Clinical trial NCT04631016
Conditions: Chronic Obstructive Pulmonary Disease (COPD) Chronic Bronchitis
Keywords: MEDI3506 IL-33 COPD Chronic Bronchitis Lung function Inflammation
Sponsor: AstraZeneca
Start date: 2020-12-14; Completion date: 2023-11-13
Enrollment: 137 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a research study to determine the efficacy and safety of investigational drug MEDI3506 for the treatment of adult participants with Chronic Obstructive Pulmonary Disease and Chronic Bronchitis.

Detailed description:
Study D9180C00002 is a Phase II, randomised, double-blind, placebo-controlled, parallel group, proof of concept study to evaluate the efficacy and safety of MEDI3506 in adult participants with moderate to severe Chronic Obstructive Pulmonary Disease and Chronic Bronchitis.

Approximately 85 sites globally will participate in this study. Approximately 144 participants will be randomized to 2 treatment groups in a 1:1 ratio to receive MEDI3506 or placebo.

Arms: arm 1: Participants received 7 doses of subcutaneous (SC) tozorakimab Dose Level 1 injection once every 4 weeks (Q4W). arm 2: Participants received 7 doses of SC placebo injection matched to tozorakimab once Q4W.
Interventions: intervention 1: Tozorakimab intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive SC injection of tozorakimab as stated in arm description. intervention 2: Participants will receive SC injection of placebo as stated in arm description.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol – Amendment Number 5.0
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Clinical Study Protocol 
Study Intervention
MEDI3506 
Study Code
D9180C00002
Amendment Number 5.0
Date
16 February 2022
A Phase II, Randomized, Double-blind, Placebo-controlled Study 
to Assess the Efficacy, Safety and Tolerability of MEDI3506 in 
Participants with Moderate to Severe Chronic Obstructive 
Pulmonary Disease and Chronic Bronchitis (FRONTIER 4)
Sponsor Name: 
AstraZeneca AB, 15185 Södertälje, Sweden 
Regulatory Agency Identifier Numb r(s):
IND:147640
EudraCT number: 2020-000571 20
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: D9180C00002
Amendment Number: 5.0
Study Intervention: MEDI3506
Study Phase: Phase 2
Short Title: A Phase II, Randomized, Double-blind, Placebo-controlled Study to Assess the 
Efficacy, Safety and Tolerability of MEDI3506 in Participants with COPD and Chronic 
Bronchitis 
Acronym: FRONTIER 4 
Medical Monitor Name and Contact Information will be provided separately
International co-ordinating investigator
Medicine Evaluation Unit
The Langley Building, Southmoor Road
Wythenshawe, Manchester
M23 9QZ
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 5
16-Feb-202
Amendment 4
23-Jul-2021
Amendment 3
01-Jun-2021
Amendment 2
08-Feb-2021
Amendment 1
01-Oct-2020
Original Protocol
03-Jul-2020
Amendment 5 (16 February 2022)
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 
because it either significantly impacts the safety or physical/mental integrity of participants or 
the scientific value of the study.
Overall Rationale for the Amendment:
To update the sample size and assumptions underlying its calculation and revise certain 
inclusion and exclusion criteria in response to investigator feedback.
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-
substantial
Section 1.1 Synopsis, 
Section 9.2 Sample 
Size Determination
Participants r ndomly 
assign d to study intervention 
and number of evaluable 
participants amended. 
Statistical methods section: 
Updated with new participant 
numbers and sample size 
justification. 
After consideration of newly 
published clinical trial results 
(Rabe et al 2021) with another 
anti-IL-33 monoclonal antibody 
in COPD, the number of 
participants has been re-
evaluated and updated.
Substantial
Section 1.3 Schedule 
of Activities.
Advice on spirometry 
assessment timing clarified.
To reduce the risk of a protocol 
deviation.
Non-substantial.
Table 2 and Table 3 Salivary 
sample added as an additional 
option for the SARS-CoV-2 
nucleic acid test.
To reflect latest procedures and 
provide an additional option to 
Non-substantial
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Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-
substantial
To minimise patient and site 
burden as baseline samples are 
collected at SV3
Non-substantial.
To minimise patient and site 
burden.
Non-substantial.
Tables 2 and 3: Minor updates 
and reordering of footnotes 
Consistency
Non-substantial.
Section 2.3.1 Risk 
Assessment, Table 4.
Updated risk assessment 
related to progression of heart 
failure.
To provide information based 
on current data.
Non-substantial.
Section 2.3.1 Risk 
Assessment, Table 4 
CT risk mitigations revised.
The previously stated effective 
dose in mSv is not possible to 
determine accurately on an 
individual basis, but is still 
relevant on a population level. 
This is described in detail in the 
Radiology Manual. Target 
radiation exposure levels for the 
study have not changed.
Non-substantial.
Section 3 Objectives 
and Endpoints, 
Table 5.
To simplify operational 
logistics.
Non-substantial.
Clarification
Non-substantial.
Correction
Non-substantial.
Section 4.1 Overall 
Design
Number of participants to be 
randomized has been updated 
and the expected percentage of 
participants in baseline and 
ICS strata removed
Consistency and to ensure that 
the final recruited population 
will more closely represent the 
eligible population.
Substantial
Advice on ensuring adequate 
time for CT and 
echocardiogram assessments
To provide additional guidance
Non-substantial.
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Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-
substantial
Use of eDiary and advice on 
spirometry assessment timing 
clarified. 
To reduce the risk of a protocol 
deviation and consistency with 
other sections.
Non-substantial.
Reduced overall number of 
patients in the CT sub study to 
remain proportionate to the 
reduced size of the main 
study. 
To facilitate the sub study as 
optional and not a barrier to 
participation in the main study.
Non-substantial.
When to perform 
echocardiogram in cases of 
suspected heart failure 
clarified.
Suspected heart failure should 
always be assessed irrespective 
of whether during an 
exacerbation or not.
Substantial
Section 4.1.2 Study 
Conduct Mitigation 
During Study 
Disruptions
Service not available for this 
study
Non-substantial
Section 4.2 Scientific 
Rationale for Study 
Design
Details of monitoring the 
phenotype of participants 
removed.
To ensure that the final recruited 
population will more closely 
represent the eligible 
population.
Substantial
Reduced overall number of 
patients in the CT sub tudy to 
remain proportionate to the 
reduced size of the main 
study.
To facilitate the sub study as 
optional and not a barrier to 
participation in the main study
Non-substantial
Section 5.1 Inclusion 
Criteria.
Criterion 1: Upper age limit 
chang d from 75 years to 
80 years
Older age allowed as other 
exclusion criteria prevent those 
with significant comorbidities 
from being included in the study
Substantial
Criterion 3 relating to 
vaccination removed and 
vaccination guidance included 
in concomitant medications 
(Section 6.5). Replaced with: 
This inclusion criterion has 
been removed.
To permit inclusion of patients 
who did not receive 
pneumococcal and influenza 
vaccination where 
recommended by local 
guidelines 
Substantial.
Criterion 4: Acceptable 
documentation for evidence of 
COPD and requirement to 
document updated.
Clarification of acceptable 
documentation. 
Non-substantial
Criterion 5: Lower limit for 
FEV1 changed to 20%
To permit participation of 
patients with more severe 
Substantial
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Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-
substantial
COPD who are otherwise 
potential treatment responders 
whilst excluding those with 
significant comorbidity or end-
organ failure such as cor 
pulmonale or requiring LTOT
Criterion 8: Acceptable 
documentation for evidence of 
stable dual or triple therapy 
and requirement to document 
updated.
Clarification of acceptable 
documentation.
Non-substantial
Criterion 9: Updated to 
confirmation by participant of 
self-administration of rescue 
medication for an acute 
exacerbation
Clarification of verbal 
confirmation and requirement to 
record in participant's source 
document
Non-substantial
Criterion 13: Upper limit of 
body mass index increased to 
40 mg/m2
High r BMI allowed as other 
exclusion criteria prevent those 
with significant comorbidities 
from being included in the study
Substantial
Section 5.2 Exclusion 
Criteria, Medical 
Conditions and 
Diagnostic 
Assessments
Criterion 1: Rescreening 
allowed for participants with a 
positive diagnostic ucleic 
acid test for SARS-CoV-2 
Clarification that participants 
with asymptomatic or mild 
disease are eligible.
Substantial
Criterion 3a: Excepti n to 
exclusion from participation in 
study amended for diabetes 
mellitus 
Clarification, and removal of 
HbA1c marker example.
Criterion 3c: Arrhythmia 
noted as including atrial 
fibrillation
Clarification
Criterion 3e revised to indicate 
systemic hypertension should 
be well controlled and stable 
for at least 3 months according 
to the investigator and remove 
the upper limit of two 
medications.
To include the need for 
investigator assessment and to 
reflect variation in global 
practice.
Criterion 3f revised to exclude 
clinically significant cor 
pulmonale
Clarification
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Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-
substantial
Criterion 5: Reworded asthma 
exclusion criterion
Clarification 
Criterion 9e removed and 
replaced with: This exclusion 
criterion has been removed
Redundant
Criterion 9g: Chest CT scan 
findings requiring surveillance 
revised
Clarification
Criterion 10: Removed and 
replaced with: This exclusion 
criterion has been removed
Based on high intra-patient 
variability nature of NT-
proBNP in the COPD 
population, updated risk 
assessment (see IB for details) 
and presen e of other exclusion 
criteri  ensure absence of heart 
failure in participants.
Criterion 15: Revised text 
related to LTOT
Simplification of text 
Criterion 23: Revised text 
associated with hepatitis
Simplification of text
Criterion 24: Revised text 
associated with HIV
Clarification
Section 5.2 Exclusion 
Criteria, Prior 
Therapy
Criterion 34h: Re ised to 
allow chronic macrolide or 
other antibiotic therapy 
provid d criteria re met
Consistency with product 
development program
Non-substantial
Criterion 34i: Examples of 
PDE4 inhibitors added and 
guidance revised to allow 
PDE4 inhibitors provided 
criteria are met
Consistency with product 
development program
Criteria 34k, and l: Updated 
and aligned with Section 6.5.5  
Clarification and consistency
Section 5.2 Exclusion 
Criteria Other 
Exclusions
Criterion 41: Removed as 
there is no longer capping of 
strata 
Clarification.
Non-substantial
Section 5.2 Exclusion 
Criteria for Imaging 
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Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-
substantial
Section 6.3.1 
Methods for 
Assigning Study 
Intervention Groups
Removal of text around strata 
caps and safety alerts
To align with Section 5 and 
correction
Non-substantial
Section 6.3.2 
Methods to Ensure 
Blinding
Removal of text on safety 
alerts for certain hematology 
tests
Alerts not necessary 
Non-substantial
Section 6.5 
Concomitant Therapy
Vaccination against influenza 
and pneumonia advice revised.
To permit inclusion of patients 
who did not receive 
pneumococcal and influenza 
vaccination where 
recommended by local 
guid lines
Substantial
Section 6.5.5 
Restricted and 
Prohibited 
Medications
Revised text related to 
Macrolide therapy and LTOT
Simplifica ion of text and 
alignment with Section 5.2
Non-substantial
Baseline audiometry testing 
required to be documented 
before randomisation.
To ensure safety of participants 
during study participation. 
There is an identified risk of 
macrolides causing ototoxicity. 
Substantial
Section 8.1.3 Home 
Spirometry and 
eDiary
Advice on spirometry 
assessment timing clarified. 
To reduce the risk of a protocol 
deviation and consistency with 
other sections.
Non-substantial.
Added text on importance of 
transmitting data daily
To emphasise the need for this 
to be done
Section 8.5.2 
Immunogenicity 
Assessments
Revised text to add 
circumstances in which ADA 
samples might be collected 
after the follow up period
Clarification
Non-substantial
Section 9.2 Sample 
Size Determination
To reflect the expectation of 
determining an effect in a 
smaller sample of 20 patients 
per arm.
Non-substantial
Section 9.4.2.2 
Subgroup Analyses
Removed numerical range for 
extent of emphysema
Redundant, will be described in 
the SAP
Non-substantial
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ADA = Anti-drug antibody(ies); BMI = Body mass Index; COPD = Chronic obstructive; pulmonary disease; 
CT = computer tomography; FEV1 = Forced expiratory volume in 1 Second; HbA1c = glycated haemoglobin; 
IB = Investigators’ Brochure; IL-33 = Interleukin 33; LTOT = Long term oxygen therapy; 
NT-proBNP = N-terminal pro-brain natriuretic peptide; PDE4 = Phosphohipidesterase-4; SAP = Statistical 
analysis plan; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; 
 SV = Study visit.
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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.................................... 3
TABLE OF CONTENTS.................................................................................................... 10
1
PROTOCOL SUMMARY................................................................................ 15
1.1
Synopsis ........................................................................................................... 15
1.2
Schema............................................................................................................. 18
1.3
Schedule of Activities....................................................................................... 19
2
INTRODUCTION............................................................................................ 27
2.1
Study Rationale ................................................................................................ 27
2.2
Background ...................................................................................................... 27
2.3
Benefit/Risk Assessment.......................
........................................................ 28
2.3.1
Risk Assessment..................................... .... .................................................. 28
2.3.2
Benefit Assessment................................. ........................................................ 32
2.3.3
Overall Benefit: Risk Conclusion...... ... ........................................................... 32
3
OBJECTIVES AND ENDPOINTS.......
........................................................ 33
4
STUDY DESIGN ...........................
............................................................. 38
4.1
Overall Design..................... ....... ................................................................... 38
4.1.1
Study (and Sub-Study) Conduct and Planned Mitigations During COVID-19 
Pandemic........................ ............................................................................... 41
4.1.1.1
Vaccination Against COVID-19 ....................................................................... 43
4.1.2
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 44
4.2
Scientific Rationale for Study Design ............................................................... 45
4.2.1
Rationale for Study P pulation ......................................................................... 46
4.2.2
Rationale for Prima y Endpoint......................................................................... 47
4.2.3
Rationale for Intervention Period Duration........................................................ 47
4.2.4
Participant Input into Design............................................................................. 48
4.3
Justification for Dose........................................................................................ 48
4.4
End of Study Definition.................................................................................... 49
4.4.1
Study Stopping Criteria..................................................................................... 49
5
STUDY POPULATION ................................................................................... 50
5.1
Inclusion Criteria .............................................................................................. 50
5.2
Exclusion Criteria ............................................................................................. 53
5.3
Lifestyle Considerations ................................................................................... 58
5.3.1
Meals and Dietary Restrictions ......................................................................... 58
5.3.2
Caffeine, Alcohol, and Tobacco........................................................................ 59
5.3.3
Activity............................................................................................................. 59
5.4
Screen Failures ................................................................................................. 59
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6
STUDY INTERVENTION............................................................................... 60
6.1
Study Intervention Administered....................................................................... 60
6.1.1
Study Interventions........................................................................................... 60
6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 61
6.2.1
Study Intervention Inspection ........................................................................... 61
6.2.2
Dose Preparation Steps ..................................................................................... 61
6.2.2.1
Study Intervention Administration.................................................................... 62
6.2.2.2
Monitoring Dose Administration....................................................................... 63
6.2.3
Accountability .................................................................................................. 63
6.3
Measures to Minimise Bias: Randomization and Blinding ................................ 63
6.3.1
Methods for Assigning Study Intervention Groups............................................ 63
6.3.2
Methods to Ensure Blinding.............................................................................. 64
6.3.3
Methods for Unblinding.................................................................................... 64
6.3.3.1
Unblinding for Analysis Purposes..................................................................... 65
6.4
Study Intervention Compliance............. .......................................................... 66
6.5
Concomitant Therapy.............................. .... .................................................. 66
6.5.1
Required Maintenance Therapy for COPD........................................................ 66
6.5.2
6.5.3
Medication Withhold Periods......... ... ..... ....................................................... 67
6.5.4
Treatment of Exacerbations of COPD ............................................................... 67
6.5.5
Restricted and Prohibited Medications ............................................................. 67
6.5.6
COVID-19 Vaccination .............. ................................................................... 69
6.6
Dose Modification ............ ..
........................................................................ 69
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.......................................................... 69
7.1
Discontinuation of Study Intervention............................................................... 69
7.2
Participant Withdrawal from the Study ............................................................. 70
7.3
Lost to Follow-up ..... ..................................................................................... 71
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 71
8.1
Efficacy Assessments........................................................................................ 72
8.1.1
Clinic Spirometry ............................................................................................. 72
8.1.1.1
General Requirements....................................................................................... 72
8.1.1.2
Post-BD Spirometry.......................................................................................... 73
8.1.2
Airwave Oscillometry....................................................................................... 73
8.1.3
Home Spirometry and eDiary............................................................................ 74
8.1.4
Objective Cough Monitoring............................................................................. 75
8.1.5
COPDCompEx ................................................................................................. 76
8.1.6
COPD Exacerbations (AECOPD) ..................................................................... 76
8.1.6.1
Severity of AECOPD........................................................................................ 77
8.1.6.2
Duration of AECOPD....................................................................................... 77
8.1.6.3
COPD Exacerbation eCRF................................................................................ 78
8.1.7
8.1.8
Patient Reported Outcome Questionnaires ........................................................ 78
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LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 104
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 109
Appendix C
Handling of Human Biological Samples ................................................ 114
Appendix D
Optional Genomics Initiative Sample..................................................... 116
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 119
Appendix F
Contraception Guidance......................................................................... 126
Appendix G
Major and Minor Symptoms of COPD................................................... 127
Appendix H
National Institute of Allergy and Infectious Diseases and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis............ 129
Appendix I
Signs and Symptoms and Management of Acute Anaphylaxis ............... 130
Appendix J
Example of Patient COVID-19 Screening Questionnaire ....................... 133
Appendix K
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster  or Public Health Crisis ............................ 134
Appendix L
Abbreviations ................. .................................................................... 137
Appendix M
Protocol Amendment History................................................................. 141
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Participants will be enrolled for at least a 4-week screening/run-in period, a 28-week 
intervention period (during which they receive 7 doses SC Q4W), and an 8-week follow-up 
period.
