected, labeled, stored, and shipped, as detailed in the Laboratory 
Manual. 
8.5.2.2 
SARS-CoV-2 Serology 
Serum samples will be collected to assess SARS-CoV-2 antigen-specific antibody levels from 
all participants according to the SoA (Table 1 for Cohort 1 and Table 2 for Cohort 2). Baseline 
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serostatus and time to seroconversion in participants receiving AZD7442 versus placebo may 
be determined in a validated SARS-CoV-2 nucleocapsid antigen assay operated by an 
authorized laboratory. Serologic assessment to S (spike), RBD, and nucleocapsid antigens 
may also be assessed quantitatively using a validated multiplexed MSD immunoassay. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI
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CCI
CCI
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CCI
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8.6 
Human Biological Sample 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 SoA (see Table 1 for Cohort 1 and Table 2 for Cohort 2).
 
 
Details for sample collection, 
processing, and testing will be provided in the Laboratory Manual. 
 
 
 
 
 
 
 
 
 
 
 
 
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 classified as either 
having severe COVID-19 symptoms or death from any cause, or not. Efficacy will be 
FDOFXODWHGDVWKH555GHILQHGDVí5HODWLYH5LVN7KHQXOOK\SRWKHVLVLVWKH555RIVHYHUH
COVID-19 or death from any cause through Day 29 in participants on AZD7442 compared 
with those on placebo is equal to zero. The alternative hypothesis is that the RRR is not equal 
to zero.  
The primary efficacy endpoint will be formally assessed at one primary analysis 30 days after 
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approximately 43 primary endpoint events have been confirmed in the primary analysis 
population. The type I error rate will be controlled by a 2-sided alpha = 0.05. The 
methodology used to conserve alpha is detailed in Section 9.4.5. 
9.2 
Sample Size Determination 
Enrollment of up to approximately 1700 participants is planned. At least 60% of participants 
will meet the protocol definition of being at high-risk of progression to severe COVID-19 (see 
Section 4.1 for definition of high-risk). 
Note: “Enrolled” means a participant’s, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study, 
can be re-screened once. If they are not subsequently randomly assigned in the study, they are 
considered “screen failures”. 
Up to approximately 1700 participants, allowing for variability of the placebo groups primary 
endpoint event rate, will be randomized in a 1:1 ratio to receive a single IM 600 mg dose of 
AZD7442 (n = up to approximately 850) or placebo (n = up to approximately 850) on Day 1. 
 
 
 
 
 
 
This is an event-driven study with a primary analysis initiated 30 days after approximately 
43 primary endpoint events have occurred in the primary analysis population. The study 
 
 to detect a relative reduction 
 in the incidence of severe COVID-
19/death between the study groups (AZD7442 vs placebo), 
 
9.3 
Populations for Analyses 
The following populations are defined in Table 7. 
Table 7 
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. 
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Table 7 
Populations for Analysis 
Population/Analysis Set 
Description 
Full analysis set 
All randomized participants who received 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. 
Modified full analysis set 
All participants in the full analysis set ZKRUHFHLYHG,03GD\VIURP
symptom onset and were not hospitalized at baseline 'D\ for isolation 
purposes. 
Early intervention analysis set 
All participants in the modified full analysis set who received IMP  5 days 
from symptom onset. 
Seronegative analysis set 
All participants in the modified full analysis set who were seronegative at 
baseline.  
Safety analysis set 
The safety analysis set consists of all participants who have received 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 received active IMP is classified as active. 
PK analysis set 
Dosed participants for whom an adequate (measurable drug concentration) 
PK profile has been obtained. 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. 
Virology analysis set  
The Virology analysis set consists of all participants in Cohort 1, who 
undergo more intensive virologic and immunologic assessments. 
Participants will be analyzed according to their received 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. 
IMP Investigational medicinal product; PK Pharmacokinetic. 
 
