Clinical trial NCT04568031
Conditions: COVID-19
Keywords: COVID-19 Vaccine
Sponsor: AstraZeneca
Start date: 2020-08-23; Completion date: 2021-11-22
Enrollment: 256 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The COVID-19 pandemic has caused major disruption to healthcare systems with significant socioeconomic impacts. Currently, there are no licensed preventions available against COVID-19 and accelerated vaccine development is urgently needed. A safe and effective vaccine for COVID 19 prevention would have significant global public health impact.

Detailed description:

Arms: arm 1: Cohort C will include healthy participants aged 18 to 55 years. Cohort D will include healthy elderly participants aged ≥ 56 years. In Cohort D, the elderly population is further divided into 2 different age subgroups; aged 56 to 69 years (Subcohort D1) and aged ≥ 70 years (Subcohort D2). At least 30% of participants in Cohort D will be secured for participants with age ≥ 70 years. arm 2: Cohort C will include healthy participants aged 18 to 55 years. Cohort D will include healthy elderly participants aged ≥ 56 years. In Cohort D, the elderly population is further divided into 2 different age subgroups; aged 56 to 69 years (Subcohort D1) and aged ≥ 70 years (Subcohort D2). At least 30% of participants in Cohort D will be secured for participants with age ≥ 70 years.
Interventions: intervention 1: AZD1222 intervention 2: 0.9% (w/v) saline
Intervention descriptions: intervention 1: For subjects in part 1 will have that route of Administration as Intramuscular, 5 × 1010 vp (nominal, ± 1.5 × 1010 vp) on V2 intervention 2: For subjects in placebo will have that route of Administration as Intramuscular 0.9% (w/v) saline on V2 and V6.

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol
Study Intervention
AZD1222
Study Code
D8111C00002
Version
4.0
Date
18Jan2021
A Phase I/II Randomized, Double-blind, Placebo-controlled 
Multicentre Study in Participants Aged 18 Years or Older to 
Determine the Safety and Immunogenicity of AZD1222, a 
Non-replicating ChAdOx1 Vector Vaccine, for the Prevention of 
COVID-19
Sponsor Name: AstraZeneca K.K
Address: AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan
Regulatory Agency Identifier Number(s): NCT04568031
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.


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Protocol Number: D8111C00002
Amendment Number: 3
Study Intervention: AZD1222
Study Phase: I/II
Short Title: Phase I/II Study in Participants Aged 18 Years or Older of AZD1222 for the 
Prevention of COVID-19
Study Physician Name and Contact Information will be provided separately


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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 3
18 January 2021
Amendment 2
19 November 2020
Amendment 1
13 August 2020
Original Protocol
24 July 2020
Amendment 3 (18-January-2021)
Overall Rationale for the Amendment:
In the context of the current Japan health emergency, the primary analysis has been changed to 
include immunogenicity data up to Day 57 of a subset of participants in whom 
immunogenicity results will be available significantly earlier than in the rest of the study 
population. Delayed immunogenicity results availability for the rest of the study population 
which includes the participates who enrolled after restarting the study (30 September 2020) is 
a consequence of a temporary study interruption that occurred on the 07 September 2020 to 
allow a review of safety data, following the occurrence of a serious adverse event in a 
University Oxford-sponsored study in the UK. The immunogenicity data analysis including 
data up to Day 57 in all participants will be provided through an additional analysis, when 
available.
Section # and 
Name
Description of Change
Brief Rationale
1.1 Synopsis
The synopsis was updated to align with changes to the 
body of the protocol.
To ensure consistency 
between the protocol and the 
Synopsis.
2.2 Background
Updated information on the current situation of 
COVID-19 in Japan. 
To include updated 
information.
2.2 Background
Added the situation of vaccine/license authorization of 
AZD1222 in UK.
To include updated 
information.
6.5.2 Prohibited 
Concomitant 
Medications
Added the description that the short courses of steroids
are allowed as concomitant medication.
To make the management of 
participants conditions easier 
for the study sites.
8 STUDY 
ASSESSMENTS 
AND 
PROCEDURES
Changed the amount of blood collected from each 
participant at Visit 1.
Due to correct the erroneous 
description.
8.5.2.1 SARS-CoV-
2 Serology 
Assessments
Changed the description of SARS-CoV-2 Serology 
Assessments.
Due to correct the erroneous 
description.


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Section # and 
Name
Description of Change
Brief Rationale
9.1 Statistical 
Hypotheses
Added “where p is the proportion of seroresponse 
participants”.
To describe the statistical 
hypotheses precisely.
9.2 Sample Size 
Determination
Changed the description about the power of the 
primary analysis for immunogenicity.
Due to a change in the 
number of participants to be 
included in the primary 
analysis for immunogenicity.
9.4 Statistical 
Analysis
Primary immunogenicity analysis plan has been 
changed to be based on a subset of the study 
population enrolled before the study interruption, and 
an additional analysis including Day 57 
immunogenicity data in all subjects will be conducted 
when data will be available. 
Acceleration in context of
Japan health emergency.


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3
TABLE OF CONTENTS ...................................................................................................... 5
1
PROTOCOL SUMMARY .................................................................................. 9
1.1
Synopsis ............................................................................................................. 9
1.2
Schema............................................................................................................. 14
1.3
Schedule of Activities ....................................................................................... 15
2
INTRODUCTION............................................................................................ 17
2.1
Study Rationale ................................................................................................ 17
2.2
Background ...................................................................................................... 17
2.3
Benefit/Risk Assessment................................................................................... 20
2.3.1
Risk Assessment ............................................................................................... 20
2.3.2
Benefit Assessment........................................................................................... 20
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 20
3
OBJECTIVES AND ENDPOINTS................................................................... 21
4
STUDY DESIGN ............................................................................................. 23
4.1
Overall Design.................................................................................................. 23
4.1.1
Screening Visit.................................................................................................. 23
4.1.2
Vaccination Visit............................................................................................... 23
4.1.3
Subsequent Visits.............................................................................................. 24
4.1.4
COVID-19 Symptomatic Participant................................................................. 25
4.2
Scientific Rationale for Study Design ............................................................... 25
4.2.1
Rationale for Study Design and Participant Population ..................................... 25
4.2.2
Rationale for Study Endpoints .......................................................................... 25
4.3
Justification for Dose........................................................................................ 26
4.4
End of Study Definition.................................................................................... 27
5
STUDY POPULATION.................................................................................... 27
5.1
Inclusion Criteria .............................................................................................. 27
5.2
Exclusion Criteria ............................................................................................. 28
5.3
Lifestyle Considerations ................................................................................... 30
5.4
Screen Failures ................................................................................................. 30
6
STUDY INTERVENTION ............................................................................... 30
6.1
Study Intervention(s) Administered................................................................... 31
6.1.1
Investigational Products.................................................................................... 31
6.1.2
Dosing Instructions........................................................................................... 31
6.2
Preparation/Handling/Storage/Accountability ................................................... 32
6.2.1
Dose Preparation and Administration................................................................ 32


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6.2.1.1
AZD1222.......................................................................................................... 32
6.2.1.2
Placebo............................................................................................................. 33
6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 33
6.3.1
Randomisation.................................................................................................. 33
6.3.2
Blinding............................................................................................................ 33
6.3.3
Procedures for Unblinding ................................................................................ 34
6.4
Study Intervention Compliance......................................................................... 34
6.5
Concomitant Therapy........................................................................................ 35
6.5.1
Permitted Concomitant Medications ................................................................. 35
6.5.2
Prohibited Concomitant Medications ................................................................ 35
6.6
Dose Modification ............................................................................................ 35
6.7
Intervention After the End of the Study............................................................. 36
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 36
7.1
Discontinuation of Study Intervention............................................................... 36
7.2
Participant Withdrawal from the Study.............................................................. 36
7.3
Lost to Follow up.............................................................................................. 37
7.4
Criteria for Discontinuation or Suspension of All or Part of the Study............... 37
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 37
8.1
Descriptive Efficacy Assessments..................................................................... 38
8.2
Safety Assessments........................................................................................... 39
8.2.1
Physical Examinations...................................................................................... 39
8.2.2
Vital Signs ........................................................................................................ 39
8.2.3
Clinical Safety Laboratory Assessments............................................................ 39
8.3
Adverse Events and Serious Adverse Events..................................................... 40
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 41
8.3.2
Follow-up of AEs and SAEs ............................................................................. 41
8.3.3
Causality Collection.......................................................................................... 42
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 42
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 42
8.3.6
Hy’s Law.......................................................................................................... 43
8.3.7
Solicited Adverse Events .................................................................................. 43
8.3.8
Adverse Events of Special Interest.................................................................... 44
8.3.8.1
Potential Neurological AESIs............................................................................ 45
8.3.9
Reporting of Serious Adverse Events ................................................................ 47
8.3.10
Pregnancy......................................................................................................... 47
8.3.10.1
Maternal Exposure............................................................................................ 47
8.3.11
Medication Error............................................................................................... 48
8.4
Overdose .......................................................................................................... 48
8.5
Human Biological Samples............................................................................... 49
8.5.1
Pharmacokinetics.............................................................................................. 49
8.5.2
Immunogenicity Assessments ........................................................................... 49
8.5.2.1
SARS-CoV-2 Serology Assessments................................................................. 49


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8.5.2.2
SARS-CoV-2 Neutralising Antibody Assessments ............................................ 50
8.5.3
Pharmacodynamics........................................................................................... 50
8.6
Human Biological Sample Biomarkers ............................................................. 50
8.7
Optional Genomics Initiative Sample................................................................ 50
8.8
Medical Resource Utilisation and Health Economics ........................................ 50
9
STATISTICAL CONSIDERATIONS................................................................ 50
9.1
Statistical Hypotheses....................................................................................... 50
9.2
Sample Size Determination............................................................................... 50
9.3
Populations for Analyses................................................................................... 51
9.4
Statistical Analyses ........................................................................................... 52
9.4.1
General Considerations..................................................................................... 52
9.4.2
Efficacy (Including Immunogenicity)................................................................ 53
9.4.2.1
Primary Endpoint(s).......................................................................................... 53
9.4.2.2
Secondary Endpoint.......................................................................................... 54
9.4.2.3
Exploratory Endpoint(s).................................................................................... 54
9.4.3
Safety ............................................................................................................... 55
9.4.3.1
Primary Endpoints ............................................................................................ 55
9.4.3.2
Secondary Endpoints ........................................................................................ 55
9.5
Subgroup Analyses ........................................................................................... 55
9.6
Interim Analyses............................................................................................... 56
9.7
Data Monitoring Committee ............................................................................. 56
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ........................................................................................ 56
11
REFERENCES................................................................................................. 85
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 14
Figure 2
Neurology Testing Algorithm .................................................................. 46
LIST OF TABLES
Table 1
Schedule of Activities.............................................................................. 15
Table 2
Objectives and Endpoints......................................................................... 21
Table 3
Highly Effective Methods of Contraception............................................. 28
Table 4
Investigational Products........................................................................... 31
Table 5
Laboratory Safety Variables..................................................................... 40


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Table 6
List of Predefined Solicited Adverse Events for Reactogenicity 
Assessment.............................................................................................. 44
Table 7
Populations for Analysis .......................................................................... 51
Table 8
Tables for Clinical Abnormalities: Local Reactions to Injectable Product 69
Table 9
Tables for Clinical Abnormalities: Vital Signs......................................... 70
Table 10
Tables for Clinical Abnormalities: Systemic (General or Illness) ............. 71
Table 11
Adverse Events of Special Interest........................................................... 72
Table 12
List of Potential Immune-mediated Medical Conditions........................... 74
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 57
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 62
Appendix C
Handling of Human Biological Samples .................................................. 67
Appendix D
Toxicity Grading Scales for Solicited Adverse Events ............................. 69
Appendix E
Adverse Events of Special Interest........................................................... 72
Appendix F
Abbreviations .......................................................................................... 77
Appendix G
Protocol Amendment History................................................................... 79


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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase I/II Randomized, Double-blind, Placebo-controlled Multicentre 
Study in Participants Aged 18 Years or Older to Determine the Safety and Immunogenicity of 
AZD1222, a Non-replicating ChAdOx1 Vector Vaccine, for the Prevention of COVID-19
Short Title: Phase I/II Study in Participants Aged 18 Years or Older of AZD1222 for the 
Prevention of COVID-19
Rationale:
The COVID-19 pandemic has caused major disruption to healthcare systems with significant 
socioeconomic impacts. Currently, there are no licensed preventions available against 
COVID-19 and accelerated vaccine development is urgently needed. A safe and effective 
vaccine for COVID-19 prevention would have significant global public health impact.
Objectives and Endpoints
Objectives
Endpoints
Primary (Immunogenicity)

To assess antibody responses to AZD1222 
Spike antigen following 2 IM doses of 
AZD1222 or placebo.

The proportion of participants who have a 
post-treatment seroresponse (≥ 4-fold rise in titres
from Day 1 baseline value) to Spike antigen of 
AZD1222 (MSD serology assay) at Day 57.
Primary (Safety)

To assess the safety, tolerability, and 
reactogenicity profile of the candidate 
vaccine AZD1222.
(a)
Occurrence of solicited local reactogenicity signs 
and symptoms for 7 days following throughout
vaccination.
(b)
Occurrence of solicited systemic reactogenicity 
signs and symptoms for 7 days following 
throughout vaccination.
(c)
Occurrence of AEs, SAEs and AESIs for 28 days 
following throughout vaccination.
(d)
Change from baseline for safety laboratory 
measures.
Secondary (Immunogenicity)

To assess antibody responses to AZD1222 
RBD antigen following 2 IM doses of 
AZD1222 or placebo.

The proportion of participants who have a 
post-treatment seroresponse (≥ 4-fold rise in titres 
from Day 1 baseline value) to RBD antigen of 
AZD1222 (MSD serology assay) at Day 57.


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Objectives
Endpoints

To assess time course of antibody to 
AZD1222 Spike and RBD antigens of 
AZD1222 (MSD serology assay)

GMT and GMFR of immunogenicity against Spike 
and RBD antigens of AZD1222 (MSD serology 
assay) at each time point up to Day 365.

To assess the function of nAb against 
SARS-CoV-2 spike protein

Proportion of participants who have a 
post-treatment seroresponse (≥ 4-fold rise in titres 
from Day 1 baseline value) to AZD1222 as 
measured by SARS-CoV-2 nAb (wild-type assay or 
pseudoneutralisation assay) at Day 57.

GMT and GMFR of immunogenicity against Spike 
antigen of AZD1222 as measured by SARS-CoV-2 
nAb at each time point up to Day 365.
Secondary (Safety)

To assess the safety of the candidate vaccine 
AZD1222.

Occurrence of SAEs and AESIs throughout the 
study duration up to Day 365. 
Exploratory (Descriptive efficacy)

To describe occurrence of symptomatic 
COVID-19 in recipients of AZD1222 and 
placebo.

Virologically confirmed (RT-PCR positive) 
symptomatic cases of COVID-19.

To describe occurrence of severe COVID-19
and seroresponse to non-Spike SARS-CoV-
2 antigens.
(a)
Hospital admissions associated with COVID-19.
(b)
Intensive care unit admissions associated with 
COVID-19.
(c)
Deaths associated with COVID-19.
(d)
Seroresponse against non-Spike (nucleocapsid) 
SARS-CoV-2 antigens (MSD serology assay).
AE = adverse event; AESI = adverse event of special interest; GMFR = geometric mean fold rise; GMT = 
geometric mean titre; IM = intramuscular; MSD = Meso Scale Discovery; nAb = neutralising antibodies; RBD = 
receptor-binding domain; RT-PCR = reverse transcriptase-polymerase chain reaction; SAE = serious adverse 
event; SARS-CoV-2 = severe acute respiratory syndrome-coronavirus-2
Overall Design
This is a multicentre, randomised, double-blind, parallel-group, placebo-controlled, 52-week 
Phase I/II study. In this study, 256 eligible participants will be randomised in a 3:1 ratio to 
receive 2 intramuscular (IM) doses of either AZD1222 with 5 × 1010 viral particles (vp)
(nominal) or placebo administered 4 weeks apart.
The study has 2 cohorts with different age populations. Cohort C will include healthy 
participants aged 18 to 55 years. Cohort D will include healthy elderly participants aged ≥56 
years. In Cohort D, the elderly population is further divided into 2 different age subgroups; 
aged 56 to 69 years (Subcohort D1) and aged ≥70 years (Subcohort D2). At least 30% of 


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participants in Cohort D will be secured for participants with age ≥70 years. Regarding 
Cohorts C and D, 128 participants will be randomised in a 3:1 ratio to receive either AZD1222 
or placebo within each cohort.
An independent Neurological AESI Expert Committee will be available to review and provide 
advice to the Company about the diagnosis and causality assessment of selected neurological 
AESIs.
Disclosure Statement: This is a parallel-group preventive study with 2 arms that is 
participant-, investigator-, and Sponsor-blinded.
Number of Participants:
Approximately 307 participants will be screened to achieve 256 participants randomly 
assigned in a 3:1 ratio to receive either AZD1222 or placebo.
Intervention Groups and Duration:
In this study, 256 eligible participants will be randomised in a 3:1 ratio to receive 2 IM doses 
of either AZD1222 with 5 × 1010 vp (nominal) or placebo, administered 4 weeks apart.
After completion of clinical data lock for primary analysis, the study will become single blind, 
where only participants are blinded from allocation of investigational product. All participants 
will be unblinded and participants on the placebo arm may be vaccinated when a licensed 
vaccine for COVID-19 becomes available in Japan for the general population. For participants 
who cannot make scheduled visits after the vaccinations, the follow-up should be made as 
much as possible using telephone call and/or other appropriate way until Day 365.
Data Monitoring Committee: Not applicable
Statistical Methods
Sample Size
These sample sizes (96 for AZD1222 versus 32 for placebo) were determined mainly for 
safety evaluation and based on feasibility. With the sample size of 96 participants in the 
AZD1222 treatment arm in each cohort, at least 1 participant with an adverse event (AE) of 
incidence rate of 2.5% can be detected with probability of about 90%. The placebo arm is 
needed for securing the objectivity of the safety evaluation of the AZD1222 arm and it is also 
needed as a control for evaluating immunogenicity as stated below. For these purposes, the 
minimum sample size was given to the placebo arm (1/3 of the AZD1222 arm).
It is difficult to calculate an accurate sample size necessary for comparing the proportion of 
participants who have a seroresponse to severe acute respiratory syndrome-coronavirus 2
(SARS-CoV-2) spike protein between the AZD1222 and placebo arms because of insufficient 


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information on immunogenicity in both arms at the moment. It is expected that the minimum 
number of participants per cohort will be about 36 in the primary analysis. Under a slightly 
conservative assumption about seroresponse rates of 10% assumed on placebo and over 75% 
on AZD1222, it is expected that the sample size of 36 (27 for AZD1222 vs 9 for placebo) will 
provide 93% power for showing the superiority of seroresponse of the AZD1222 treatment 
compared with placebo based on Fisher’s exact test at 2-sided 5% alpha.
Analysis steps
The analysis will be done in the following three steps:

The Primary analysis will include immunogenicity data up to Day 57 from subjects 
enrolled before the study interruption and safety data gathered in all participants up to 
Day 57. 

The additional analysis will include immunogenicity data in all participants up to Day 57.

The final analysis will include all endpoints up to Day 365 in all participants.
Primary Immunogenicity Endpoint
The primary immunogenicity endpoint is the proportion of participants who have a 
post-treatment seroresponse (≥4-fold rise in titres from Day 1 baseline value) to the Spike 
antigens of AZD1222 (Meso Scale Discovery [MSD] serology assay) at Day 57, and will be 
calculated along with its 95% confidence interval (CI) based on the Clopper-Pearson method 
in each treatment groups in each cohort (C and D) and also Subcohorts D1 and D2 separately. 
The proportion of participants who have a post-treatment seroresponse will be compared 
between AZD1222 treatment and placebo using Fisher’s exact test for each cohort. Fisher’s 
exact test will not be presented for Subcohorts D1 and D2. No adjustment for multiple testing 
will be made.
Primary Safety Endpoint
The safety of AZD1222 will primarily be assessed by: 

The incidence of local and systemic solicited reactogenicity signs and symptoms for 
7 days following throughout vaccination (Day 1 to 8 and Day 29 to 36).

The incidence of AEs, serious adverse events (SAEs) and adverse events of special 
interest (AESIs) collected from Day 1 through Day 57. 

The change from baseline for safety laboratory measures at Day 8, Day 29, Day 36, and 
Day 57.


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AE severity will be graded according to the US Food and Drug Administration (FDA)
guidance (FDA, 2007) and coded using the most recent version of the Medical Dictionary for 
Regulatory Activities. AEs will be presented for each treatment group by system organ class 
and preferred term. Summaries will include the number and percentage of participants 
reporting at least 1 event, where appropriate.
An overview of AEs will be presented for each treatment group, including the number and 
percentage of participants with any AE, AEs with outcome of death, and SAEs. Summaries 
will present the relationship to study intervention as assessed by the investigator, maximum 
intensity, seriousness, and death. A listing will cover details for each individual AE.
Secondary Immunogenicity Endpoint
The proportion of participants who have a post-treatment seroresponse (≥4-fold rise in titres 
from Day 1 baseline value) to the receptor-binding domain (RBD) antigens of AZD1222 
(MSD serology assay) at Day 57, will be analysed in the same way as the primary 
immunogenicity endpoint.
Geometric mean titre (GMT) and geometric mean fold rise (GMFR) of immunogenicity 
against Spike and RBD antigens of AZD1222 (MSD serology assay) with the associated 95% 
CIs will be computed at each time point in each treatment arm in each cohort (C and D) and 
also in Subcohorts D1 and D2 separately.
The proportion of participants who have a post-treatment seroresponse (≥4-fold rise in titres
from Day 1 baseline value) to AZD1222 as measured by SARS-CoV-2 neutralising antibodies 
(nAbs) (wild-type assay or pseudoneutralisation assay) at Day 57, will be analysed in the same 
way as the primary immunogenicity endpoint. GMT and GMFR of SARS-CoV-2 nAbs and 
the associated 95% CIs will be presented at each time point in each treatment arm in each 
cohort (C and D) and also in Subcohorts D1 and D2 separately.
Secondary Safety Endpoints
The secondary safety endpoints are the occurrence of SAEs and AESIs collected from Day 1 
through Day 365.