Participants must be on stable doses of dual therapy (ICS + LABA, or LABA + LAMA) or 
triple therapy (ICS + LABA + LAMA) for ≥3 months prior to enrolment and should remain 
so during the study. There should have been no change in maintenance COPD treatment after 
a previous exacerbation prior to entering into the study.
There is one sub-study included as part of the trial: 
.
Disclosure Statement: This is a parallel group treatment study with 2 arms (MEDI3506 and 
placebo) that is participant, investigator, and sponsor blinded.
Number of Participants:
Approximately 144 participants will be randomly assigned to study intervention (MEDI3506 
or placebo) such that approximately 140 participants are evaluable for the primary analysis.
Intervention Groups and Duration:
All participants passing the initial screening visit will enter a run-in period of at least 4 weeks 
on their usual standard of care treatment. Participants will be randomized to MEDI3506 or 
placebo if they continue to meet all eligibility criteria, including adherence to home 
assessments and spirometry criteria using data from the run-in period. 
Approximately 144 participants will be randomized 1:1 to MEDI3506 
 SC Q4W or 
placebo for 7 doses.
Data Monitoring Committee: 
A DSMB has been established to oversee the MEDI3506 clinical development program. In 
addition to a full DSMB 6-month periodic review of safety data, the DSMB chair will review 
unblinded safety data summaries every 3 months; the DSMB can meet on an ad hoc basis. A 
blinded study-specific safety committee (or Medical Monitor) will also review SAEs and 
SUSARs.
Statistical Methods:
A sample size of 140 participants (70 participants per arm) will provide 80% power to detect a 
difference in mean change from baseline in FEV1 of 90 mL (assumed standard deviation of 
250 mL) between the two randomized groups at a one-sided 10% level of statistical 
significance. To allow for 2% of participants being ineligible for the primary analysis, 
approximately 144 participants will be randomized in the study (72 per arm). 
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Statistical Analyses:
The primary estimand is a ‘Treatment Policy’ estimand, as follows: The difference in mean 
change from baseline in FEV1 at Week 12 (MEDI3506 – placebo) will be estimated using a 
repeated measures mixed effects analysis of covariance model, for the ITT population. This 
will include all available data from all visits up to and including Week 12, irrespective of 
whether the participant discontinued study intervention or received reliever therapy. The 
model will include fixed effects for baseline, eosinophil strata, background medication strata, 
visit, study intervention, and the baseline by visit, and study intervention by visit interactions. 
An unstructured covariance matrix will be used to describe the correlations between 
observations on a participant between visits.
A similar approach will be taken for the analysis of cough VAS, BCSS, 
 SGRQ, and 
. Data may be log-transformed prior to analysis where appropriate. Change 
from baseline in objective cough parameters and oscillometry parameters at Week 12 will be 
analyzed using analysis of covariance.
Analysis of time to event 
 will include available data (up to 
Week 28 where this is available) for all participants  Time to event endpoints will be analyzed 
using a Cox proportional hazards model. 
Safety endpoints including AEs, SAEs, AESIs, laboratory parameters, vital signs, ECGs, and 
physical examinations will be summarized using descriptive statistics.
1.2
Schema
The general study design is summarized in Table 1.
Table 1
Study Design
Study 
Period
Screening 
/ Run-in
Intervention Period
Follow-up
Visit 
Number
SV1 and 
SV2
SV3
SV4 to 
SV7
SV8
SV9 to 
SV11
SV12
SV13 and 
SV14
Study 
Week
-5 to -1
0
0 to 8
12
16 to 
24
28
32 to 36
Enrolment, 
Screening, 
Run-in
Randomization 
and Dose 1
Doses 2 
and 3
Primary
Endpoint 
Assessment 
and Dose 4
Doses 
5 to 7
End of 
Intervention 
Visit
Follow-up
R = randomization; SV = study visit.
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Participants will receive 7 administrations of study intervention Q4W. SV12 (Week 28) will 
serve as the end of intervention visit (see Section 4.1). The primary endpoint visit occurs at 
SV8 (Week 12).
1.3
Schedule of Activities
Patient reported outcome questionnaires to be completed at site visits must be completed prior 
to study intervention administration and ideally before any discussions of health status or 
other study procedures, such as collection of laboratory samples, to avoid biasing the 
participant’s responses to the questions. All daily ePRO assessments for the morning and 
evening eDiary at home should be completed within the set time window programmed into the 
device; device alerts will notify the participant when it is time to respond to the questions. 
After each study visit, participants will return to the normal schedule of answering the eDiary 
at home.
Order of procedures:
!
All assessments should be performed prior to administration of investigational product 
except where otherwise indicated (eg, post-dose vital signs)
!
Participants will be instructed to perform all home spirometry assessments before use of 
their usual standard-of-care inhaled medication. Whenever vital signs, ECGs, and blood 
draws are scheduled for the same nominal time, the order should be as follows: ECG, 
vital signs (vital signs can occur imm diately after ECG using the same rest period), then 
blood draws. The timing of the fir t 2 assessments should be such that it allows the blood 
draw (eg, PK blood sample) to occur at the assigned nominal time.
!
AO assessments should take place before spirometry.
!
Sputum samples should be taken after procedures requiring a BD withhold (including 
spirometry and AO).
!
If both nasal epithelial li ing fluid and mucosal samples are required on the same day 
then the epithelial lining fluid sample should be taken prior to the mucosal sample.
Refer to Section 8 for additional information on assessment ordering (eg, pre-, post-dose or 
multiple timepoints within a visit).
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Table 2
Screening Procedures
Study Period
Screening / Run-in
Visit Number
SV1
SV2
Procedure / Study Day
Day -35 to 
Day -28
Day -21 to Day -7
Study Week
Week -5 to -4
Week -3 to -1
Written informed consent/assignment of E-code a
X
Written informed consent for future use and/or genetic 
analysis (optional) a
X
Written informed consent for CT sub-study (as applicable) a
X
Verify eligibility criteria
X
X
Safety Assessments
Demography
X
Medical and COPD/chronic bronchitis history including 
assessment of COPD exacerbations and evaluation of 
predominant emphysema by physician diagnosis
X
Smoking History
X
Physical examination (full)
X
Weight, height
X
ECG
X
Vital signs
X
Assessment of AEs/SAEs
X
X
Concomitant medications
X
X
Echocardiogram a, b
X
CT a, b, c
X
SARS-CoV-2 nucleic acid test (nasopharyngeal swab or 
salivary sample) d
X
X
Efficacy assessments
Clinic Spirometry (pre-BD)
X
Clinic Spirometry (post-BD)
X
Airwave oscillometry
X
Provision, and training on use, of at home spirometer and 
eDiary for use every day
X
Assess adherence to the completion of eDiary entries and 
home device use
X
Provision of and training of use of cough monitoring 
followed by 24 hour monitoring post clinical visit
X
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Table 2
Screening Procedures
Study Period
Screening / Run-in
Visit Number
SV1
SV2
Procedure / Study Day
Day -35 to 
Day -28
Day -21 to Day -7
Study Week
Week -5 to -4
Week -3 to -1
On-site ePROs: 
CAT
X
Collect blood for:
Serum chemistry
X
NT-proBNP
X
Haematology
X
Coagulation parameters
X
Hepatitis B, C; HIV-1; virology
X
Serum pregnancy test (female participants of childbearing 
potential only)
X
FSH (if needed to confirm post-menopausal status in female 
participants aged < 50 years)
X
IGRA (TB test)
X
Collect other samples:
Collect urine for:
Urinalysis
X
Pregnancy test (female participant  of childbearing potential 
only) f
X
See CT scan collected as part of the safety assessments above
Pandemic impact assessment
X
X
b
Echocardiogram and CT dates will be scheduled at SV1, to occur post-confirmation of eligibility at SV2.
d
May be performed on a separate day ahead of study visit if required. The analysis can either be performed 
locally or centrally.
f
Only required if a CT scan as part of SV2 is performed. If required must be done prior to CT scan.
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AE = Adverse event; BD = Bronchodilator; CAT = COPD assessment test; COPD = Chronic obstructive 
pulmonary disorder; CT = Computed tomography; ECG = Electrocardiogram; ePRO = Electronic patient 
reported outcomes; FEV1 = Forced expiratory volume in 1 second; FSH = Follicle stimulating hormone; HIV = 
Human immunodeficiency disease; IGRA = Interferon gamma release assay; NT-proBNP = N-terminal pro-brain 
natriuretic peptide; PEF = Peak expiratory flow; SAE = Serious adverse event; SARS-CoV-2 = severe acute 
respiratory syndrome coronavirus 2; SGRQ = St George’s Respiratory Questionnaire; SV = Study visit; 
TB = Tuberculosis.
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Table 3
Schedule of Activities: Study Intervention and Follow-up
Study Period
Intervention Period
Follow-up
E/D
E/A a
Visit Number
SV3
SV4 TC
SV5
SV6
SV7
SV8
SV9
SV10
SV11 
SV12
SV13
SV14
Study Day (SV5 to SV14 window: ± 3 
days)
1
2
15
29
57
85
113
141
169
197
225
253
Study Week
0
0
2
4
8
12
16
20
24
28
32
36
Efficacy assessments
Clinic spirometry (pre-BD)
X
X
X
X
X
X
X
X
X
X
X
X
Clinic spirometry (post-BD)
X
X
X
Airwave oscillometry
X
X
X
X
Use of at home spirometry b
and eDiary c
Every day throughout inter ention and follow-up periods
Assess adherence to the completion of 
eDiary entries and home device use 
(including PEF)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cough monitoring (24 hour monitoring 
post clinic visit)
X
ePRO: SGRQ
X
X
X
X
X
Study Participant Feedback 
Questionnaire (Optional)
X
X
X
X
Assessment of COPD exacerbations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety assessments
Physical examination a, c
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
ECG
X
X
X
X
X
Vital signs d
X
X
X
X
X
X
X
X
X
X
X
X
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Table 3
Schedule of Activities: Study Intervention and Follow-up
Study Period
Intervention Period
Follow-up
E/D
E/A a
Visit Number
SV3
SV4 TC
SV5
SV6
SV7
SV8
SV9
SV10
SV11 
SV12
SV13
SV14
Study Day (SV5 to SV14 window: ± 3 
days)
1
2
15
29
57
85
113
141
169
197
225
253
Study Week
0
0
2
4
8
12
16
20
24
28
32
36
Assessment of AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Echocardiogram e
X f
X f
Injection site reactions
X
X
X
X
X
X
X
X
X
X
X
Nasopharyngeal swab or salivary 
sample for SARS-CoV-2 nucleic acid 
test g
X
X
X
X
X
X
X
X
X
X
X
X
Collect blood for
Serum Chemistry 
X
X
X
X
X
X
X
X
X
NT-proBNP e
X
X
X
Haematology
X
X
X
X
X
X
X
X
X
PK
X
X
X
X
X
X
X
X
X
X
Immunogenicity
X
X
X
X
X
X
X
X
X
X
Genetic analysis (optional)
X i
SARS-CoV-2 serology test (serum)
X
X
X
X
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Table 3
Schedule of Activities: Study Intervention and Follow-up
Study Period
Intervention Period
Follow-up
E/D
E/A a
Visit Number
SV3
SV4 TC
SV5
SV6
SV7
SV8
SV9
SV10
SV11 
SV12
SV13
SV14
Study Day (SV5 to SV14 window: ± 3 
days)
1
2
15
29
57
85
113
141
169
197
225
253
Study Week
0
0
2
4
8
12
16
20
24
28
32
36
Collect urine for
Urinalysis
X
X
X
X
X
Pregnancy test (female participants of 
childbearing potential only)
X
X
X
X
X
X
X
X
X
X
Collect other samples
Nasal epithelial lining fluid
X
X
X
X
X
X
X
Verify eligibility criteria
X
Randomization
X
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2
INTRODUCTION
MEDI3506 is a human IgG1 mAb that binds to human IL-33, which is being developed for 
the treatment of asthma, atopic dermatitis, COPD, and diabetic kidney disease. 
2.1
Study Rationale
The MEDI3506 pre-clinical profile suggests that MEDI3506 can reduce airway inflammation, 
improve epithelial integrity, reduce mucus production, and improve muco-ciliary transport. As 
such, MEDI3506 is hypothesized to impact COPD status by increasing FEV1 (and other 
physiological measures of lung function) and reducing frequency and severity of COPD 
exacerbations, thereby improving quality of life.
One Phase I clinical study of MEDI3506 (Study D9180C00001) was completed in 
December 2019. Study D9180C00001 was a first-in-human, randomized, placebo-controlled, 
blinded (investigator and participant blinded; sponsor unblinded) clinical study in 
88 participants to evaluate the safety, tolerability, PK, and immunogenicity of single and 
repeated doses of MEDI3506. MEDI3506 was generally found to be safe and well tolerated. 
For further details refer to the IB.
The purpose of this proof-of-concept study is to evaluate the safety and efficacy of MEDI3506 
in participants with COPD and chronic bronchitis. 
2.2
Background
Chronic obstructive pulmonary disease is the fourth leading cause of death in the world and is 
projected to be the third leading caus  of death worldwide by 2030 (Adeloye et al 2015). 
Chronic obstructive pulmonary disease is characterized by persistent respiratory symptoms 
and airflow limitation (post-BD FEV1/FVC < 0.70) that is due to airway and/or alveolar 
abnormalities, usually caused by significant exposure to noxious particles or gases, and 
influenced by host factors including abnormal lung development. Significant comorbidities 
may have an impact on morbidity and mortality (GOLD 2020). Chronic obstructive 
pulmonary disease is not fully reversible, usually progressive and associated with an enhanced 
chronic inflammatory response in the lung. Patients with active chronic bronchitis symptoms 
bear a greater burden of disease than those without and are characterized by more rapid loss of 
lung function, increased mortality and increased risk of exacerbation (Kim et al 2011;
de Oca et al 2012; Corhay et al 2013; Kim and Criner 2013; Woodruff et al 2016;
Lahousse et al 2017). Mucus hypersecretion with accumulation in the small airways in COPD 
is present independent of symptoms of cough and sputum production (Caramori et al 2004;
Burgel and Nadel 2008) and can coexist with extensive emphysema (Dunican et al 2021;
Kim et al 2021). Mucus plugging is evident at all stages of severity of COPD, but is greatest 
in those with most severe disease. The correlation between extent of emphysema and mucus 
plugging is not well defined but both independently negatively correlate with FEV1. Patients 
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with recurrent COPD exacerbations have higher sputum inflammatory markers 
(Bhowmik et al 2000) which suggests that underlying inflammation may lead to disease 
progression (Crooks et al 2000; Anzueto 2010). Interleukin-33 expression is upregulated in 
the lungs of patients with COPD, is inversely correlated with lung function, and has a role in 
inflammatory and epithelial processes in COPD. 
MEDI3506 is a mAb that binds to IL-33 and potently and specifically blocks all forms of 
IL-33 to prevent their signalling. Interleukin-33 is an alarmin cytokine from the IL-1 family. 
Interleukin-33 is localized in the nucleus, and following injury, stress or cell death, it is 
released from the cell, and exerts a pro-inflammatory biological function, which is skewed 
towards a pro-inflammatory Th1 cytokine profile and broad responder cell population on the 
background of smoke-induced inflammation (Kearley et al 2015). Interleukin-33 pathway 
blockade prevents exacerbation of viral-induced inflammation in a mouse smoke exposure 
model (Kearley et al 2015), and IL-33 has been shown to have a role in goblet cell 
hypertrophy, mucus hypersecretion and the ratio of mu us producing to ciliated cells in 
airway epithelium in mouse models of prolonged lung inflammation (Schmitz et al 2005;
Allinne et al 2019). As such, MEDI3506 mode of action is hypothesized to impact airway
inflammation, mucus and cough symptoms and lung function endpoints in COPD, and 
through modification of these factors, reduce frequency and severity of exacerbations. This 
proposed mode of action of MEDI3506 suggests that COPD patients with chronic bronchitis 
may be most likely to gain benefit from MEDI3506 treatment, and therefore COPD 
participants with chronic bronchitis are an appropriate population to begin efficacy testing of 
MEDI3506. 
A detailed description of the chemistry, pharmacology, mechanism of action, and safety of
MEDI3506 is provided in the IB.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
MEDI3506 may be found in the IB.
2.3.1
Risk Assessment
To date, there are no identified risks associated with MEDI3506. Potential risks for 
MEDI3506 are described in Table 4 and in more detail in the IB.
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As per above, serious infections (including those with SARS-CoV-2) are also a potential risk 
of MEDI3506. AstraZeneca is not aware of any current evidence of a direct link between 
IL-33, or IL-33 suppression, and contracting SARS-CoV-2 and early stages of COVID-19 
illness post infection. Moreover, it is hypothesised that IL-33 suppression might be beneficial 
in the later, hyperinflammatory phase of severe COVID-19 illness; MEDI3506 will be tested 
in patients with severe COVID-19 infections as part of the ACcelerating COVID-19 Research 
and Development (ACCORD) Study 2 (ACCORD-2; EudraCT number 2020-001736-95).