9.4 
Statistical Analyses 
The first version of the SAP was finalized prior to the first meeting of the DSMB and it 
includes 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 be completely double-blind until the primary analysis (ie, blind for participants, 
Investigators/site staff, and Sponsor/designated clinical research organization), in which case 
members of Sponsor/designated clinical research organization associated with the analysis, 


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write-up and submission will be unblinded. The site personnel, participants, and the study 
team members who participate in the advice or decisions involving study conduct or day-to-
day interactions with the site, will remain blinded until the end of the study (ie, all participants 
have completed Day 457 visit) to ensure the trial integrity is maintained. 
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. 
 
 
 
 
 
 
 
 
 
 
9.4.2 
Efficacy  
9.4.2.1 
Primary Endpoint(s) 
The primary efficacy endpoint is a composite of either severe COVID-19 or death from any 
cause through Day 29. 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 (Appendix F). 
The primary estimand will be used for the analysis of the primary efficacy endpoint. It will be 
based on participants in the modified full analysis set defined in Table 7.
 
 
 
 
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For the primary efficacy analysis, the stratified CMH method will be used. The RR will be 
estimated by the CMH method, and the efficacy will be calculated as the RRR = 100 × 
í55ZKLFKUHSUHVHQWVWKHSHUFHQWUHGXFWLRQLQLQFLGHQFHRIVHYHUH&29,'-19 or death 
from any cause in the AZD7442 group relative to the placebo group. The 95% 2-sided CI will 
be presented. Participants who do not have an event and do not remain in the study until the 
Day 29 assessment, will be treated as having a missing primary endpoint. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
To support the primary analysis, Kaplan-Meier curves for time to severe COVID-19 or death 
from any cause during the first 28 days of follow-up will be generated for each randomized 
group. The Kaplan-Meier cumulative incidences will be reported. A stratified Log-Rank test 
will be conducted to assess the difference between the curves. A Cox-Proportional Hazards 
model will be conducted to obtain hazard ratios and their respective 95% CIs. The 
stratification factors will be included as covariates in the Cox model. Absence of data 
following participants’ withdrawal/lost to follow-up will be treated as missing and censored at 
the date of last known status. Additionally, the absolute risk reduction of AZD7442 with 
respect to placebo in preventing severe COVID-19 or death from any cause at Day 29, will be 
presented, along with the 2-sided 95% CI using the stratified Miettinen and Nurminen’s score 
method (Miettinen and Nurminen 1985).  
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9.4.2.2 
Secondary Endpoint(s) 
The key secondary endpoint is a composite of either death from any cause or hospitalization 
for COVID-19 complications or sequelae during the 168-day post-dose period (Day 1 to 
Day 169) and will be analyzed in participants in the modified full analysis set. 
 
 
 
 
 
  
For the key secondary efficacy analysis, the RRR will be calculated at Day 169, as described 
for the primary efficacy analysis. The analysis will be conducted once, when all participants 
complete their Day 169 visit. The point estimate of the RRR of the key secondary endpoint by 
AZD7442 compared to placebo, as well as the 95% CI, will be calculated and reported 
following the same methodology as described for the primary efficacy analysis. The null 
hypothesis that “the RRR of the key secondary efficacy endpoint by AZD7442 compared to 
placebo is equal to zero” will be tested at an alpha level of 5%. The key secondary efficacy 
endpoint will only be considered statistically significant if the statistical significance of the 
primary efficacy endpoint and all supportive estimands for the primary endpoint is 
demonstrated. If the significance of the primary efficacy endpoint and all supportive 
estimands is not achieved, then the p-value for testing the key secondary efficacy endpoint 
will be considered nominal. 
To support the key secondary analysis, Kaplan-Meier curves for time to death from any cause 
or first hospitalization for COVID-19 complications or sequelae during the Day 169 follow-up 
will be generated for the 2 treatment groups. The Kaplan-Meier cumulative incidences will be 
reported. A stratified Log-Rank test will be conducted to assess the difference between the 
curves. A Cox-Proportional Hazards model will be used to obtain hazard ratios and their 
respective 95% CIs. The stratification factors will be included as covariates in the Cox model. 
Other secondary endpoints, that are derived from binary outcomes or have binary outcome 
components, will be analyzed and reported similarly using the primary analysis statistical 
method, except for detectability, and include: 
x 
The proportion of participants with respiratory failure, through Day 29, defined as a 
requirement for mechanical ventilation, ECMO, non-invasive ventilation, or high flow 
cannula oxygen delivery. 
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x 
The proportion of participants with progression, through Day 29, of one or more 
COVID-19-associated symptoms to worse status than recorded in the participant-reported 
symptom diary entry prior to start of AZD7442 or placebo. 
 