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1.2
Schema
Figure 1
Study Design
n = number of participants; VP = viral particles


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1.3
Schedule of Activities
Table 1
Schedule of Activities
Study Procedure
Screening
Vaccinations/Follow-up
Details in 
CSP Section 
or Appendix
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
Timeline (days)
-14 to 1
1
4
8
15
29
32
36
43
57
183
365
Time window (days)
± 1
± 2
± 2
± 2
± 1
± 2
± 2
± 2
± 7
± 30
Informed consent
X
Section 5.1
Verify eligibility criteria
X
X
Sections 5.1
and 5.2
Demography
X
Medical and surgical history
X
X
Prior/concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
Vaccination
X
X
Telephone call
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
Section 8.2.2
Complete physical examination
X
Section 8.2.1
Targeted physical examination
X
X
X
X
X
X
X
X
X
Section 8.2.1
Urine pregnancy test (WOCBP only)
X
X
(pre-
dose)
X
(pre-
dose)
AEs
X
X
X
X
X
X
X
X
X
Section 8.3
SAEs
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.3
AESIs
X
X
X
X
X
X
X
X
X
X
X
Section 8.3.8
SARS-CoV-2 infection
X
←―――――――――――――――――――――――――――――――→


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Study Procedure
Screening
Vaccinations/Follow-up
Details in 
CSP Section 
or Appendix
Visit
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
Timeline (days)
-14 to 1
1
4
8
15
29
32
36
43
57
183
365
Time window (days)
± 1
± 2
± 2
± 2
± 1
± 2
± 2
± 2
± 7
± 30
e-Diary provideda
X
X
e-Diary collected
X
X
Clinical safety laboratory assessments 
X
X
X
X
X
X
Section 8.2.3
Test for antibody against SARS-CoV-2 
antigen (lateral flow type test)
X
Section 5.2
Saliva sample for RT-PCR test: 
SARS-CoV-2 genome detection
X
Section 5.2
Serum sample for SARS-CoV-2 serology 
(central test, MSD serology assay)
X
X
(pre-
dose)
X
X
(pre-
dose)
X
X
X
X
Section
8.5.2.1
Serum for SARS-CoV-2 nAb assessment 
(central test)
X
(pre-
dose)
X
(pre-
dose)
X
X
X
Section
8.5.2.2
AE = adverse event; AESI = adverse event of special interest; CSP = clinical study protocol; MSD = Meso Scale Discovery; nAb = neutralising antibody; 
RT-PCR = reverse transcriptase-polymerase chain reaction; SAE = serious adverse event; SARS-CoV-2 = severe acute respiratory syndrome-coronavirus-2; 
WOCBP = women of childbearing potential
Note: After completion of clinical data lock for primary analysis, the study will become single blind, where only participants are blinded from allocation of 
investigational product. All participants will be unblinded and participants on the placebo arm may be vaccinated when a licensed vaccine for COVID-19 
becomes available in Japan for the general population.
a: If a participant has a smart phone, he/she will download app which is used for Diary. If a participant does not have one, e-Diary will be provided and he/she
should use it in order to report their condition.


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2
INTRODUCTION
AZD1222 is being developed for the prevention of COVID-19. AZD1222 is a recombinant 
replication-defective chimpanzee adenovirus expressing the severe acute respiratory 
syndrome-coronavirus 2 (SARS-CoV-2) Spike (S) surface glycoprotein driven by the human 
cytomegalovirus major immediate early promoter that includes intron A with a human tissue 
plasminogen activator (tPA) leader sequence at the N-terminus. 
2.1
Study Rationale
The COVID-19 pandemic has caused major disruption to healthcare systems with significant 
socioeconomic impacts. Currently, there are no licensed preventions available against 
COVID-19 and accelerated vaccine development is urgently needed. A safe and effective 
vaccine for COVID-19 prevention would have significant global public health impact.
2.2
Background
In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a 
seafood wholesale market in Wuhan, China and were later confirmed to be infected with a 
novel coronavirus, known as 2019-nCoV (Zhu et al, 2020). The virus was subsequently 
renamed to SARS-CoV-2 because it is similar to the coronavirus responsible for SARS-CoV, a 
lineage B Betacoronavirus. SARS-CoV-2 shares more than 79% of its sequence with 
SARS-CoV, and 50% with the coronavirus responsible for Middle East respiratory syndrome 
(MERS-CoV), a member of the lineage C Betacoronavirus (Lu et al, 2020). COVID-19 is the 
infectious disease caused by SARS-CoV-2. By January 2020 there was increasing evidence of 
human-to-human transmission as the number of cases rapidly began to increase in China. 
Spread of the virus has been rapid and now encompasses the globe. The World Health 
Organization (WHO) declared the novel coronavirus a pandemic on 11 March 2020. As of 
18 October 2020, there have been more than 40 million confirmed cases and > 1.1 million
deaths globally (WHO 2020a). As of 22 December 2020, there have been 198 523 cases of 
COVID-19 and 2 900 people have died due to the disease in Japan
(https://www.mhlw.go.jp/stf/covid-19/kokunainohasseijoukyou_00006.html#1-1).
It is believed that evolution of the pandemic will vary across countries, affected in part by 
different containment strategies ranging from extreme lockdown to relative inaction. As a 
result, there may be regional waves of the disease and pockets of vulnerable populations. 
Globally, governments have acknowledged that an effective vaccine against COVID-19 is the 
only way to guarantee a safe and sustained exit strategy from repeated lockdowns.
Coronaviruses are spherical, enveloped, large positive-sense single-stranded RNA genomes. 
One-fourth of their genome is responsible for coding structural proteins, such as the S 
glycoprotein, envelope (E), membrane (M), and nucleocapsid (N) proteins. E, M, and N 
proteins are mainly responsible for virion assembly while the S protein is involved in receptor 


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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 
Betacoronavirus and it recognises the angiotensin-converting enzyme 2 (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. 
AZD1222 is a recombinant replication-defective chimpanzee adenovirus expressing the 
SARS-CoV-2 S protein. Development of AZD1222, previously referred to as ChAdOx1 
nCoV-19, was initiated by the University of Oxford with subsequent transfer of development 
activities to the Sponsor. Nonclinical studies found AZD1222 to be immunogenic in BALB/c 
and CD-1 mice, ferret, porcine, and non-human primate (NHP) models. Whilst a single dose 
of AZD1222 induced antigen-specific antibody and T-cell responses, a booster immunization 
enhanced antibody responses, particularly in pigs, with significant increases in SARS-CoV-2 
neutralising antibody titres (Graham et al 2020). Further, in a SARS-CoV-2 challenge model, 
a single administration of AZD1222 significantly reduced viral load in bronchoalveolar lavage 
fluid and respiratory tract tissue of vaccinated rhesus macaques as compared with vector 
controls. Importantly, no evidence of vaccine-associated enhanced respiratory disease 
(VAERD) following SARS-CoV-2 challenge in vaccinated rhesus macaques was observed 
(van Doremalen et al 2020b).
The clinical development program for AZD1222 was initiated by the University of Oxford, 
and currently has 4 ongoing studies being conducted in the UK (COV001 [NCT04324606], 
COV002 [NCT04400838]), Brazil (COV003 [ISRCTN89951424]), and South Africa 
(COV005 [NCT04444674]). The Sponsor, in addition to this study, has 2 ongoing studies in 
United States of America (D8110C00001[NCT04516746]) and Russia (D8111C00001 
[NCT04540393]).
Preliminary unblinded data are available for the first in human Study COV001 and Study 
COV002. Study COV001 enrolled the first participant on 23 April 2020 and completed 
enrolment on 21 May 2020 with 1 077 participants. Preliminary data as of 24 July 2020 from
544 participants who received at least one dose of 5 × 1010 viral particles (vp) AZD1222 and 
10 participants who received a second dose of 5 × 1010 vp AZD1222 28 days later found the 
vaccine was generally tolerated, with no treatment-related SAEs reported through 28 days post 
dose. The most common local solicited adverse events (AEs) were vaccination site pain and 
tenderness. The most common systemic solicited AEs were chills, feverishness, fever, 
headache, malaise, and myalgia. The majority of events were mild or moderate in severity and 
resolved within 1 to 7 days. Following the second dose, a general attenuation in the incidence 
and severity of local and systemic solicited AEs was observed. 
Preliminary immunogenicity data from Study COV001 suggest that a single dose can elicit 
both humoral and cellular immunogenicity responses and that antibody responses are boosted 


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after a second dose. S-specific T-cell responses peaked on Day 14. Anti-S IgG responses rose 
by Day 28, and were boosted 3-fold following a second dose. 
Neutralising antibody (nAb) responses against SARS-CoV-2 were detected in 32 (91%) of 35 
participants after a single dose when measured in microneutralization assay (MNA80) and in 
35 (100%) participants when measured in plaque reduction neutralization test (PRNT50). After 
the second dose, all participants had neutralizing activity (9 of 9 in MNA80 at Day 42 and 10 
of 10 in Marburg virus neutralization assay on Day 56). Neutralizing antibody responses 
correlated strongly with antibody levels measured by ELISA (Folegatti et al 2020b). 
As of 01 October 2020, Study COV002 enrolled 10 013 participants, including 
5 152 participants who received at least one dose of AZD1222 ranging from 2.2 × 1010 vp to 
5 × 1010 vp. Based on preliminary data as of 24 July 2020, the local and systemic solicited AE 
profile following a single dose of 5 × 1010 vp in participants 18 to 55 years of age was 
generally comparable to results in Study COV001. In general, a decline in the incidence and 
severity of solicited AEs was observed across the age groups (18-55, 56-69, and ≥ 70 years).
Another ChAdOx1-vectored vaccine expressing the full-length S protein from a related 
betacoronavirus, MERS-CoV, has been given to 53 participants as part of 2 ongoing 
dose-escalation Phase I studies (MERS001 [NCT03399578] and MERS002 [NCT04170829], 
sponsored by the University of Oxford) at doses ranging from 5 × 109 vp to 5 × 1010 vp. 
Preliminary immunogencity data from MERS001 suggested that a single dose of ChAdOx1 
MERS can elicit both humoral and cellular responses. Overall, the vaccine was safe and 
generally well tolerated, with no serious adverse reactions reported in either study.
The ChAdOx1 platform has been used in 14 clinical studies sponsored by the University of 
Oxford with immunogens from multiple pathogens such as influenza, tuberculosis, malaria, 
Chikungunya, Zika, MERS-CoV, and meningitis B. Over 360 healthy participants have 
received ChAdOx1-vectored vaccines in these studies. The vaccines demonstrated robust 
immunogenicity after a single dose and favourable safety profiles, with no vaccine-related 
SAEs. As of 30 December 2020, vaccine/license authorization of AZD1222 was granted in 
UK.
See the AZD1222 Investigator’s Brochure (IB), Sections 4 and 5 for additional information on 
nonclinical and clinical studies of AZD1222 and related ChAdOx1-vectored vaccines, 
respectively. Detail on the development and chemistry of AZD1222 is provided in the IB, 
Section 3.
Overall, the preliminary data from the AZD1222 clinical and nonclinical studies, and the 
acceptable safety and immunogenicity data for the MERS-CoV vaccine and other ChAdOx1-
vectored vaccines, support further development of AZD1222 for the prevention of COVID-19.


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2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
AZD1222 can be found in the AZD1222 IB.
2.3.1
Risk Assessment
AZD1222
The most common local solicited AEs were vaccination site pain, and tenderness. Common 
systemic solicited AEs across the 2 studies included chills, feverishness, fever, fatigue, 
headache, joint pain, malaise, and myalgia. The majority of events were mild or moderate in 
severity and resolved within 1 to 7 days (Section 2.2).
There are no identified risks for AZD1222. Important potential risks are immunologic 
reactions: serious hypersensitivity (anaphylactic reactions) and vasculitides; neurologic 
reactions: demyelinating diseases; and vaccine-associated enhanced respiratory disease. A 
summary of risks associated with AZD1222 and safety information reported across the 
AZD1222 clinical studies are provided in the current version of the AZD1222 IB.
2.3.2 Benefit Assessment
Recipients of AZD1222 do not have any guaranteed benefit; however, AZD1222 may be 
efficacious and offer participants protection from COVID-19. The information gained from 
this study will inform development decisions. 
2.3.3 Overall Benefit: Risk Conclusion
For the safety of participants, the protocol has incorporated various risk mitigation measures 
including appropriate inclusion and exclusion criteria, close monitoring of participants, and 
stopping criteria. Taking these measures into account, the potential risks identified in 
association with AZD1222 are justified by the anticipated benefits that may be afforded to 
participants for the prevention of COVID-19.


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3
OBJECTIVES AND ENDPOINTS
Table 2
Objectives and Endpoints
Objectives
Endpoints
Primary (Immunogenicity)

To assess antibody responses to AZD1222 
Spike antigen following 2 IM doses of 
AZD1222 or placebo.

The proportion of participants who have a
post-treatment seroresponse (≥ 4-fold rise in titres
from Day 1 baseline value) to Spike antigen of 
AZD1222 (MSD serology assay) at Day 57.
Primary (Safety)

To assess the safety, tolerability, and 
reactogenicity profile of the candidate 
vaccine AZD1222.
(a)
Occurrence of solicited local reactogenicity signs 
and symptoms for 7 days following throughout
vaccination.
(b)
Occurrence of solicited systemic reactogenicity 
signs and symptoms for 7 days following 
throughout vaccination.
(c)
Occurrence of AEs, SAEs and AESIs for 28 days 
following throughout vaccination.
(d)
Change from baseline for safety laboratory 
measures.
Secondary (Immunogenicity)

To assess antibody responses to AZD1222 
RBD antigen following 2 IM doses of 
AZD1222 or placebo.

The proportion of participants who have a 
post-treatment seroresponse (≥4-fold rise in titres 
from Day 1 baseline value) to RBD antigen of 
AZD1222 (MSD serology assay) at Day 57.

To assess time course of antibody to 
AZD1222 Spike and RBD antigens of 
AZD1222 (MSD serology assay)

GMT and GMFR of immunogenicity against Spike 
and RBD antigens of AZD1222 (MSD serology 
assay) at each time point up to Day 365.

To assess the function of nAb against 
SARS-CoV-2 spike protein

Proportion of participants who have a 
post-treatment seroresponse (≥ 4-fold rise in titres 
from Day 1 baseline value) to AZD1222 as 
measured by SARS-CoV-2 nAb (wild-type assay or 
pseudoneutralisation assay) at Day 57.

GMT and GMFR of immunogenicity against Spike 
antigen of AZD1222 as measured by SARS-CoV-2 
nAb at each time point up to Day 365.
Secondary (Safety)

To assess the safety of the candidate vaccine 
AZD1222.

Occurrence of SAEs and AESIs throughout the 
study duration up to Day 365. 


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Objectives
Endpoints
Exploratory (Descriptive efficacy)

To describe occurrence of symptomatic 
COVID-19 in recipients of AZD1222 and 
placebo.

Virologically confirmed (RT-PCR positive) 
symptomatic cases of COVID-19.

To describe occurrence of severe COVID-19 
and seroresponse to non-Spike SARS-CoV-
2 antigens.
(a)
Hospital admissions associated with COVID-19.
(b)
Intensive care unit admissions associated with 
COVID-19.
(c)
Deaths associated with COVID-19.
(d)
Seroresponse against non-Spike (nucleocapsid) 
SARS-CoV-2 antigens (MSD serology assay).
AE = adverse event; AESI = adverse event of special interest; GMFR = geometric mean fold rise; GMT = 
geometric mean titre; IM = intramuscular; MSD = Meso Scale Discovery; nAb = neutralising antibodies; RBD = 
receptor-binding domain; RT-PCR = reverse transcriptase-polymerase chain reaction; SAE = serious adverse 
event; SARS-CoV-2 = severe acute respiratory syndrome-coronavirus-2


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4
STUDY DESIGN
4.1
Overall Design
This is a multicentre, randomised, double-blind, parallel-group, placebo-controlled, 52-week 
Phase I/II study. In this study, 256 eligible participants will be randomised in a 3:1 ratio to 
receive 2 IM doses of either AZD1222 with 5 × 1010 vp (nominal) or placebo administered 
4 weeks apart. 
The study has 2 cohorts with different age populations. Cohort C will include healthy 
participants aged 18 to 55 years. Cohort D will include healthy elderly participants aged ≥56 
years. In Cohort D, the elderly population is further divided into 2 different age subgroups; 
aged 56 to 69 years (Subcohort D1) and aged ≥70 years (Subcohort D2). Regarding Cohorts
C and D, 128 participants will be randomised in a 3:1 ratio to receive either AZD1222 or 
placebo within each cohort.
An independent Neurological AESI Expert Committee will be available to review and provide 
advice to the Company about the diagnosis and causality assessment of selected neurological 
AESIs.
4.1.1
Screening Visit
All potential participants will have a screening visit, which may take place up to 14 days prior 
to Day 1. Informed consent will be taken before screening/enrolment. At the time of obtaining 
consent, for female participants who are of childbearing potential it will be recorded that they 
verbally confirmed that they have used one highly effective form of birth control for at least 
28 days prior to the planned vaccination. If written consent is obtained, the procedures 
indicated in the schedule of attendances will be undertaken including a medical history, 
physical examination, height and weight, and blood tests, including a SARS-CoV-2 screening 
test and clinical safety laboratory assessments (biochemistry and haematology). Abnormal 
blood tests at screening will be assessed. The eligibility of the participants will be reviewed at 
the end of the screening visit and again when all results from the screening visit have been 
considered. Decisions to exclude the participant from enrolling in the trial or to withdraw a 
participant from the trial will be at the discretion of the Investigator. If eligible, a Day 1 visit 
will be scheduled for the participant to receive AZD1222 or placebo and subsequent follow-
up.
4.1.2
Vaccination Visit
Participants will be considered enrolled into the trial at the point of vaccination. Before 
vaccination, the eligibility of the participant will be reviewed. Body temperature will be 
observed and if necessary, a medical history and physical examination may be undertaken to 
determine need to postpone vaccination or withdraw the participation. Women who are of 
childbearing potential will be confirmed with negative pregnancy test (urine test) before 


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vaccination.
In this study, 2 doses of AZD1222 with 5 × 1010 vp (nominal) or 2 doses of placebo at 3:1 
allocation will be distributed to healthy volunteers. Vaccines will be prepared out of sight of 
the participant.
All vaccines will be administered by IM injection. The injection site will be wiped with 
alcohol cotton and be covered with a sterile hermetic dressing and the participant will stay in 
the study site for observation for at least 30 minutes after vaccination, in case of immediate 
AEs. After the observation at the site, the study staff will attach a hermetic transparent 
dressing to the injection site. The application of the dressing will continue until the next visit.
If the dressing comes off before the next visit, the participant should be instructed to put on 
the spare dressing. In addition, the peeled dressing should be properly stored in a sealed waste 
bag distributed beforehand. The participants will be instructed to bring it to the site at the next 
visit, and the study staff should collect it at the next visit. The staff will dispose of it properly.
All participants will be given an axillary thermometer, tape measure and app for e-Diary, with 
instructions on use. All participants will be asked to report on solicited signs and symptoms 
for 7 days following throughout vaccination (Days 1 to 8 and Days 29 to 36). e-Diary will 
collect information on the timing and severity of the solicited signs and symptoms shown in 
Table 6.
4.1.3
Subsequent Visits
Follow-up visits will take place as per the schedule of assessment described in Table 1 with 
respective windows. All participants will be assessed for local and systemic AE, physical 
examination, review of e-Diary and blood tests at these time points as detailed in the schedule 
of assessment. Blood will also be taken for immunology purposes. Visit 3 (Day 4) and Visit 7 
(Day 32) are performed as a telephone visit to confirm solicited events.
After completion of clinical data lock for primary analysis, the study will become single blind, 
where only participants are blinded from allocation of investigational product. All participants 
will be unblinded and participants on the placebo arm may be vaccinated when a licensed 
vaccine for COVID-19 becomes available in Japan for the general population. For participants 
who cannot make scheduled visits after the vaccinations, the follow-up should be made as 
much as possible using telephone call and/or other appropriate way until Day 365 in order to 
collect information on event of SARS-CoV-2 infection, which includes 1) hospital admissions 
associated with COVID-19, 2) intensive care unit admissions associated with COVID-19, and 
3) deaths associated with COVID-19, as well as any SAEs/adverse events of special interest 
(AESIs).


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4.1.4
COVID-19 Symptomatic Participant
Participants who become symptomatic during follow-up will be instructed to call the trial staff 
who will then advise on how to proceed with clinical testing for COVID-19 if necessary. 
When participants are suspected of being infected with SARS-CoV-2 based on their symptom 
(fever or cough or shortness of breath or anosmia/ageusia) and/or positive reverse 
transcriptase-polymerase chain reaction (RT-PCR) testing, they will be advised to contact 
hospitals/clinics designated for treatment of COVID-19 per local guidance. Symptomatic 
participants may be regularly contacted over the phone for safety monitoring until symptom 
resolution.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Design and Participant Population
The placebo arm is needed for securing the objectivity of the safety evaluation of the 
AZD1222 arm and it is also needed as a control for evaluating immunogenicity.
The participant population is males and females ≥ 18 years of age who have no seropositivity 
to SARS-CoV-2 and a negative RT-PCR test for SARS-CoV-2. Inclusion of older participants 
is based on data that are is being gathered from the ongoing University of Oxford-sponsored 
studies. Study COV001 enrolled participants 18 to 55 years of age. Study COV002 is pursuing 
an age-escalation design and it is anticipated that at least 60 participants who are 56 to 
69 years of age and 100 participants aged ≥ 70 will have received AZD1222 prior to initiation 
of this study.
The study will exclude females who are pregnant or breastfeeding and children < 18 years of 
age. Women who are pregnant or breastfeeding are excluded at this point as nonclinical 
developmental and reproductive toxicity studies to support vaccinating these individuals have 
yet to be performed. Additionally, it is planned that children and adolescents will be evaluated 
for their response to the vaccine once safety and efficacy have been established in older 
participants.
4.2.2
Rationale for Study Endpoints
Seroresponse is defined as ≥ 4-fold rise in titres from Day 1 baseline value, and the proportion 
of participants who have a post-treatment seroresponse to Spike antigen of AZD1222 for the 
primary immunogenicity endpoint. Assessment of rise in titres of antibody is used in various 
development trials of vaccine as measurements of immunogenicity endpoint 
(https://www.pmda.go.jp/files/000206153.pdf.)
Solicited AEs will be collected for 7 days following each dose of study intervention, a period 
that has proven adequate to describe reactogenicity events. For all participants, AEs will be 
collected through 28 days post each dose of study intervention. SAEs and AESIs and will be 


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collected throughout the study. AESIs include terms identified by the Brighton Collaboration 
involving events associated with vaccination in general (SPEAC, 2020).
4.3
Justification for Dose
The AZD1222 dose of 5 × 1010 vp was selected based on accumulated clinical experience with 
this vaccine in ongoing clinical studies sponsored by the University of Oxford (see 
Section 2.2). Safety and immunogenicity data from an additional clinical study, MERS001, 
using the same ChAdOx1 vector, also helped inform dose selection. 
MERS001 was the first clinical study of a ChAdOx1-vectored vaccine expressing the 
full-length S protein from a separate, but related, betacoronavirus. ChAdOx1 MERS has been 
given to 31 participants to date at doses ranging from 5 × 109 vp to 5 × 1010 vp. Despite higher 
reactogenicity observed at the 5 × 1010 vp, this dose was safe, with self-limiting AEs and no 
serious adverse reactions recorded. The 5 × 1010 vp was the most immunogenic, in terms of 
inducing nAbs against MERS-CoV using a live virus assay (Folegatti et al, 2020). Given the 
immunogenicity findings and safety profile observed with the ChAdOx1-vectored vaccine 
against MERS-CoV, the 5 × 1010 vp dose was chosen for AZD1222. See the AZD1222 IB.
Based on accumulating nonclinical and clinical data gathered for AZD1222 as well as for 
other SARS-CoV-2 vaccines in development, a 2-dose regimen was selected for the study in 
order to enhance the immune responses to the virus (AZD1222 IB).
In an NHP challenge study, 6 macaques received a second dose of AZD1222 4 weeks after the 
first dose. The second dose resulted in increases in both ELISA and nAb titres, and fewer 
areas of the lung contained viral RNA in prime boost group compared with the prime group. 
In a porcine model, 3 pigs also received a second dose of AZD1222 4 weeks after the first 
dose. In the animals that received the booster dose, both antibodies to the SARS-CoV-2 
receptor-binding domain and nAbs were boosted after the second dose.
In Study COV001, 10 participants received a second dose of AZD1222 4 weeks after the first 
dose. Antibody responses to both the first and second doses were evaluated using an ELISA 
assay, through the Meso Scale Discovery (MSD) platform and by both neutralisation and
pseudo-neutralisation assays. Notable increases in antibody levels to the S protein were seen 
with the ELISA assay and increases to both the S protein and receptor-binding domain were 
noted using the MSD platform. Similarly, increases in antibody levels following the second 
dose were also seen with neutralisation and pseudo-neutralisation assays. Safety data found 
the vaccine was generally tolerated, with no treatment-related SAEs reported through 28 days 
post dose.
The 4-week interval was selected based on the interval used in the nonclinical studies and 
Study COV001.