2.3.2
Benefit Assessment
The purpose of this proof-of-concept study is to evaluate the safety and efficacy of MEDI3506 
in participants with COPD and chronic bronchitis. For participants randomized to MEDI3506, 
there is a potential benefit in terms of improvement of their COPD disease status and 
reduction in COPD exacerbations. However, since at this early stage of clinical development, 
it is yet to be determined if MEDI3506 has an effect in patients with COPD with chronic 
bronchitis, participants might not receive any individual benefit from participating in this 
study. Participants will be required to continue all their COPD maintenance treatment 
throughout the study to minimize the risk of disease status worsening during the study. 
To date, efficacy of MEDI3506 has not been assessed in patients with COPD and, hence, there 
are no clinical data that show benefit in this population. However, safety data obtained during 
Phase I in participants with COPD and the pre-clinical scientific data support clinical 
development of MEDI3506 in COPD.
2.3.3
Overall Benefit: Risk Conclusion
Taking into account the measures taken to minimize risk to participants in this study, the 
potential risks identified in association with MEDI3506 are justified by the anticipated 
benefits that may be afforded to participants with COPD with chronic bronchitis.
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Table 5
Objectives and Endpoints
Objective
Endpoint
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4
STUDY DESIGN
4.1
Overall Design
For an overview of the study design see Table 1. For details on study interventions given 
during the study, see Section 6. For details on what is included in the efficacy and safety
endpoints, see Section 3. For further details on assessments, including screening assessments, 
see Section 8.
This is a Phase II, randomized, double-blind, placebo-controlled, proof-of-concept study to 
assess the efficacy, safety and tolerability of MEDI3506, administered SC Q4W for 7 doses, 
in participants with moderate or severe COPD receiving standard of care (dual or triple 
therapy) as maintenance therapy, with a history of ≥1 moderate or severe acute exacerbation 
in the previous 24 months while on stable background treatment, and moderate to severe 
chronic bronchitis, with active sputum and cough symptoms. The intervention period lasts 
28 weeks (7 doses).
Improvement in FEV1 (primary endpoint) is considered important but not sufficient to show 
the potential of MEDI3506 to meet the unmet medical need in COPD. Therefore, 
COPDCompEx (secondary endpoint) will be used to assess whether MEDI3506 has wider 
clinical efficacy, specifically, that treatment with MEDI3506 has the potential to reduce acute 
exacerbations. To enable evaluation of COPDCompEx, an intervention period of 28 weeks 
(7 doses) has been selected (see Section 4.2.3).
Approximately 144 participants will be randomized in a 1:1 ratio to placebo or 
 of 
MEDI3506 SC Q4W, for 7 doses. The randomization will be stratified by 
 and background medication (includes ICS vs 
does not include ICS). 
There are 3 study periods: screening and run-in; intervention period; and follow-up (Table 1).
Screening/Run-in Period
Informed consent and evaluation of inclusion/exclusion criteria (with the exception of CT, 
echocardiogram measures, and eDiary compliance) will be assessed at SV1. Only participants 
who meet all other eligibility criteria will be required to perform echocardiogram, CT and 
other scheduled assessments at screening SV2. Echocardiogram and CT dates will be 
scheduled at SV1, to occur post-confirmation of eligibility at SV2. SV1 and SV2 may be 
conducted over more than one clinic appointment to accommodate informed consent, 
echocardiogram, CT and sputum assessments; however, these must be completed in 
accordance with the SV window, per Table 2, and to allow sufficient time for a radiologist 
review prior to SV3 (Randomization Visit). 
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At the completion of initial enrolment at SV1, participants will proceed to the run-in period 
for at least 4 weeks, to allow adequate time for all the eligibility criteria to be evaluated. At 
approximately 1 to 3 weeks into the study period, SV2 will be conducted to further assess 
participant eligibility, including CT assessment of emphysema and echocardiogram. Sites 
should ensure there is adequate time to ensure results of CT and echocardiogram are available 
to determine eligibility. Computed tomography emphysema percentage will be calculated 
using automated software by an external vendor. Where an automated report is not possible 
due to technical issues, if possible, the CT scan emphysema percentage will be reported by a 
suitably qualified radiologist provided by the external vendor. Moreover, a suitably qualified 
radiologist at the clinic site (for clinical findings outside of emphysema and morphometric 
assessment) will be required to review the CT for additional findings, before SV3. 
Presence or absence of excessive improvement in FEV1 will be assessed between SV1 and 
SV3 (period of at least 4 weeks). Acceptable adherence of eDiary completion, at-home 
assessments, and BCSS average score in cough and sputum domains will be assessed over the 
14 days preceding SV3. Participants who meet the eligibility criteria will be randomized to 
study intervention.
During the screening period, the participant must undergo all assessments per Table 2
including biosampling and baseline CT evaluation, with the exception of blood sampling for 
genomic assessments, which is optional. A previously performed chest CT scan may be 
acceptable for baseline evaluation, see Section 8.1.9.
Participants will be given a device at SV1, incorporating a spirometer for PEF/FEV1 and an 
eDiary for recording symptom and medication use including as-needed medication at home. 
This will be used to collect baseline data of spirometry, the eDiary (ER-S:COPD, BCSS, 
cough VAS item), and adherenc  during the screening/run-in period (at least 4 weeks). 
Participants will be instructed to perform all home spirometry assessments before use of their 
usual standard-of-care inhaled medication.
Participants entering the sub-study
will have additional requirements during the 
screening period as set out in Section 8, as long as sub-study eligibility is confirmed for the 
individual participants. Sub-study participation is dependent on site expertise / capability.
Participants will continue with stable doses of permitted concomitant COPD medications from 
the screening through to the randomization visit. 
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Intervention Period: 7 doses and EOT visit
Section 6.5.5 provides a list of medication restrictions and prohibitions to be followed 
throughout the conduct of the clinical trial.
A DSMB has been established to oversee the MEDI3506 clinical development program. 
Further details of the DSMB are found in Section 9.6.
Participants will be maintained on their currently prescribed maintenance therapies from 
enrolment throughout the run-in, intervention period and follow-up period. During the 
intervention period, the participant must undergo all assessments per Table 3, with the 
exception of blood sampling for genomic assessments which is optional, and repeat 
 which is at the investigator’s discretion as detailed in 
Section 8.6.1.2.
Intervention Period
Participants fulfilling all eligibility criteria, including hose requiring a review of data gathered 
at SV2 assessment and SV3 pre-dose, will begin a randomized, placebo-controlled 
intervention period of 7 doses. The primary endpoint assessment occurs at Week 12. The final 
dose is administered at Week 24. The End of Intervention visit is at Week 28. MEDI3506 or 
placebo will be administered by SC injection Q4W.
Participants will be reviewed by a telephone visit after first dose visit and attend on site visits 
to perform assessments including biosampling, spirometry and other functional measurements 
such as AO, as per the SoA (Secti n 1.3).
Participants will remain at the investigational site:
!
After the first and second dose of study intervention: At least 2 hours post dose for 
observation; or until participant is stable; or the time taken to complete SoA, whichever is 
longest
!
After Doses 3, 4, 5, 6 and 7: At least 1 hour post dose for observation; or until participant 
is stable; or the time taken to complete SoA, whichever is longest
Participants will be asked to complete the eDiary, home spirometry. In addition, all 
participants will be asked to wear a cough monitoring device for 24 hours immediately 
following study visits as per SoA (Section 1.3).
An automated alert will be provided to the participant and site if there is a significant 
deterioration in the eDiary data points, prompting the participant to contact the site or their 
treating physician for further clinical review and management of a possible AECOPD.
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At clinic visits, participants will undergo a short assessment to confirm moderate or severe 
AECOPD including assessments of appropriate management.
Follow up Period
Follow-up visits will occur 4 and 8 weeks after EOT visit to allow for determination of 
immunogenicity and potential prolonged PD effects, and evaluation of safety. Participants will 
be discharged from follow-up 3 months after the last dose of study intervention.
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 450 mL in 3 months. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Additional Visits
A clinical assessment of any potential exacerbation during the intervention and follow up 
periods will occur either at the next scheduled visit or, if necessary, an additional E/A visit 
prior to the next scheduled visit (see the SoA in Section 1.3).
For any participants with suspected heart failure during participation in the study, an ad hoc 
echocardiogram and NT-proBNP measurements are required. In addition, for these 
participants, vital signs, physical examinations and any other examinations (eg, chest X-ray) 
can be performed at the investigator’s discretion, following local standard practice.
4.1.1
Study (and Sub-Study) Conduct and Planned Mitigations During 
COVID-19 Pandemic 
Coronavirus disease 2019 has emerged as a worldwide pandemic disease with significant 
implications for public health. AstraZeneca accepts that a careful risk-benefit analysis should 
be performed in each region before initiating clinical research that impacts the clinical 
resources needed for the COVID-19 pandemic. Hence, AstraZeneca will monitor countries 
and sites, and the study will not begin until local and national governments and clinical sites 
have indicated that it is acceptable to conduct clinical studies, any stay-in-place or lockdown 
orders have been lifted, and the safety of site staff and participants can be ensured. 
Furthermore, each study site must have appropriate measures to ensure safety of site staff and 
participants.
It is recognised that depending on the location and facilities of a clinical site, study visit 
attendance may place participants at risk of exposure to SARS-CoV-2. Where visits need to 
occur at locations other than the primary study site (eg, CT scans or echocardiograms), then 
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the investigator should select appropriate locations given the current environment. It is 
accepted that additional visits (eg, as part of 
 participation) necessarily entail an 
additional risk of exposure to SARS-CoV-2.
Furthermore, it is recognised that more general population-level measures to reduce infection 
rates (eg, travel restrictions) may inhibit the ability of participants to attend study visits. 
Necessary healthcare responses at sites to the pandemic (eg, additional infection control 
measures) may also inhibit the ability of a clinical site to effectively and properly conduct the 
study. Study visit attendance for dosing and for clinical assessments of treatment response are 
critical for the scientific value of the study.
Therefore, investigators should not enrol participants unless they have reasonable confidence 
that throughout the duration of the study:
!
Participants will be able to attend study visits, whilst avoiding contact with concentrations 
of COVID-19 patients (eg, hospital entrances used by such patients); and
!
The site will be able to conduct the study effectively and safely, considering relevant 
national and local factors.
The primary endpoint will be analyzed using a repeated measures mixed effect model which, 
in the event of missing data, uses all data that are available.
AstraZeneca will routinely conduct risk-based enrolment assessments on a country and site 
level during the pandemic phase of COVID-19, and study monitoring will include:
!
AEs associated with new onset SARS-CoV-2 infection
!
Participants withdrawn due to COVID-19 illness
!
Missed visits due t  COVID-19 related issues
!
Other missing data.
It is accepted due to age, disease under study and common comorbidities the target population 
has risk-factors for severe COVID-19 illness. The ability to exclude the most at-risk patients 
whilst maintaining the target population and the relevance of the study is necessarily limited.
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COPD may be a risk-factor for severe COVID-19 illness, and the following participants will 
not be included in the study (see Exclusion Criteria 1 and 2, Section 5.2):
1
Participants with active COVID-19 infection at screening.  
2
Participants with a history of significant COVID-19 illness within 6 months of enrolment 
defined as:
(a) A diagnosis of COVID-19 pneumonia based on radiological assessment. 
(b) A diagnosis of COVID-19 with significant new findings from pulmonary imaging 
tests.
(c) A diagnosis of COVID-19 requiring hospitalisation and/or oxygen supplementation 
therapy.
Because the screening/run-in period is at least 4 weeks, participants will be tested for active 
SARS CoV-2 infection using a nucleic acid test targeting SARS-CoV-2 at both screening 
visits (see SoA [Table 2]), and those with a positive result at either screening visit will become 
screen failures. This test may be performed either at a local laboratory or at the central
laboratory.
Participants suspected of having contracted COVID-19 should be managed according to local 
and national guidelines to prevent spread of COVID-19 infection to staff and patients. These 
participants, as well as any who test positive for SARS-CoV-2, should not be automatically 
discontinued from investigational product or be withdrawn from the study. Investigators 
should refer to Section 7 when considering participant discontinuation or withdrawal 
decisions. Sites will be required to provide documentation of a COVID-19 screening and 
mitigation plan that describes how and where participants would be tested if they are 
suspected to have SARS-CoV-2 infection. The plans should also describe mitigation activities 
designed to protect site staff a d others at the site, including other participants and patients. 
Appendix J contains an example screening questionnaire that may be used prior to each visit 
to identify participants with symptoms of, or recent risk factors for, SARS-CoV-2 infection.
Infection control measures should be followed in accordance with local and national 
guidelines including, but not limited to, staff screening and use of personal protective 
equipment.
4.1.1.1
Vaccination Against COVID-19
There is no clinical data available to assess the interaction (if any) of MEDI3506 with any 
COVID-19 vaccine.
The sponsor accepts that vaccination against COVID-19, when and where it is available and 
participants are eligible according to applicable guidelines, is in the participant’s best interest. 
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Consequently, vaccination during the study is, in general, permitted and any delays in 
vaccination due to study participation should be minimized.
To help ensure the interpretability of safety data, receipt of COVID-19 vaccine (either first or 
subsequent dose) is prohibited within 30 days before randomization or within 7 days before or 
after any dose of IP (Section 6.5.5). Receipt of, at least, the first dose of COVID-19 vaccine 
more than 30 days before randomization, without significantly delaying enrolment, should be 
preferred but may not be possible, eg, not locally available at the time, participant not eligible 
at the time, express participant decision not to be vaccinated. Otherwise, vaccination may be 
performed at any time outside the prohibited 7-day window before or after any dose of IP. If 
the (approximate) date of a subsequent dose of COVID-19 vaccination is known, then 
enrolment of the participant should be timed so that that dose is not within 30 days prior to 
scheduled randomization. If this date is not known then enrolment into study should not be 
delayed. If an enrolled participant does (unexpectedly) receive COVID-19 vaccine within 30 
days prior to scheduled randomization, the site should contact the AstraZeneca Study
Physician for advice on how the situation should be managed.
4.1.2
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this protocol and 
should only be implemented during cases of civil crisis, natural disaster or public health crisis 
(eg, during quarantines and resulting site closures, regional travel restrictions, and 
considerations if site personal or study participants become infected with SARS-CoV-2 or 
similar pandemic infections), which would prevent the conduct of study-related activities at 
sites, thereby compromising the study site staff or the participant’s ability to conduct the 
study. The investigator or designee should contact the study Sponsor to discuss whether the 
mitigation plans below sho ld be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with GCP, and minimise risks to study integrity.
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Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options:
!
Pausing recruitment and screening of new participants
!
If, for reasons related to the COVID-19 pandemic, a participant is not able to attend their 
scheduled visit within the ± 3 day visit window, they can have their visit rescheduled 
within 14 days of the original scheduled visit; however, visits that cannot be rescheduled 
within a 14 day window must be skipped and participants should continue at the next 
scheduled visit.
!
During the COVID-19 pandemic, on-site visits may be replaced by a telemedicine visit. 
Having a telemedicine visit with the participants will allow collection of data for AEs, 
concomitant medications, and adherence to the eDiary and ePRO measures to be reported 
and documented. The term telemedicine visit refers to remote contact with the 
participants using telecommunications technology including phone calls, virtual or video 
visits, and mobile health devices.
!
Performance of clinic spirometry at an alternative location where the participant may 
perform spirometry manoeuvres under supervision, eg  conducted at participant’s home 
by qualified site staff.
For further details on study conduct during civil crisis, natural disaster or public health crisis, 
refer to Appendix K.
4.2
Scientific Rationale for Study Design
Chronic obstructive pulmonary disease is a heterogeneous disease (Segal and Martinez 2018)
and as such any proposed treatment should be targeted at the participants within that diagnosis 
most likely to respond, and with the greatest unmet burden of disease. Chronic obstructive 
pulmonary disease is characterized by airflow limitation (post-BD FEV1/FVC < 0.70) that is 
not fully reversible, usually progressive and associated with an enhanced chronic 
inflammatory response in the lung. The Evaluation of COPD Longitudinally to Identify
Surrogate Endpoints (ECLIPSE) observational study of 2163 participants with
moderate-to-severe COPD found a mean rate of decline of FEV1 of 33 mL/year over 3 years, 
with higher rates of FEV1 decline in the presence of current smoking, emphysema, and BD 
reversibility (Vestbo et al 2011). Research on the impact of chronic bronchitis in COPD 
patients on mortality and FEV1 decline in a population-based cohort, showed that COPD 
participants with chronic bronchitis (n = 172) had a greater FEV1 decline (-38 mL/year, 95% 
CI -61.7 to -14.6; p = 0.024) compared with COPD participants without chronic bronchitis, 
and also a higher risk of respiratory mortality (hazard ratio 2.16, 95% CI 1.12 to 4.17; 
p = 0.002) and increased risk of acute exacerbations (objective response 4.0, 95% CI 2.7 to 
5.9; p < 0.001) (Lahousse et al 2017). However, emerging evidence (Dunican et al 2021;
Kim et al 2021) demonstrates mucus hypersecretion at all stages of COPD, evident on CT 
imaging alongside even very extensive emphysema. This accumulation of mucus in the small 
airways can occur in the absence of significant symptoms (Hogg et al 2007), likely as a result 
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of the lack of cough receptors in the peripheral airways (Burgel and Nadel 2008). Patients 
with recurrent exacerbations have higher sputum inflammatory markers (Bhowmik et al 2000)
which suggests that underlying inflammation may lead to disease progression, but yet may 
still contribute to the ongoing inflammation associated with disease progression 
(Anzueto 2010; Crooks et al 2000). 