The proportion of participants with undetectable SARS-CoV-2 over time (through Day 29) 
will be analyzed using a Kaplan-Meier analysis for time to first undetectable result. This 
analysis will only be conducted in the Virology analysis set.  
The proportion of participants who return to usual health over time (through Day 29) will also 
be analyzed using a Kaplan-Meier analysis for time to return to usual health. 
The only difference in the analysis and reporting of these secondary endpoints, compared to 
the key secondary endpoint, is that all CIs and p-values will be considered nominal.  
For non-binary components and endpoints, the following methods of analysis are planned. 
x 
The change from baseline of SARS-CoV-2 RNA, and RNA levels at each treatment visit, 
from nasal swabs will be summarized using descriptive statistics. For Cohort 1, treatment 
groups will be compared at each post-baseline assessment using a Mixed Model for 
Repeated Measures. This analysis will be conducted at the interim analysis. For all 
participants pooled, ie, Cohort 1 and Cohort 2, treatment groups will be compared at 
Day 6 using an Analysis of Covariance model. Both models will include baseline values 
as a fixed covariate. 
x 
Duration of fever, and time to return to usual health through Day 29, will be summarized 
using descriptive statistics. Treatment groups will be compared using a 2-sided Wilcoxon 
Rank Sum test at an alpha level of 5%. The Hodges-Lehmann estimate and its 95% CI for 
the location shift between the 2 groups will be reported. 
x 
Participant-reported COVID-19 symptom severity assessments will be summarized by 
symptom and over time using descriptive statistics to tabulate actual and change from 
baseline summaries. A mixed model for repeated measures may be used to assess 
differences between treatment groups over time. For each symptom, shift tables will be 
used to show the proportion of participants shifting from baseline severity score to 
maximum post-baseline severity score. For each symptom, the proportion of participants 
ZKRH[SHULHQFHGD-point reduction in severity from baseline to maximum severity 
post baseline will be tabulated. 
 
Details regarding the calculation of these endpoints and related imputation (if applicable), will 
be described in the SAP. 
Specific technical details will be documented and explained in the SAP. 


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9.4.3 
Safety 
9.4.3.1 
Primary Endpoint(s) 
The safety of AZD7442 will primarily be assessed by: 
x 
Incidence of AEs through end of study 
x 
Incidence of SAEs through end of study 
x 
Incidence of AESIs through end of study 
 
AE intensity will be graded according to Appendix B 2. 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) 
x 
Laboratory parameters (hematology, clinical chemistry, coagulation, and urinalysis) 
x 
Vital signs (pulse rate, pulse oximetry, blood pressure, and body temperature) 
x 
Physical examination 
x 
ECG 
 
Laboratory assessments will be performed for hematology, clinical chemistry, coagulation, 
and urinalysis parameters.  
All parameters from laboratory, vital signs, physical examination, and ECG assessments will 
be summarized with descriptive statistics based on data type (continuous, categorical, etc). No 
hypothesis testing or CIs will be performed or calculated, unless otherwise specified. Full 
details of safety endpoints analysis will be provided in the SAP. 
 