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4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including their last scheduled procedure.
The end of the study is defined as the date of the last scheduled procedure for the last 
participant in the study.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1
Participants aged 18 to 55 years (Cohort C), aged 56 to 69 years (Subcohort D1), or aged
≥70 years (Subcohort D2).
Type of Participant
2
Willing to allow the investigators to discuss the participant’s medical history with their 
General Practitioner and access all medical records when relevant to study procedures.
3
Agreement to refrain from blood donation during the course of the study.
Reproduction
4
Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
5
Female participants:
(a) Women of childbearing potential must:

Have a negative pregnancy test on day of screening and on Day 1

Use one highly effective form of birth control for at least 28 days prior to Day 1 
and agree to continue using one highly effective form of birth control through 
60 days following administration of last dose of study intervention. 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 (see Table 3). 
Periodic abstinence, the rhythm method, and withdrawal are NOT acceptable 
methods of contraception.
(b) Women are considered of childbearing potential unless they meet either of the 
following criteria:

Surgically sterilised (including bilateral tubal ligation, bilateral oophorectomy, or 
hysterectomy), or 


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
Post-menopausal

For women aged < 50 years, post-menopausal is defined as having both:
o
A history of ≥12 months amenorrhea prior to randomisation, without 
an alternative cause, following cessation of exogenous sex-hormonal 
treatment, and
o
A follicle-stimulating hormone level in the post-menopausal range
Until follicle-stimulating hormone is documented to be within menopausal 
range, the participant is to be considered of childbearing potential.

For women aged ≥50 years, post-menopausal is defined as having a history 
of ≥12 months amenorrhea prior to randomisation, without an alternative 
cause, following cessation of exogenous sex-hormonal treatment.
Table 3
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
•
Intrauterine device
•
Intrauterine hormone-releasing system 
(IUS) a
•
Bilateral tubal occlusion
•
Vasectomised partner b
•
Sexual abstinence c
•
Combined (oestrogen- and progestogen-containing 
hormonal contraception) - oral (combined pill)
a
This is also considered a hormonal method.
b
Provided that partner is the sole sexual partner of the woman of childbearing potential study participant
and that the vasectomised partner has received medical assessment of the surgical success.
c
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the 
participant.
6
Male participants: Agree to continue contraception from the first vaccination until
74 days after the last vaccination.
Informed Consent
7
Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Known past laboratory-confirmed SARS-CoV-2 infection.
2
Positive SARS-CoV-2 RT-PCR test at screening.


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3
Seropositivity to SARS-CoV-2 at screening.
4
Significant infection or other illness, including fever > 37.8°C on the day prior to or day 
randomisation
5
Any confirmed or suspected immunosuppressive or immunodeficient state; asplenia; 
recurrent severe infections and use of immunosuppressant medication within the past 
6 months, except topical steroids or short-term oral steroids (course lasting ≤14 days).
6
History of allergy to any component of the vaccine
7
Any history of anaphylaxis or angioedema.
8
Current diagnosis of or treatment for cancer (except basal cell carcinoma of the skin and 
uterine cervical carcinoma in situ).
9
History of serious psychiatric condition likely to affect participation in the study.
10 Bleeding disorder (eg, factor deficiency, coagulopathy or platelet disorder), or prior 
history of significant bleeding or bruising following IM injections or venepuncture.
11 Suspected or known current alcohol or drug dependency.
12 History of Guillan-Barré syndrome or any other demyelinating condition.
13
Any other significant disease, disorder or finding which 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.
14 Severe and/or uncontrolled cardiovascular disease, respiratory disease, gastrointestinal 
disease, liver disease, renal disease, endocrine disorder and neurological illness 
(mild/moderate well controlled comorbidities are allowed).
Prior/Concomitant Therapy
15 Receipt of any vaccine (licensed or investigational) other than the study intervention 
within 30 days before and after each study vaccination.
16 Prior or planned receipt of an investigational or licensed vaccine or product likely to 
impact on interpretation of the trial data (eg, adenovirus vectored vaccines, any 
coronavirus vaccines). Note: Participants on the placebo arm are allowed to be vaccinated 
when a licensed vaccine for COVID-19 becomes available in Japan for the general 
population.
17 Administration of immunoglobulins and/or any blood products within the 3 months 
preceding the planned administration of the vaccine candidate.
18 Continuous use of anticoagulants, such as coumarins and related anticoagulants (ie,
warfarin) or novel oral anticoagulants (ie, apixaban, rivaroxaban, dabigatran and 
edoxaban).


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Prior/Concurrent Clinical Study Experience
19 Participation in COVID-19 prophylactic drug trials for the duration of the study. Note: 
Participation in COVID-19 treatment trials is allowed in the event of hospitalisation due 
to COVID-19.
Other Exclusions
20 For women only - currently pregnant (confirmed with positive pregnancy test) or 
breastfeeding.
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 study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened only with the approval of the sponsor’s physician (or designee). Only a single
rescreening is allowed in the study. Rescreened participants are required to sign a new ICF 
(Appendix A 3) and will be assigned a new participant number for the rescreening.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s) or 
placebo intended to be administered to or medical device(s) utilised by a study participant 
according to the study protocol. For this study, study intervention is defined as AZD1222 or 
placebo (Table 4).


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6.1
Study Intervention(s) Administered
6.1.1
Investigational Products
Table 4
Investigational Products
Intervention Name
AZD1222
Placebo
Type 
Vaccine
Placebo
Dose Formulation
10 mM histidine, 7.5% (w/v) sucrose, 
35 mM sodium chloride, 1 mM magnesium 
chloride, 0.1% (w/v) polysorbate 80, 0.1 mM 
edetate disodium, 0.5% (w/v) ethanol, at 
pH 6.6.
0.9% (w/v) saline
Unit Dose Strength(s)
≥0.7 × 1011 vp/mL
Dosage Level(s)
5 × 1010 vp (nominal, ± 1.5 × 1010 vp)
Route of Administration
Intramuscular
Intramuscular
Use
Experimental
Placebo
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the Sponsor 
Sourced locally
Packaging and Labelling
Will be provided in vials within a carton. 
Each carton and vial will be labelled as 
required per country requirement
Not applicable
Current/Former Name or Alias
ChAdOx1 nCoV-19
Not applicable
IMP = investigational medicinal product; NIMP = non-investigational medical product; vp = viral particles.
AZD1222 
AZD1222 will be supplied by AstraZeneca as a vial solution for injection. It is a sterile, clear 
to slightly opalescent solution, practically free from visible particles, with a label-claim 
volume of 5 mL.
Unopened vials of AZD1222 must be stored at 2°C to 8°C (36°F to 46°F) for the duration of 
assigned shelf-life and must not be frozen. AZD1222 must be kept in original packaging until 
use to prevent prolonged light exposure.
Placebo
Commercially available 0.9% (w/v) saline for injection will be sourced locally for placebo.
6.1.2 Dosing Instructions
Participants will receive doses of AZD1222 or placebo on Day 1 and Day 29. 
It is recommended that the study interventions be administered as an IM injection into the 


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deltoid of the non-dominant arm. If IM injection in the deltoid of the non-dominant arm is not 
possible (local injury, tattoo, other) then IM injection in the deltoid of the dominant arm may 
be used.
The injection site should be wiped with alcohol cotton and covered with a dressing. All 
participants will be observed for 30 minutes after vaccination at the study site. After the 
observation at the site, the study staff will attach a hermetic transparent dressing to the 
injection site. The application of the dressing will continue until the next visit. If the dressing 
comes off before the next visit, the participant should be instructed to put on the spare 
dressing. In addition, the peeled dressing should be properly stored in a sealed waste bag 
distributed beforehand. The participants will be instructed to bring it to the site at the next 
visit, and the study staff should collect it at the next visit. The staff will dispose of it properly.
Allergic reactions to vaccines are possible. Therefore, appropriate drugs and medical 
equipment to treat acute anaphylactic reactions must be immediately available, and study 
personnel must be trained to recognise and treat anaphylaxis. 
6.2
Preparation/Handling/Storage/Accountability
1)
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2)
Only participants enrolled in the study may receive study intervention and only authorised 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labelled storage conditions with access limited to the investigator 
and authorised site staff.
3)
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4)
Further guidance and information for the final disposition of unused study interventions 
are provided in the Pharmacy manual or specified handling instructions.
6.2.1
Dose Preparation and Administration
6.2.1.1
AZD1222
Doses of AZD1222 must be prepared by the unblinded pharmacist (or designee in accordance 
with local and institutional regulations) using aseptic technique. Each dose is prepared by 
withdrawing 0.5 mL from a vial of AZD1222 in a sterile 1 mL or equivalent syringe.
AZD1222 does not contain preservatives, each vial must be assigned a beyond-use-date of 
4 hours from first needle puncture of the AZD1222 vial, after which any unused portion must 


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be discarded. Once an AZD1222 dose is drawn into a syringe for administration, the dose 
must be administered according to the beyond-use-date of the vial. If AZD1222 dose 
administration is not completed within the 4 hour beyond-use-date, a new dose must be 
prepared from a new vial.
Each vial of AZD1222 has a label-claim volume of 5 mL and can provide up to ten 
0.5 mL doses.
6.2.1.2
Placebo
Doses of placebo must be prepared by the unblinded pharmacist (or designee in accordance 
with local and institutional regulations) using aseptic technique. Each placebo dose is prepared 
by withdrawing 0.5 mL from a 0.9% (w/v) saline vial or intravenous (IV) bag in a sterile 1 mL 
or equivalent syringe. If 0.9% (w/v) saline is extracted from IV bags, the manufacturers 
recommendation for maximum number of needle punctures of the IV bag port must not be 
exceeded.
Saline (0.9% [w/v]) does not contain preservatives, each IV bag or vial must be assigned a 
beyond use date of 4 hours from first needle puncture, after which any unused portion must be 
discarded. Once a placebo dose is drawn into a syringe for administration, the dose must be 
administered according to the beyond-use-date of the vial. If placebo dose administration is 
not completed within the 4-hour beyond-use-date, a new dose must be prepared from a new 
vial or IV bag.
6.3
Measures to Minimise Bias: Randomisation and Blinding
6.3.1
Randomisation
All participants will be centrally assigned to randomised study intervention using an 
Interactive Response Technology (IRT). Before the study is initiated, user guides, the log in 
information, and directions for the IRT will be provided to each site.
The randomisation will be done separately within each Cohort. In Cohort D, participants will 
be stratified at randomisation by age group within cohort, but in Cohort C stratification will 
not be done.
Where a participant does not meet all the eligibility criteria but is randomised in error, or 
incorrectly received study intervention, the investigator should inform the sponsor’s physician 
immediately, and a discussion should occur between the sponsor’s 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 


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intervention received until completion of clinical data lock for primary analysis. Only 
participants will be blinded from their investigational product assignment after clinical data 
lock for primary analysis. The study will become open label in order to inform participants of 
their investigational product assignment when a licensed vaccine for COVID-19 becomes 
available in Japan for the general population. Since AZD1222 and placebo are visually distinct 
prior to dose preparation (due to differences in container closure), investigational medicinal 
product will be handled by an unblinded pharmacist (or designee in accordance with local and 
institutional regulations) at the study site. Once drawn into syringes for administration, 
AZD1222 and placebo are not visually distinct from each other.
The IRT will provide to the investigator(s) or pharmacists a dose tracking number to be 
allocated to the participant at the vaccination visit. Routines for this will be described in the 
IRT user manual that will be provided to each site.
The randomisation code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment randomisation.
The Sponsor retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational medicinal product and that potentially 
require expedited reporting to regulatory authorities. Randomisation 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 study intervention will affect the immediate 
management of the participant’s condition (eg, antidote available), the investigator has the 
sole responsibility for determining if unblinding of a participants’ intervention assignment is 
warranted. Participant safety must always be the first consideration in making such a 
determination. If a participant’s intervention assignment is unblinded, the Sponsor must be 
notified within 24 hours after breaking the blind.
6.4
Study Intervention Compliance
When participants are dosed at the study site, they will receive study intervention directly 
from the investigator or designee, under medical supervision. The date, and time if applicable, 
of dose administered will be recorded in the source documents and recorded in the electronic 
Case Report Form (eCRF). The dose of study intervention and study participant identification 
will be confirmed at the time of dosing by a member of the study site staff other than the 
person administering the study intervention.


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6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines) that the 
participant is receiving at the time of enrolment or receives during the period specified in the 
Schedule of Activities (SoA, Section 1.3) must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.5.1
Permitted Concomitant Medications
Participants may take concomitant medications prescribed by their primary care provider for 
management of medical conditions and/or for health maintenance.
6.5.2
Prohibited Concomitant Medications

Receipt of any vaccine (licensed or investigational) other than the study intervention 
(within 30 days before and after each study vaccination).

Receipt of a product likely to impact on interpretation of the trial data (eg, adenovirus 
vectored vaccines, any coronavirus vaccines) (within 30 days before study vaccination 
until the end of study). Note: Participants on the placebo arm are allowed to be vaccinated 
when a licensed vaccine for COVID-19 becomes available in Japan for the general 
population.

Receipt of any investigational drug (from provision of informed consent to the end of 
study).

Receipt of any immunosuppressant medication (within 6 months prior to enrolment until 
the end of study) other than the topical steroids and short courses of steroids (course 
lasting ≤ 14 days).

Receipt of immunoglobulins and/or any blood products (from provision of informed 
consent to the end of study).

Receipt of oral anticoagulants, such as coumarins and related anticoagulants (ie, warfarin) 
or novel oral anticoagulants (ie, apixaban, rivaroxaban, dabigatran and edoxaban) (from 
provision of informed consent to the end of study).
6.6
Dose Modification
Study intervention will be administered as described in Section 6.1.2. Dose modification is not 
permitted. 


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6.7
Intervention After the End of the Study
Not applicable.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
Each participant will receive 2 doses of study intervention. An individual participant will not 
receive study intervention if any of the following occur in the participant in question:

Withdrawal of consent after signing informed consent

Participant meets one or more of the exclusion criteria or fails to meet all inclusion 
criteria for study participation 

Participant is pregnant or nursing

Any Grade ≥ 3 allergic reaction including anaphylaxis that is assessed as related to 
AZD1222 

Any SAE assessed as related to study intervention

Any AE that, in the judgment of the site investigator, is related to study intervention and 
may jeopardise the safety of the study participant 
Each participant who has received at least one dose of study intervention will be followed for 
the full study period, unless consent is withdrawn specifically from further study participation, 
or the participant is lost to follow-up. Participants who have not received study intervention, 
regardless of reason, will not be followed.
7.2
Participant Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural,
compliance, or administrative reasons. This is expected to be uncommon.

A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried out in line with what was stated in the informed consent and local regulation. The 


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investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team.

For participants who cannot make scheduled visits after the vaccinations, the follow-up 
should be made as much as possible using telephone call and/or other appropriate way 
until Day 365.
7.3
Lost to Follow up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and,
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
7.4
Criteria for Discontinuation or Suspension of All or Part of the 
Study
The study sponsor may decide to prematurely terminate or suspend the whole study or a 
component of the study at any time. The reasons for prematurely terminating or temporarily 
suspending the study may include, but are not limited to, any death, SAE, or other safety 
finding assessed as related to study intervention that in the opinion of the Sponsor may 
preclude further administration of study intervention.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarised in the SoA (Section 1.3). Protocol
waivers or exemptions are not allowed.


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
Immediate safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA
(Section 1.3), is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA (Section 1.3).
The amount of blood collected from each participant will be as follows:

The amount of blood collected from each participant is Visit 1: 14.0 mL, Visit 2: 13 mL, 
Visit 4: 4.5 mL, Visit 5: 8.5 mL, Visit 6: 13 mL, Visit 8: 4.5 mL, Visit 9: 8.5 mL, 
Visit 10: 13 mL, Visit 11: 8.5 mL, Visit 12: 8.5 mL. Repeat or unscheduled samples may 
be taken for safety reasons or for technical issues with the samples.
8.1
Descriptive Efficacy Assessments
Primary and secondary immunogenicity endpoint assessments are described in Section 8.5.2.1
and Section 8.5.2.2, respectively.
In addition, the following occurrences will be described in AZD1222 and placebo recipients:

Virologically confirmed (RT-PCR positive) symptomatic cases of COVID-19.

Evaluation of severe COVID-19 in virologically confirmed (RT-PCR positive) 
symptomatic cases of COVID-19:

Hospital admissions associated with COVID-19.

Intensive care unit admissions associated with COVID-19.

Deaths associated with COVID-19.

Seroresponse against non-spike (nucleocapsid) SARS-CoV-2 antigens (MSD serology 
assay); see Section 8.5.2.1 for details.


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8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1
Physical Examinations
A complete physical examination will be performed at screening followed by targeted 
physical examinations as specified in the SoA (Section 1.3). 

A complete physical examination will include, but not be limited to, assessment of height 
and weight, general appearance, head, ears, eyes, nose, throat, neck, skin, as well as 
cardiovascular, respiratory, abdominal, and nervous systems. Each clinically significant 
abnormal finding at screening will be recorded in the medical history.

A targeted physical examination will include areas suggested by medical history. Each 
clinically significant abnormal finding following vaccination will be recorded as an AE.

All physical examinations will be performed by a licensed healthcare provider 
(eg, physician). 
8.2.2
Vital Signs
Vital signs, including heart rate, blood pressure, and body temperature, will be performed as 
specified in the SoA (Section 1.3). The participant should be resting prior to the collection of 
vital signs.
Situations in which vital sign results should be reported as AEs are described in Section 8.3.5.
8.2.3
Clinical Safety Laboratory Assessments
A Laboratory Manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical study.
For women participants of childbearing potential, a urine sample for pregnancy testing will be 
collected according to the SoA (Section 1.3). Urine pregnancy tests for beta human chorionic 
gonadotropin (-hCG) may be performed at the site using a licensed test (dipstick). If urine 
tests positive or indeterminate, a quantitative serum β-hCG will be performed for 
confirmation.
Blood samples for determination of clinical chemistry and haematology will be taken at the 
visits indicated in the SoA (Section 1.3).
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date and time of collection will be recorded on the appropriate eCRF.


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The clinical chemistry and haematology analyses will be performed at a central laboratory.
The following laboratory variables will be measured.
Table 5
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin (Hb)
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total
B-Leukocyte differential count (absolute count)
S/P-Alkaline phosphatise (ALP)
B-Platelet count
S/P-Aspartate aminotransferase (AST)
S/P-Alanine aminotransferase (ALT)
S/P-Albumin
S/P-Potassium
S/P-Calcium, total
S/P-Sodium
S/P-Creatine kinase (CK)
B = blood; P = plasma; S = serum
NB. In case a participant shows an aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) ≥3 × upper limit of normal (ULN) together with total bilirubin (TBL)
≥2 × ULN please refer to Section 8.3.6.
8.3
Adverse Events and Serious Adverse Events
The Principal investigator (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.
All AEs are considered to be unsolicited AEs (collected by ‘open question’ at study visits) 
unless categorised as solicited AEs.
Solicited AEs are local or systemic predefined events for assessment of reactogenicity. 
Solicited AEs will be collected in an e-Diary (see Section 8.3.7), and will be assessed 
separately from the (unsolicited) AEs collected during the study.
General information for AEs in this protocol excludes solicited AEs. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant’s legally authorised representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 


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events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
AEs will be recorded 28 days after each dose of study intervention.
Solicited AEs will be recorded for 7 days following each dose of study intervention.
SAEs will be recorded from the time of signing of the ICF through the last participant contact.
AESIs will be recorded from Day 1, post-treatment, through the last participant contact.
If the investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention that occurs after the end of the clinical study in a participant treated by him or 
her, the investigator shall, without undue delay, report the SAE to the sponsor.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the investigator for as long as medically indicated, but without further recording in the 
eCRF. AstraZeneca retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse event variables
The following variables will be collected for each AE;

AE (verbatim)

The date when the AE started and stopped

Severity grade/max severity grade/changes in severity grade

Whether the AE is serious or not

Investigator causality rating against the investigational product(s) (yes or no)

Action taken with regard to investigational product(s)

AE caused participant’s withdrawal from study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date investigator became aware of SAE

AE is serious due to

Date of hospitalisation


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
Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication
The grading scales from US Food and Drug Administration (FDA) guidance for healthy 
volunteers enrolled in a preventive vaccine clinical study (FDA, 2007) will be utilised for all 
unsolicited events with an assigned severity grading. 
8.3.3 Causality Collection
The investigator should assess causal relationship between investigational product 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 investigational product?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant 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.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the Clinical Study Report (CSR).
Deterioration as compared with baseline in protocol-mandated laboratory values or vital signs 
should therefore only be reported as AEs if they fulfil any of the SAE criteria, are the reason 
for discontinuation of treatment with the investigational product or are considered to be 


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clinically relevant as judged by the investigator (which may include but not limited to 
consideration as to whether treatment or non-planned visits were required).
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, anaemia versus low haemoglobin 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.
8.3.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation. Any occurrences of AST or ALT ≥3 × ULN together with TBL ≥2 × ULN and 
confirmed as a Hy’s law case should be reported as SAEs.
Hy’s Law
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other reason, other than the 
study intervention, can be found to explain the combination of increases, eg, elevated alkaline 
phosphatase indicating cholestasis, viral hepatitis, another drug. The elevation in 
aminotransferases 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 aminotransferases and 
TBL must occur.
8.3.7 Solicited Adverse Events
Local and systemic predefined solicited AEs for reactogenicity assessment will be collected in 
an e-Diary for 7 days following administration of each dose of study intervention. 
Solicited AEs should not be reported as unsolicited AEs (see Section 8.3). However, solicited 
AEs should be reported as SAEs if they fulfil the criteria (see Section 8.3.9).