Patients with COPD and mucus hypersecretion therefore present a high unmet need. Current 
therapy for these patients consists of dual (ICS + LABA or LABA + LAMA) or triple 
therapies (ICS + LABA + LAMA), with add-on in the event of increased exacerbation history
of such treatments as PDE4 inhibitors, and chronic macrolide (such as azithromycin) 
treatment. These add-on treatments, however, have issues associated with individual 
tolerability and antibiotic resistance which have hampered their use. 
As discussed in Section 2.2, MEDI3506 mode of action is hypothesized to impact airway 
inflammation, mucus and cough symptoms, and lung function endpoints in COPD, and 
through modification of these factors, reduce frequency and severity of exacerbations.
This study tests the hypothesis that MEDI3506 will improve lung function in participants with 
COPD and chronic bronchitis, using FEV1 as the primary outcome measure. The study uses 
secondary outcomes to gather evidence to support the mode of action of MEDI3506, 
concentrating on lung physiology, mucus, cough, and ePROs related to symptoms and disease 
impact. 
There will be one sub-study in this trial: 
4.2.1
Rationale for Study Population
Chronic bronchitis by physician assessment of participant disease history (presence of cough 
and phlegm on most days for ≥ 3 months/year for ≥ 2 years) and BCSS average score ≥ 2 in 
cough and sputum domains over the 4-week run-in period allow not only the standard 
definition of chronic bronchitis history to be used to define participants who could benefit, but 
also to increase the chances of seeing a measurable effect size in BCSS and other symptom 
related measures. This BCSS inclusion criterion helps to identify those patients with 
symptomatic mucus hypersecretion most likely to respond to MEDI3506 due to its mechanism 
of action. However, the ability to score severity of emphysema on CT scan will also allow for 
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analysis of subpopulations of patients with COPD based upon extent of emphysema to further 
examine the relationship between emphysema and response to MEDI3506.
During the ongoing COVID-19 pandemic, as a result of changed patient behaviour, there has 
been a significant reduction in exacerbation frequency compared with previous years. Data 
from the UK suggested a 50% reduction in exacerbation related-hospital admissions compared 
with pre-pandemic (Tan et al 2020; Alsallakh et al 2021), and a 39% reduction in primary care 
consultations related to COPD. This picture is replicated in other countries. Leaving the 
requirement for at least one moderate or severe exacerbation in the previous 12 months 
unchanged would lead to the exclusion of patients who in previous years would have been 
included.
In this study, participants are required to have at least one moderate or severe exacerbation in 
the previous 24 months, as participants with frequent exacerbations have been shown to have 
an increased symptom burden and likelihood of subsequent exacerbations (Hurst et al 2010), 
and a history of exacerbation also results in poor outcomes irrespective of ICS use and for 
exacerbation history of ≥ 1 moderate exacerbation (Calverley et al 2017). Participants should 
be clinically stable and free from an exacerbation of COPD for 1 month prior to SV1 and prior 
to Day 1.
4.2.2
Rationale for Primary Endpoint
The primary endpoint is change from baseline to Week 12 in clinic pre-BD FEV1.
Forced expiratory volume in 1 second is a validated and clinically important endpoint in 
COPD studies, and has been used extensively in trials used to support registration of add on 
therapy to current standard of care (dual/triple therapy) in a similar chronic bronchitis patient 
population (Martinez et al 2015). 
4.2.3
Rationale for Intervention Period Duration
The last dose is administered at Week 24 and the end of treatment is 4 weeks later (Week 28).
Based on available data, the improvement in FEV1 assumed in the sample size determination 
(Section 9.2) is expected to be achieved by Week 12. However, improvement in FEV1 is 
considered important but not sufficient to meet the unmet medical need in COPD. To enable 
evaluation of the secondary endpoint of COPDCompEx, the treatment is continued after 
collection of primary endpoint data, to collect further events.
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4.2.4
Participant Input into Design
The AstraZeneca Patient Partnership Program is an internal working group that enables study
participant feedback on clinical trial study designs. During study development, the Patient 
Partnership Program influenced the following aspects of the study design:
!
Provision written into the CSP to rotate injection sites.
!
Participant training for the eDiary and spirometry devices used at home will be supported 
by trouble shooting and technical guidance
!
Participants may be provided with a single source study guide providing study rationale 
and guidance in seeking additional support from sites (does not directly affect the CSP).
!
There may be ongoing communications with participants such as newsletters and regular 
site contact (does not directly affect the CSP).
!
Site facilities were explored to support participant focused visits such as out of office or 
TC visits (does not directly affect the CSP).
!
A centralized recruitment program may be used.
!
Nasal sampling will not be repeated in participants that are unsuitable for repeat sampling 
as judged by the Investigator.
In addition, a study coordinator review of the SoA took place in order to ensure the SoA was 
feasible and realistic, particularly in terms of visit duration. This consultation led to the 
following alterations to the SoA:
!
Provision for allowing informed c nsent at a separate, stand-alone visit has been included 
in the CSP.
!
Detailed guidance has been included to clarify the order of assessments in Section 8.
!
Duration estimates for visits were confirmed.
4.3
Justification for Dose
In this proof-of-concept study, a dose regimen of
 Q4W SC will be administered for 
7 doses. This dose is predicted to have a lower exposure, in terms of Cmax,ss (approximately 
2.4-fold) and AUC (approximately 1.1-fold), compared with the highest dose administered (ie, 
single dose of 
 IV MEDI3506) in the Phase I clinical study (Study D9180C00001; 
refer to IB for further details).
Exposures (ie, Cmax,ss of 1276 μg/mL and AUC0-4 weeks of 28012 μg day/mL) achieved at the 
26-week no observed adverse effect level of 150 mg/kg in cynomolgus monkeys (refer to the 
IB for further detail) are approximately 38- to 47-fold higher than predicted at the proposed 
maximum dose of 
 SC Q4W in this Phase II clinical study. 
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The optimal serum concentration for MEDI3506 efficacy in COPD is not known. A mouse 
challenge model suggests a target concentration of 20 μg/mL (refer to the IB for additional 
details). Analysis of the PK data from the Phase I clinical study of MEDI3506 predicts that 
 SC Q4W will achieve an average steady-state concentration of 21 μg/mL, similar to 
the target concentration established in the mouse model. In addition, this dose is predicted to 
achieve > 90% suppression of IL-33 in the sputum based on the theoretical PK/PD model. If
replicated in humans with COPD, 
 SC Q4W is anticipated to achieve near-maximum 
efficacy based on the mouse and PK/PD models.
4.4
End of Study Definition
The end of the study is defined as the date of last scheduled procedure shown in the SoA 
(Table 3) for the last participant in the study globally.
4.4.1
Study Stopping Criteria
Discontinuation of specific sites or of the study as a whole are handled in accordance with 
Appendix A 9.
The study may be put on hold pending a full safety data review, if any of the following criteria 
are met:
!
Five or more (in different participants) reports of new onset symptomatic heart failure 
confirmed by echocardiography 1
!
Four or more (in different participants) reports of Grade 5 severity infection (excluding 
COVID‑19 infection), not ass ciated with a COPD exacerbation 1
!
Two or more (in different participants) reports of new onset non‑infective colitis, 
confirmed histopathologically
!
Two or more cases of ≥Grade 4 severity hypersensitivity reactions (eg, anaphylaxis), 
except where a specific alternative causative allergen is identified 1
!
Ten or more (in different participants) other clinically significant (≥ Grade 4 severity)
AEs (excluding those described in any of the preceding criteria) in the same system organ 
class (excluding COVID-19 infection and COPD exacerbations) that preclude continuing 
dosing of the participant, unless obviously not related to the IP (eg, motor vehicle 
accident) 1
!
Participant enrolment is unsatisfactory
!
Non-compliance that might significantly jeopardize the validity or integrity of the trial, or 
safety of the participant(s)
!
Sponsor decision to terminate development.
                                               
1 Except if the DSMB confirm that there is no evident significant adverse imbalance between treatment groups 
and hence this criterion need not apply.
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If the sponsor determines that temporary suspension or termination of the study is required, 
the sponsor will discuss the reasons for taking such action with all participating investigators 
(or heads of the medical institutions, where applicable). When feasible, the sponsor will 
provide advance notice to all participating investigators (or heads of the medical institutions, 
where applicable) of the impending action.
If the study is suspended or terminated for safety reasons, the sponsor will promptly inform all 
investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study. The sponsor will also promptly inform the relevant regulatory
authorities of the suspension/termination along with the reasons for such action. Where 
required by applicable regulations, the investigator or head of the medical institution must 
inform the IRB/IEC promptly and provide the reason(s) for the suspension/termination. If the 
study is suspended for safety reasons and it is deemed appropriate by the sponsor to resume 
the study, approval from the relevant regulatory authorities (and IRBs/IECs when applicable) 
will be obtained prior to resuming the study. The investigator shall also promptly inform the 
participant of the study suspension/termination and should assure appropriate participant 
therapy and/or follow-up.
5
STUDY POPULATION
Each participant must meet all the inclusion criteria and none of the exclusion criteria 
(excluding sub-study specific criteria) for this study in order to be assigned/randomized to the 
study intervention. Under no circumst nces can there be exceptions to this rule. Participants 
who do not meet the eligibility requirements are screen failures (refer to Section 5.4). 
Participants who provide informed consent to participate in the CT sub-study but are 
subsequently found not to meet all of the inclusion criteria and/or meet any of the exclusion 
criteria, applicable to the sub study, should not participate further in the sub-study but should 
continue to participate in the main study so long as they are eligible as described above.
In this CSP, “enrolled” participants are defined as those who sign the ICF. “Randomized” 
participants are defined as those who undergo randomization within the RTSM system. 
Prospective approval of CSP deviations to eligibility criteria, also known as CSP 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
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Type of Participant and Disease Characteristics:
2
Participants who are current or ex-smokers with a tobacco history of ≥10 pack-years. 
Pack-years are calculated as average number of cigarettes per day × number of years / 20. 
For example, 1 pack-year = 20 cigarettes smoked per day for 1 year or 10 cigarettes per 
day for 2 years.
3
This inclusion criterion has been removed.
4
Participants who have a documented history of COPD for at least 1 year. A verbal history
of symptoms consistent with COPD from the participant is not sufficient. Acceptable 
documentation includes
∀
Clinic visit (primary or specialist HCP) notes or emergency room/hospital records 
listing COPD as a current diagnosis
∀
Verbal discussion confirming the diagnosis of COPD between the investigator and 
physician who has access to the participant’s medical record. The investigator is 
required to clearly document this conversation in participant’s source document. 
5
Participants who have a post-BD FEV1/FVC < 0.70 and a post-BD FEV1 > 20% and 
< 80% predicted normal value at screening. Centralized spirometry will be used for this 
criteria assessment.
6
Participants who have a physician confirmed history of chronic bronchitis as defined as 
presence of cough and sputum on most days for ≥3 months/year in at least the 2 year 
period immediately prior to SV1 (screening). Assessment based on a verbal history
consistent with chronic bronchitis is sufficient.
7
Participants who have an av rage BCSS score of ≥2 in cough and ≥2 in sputum domains 
assessed over the 14 days preceding SV3.
8
Participants who h ve a documented stable regimen of dual therapy or triple therapy for 
≥3 months prior to enrolment; there should have been no change in treatment after the 
previous exacerbation prior to entering into the study. Where dual therapy consists of
ICS + LABA or LABA + LAMA, and triple therapy consists of ICS + LABA + LAMA. 
Both dual and triple therapy may be in the form of separate inhalers of fixed dose 
combination inhalers but may not be in nebulized form. However, all inhalers must be 
locally approved for the maintenance treatment of COPD. See Section 6.5.1. Acceptable 
documentation includes:
∀
Recent, active medication list as per HCP note
∀
Filled prescriptions based on a pharmacy record
∀
Another acceptable medical record as per local clinical practice
∀
Verbal discussion confirming treatment regimen between investigator and HCPs who 
have access to participant’s medical record. The investigator is required to clearly
document this conversation in participant’s source document.
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9
Participants who have a documented history of ≥1 moderate or severe AECOPD 
requiring systemic corticosteroids and/or antibiotics for at least 3 days duration (or 
1 injection of depot formulation), or hospitalization for reason of AECOPD in the 
previous 24 months prior to screening. A verbal history from the participant of AECOPD 
is not sufficient. Acceptable documentation is:
∀
Clinic visit (primary or specialist HCP) notes or emergency room/hospital records 
providing evidence of ≥1 moderate or severe AECOPD in the previous 24 months 
prior to enrolment.
∀
Documented prescription of systemic corticosteroids of at least 3 days duration (or 
1 injection of depot formulation) and/or antibiotics for treatment of exacerbation
∀
Discharge summaries from a hospital, emergency room, or an urgent care facility 
indicating that a participant was hospitalized or treated with systemic corticosteroids 
for a COPD exacerbation.
∀
Verbal confirmation from the patient that they have self-administered rescue 
medication for an acute exacerbation, characterised as above, in the previous 24 
months, despite confirmation of compliance with usual inhaled medication. This 
needs to be clearly documented in the participant's source document by the 
investigator.
10 Participants who are clinically stable and free from an exacerbation of COPD for 1 month 
prior to SV1 (screening) and prior to Day 1.
11 Participants who are at least 70% compliant with the eDiary and home spirometry during 
the 14 days preceding SV3 based on the eDiary. 
12 Participants who are able to read, write, and use electronic devices.
Weight:
13 Body mass index within the range 18 to 40 kg/m2 (inclusive).
Sex/Reproduction:
14 Female participants of childbearing potential, must have negative pregnancy tests at 
screening SV1 (serum pregnancy test), and then subsequently at SV2 (urine pregnancy 
test, only if a CT scan is performed) and pre-dose of study intervention at SV3 (Day 1; 
urine pregnancy test).
15 Female participants of childbearing potential who are sexually active with a male partner 
must agree to use a highly effective method of contraception from screening until the end 
of the follow-up period at SV14 of the study. See Appendix F for definitions of 
childbearing potential and highly effective methods of contraception. In countries where 
spermicide is available, it is strongly recommended for the male partner of a female 
participant of childbearing potential to also use male condom plus spermicide throughout 
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this period. 
In countries where spermicide is not available, it is strongly recommended for the male 
partner of a female participant of childbearing potential to also use male condom
throughout this period.
Note there are no contraception requirements for female participants who are not of 
childbearing potential. However, all female participants should refrain from egg cell 
donation and breastfeeding throughout the study.
16 In countries where spermicide is available, male participants who are sexually active with 
a female partner of childbearing potential must agree to use a male condom with
spermicide and another highly effective method of contraception during the intervention 
and follow-up periods from Day1 through to SV14 of the study. 
In countries where spermicide is not available, male participants who are sexually active 
with a female partner of childbearing potential must agree to use a male condom and 
another highly effective method of contraception during the intervention and follow‑up 
periods from Day 1 through to SV14 of the study.
See Appendix F for definitions of childbearing potential and highly effective methods of 
contraception. Male participants should also refrain from biologically fathering a child or 
donating sperm during the same period.
Informed Consent:
17 Capable of giving signed informed consent as described in Appendix A, which includes 
compliance with the requirements and restrictions listed in the ICF and in this CSP.
Informed Consent (Sub-studies):
18 Provision of signed and dated written informed consent for sub-study enrolment (if 
applicable). 
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions and Diagnostic Assessments
1
Participants with a positive diagnostic nucleic acid test for SARS-CoV-2 at SV1 or SV2. 
Subjects with mild or asymptomatic disease could be rescreened.
2
Participants with a significant COVID-19 illness within 6 months of enrolment defined 
as:
(a) A diagnosis of COVID-19 pneumonia based on radiological assessment. 
(b) A diagnosis of COVID-19 with significant new findings from pulmonary imaging 
tests.
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(c) A diagnosis of COVID-19 requiring hospitalisation and/or oxygen supplementation 
therapy.
3
As judged by the investigator, any evidence of any active medical or psychiatric condition 
or other reason (at screening [SV1 and SV2] and SV3 [pre-dose]) which in the 
investigator's opinion makes it undesirable for the participant to participate in the study.
This includes but is not limited to:
(a) Diabetes mellitus, except for participants with type 2 diabetes mellitus who are well 
controlled in the opinion of the investigator.
(b) History of heart failure.
(c) Clinically significant or unstable ischemic heart disease, arrhythmia including atrial 
fibrillation (except first degree heart block), or cardiomyopathy, including acute 
coronary syndrome within the last 6 months; or any history of myocardial infarction. 
(d) Clinically significant aortic stenosis.
(e) Systemic hypertension, except if well controlled and stable for at least 3 months in 
the opinion of the investigator.
(f) Pulmonary arterial hypertension to exclude participants with known history of
primary pulmonary arterial hypertension or clinically significant cor pulmonale.
(g) History of an underlying condition that predisposes the participant to infections 
(eg, history of splenectomy, known primary or secondary immune deficiency
syndromes).
(h) History of ulcerative colitis  Crohn’s disease, or microscopic colitis diagnosed by 
either a gastroenterologist or by histopathology.
4
This exclusion criterion has been removed.
5
Current diagnosis of asthma or past diagnosis of asthma which persisted beyond the age 
of 25 years. A misdiagnosis of asthma is not exclusionary if any of the following are met:
(a) A diagnosis of asthma that was, within 2 years of original diagnosis, determined to be 
a misdiagnosis by he then treating physician.