  
 
 
 
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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, region, time 
from symptom onset to IMP, risk groups defined as ‘high’ or ‘low’, comorbidity, baseline 
levels of vitamin D and zinc, standard of care, and baseline serostatus. Given data availability, 
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efficacy by viral variants may be explored. 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 Analysis  
Not applicable. 
9.6 
Data Safety Monitoring Board 
An independent DSMB will provide oversight, to ensure safe and ethical conduct of the study. 
They will review safety data through Day 8 from the sentinel group in Cohort 1 composed of 
the first 20 participants to be dosed (approximately 10 participants allocated to the AZD7442 
group and 10 allocated to the placebo group) and provide a recommendation to continue or to 
halt dosing of additional participants.  
The DSMB will make any necessary recommendations to the Sponsor based on their 
evaluations of emerging safety data. For details on the DSMB, refer to Appendix A 5. In 
addition, the composition and operation of the independent DSMB will be described in a 
DSMB Charter. 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 


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Appendix A Regulatory, Ethical, and Study Oversight Considerations 
A 1 
Regulatory and Ethical Considerations 
x 
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 
x 
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. 
x 
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. 
x 
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. 
x 
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 
x 
Prompt notification by the investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
x 
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/ IEC, and investigators. 
x 
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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x 
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will 
review and then file it along with the IB 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 
x 
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. 
x 
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. 
x 
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. 
x 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
x 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
 
A participant who is re-screened is not required to sign another ICF. 
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The investigator or authorized 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 


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A 4 
Data Protection 
x 
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information, which would make the participant identifiable, will not be 
transferred. 
x 
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.  
x 
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 
Committee 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 independent DSMB will monitor and protect the safety of the participants throughout the 
study. The DSMB members will be selected for their expertise. The voting members of the 
DSMB will be comprised of external individuals, including the DSMB chair. 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. 
The DSMB will review safety data on a regular basis as set out in the DSMB Charter, 
including, but not limited to, reviewing the safety data through Day 8 from all participants in 
the sentinel group.  
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 


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countries in which the study is conducted. 
A 7 
Data Quality Assurance 
x 
All participant data relating to the study will be recorded on eCRF unless transmitted to 
the Sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF. 
x 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
x 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
x 
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. 
x 
The Sponsor or designee is responsible for the data management of this study, including 
quality checking of the data. 
x 
The Sponsor assumes accountability for actions delegated to other individuals (eg, 
CROs). 
x 
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. 
x 
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 
x 
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. 
x 
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 


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need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available. 
x 
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: 
x 
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 
x 
Inadequate recruitment of participants by the investigator 
x 
Discontinuation of further study intervention development 
 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any 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 
x 
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. 
x 
The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a co-ordinating investigator will be designated by mutual agreement. 


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x 
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 (for example 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 fulfils one or more of the following criteria: 
x 
Results in death 
x 
Is immediately life-threatening 
x 
Requires inpatient hospitalization or prolongation of existing hospitalization  
x 
Results in persistent or significant disability or incapacity  
x 
Is a congenital abnormality or birth defect 
x 
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 judgment on an individual event basis should be 
applied to clarify that the malignant tumor event should be assessed and reported as a 
non-serious AE. For example, if the tumor is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfil the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumors, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as non-serious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 


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


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x 
Grade 3: A severe event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the clinical status of the 
participant. 
x 
Grade 4: An event, and/or its immediate sequelae, that is associated with an imminent risk 
of death. 
x 
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. 
x 
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? 
x 
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? 
x 
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug? 
x 
No alternative cause. The AE cannot be reasonably explained by another etiology, such as 
the underlying disease, other drugs, other host, or environmental factors. 
x 
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. 
x 
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: 
x 
Is this a recognized feature of overdose of the drug? 
x 
Is there a known mechanism? 
 
Causality of ‘related’ is made if, following a review of the relevant data, there is evidence for 
a ‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data, including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 
B 4 
Medication Error 
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:  
x 
Occurred 
x 
Was identified and intercepted before the participant received the drug 
x 
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: 
x 
Drug name confusion 
x 
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant 
x 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
x 
Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet  