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Table 6
List of Predefined Solicited Adverse Events for Reactogenicity 
Assessment
Local 
Systemic 
Pain at the site of injection 
Fever (> 100°F or 37.8°C)a
Erythema/redness at the site of injectionb
Chills
Tenderness
Muscle pains
Swelling at the site of the injectionb
Fatigue
Induration at the site of the injectionb
Headache
Malaise
Nausea
Vomiting
a
Fever measured by any route. Investigators who consider a temperature lower than this cutoff as a fever 
or a ‘fever’ reported by participants without documentation by a thermometer should record the event as 
‘elevated body temperature.’ 
b
Swelling, redness, and induration must be ≥ 0.6 centimetres in diameter.
e-Diary for Recording Solicited AEs 
On Day 1, participants will be given an axillary thermometer, tape measure, and access to app 
for the Solicited AE e-Diary, with instructions on use, along with the emergency 24-hour 
telephone number to contact the on-call study physician if needed. 
Participants will be instructed to record for 7 days following administration of each dose of 
study intervention, the timing and severity of local and systemic solicited AEs, if applicable, 
and whether medication was taken to relieve the symptoms.
Severity Assessment of Solicited AEs
Severity will be assessed for solicited AEs by the participant according to toxicity grading 
scales adopted from US FDA Guidance (FDA, 2007) as defined in Appendix D. Because 
solicited AEs are expected to occur after vaccination, they will not be assessed for relationship 
to study intervention.
8.3.8
Adverse Events of Special Interest
AESIs will be collected according to the time points specified in the SoA (Section 1.3). 
AESIs are events of scientific and medical interest specific to the further understanding of 
study intervention safety profile and require close monitoring and rapid communication by the 
investigators to the Sponsor. AESIs for AZD1222 are based on Brighton Collaboration case 
definitions (SPEAC, 2020), clinical experience, and scientific interest. See Appendix E for a 
listing and description of AZD1222 AESIs.


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An AESI can be serious or non-serious. All AESIs will be recorded in the eCRF. If any AESI 
occurs in the course of the study, investigators or other site personnel will inform the 
appropriate Sponsor representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it. Serious AESIs will be recorded and reported 
as per Section 8.3.9.
8.3.8.1
Potential Neurological AESIs
If a participant experiences new onset (acute or subacute) motor and sensory disturbances 
(eg, weakness, numbness, paresthesias, hypoesthesia, hyperesthesia, dysesthesias), 
bowel/bladder dysfunction, gait impairment, visual disturbance, or any event of myelitis, 
encephalomyelitis, transverse myelitis, or other sudden neurological deficit, there should be 
prompt neurological evaluation. See Figure 2 for a recommended testing algorithm. 
An independent Neurological AESI Expert Committee will review and provide advice on the 
diagnosis and causality assessment of selected neurological AESIs occurring in the AZD1222 
clinical development program (see Appendix A 5). 


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Figure 2
Neurology Testing Algorithm
a
Adapted from (Rovira et al 2015)
Ab = antibody; ACE = angiotensin converting enzyme; ADC = apparent diffusion coefficient; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic 
antibodies; AQP4 = aquaporin 4; CMV = cytomegalovirus; CNS = central nervous system; CRP = c-reactive protein; CSF = cerebral spinal fluid; CT = 
computed tomography; DWI = diffusion-weighted image; EBV = Epstein-Barr virus; ED = emergency department; ENA = extractable nuclear antigen 
antibodies; ESR = erythrocyte sedimentation rate; FLAIR = fluid-attenuated inversion recovery; GRE = gradient echo; HIV = human immunodeficiency virus; 
HSV = herpes simplex virus; IgG = immunoglobulin G; MOG = myelin oligodendrocyte glycoprotein; MRI = magnetic resonance image; PCR = polymerase 
chain reaction; RF = rheumatoid factor; RPR = rapid plasma reagin; STIR = short T1 inversion recovery; SWI = susceptibility-weighted imaging; TSH = thyroid 
stimulating hormone; TM = transverse myelitis; VDRL = Venereal Disease Research Laboratories; VZV = varicella-zoster virus.


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8.3.9
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate AstraZeneca representatives within one day ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day, ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the investigators or other site personnel indicate an AE is serious in the electronic data 
capture system, an automated email alert is sent to the designated AstraZeneca representative.
If the electronic data capture system is not available, then the investigator or other study site 
staff reports a SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the investigator/study site staff how to proceed.
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study 
Protocol.
The reference document for definition of expectedness is the AZD1222 IB.
8.3.10
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study participant has received any study 
intervention
8.3.10.1
Maternal Exposure
Female participants who are pregnant or have a confirmed positive pregnancy test at screening 
or Day 1 will be excluded from the study (see Section 5.2). Pregnancy itself is not regarded as 
an AE unless there is a suspicion that the investigational product under study may have 


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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 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.9) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module is used to report the outcome of the pregnancy.
8.3.11
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 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is 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 guidance refer to AstraZeneca standard operating procedure Reporting of Individual 
Safety Events in Clinical Studies. 
For this study, any dose of study intervention exceeding that specified in the protocol will be 
considered an overdose.
There is no specific treatment for an overdose with AZD1222. If overdose occurs, the 
participant should be treated supportively with appropriate monitoring as necessary.


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
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study intervention occurs 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 1 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 are provided in 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. 
8.5.1
Pharmacokinetics
Pharmacokinetic parameters are not evaluated in this study.
8.5.2
Immunogenicity Assessments
Serum samples for immunogenicity assessments will be collected according to the SoA 
(Section 1.3). Samples will be collected, labelled, stored, and shipped as detailed in the 
Laboratory Manual.
8.5.2.1
SARS-CoV-2 Serology Assessments
Serum samples will be collected to assess SARS-CoV-2 antigen-specific antibody levels from 
all participants according to the SoA (Section 1.3). Authorised laboratories will assess 
seroresponse to AZD1222 by a validated immunoassay directed at the SARS-CoV-2 S 
antigen. The rate of asymptomatic SARS-CoV-2 infection in participants receiving AZD1222 
versus placebo will be determined by seroresponse to SARS-CoV-2 N by an immunoassay 
operated by an authorised laboratory. Serologic assessment to S and receptor-binding domain 
(RBD) antigens will also be assessed quantitatively using a validated multiplexed MSD 
immunoassay.


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8.5.2.2
SARS-CoV-2 Neutralising Antibody Assessments
Serum samples to measure SARS-CoV-2 nAb levels will be collected according to the time 
points specified in the SoA (Section 1.3). Authorised laboratories will measure nAbs to 
SARS-CoV-2 using validated wild-type neutralisation assay or pseudoneutralisation assays.
8.5.3
Pharmacodynamics
Pharmacodynamics are not evaluated in this study.
8.6
Human Biological Sample Biomarkers
Biomarkers are not evaluated in this study.
8.7
Optional Genomics Initiative Sample
Optional Genomics Initiative research is not applicable in this study.
8.8
Medical Resource Utilisation and Health Economics
Medical resource utilisation and health economics are not applicable in this study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The primary immunogenicity endpoint is the proportion of participants who have a 
post-treatment seroresponse (≥ 4-fold rise in titres from Day 1 baseline value) to the Spike 
antigens of AZD1222 (MSD serology assay) at Day 57.
Let pactive and pplacebo denote the proportion of participants who have a post-treatment 
seroresponse for the AZD1222 treatment and placebo group, respectively, then the null 
hypothesis and alternative hypothesis are defined as follows:

Null hypothesis: pactive = pplacebo

Alternative hypothesis: pactive ≠ pplacebo
where p is the proportion of seroresponse participants.
The proportion of participants who have a post-treatment seroresponse will be compared 
between AZD1222 treatment and placebo using the Fisher’s exact test at the 2-sided 5% alpha 
level for each cohort. No adjustment for multiple testing will be made.
9.2
Sample Size Determination
Regarding Cohort C, 128 participants will be randomised in a 3:1 ratio to receive either 
AZD1222 or placebo. Regarding Cohort D, in a similar way, 128 participants will be 
randomised in a 3:1 ratio to receive either AZD1222 or placebo, but participants will be 


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stratified at randomisation by age group (ie Subcohorts D1 vs D2). At least 30% of 
participants in Cohort D will be secured for participants with age ≥70 years.
These sample sizes (96 for AZD1222 versus 32 for placebo) were determined mainly for 
safety evaluation and based on feasibility. With the sample size of 96 participants in the 
AZD1222 treatment arm in each cohort, at least 1 participant with an AE of incidence rate of 
2.5% can be detected with probability of about 90%. The placebo arm is needed for securing 
the objectivity of the safety evaluation of the AZD1222 arm and it is also needed as a control 
for evaluating immunogenicity as stated below. For these purposes, the minimum sample size 
was given to the placebo arm (1/3 of the AZD1222 arm).
It is difficult to calculate an accurate sample size necessary for comparing the proportion of 
participants who have a seroresponse to SARS-CoV-2 spike protein between the AZD1222 
and placebo arms because of insufficient information on immunogenicity in both arms at the 
moment. It is expected that the minimum number of participants per cohort will be about 36 in 
the primary analysis. Under a slightly conservative assumption about seroresponse rates of 
10% assumed on placebo and over 75% on AZD1222, it is expected that the sample size of 36 
(27 for AZD1222 vs 9 for placebo) will provide 93% power for showing the superiority of 
seroresponse of the AZD1222 treatment compared with placebo based on Fisher’s exact test at 
2-sided 5% alpha.
9.3
Populations for Analyses
The following populations are defined:
Table 7
Populations for Analysis
Population/Analysis set
Description
All participants analysis set 
All participants screened who signed informed consent form for the study, 
to be used for reporting disposition and screening failures.
Total vaccinated analysis set
(TVS)
All participants who have received at least one dose of study intervention. 
Erroneously vaccinated participants (eg, those randomised to placebo 
treatment but were actually given active vaccine treatment) are accounted 
for in this analysis set by assigning them to the treatment they actually 
received.
This analysis set will be used for the analysis of safety, exploratory efficacy 
and immunogenicity endpoints.


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Population/Analysis set
Description
Fully vaccinated analysis set 
(FVS) for immunogenicity
All participants in the TVS who have received two doses of study 
intervention and have no important protocol deviations judged to have the 
potential to interfere with the generation or interpretation of immune 
responses. Protocol deviations will be reviewed by the study team before 
unblinding to determine exclusion from the immunogenicity. Participants 
who have a postbaseline seroresponse (≥ 4-fold rise in titres from Day 1 
baseline value) to nucleocapsid antibodies by MSD serology assay at 
post-baseline up to Day 57 will be excluded from this analysis set.
This analysis set will be used for the analysis of immunogenicity endpoints.
Fully vaccinated analysis set 
(FVS) for efficacy
All participants in the TVS who have received two doses of study 
intervention, and who remain on-study 15 days after their second dose 
without having had a prior SARS-CoV-2 reverse transcriptase-polymerase 
chain reaction (RT-PCR) positive confirmed COVID-19 infection.
This analysis set will be used for applicable exploratory endpoints.
FVS = fully vaccinated analysis set; MSD = Meso Scale Discovery; RT-PCR = reverse transcriptase-polymerase 
chain reaction; SARS-CoV-2 = severe acute respiratory syndrome-coronavirus-2; TVS = total vaccinated 
analysis set
9.4
Statistical Analyses
9.4.1
General Considerations
The study has been interrupted to allow a safety review, following the occurrence of a SAE in 
an Oxford University-sponsored trial in the UK. By that time (07 September 2020), 
99 participants had been vaccinated. In order not to delay the local (Japan) vaccine 
assessment, the analysis strategy has been updated.  
The analysis will be done in the following three steps:

The Primary analysis will include immunogenicity data up to Day 57 from subjects 
enrolled before the study interruption and safety data gathered in all participants up to 
Day 57. 

The additional analysis will include immunogenicity data in all participants up to Day 57.

The final analysis will include all endpoints up to Day 365 in all participants.
The clinical data lock for the primary analysis will occur after all participants have completed 
visit Day 57 or discontinued early, whichever occurs first. All safety data up to Day 57 in all 
subjects will be included. This primary analysis will also include immunogenicity data up to 
Day 57 from subjects enrolled before the study interruption.
After completion of the clinical data lock for the primary analysis, the study will become 
single blind, where only participants are blinded from allocation of investigational product. 


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Final clinical data lock will occur when all participants have completed the study or 
discontinued early.
The statistical analysis plan (SAP) will be finalised prior to the clinical data lock for the 
primary analysis and it will include a more technical and detailed description of the statistical 
analyses described in this section. This section is a summary of the planned statistical analyses 
of the most important endpoints including primary and main secondary endpoints.
All personnel involved in the analyses of the study will remain blinded until the clinical data 
lock for the primary analysis is achieved and protocol deviations are identified.
The additional analysis including immunogenicity data up to Day 57 in all participants will be 
performed when these data become available. In addition, the final analysis will be performed 
when all participants have completed Day 365 visit or discontinued early.
Analyses will be performed by the Sponsor or its representatives.
Categorical variables will be summarised using frequency and percentages, where the 
denominator for calculation is the underlying analysis set population unless otherwise 
specified.
Continuous variables will be summarised 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 together with a 95% confidence interval (CI), unless 
otherwise specified. P-values, corresponding to a 2-sided test, will be presented for 
comparisons between treatments.
Demography and baseline characteristics will be summarised by treatment for the total 
vaccinated analysis set (TVS) and fully vaccinated analysis set (FVS) for efficacy.
9.4.2
Efficacy (Including Immunogenicity)
Unless otherwise specified, all summaries and figures for immunogenicity will be presented 
by Cohorts C, D, and Subcohorts D1 and D2, and total participants of Cohort C plus Cohort D 
separately, based on the TVS and FVS for immunogenicity. Exploratory efficacy analysis will 
be based on TVS and FVS for efficacy.
9.4.2.1
Primary Endpoint(s)
The primary immunogenicity endpoint is the proportion of participants who have a 
post-treatment seroresponse (≥4-fold rise in titres from Day 1 baseline value) to the Spike 
antigens of AZD1222 (MSD serology assay) at Day 57, and will be calculated along with its 
95% CI based on the Clopper-Pearson method in each treatment groups in each cohort (C and


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D) and also Subcohorts D1 and D2 separately. The proportion of participants who have a 
post-treatment seroresponse will be compared between AZD1222 treatment and placebo using 
Fisher’s exact test for each cohort. Fisher’s exact test will not be presented for Subcohorts D1 
and D2. No adjustment for multiple testing will be made.
9.4.2.2
Secondary Endpoint
The proportion of participants who have a post-treatment seroresponse (≥4-fold rise in titres 
from Day 1 baseline value) to RBD antigen of AZD1222 (MSD serology assay) at Day 57, 
will be analysed in the same way as the primary immunogenicity endpoint.
Geometric mean titre (GMT) and geometric mean fold rise (GMFR) of immunogenicity 
against Spike and RBD antigens of AZD1222 (MSD serology assay) with the associated 95% 
CIs will be computed at each time point in each treatment arm in each cohort (C and D) and 
also in Subcohorts D1 and D2 separately.
The proportion of participants who have a post-treatment seroresponse (≥4-fold rise in titres 
from Day 1 baseline value) to AZD1222 as measured by SARS-CoV-2 nAbs (wild-type assay 
or pseudoneutralisation assay) at Day 57, will be analysed in the same way as the primary 
immunogenicity endpoint. GMT and GMFR of SARS-CoV-2 nAbs and the associated 95% 
CIs will be presented at each time point in each treatment arm in each cohort (C and D) and 
also in Subcohorts D1 and D2 separately.
9.4.2.3
Exploratory Endpoint(s)
Exploratory analyses will be conducted to describe occurrence of symptomatic COVID-19 in 
recipients of AZD1222 and placebo and occurrence of severe COVID-19 and seroresponse to 
non-Spike SARS-CoV-2 antigens. The exploratory efficacy endpoint will be the incidence of 
the first virologically confirmed (RT-PCR positive) symptomatic cases of COVID-19 post first 
dose of study intervention, analysed for the TVS, and the incidence of the first virologically 
confirmed (RT-PCR positive) symptomatic cases of COVID-19 occurring ≥15 days post 
second dose of study intervention, analyzed for the FVS for efficacy.
Kaplan-Meier curves will be presented for each cohort in the AZD1222 and placebo treatment 
group, showing the cumulative incidence of the first case of RT-PCR positive symptomatic 
COVID-19 post first dose of study intervention or occurring ≥15 days post second dose of 
study intervention, respectively. In addition, descriptive statistics will also be produced. 
Similar descriptive analysis will be conducted on the following more severe cases of 
COVID-19.

Hospital admissions associated with COVID-19

Intensive care unit admissions associated with COVID-19

Deaths associated with COVID-19


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
Seroresponse against non-Spike (nucleocapsid) SARS-CoV-2 antigens (MSD serology 
assay) will also be assessed using a methodology similar to the one described in 
Section 9.4.2.1.
Full details of these exploratory efficacy analyses will be documented in the SAP.
9.4.3
Safety
9.4.3.1
Primary Endpoints
The safety of AZD1222 will primarily be assessed by: 

The incidence of local and systemic solicited reactogenicity signs and symptoms for 
7 days following throughout vaccination (Day 1 to 8 and Day 29 to 36). A list of 
predefined solicited AEs for reactogenicity assessment can be found in Table 6.

The incidence of AEs, SAEs and AESIs collected from Day 1 through Day 57. 

The change from baseline for safety laboratory measures at Day 8, Day 29, Day 36, and 
Day 57.
AE severity will be graded according to the US FDA guidance (FDA, 2007) and coded using 
the most recent version of the Medical Dictionary for Regulatory Activities. AEs will be 
presented for each treatment group by system organ class and preferred term. Summaries will 
include the number and percentage of participants reporting at least 1 event, where 
appropriate.
An overview of AEs will be presented for each treatment group, including the number and 
percentage of participants with any AE, AEs with outcome of death, and SAEs. Summaries 
will present the relationship to study intervention 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
Secondary Endpoints
The secondary safety endpoints are the occurrence of SAEs, AESIs (defined in Section 8.3.8) 
collected from Day 1 through Day 365.
9.5
Subgroup Analyses
Subgroup analyses will be carried out to assess the consistency of the treatment effect across 
subgroups. These analyses will focus on the primary and secondary immunogenicity 
endpoints, and they may be performed on primary safety endpoint of unsolicited AEs. The list 
of subgroups includes, but may not be limited to: gender, and BMI at baseline. Full details of 
all subgroup analyses will be described in the SAP.


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9.6
Interim Analyses
Not applicable.
9.7
Data Monitoring Committee
Not applicable.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Standards stipulated in Article 14, Paragraph 3 and Article 80-2 of the “Law on 
Securing Quality, Efficacy and Safety of Products including Pharmaceuticals and 
Medical Devices”, and “Ministerial Ordinance on Good Clinical Practice for Drugs”.

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 International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
Contract Research Organisation but the accountability remains with AstraZeneca.

The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to ICH guidelines and all applicable local regulations.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies except those utilising medical devices, investigator safety reports must be 
prepared for SUSARs according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.


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
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements.
A 2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorised 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 centre.

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 authorised person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative.
Participants who are rescreened are required to sign a new ICF.
A 4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 


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names or any information which would make the participant identifiable will not be 
transferred.

The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees Structure
The safety of all Sponsor clinical studies is closely monitored on an ongoing basis by Sponsor 
representatives in consultation with Patient Safety. Issues identified will be addressed; for 
instance, this could involve amendments to the Clinical Study Protocol and letters to 
investigators.
An independent Neurological AESI Expert Committee will be available to review and provide 
advice to the Company about the diagnosis and causality assessment of selected neurological 
AESIs.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com as will the summary of the study results when 
they are available. The clinical study and/or summary of study results may also be available 
on other websites according to the regulations of the countries in which the study is 
conducted.
A 7
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 


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noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, 
contract research organisations).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available.
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
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 


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and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organisation(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 may have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered.
B 2
Definition of Serious Adverse Events
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-participant hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity. 

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above.
Adverse events (AEs) for malignant tumours reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement on an individual 
event basis should be applied to clarify that the malignant tumour event should be assessed 
and reported as a non-serious AE. For example, if the tumour is included as medical history 
and progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfil the attributes for being assessed as 
serious, although reporting of the progression of the malignant tumour as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalisation, 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).
Hospitalisation
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the participant was enrolled in the study, provided that it did not deteriorate in an unexpected 
way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
Intensity Rating Scale:
The grading scales found in the US FDA guidance for healthy volunteers enrolled in a 
preventive vaccine clinical study (FDA, 2007) will be utilised for all events with an assigned 
severity grading. 
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 


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intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 


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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 study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error. 

Occurred

Was identified and intercepted before the participant received the drug

Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 

Wrong participant received the medication (excluding IRT/Randomisation and Trial 
Supply Management [RTSM] errors)

Wrong drug administered to participant (excluding IRT/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT/RTSM - including those which lead to one of the 
above listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose)


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


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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples while at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers.
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
C 2
International Airline Transportation Association 6.2 Guidance 
Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A Pathogens are, eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B


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
are to be packed in accordance with UN 3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content


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Appendix D
Toxicity Grading Scales for Solicited Adverse Events
The toxicity grading scales for the solicited AEs were modified and abridged from the 
US FDA Guidance on Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials (FDA, 2007).

Table 8
: Clinical Abnormalities, Local Reactions to Injectable Product

Table 9
: Clinical Abnormalities, Vital Signs

Table 10 : Clinical Abnormalities, Systemic (General or Illness)
Table 8
Tables for Clinical Abnormalities: Local Reactions to Injectable Product
Local Reaction to 
Injectable Product
Reaction Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Life Threatening 
(Grade 4)
Pain
Does not interfere 
with activity
Repeated use of 
non-narcotic pain 
reliever > 24 hours 
or interferes with 
activity
Any use of narcotic 
pain reliever or 
prevents daily 
activity
ER visit or 
hospitalisation
Tenderness
Mild discomfort 
to touch
Discomfort with 
movement
Significant 
discomfort at rest
ER visit or 
hospitalisation
Erythema/redness a, b
1-2 inches
(2.5–5 cm)
> 2-4 inches
(5.1–10 cm)
> 4 inches
(> 10 cm)
Necrosis or 
exfoliative 
dermatitis
Induration/swelling a, b 
1-2 inches
(2.5–5 cm)
>2-4 inches
(5.1–10 cm)
> 4 inches
(> 10 cm)
Necrosis
a
In addition to grading the measured local reaction at the greatest single diameter, the measurement should 
be recorded as a continuous variable. Reactions < ¼ inch (< 0.6 cm) in diameter will not be recorded.
b
Grade 4 erythema or induration is determined by site with participant input rather than being recorded 
directly in e-Diary.
ER = emergency room.