(b) A brief episode of asthma-like symptoms without longer-term asthma treatment 
confirmed by the investigator to be a misdiagnosis.
(c) A diagnosis of asthma made when the subject was aged ≥40 years, confirmed by the 
investigator to be a misdiagnosis after discussion with and agreement of the 
AstraZeneca Study Physician.
6
Clinically important pulmonary disease other than COPD (eg, active lung infection, 
clinically significant bronchiectasis, pulmonary fibrosis, cystic fibrosis, hypoventilation 
syndrome associated with obesity, lung cancer, alpha-1 anti-trypsin deficiency and 
primary ciliary dyskinesia) or another diagnosed pulmonary or systemic disease that is 
associated with elevated peripheral eosinophil counts (eg, allergic bronchopulmonary
aspergillosis/mycosis, Churg-Strauss syndrome, hypereosinophilic syndrome), 
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radiological findings, and/or laboratory findings suggestive of a respiratory disease other 
than COPD that is contributing to the participant's respiratory symptoms.
7
Increased pre-BD FEV1 at randomization visit (SV3) compared to Screening SV1 of 
≥400 mL or ≥25% of SV1 FEV1.
8
Known history of allergy or reaction to any component of the study intervention 
formulation, including hereditary fructose intolerance. 
9
Any other clinically relevant abnormal findings on physical examination, laboratory
testing including hematology, coagulation, serum chemistry, or urinalysis; or chest CT 
scan at screening or randomization, which in the opinion of the investigator or medical 
monitor may compromise the safety of the participant in the study or interfere with
evaluation of the study intervention or reduce the participant’s ability to participate in the 
study. Abnormal findings include, but are not limited to:
(a) ALT or AST > 2 × ULN.
(b) TBL > 2 × ULN (unless due to Gilbert’s diseas )
(c) Evidence of chronic liver disease
(d) Abnormal vital signs, after 10 minutes of being in a comfortable supine position 
(confirmed by 1 controlled measurement), defined as any of the following:
(i)
Systolic BP < 80 mmHg or ≥ 150 mmHg.
(ii) Diastolic BP < 50 mmHg or ≥ 95 mmHg.
(iii) Pulse < 45 or > 100 beats per minute.
(e) This exclusion criterion has been removed.
(f) Any clinically significant rhythm, conduction, or morphology abnormalities in the 
12-lead ECG including but not limited to corrected QT interval (Fridericia) 
(Vandenberk et al 2016) > 450 ms.
(g) Chest CT scan finding  requiring further investigation or repeat CT surveillance 
before SV14.
10 This exclusion criterion has been removed.
11 A family history of heart failure defined as either of the following: ≥2 first degree 
relatives with clinically significant heart failure, or ≥1 first degree relative with heart 
failure known to be heritable (eg, hypertrophic cardiomyopathy), unless inheritance is 
excluded by genetic testing.
12 A LVEF < 45% measured by echocardiogram during screening, between the time of 
signing informed consent and prior to randomization. 
13 History of a clinically significant infection (viral, bacterial, or fungal) within 4 weeks 
prior to Day 1 (SV3) (including unexplained diarrhea) or clinical suspicion of infection at 
time of dosing. Clinically significant infections are defined as requiring systemic 
antibiotics, antiviral, or antifungal medication for > 7 days. 
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14 Prior history of/planned: lung pneumonectomy for any reason, or lung volume reduction 
procedures (including bronchoscopic volume reduction) for COPD. Note: Surgical 
biopsy, or segmentectomy, or wedge resection, or lobectomy for other diseases would not 
be excluded.
15 Long term oxygen therapy (a requirement for continuous oxygen therapy > 16 hours per 
day). 
16 Use of any non-invasive positive pressure ventilation device. 
17 Current diagnosis of cancer.
18 History of cancer, except if treated with apparent success with curative therapy (response 
duration of > 5 years).
19 A known history of severe reaction to any medication including biologic agents or human 
gamma globulin therapy. 
20 A helminth parasitic infection diagnosed within 6 months prior to SV1 that has not been 
treated with, or has failed to respond to, standard of care therapy.
21 History of herpes zoster within 3 months prior to r ndomization (Day 1). 
22 History of, or a reason to believe a participant has a history of, drug or alcohol abuse 
within the past 2 years prior to screening.
23 Positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core 
antibody, at screening
24 A positive test for HIV or known to have HIV infection. 
25 Evidence of active or untreated latent TB infection (LTBI) as evidenced by
(a) Positive IGRA test and evidence of symptoms suggestive of active TB
(b) Positive IGRA, or repeated indeterminate IGRAs, no evidence of active TB and 
untreated for latent infection, unable to be treated for, or declines treatment of latent 
TB infection. 
(c) Participants newly diagnosed with LTBI on initial screening could be considered for 
rescreening if they complete a full course of treatment for latent TB in accordance 
with recommended treatment guidelines prior to rescreening. In this situation, repeat 
IGRA test is not required after completion of treatment for LTBI.
(d) Participants with an indeterminate IGRA should undergo repeat test and if still 
indeterminate may only be enrolled after treatment for latent TB infection.
26 Change in smoking status in 12 weeks prior to enrolment or intention to change smoking 
status between enrolment and end of follow-up.
Prior/Concomitant Therapy
27 Participants currently receiving background therapy that is not approved by regulatory
authorities in the country of study for COPD are not eligible for the study. 
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28 History of treatment with cardiotoxic medications (eg, as part of cancer therapy) 
including thiazolidinediones.
29 Major surgery within 8 weeks prior to screening or planned inpatient surgery or 
hospitalization during the study period. Elective hospitalizations that cannot be delayed 
until after the end of the study need to be discussed with the sponsor’s medical monitor. 
30 Treatment with broad spectrum antibiotic within 4 weeks prior to randomization (Day 1). 
31 Donation of blood or blood products in excess of 500 mL within 3 months prior to 
screening. 
32 History of allogeneic bone marrow transplant. 
33 Treatment with allergy immunotherapy within 90 days prior to SV1. 
34 Receiving any of the prohibited concomitant medications as specified in the CSP:
(a) Acute systemic (oral or injectable) corticosteroids within 4 weeks of SV1 
(b) Any other immunosuppressive therapy (including methotrexate, cyclosporine or 
maintenance systemic steroid treatment) within 3 months of randomization.
(c) Immunoglobulin or blood products within 4 weeks of SV1.
(d) Live or attenuated vaccines within 4 weeks of SV1. (Note: Vaccines with adenoviral 
vectors that are unable to replicate, eg  ChAdOx1, are not considered live or 
attenuated).
(e) Interferon gamma within 3 months of randomization.
(f) Investigational products within 4 months or 5 half-lives of randomization, whichever 
is longer.
(g) Marketed biologics within 4 months or 5 half-lives of randomization, whichever is 
longer.
(h) Any add-on therapy for COPD including theophylline. Chronic macrolide or other 
antibiotic therapy is allowed provided the participant has been on a stable 
dose/regimen for ≥ 3 months prior to enrolment and has had at least one COPD 
exacerbation while on stable therapy.
(i)
PDE4 inhibitors (e.g. roflumilast, Daxas®, Daliresp®) commenced within 3 months 
of SV1. PDE4 inhibitors are allowed provided the participant has been on a stable 
dose/regimen for ≥ 3 months prior to enrolment and has had at least one COPD 
exacerbation while on stable therapy. 
(j)
Vaccination against COVID-19 (either first or subsequent dose) within 30 days prior 
to randomization.
(k) Any immunotherapy within 3 months of randomization.
(l)
Antitussive and mucolytic medications commenced within 4 weeks prior to SV1. 
Antitussive and mucolytic medications are allowed provided the participant has been 
on a stable therapy/regimen for greater than 4 weeks.
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35 Participation in, or scheduled for, an intensive COPD rehabilitation program at any time 
during the intervention period (note: participants are permitted to be in the maintenance 
phase of a rehabilitation program). 
Prior/Concurrent Clinical Study Experience
36 Concurrent enrolment in another clinical study involving an investigational treatment.
Exclusion Criteria for Optional Genetic Sample Only
37 Non-leukocyte depleted whole blood transfusion within 120 days of optional genetic 
sample collection.
Other Exclusions
38 Participant is an investigator, sub-investigator, study coordinator, or employee of the 
participating site or Sponsor, or is a first-degree relative of the aforementioned. 
39 Inability to perform technically acceptable spirometry.
40 Pregnancy or intention to become pregnant during the study, breastfeeding, or 
unwillingness to use a highly effective method of contraception throughout the study in 
female participants of childbearing potential. 
41 This criterion has been removed.
5.3
Lifestyle Considerations
Participants must abstain from donating blood and plasma from the time of informed consent, 
and for 16 weeks (5 half-lives) after last dose of study intervention.
5.3.1
Meals and Dietary Restrictions
Participants should avoid eating a large meal for at least 2 hours prior to all scheduled lung 
function and AO assessments at the site.
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5.3.2
Caffeine, Alcohol, and Tobacco
Chronic alcohol or drug abuse within 2 years is restricted prior to SV1 and throughout the 
conduct of the study.
Current tobacco smokers or prior tobacco smokers, with smoking history ≥10 pack-years 
(1 pack-year = 20 cigarettes smoked per day for 1 year) at SV1 are allowed. Never smokers 
are not allowed to enter the study. Any change in smoking status in 12 weeks prior to 
enrolment or intention to change smoking status between enrolment and end of follow-up will 
result in a screen failure. However, following change in smoking status, they will be eligible 
for re-screening. Smoking status changes during the course of the study will be captured on 
the eCRF but the participant will be permitted to continue in the study. See also Section 8.
The use of e-cigarettes (eg, JUUL) is allowed during the course of the study. 
5.3.3
Activity
1
Participants should avoid engaging in strenuous exertion for at least 30 minutes prior to 
all scheduled lung function assessments, AO and blood collection at the site.
2
Participants should avoid showers/bathing and any activity that will cause heavy
perspiration whilst wearing the cough monitor, as the cough monitor must not come into 
contact with water.
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 t ansparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials publishing requirements and to respond to 
queries from regulatory authorities. Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAEs.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened, if there is reason to believe the reason for ineligibility was temporary (eg. 
exacerbation and/or background medication stability periods). Only one rescreening per 
participant is allowed in the study, when there is a reasonable expectation that the participant 
will become eligible for the study. Prior to rescreening, participants must be reconsented. 
Participants in rescreening retain their previous E-code.
Where individuals are rescreened, the results of echocardiogram and IGRA (TB test) carried 
out as part of the original screening process can be included as long as they are within the last 
3 months and there have been no specific risks of TB infection such as foreign travel to a high 
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incidence area and no recent cardiac events which may affect the echocardiogram. 
All other tests must 
be performed as per the schedule of events (Table 2).
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the CSP. Study intervention in this study refers to MEDI3506 and placebo.
6.1
Study Intervention Administered
6.1.1
Study Interventions
Table 6
Study Interventions
ARM Name
MEDI3506 
Placebo
Intervention Name
MEDI3506 
Placebo
Type 
Biologic
Drug
Dose Formulation
Unit Dose Strength(s)
Not applicable
Dosage Level(s)
Route of Administration
Use
Experimental
Placebo-comparator
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the Sponsor 
Provided centrally by the Sponsor 
Packaging and Labelling
IMP = Investigational medicinal product; NIMP = Non-investigational medical product; Q4W = Every 4 weeks; 
SC = Subcutaneous; w/v = Weight per volume.
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6.2
Preparation/Handling/Storage/Accountability of Interventions
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
MEDI3506 does not contain preservatives and, therefore, any unused portion must be 
discarded.
The unblinded study intervention manager will select the appropriate kits allocated by the 
RTSM system to prepare the participant’s dose. The unblinded study intervention manager 
must ensure that only the unblinded team members have access to the areas of the pharmacy 
where the study intervention is being stored and prepared.
6.2.1
Study Intervention Inspection
Each vial allocated for dose preparation should be inspected. MEDI3506 and placebo are 
supplied as a clear to opalescent sterile liquids  
If there are any defects noted with the study intervention, the investigator and site monitor 
should be notified immediately. Refer to the Product Complaint section in the IMP manual for 
further instructions.
6.2.2
Dose Preparation Steps
No incompatibilities between MEDI3506 and plastics (ie, polypropylene and polycarbonate 
syringes) have been observed.
MEDI3506 and placebo do not contain preservatives and any unused portion must be 
discarded. Preparation of study intervention is to be performed aseptically. Total in use 
storage time from needle puncture of the study intervention vial to start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2 °C to 8 °C (36 °F to 46 °F). If 
storage time exceeds these limits, a new dose must be prepared from new vials assigned by the 
RTSM system.
A vial should be used only 1 time to prepare a single dose.
To prepare the participant’s dose, the unblinded study intervention manager will select study
intervention for administration according to the kit identification numbers assigned. A 
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summary of the study intervention volumes required and syringes to prepare for SC dose 
administration in each study intervention group is provided (Table 7).
Table 7
Study Intervention Dose Preparation
Contents of 
vial(s)
Number of kits
Volume 
required
Syringes to 
prepare
Size of 
syringe
Total volume of 
study 
intervention
 MEDI3506 intervention group 
MEDI3506
Placebo intervention group
Placebo
The dose preparation steps are as follows:
1
Prepare the assigned MEDI3506 and/or placebo vials for the particular study intervention 
group as per Table 7.
2
Withdraw the required volume of MEDI3506 or placebo from each vial using a separate, 
appropriately sized syringe and a separate 18 to 20-gauge 1 to 1.5 inch needle, 
respectively.
6.2.2.1
Study Intervention Administration
The first day of dosing is considered SV3 (Day 1).
Female participants of childb
ring potential, must have a negative urine pregnancy test prior 
to receiving each dose of study intervention.
MEDI3506 and placebo are 
 The syringes should be 
kept out of sight of all blinded persons, including the participant, to maintain the blind. Study
intervention will be administered
by unblinded site personnel 
to the abdomen, back of the arms, or thigh. 
apart in the same anatomical region. 
administering the dose will wipe the skin surface of the administration sites with alcohol and 
allow the skin surface to air dry. The skin will be pinched to isolate the SC tissue from the 
muscle. The needle will be fully inserted at a 45 degree angle into the SC tissue. The study 
intervention will be slowly injected (at least 5 seconds duration is recommended). The area 
should not be massaged after injection.
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It is advised that the site of injection be rotated so that the participant receives study 
intervention injections in different anatomical regions from one visit to the next. In cases 
when rotation of the injection site is not feasible and/or the participant prefers not to rotate 
injection sites, the reason for not rotating the injection site should be documented in the source 
documents.
Each injection site must be documented on the eCRF and in the source documents at each 
study intervention visit.
6.2.2.2
Monitoring Dose Administration
After the administration of study intervention, vital signs will be assessed according to the 
SoA (Section 1.3), and SC injection sites will be assessed for any reactions as detailed in 
Section 8.2.3.
As with any biologic product, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat anaphylaxis 
(Appendix I).
6.2.3
Accountability
The site’s designated unblinded study intervention manager is required to maintain accurate 
study intervention accountability records. Upon completion of the study, copies of study
intervention accountability records will be returned to AstraZeneca. All unused study
intervention and vials will be disposed of following site procedures and upon authorization by 
AstraZeneca, or will be returned to an AstraZeneca-authorized depot if a site is unable to 
dispose of unused study intervention. The outer carton should be kept onsite to assist with kit 
assignment checks, if permitted by site procedures.
6.3
Measures to Minimise Bias: Randomization and Blinding
6.3.1
Methods for Assigning Study Intervention Groups
All participants will be centrally assigned to randomised study intervention using an RTSM 
system and will be stratified by baseline eosinophil count (< 300 cells/μL, ≥300 cells/μL) and 
background medication usage (ICS or no ICS). 
Before each site is initiated, the login information and directions for the RTSM system will be 
provided.
Study intervention will be dispensed at the study visits summarized in SoA (Section 1.3). 
The RTSM system will provide to the investigator(s) or pharmacists the kit identification 
numbers to be allocated.
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Routines for this will be described in the RTSM system user manual that will be provided to 
each centre.
6.3.2
Methods to Ensure Blinding
Participants will be randomly assigned in a 1:1 ratio to receive study intervention (MEDI3506 
 or placebo). Investigators will remain blinded to each participant’s assigned study
intervention throughout the course of the study.
Since MEDI3506 and placebo are not identical, study intervention will be handled by an 
unblinded study intervention manager at the site and will be administered by an unblinded 
study team member who will not be involved in the management of study participants. An 
independent study intervention monitor will also be unblinded to perform study intervention 
accountability. In the event that the study intervention allocation for a participant becomes 
known to the investigator or other study staff involved in the management of study
participants, AstraZeneca must be notified immediately. If the study intervention allocation for 
a participant needs to be known to treat an individual participant for an AE (Section 6.3.3), the 
investigator must notify AstraZeneca immediately. The site will maintain a written plan 
detailing which staff members are blinded/unblinded and the process of study intervention 
preparation and administration used to maintain the blind.
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study intervention records at the site(s) to verify that randomization/dispensing has been done 
accurately.
To facilitate the in-stream analy is of PK and ADA samples, the randomisation schedule may 
be provided to limited personnel who have responsibility for analysing the samples. These 
unblinded sample analysts will not have any other involvement with the conduct of the study.
MEDI3506 could reduce eosinophil counts in blood over time. As a precaution, eosinophil, 
basophil, and monocyte data from the hematology laboratory tests will not be communicated 
to blinded sponsor or site personnel during the intervention and follow-up periods. These data 
do not require blinding at baseline (SV1 to SV3 pre-dose).