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x 
Drug not stored as instructed eg, kept in the fridge when it should be at room temperature  
x 
Wrong participant received the medication (excluding IRT/RTSM errors) 
x 
Wrong drug administered to participant (excluding IRT/RTSM errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
x 
Errors related to or resulting from IRT/RTSM – including those which lead to one of the 
above listed events that would otherwise have been a medication error  
x 
Participant accidentally missed drug dose(s) eg, forgot to take medication 
x 
Accidental overdose (will be captured as an overdose) 
x 
Participant failed to return unused medication or empty packaging 
x 
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 life cycle. 
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 during for 
the remainder of the sample life cycle. 
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is 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: 
x 
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate. 
x 
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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x 
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 study site is notified. 
C 3 
International Airline Transportation Association 6.2 Guidance 
Document 
LABELING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B, or Exempt 
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  
Category A Pathogens are, eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria, which cause disease in humans or both in humans and animals, must be assigned to 
UN 2814. Infectious substances, which cause disease only in animals, must be assigned to 
UN 2900. 
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, for example, Hepatitis A, C, D, and E 
viruses. They are assigned the following UN number and proper shipping name: 
x 
UN 3373 – Biological Substance, Category B 
x 
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. 
x 
Clinical study samples will fall into Category B or exempt under IATA regulations 
x 
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) 
x 
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content 
 


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Appendix D Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law 
D 1 
Introduction 
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and HL cases. It is not intended to be a comprehensive 
guide to the management of elevated liver biochemistries.  
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets 
potential PHL criteria at any point during the study. 
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits, including central and all 
local laboratory evaluations, even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory.  
The investigator will also review 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 Drug Induced Liver Injury (DILI) caused by the IMP.  
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes. 
D 2 
Definitions 
Potential Hy’s Law 
$67RU$/7 3 × ULN together with 7%/ 2× ULN at any point during the study 
following the start of study medication irrespective of an increase in ALP.  
Hy’s Law 
$67RU$/7 3× ULN together with 7%/ 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.  
For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 


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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: 
x 
$/7 3 × ULN 
x 
$67 3 × ULN 
x 
7%/ 2 × ULN 
 
Central Laboratories Being Used: 
When a participant meets any of the PHL identification criteria, in isolation or in combination, 
the central laboratory will immediately send an alert to the investigator (also sent to 
AstraZeneca representative).  
The investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met; where this is the case, the investigator will: 
x 
Notify the AstraZeneca representative 
x 
Request a repeat of the test (new blood draw) by the central laboratory without delay 
x 
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: 
x 
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 Being Used: 
The investigator will, without delay, review each new laboratory report and if the 
identification criteria are met, will: 
x 
Notify the AstraZeneca representative 
x 
Determine whether the participant meets PHL criteria (see Section D 2 for definition) by 
reviewing laboratory reports from all previous visits 


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x 
Promptly enter the laboratory data into the laboratory eCRF 
 
D 4 
Follow-up 
D 4.1 
Potential Hy’s Law Criteria not met 
If the participant does not meet PHL criteria, the investigator will: 
x 
Inform the AstraZeneca representative that the participant has not met PHL criteria 
x 
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: 
x 
Notify the AstraZeneca representative who will then inform the central Study Team  
x 
Within one day of PHL criteria being met, the investigator will report the case as an SAE 
of Potential Hy’s Law; serious criteria ‘Important medical event’ and causality 
assessment ‘yes/related’ according to CSP process for SAE reporting 
x 
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 
x 
The Study Physician will contact 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 
x 
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. This includes deciding which the tests available 
in the HL lab kit should be used.  
 
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. 


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D 5 
Review and Assessment of Potential Hy’s Law Cases 
The instructions in this section should be followed for all cases where PHL criteria are met. 
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria, other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days from 
date PHL criteria was met. The AstraZeneca Global Clinical 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: 
x 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF 
x 
If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE eCRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AstraZeneca standard processes. 
 
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP: 
x 
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: 


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x 
Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE reporting. 
x 
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined. 
 