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Table 9
Tables for Clinical Abnormalities: Vital Signs
Vital Signs a
Vital Signs Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening (Grade 4)
Fever (°C) b
(°F) b
37.9-38.4
100.1-101.1
38.5-38.9
101.2-102.0
39.0-40
102.1-104
> 40
> 104
Tachycardia 
(beats/minute)
101-115
116- 130
> 130
ER visit or 
hospitalisation for 
arrhythmia
Bradycardia 
(beats/minute) c
50-54
45-49
< 45
ER visit or 
hospitalisation for 
arrhythmia
Hypertension; systolic 
(mm Hg)
141-150
151-155
> 155
ER visit or 
hospitalisation for 
malignant hypertension
Hypertension; diastolic 
(mm Hg)
91-95
96-100
> 100
ER visit or 
hospitalisation for 
malignant hypertension
Hypotension; systolic 
(mm Hg)
85-89
80-84
< 80
ER visit or 
hospitalisation for 
hypotensive shock
Respiratory rate 
(breaths/minute)
17-20
21-25
> 25
Intubation
Note: Record vital signs as adverse events only if clinically relevant and changed from baseline.
a
Participant should be at rest for vital signs measurements.
b
No recent hot or cold beverages or smoking.
c
Use clinical judgment when characterising bradycardia among some healthy participant populations, for 
example, conditioned athletes.
ER = emergency room; Hg = mercury.


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Table 10
Tables for Clinical Abnormalities: Systemic (General or Illness)
Systemic (General)
Systemic Grade
Mild 
(Grade 1)
Moderate
(Grade 2)
Severe 
(Grade 3)
Potentially Life 
Threatening 
(Grade 4)
Nausea/vomiting
No interference 
with activity or 
1-2 episodes/24 hrs
Some interference 
with activity or 
> 2 episodes/24 hrs
Prevents daily 
activity, required 
outpatient IV 
hydration
ER visit or 
hospitalization 
for hypotensive 
shock
Chills
No interference 
with activity
Some interference 
with activity
Significant, prevents 
daily activity
ER visit or 
hospitalization
Headache
No interference 
with activity
Repeated use of 
non-narcotic pain 
reliever > 24 hrs or 
some interference 
with activity
Significant; any use 
of narcotic pain 
reliever or prevents 
daily activity
ER visit or 
hospitalization
Fatigue
No interference 
with activity
Some interference 
with activity
Significant; prevents 
daily activity
ER visit or 
hospitalization
Myalgia
No interference 
with activity
Some interference 
with activity
Significant; prevents 
daily activity
ER visit or 
hospitalization
Systemic Illness
Illness or clinical 
adverse event (as 
defined according to 
applicable regulations)
No interference 
with activity
Some interference 
with activity not 
requiring 
intervention
Prevents daily 
activity and required 
medical intervention
ER visit or 
hospitalization
ER = emergency room; hrs = hours; IV = intravenous.


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Appendix E
Adverse Events of Special Interest
AZD1222 AESIs are based on Brighton Collaboration case definitions (SPEAC, 2020), 
clinical experience, and scientific interest. There is no current evidence to suggest that 
AZD1222 is associated with these AESIs.
Table 11
Adverse Events of Special Interest
AESI
Medical Concept
Neurologic
Generalized convulsion: Seizures are episodes of neuronal hyperactivity most 
commonly resulting in sudden, involuntary muscular contractions. They may also 
manifest as sensory disturbances, autonomic dysfunction and behavioral abnormalities, 
and impairment or loss of consciousness.
Guillain-Barré syndrome: GBS is a peripheral nerve demyelinating disease, which can 
present as temporary ascending paralysis.
Acute disseminated encephalomyelitis: ADEM is defined as a uniphasic syndrome of 
brain inflammation and demyelination occurring in temporal association with an 
antecedent immunologic challenge, such as infection or an immunization. ADEM most 
commonly occurs in the pediatric population.
Other neurologic events: These events would include new onset event (acute or 
subacute) motor and sensory disturbances (eg, weakness, numbness, paresthesias, 
hypoesthesia, hyperesthesia, dysesthesias), bowel/bladder dysfunction, gait 
impairment, or visual disturbance, or any event of myelitis, encephalomyelitis, myelitis 
transverse, or other sudden neurological deficit.
Vascular
Thrombotic, thromboembolic, and neurovascular events: These are events that can 
manifest as transient or permanent vision problems, dizziness, trouble understanding, 
facial droop, slurred speech, unilateral weakness, deep vein thrombosis with swollen, 
warm or painful leg, pulmonary embolism with shortness of breath, chest pain or 
irregular heart rate
Hematologic
Thrombocytopenia: Thrombocytopenia is a disorder in which there is an abnormally 
low platelet count; a normal platelet count ranges from 150 000 to 450 000 platelets 
per μL.
Immunologic
Vasculitides: Vasculitides are a group of related disorders characterized by 
inflammation of blood vessels (vasculitis) leading to tissue or end-organ injury.
Anaphylaxis: Anaphylaxis an acute hypersensitivity reaction with multi-organ-system 
involvement that can present as, or rapidly progress to, a severe life-threatening 
reaction requiring immediate medical attention.


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AESI
Medical Concept
Immunologic 
(Continued)
Vaccine-associated enhanced respiratory disease: The pathogenicity of VAERD has 
been linked to a vaccine immune response characterized by induction of 
non-neutralizing antibodies, and a T-cell response of the Th2 type with 
hypereosinophilia (Lambert et al 2020). VAERD may manifest as a severe form of 
respiratory disease with prolonged fever, and diverse clinical manifestations of disease 
severity and pathological changes marked by increased areas of lung consolidation, 
broncho-interstitial pneumonia, and necrotizing bronchiolitis (Rajão et al 2016).
Potential immune-mediated conditions: These conditions are a group of autoimmune 
inflammatory disorders characterized by an alteration in cellular homeostasis, which 
may or may not have an autoimmune aetiology. A list of events is provided in 
Table 12. 
ADEM = acute disseminated encephalomyelitis; AESI = adverse event of special interest; GBS = Guillain-
Barré syndrome; VAERD = vaccine-associated enhanced respiratory disease.


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Table 12
List of Potential Immune-mediated Medical Conditions
Category
Condition
Gastrointestinal disorders
Celiac disease
Crohn’s disease
Ulcerative colitis
Ulcerative proctitis
Liver disorders
Autoimmune cholangitis
Autoimmune hepatitis
Primary biliary cirrhosis
Primary sclerosing cholangitis
Metabolic diseases
Addison’s disease
Autoimmune thyroiditis (including Hashimoto thyroiditis)
Diabetes mellitus type I
Grave's or Basedow’s disease
Musculoskeletal disorders
Antisynthetase syndrome
Dermatomyositis
Juvenile chronic arthritis (including Still’s disease)
Mixed connective tissue disorder
Polymyalgia rheumatic
Polymyositis
Psoriatic arthropathy
Relapsing polychondritis
Rheumatoid arthritis
Scleroderma, including diffuse systemic form and CREST syndrome
Spondyloarthritis, including ankylosing spondylitis, reactive arthritis 
(Reiter's Syndrome) and undifferentiated spondyloarthritis
Systemic lupus erythematosus
Systemic sclerosis


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Category
Condition
Neuroinflammatory disorders
Acute disseminated encephalomyelitis, including site specific variants 
(eg, non-infectious encephalitis, encephalomyelitis, myelitis, 
radiculomyelitis)
Cranial nerve disorders, including paralyses/paresis (eg, Bell’s palsy)
Guillain-Barré syndrome, including Miller Fisher syndrome and other 
variants
Immune-mediated peripheral neuropathies and plexopathies, including 
chronic inflammatory demyelinating polyneuropathy, multifocal motor 
neuropathy and polyneuropathies associated with monoclonal 
gammopathy
Multiple sclerosis
Neuromyelitis optica spectrum disorder
Narcolepsy
Optic neuritis
Transverse myelitis
Myasthenia gravis, including Eaton-Lambert syndrome
Skin disorders
Alopecia areata
Autoimmune bullous skin diseases, including pemphigus, pemphigoid and 
dermatitis herpetiformis
Cutaneous lupus erythematosus
Erythema nodosum
Morphoea
Lichen planus
Psoriasis
Rosacea
Sweet’s syndrome
Vitiligo
Vasculitides
Large vessels vasculitis including: giant cell arteritis such as Takayasu's 
arteritis and temporal arteritis
Medium sized and/or small vessels vasculitis including: polyarteritis 
nodosa, Kawasaki's disease, microscopic polyangiitis, Wegener's 
granulomatosis, Churg– Strauss syndrome (allergic granulomatous 
angiitis), Buerger’s disease, thromboangiitis obliterans, necrotizing 
vasculitis and anti-neutrophil cytoplasmic antibody (ANCA) positive 
vasculitis (type unspecified), Henoch-Schonlein purpura, Behcet's 
syndrome, leukocytoclastic vasculitis


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Category
Condition
Other
Antiphospholipid syndrome
Autoimmune hemolytic anemia
Autoimmune glomerulonephritis (including IgA nephropathy, 
glomerulonephritis rapidly progressive, membranous glomerulonephritis, 
membranoproliferative glomerulonephritis, and mesangioproliferative 
glomerulonephritis)
Autoimmune myocarditis/cardiomyopathy
Autoimmune thrombocytopenia
Goodpasture syndrome
Idiopathic pulmonary fibrosis
Pernicious anemia
Raynaud’s phenomenon
Sarcoidosis
Sjögren’s syndrome
Stevens-Johnson syndrome
Uveitis


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Appendix F
Abbreviations
Abbreviation or special 
term
Explanation
β-hCG
beta human chorionic gonadotropin
ACE2
angiotensin-converting enzyme 2
ADEM
acute disseminated encephalomyelitis
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BMI
body-mass index
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CONSORT
Consolidated Standards of Reporting Trials
CSR
Clinical Study Report
E
envelope (protein)
eCRF
electronic Case Report Form
ELISA
enzyme-linked immunosorbent assay
FDA
United States Food and Drug Administration
FVS
Fully vaccinated analysis set
GCP
Good Clinical Practice
GMFR
geometric mean fold rise
GMT
geometric mean titre
HIPAA
Health Insurance Portability and Accountability Act
IB
Investigator’s Brochure
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IM
intramuscular
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
IV
intravenous


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Abbreviation or special 
term
Explanation
M
membrane (protein)
MERS
Middle East respiratory syndrome
MSD
Meso Scale Discovery
N
nucleocapsid (protein)
nAb
neutralising antibody
NHP
non-human primate
PI
Principal investigator 
RBD
receptor-binding domain
RT-PCR
reverse transcriptase-polymerase chain reaction
RTSM
Randomisation and Trial Supply Management
S
Spike (protein)
SAE
serious adverse event 
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome-coronavirus 2
SoA
Schedule of Activities
SUSAR
suspected unexpected serious adverse reaction
TBL
total bilirubin
TVS
Total vaccinated analysis set
tPA
tissue plasminogen activator
ULN
upper limit of normal
VAERD
vaccine-associated enhanced respiratory disease.
vp
viral particles
WHO
World Health Organization


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Appendix G
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Amendment 2 (19-November-2020)
Overall Rationale for the Amendment:
The major reasons for this amendment were to expand AESI evaluation, add secondary 
immunogenicity objective and endpoint, revise the analysis sets and statistical analyses, and 
add an independent Neurological AESI Expert Committee. Other key revisions included 
updating the AZD1222 safety profile.
Section # and 
Name
Description of Change
Brief Rationale
Title Page
Added ClinicalTrials.gov number
To align with updated 
information
1.1 Synopsis
The synopsis was updated to align with changes to the 
body of the protocol.
To ensure consistency 
between the protocol and the 
Synopsis.
2.2 Background
Updated information on the nonclinical and clinical 
AZD1222 development program
To align with information in 
the updated AZD1222 IB
2.3.1 Risk 
Assessment
Revised important potential risks
3 Objectives and 
Endpoints
Added secondary immunogenicity endpoints.
To aligned with protocol 
D8110C00001
3 Objectives and 
Endpoints
Added the term of “receptor-binding domain (RBD)” 
for secondary immunogenicity objective and 
endpoints.
To align with protocol 
D8110C00001.
3 Objectives and 
Endpoints
Added geometric mean fold rise (GMFR) for 
secondary immunogenicity endpoints.
To align with protocol 
D8110C00001.
3 Objectives and 
Endpoints
Removed ‘throughout the study duration up to Day 
365’ from exploratory efficacy endpoints.
The analysis of exploratory 
efficacy will be based on 
different periods throughout 
the study.
4.1
Overall Design
Added a description of the independent Neurological 
AESI Expert Committee
New committee to provide 
advice on selected 
neurological AESIs


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Section # and 
Name
Description of Change
Brief Rationale
8.1 Descriptive 
Efficacy 
Assessment
Removed ‘throughout the study duration up to Day 
365’ from exploratory efficacy endpoints.
The analysis of exploratory 
efficacy will be based on 
different periods throughout 
the study.
8.3.8 Adverse 
Events of Special 
Interest
Expanded the AESI list and specified that AESIs will 
be reported to the Sponsor within one day of 
becoming aware of the event
To permit close monitoring 
and rapid communication of 
safety information, and 
further understanding of the 
AZD1222 safety profile
8.3.8.1 Potential 
Neurological AESIs
New section for evaluation of potential neurological 
AESIs
For additional safety 
monitoring
9.3 Populations for 
Analyses
Refined definition for analysis populations. 
To fine tune the definition for 
analysis populations.
9.4.1
General 
Considerations
Changed analysis set for demography and baseline 
characteristics to “total vaccinated analysis set (TVS) 
and fully vaccinated analysis set (FVS) for efficacy” 
form safety analysis set.
To fine tune the definition for 
analysis populations.
9.4.2
Efficacy (Including 
Immunogenicity)
Added general information of analysis for efficacy 
including Immunogenicity.
To summarise analysis for 
efficacy including 
Immunogenicity.
9.4.2.1
Primary Endpoint(s)
Added “Fisher’s exact test will not be presented for 
Subcohorts D1 and D2”.
To clarify which cohorts will 
be used for analysis.
9.4.2.1
Primary Endpoint(s)
Removed description of participants to be excluded 
from analyses of immunogenicity.
This description is added to 
the newly defined analysis set 
and no longer required in this 
context.
9.4.2.2 Secondary 
Endpoint
Added secondary immunogenicity endpoints.
To align with protocol 
D8110C00001.
9.4.2.2 Secondary 
Endpoint
Added geometric mean fold rise (GMFR) for 
secondary immunogenicity endpoints.
To align with protocol 
D8110C00001.
9.4.2.2 Secondary 
Endpoint
Added the term of “receptor-binding domain (RBD)” 
for secondary immunogenicity objective and endpoint.
To align with protocol 
D8110C00001.
9.4.2.3 Exploratory 
Efficacy Analyses
Moved Section 9.4.4 to this new section and removed 
‘throughout the study duration up to Day 365’ from 
exploratory efficacy endpoints. Also added 
information for analysis to be conducted post first 
dose of study intervention or occurring ≥ 15 days post 
second dose of study intervention
The analysis of exploratory 
efficacy is better fitted in this 
section, and analysis will be 
based on different periods 
throughout the study.
9.5 Subgroup 
Analyses
New section added for subgroup analyses.
To align with protocol 
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Section # and 
Name
Description of Change
Brief Rationale
Appendix A5 
Committee 
Structure
Added a description of the independent Neurological 
AESI Expert Committee
New committee to provide 
advice on selected 
neurological AESIs
Appendix D
Toxicity Grading 
Scales for Solicited 
Adverse Events
Changed the temperature of mild fever in Table 9 to 
37.9.
To align with protocol 
D8110C00001.
Appendix E
Adverse Events of 
Special Interest 
a)
Expanded the AESI list and provided a 
description of the events
b)
Added new table listing potential immune-
mediated conditions to provide more detail on 
this new AESI 
To permit close monitoring 
and rapid communication of 
safety information and further 
understand the AZD1222 
safety profile
Amendment 1: (13-August-2020)
Overall Rationale for the Amendment
The main changes are to change the vaccination regimen. The regimen of single intramuscular 
(IM) dose of either AZD1222 or placebo was removed and the regimen of 2 IM doses of either 
AZD1222 or placebo was only adopted. The cohorts with different age populations are 
Cohorts C and D, Subcohorts D1 and D2. Cohorts A and B, Subcohorts B1 and B2 were 
removed.
Section # and 
Name
Description of Change
Brief Rationale
1.1
Synopsis
The synopsis was updated to align with changes to the 
body of the protocol.
To ensure consistency 
between the protocol and the 
Synopsis.
1.2
Schema
The part of single dose was removed, and the number 
of participants was changed. 
To change the study design.
1.3
Schedule of 
Activities
The table of “Schedule of Activities (Part I, Single 
Dose)” was removed.
To change the study design.
1.3
Schedule of 
Activities
The description of the way of eDiary provision was 
added in a footnote.
To clarify the way of
providing eDiary.
2.2
Background
The description of other studies was updated according 
to the updated information in Investigator’s Brochure.
To update the other studies 
information.
2.3.1
Risk Assessment
The description of other studies was updated according 
to the updated information in Investigator’s Brochure.
To update the other studies 
information.


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Section # and 
Name
Description of Change
Brief Rationale
3
OBJECTIVES 
AND ENDPOINTS
The description of objectives and endpoints for single 
dose was removed.
To change the study design.
3
OBJECTIVES 
AND ENDPOINTS
For primary immunogenicity endpoint, the description 
of the proportion of participants who have a post 
treatment seroresponse to Spike antigen of AZD1222 at 
Day 29 was removed.
To change the study design.
3
OBJECTIVES 
AND ENDPOINTS
For primary safety endpoint, the endpoint after single 
dose was removed.
To change the study design.
3
OBJECTIVES 
AND ENDPOINTS
The objective of “(2 dose schedules for Part II only) To 
assess the safety of a booster dose of AZD1222” was 
removed.
To change the study design.
3
OBJECTIVES 
AND ENDPOINTS
For the primary safety endpoint for 28 days following 
throughout vaccination, the occurrence of SAEs and 
AESIs was added.
To change the study design.
3
OBJECTIVES 
AND ENDPOINTS
For secondary immunogenicity endpoint, the
description of the proportion of participants who have a 
post treatment seroresponse to AZD1222 as measured 
by SARS-CoV-2 nAb at Day 29 was removed.
To change the study design.
3
OBJECTIVES 
AND ENDPOINTS
The description of exploratory objectives and endpoints
was changed.
To change the study design.
4.1
Overall Design
The number of participants with single dose and the 
method of randomization were removed.
To change the study design.
4.1
Overall Design
“128 eligible participants” was changed to “256 
eligible participants”.
To change the study design.
4.1.2
Vaccination Visit
The method of randomization of participants with 
single dose was removed.
To change the study design.
4.1.2
Vaccination Visit
Thermometer given to participants was change from 
“oral thermometer” to “axillary thermometer”.
To change the device.
4.1.3
Subsequent Visits
The transition from double blind to open-label and the 
timing of unblind were changed.
To change the study design.
4.1.3
Subsequent Visits
The timing when participants in placebo group may 
receive licensed vaccine was mentioned.
To change the study design.
4.4
End of Study 
Definition
The description of “(which will differ for participants 
randomised to AZD1222 and to placebo)” was 
removed.
To change the study design.
5.2
Exclusion Criteria
The timing when participants in placebo group may 
receive licensed vaccine was mentioned.
To change the study design.


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Section # and 
Name
Description of Change
Brief Rationale
6.3.2
Blinding
The transition from double blind to open-label and the 
timing of unblind were changed.
To change the study design.
6.3.2
Blinding
The timing when participants in placebo group may 
receive licensed vaccine was mentioned.
To change the study design.
6.5.2
Prohibited 
Concomitant 
Medications
The timing when participants in placebo group may 
receive licensed vaccine was mentioned.
To change the study design.
7.1
Discontinuation of 
Study Intervention
The description of (which is a shorter period for those 
randomised to placebo)” was removed.
To change the study design.
8
STUDY 
ASSESSMENTS 
AND 
PROCEDURES
The amount of blood collection of single dose was 
removed.
To change the study design.
8.1
Descriptive Efficacy 
Assessments
The description of exploratory objectives and endpoints
was changed.
To change the study design.
8.3.7
Solicited Adverse 
Events
Thermometer given to participants was change from 
“oral thermometer” to “axillary thermometer”.
To change the device.
9.1
Statistical 
Hypotheses
The primary immunogenicity endpoint at Day 29 was 
removed.
To change the study design.
9.2
Sample Size 
Determination
The number of participants in Cohorts C and D was 
changed from 64 to 128. The number of participants 
with AZD1222 was changed from 48 to 96, and 
participants with placebo was changed from 16 to 32 
within each cohort. In addition, the sample size 
determination of these participants was updated.
To change the study design.
9.4.1
General 
Considerations
The timing of database lock for single dose was 
removed and the transition from double blind to open-
label was changed.
To change the study design.
9.4.2.1
Primary Endpoint(s)
For primary immunogenicity endpoint, the description 
of the proportion of participants who have a post 
treatment seroresponse to Spike antigen of AZD1222 at 
Day 29 was removed.
To change the study design.
9.4.2.2
Secondary Endpoint
For secondary immunogenicity endpoint, the
description of the proportion of participants who have a 
post treatment seroresponse to AZD1222 as measured 
by SARS-CoV-2 nAb at Day 29 was removed.
To change the study design.


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Section # and 
Name
Description of Change
Brief Rationale
9.4.3.1
Primary Endpoints
For the primary safety endpoint for 28 days following 
vaccination, the occurrence of SAEs and AESIs was 
added.
To change the study design.
9.4.4
Exploratory 
Efficacy Analyses
The description of exploratory endpoints was changed.
To change the study design.