6.3.3
Methods for Unblinding
The randomization code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the study intervention 
randomization. The investigator documents and reports the action to AstraZeneca, without 
revealing the study intervention given to participant to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
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reporting to regulatory authorities. Randomization codes will not be broken for the planned 
analyses of data until all decisions on the evaluability of the data from each individual 
participant have been made and documented.
The RTSM system 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, 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. The investigator documents and reports the 
action to AstraZeneca, without revealing the study intervention given to participant to the 
AstraZeneca staff.
6.3.3.1
Unblinding for Analysis Purposes
An interim analysis may be included in this study prior to the Primary Analysis. Should an 
interim be conducted, the purpose will be to inform decisions on future development options 
for MEDI3506 or other programs. No termination of this study or adjustments to the study
design are planned since the interim analysis would be for administrative purpose only. 
An interim analysis will require unblinding of a group of sponsor staff or designated 
representatives including those with clinical  medical, statistical, and programming expertise, 
who will form a firewalled unblinded r view committee for administrative purposes. The 
unblinded review committee will be responsible for reviewing the interim results and will 
ensure that the review is performed in a way that maintains the integrity of the trial, and in 
accordance with the interim analysis unblinding plan, which will be prepared prior to the 
interim analysis. Sponsor staff and designated sponsor representatives who conduct the 
interim analysis will take no f rther part in any study activities after they are unblinded. They 
will not reveal the interim analysis results or study intervention codes to any of the study team
member (sponsor staff or representative) who will remain blinded and continue to be involved 
in the study’s conduct until completion as originally planned. In addition, interim analysis 
results will not be shared with investigators or participants. The scope and additional details 
on interim analyses are provided in Section 9.5.
There are 3 planned analyses for this study as described in Section 9.5. Personnel from 
AstraZeneca or its representatives directly associated with the conduct of this study will
remain blinded until the completion of the Primary Analysis. Personnel from the study sites, 
and the study participants, will remain blinded until the completion of the Final Analysis.
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6.4
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from an
unblinded Product Administrator, who is appropriately trained. The date and time of the dose 
administered (first injection) in the clinic will be recorded in the source documents and 
recorded in the eCRF.
6.5
Concomitant Therapy
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the final study visit. Any concomitant medication(s), including herbal 
preparations, taken during the study will be recorded in the eCRF.
Investigators may prescribe concomitant medications or treatments that are:
!
not prohibited (see Section 6.5.5),
!
neither compromise participant safety not affect study data, as judged by the investigator; 
and
!
deemed necessary to provide adequate supportive care.
Specifically, participants should receive full supportive care during the study, including 
intermittent treatment with antibiotics, anti metics, anti-diarrheals, and analgesics, and other 
care as deemed appropriate, and in accordance with their institutional guidelines. The Medical 
Monitor should be contacted if there are any questions regarding concomitant or prior therapy.
Participants are recommended to be vaccinated against influenza and pneumonia according to 
local schedule. Vaccination is permitted during the study but not within ±7 days of dosing.
6.5.1
Required Maintenance Therapy for COPD
All participants are required to be treated with stable doses of maintenance dual inhaled 
(ICS + LABA or LABA + LAMA) or triple inhaled therapy (ICS + LABA + LAMA) for 
COPD for at least 3 months prior to enrolment (SV1). Both dual and triple therapy may be in 
the form of separate inhalers or fixed dose combination inhalers but may not be in nebulized 
form. However, all inhalers must be locally approved for the maintenance treatment of COPD. 
Maintenance treatment should remain unchanged throughout the duration of the study (except 
for treatment of COPD exacerbations, see Section 6.5.4). If a change in COPD maintenance 
treatment is required, it must be discussed with the medical monitor.
Note: The Spiriva Respimat device is considered to be an inhaler.
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6.5.2
6.5.3
Medication Withhold Periods
The following medication withhold periods should be observed prior to scheduled spirometry
and AO at site:
!
SABA and SAMA for at least 6 hours prior.
!
Twice daily LABA or LAMA-containing therapies for at least 12 hours prior.
!
Once daily LABA or LAMA-containing therapies for at least 24 hours prior.
If any of the restrictions are not met and the spirometry s ssion cannot be sufficiently delayed 
on the day, it should be rescheduled within the allowed visit window.
Spirometry assessments will also be performed at home daily (except on days when the 
participant is attending at site visits). Instructions regarding the participant’s medication and 
home spirometry sequence are described in Section 8.1.3
6.5.4
Treatment of Exacerbations of COPD
In general exacerbations of COPD should be treated according to the judgment of the treating 
physician in line with local guidelines.
Both systemic corticosteroids and antibiotics used to treat a COPD exacerbation should not be 
used for more than 14 day  If treatment duration is expected to exceed 14 days, the medical 
monitor must be contacted  An increased dose of ICS may be used alongside OCS, however it 
should be returned to usual maintenance dose at resolution of the exacerbation.
Medications may be administered by nebulizer if required during the course of an 
exacerbations. Scheduled use of SABA/SAMA and oxygen supplementation is permitted 
during the course of an exacerbation.
6.5.5
Restricted and Prohibited Medications
The following medications are restricted from SV1 to the end of the follow-up period, unless 
clinically indicated, as determined by a physician:
!
Acute systemic (oral or injectable) corticosteroids within 4 weeks of SV1 until the end of 
the follow-up period, except for treatment of acute exacerbations of COPD during the 
course of the study.
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!
Macrolide therapy except for:
∀
Chronic macrolide or other antibiotic therapy is allowed provided the participant has 
been on a stable dose/regimen for ≥ 3 months prior to enrolment and has had at least 
one COPD exacerbation while on stable therapy OR
∀
Acute use of macrolides to treat infections and exacerbations of COPD is permitted.
∀
Participants who received ≥ 6 months of macrolide treatment in the previous year 
must have a hearing assessment per local standard practice 3 months prior to 
enrolment or during the screening period; these participants must be interviewed for 
potential hearing issues/tinnitus at enrolment and any reported issues will be recorded 
as part of medical history.
!
Long term oxygen therapy (continuous oxygen therapy for > 16 hours per day). 
The following medications are prohibited (for the time periods stated):
!
Any immunosuppressive therapy (other than corticosteroids) within 3 months of 
randomization until the end of the follow-up period.
!
Any immunotherapy within 3 months of randomization
!
Interferon gamma within 3 months of randomization until the end of the follow-up period.
!
Investigational products other than MEDI3506 within 4 months or 5 half-lives (whichever 
is longer) prior to randomization until the end of the follow-up period.
!
Marketed biologics within 4 months or 5 half-lives (whichever is longer) prior to 
randomization until the end of the follow-up period.
!
Immunoglobulin or blood products within 4 weeks of SV1 until the end of the follow-up 
period.
!
Live or attenuated vaccines within 4 weeks of SV1 until the end of the follow-up period 
(Note: Vaccines with adenoviral vectors that are unable to replicate, eg, ChAdOx1, are 
not considered live or attenuated).
!
Vaccination against COVID-19 (either first or subsequent dose) within 30 days before 
randomization or within 7 days before or after any dose of IP
!
Antitussives medications commenced within 4 weeks prior to SV1 until the end of the 
follow-up period
!
Mucolytic medications (eg. carbocysteine) commenced within 4 weeks prior to SV1 until 
the end of the follow-up period 
!
Roflumilast (Daxas®, Daliresp®) and other PDE4 inhibitors commenced within 3 months 
of randomization until the end of the follow-up period.
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Other than the permitted medications, use of concomitant medications or therapies from 
screening through to the early discontinuation visit/end of study is discouraged. Medications 
or therapies that are not prohibited and neither compromise participant safety nor affect study
data, as judged by the investigator, will be permitted.
6.5.6
COVID-19 Vaccination
If and when a participant receives a COVID-19 vaccination, the following information (if 
available) should be recorded in the participant notes:
!
Brand name (or alternatively name of manufacturer)
!
Date of administration
!
Whether dose was first or second dose
!
Dose
!
Anatomical site/region of administration (eg, left deltoid)
!
Lot number
Details for how this information should be entered into the eCRF will be provided in separate 
guidelines.
Any AEs suspected due to the vaccination should be captured in the AE form along with the 
causality assessment if related to COVID-19 vaccine.
6.6
Dose Modification
Not applicable.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
The PI may determine it necessary on medical grounds for a participant to permanently 
discontinue (definitive discontinuation) study intervention. Note that discontinuation from
study intervention is NOT the same thing as withdrawal from the study.
If study intervention is permanently discontinued, the participant will remain in the study and 
attend all remaining intervention period and follow-up period visits.
See the SoA (Section 1.3) for data to be collected at the time of discontinuation of study
intervention and follow-up and for any further evaluations that need to be completed.
An individual participant will not receive any further study intervention if any of the 
following occur in the participant in question:
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1
Withdrawal of consent to further treatment with study intervention.
2
Lost to follow-up.
3
Any anaphylactic reaction to study intervention requiring epinephrine administration.
4
Any treatment-emergent AE that is Grade ≥ 4 in severity (see Appendix B).
5
Any treatment-emergent SAE that is in the cardiac disorders system organ class, except 
atrial arrhythmias.
6
Confirmed diagnosis of new onset of heart failure during the study (except for transient 
heart failure secondary to atrial arrhythmia). For a participant with suspected new onset of 
heart failure, the participant should not be administered study intervention unless and 
until the diagnosis is refuted. Study intervention should also be temporarily withheld 
during any episode of transient heart failure secondary to atrial arrhythmia.
7
Any other AE that, in the opinion of the investigator or the sponsor, warrants 
discontinuation of further dosing of study interv ntion.
8
Pregnancy.
9
Following randomization, the participant meets ≥1 of the exclusion criteria or fails to 
meet all of the inclusion criteria for study participation.
10 Any AECOPD with duration > 14 days.
11 The participant misses 2 consecutive doses.
7.2
Participant Withdrawal from the Study
!
A participant may withdraw from the study at any time at his/her own request. 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 physi ian, or information from medical records).
!
At the time of withdrawal from the study, if possible, an E/D should be conducted, as 
shown in the SoA (Section 1.3). See SoA for data to be collected at the time of study
withdrawal and follow-up and for any further evaluations that need to be completed.
∀
The participant will discontinue the study intervention and be withdrawn from the 
study at that time.
!
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 in line with what was stated in the informed consent and local regulation. The
investigator must document the decision on use of existing samples in the site study
records and inform the Global Study Team.
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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. 
!
Site personnel, or an independent third party, will attempt to collect the vital status of the
participant within legal and ethical boundaries for all participants randomised, including 
those who did not get study intervention. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information.
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix A 9.
8
STUDY ASSESSMENTS AND PROCEDURES
!
Study procedures and their timing are summarized in the SoA (Section 1.3). Clinical 
study protocol waivers or exemptions are not allowed.
!
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.
!
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
!
All screening evaluations must be completed and reviewed to confirm that potential
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
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8.1
Efficacy Assessments
8.1.1
Clinic Spirometry
8.1.1.1
General Requirements
All spirometry is performed pre-dose.
Lung function (FEV1 and FVC) will be measured by spirometry using equipment provided by 
a central vendor. Spirometry will be performed by the investigator or authorized delegate 
according to ATS/ERS guidelines (Miller et al 2005).
The vendor providing central spirometry is responsible for assuring that the spirometer meets 
ATS/ERS recommendations and that the site personnel who will be performing the testing are 
properly certified. Spirometry calibration and data quality checks (including monitoring of 
unexpectedly high variability of results) will be detailed in a separate spirometry procedures 
manual and in the monitoring plan. Participants who exhibit unexpectedly high variability of
FEV1 will be evaluated by the investigator for etiology of variability, necessary follow-up 
actions, and assessment of continued participant eligibility. The investigator will discuss 
unexpectedly high variability with the AstraZeneca Study Physician.
Participants should observe the relevant medication withhold periods and other restrictions 
beforehand (see Section 5.3 and Section 6.5.3)  If any of the restrictions are not met and the 
session cannot be sufficiently delayed on the day, the site visit and dosing should be 
rescheduled within the allowed visit window. All lung function measurements should take 
place prior to dosing, if dosing is also scheduled at the same visit.
Usual infection control measures should be followed including use of filters, per the 
instructions of the central vendor  Any additional infection control measures in accordance 
with COVID-19 related loc l and national guidelines should also be followed.
Time of day for scheduled site visit spirometry
Spirometry testing should be performed at specified visits according to the SoA (Section 1.3). 
Spirometry testing must be initiated in the morning between 6:00 AM and 11:00 AM during 
the screening period and at the randomization visit (SV3). 
All post-randomization spirometry assessments should be performed within ± 1.5 hours of the 
time that the randomization spirometry was performed. For example, if the randomization 
spirometry was started at 8:00 AM, then all subsequent spirometry testing needs to be initiated 
between 6:30 AM and 9:30 AM.
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Spirometry technique
Detailed procedure for performing spirometry will be described in an instruction manual. 
Details regarding assessment of the quality of spirometry and the Best Test Review process 
will also be detailed in the manual and Monitoring Plan. 
Spirometry references
The Global Lung Function Initiative equations will be used to determine the PNV and are pre-
programmed into the spirometer (Quanjer et al 2012). 
Forced expiratory volume in 1 second expressed as percent of the PNV, will be calculated as 
follows:
FEV1% of PNV = (FEV1 measured/FEV1PNV) × 100
8.1.1.2
Post-BD Spirometry
Post-BD spirometry will be performed at specified visits as detailed in the SoA (Section 1.3).
Endpoint maximal BD will be induced using albuterol (90 μg metered dose) or salbutamol 
(100 μg metered dose) with or without a spacer device up to a maximum of 4 inhalations 
within 30 minutes ± 15 minutes of the final pre-BD spirometry measurement. Post-BD 
spirometry will be performed 15 to 30 minute  later.
Order of administration for the COPD maintenance medication and study intervention
relative to the scheduled pre- and post-BD spirometry
The participant’s usual COPD morning maintenance therapy must not be given until 
spirometry are complete in order to maintain the integrity of planned efficacy analyses around 
lung function improvement. Study intervention dosing should also be withheld until 
pre-BD/post-BD spirometry is complete. 
Record keeping
A signed and dated copy of the pre- and post-BD printout must be kept at study centre for 
source data verification. The printout must be marked with the study code, enrolment code, 
date and time of measurement, visit number. If a printout cannot be printed, the mean value of 
the measurements will be recorded in the participant’s charts.
8.1.2
Airwave Oscillometry
Airwave oscillometry will be performed at specified visits as detailed in the SoA
(Section 1.3), using the endpoints of R5-R20, R5, R20, and AX. Airwave oscillometry is a 
non-invasive lung function test included in this study, which will be assessed using an AO 
device. It is assessed during quiet, tidal breathing with no participant effort required, by 
superimposing a multi-frequency oscillation onto the participant’s natural breathing, to 
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evaluate study intervention effect on small airway function. A centralized vendor will provide 
the equipment for testing.
A calibrated system will be used for measurements. Detailed procedures for equipment 
calibration, performance of measures, recording and analyzing AO data will be described in a 
separate manual provided to each site. Details regarding assessment of the quality of the AO 
process will also be detailed in the manual.
!
All AO function measurements should take place prior to dosing, if dosing is also 
scheduled at the same visit, and prior to spirometry.
!
Participants should observe the medication withhold periods and lifestyle considerations 
stated in Section 6.5.3 and Section 5.3, respectively.
Note: If any of the above restriction are not met, the AO assessment should be rescheduled 
within the allowed visit window and should be conducted prior to spirometry.
8.1.3
Home Spirometry and eDiary
During the intervention period, participants will be required to monitor lung function at home 
using an at‑home spirometry device for daily recording of FEV1 and PEF. This will be done 
once daily in the morning, with the same time window recommendation as the clinic 
spirometry; however, the time window is not compulsory (ie, all data will be used for 
analyses). Participants will be instructed t  perform all home spirometry assessments before 
use of their usual standard-of-care inhaled medication.
Further details will be provided in a separate instruction manual provided to each site.
Participants will be trained on at-home use of the eDiary at SV1. The site staff will set 
assessment reminder alarms on the device (morning and evening). Training will emphasize the 
importance of completi g the eDiary assessments as scheduled to capture the participant’s 
experience and meet the objectives of the study. 
The investigator/authorized delegate will check participant’s adherence to the eDiary 
assessment schedule and also emphasize the importance of transmitting data daily as is 
necessary, to minimize missing data, and at each study visit. 
Every morning participants will perform home spirometry and use the eDiary answer the 
following questions / questionnaires:
!
Major COPD symptoms (dyspnea, sputum volume, and sputum color, see Appendix G)
∀
Participant-reported worsening of 1 or more major COPD symptoms will trigger 
assessment of minor COPD symptoms (sore throat, cold, fever without other cause, 
cough, and wheeze).
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!
Nighttime awakening due to respiratory symptoms
!
Maintenance medication adherence (not considering reliever usage).
Every evening participants will use the eDiary to answer the following questions / 
questionnaires:
!
BCSS individual symptoms scores (cough, sputum, breathlessness, see Section 8.1.8.3)
!
The ER-S:COPD (see Section 8.1.8.1)
!
Cough VAS (see Section 8.1.8.2)
The eDiary will generate an alert to the participant and the investigational site if any of the 
following criteria are met:
!
Worsening of 1 major COPD symptom and at least 1 other major or minor symptom for 
2 consecutive days.
!
Fall in PEF by ≥30% from baseline for 2 consecutive days
Baseline is defined as the average of 14 days prior to first dose of investigational product.