D 6 
Laboratory Tests 
The list below represents the standard, comprehensive list of follow-up tests, which are 
recommended but not mandatory when using a central laboratory. For studies using a local 
laboratory, the list may be modified based on clinical judgment. Any test results need to be 
recorded. 
Hy’s Law Lab Kit for Central Laboratories  
Additional standard chemistry and coagulation tests 
GGT (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 Ab (Anti-LKM) 
Anti-Smooth Muscle Ab (ASMA) 
Metabolic diseases 
alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin c 
Transferrin saturation 


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aHBV DNA is only recommended when IgG anti-HBc is positive 
bHCV RNA is only recommended when IgG anti-HCV is positive or inconclusive  
cCD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly 
 
 


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Appendix E Abbreviations 
Abbreviation or special 
term 
Explanation 
ACE2 
angiotensin-converting enzyme 2 
ADA 
anti-drug antibody 
ADE 
adverse device effect 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase/transaminase 
AST 
aspartate aminotransferase/transaminase 
AUC 
area under the curve 
BMI 
body mass index 
CDC 
Centers for Disease Control and Prevention 
CI 
confidence interval 
Cmax 
maximum concentration 
CMH 
Cochran-Mantel-Haenszel 
COVID-19 
Coronavirus 2019 
CRO 
Contract Research Organisation 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
DILI 
Drug Induced Liver Injury 
DNA 
deoxyribonucleic acid  
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
ECMO 
extracorporeal membrane oxygenation 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
Fc 
fragment crystallizable region 
)FȖ5 
Fc gamma receptor(s) 
FcRn 
neonatal Fc receptor(s) 
FTIH 
first time in human 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HIV 
human immunodeficiency virus 
HL 
Hy’s Law 


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Abbreviation or special 
term 
Explanation 
IB 
Investigator’s Brochure 
IC50 
50% maximal inhibitory concentration  
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IM 
intramuscular 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IV 
intravenous 
mAb 
monoclonal antibody 
MERS-CoV 
Middle East respiratory syndrome coronavirus 
NHP 
Non-human primate 
NOAEL 
no-observed-adverse-effect level 
NP 
nasopharyngeal 
OF 
O'Brien Fleming 
PBMC 
peripheral blood mononuclear cell 
PD 
pharmacodynamic 
PHL 
Potential Hy’s Law 
PI 
Principal investigator  
PK 
pharmacokinetic(s) 
RBD 
receptor binding domain 
RNA 
ribonucleic acid 
RR 
risk ratio 
RRR 
relative risk reduction 
RSV 
respiratory syncytial virus 
RT-PCR 
reverse transcription polymerase chain reaction 
RTSM 
Randomization and Trial Supply Management 
SAE 
serious adverse event  
SAP 
statistical analysis plan 
SARS-CoV-2 
severe acute respiratory syndrome-coronavirus 2 
SoA 
Schedule of Activities 
SpO2 
oxygen saturation 


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Abbreviation or special 
term 
Explanation 
t1/2 
terminal half-life 
TBL 
total bilirubin 
TCR 
tissue cross-reactivity 
TM 
triple mutation 
ULN 
upper limit of normal 
VAERD 
Vaccine-associated enhanced respiratory disease 
WHO 
World Health Organization 
 
CCI


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Appendix F
WHO Clinical Progression Scale for COVID-19
*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. 
Source: WHO Working Group 2020
Note: See also Appendix H for further guidance on the definition of hospitalization in this study.


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Appendix G Participant-reported Symptom Diary 


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Appendix H Hospitalization Definition 
Amid a rising number of coronavirus disease 2019 (COVID-19) hospitalizations across the 
world, leading to a shortage of hospital beds, temporary facilities are being utilized 
increasingly to manage severe COVID-19 patients who would have usually been treated in a 
traditional hospital setting. 
Please note that in the TACKLE clinical study protocol, “hospitalization” is defined as 
 24 hours of acute care, in a hospital or similar acute care facility, including emergency 
rooms or temporary facilities instituted to address medical needs of those with severe 
COVID-19 during the COVID-19 pandemic. 
As hospitalizations are an integral component of both the primary and key secondary 
endpoints in the study, further guidance is provided regarding what constitutes these 
temporary facility or alternate care sites used for managing participants with severe 
COVID-19. 
For the purposes of ascertaining an exclusion criterion or an endpoint event, individuals with 
severe COVID-19 will be considered “hospitalized” if they are   
1 
Managed in an alternative care site set up or authorized by states, provinces or equivalent 
jurisdictions or  
2 
Provided with acute hospital care at home meeting the criteria below 
(a) Physician determines the patient’s condition as being appropriate for “acute in-
patient hospitalization”  
(b) Treating physician should have appropriate screening protocols before care at home 
begins, to assess both medical and non-medical factors, including patient’s 
preference, working utilities and assessment of physical barriers 
(c) Patients are evaluated daily either in person or remotely by a qualified health care 
provider/treating physician, and are managed appropriately based on the patient’s 
treatment plan and local standards for COVID-19 management. 
 