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11
REFERENCES
FDA. (Food and Drug Administration). Guidance for Industry. Toxicity grading scale for 
healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials. 
https://www.fda.gov/media/73679/download. Published 2007. Accessed 20 June 2020.
Folegatti PM, Bittaye M, Flaxman A, Lopez FR, Bellamy D, Kupke A et al. Safety and 
immunogenicity of a candidate Middle East respiratory syndrome coronavirus viral-vectored 
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Lancet Infectious Diseases. 2020;20(7):816-26.
Folegatti PM, Ewer KJ, Aley PK, Angus B, Becker S, Belij-Rammerstorfer S et al. Safety and 
immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary 
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Graham SP, McLean RK, Spencer AJ, Belij-Rammerstorfer S, Wright D, Ulaszewska M et al. 
Evaluation of the immunogenicity of prime-boost vaccination with the replication-deficient 
viral vectored COVID-19 vaccine candidate ChAdOx1 nCoV-19. npj Vaccines. 2020;5(1):69.
Lambert P-H, Ambrosino DM, Andersen SR, Baric RS, Black SB, Chen RT et al. Consensus 
summary report for CEPI/BC March 12–13, 2020 meeting: Assessment of risk of disease 
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Li F. Structure, Function, and Evolution of Coronavirus Spike Proteins. Annual review of 
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Lu R, Zhao X, Li J, Niu P, Yang B, Wu H et al. Genomic characterisation and epidemiology 
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(London, England). 2020;395(10224):565-74.
Rajão DS, Chen H, Perez DR, Sandbulte MR, Gauger PC, Loving CL et al. Vaccine-
associated enhanced respiratory disease is influenced by haemagglutinin and neuraminidase in 
whole inactivated influenza virus vaccines. The Journal of general virology. 2016;97(7):1489-
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Rovira À, Wattjes MP, Tintoré M, Tur C, Yousry TA, Sormani MP et al. MAGNIMS 
consensus guidelines on the use of MRI in multiple sclerosis—clinical implementation in the 
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SPEAC. (Safety Platform for Emergency Vaccines) D2.3 Priority list of adverse events of 
special interest: COVID-19. Work Package: WP2 Standards and Tools. v1.1. 05 March 2020. 
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van Doremalen N, Lambe T, Spencer A, Belij-Rammerstorfer S, Purushotham JN, Port JR et 
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SAP_001.pdf: 
AstraZeneca
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Statistical Analysis Plan
Page 1 of 59
STATISTICAL ANALYSIS PLAN
D8111C00002
A PHASE I/II RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
MULTICENTRE STUDY IN PARTICIPANTS AGED 18 YEARS OR OLDER 
TO DETERMINED THE SAEFTY AND IMMUNOGENICITY OF AZD1222, A 
NON-REPLICATING 
CHADOX1
VECTOR 
VACCINE,
FOR 
THE 
PREVENTION OF COVID-19
AUTHOR:
VERSION NUMBER AND DATE: V3.0, 9DEC2021
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE
Statistical Analysis Plan v3.0 (dated 9Dec2021) for protocol D8111C00002.
Name
Signature
Date (DDMmmYYYY)
Author:
Refer to eSignature
Position:
Company:
IQVIA
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this study.
Name
Signature
Date (DDMmmYYYY)
Approved by:
Refer to eSignature
Position:
Senior Statistician
Company:
AstraZeneca
Approved by:
Refer to eSignature
Position:
Global Product Statistician
Company:
AstraZeneca
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Statistical Analysis Plan
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MODIFICATION HISTORY
Unique 
Identifier for 
this Version
Date of the 
Document 
Version
Author
Significant Changes from 
Previous Version
1.0
29Oct2020
Not Applicable – First Version
1.1
28Dec2020
Section 1
- Updated protocol version.
Section 2.2
- Added the objective to assess antibody 
responses to AZD1222 RBD antigen.
Section 3.3
- Removed previously added items, and 
updated this to ‘There is no changes to the 
analyses planned in the protocol’.
Section 4.3 to Section 4.5
- Updated the defintions for primary and final 
analyses.
- Added a additional analysis. 
Section 7.1
- Updated this section as per latest protocl 
amendment update.
Section 9.1
- Added new analyses of: number of 
participants with at least 28 days follow-up 
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post 1st dose; number of participants who 
received 1st dose and discontinued from study 
intervention and discontinued from study, or 
remained in study follow up or completed 
study.
Section 16.2.1
-Updated the calculation of GMT and GMFR 
to be based on log base 2 transformation of 
titer.
Section 17.1.2.3
- Added a new analysis of AESIs by 
relationship to study intervention.
APPENDIX 4
- The lower bound of mild fever is updated 
from 38.0 °C to 37.9 °C.
1.2
18Jan2021
Section 3.1
- Added a brief description for timing of 
primary analysis.
Section 3.3
- Solicited AEs to be analyzed between Day 1-
7 and Day 29 – 35.
Section 16.1.3
- Added a definition for P used in hypotheses.
Section 17.1.2.4
- Updated analysis for solicited AEs to be 
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presented for 7 days.
Section 17.5
- Updated section title from ‘Other Safety 
Assessments’ to ‘Immunologic Responses’.
2.0
20Jan2021
Section 1
- Updated the protocol amendment date.
Section 17.5.1
- Updated sub-header to ‘Neutralizing 
Antibodies: Immunoglobulins G and M’.
2.1
4Nov2021
Section 1
- Added text to explain that updates to this 
latest version apply to Final Analysis.
Section 7.10, Section 16.2.5, Section 16.3.4
and Section 17.1.1.3
- Added new sections to explain data handling 
for subjects who were inoculated with 
non-study COVID-19 vaccine.
Section 16.3.1.1
- Added a new censor derivation for subjects 
who were inoculated with non-study COVID-
19 vaccine. 
Various sections
- Added a paragraph to explain whether the 
analysis will be included in the Final Analysis.
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2.2
9Nov2021
Section 17.1.1.3
Added new AE analyses for subjects who were 
inoculated with non-study COVID-19 vaccine 
that only include AE data that started post 
inoculation of non-study COVID-19 
vaccination.
3.0
9Dec2021
Final version
PPD
PPD
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TABLE OF CONTENTS
1.
INTRODUCTION .........................................................................................................12
2.
STUDY OBJECTIVES .................................................................................................12
2.1.
Primary Objectives ................................................................................................................................. 12
2.2.
Secondary Objectives.............................................................................................................................. 12
2.3.
Exploratory Objectives........................................................................................................................... 13
3.
STUDY DESIGN ...........................................................................................................13
3.1.
General Description ................................................................................................................................ 13
3.2.
Schedule of Events .................................................................................................................................. 14
3.3.
Changes to Analyses from Protocol ........................................................................................................ 14
4.
PLANNED ANALYSES................................................................................................14
4.1.
Data Monitoring Committee................................................................................................................... 14
4.2.
Interim Analysis...................................................................................................................................... 14
4.3.
Primary Analysis..................................................................................................................................... 14
4.4.
Additional Analysis................................................................................................................................. 15
4.5.
Final Analysis.......................................................................................................................................... 15
5.
ANALYSIS SETS..........................................................................................................15
5.1.
All Participants Analysis Set................................................................................................................... 15
5.2.
Total Vaccinated Analysis Set................................................................................................................. 15
5.3.
Fully Vaccinated Analysis Set for Immunogenicity................................................................................ 16
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5.4.
Fully Vaccinated Analysis Set for Efficacy............................................................................................. 16
6.
GENERAL CONSIDERATIONS.................................................................................16
6.1.
Reference Start Date and Study Day...................................................................................................... 16
6.2.
Baseline ................................................................................................................................................... 17
6.3.
Unscheduled Visits, and Early Termination Data.................................................................................. 17
6.4.
Windowing Conventions......................................................................................................................... 17
6.5.
Common Calculations............................................................................................................................. 18
7.
STATISTICAL CONSIDERATIONS..........................................................................18
7.1.
Sample Size Calculation.......................................................................................................................... 19
7.2.
Missing Data............................................................................................................................................ 19
7.3.
Statistical Tests........................................................................................................................................ 20
7.4.
Multiple Comparisons/ Multiplicity ....................................................................................................... 20
7.5.
Multicenter Studies................................................................................................................................. 20
7.6.
Adjustments for Covariates and Factors to be Included in Analyses .................................................... 20
7.7.
Examination of Subgroups...................................................................................................................... 20
7.8.
Analysis by Cohort.................................................................................................................................. 21
7.9.
Software Version..................................................................................................................................... 21
7.10.
Subjects who Were Inoculated with Non-Study COVID-19 Vaccine..................................................... 21
8.
OUTPUT PRESENTATIONS ......................................................................................21
9.
DISPOSITION AND WITHDRAWALS......................................................................21
9.1.
Disposition............................................................................................................................................... 22
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9.2.
Protocol Deviations ................................................................................................................................. 23
10.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.......................23
10.1.
Derivations .............................................................................................................................................. 24
11.
MEDICAL HISTORY...................................................................................................24
12.
CONCOMITANT ILLNESSES....................................................................................24
13.
MEDICATIONS............................................................................................................25
14.
EXPOSURE TO STUDY INTERVENTION ...............................................................26
15.
COMPLIANCE WITH STUDY INTERVENTION ....................................................26
16.
EFFICACY ENDPOINTS (INCLUDING IMMUNOGENICITY).............................26
16.1.
Primary Immunogenicity........................................................................................................................ 26
16.1.1.
Primary Immunogenicity Endpoint .................................................................................................... 26
16.1.2.
Data Imputation Method for Primary Immunogenicity Endpoint......................................................... 26
16.1.3.
Primary Analysis of Primary Immunogenicity Endpoint..................................................................... 27
16.1.3.1.
Subgroup analysis for immunogenicity....................................................................................... 27
16.1.4.
Sensitivity Analyses for Primary Immunogenicity Endpoint............................................................... 27
16.2.
Secondary Immunogenicity .................................................................................................................... 28
16.2.1.
GMTs and GMFRs............................................................................................................................ 28
16.2.1.1.
Subgroup analysis for immunogenicity....................................................................................... 29
16.2.2.
Seroresponse Rate ............................................................................................................................. 29
16.2.2.1.
Subgroup analysis for seroresponse rate ..................................................................................... 29
16.2.3.
Data Imputation Method for Secondary Immunogenicity Endpoints ................................................... 29
16.2.4.
Sensitivity Analyses for Secondary Immunogenicity Endpoint ........................................................... 30
16.2.5.
Data Handling for Subjects Inoculated with Non-Study COVID-19 Vaccine....................................... 30
16.3.
Exploratory Efficacy............................................................................................................................... 30
16.3.1.
Exploratory Efficacy Endpoints......................................................................................................... 30
16.3.1.1.
Virologically confirmed (RT-PCR positive) symptomatic cases of COVID-19............................ 30
16.3.1.2.
Hospital admission associated with COVID-19 .......................................................................... 32
16.3.1.3.
Intensive care unit admissions associated with COVID-19.......................................................... 33
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16.3.1.4.
Deaths associated with COVID-19............................................................................................. 33
16.3.1.5.
Seroresponse against non-Spike (nucleocapsid) SARS-CoV-2 antigens (MSD serology assay).... 33
16.3.2.
Data Imputation Method for Exploratory Efficacy Endpoints ............................................................. 34
16.3.3.
Sensitivity Analyses for Exploratory Efficacy Endpoints.................................................................... 34
16.3.4.
Data Handling for Subjects Inoculated with Non-Study COVID-19 Vaccine....................................... 34
17.
SAFETY ENDPOINTS .................................................................................................34
17.1.
Adverse Events........................................................................................................................................ 35
17.1.1.
All Adverse Events............................................................................................................................ 35
17.1.1.1.
Severity grading for AEs............................................................................................................ 35
17.1.1.2.
Relationship to study intervention .............................................................................................. 35
17.1.1.3.
Data Handling for Subjects Inoculated with Non-study COVID-19 Vaccine................................ 36
17.1.2.
Primary Safety Endpoints .................................................................................................................. 36
17.1.2.1.
Occurrence of unsolicited AEs for 28 days following throughout vaccination ............................. 36
17.1.2.2.
Occurrence of serious AEs for 28 days following throughout vaccination ................................... 37
17.1.2.3.
Occurrence of Adverse Events of Special Interest for 28 days following throughout vaccination . 37
17.1.2.4.
Occurrence of solicited AEs for 7 days following throughout vaccination ................................... 37
17.1.3.
Secondary Safety Endpoints .............................................................................................................. 39
17.1.3.1.
Occurrence of serious AEs throughout the study duration up to Day 365..................................... 39
17.1.3.2.
Occurrence of AESIs throughout the study duration up to Day 365............................................. 39
17.1.4.
Other Adverse Event Safety Endpoints .............................................................................................. 39
17.1.4.1.
Adverse Events with an Outcome of Death................................................................................. 39
17.1.4.2.
AEs Leading to Discontinuation of Study Intervention ............................................................... 39
17.2.
Laboratory Evaluations .......................................................................................................................... 40
17.2.1.
Laboratory Toxicity Grades............................................................................................................... 40
17.3.
Vital Signs ............................................................................................................................................... 41
17.4.
Physical Examination.............................................................................................................................. 41
17.5.
Immunologic Responses.......................................................................................................................... 42
17.5.1.
Neutralizing Antibodies: Immunoglobulin G and M Antibodies ......................................................... 42
18.
REFERENCES..............................................................................................................43
APPENDIX 1.
PARTIAL DATE CONVENTIONS............................................................44
Algorithm for Prior / Concomitant Medications ............................................................................................... 44
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APPENDIX 2.
PROGRAMMING CONVENTIONS FOR OUTPUTS .............................47
Dates & Times .................................................................................................................................................... 47
Spelling Format.................................................................................................................................................. 47
Paper Size, Orientation, and Margins................................................................................................................ 47
Fonts 47
Presentation of Treatment Groups .................................................................................................................... 47
Presentation of Nominal Visits........................................................................................................................... 48
Descriptive Statistics........................................................................................................................................... 49
Percentages......................................................................................................................................................... 49
p-values............................................................................................................................................................... 49
Listings ............................................................................................................................................................... 49
APPENDIX 3.
TABLES FOR CLINICAL ABNORMALITIES: LOCAL REACTIONS 
TO INJECTABLE PRODUCT ..............................................................................................51
APPENDIX 4.
TABLES FOR CLINICAL ABNORMALITIES: VITAL SIGNS.............52
APPENDIX 5.
TABLES FOR CLINICAL ABNORMALITIES: SYSTEMIC (GENERAL 
OR ILLNESS) 53
APPENDIX 6.
LABORATORY ASSESSMENTS..............................................................54
APPENDIX 7.
TABLES FOR LABORATORY ABNORMALITIES ...............................55
APPENDIX 8.
ABBREVIATIONS......................................................................................57
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1. INTRODUCTION
This statistical analysis plan (SAP) describes the rules and conventions to be used in the presentation and analysis of 
efficacy (including immunogenicity) and safety data for protocol D8111C00002. It describes the data to be 
summarized and analyzed, including specifics of the statistical analyses to be performed. 
This SAP is based on protocol amendment 3, dated 18 January 2021.
This SAP is updated post Primary and Additional Analyses, and prior to database lock for the Final Analysis. All 
changes made to this version of the SAP are marked in italics. 
2. STUDY OBJECTIVES
2.1.
PRIMARY OBJECTIVES
The primary objectives are:
!
To assess antibody responses to AZD1222 Spike antigen following 2 intramuscular (IM) doses of AZD1222 or 
placebo.
!
To assess the safety, tolerability, and reactogenicity profile of the candidate vaccine AZD1222.
2.2.
SECONDARY OBJECTIVES
The secondary objectives are:
!
To assess antibody responses to AZD1222 receptor-binding domain (RBD) antigen following 2 IM doses of 
AZD1222 or placebo.
!
To assess time course of antibody to AZD1222 Spike and RBD antigens of AZD1222 (Meso Scale Discovery 
[MSD] serology assay).
!
To assess the function of neutralizing antibody (nAb) against severe acute respiratory syndrome-coronavirus 2 
(SARS-CoV-2) spike protein.
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!
To assess the safety of the candidate vaccine AZD1222.
2.3.
EXPLORATORY OBJECTIVES
The exploratory objectives are:
!
To describe occurrence of symptomatic Coronavirus Disease 2019 (COVID-19) in recipients of AZD1222 and 
placebo.
!
To describe occurrence of severe COVID-19 and seroresponse to non-Spike SARS-CoV-2 antigens.
3. STUDY DESIGN
3.1.
GENERAL DESCRIPTION
This is a multicentre, randomised, double-blind, parallel-group, placebo-controlled, 52-week Phase I/II study. In this 
study, 256 eligible participants will be randomised in a 3:1 ratio to receive 2 IM doses of either AZD1222 with 
5 × 1010 viral particles (vp) (nominal) or placebo administered 4 weeks apart.
The study has 2 cohorts with different age populations. Cohort C will include healthy participants aged 18 to 55 
years. Cohort D will include healthy elderly participants aged ≥ 56 years. In Cohort D, the elderly population is 
further divided into 2 different age subgroups; aged 56 to 69 years (Subcohort D1) and aged ≥ 70 years (Subcohort 
D2). At least 30% of participants in Cohort D will be secured for participants with age ≥ 70 years. Regarding 
Cohorts C and D, 128 participants will be randomised in a 3:1 ratio to receive either AZD1222 or placebo within 
each cohort.
After completion of clinical data lock for primary analysis, 57 days after first vaccination and 28 days after second 
vaccination, the study will become single blind, where only participants are blinded from allocation of 
investigational product. All participants will be unblinded and participants on the placebo arm may be vaccinated 
when a licensed vaccine for COVID-19 becomes available in Japan for the general population.
Table A:
Study Design
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3.2.
SCHEDULE OF EVENTS
Schedule of events can be found in protocol Section 1.3.
3.3.
CHANGES TO ANALYSES FROM PROTOCOL
It is defined in protocol that the incidence of local and systemic solicited reactogenicity signs and symptoms are to 
be collected for 7 days following throughout vaccination from Day 1 to 8 and Day 29 to 36. This has been updated 
in Section 17.1.2.4 to present solicited AEs collected in eDiary for 7 days, from Day 1 to 7 and Day 29 to 35. Date 
of agreement of change is 15 Jan 2021, during meeting discussion between IQVIA and AstraZeneca statistical team.  
4. PLANNED ANALYSES
4.1.
DATA MONITORING COMMITTEE
There will be no Data Monitoring Committee for this study.
4.2.
INTERIM ANALYSIS
There will be no interim analysis for this study.
4.3.
PRIMARY ANALYSIS
The primary analysis will include immunogenicity data up to Day 57 from participants enrolled before the study 
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interruption and safety data gathered in all participants up to Day 57.
All planned primary analyses identified in this SAP (exept for exploratory efficacy analysis, which will only be 
performed at final analysis) will be performed by IQVIA Biostatistics following Sponsor authorization of this SAP, 
Sponsor authorization of the analysis sets, clinical data lock, and general study unblinding.
4.4.
ADDITIONAL ANALYSIS
The additional analysis will include immunogenicity data in all participants up to Day 57.
Immunogenicity analyses performed at primary analysis will be repeated for all participants up to Day 57. These 
analyses will be performed by IQVIA Biostatistics.  The Sponsor authorization of the SAP, Sponsor authorization of 
the analysis sets, clinical data lock, and general study unblinding will be performed at primary analysis and not at 
the timing of additional analysis.
4.5.
FINAL ANALYSIS
The final analysis will include all endpoints up to Day 365 in all participants.
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics following Sponsor 
authorization of this SAP, Sponsor authorization of the analysis sets, and clinical data lock.
5. ANALYSIS SETS
5.1.
ALL PARTICIPANTS ANALYSIS SET
The all participants analysis set will contain all participants screened who signed informed consent form for the 
study, to be used for reporting disposition and screening failures.
5.2.
TOTAL VACCINATED ANALYSIS SET
The total vaccinated analysis set (TVS) will contain all participants who received at least one dose of study 
intervention. Erroneously vaccinated participants (eg, those randomised to placebo treatment but were actually given 
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active vaccine treatment) are accounted for in this analysis set by assigning them to the treatment they actually 
received.
This analysis set will be used for the analysis of safety, exploratory efficacy and immunogenicity endpoints.
5.3.
FULLY VACCINATED ANALYSIS SET FOR IMMUNOGENICITY
The fully vaccinated analysis set (FVS) for immunogenicity will include all participants in the TVS who have 