This alert should trigger a contact betwe n the participant and the investigational site. Alerts 
will only be received by site when eDiary uploads/syncs, subject to connection availability, 
therefore participants may initiate contact with the investigator for assessment of possible 
AECOPD regardless of any prompts from the site, or the eDiary and spirometry.
The investigator then makes th  decision whether or not to initiate (or escalate, as appropriate) 
treatment for a COPD exacerbation. The investigator site is responsible for documenting the 
action taken for every alert, in the source notes and relevant eCRF modules, regardless who 
initiates contact (site or participant).
8.1.4
Objective Cough Monitoring
Objective cough frequency over 24 hours will be measured using an ACM (VitaloJAK™; 
Vitalograph, Buckinghamshire, UK), which will be fitted and worn by the participants for 
approximately 24 hours after the visits detailed in the SoA (Section 1.3). Set up of the cough 
monitors should be performed as the final assessment at each visit.
The sites will receive training to ensure the ACM is correctly fitted and activated by site staff, 
and the site staff will be given instructions to provide to the participants on how the ACM 
should be worn during the 24 hour period, to ensure data are recorded correctly. Advice 
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includes avoiding showers/bathing and any activity that will cause heavy perspiration whilst 
wearing the cough monitor, as the cough monitor must not come into contact with water (see 
Section 5.3.3).
The digitally recorded data recorded on the ACM will be sent to Vitalograph who will 
undertake cough counting for all participants using a standardized process. Details on the 
process to follow will be provided to the sites as part of the ACM training.
Detailed procedures for set up of device, recording and analyzing objective cough data will be 
described in a separate manual provided to each site. Details regarding assessment of the 
quality of objective cough monitoring undertaken by the Vendor will also be detailed in the 
manual.
8.1.5
COPDCompEx
The COPDCompEx is a composite endpoint for exacerbations in COPD. The COPDCompEx 
combines exacerbations with events defined from participant e-Diaries and PEF. The 
definitions for both types of exacerbation are as follows:
!
COPDCompEx defined exacerbations: episodes leading to one or more of the following: 
hospitalization, emergency room visit, treatment with OCS, or treatment with antibiotics. 
Note, this definition is not exactly the same as is used in Section 8.1.6.
!
Diary events: defined by threshold and lope criteria using the following diary and home 
spirometry variables: overall symptom rating, nighttime awakenings due to symptoms, 
.
More details on the derivation and analy is of this variable will be given in the SAP.
8.1.6
COPD Exacerbations (AECOPD)
An AECOPD will be defined as a change in the subject’s usual COPD symptoms that lasts 
2 or more days, is beyond normal day-to-day variation, is acute in onset, and may warrant a 
change in regular medication. The change in symptoms must include at least one major COPD 
symptom and at least one other major or minor symptom from the list below:
!
Major COPD symptoms: dyspnea, sputum volume, and sputum color 
!
Minor COPD symptoms: cough, wheeze, sore throat, cold symptoms (rhinorrhea or nasal 
congestion), and fever without other cause.
These symptoms are captured by the eDiary (see Section 8.1.3). If an AECOPD event is not 
associated with eDiary alert due to COPD symptoms (eg, technical issue with the eDiary), the 
investigator should interview the participant and evaluate potential worsening and duration of 
major and minor symptoms.
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If symptoms are acute or have progressed rapidly and require treatment less than 2 days from 
onset of symptoms, the investigator will have to justify the decision for defining the event as 
an exacerbation and record it in the eCRF.
If a subject’s symptoms and the overall clinical findings support the diagnosis of a COPD 
exacerbation, but the subject has not experienced a worsening of at least one major COPD 
symptom and at least one other major or minor symptom (eg, rapid worsening leading to 
intubation), the investigator will have to justify the decision for defining the event as an 
exacerbation and record it in the eCRF.
A clinical assessment of any potential exacerbation during the intervention and follow up 
periods will occur either at the next scheduled visit or, if necessary, an additional E/A visit 
prior to the next scheduled visit (see the SoA in Section 1.3).
8.1.6.1
Severity of AECOPD
An AECOPD will be classified as mild, moderate, or severe based on the following criteria.
An AECOPD will be considered severe if it results in:
!
An inpatient COPD-related hospitalization (documentation stating that the subject was
hospitalized for the COPD exacerbation or a record of the subject being admitted for 
≥24 hours to an observation area, the emergency department, or other equivalent 
healthcare facility depending on the country and healthcare system).
!
COPD-related death
An AECOPD that is not considered severe will be considered moderate if it results in:
!
Use of systemic corticosteroids and/or antibiotics for at least 3 days; a single depot
injectable dose of cortic steroids will be considered equivalent to a 3-day course of
systemic corticosteroids
Exacerbations that are neither considered moderate or severe will be considered mild.
8.1.6.2
Duration of AECOPD
The start and stop dates of COPD exacerbations will determined as follows:
The start and stop dates of mild AECOPD will be the onset and resolution of worsened 
symptoms respectively.
The start dates of moderate and severe AECOPD will be the earliest of:
!
Start date of systemic corticosteroids for AECOPD
!
Start date of antibiotics for AECOPD
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!
Date of hospital admission due to AECOPD
The stop dates of moderate and severe AECOPD will be the latest of:
!
End date of systemic corticosteroids for AECOPD
!
End date of antibiotics for AECOPD
!
Date of hospital discharge due to AECOPD
If less than 7 days have elapsed since the end date of an AECOPD and the start date of a new 
AECOPD, the second event will be considered a relapse of the prior AECOPD in the 
statistical analysis.
8.1.6.3
COPD Exacerbation eCRF
The investigator should record all pertinent findings and symptoms associated with the 
exacerbation event and their duration in source documents and in the COPD exacerbation 
eCRF. In particular, the investigator should also note any changes in medications related to 
cardiovascular function at any AECOPD event to enable cardiac event evaluation in this eCRF 
module.
Associated symptoms of COPD are considered as symptoms of disease under study and will
not be recorded as AEs unless considered an SAE.
All COPD related SAEs will also be recorded on the SAE eCRF. 
8.1.7
8.1.8
Patient Reported Outcome Questionnaires
Electronic PRO questionnaires will be completed every day at home and at site visits (as 
specified in the SoA [Section 1.3]) using a hand-held device. Site personnel and participants 
will be provided training on the use of the device. For home use, the device will be 
programmed to automatically alert the participants when to fill out the ePROs. In addition, 
participants will bring their device to study visits, to use for collection of clinic ePROs, which 
should be completed as the first clinic assessment. The clinic ePROs will be filled out in this 
order: ER-S:COPD, cough VAS, BCSS, 
 SGRQ, CAT, 
and Study 
Participant Feedback Questionnaire. Detailed procedures for using the device will be 
described in a separate instruction manual provided to each site.
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8.1.8.1
Exacerbations of Chronic Pulmonary Disease Tool– Patient-reported 
Outcome (EXACT-PRO) and Evaluating Respiratory Symptoms in COPD 
(E-RS™:COPD)
The EXACT-PRO is a 14-item ePRO instrument developed to assess the frequency, severity 
and duration of COPD exacerbations (Jones et al 2011; Leidy et al 2011). The instrument was 
developed for daily, at home, administration using a handheld electronic device. Respondents 
are instructed to complete the diary each evening just prior to bedtime and to answer the 
questions while considering their experiences “today”. The daily EXACT-PRO total score has 
a range of 0 to 100 with higher scores indicative of greater severity. Total score changes are 
used to identify the onset and recovery from an EXACT-PRO defined exacerbation event. In 
identifying event onset and recovery, the EXACT-PRO can provide information on event 
frequency and duration as well as event severity.
The E-RS™:COPD is an 11-item ePRO developed to evaluate the severity of respiratory
symptoms of COPD (Leidy et al 2014a; Leidy et al 2014b). The E-RS™:COPD is a subset of 
items from the EXACT-PRO. The E-RS™:COPD was designed to be captured as part of the 
daily EXACT-PRO assessment. Summation of E-RS™:COPD item responses produces a total 
score ranging from 0 to 40, with higher scores indicating greater severity. In addition to the 
total score, symptom domain scores can be calculated for breathlessness (5 items; score range: 
0 to 17), cough and sputum (3 items; score range: 0 to 11) and chest symptoms (3 items; score 
range: 0 to 12) by summing the responses of items within a respective domain. As with the 
total score, higher domain scores indicate greater severity. The EXACT-PRO will be captured 
daily each evening in this study via the eDiary.
8.1.8.2
Cough Visual Analogue Scale (Cough VAS)
Participants will be asked to complete a cough severity VAS (100 mm linear scale marked 
with a horizontal line by the participant, with 0 mm representing ‘‘no cough’’ and 100 mm 
representing “worst cough ) m asuring subjective assessment by the participant of the prior 
24 hrs for severity of cough symptoms (Smith et al 2006). The cough VAS will be completed 
each evening in the eDiary.
8.1.8.3
Breathlessness, Cough and Sputum Scale (BCSS©)
The BCSS©, is a 3-item daily diary (Leidy et al 2003) that assesses the severity of the 
3 symptoms: breathlessness, sputum, and cough, each on a 5-point scale. Item scores can be 
reported as domains scores and are summed to yield a total score. Higher scores for each 
domain, and thus for total score, indicate more severe symptoms. The BCSS will be captured 
each evening via the eDiary.
8.1.8.4
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8.1.8.5
St George’s Respiratory Questionnaire (SGRQ)
The SGRQ is a 50-item ePRO instrument developed to measure the health status of 
participants with airway obstruction diseases (Jones et al 1991). The questionnaire is divided 
into 2 parts: Part 1 consists of 8 items pertaining to the severity of respiratory symptoms in the 
preceding 4 weeks; Part 2 consists of 42 items related to the daily activity and psychosocial 
impacts of the individual’s respiratory condition. The SGRQ yields a total score and 3 domain 
scores (symptoms, activity, and impacts). The total score indicates the impact of disease on 
overall health status. This total score is expressed as a percentage of overall impairment, in 
which 100 represents the worst possible health status and 0 indicates the best possible health 
status. Likewise, the domain scores range from 0 to 100, with higher scores indicative of 
greater impairment. Based on empirical data and interviews with patients, a change of 4 units 
is associated with a minimum clinically important difference. Specific details on the scoring 
algorithms are provided by the developer in a user manual (Jones and Forde 2009). The 
SGRQ will be completed using eDiary in accordance with the SoA (Section 1.3) and a 4 week 
recall version will be used.
8.1.8.6
COPD Assessment Test (CAT)
Participants will be asked to complete a CAT at SV1. The CAT is designed to measure the 
impact of COPD on a person's life (Jones et al 2009). The CAT consists of eight questions that 
ask the participant to rate items relating to symptoms and impact on quality of life (such as 
normal activity and sleep). Each question is performed on a scale from 0 to 5 with 0 being the 
best possible health status or least impairment and 5 being the worst health status or greatest 
impairment. The CAT will be performed at the baseline visit (SV1) only to enable 
sub-analyses based on baseline disease activity status via the eDiary, which will be further 
described in the SAP.
8.1.8.7
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8.1.8.8
Study Participant Feedback Questionnaire
This study will include as an option for participants to complete an anonymized questionnaire, 
‘Study Participant Feedback Questionnaire’ for participants to provide feedback on their 
clinical trial experience. Individual participant level responses will not be reviewed by 
investigators. Responses will be used by AstraZeneca to understand where improvements can 
be made in the clinical trial process. This questionnaire does not collect data about the 
participant’s disease, symptoms, study intervention effect or AEs and therefore would not be 
study data. The Study Participant Feedback Questionnaire will be captured electronically at 
time points indicated in the SoA (Section 1.3) and is subject to agreement in the ICF.
8.1.9
Chest CT
Where an inspiratory chest CT scan has been performed within 6 months of informed consent 
and can be obtained and is adequate for quantitative as essment it shall serve as the baseline 
scan. Otherwise, a CT scan will be performed, per Table 2, to serve as the baseline scan.
In order to avoid unnecessary radiation exposure  a CT scan to serve as the baseline scan 
should only be performed if all of the following criteria are met.
!
The participant has not had an inspiratory chest CT scan within 6 months of informed 
consent, which can be obtained and is adequate for quantitative assessment, and
!
The participant is believed to be eligible, at the time, according to all inclusion and 
exclusion criteria
Quantitative assessment for the extent of emphysema of the baseline scan will be performed, 
using procedures described in the Vendor manual provided to sites. 
All CT scans performed (or used) for the purposes of this study should be locally reviewed by 
a suitably qualified radiologist for clinical findings outside of emphysema and morphometric 
assessment, to ensure any incidental clinically important findings are identified and 
referred/treated appropriately (eg, suspected cancer). (This local review may be performed 
remotely in accordance with local practices.) If a participant is found to have low-risk 
abnormalities (eg. nodules) that, according to local guidelines, only require surveillance where 
the first surveillance scan would be required after SV14 then that participant may be included 
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at the discretion of the investigator. Participants that require earlier surveillance scans or more 
active investigation must not be randomized, per Exclusion Criterion 9(g).
New CT scans must be performed in a standardized way:
All new CT scans should be performed post-BD, ie, within 60 minutes of using up to 
4 inhalations of albuterol or salbutamol. When these are undertaken at the same visit as 
spirometry and small airway measurements, CT should be performed after these assessments, 
so as not to confound the BD withhold periods. If BD is performed as part of the spirometry
assessments, this should be repeated if the BD occurred in excess of 60 minutes prior to the 
CT scan.
A radiology manual, as well as further training by the imaging vendor, will describe both the 
process of obtaining new scans and how to submit scans (historical and new) to the imaging 
vendor. An optimized CT protocol will also be provided to the sites that includes all required 
scan parameters.
Any clinical findings from historical CT should be recorded on the specific imaging eCRF 
page for SV1. Any findings based on the local assessment of a new CT scan performed during 
screening/run-in must be recorded in the corr sponding eCRF section for SV3.
All CT images submitted to the imaging vendor must first be de-identified at the site to 
remove any participant identifiers. No clinical interpretation of the CT scans will be 
performed by the central imaging vendor.
8.1.9.1
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8.1.10
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1
Medical, Surgical, and COPD History
Complete medical and surgical history will include history of COVID-19 and COVID-19 
vaccination if applicable, prior and current, medical conditions, past or present cardiovascular 
disorders, respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, lymphatic, 
hematologic, immunologic, psychiatric, genit urinary, drug and surgical history, or any other 
diseases, disorders, or surgical procedures
The participant’s COPD history will also be collected including questions related to the 
participant’s COPD history, durati n of COPD, and COPD medications (both past and 
current).
8.2.2
Physical Examinations, Weight and Height
!
Complete and brief physical examinations will be performed by a licensed HCP 
(eg, physician, physician’s assistant, or licensed nurse practitioner). A complete physical 
examination will include, but will not be limited to, assessment of general appearance, 
head, ears, eyes, nose, throat, neck, skin, as well as cardiovascular, respiratory, 
abdominal, and nervous systems. 
!
A brief physical examination will include, at a minimum, assessments of cardiovascular, 
respiratory, and nervous systems. Each clinically significant abnormal finding will be 
recorded in the medical history, and each treatment emergent abnormality, including 
injection site reactions identified by assessing SC injection sites, will be recorded as an 
AE.
!
Physical examinations, weight and height will be recorded at timepoints specified in the 
SoA (Section 1.3).
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8.2.3
Vital Signs
The nominal timing of vital signs is described in the SoA (Section 1.3). The participant should 
be in a resting supine position for at least 10 minutes prior to the collection of vital signs, as 
follows: 
!
Oral or tympanic temperature
!
DBP
!
SBP
!
Heart (pulse) rate
!
Respiratory rate
For the first 2 doses of study intervention, participants are to remain at the site for ≥2 hours or 
until stable, whichever is later. In addition, vital signs will be taken before and immediately 
after administration of study intervention, and at 30, 60, and 120 minutes (± 5 minutes) 
thereafter or until stable, whichever is later. For the subsequent doses of study intervention, 
participants are to remain at the site for ≥ 1 hour or until stable, whichever is later. In addition,
vital signs will be taken before and immediately after administration of study intervention, and 
at 30 and 60 minutes (± 5 minutes) thereafter  Following the observation period, participant 
discharge will be at the discretion of the investigator.
8.2.4
Electrocardiograms
Electrocardiograms will be performed t timelines as specified in the SoA (Section 1.3) and 
prior to vital signs, and blood sampling. Electrocardiograms will be done as a single 
measurement. 
The nominal timing of ECGs is described in the SoA (Section 1.3). The ECG assessment 
should be performed before interventions with the participant (eg, spirometry and 
administration of the COPD related medications and study intervention). The participant 
should be in a resting supine position for at least 10 minutes prior to the collection of ECGs. 
At baseline, pre-dose of study intervention at SV3 (Day 1), triplicate ECGs will be performed 
(all 3 ECGs within a 5-minute time period, at least 1 minute apart). The mean value of each 
parameter from the triplicate will be used as the baseline value. Electrocardiograms taken at 
all other times will be single assessments. 
Electrocardiograms will be recorded with 12-lead digital ECG devices at a speed of 
25 mm/second with amplitude recording of 10 mm/mV. Where possible the same make and 
model ECG device should be used for recording all ECGs for a particular participant. At least 
3 full complexes must be recorded. Date and time settings should be checked regularly and 
following time changes for daylight savings time. Skin preparation should be thorough and 
electrode positions should be according to standard 12-lead ECG placements.
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Electrocardiogram device software will be used to assess ECG parameters. All ECGs must be 
reviewed by the PI or a qualified designee before the participant is permitted to leave the 
clinic. Abnormalities and obvious changes in ECG parameters from baseline will be assessed 
by the principal investigator for clinical significance.