The appropriate WHO Clinical Progression Scale for COVID-19 score assigned to grade the 
participant’s condition would depend on the level of oxygen/ventilation support provided in 
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occurred. This period, of 30 days, allows sufficient time for the 52nd event to be monitored, 
and any other events occurring during this time interval will also be evaluated. Enrollment 
will stop after the 52nd event has occurred. 
Given recent efficacy results reported in treatment studies using other anti-SARS-CoV-2 
monoclonal antibodies the standard of efficacy needed appears to be higher than those 
based on assumptions in place at the beginning of the pandemic, therefore, the sample size, 
the RRR and assumed incidence of severe COVID-19/death have been reassessed.  
Synopsis, Sections 1.2 (Schema), 4.1 (Overall Design), 9.4.1 (General Considerations), 
9.5 (Interim Analysis), 9.4.2.1 (Primary Endpoint(s)), 9.6 (Data Safety Monitoring 
Board) and A5 (Committee Structure): To reflect the change in primary analysis and 
resulting time change the interim analysis has been removed.  
Synopsis and Section 4.1 (Overall Design): To improve participant enrollment the total 
number of sites has been changed from ‘approximately 85 to 95 sites’ to ‘approximately 
130 to 140 sites’. 
Synopsis, Sections 4.1 (Overall Design), 9.2 (Sample Size Determination): As described 
above, sample size has been adjusted from "approximately" 1700 participants to "up to 
approximately" 1700 participants, and the 95% power to detect
 
 
 
Synopsis, Sections 4.1 (Overall Design), 9.1 (Statistical Hypotheses), 9.4 (Statistical 
Analyses), 9.4.1 (General Considerations), 9.4.2.1 (Primary Endpoint(s)), Section 9.4.5 
(Methods for Multiple Testing Control): As described above, the primary analysis has 
been changed from ‘90 primary endpoint events’ to ‘30 days after the 52nd primary endpoint 
event’. Furthermore, enrollment will stop after the 52nd event has occurred. 
Synopsis, Sections 4.1 (Overall Design) and 6.3.1 (Randomization): In order to ensure 
the high-risk proportion of participants of more than 60% is reached enrollment of low-risk 
participants has stopped. To make this clear, the statement ‘The enrollment of low-risk 
participants has stopped’ has been added to the CSP.  
Table 1 (Schedule of Activities for Cohort 2) and Table 2 (Schedule of Activities for 
Cohort 2): Due to the overlap in visit windows for Day 6 and Day 8 a note has been added 
that these assessments must be performed on different days. According to the exploratory 
endpoints, the household infection report is only required through Day 169, and therefore, 
its collection has been removed from Day 366. 
Section 8.2.4 (Clinical Safety Laboratory Assessments): Text added to confirm that sites 
CCI