received two doses of study intervention and have no important protocol deviations judged to have the potential to 
interfere with the generation or interpretation of immune responses. Protocol deviations will be reviewed by the 
study team before unblinding to determine exclusion from the immunogenicity. Participants who have a post-
baseline seroresponse (≥ 4 fold rise in titers from Day 1 baseline value) to nucleocapsid antibodies by MSD serology 
assay at post-baseline up to Day 57 will be excluded from this analysis set.
This analysis set will be used for the analysis of immunogenicity endpoints. 
5.4.
FULLY VACCINATED ANALYSIS SET FOR EFFICACY
The fully vaccinated analysis set (FVS) for efficacy will include all participants in the TVS who have received two
doses of study intervention, and who remain on-study 15 days after their second dose without having had a prior 
SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR) positive confirmed COVID-19 infection.
This analysis set will be used for applicable exploratory endpoints.
6. GENERAL CONSIDERATIONS
6.1.
REFERENCE START DATE AND STUDY DAY
Study Day will be calculated from the reference start date and will be used to show start/stop day of assessments and 
events. Reference start date is defined as the day of the first dose of study intervention i.e., Day 1.
Study Day will be computed as follows:
!
Study Day = (Date of event – Date of first dose of study intervention + 1) if the date of the event is on or after 
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the date of the first dose of study intervention;
!
Study Day = (Date of event – Date of first dose of study intervention) if the date of the event is prior to the date 
of the first dose of study intervention.
In addition, day relative to vaccination will be derived for each vaccination dose. For example, day relative to the 
first dose will be equal to the Study Day. Day relative to the second dose will start with a value of 1 on the day of 
the second dose.
In the situation where the event date is partial or missing, Study Day and any corresponding durations will appear 
partial or missing in the listings.
6.2.
BASELINE
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to the first dose of 
study intervention (including unscheduled assessments). In the case where the last non-missing measurement and the 
date and time of the first dose of study intervention coincide, that measurement will be considered pre-baseline, but 
adverse events (AEs) and medications commencing on the date of the first dose of study intervention will be 
considered post-baseline.
6.3.
UNSCHEDULED VISITS, AND EARLY TERMINATION DATA
For by-visit summaries, data recorded at the nominal visit will be presented. That is, unscheduled, and early 
termination measurements will not be included in by-visit summaries but might contribute to the baseline timepoint
and/or maximum value, where required (e.g. shift table). An exception to this rule applies to immunogenicity 
analysis as stated in Section 6.4.
Listings will include scheduled, unscheduled, retest and early discontinuation data.
6.4.
WINDOWING CONVENTIONS 
A windowing convention will be used to determine the analysis value for a given study visit for immunogenicity 
data analyses. The window conventions are:
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1. A window of +/- 7 days from the target day is applied to the following visits: Study Days 15, 29, 43, 57 (for Day 
29, the date and time of second dose of study intervention can be used as upper bound);
2. A window of +/- 30 days from the target day is applied to the following visits: Study Day 183 and Day 365; 
Table B:
Analysis windows for immunogenicity by visit
Dosing 
Period
Visit
Day Relative to Dose 
within the Dosing Period (b)
Visit Window (Study Day) 
Relative to the Dosing Period
Period 1 
(Relative 
to Dose 1)
Baseline (a)
≤ 1
≤ 1
Day 15
15
8 - 21
Day 29
29
22 - 35
Period 2 
(Relative 
to Dose 2)
Day 43
15
8 - 21
Day 57
29
22 - 35
Day 183
155
125 - 185
Day 365
337
307 - 367
(a) Where time is available, the time of the collection must be prior to the first dose of study intervention. Day 1 observations taken after the first 
dose are considered post-baseline values.
(b) For each dosing period, the administration of the study intervention is designated as Study Day 1. For analyses within a period, the study day 
value is incremented by 1 for each date following the vaccine administration.
One or more results for a particular immunogenicity variable may be obtained in the same visit window. In such an 
event, the result with the date closest to the expected visit date will be used in the analysis. In the event that two 
observations are equidistant from the expected visit date, the later observation will be used in the analysis.
Beside the immunogenicity analyses, no visit windowing will be performed for analysis of other variables in this 
study.
6.5.
COMMON CALCULATIONS
Change from baseline will be calculated as:
!
Change from baseline = Test value at post-baseline visit – Baseline value
7. STATISTICAL CONSIDERATIONS
For continuous data, descriptive statistics (i.e., n [number of participants with available data], mean, standard 
deviation [SD], median, minimum, and maximum, and quartiles where appropriate) will be presented by treatment 
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group and visit, when applicable.
For categorical data, the number and percentages of participants in each category will be presented by treatment 
group and visit, when applicable. The denominator for percentage calculation is the underlying analysis set 
population unless otherwise specified.
7.1.
SAMPLE SIZE CALCULATION
Regarding Cohort C, 128 participants will be randomised in a 3:1 ratio to receive either AZD1222 or placebo. 
Regarding Cohort D, in a similar way, 128 participants will be randomised in a 3:1 ratio to receive either AZD1222 
or placebo, but participants will be stratified at randomisation by age group (i.e., Subcohorts D1 vs D2). At least 
30% of participants in Cohort D will be secured for participants with age ≥ 70 years.
These sample sizes (96 for AZD1222 versus 32 for placebo) were determined mainly for safety evaluation and based 
on feasibility. With the sample size of 96 participants in the AZD1222 treatment arm in each cohort, at least 1 
participant with an AE of incidence rate of 2.5% can be detected with probability of about 90%. The placebo arm is 
needed for securing the objectivity of the safety evaluation of the AZD1222 arm and it is also needed as a control for 
evaluating immunogenicity as stated below. For these purposes, the minimum sample size was given to the placebo 
arm (1/3 of the AZD1222 arm).
It is difficult to calculate an accurate sample size necessary for comparing the proportion of participants who have a 
seroresponse to SARS-CoV-2 spike protein between the AZD1222 and placebo arms because of insufficient 
information on immunogenicity in both arms at the moment. It is expected that the minimum number of participants 
per cohort will be about 36. Under a slightly conservative assumption about seroresponse rates of 10% assumed on 
placebo and over 75% on AZD1222, it is expected that the sample size of 36 (27 for AZD1222 vs 9 for placebo) will 
provide 93% power for showing the superiority of seroresponse of the AZD1222 treatment compared with placebo 
based on Fisher’s exact test at 2-sided 5% alpha.
7.2.
MISSING DATA
Missing efficacy data (including immunogenicity data) and safety data will not be imputed. 
Partial or completely missing medication/medical history/concomitant illnesses/related procedures dates will be 
handled as described in APPENDIX 1.
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7.3.
STATISTICAL TESTS
All statistical tests will be conducted at the two-sided 5% significant level, unless otherwise specified in the 
description of the analyses. Confidence Intervals (CIs) will be two-sided with 95% coverage.
7.4.
MULTIPLE COMPARISONS/ MULTIPLICITY
Given the exploratory nature of this study, no adjustment for multiple comparisons and multiplicity will be 
performed. That is, only nominal p-values will be provided for the immunogenicity endpoints.
No statistical testing will be performed for the safety endpoints.
7.5.
MULTICENTER STUDIES
This study will be conducted by multiple investigators at multiple centers in Japan. Data from all centers will be 
pooled together in the analyses and there are no plans to perform an analysis of homogeneity of the results across 
centers.
7.6.
ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED 
IN ANALYSES
No adjustments for covariates and factors are to be consiered for the analyses.
7.7.
EXAMINATION OF SUBGROUPS
Subgroup analyses will be conducted as stated in Section 16.2.1, Section 16.2.2 and Section 17.1.2.1.
The subgroups are:
!
Baseline Body Mass Index (BMI) group (<30 kg/m2 and ≥30 kg/m2), derivation of BMI given in Section 10.1;
!
Gender (male and female).
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7.8.
ANALYSIS BY COHORT
All analyses will be presented by Cohorts C and D, and Subcohorts D1 and D2, and total participants of Cohort C 
plus Cohort D, unless otherwise specified. Within each cohort, the analysis of AZD1222 and placebo will also be 
presented, unless otherwise specified.
For disposition, demographic, baseline characteristics, medical history, concomitant illnesses, related procedures,
prior and concomitant medication, and exposure, the analysis summary will be presented with AZD1222, placebo 
and overall.
7.9.
SOFTWARE VERSION
All analyses will be conducted using SAS version 9.4 or higher. 
7.10. SUBJECTS WHO WERE INOCULATED WITH NON-STUDY COVID-19
VACCINE
It is reported that post Primary Analysis, some subjects were inoculated with licensed non-study vaccines for 
COVID-19 when the vaccines became available to the general public in Japan. For the Final Analysis, the data 
handling of these subjects’ data are explained in following sections, Section 16.2.5 (immunogenicity analysis), , 
Section 16.3.1.1 and Section 16.3.4 (efficacy analysis) and Section 17.1.1.3 (safety analysis).   
8. OUTPUT PRESENTATIONS
APPENDIX 2 shows conventions for presentation of data in outputs. 
The templates provided with this SAP describe the presentations for this study and therefore, the format and content 
of the summary tables, figures, and listings to be provided by IQVIA Biostatistics.
9. DISPOSITION AND WITHDRAWALS
All participants who provide informed consent will be accounted for in this study. All analyses will be presented by 
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Cohorts C, D and Subcohorts D1, D2, and total participants of Cohort C plus Cohort D separately.
Analyses for patients dispostion and protocol deviations described in this section will be updated for the Final 
Analysis.
9.1.
DISPOSITION
Number of participants screened will be presented for the all participants analysis set. Number and percentages of 
participants with screen failure and reason for screen failure will also be presented based on the all participants
analysis set. A listing will present participants not meeting all eligibility criteria with the details of criteria not met.
Number of participants randomized will be presented for the all participants analysis set. Number of participants 
randomized but not vaccinated (including reason for withdrawal) will also be presented for the all participants 
analysis set.
Number of participants with at least 28 days follow-up post first dose will be presented for the all participants 
analysis set.
Number of participants who received first dose and discontinued from study intervention will be presented for the 
following:
-
discontinued from study.
-
remained in study follow-up.
-
completed study.
Similar summaries will be provided for each dose:
!
Number and percentages of participants vaccinated for first dose, in study after first dose and before second 
dose, discontinued the study intervention (including reason for withdrawal) after first dose and before second 
dose and discontinued the study (including reason for withdrawal) after first dose and before second dose will 
be presented. 
!
Number and percentages of participants vaccinated for second dose, in study (for primary analysis only) after 
28 days post second dose and discontinued from study (including reason for withdrawal) before 28 days post 
second dose and who discontinued early from the study (including reason for withdrawal) after 28 days
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(including 28 days) post second dose will be presented. 
The analysis of number of ongoing participants after first or second dose will only be presented for primary analysis 
and will not be included in the final analysis.
Number of participants included and excluded from each analysis set (including reason for exclusion) will be 
summarized based on the all participants analysis set. A listing showing inclusion and exclusion of each participant
from each analysis set, including reason for exclusion, will be provided.
9.2.
PROTOCOL DEVIATIONS
Number and percentages of participant with important protocol deviations, as identified by the study team in a 
blinded fashion before the clinical data lock, will be provided based on the TVS for each category of protocol 
deviations specified in the Protocol Deviations Management Plan.
A listing of protocol deviations identified by the study team (important or not) will be provided.
10.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
The following demographic and other baseline characteristics will be presented by Cohorts C, D and Subcohorts D1,
D2, and total participants of Cohort C plus Cohort D separately:
!
Age (years) – at the date of signed informed consent
!
Age group (years), applicable only to Subcohort D1: < 65 and ≥65
!
Sex
!
Race
!
Childbearing potential for female participants only
!
Ethnicity
!
Weight (kg)
!
Height (cm)
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!
BMI (kg/m2)
Continuous demographic and other baseline characteristics will be summarized using descriptive statistics based on 
the TVS and FVS for efficacy. For categorical demographic and other baseline characteristics, number and 
percentages of participants in each category will be provided based on the TVS. No statistical testing will be carried 
out for demographic or other baseline characteristics.
Analysis for demographic and baseline characteristics described in this section will not be updated for the Final 
Analysis.
10.1. DERIVATIONS
BMI, in kg/m2, will be calculated as follows, and presented with 2 decimal points: 
!
BMI (kg/m2) = weight (kg)/[height (m)2]
11.
MEDICAL HISTORY
Medical history is defined as any medical conditions/diseases that started and stopped before the first dose of study 
intervention. 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 23.0 or 
later, and will be summarized by System Organ Class (SOC) and Preferred Term (PT) based on the TVS. A 
participant having more than one medical condition/disease within the same SOC/PT will be counted only once for 
that SOC or PT.
All medical history will be listed.
Analysis of medical history described in this section will not be updated for the Final Analysis, only listing of 
medical history will be updated for the Final Anlaysis.
12.
CONCOMITANT ILLNESSES
Concomitant conditions/illnesses are defined as any medical conditions/illnesses that started before the first dose of 
study intervention AND were ongoing at the time of the first dose of study intervention or ended on the day of first 
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dose of study intervention.
Concomitant conditions/illnesses will be coded using the MedDRA, version 23.0 or later, and will be summarized 
by SOC and PT based on the TVS. A participant having more than one medical condition/illness within the same 
SOC or PT will be counted only once for that SOC or PT.
All concomitant conditions/illnesses will be listed.
Analysis of concomitant illnesses described in this section will not be updated for the Final Analysis, only listing of 
concomitant illnesses will be updated for the Final Analysis.
13.
MEDICATIONS
!
Prior medications are defined as any medication that started and stopped prior to the first dose of study 
intervention.
!
Concomitant medications are defined as:
o
Any medication that started before the first dose of study intervention AND was ongoing at the time of 
the first dose of study intervention or ended on the date of first dose of study intervention;
o
Any medication that started on or after the day of first dose of study intervention.
Partially or completely missing medication start and stop dates will be handled as described in APPENDIX 1.
All medications will be coded using the World Health Organization (WHO) Drug Global dictionary, version B3 
March 2020 or later.
Prior and concomitant medications will be summarized by Anatomical Therapeutic Class (ATC) level 2 and 
preferred drug name based on the TVS. A participant having more than one medication within the same ATC Level 
2 or preferred drug name will be counted only once for that ATC Level 2 or preferred drug name.
All prior and concomitant medications will be listed.
Analyses of prior and concomitant medications described in this section will be updated for the Final Analysis.
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14.
EXPOSURE TO STUDY INTERVENTION
Due to the simplicity of dosing for this study, exposure is summarized in the Disposition table. No other summary 
will be reported. A listing will provide exposure information for all participants in the TVS.
Report of overdose and medication error, if any, will be listed for the TVS.
Listings of exposure to study invention and of overdose will not be updated for the Final Analysis.
15.
COMPLIANCE WITH STUDY INTERVENTION
Compliance will not be calculated since participants are vaccinated within clinic.
16.
EFFICACY ENDPOINTS (INCLUDING IMMUNOGENICITY)
Unless otherwise specified, all summaries and figures for immunogenicity will be presented by Cohorts C, D, and 
Subcohorts D1 and D2, and total participants of Cohort C plus Cohort D separately, based on the TVS and FVS for 
immunogenicity. Exploratory efficacy analysis will be based on TVS and FVS for efficacy.
16.1. PRIMARY IMMUNOGENICITY
Primary immunogenicity analysis described in this section will not be updated for the Final Analysis.
16.1.1.
PRIMARY IMMUNOGENICITY ENDPOINT
The primary immunogenicity endpoint is the proportion of participants who have a post-treatment seroresponse 
(≥4-fold rise in titers from Day 1 baseline value) to the Spike antigens of AZD1222 (MSD serology assay) at
Day 57.
16.1.2.
DATA IMPUTATION METHOD FOR PRIMARY IMMUNOGENICITY ENDPOINT
A titer value measured below the lower limit of quantification (LLoQ) will be imputed to a value that is half of the 
LLoQ in summaries and analyses, but will be listed as reported in the raw serology data. For example, a serologic 
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assay with LLoQ = 30 generally reports value below LLoQ as “<30”. The data listings will present the value as 
“<30”, while value of 15 (i.e., 30/2) is to be used in the summaries and analyses.
Titer values measured as above the upper limit of quantification (ULoQ) will be imputed at the ULoQ value.
16.1.3.
PRIMARY ANALYSIS OF PRIMARY IMMUNOGENICITY ENDPOINT
Seroresponse is a binary outcome where a success is when the fold rise in titers compared to baseline is ≥4. The 
fold rise in titers is calculated as the ratio of the post-vaccination titer level to the baseline titer level.
The number and proportion of participants who have a seroresponse to the Spike antigens of AZD1222 based on 
MSD serology assay at Day 57 will be summarized for AZD1222 and placebo. The summary will also include the 
95% CI of the proportion of participants achieving seroresponse at Day 57, calculated based on the Clopper-Pearson 
method. This summary will be repeated for Cohorts C, D and Subcohorts D1, D2, and total participants of Cohort C 
plus Cohort D separately.
The proportion of participants who have a post-treatment seroresponse at Day 57 will be compared between 
AZD1222 and placebo using the Fisher’s exact test at the 2-sided 5% alpha level for each cohort. Fisher’s exact test 
will not be presented for Subcohorts D1 and D2.
The null hypothesis and alternative hypothesis to be tested are defined as follows:
Null hypothesis: Pactive = Pplacebo
Alternative hypothesis: Pactive ≠ Pplacebo
where P is the proportion of seroresponse participants.
16.1.3.1.
Subgroup analysis for immunogenicity
The analysis of seroresponse to the Spike antigens of AZD1222 at Day 57 will be repeated for the subgroups defined 
in Section 7.7. Fisher’s exact test will not be presented for subgroup analysis.
16.1.4.
SENSITIVITY ANALYSES FOR PRIMARY IMMUNOGENICITY ENDPOINT
No sensitivity analyses will be performed for the primary immunogenicity endpoint.
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16.2. SECONDARY IMMUNOGENICITY
The secondary immunogenicity endpoints are:
!
Geometric mean titers (GMT) and geometric mean fold rise (GMFR) of immunogenicity against Spike and 
RBD antigens of AZD1222 (MSD serology assay) at each time point up to Day 365.
!
Proportion of participants who have a post-treatment seroresponse (≥ 4-fold rise in titers from Day 1 baseline 
value) to RBD antigen of AZD1222 based on MSD serology assay at Day 57.
!
Proportion of participants who have a post-treatment seroresponse (≥ 4-fold rise in titers from Day 1 baseline 
value) to AZD1222 as measured by SARS-CoV-2 nAb (wild-type assay or pseudoneutralisation assay) at 
Day 57.
!
GMT and GMFR of nAb to SARS-CoV-2 at each time point up to Day 365.
For analyses described above, only the analysis of GMT and GMFR up to Day 365 will be updated for the Final 
Analysis.
16.2.1.
GMTS AND GMFRS
GMTs and GMFRs will be calculated for AZD1222 and placebo and will be summarized at each scheduled visit 
(refer to protocol Section 1.3), for the following titer measurements:
!
Antibodies against Spike and RBD antigens of AZD1222 based on MSD serology assay
!
Antibodies against nAb to SARS-CoV-2
Descriptive statistics for GMTs and GMFRs will include number of participants, geometric mean, 95% CI, 
minimum and maximum and will be presented by Cohorts C, D and Subcohorts D1, D2, and total participants of 
Cohort C plus Cohort D separately. 
The GMT will be calculated as the antilogarithm of Σ (log base 2 transformed titer/n), i.e., as the antilogarithm 
transformation of the mean of the log-transformed titer, where n is the number of participants with titer information. 
The 95% CI will be calculated as the anti-logarithm transformation of the upper and lower limits for a two-sided CI 
for the mean of the log-transformed titers.
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The fold rise is calculated as the ratio of the post-vaccination titer level to the pre-vaccination titer level. GMFR will 
be calculated as anti-logarithm of Σ (log base 2 transformed (post-vaccination titer/ pre-vaccination titer)/n). The 
95% CIs for GMFR will be calculated similarly to those for GMT.
Individual Spike and RDB antigens of AZD1222 based on MSD serology assay and nAb to SARS-CoV-2 at 
different timepoints will be presented in a plot where data for all placebo participants will be pooled and participants 
in AZD1222 of Cohorts C, D1 and D2, and total participants of Cohort C plus Cohort D will be presented 
separately.
16.2.1.1.
Subgroup analysis for immunogenicity
The analysis of antibodies against Spike and RBD antigens of AZD1222 (based on MSD serology assay) and
antibodies against nAb to SARS-CoV-2 will be repeated for the subgroups defined in Section 7.7.
16.2.2.
SERORESPONSE RATE
Seroresponse is defined in Section 16.1.3. The number and proportion of participants who have a seroresponse to the 
RBD antigen (as measured by MSD serology) and seroresponse to AZD1222 (as measured by nAb) at Day 57 will 
be summarized separately for AZD1222 and placebo. The summary will also include the 95% CI of the proportion 
of participants achieving seroresponse at Day 57, calculated based on the Clopper-Pearson method. This summary 
will be repeated for Cohorts C, D and Subcohorts D1, D2, and total participants of Cohort C plus Cohort D
separately. A similar analysis for RDB antigens of AZD1222 will also be performed.
Seroresponse rate will be compared between AZD1222 and placebo using the Fisher’s exact test at the 2-sided 5% 
alpha level for each cohort, Cohorts C, D, and total participants of Cohort C plus Cohort D separately. 
16.2.2.1.
Subgroup analysis for seroresponse rate
The analysis of seroresponse rate will be repeated for the subgroups defined in Section 7.7.
16.2.3.
DATA IMPUTATION METHOD FOR SECONDARY IMMUNOGENICITY ENDPOINTS
Data imputation rules as described in Section 16.1.2 will be applicable to the secondary immunogenicity endpoints.
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16.2.4.
SENSITIVITY ANALYSES FOR SECONDARY IMMUNOGENICITY ENDPOINT
No sensitivity analyses will be performed for the secondary immunogenicity endpoint.
16.2.5.
DATA HANDLING FOR SUBJECTS INOCULATED WITH NON-STUDY COVID-19 VACCINE
For subjects who were inoculated with non-study COVID-19 vaccine, their immunogenicity data from the time of the 
non-study COVID-19 vaccination will not be included in the analysis, ie, any immunogenicity data collected after 
the date of non-study COVID-19 vaccination will be removed, however this data will be provided in listings. The
date of non-study COVID-19 vaccination can be obtained from the Concomitant Medication eCRF page.
16.3. EXPLORATORY EFFICACY
The exploratory efficacy endpoints are:
!
Virologically confirmed (RT-PCR positive) symptomatic cases of COVID-19.
!
Hospital admissions associated with COVID-19.
!
Intensive care unit admissions associated with COVID-19.
!
Deaths associated with COVID-19.
!
Seroresponse against non-Spike (nucleocapsid) SARS-CoV-2 antigens (MSD serology assay).
Exploratory efficacy analyses were not performed for the Primary Analysis and will be presented for the Final 
Analysis.
16.3.1.
EXPLORATORY EFFICACY ENDPOINTS
16.3.1.1.
Virologically confirmed (RT-PCR positive) symptomatic cases of COVID-19
The incidence of the first virologically confirmed (RT-PCR positive) symptomatic cases of COVID-19 will be
summarized for the TVS and the incidence of the first virologically confirmed (RT-PCR positive) symptomatic
cases of COVID-19 occurring ≥ 15 days post second dose of study intervention will be summarized for the FVS for 
efficacy and presented for AZD1222 and placebo by Cohorts C and D and Subcohorts D1 and D2, and total
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participants of Cohort C plus Cohort D separately.
A participant who is found to be positive to COVID-19 based on the SARS-CoV-2 RT-PCR test is considered as 
having symptomatic case of COVID-19. This is because, according to current medical practice in Japan, only 
participants with symptomatic symptoms of COVID-19 are likely to be prescribed the SARS-CoV-2 RT-PCR test. 
A participant could have multiple assessments of SARS-CoV-2 RT-PCR test throughout the study duration, but only 
the first positive SARS-CoV-2 RT-PCR test, occurring post first dose of study intervention for the analysis based on 
TVS and occurring ≥15 days post second dose of study intervention for the analysis based on FVS for efficacy, will 
be counted.
Kaplan-Meier curves will be presented for AZD1222 and placebo in the TVS and FVS for efficacy, showing the 
cumulative incidence of the first case of SARS-CoV-2 RT-PCR-positive symptomatic COVID-19 post first dose of 
study intervention or occurring ≥15 days post second dose of study intervention, respectively. The time to event is 
calculated as follows:
!
For analysis based on TVS: 
(Date of Onset of Symptomatic SARS-CoV-2 RT-PCR Positive Event) – (Date of First Dosing) + 1.
!
For analysis based on FVS for efficacy: 
(Date of Onset of Symptomatic SARS-CoV-2 RT-PCR Positive Event) – (Date of Second Dosing + 15) + 1. 
For participants who were inoculated with non-study COVID-19 vaccine and did not meet the virologically 
confirmed (RT-PCR) symptomatic cases of COVID-19 post first dose of study intervention and up to the time of non-