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primary analysis.  
Table 1 (Schedule of Activities for Cohort 1) and Table 2 (Schedule of Activities for 
Cohort 2): Footnote updated to clarify that COVID-19 related symptoms should be 
collected pre- and post-dose on Day 1. 
To ensure the correct assessment is performed, rows labelled ‘ECG’ have been changed to 
‘Triplicate 12-lead ECG’. The Remote visit has been defined as either a phone call or a 
web-based virtual assessment.  
To the symptom diary entry, the following footnote has been added: ‘If Day 29 visit is 
conducted earlier in ± 4 day window, participant should retain symptom diary in order to 
complete required daily entries through Study Day 29’. 
Table 2 (Schedule of Activities for Cohort 2): A footnote has been added to the IMP 
administration to describe required safety monitoring. This had been previously omitted 
from the CSP text.  
Sections 4.1 (Overall Design), 5.1 (Inclusion Criteria), 5.2 (Exclusion Criteria), 8.3.10 
(Pregnancy), 8.3.10.1 (Maternal Exposure), Table 1 (Schedule of Activities for Cohort 
1) and Table 2 (Schedule of Activities for Cohort 2): Based on the low-risk to pregnant or 
breast feeding women and the potential benefit pregnant women may receive from mAb 
treatment the exclusion Criterion 16, excluding pregnant and breast feeding women has 
been removed and inclusion Criterion 8(b) has been amended to remove the requirement for 
a negative pregnancy test. Pregnancy has also been added to the list of high-risk factors that 
can lead to progression to severe COVID-19.  
Section 5.1 (Inclusion Criteria): In response to health authority feedback recommending 
that a minimum score of > 0 on the clinical progression scale is not appropriate, Criterion 3 
has been changed from ‘WHO Clinical Progression Scale score > 0 and < 4’ to ‘WHO 
Clinical Progression Scale score > 1 and < 4’. 
Section 5.1 (Inclusion Criteria): To Criterion 4, the equivalent Fahrenheit temperature has 
been added alongside Celsius.  
Section 5.1 (Inclusion Criteria): To Criterion 8(a), condom use for male participants has 
been changed from ‘365 days following administration of IMP’ to ‘90 days following 
administration of IMP’. As the mAbs have no human target and fetal TCR studies showed 
no mAb presence the risk of transmission is low, and therefore the number of days has been 
reduced to reflect approximately 1 half-life.  
Section 5.2 (Exclusion Criteria): To ensure that individuals likely to receive a vaccine 


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during their country’s immediate roll out are not included in the study, Criterion 4 changed 
from ‘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’ to ‘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 
administration immediately after enrollment’. 
Section 5.2 (Exclusion Criteria): Criterion 5 language clarified: ‘requirement for 
mechanical ventilation’ changed to ‘current requirement for mechanical ventilation’. 
Table 5 (Summary of Permitted, Prohibited, or Restricted Medications): To avoid 
confusion at study sites, the table has been updated with the following clarifications:  
x 
Allergen immunotherapy should be allowed if participant has been receiving stable 
desensitization therapy for allergies for at least 30 days prior to Day 1 and there is no 
anticipated change during the treatment period. Non-prescription treatments for 
allergies such as antihistamines, decongestants, and nasal steroids are permitted. 
x 
To ensure participants who become ill with COVID-19 receive all possible treatments 
available to them, no restrictions to these treatments are included in the study. 
Instructions have been added to confirm that participants hospitalized with COVID-19 
may receive investigational agents under emergency use authorization or equivalent 
regulations if available.  
x 
Blood/plasma donation is restricted for one-year. 
 
Section 8.1.6 (Household Infection Report): Clarification to text that all members of a 
participant’s household should be considered for the infection report. 
Section 8.2.1 (Physical Examination): To ensure the correct recording and implementation 
of the targeted physical examination, the text has been updated to confirm that where no 
new complaints or findings are observed this should be documented. Abnormal clinical 
findings after randomization should be reported per the AE and SAE reporting guidelines 
within the CSP.  
Sections 6.5 (Concomitant Therapy) and 8.3.10.1 (Maternal Exposure): In response to 
health authority comments and for the safety of participants, restriction on ova donation for 
at least 365 days after IMP dosing has been added. 
Sections 6.5 (Concomitant Therapy) and 8.3.10.2 (Paternal Exposure): In response to 
health authority comments and for the safety of participants, restriction on sperm donation 
for at least 365 days after IMP dosing has been added. 




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clarity to Investigators. 
Corrected typos are not listed above. 
 


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