study COVID-19 vaccine inoculation for TVS or ≥15 days post second dose of study intervention and up to the time 
of non-study COVID-19 vaccine inoculation for FVS for efficacy, time to event is censored and calculated as 
follows.
!
For analysis based on TVS: 
(Date of non-study COVID-19 vaccination) – (Date of First Dosing) + 1.
!
For analysis based on FVS for efficacy:
(Date of non-study COVID-19 vaccination) – (Date of Second Dosing + 15) + 1.
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For other participants who do not meet the virologically confirmed (RT-PCR) symptomatic cases of COVID-19 post 
first dose of study intervention for TVS or ≥15 days post second dose of study intervention for FVS for efficacy, 
time to event is calculated as follows:
(a) Participants who completed the study or discontinued the study early without a virologically confirmed (RT-
PCR) positive test.
For these participants, the time to event will be censored and calculated as,
!
For analysis based on TVS: 
(Date of End of Study or Date of Last RT-PCR Assessment, whichever is later) – (Date of First Dosing) + 1.
!
For analysis based on FVS for efficacy:
(Date of End of Study or Date of Last RT-PCR Assessment, whichever is later) – (Date of Second Dosing + 15) 
+ 1.
(b) For participants who are not tested positive SARS-CoV-2 as confirmed by RT-PCR and remained in the study
at the time of primary analysis.
These participants will be censored and the data cut-off date will be used in the time to event calculation as 
follow,
!
For analysis based on TVS:
(Date of Data Cut-Off) – (Date of First Dosing) + 1.
!
For analysis based on FVS for efficacy:
(Date of Data Cut-Off) – (Date of Second Dosing + 15) + 1.
16.3.1.2.
Hospital admission associated with COVID-19
The number and proportion of participants with COVID-19 related hospital admission will be summarized for the 
TVS and the FVS for efficacy and presented by treatment group.
In the analysis based on the FVS for efficacy, only COVID-19 related hospital admission occurring ≥15 days post 
second dose of study intervention will be counted.
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COVID-19 related hospital admissions are captured in the Serious Adverse Events electronic Case Report Form 
(eCRF) page.
16.3.1.3.
Intensive care unit admissions associated with COVID-19
The number and proportion of participants with COVID-19 related ICU/HDU will be summarized for the TVS and 
the FVS for efficacy and presented by treatment group.
In the analysis based on the FVS for efficacy, only COVID-19 related ICU/HDU occurring ≥15 days post second 
dose of study intervention will be counted.
Participants who have the ICU admission date (captured in the Hospitalization eCRF page) anytime between 
COVID-19 related hospital admission date and discharge date (captured in the Serious Adverse Events eCRF page) 
will be considered as having an incidence of COVID-19 related ICU admission.
16.3.1.4.
Deaths associated with COVID-19
If any participants die during the study, death is recorded as ‘Death’ on the “Serious Adverse Events” page of the 
eCRF. The number and proportion of participants who died due to COVID-19 will be summarized for the TVS and 
the FVS for efficacy by treatment group. All deaths, regardless of the timing, will be listed.
In the the analysis based on FVS for efficacy, only participants who died due to COVID-19 ≥15 days post second 
dose of study intervention will be counted.
16.3.1.5.
Seroresponse against non-Spike (nucleocapsid) SARS-CoV-2 antigens (MSD serology 
assay)
Seroresponse is defined in Section 16.1.3. The number and proportion of participants who have seroresponse to the 
non-Spike (nucleocapsid) SARS-CoV-2 antigens based on MSD serology assay will be summarized for the TVS and 
the FVS for efficacy by treatment group.
In the the analysis based on FVS for efficacy, only participants achieving seroresponse ≥15 days post second dose 
of study intervention will be counted in this analysis.
The summary will also include the 95% CI of the proportion of participants achieving seroresponse calculated based 
on the Clopper-Pearson method.
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16.3.2.
DATA IMPUTATION METHOD FOR EXPLORATORY EFFICACY ENDPOINTS
Data imputation rules as described in Section 16.1.2 will be applicable to analysis of seroresponse to the non-Spike 
(nucleocapsid) SARS-CoV-2 antigens endpoint. Otherwise, no data imputation method will be applied to the 
exploratory efficacy analysis.
Participants who withdraw consent or have an early termination will have data analyzed up to the day of their study 
termination.
16.3.3.
SENSITIVITY ANALYSES FOR EXPLORATORY EFFICACY ENDPOINTS
No sensitivity analysis will be performed for the exploratory efficacy endpoints.
16.3.4.
DATA HANDLING FOR SUBJECTS INOCULATED WITH NON-STUDY COVID-19 VACCINE
For subjects who were inoculated with non-study COVID-19 vaccine, their efficacy data from the time of the non-
study COVID-19 vaccination will not be included in the analysis, ie, any efficacy data collected after the date of 
non-study COVID-19 vaccination will be removed, however this data will be provided in listings. The date of non-
study COVID-19 vaccination can be obtained from the Concomitant Medication eCRF page.
17.
SAFETY ENDPOINTS
All safety summaries will be presented by Cohorts C, D and Subcohorts D1, D2, and total participants of Cohort C 
plus Cohort D separately, based on the TVS There will be no statistical comparisons between the treatment groups
for safety data.
The primary safety endpoints are:
!
Occurrence of solicited local reactogenicity signs and symptoms for 7 days following throughout vaccination
!
Occurrence of solicited systemic reactogenicity signs and symptoms for 7 days following throughout 
vaccination.
!
Occurrence of AEs, serious adverse events (SAEs) and adverse events of special interest (AESIs) for 28 days 
following throughout vaccination.
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!
Change from baseline for safety laboratory measures.
The secondary safety enpoint is the occurrence of SAEs and AESIs throughout the study duration up to Day 365.
For safety analysis, only the analysis of unsolicited AEs, physical examination listing and vital sign listing will be 
updated for the Final Analysis. 
17.1. ADVERSE EVENTS
Adverse events will be coded using the MedDRA dictionary, version 23.0 or later.
17.1.1.
ALL ADVERSE EVENTS
An overall summary of number and percentages of participants within each of the categories described in the sub-
sections below will be provided based on the TVS. Should a participant experience multiple event within a category, 
the participant will be counted only once for that category.
All AEs will be listed. 
17.1.1.1.
Severity grading for AEs
Severity will be classified as Food and Drug Administration (FDA) Grading for AEs, according to Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (FDA 2007). 
FDA Gradings for AEs will be collected on AE form of eCRF. Should a participant experience multiple events 
within a SOC or PT, only the participant’s worst FDA grade will be counted for that SOC or PT.
17.1.1.2.
Relationship to study intervention
Relationship to study intervention, as indicated by the Investigator as “Relationship to study treatment” in eCRF, 
will be classified as not related, or related (increasing severity of relationship).
Should a participant experience multiple events within a SOC or PT, only the participant’s worst relationship will be 
counted for that SOC or PT.
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17.1.1.3.
Data Handling for Subjects Inoculated with Non-study COVID-19 Vaccine
The analysis of AEs will be presented with all data including safety data of subjects who were inoculated with a 
non-study COVID-19 vaccine. The same analysis will be provided for 1) after removing all safety data that started 
post non-study COVID-19 vaccination and 2) only safety data that started post non-study COVID-19 vaccination for 
subjects who were inoculated with a non-study COVID-19 vaccine. The date of non-study COVID-19 vaccination 
can be obtained from the Concomitant Medication eCRF page. For subjects who were inoculated with a non-study 
COVID-19 vaccine, AEs that started post non-study COVID-19 vaccination will be included in the overall AE 
listings.
17.1.2.
PRIMARY SAFETY ENDPOINTS
17.1.2.1.
Occurrence of unsolicited AEs for 28 days following throughout vaccination
All AEs are considered to be unsolicited AEs unless categorized as solicited AEs recorded in an eDiary. All 
unsolicited AEs will be recorded from the start of each dose for 28 days post each dose of study intervention.
Number and percentages of participants with at least one unsolicited AE will be presented by SOC and PT. Should a 
participant experience multiple events within a SOC or PT, the participant will be counted only once for that SOC or 
PT.
Number and percentage of participants with at least one unsolicited AE will be presented by PT. Should a 
participant experience multiple events within a PT, the participant will be counted only once for that PT.
Number and percentage of participants with at least one unsolicited AE will be broken down further by 28 days 
interval post each dose (based on the start date of the event), maximum severity (refer to Section 17.1.1.1),
relationship to study intervention (refer to Section 17.1.1.2).
Number and percentage of participants with at least one unsolicited AE with Grade 3 or higher will be presented by 
relationship to study intervention (refer to Section 17.1.1.2), SOC and PT.
Subgroup analysis will be performed for the overview summary of unsolicited AEs and the occurrence of 
unsolicited AEs by SOC and PT using subgroups specified in Section 7.7.
A listing of all unsolicited AEs will be provided.
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17.1.2.2.
Occurrence of serious AEs for 28 days following throughout vaccination
Serious adverse events are those events recorded as “Serious” on the AE page of the eCRF. Only SAEs that started 
or worsened in severity on or after the first dose of study intervention will be presented in the summary. 
Should a participant experience multiple events within a SOC or PT, the participant will be counted only once for 
that SOC or PT. Number and percentage of participants with at least one SAE will be broken down further by 28 
days interval post each dose (based on the start date of the event) and relationship to study intervention (refer to 
Section 17.1.1.2).
A listing of all SAEs including those prior to the first vaccination will be provided.
17.1.2.3.
Occurrence of Adverse Events of Special Interest for 28 days following throughout 
vaccination
Adverse events of special interest are defined in the protocol Section 8.3.8. AESIs will be recorded as “Yes” for 
“Was the event an AE of Special Interest?” on the AE page of the eCRF.
A summary of AESIs by SOC and PT will be presented. Should a participant experience multiple events within a 
SOC or PT during an interval, the participant will be counted only once for that SOC or PT during that particular 
interval. The summary of AESI will be broken down further by 28 days interval post each dose (based on the start 
date of the event).
Number and percentage of participants with at least one AESIs will be presented by relationship to study 
intervention (refer to Section 17.1.1.2), SOC and PT.
A listing of all AESIs will be provided.
17.1.2.4.
Occurrence of solicited AEs for 7 days following throughout vaccination
Solicited AEs are local or systemic predefined AEs for reactogenicity assessment. Solicited AEs will be collected in 
a Solicited AE eDiary for 7 days following each dose of AZD1222. The set of solicited AEs associated with 
reactogenicity are presented below: 
Table C:
List of Predefined Solicited Adverse Events for Reactogenicity Assessment
Local 
Systemic
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Pain at the site of injection 
Fever (> 100°F or > 37.8°C)a
Erythema/redness at the site of injectionb
Chills
Tenderness
Muscle pains
Swelling at the site of injectionb 
Fatigue
Induration at the site of injectionb 
Headache
Malaise
Nausea
Vomiting
a Fever measured by any route. Investigators who consider a temperature lower than this cutoff as a fever or a ‘fever’ reported by
participants without documentation by a thermometer should record the event as ‘elevated body temperature.’
b Swelling, redness, and induration must be ≥0.6 centimetres in diameter.
Severity will be assessed for solicited AEs by the participant according to toxicity grading scales modified and 
abridged from the FDA grading guidance (FDA 2007). The measurements of the longest part of redness and 
swelling of injection sites will also be collected. These measurements will be used to derive severity grades based on 
the criteria presented in APPENDIX 3. Severity grading for systemic solicited AE, i.e., fever are derived based on 
criteria presented in APPENDIX 4, and chills, fatigue, headache and nausea/vomit are derived based on criteria 
presented in APPENDIX 5. Because solicited AEs are expected to occur after vaccination, they will not be assessed 
for relationship to study intervention.
Solicited AEs for 7 days following each dose of study intervention will be summarized for each dose and overall.
Each solicited AE will be summarized at the following time intervals: Days 1-7, and Day 1 to Day 7 individually. 
For each interval, the count and percentages of participants will be determined for each of the following categories: 
participants evaluated, participants without any events, participants with any event, mild events, moderate events, 
severe events, and life-threatening events. Participants should not be double counted; therefore, the event of greatest 
severity will be used for participants with more than 1 episode of the same event. Similar count and percentages of 
participants will be presented for solicited local AEs and solicited systemic AEs. 
Quantitative and categorical summary of the day of first onset of each event and the number of days participants 
reported experiencing each event will be presented. The number of days a participant reported experiencing an event 
is calculated as the total of all days the participant reported the event, regardless of whether the symptom was 
reported on consecutive days (e.g., a headache reported on Day 1, Day 3, and Day 4 would be included with a 
duration of 3 days). 
A listing of all solicited AEs will be provided.
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17.1.3.
SECONDARY SAFETY ENDPOINTS
17.1.3.1.
Occurrence of serious AEs throughout the study duration up to Day 365
A summary of SAEs started on and after first dose of study intervention will be presented by SOC and PT 
throughout the study duration up to Day 365. Should a participant experience multiple events within a SOC or PT, 
the participant will be counted only once for that SOC or PT.
A listing of all SAEs (including SAE started prior to the start of first dose of study intervention) will be provided.
17.1.3.2.
Occurrence of AESIs throughout the study duration up to Day 365
A summary of AESIs by SOC and PT throughout the study duration up to Day 365 will be presented. Should a 
participant experience multiple events within a SOC or PT, the participant will be counted only once for that SOC or 
PT.
17.1.4.
OTHER ADVERSE EVENT SAFETY ENDPOINTS
17.1.4.1.
Adverse Events with an Outcome of Death
AEs with an outcome of death are those events which are recorded as “Fatal” on the AE page of the eCRF. A 
summary of AEs with an outcome of death by SOC and PT will be presented.
A listing of all AEs with an outcome of death will be provided.
17.1.4.2.
AEs Leading to Discontinuation of Study Intervention
AEs leading to discontinuation of study intervention are recorded as “Drug withdrawal” for the question “Action 
Taken with study treatment” on the AE pages of the eCRF. A summary of AEs leading to discontinuation of study 
intervention by SOC and PT will be presented. 
A listing of all unsolicited AEs leading to discontinuation of study intervention will be provided.
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17.2. LABORATORY EVALUATIONS
The analysis of change from baseline is also one of the primary safety endpoints.
Clinical chemistry and hematology will be performed as per the schedule of events (refer to protocol Section 1.3). A 
list of laboratory parameters to be included in the outputs is included in APPENDIX 6.
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.
The following summaries will be provided based on the TVS for each of chemistry and hematology laboratory 
parameter:
!
Observed and change from baseline in Standard International (SI) units by visit;
!
Categorical value according to FDA grading guidance (FDA 2007) toxicity grades (for quantitative parameters 
with available FDA toxicity grades; refer to Section 17.2.1) by visit;
!
A listing of participants with at least one observed value in alanine aminotransferase (ALT) value ≥3 x upper 
limit of normal (ULN) or aspartate aminotransferase (AST) value ≥3 x ULN together with total bilirubin value 
≥2 x ULN will be provided.
All laboratory data will be listed.
A urine pregnancy test will be performed at scheduled visits (refer to protocol Section 1.3). Listings of pregnancy 
test and pregnancy report, if any, will also be presented.
17.2.1.
LABORATORY TOXICITY GRADES
Quantitative laboratory parameters with available FDA toxicity grades will be categorized as follows where higher 
grades representing a more severe toxicity (refer to APPENDIX 7 for each parameter toxicity grade criteria). FDA 
grading will be categorized for laboratory parameters listed in APPENDIX 6:
!
Grade 1 (i.e., mild);
!
Grade 2 (i.e., moderate);
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!
Grade 3 (i.e., severe)
!
Grade 4 (i.e., potentially life-threatening)
Although not defined in the FDA toxicity grading system, non-missing laboratory parameter results not meeting any 
of the 4 grades defined in the FDA toxicity grading system will be categorized as ‘No Toxicity’.
17.3. VITAL SIGNS
The following vital sign parameters will be collected for this study as per the schedule of events (refer to protocol 
Section 1.3):
!
Systolic blood pressure (SBP) (mmHg)
!
Diastolic blood pressure (DBP) (mmHg)
!
Pulse rate (beats per minute [bpm])
!
Body temperature (⁰C)
Observed values of vital sign parameters will be summarized descriptively based on the TVS for all scheduled visits.
A listing of all vital sign data will also be provided.
The analysis of vital sign lisitng will be updated for the Final Analysis.
17.4. PHYSICAL EXAMINATION
Physical examinations will be conducted as per the schedule of events (refer to protocol Section 1.3). Clinically 
significant findings at screening will be recorded on the Medical History page of the eCRF while clinically 
significant changes from screening will be recorded on the AEs page of the eCRF for the post-screening visits. 
Hence, clinically significant findings/changes will be summarized though the medical history summary (refer to
Section 11), concomitant illnesses (refer to Section 12) or AE summaries (refer to Section 17.1), as appropriate. That 
is, no summaries will be specifically provided for the general physical examination.
All physical examination data will be listed.
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Only the listing of physical examination containing tests assessed up till the end of study will be updated for the 
Final Analysis.
17.5. IMMUNOLOGIC RESPONSES
17.5.1.
NEUTRALIZING ANTIBODIES: IMMUNOGLOBULIN G AND M ANTIBODIES
Immunoglobulin G (IgG) and immunoglobulin M (IgM) will be tested as per the schedule of events (refer to 
protocol Section 1.3).
All IgG and IgM antibodies data will be listed.
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18.
REFERENCES 
FDA, (Food and Drug Administration). 2007. Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Accessed August 25, 2020. 
https://www.fda.gov/media/73679/download.
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APPENDIX 1.
PARTIAL DATE CONVENTIONS
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS
START DATE
STOP DATE
ACTION
Known
Known or 
ongoing
If medication stop date < study intervention start date, assign as prior;
If medication start date < study intervention start date and (medication stop 
date ≥study intervention start date or medication is ongoing at study 
intervention start date), assign as concomitant;
If study intervention start date ≤medication start date, assign as 
concomitant.
Partial
If known components of medication stop date show that medication stopped 
before study intervention start date, assign as prior;
If medication start date < study intervention start date and (known 
components of medication stop date show that medication stopped on or 
after study intervention start date), assign as concomitant;
If study intervention start date ≤medication start date, assign as 
concomitant.
Missing, not 
ongoing
If medication stop date is missing, then it can never be assigned as prior 
only;
If medication start date < study intervention start date, assign as 
concomitant;
If study intervention start date ≤medication start date, assign as 
concomitant.
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START DATE
STOP DATE
ACTION
Partial
Known or 
ongoing
If medication stop date < study intervention start date, assign as prior;
If (known components of medication start date show that medication started 
before study intervention start date) and (medication stop date ≥study 
intervention start date or medication is ongoing at study intervention start 
date), assign as concomitant;
If known components of medication start date show that medication started 
on or after study intervention start date, assign as concomitant.
Partial
If known components of medication stop date show that medication stopped 
before study intervention start date, assign as prior;
If (known components of medication start date show that medication started 
before study intervention start date) and (known components of medication 
stop date show that medication stopped on or after study intervention start 
date), assign as concomitant;
If known components of medication start date show that medication started 
on or after study intervention start date, assign as concomitant.
Missing, not 
ongoing
Cannot be assigned as prior only;
If known components of medication start date show that medication started 
before study intervention start date, assign as concomitant;
If known components of medication start date show that medication started 
on or after study intervention start date, assign as concomitant.
Missing
Known or
ongoing
If medication stop date < study intervention start date, assign as prior;
If medication stop date >= study intervention start date or medication is 
ongoing at study intervention start date, assign as concomitant.
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START DATE
STOP DATE
ACTION
Partial
If known components of medication stop date show that medication stopped 
before study intervention start date, assign as prior;
If known components of medication stop date show that medication stopped 
on or after study intervention start date, assign as concomitant.
Missing, not 
ongoing
Assign as concomitant.
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APPENDIX 2.
PROGRAMMING CONVENTIONS FOR OUTPUTS
DATES & TIMES
Depending on data available, dates and times will take the form yyyy-mm-dd hh:mm:ss.
SPELLING FORMAT
English US. 
PAPER SIZE, ORIENTATION, AND MARGINS
The size of paper will be letter and the page orientation will be landscape. Margins will provide at least 1 inch (2.54 
centimeters) of white space all around the page.
FONTS
The font type ‘Courier New’ will be used, with a font size of 8. The font color will be black with no bolding, 
underlining, italics or subscripting.
PRESENTATION OF TREATMENT GROUPS
For outputs, treatment groups will be represented as follows and in the given order:
Treatment Group
Tables and Graphs
Listings
AZD1222
1
1
Placebo
2
2
Total [1]
3
3
Randomized, Not Vaccinated
n/a
5
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Treatment Group
Tables and Graphs
Listings
Screen Failure
n/a
6
[1] Not applicable for efficacy tables, safety tables and graphs.
PRESENTATION OF NOMINAL VISITS
For outputs, analysis visits will be represented as follows and in that order:
Long Name (default)
Short Name 
Screening
Scrn
Baseline
Base
Day 1
D1
Day 4
D4
Day 8
D8
Day 15
D15
Day 29
D29
Day 32
D32
Day 36
D36
Day 43
D43
Day 57
D57
Day 183
D183
Day 365
D365
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DESCRIPTIVE STATISTICS
If the original data has N decimal places, then the summary statistics will have the following decimal places:
!
Minimum and maximum, lower and upper bounds of two-sided 95% CI for percentages and Kaplan-Meier 
estimates: N;
!
Mean (including GMT and GMFR), median, lower and upper bounds of two-sided 95% CI* for 
GMT/GMFR: N + 1;
!
SD: N + 2
* when values are less than 0.00, 95% CI are presented to N + 2 decimal places to enable the display of meaningful
values.   
PERCENTAGES
Percentages will be reported to one decimal place. Rounding will be applied, except for percentages < 0.1 but > 0.0 
which will be presented as ‘< 0.1’ and percentages < 100.0 but >99.9 which will be presented as ‘>99.9’.
Where counts are zero, no percentages will appear in the output.
P-VALUES
p-values will be reported to three decimal places. Rounding will be applied, except for the p-values < 0.001 which 
will be presented as ‘< 0.001’ and p-values < 1.000 but > 0.999 which will be presented as ‘> 0.999’.
LISTINGS
All listings will be ordered by the following (unless otherwise indicated in the output template):
!
Randomized treatment group (or treatment received if it’s a safety output);
!
Participant ID;
!
Parameter, when applicable;
!
Date/Time, when applicable.
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!
Timepoint, when applicable
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APPENDIX 3.
TABLES FOR CLINICAL ABNORMALITIES: LOCAL 
REACTIONS TO INJECTABLE PRODUCT
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APPENDIX 4.
TABLES FOR CLINICAL ABNORMALITIES: VITAL 
SIGNS
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APPENDIX 5.
TABLES FOR CLINICAL ABNORMALITIES: SYSTEMIC 
(GENERAL OR ILLNESS)
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APPENDIX 6.
LABORATORY ASSESSMENTS
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APPENDIX 7.
TABLES FOR LABORATORY ABNORMALITIES
Note: To evaluate Grade 4 Creatinine, only test result > 2.5 is required, the assessment of dialysis is not required. 
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APPENDIX 8.
ABBREVIATIONS
Abbreviation or special term
Explanation
ADaM
Analysis Dataset Modelling
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
Anatomical Therapeutic Class
BLQ
lower limit of quantification
BMI
body mass index
bpm
beats per minute
CI
confidence interval
COVID-19
Coronavirus Disease 2019
CRM
comments resolution meeting 
DBP
diastolic blood pressure
eCRF
electronic Case Report Form
FVS
fully vaccinated analysis set
GMFR
geometric mean fold rise
GMT
geometric mean titer
HDU
High dependency unit
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Abbreviation or special term
Explanation
ICU
intensive care unit
IgG
immunoglobulin G
IgM
immunoglobulin M
IM
intramuscular
LLoQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MSD
Meso Scale Discovery
n
number of participants with available data
nAb
neutralising antibody
PT
preferred term
RBD
receptor-binding domain
RT-PCR
reverse transcriptase-polymerase chain reaction
SAE
serious adverse event 
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome-coronavirus 2
SBP
systolic blood pressure
SD
standard deviation
SDTM
Study Data Tabulation Model
SI
Standard International
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Abbreviation or special term
Explanation
SOC
system organ class
TVS
total vaccinated analysis set
ULN
upper limit of normal
ULoQ
upper limit of quantification
ULQ
upper limit of quantification
US FDA
United States Food and Drug Administration
vp
viral particles
WHO
World Health Organization
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