Electrocardiogram variables will be collected, as follows:
!
Heart (pulse) rate
!
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!
QRS interval
!
PR interval
!
QT interval
8.2.5
Echocardiogram
A transthoracic echocardiogram to assess LVEF will be performed and reported locally (see 
the SoA in Section 1.3).
It should be performed using local guidelines and standards. All echocardiograms must assess 
left ventricular end-diastolic and end-systolic volumes, and LVEF by 2D examination. An 
accepted, objective quantitative method must be used to calculate LVEF (eg, the modified 
biplane Simpson’s rule). For each participant, the same quantitative method used to assess 
LVEF at their first echocardiogram undertaken, during the screening period, must be applied 
to all subsequent assessments of LVEF.
Routine examination beyond left ventricular end-diastolic and end-systolic volumes, and 
LVEF is not required unless clini ally indicated. However, a standard 2D echocardiogram 
must be performed in any parti ipant with an abnormal LVEF (< 40%), in order to identify 
potential causes of depressed left ventricular function.
8.2.6
Clinical Safety Laboratory Assessments
The nominal timing of blood draws is described in the SoA (Section 1.3). 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 research study. Clinical laboratory safety tests will be performed in a central clinical 
laboratory with the exception of the SARS-CoV-2 nucleic acid test which may be performed 
either locally (according to local standards) or centrally. Urine pregnancy tests may be 
performed at the site using a licensed test (dipstick). Clinically significant abnormal laboratory
results should be repeated as soon as possible (preferably within 24 to 48 hours).
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The following laboratory variables will be measured (Table 8). For haematology, see blinding 
procedures for eosinophil, basophil, and monocyte data in Section 6.3.
Table 8
Laboratory Safety Variables
Haematology/haemostasis (whole blooda)
Clinical chemistry (serum)
B-Haemoglobin (Hb)
S-Creatinine
B-Leukocyte count
S-Bilirubin, total
B-Leukocyte differential count (absolute count)
S-Alkaline phosphatase (ALP)
B-Platelet count
S-AST
B-Haematocrit
S-ALT
B-Red blood cell count (RBC)
S-Albumin
Urinalysis
S-Potassium
U-Appearance and Color
S-Sodium
U-Specific gravity
S-Gamma-glutamyl transferase (GGT)
U-Hb/Erythrocytes/Blood 
S-Blood urea nitrogen
U-Glucose
S-Total Protein
U-Ketones
S-Hb1Ac
U-pH
S-NT-ProBNP
U-Bilirubin
S-Tryptase (only to be taken in event of suspected 
anaphylaxis see Appendix I)
U-Leukocytes
U-Protein
Fibrinogen (plasma)
Microscopy including white blood cell/RBC and casts 
Pregnancy test (dipstick- urine hu an chorionic 
gonadotropin) as per SoA; NOTE: addi ional timepoint 
for female participants of CT sub s dy
Coagulation
Endocrinology
Serum FSH b
a
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.
b
If needed to confirm post-menopausal status in female participants aged < 50 years.
Note for serum chemistry: Tests for AST, ALT, ALP and S-bilirubin must be conducted concurrently and 
assessed concurrently.
ALP = Alkaline phosphatase; ALT = Alanine aminotransferase; AST = Aspartate aminotransferase; B = Blood; 
 FSH = Follicle stimulating hormone; GGT = Gamma-glutamyl transferase; 
Hb = Haemoglobin; HbA1c = Hemoglobin A1c; NT-ProBNP = N-terminal pro-brain natriuretic peptide; 
RBC = Red blood cells; S = Serum; SoA = Schedule of activities; U = Urine.
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Note: In case a participant shows an AST or ALT ≥3 × ULN together with TBL ≥2 × ULN 
please refer to Appendix E ‘Actions required in cases of increases in liver biochemistry and 
evaluation of HL’, for further instructions. 
Pregnancy Test
!
Serum beta-human chorionic gonadotropin
!
Urine human chorionic gonadotropin
Other Safety Tests
!
HbA1c
!
Hepatitis B (HBsAg, anti-HBs, and anti-HBc) and C antibodies
!
HIV-1 and HIV-2 antibodies
!
IGRA (TB test)
!
Serum tryptase will only be taken in the event of suspected anaphylaxis (Appendix I)
!
SARS-CoV-2 (serology and nucleic acid test)
It is recognised that frequent routine testing of asymptomatic participants for SARS-CoV-2 at 
visits SV3 onwards may be unnecessary and not actually contribute to participant safety. In 
regions where there is no community spread of covid infection (sporadic/imported cases or 
outbreaks only) and is expected to remain as such, the medical monitor, at the request of the 
PI of a site, may authorise a less demanding schedule of SARS-CoV-2 nucleic acid testing 
from SV3 onwards at that site. This authorisation may be ended by the medical monitor, at 
any time, should the local epidemi logy change (or be expected to change).
8.3
Adverse Events and Serious Adverse Events
The PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section
The definitions of an AE or SAE can be found in Appendix B.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorised representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events and SAEs will be collected by the investigator from informed consent 
throughout the intervention period and including the follow-up period.
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If the investigator becomes aware of an SAE with a suspected causal relationship to the IMP 
that occurs after the end of the clinical study in a participant treated by him or her, the 
investigator shall, without undue delay, report the SAE to the sponsor.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the investigator for as long as medically indicated, but without further recording in the 
eCRF. AstraZeneca retains the right to request additional information for any participant with
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse event variables
The following variables will be collected for each AE:
!
AE (verbatim)
!
The date and time when the AE started and stopped
!
Severity grade 
!
Whether the AE is serious or not
!
Investigator causality rating against the study intervention (yes or no)
!
Action taken with regard to the study intervention
!
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 serious AE
!
Date investigator be ame aware of serious AE
!
AE is serious due to
!
Date of hospitalisation
!
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
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8.3.3
Causality Collection
The investigator should assess causal relationship between study intervention 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 study intervention?’
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’.
For COVID-related events, the investigator should add ‘COVID’ as part of the verbatim term.
A guide to the interpretation of the causality question is found in Appendix B.
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 probl ms 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 CSP-mandat d la oratory tests and vital signs will be summarized in the 
CSR. 
Deterioration as compared to baseline in CSP-mandated laboratory values, spirometry values 
and vital signs should therefore only be reported as AEs if:
!
They fulfil any of the SAE criteria, or
!
Are the reason for discontinuation of treatment with the study intervention, or
!
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but not limited to consideration as to whether treatment or non-planned visits were 
required or other action was taken with the study intervention, eg, dose adjustment or 
study intervention interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
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In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study.
8.3.6
Adverse Events of Special Interest
Adverse events of special interest are events of scientific and medical interest specific to 
understanding of MEDI3506 and may require close monitoring and rapid communication by 
the investigator to AstraZeneca. An AESI may be serious or non-serious. The rapid reporting 
of AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of MEDI3506.
The following AESIs will be particularly monitored in this study:
!
Hepatic function abnormality meeting the definition of HL as described in Section 8.3.7.
!
Serious hypersensitivity (including Type 1 to 4 hypersensitivity reactions), for example 
anaphylaxis and severe allergic reactions  and immune complex disease.
!
Injection site reactions.
!
Cardiac events (including angina or myocardial infarction, congestive heart failure, 
symptomatic atherosclerotic vascular disease, cor pulmonale, or arrhythmia).
!
Serious infections (including opportunistic infections and viral reactivations), for example 
herpes simplex virus/varicell  zoster virus, Epstein Barr virus/cytomegalovirus, TB, and 
all other opportunistic infections listed in the Guidelines for the Prevention and Treatment 
of Opportunistic Infections in HIV Infected Adults and Adolescents: Recommendations 
from the Centers for Disease Control and Prevention, the National Institutes of Health, 
and the HIV Medicine A ociation of the Infectious Diseases Society of America 
(NIH 2019).
!
Gastrointestinal AEs
!
Malignancy
8.3.7
Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥2 × ULN may 
need to be reported as SAEs. Please refer to Appendix E for further instruction on cases of 
increases in liver biochemistry and evaluation of HL.
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8.3.8
Disease-Under Study
Symptoms of disease under study are those which might be expected to occur as a direct result 
of COPD. Events which are unequivocally due to disease under study should not be reported 
as an AE during the study unless they meet SAE criteria or lead to discontinuation of the study
intervention. 
Acute exacerbations of COPD should be reported as AEs.
8.3.9
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the study
intervention, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel 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 works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 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 is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within 1 calendar 
day ie, immediately but no later than 24 hours of when he or she becomes aware of it.
For further guidance on the definiti n of an SAE, see Appendix B of the CSP.
The reference document for definition of expectedness/listedness is the IB for MEDI3506.
8.3.10
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except if the 
pregnancy is discovered before the study participant has received any study intervention.
8.3.10.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, study intervention should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
anomalies/birth defects and spontaneous miscarriages should be reported and handled as 
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SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital anomaly) 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 8.3.10) 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.
8.3.10.2
Paternal Exposure 
Male participants should refrain from fathering a child or donating sperm during the study and 
for 12 weeks after the last administration of study intervention.
Pregnancy of the participant’s partners is not considered to be an AE. However, the outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital anomaly), occurring from the date of the first dose until the end of 
follow-up should, if possible, be followed up and documented in the Pregnancy Report Form. 
Consent from the partner must be obtained before the Pregnancy Report Form is completed.
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 8.3.1) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B.
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8.4
Overdose
An overdose is defined as a participant receiving a dose of study intervention in excess of that 
specified in the IB, unless otherwise specified in this CSP.
!
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 Pa ient 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.
The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided to the sponsor's Patient Safety data entry site.
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 
Sample see Appendix C.
Samples will be stored for a m ximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated. 
!
PK samples will be disposed of after the Bioanalytical Report finalization or 6 months 
after issuance of the draft Bioanalytical Report (whichever is earlier), unless consented 
for future analyses. 
∀
PK samples may be disposed of or anonymised by pooling.
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8.5.1
Pharmacokinetics
Serum samples will be collected for measurement of serum concentrations of MEDI3506 as 
specified in the SoA (Section 1.3).
Samples may be collected at additional time points during the study if warranted and agreed 
upon between the investigator and the sponsor eg, for safety reasons. The timing of sampling 
may be altered during the course of the study based on newly available data (eg, to obtain data 
closer to the time of peak or trough matrix concentrations) to ensure appropriate monitoring. 
Serum samples will be used to analyse the PK of MEDI3506. Samples collected for analyses 
of MEDI3506 serum concentration may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study. Samples from participants who received 
placebo may be analysed at minimum selected time points to confirm no dosing with 
MEDI3506 took place.
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
8.5.1.1
Determination of Study Intervention Concentration
Samples for determination of study intervention concentration in serum will be assayed by 
bioanalytical test sites operated by or on behalf of AstraZeneca, using an appropriately
validated bioanalytical method. Full details of the analytical method used will be described in 
a separate bioanalytical report.
Study intervention concentration information that may unblind the study will not be reported 
to investigative sites or blinded personnel until the study has been unblinded.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report.
8.5.2
Immunogenicity Assessments
Blood samples for determination of ADA in serum will be assayed by bioanalytical test sites 
operated by, or on behalf of, AstraZeneca, using an appropriately validated bioanalytical
method. Tiered analyses will be performed to include screening, confirmatory, and titer assay
components. Full details of the methods used will be described in a separate report.
Anti-drug antibody samples may also be further tested for characterization of the ADA 
response, including possible assessment of neutralising antibody. No ADA samples will be 
collected after follow up period, except if considered necessary by the sponsor in the event of 
a potentially relevant adverse event in an individual patient.
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Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
8.5.3
Pharmacodynamics
There are no established PD measures for MEDI3506. 
8.6
8.6.1
8.6.1.1
8.6.1.2
8.6.1.3
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8.6.1.4
Collection of Samples
For storage, re-use and destruction of PD samples see Section 8.5 and Appendix C.
8.6.2
8.7
8.8
Medical Resource Utilization and Health Economics
Not applicable.
8.9
Impact of COVID-19 Pandemic
To assess the impact of the COVID-19 pandemic on the study, sites will be asked to complete 
the pandemic impact questions in the eCRF at each study visit, according to the SoA 
(Section 1.3).
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9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The primary efficacy endpoint is the Change from Baseline in pre-BD FEV1 at Week 12. A 
treatment policy estimand will be applied whereby all available data are included in the 
analysis, irrespective of whether a participant remains on study intervention or not.  
The null hypothesis is that the change from baseline in FEV1 at Week 12 on MEDI3506 is 
equal to the change from baseline in FEV1 at Week 12 on placebo. The alternative hypothesis 
is that the change from baseline in FEV1 at Week 12 on MEDI3506 is greater than the change 
from baseline in FEV1 at Week 12 on placebo, ie:
H0: Change from Baseline in FEV1 at Week 12 (MEDI3506-placebo) = 0.
H1: Change from Baseline in FEV1 at Week 12 (MEDI3506-placebo) > 0. 
Hypothesis testing will be performed at the one-sided 10% level. If the p-value is < 0.1, reject 
H0 and accept H1.
The primary analysis will act as a gate-keeper for hypothesis testing of secondary endpoints. 
Should the primary analysis hypothesis H0 be rejected, then multiplicity will be controlled for 
a subset of key secondary endpoints using Hochberg procedure. Details will be described in 
the SAP. 
9.2
Sample Size Determination
A sample size of 140 participants (70 participants per arm) will provide 80% power to detect a 
difference in mean change from baseline in FEV1 at Week 12 of 90 mL (assumed standard 
deviation of 250 mL) between the two randomized groups at a one-sided 10% level of 
statistical significance. To allow for 2% of participants being ineligible for the primary
analysis, approximately 144 participants will be randomized in the study (72 per arm).
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9.3
Populations for Analyses
The following populations are defined:
Table 9
Populations for Analysis
Population
Description
ITT population
Participants who are randomized and receive any study intervention. Participants 
will be analyzed according to their randomized study intervention group.
As-treated population
Participants who are randomized and receive any study intervention. Participants 
will be analyzed according to the study intervention they actually receive.
PK population 
Participants who received at least one dose of MEDI3506 and had at least one 
detectable serum concentration measurement post first dose of study intervention. 
Participants will be analyzed according to the study intervention they actually 
receive.
ITT = Intention-to-treat; PK = Pharmacokinetics.
The ITT population will be used to summarize all demographic and baseline characteristics, 
concomitant medications, and efficacy measures. The As-treated population will be used to 
summarize all safety measures (AEs, laboratory tests, ECG, and vital signs). The PK 
population will be used to summarize PK measures.
9.4
Statistical Analyses
All personnel involved with the analysis of the study will remain blinded until primary 
database lock and CSP deviations dentified. Analyses will be performed by AstraZeneca or 
its representatives. A comprehensive SAP will be developed and finalized before database 
lock and will describe the part cipant populations to be included in the analyses, and 
procedures for accounting for missing, unused, and spurious data. This section is a summary 
of the planned statistical analyses of the primary and secondary endpoints. Any deviations 
from this plan will be reported in the CSR.
9.4.1
General Considerations
Efficacy analyses will be performed using the ITT population.
The primary estimand is a ‘Treatment Policy’ estimand, as follows: The difference in mean 
change from baseline in FEV1 at Week 12 (MEDI3506 – placebo) will be estimated using a 
repeated measures mixed effects analysis of covariance model, for the ITT population. This 
will include all available data from all visits up to and including Week 12, irrespective of 
whether the participant discontinued study intervention or received reliever therapy.
Demography and baseline characteristics will be summarized by study intervention group for 
the ITT population.
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9.4.2
Efficacy 
9.4.2.1
Primary Endpoints
The difference in mean change from baseline in FEV1 at Week 12 (MEDI3506–placebo) will 
be estimated using a repeated measures mixed effects analysis of covariance model, for the 
ITT population. The model will include all available data from all visits up to and including 
Week 12, irrespective of whether the participant discontinued study intervention. Since a 
repeated measures model is being applied, no imputation will be made for missing data. The 
model will include fixed effects for baseline, eosinophil strata, background medication strata, 
visit, study intervention and the baseline by visit and study intervention by visit interactions. 
An unstructured covariance matrix will be used to describe the correlations between 
observations on a participant between visits. Estimates of the least square mean change from 
baseline in FEV1 for each study intervention, and the difference between them, together with 
80% CI, will be obtained from the model for each visit. The significance of the study 
intervention effect will be tested at a 10% one-sided level of significance as described in 
Section 9.1.
Additionally, the difference in mean change from baseline in FEV1 at each study visit will be 
analyzed using a repeated measures mixed effects analysis of covariance model as described 
above, including all available data from all visits through to Week 28.
9.4.2.2
Secondary Endpoints 
Time to first COPDCompEx event will be analyzed using a Cox proportional hazard model, 
with study intervention, eosinophil strata and background medication strata fitted as 
covariates. The data will also be displayed in a Kaplan-Meier plot. The COPDCompEx event 
rate will be analyzed using negative binomial regression, with the log(follow up time) 
included as an offset term. The dependent variable will be the number of COPDCompEx 
events through end of intervention, and the model will include study intervention group, 
eosinophil strata and background medication strata as fixed effects. 
Subgroup Analyses:
Subgroup analyses may be performed. These will be described in the SAP, including a 
subgroup analysis of extent of emphysema on mean change from baseline in lung function at 
Week 28.
9.4.2.3
Exploratory Endpoints
9.4.3
Safety
The occurrence of treatment-emergent AEs and SAEs will be described by system organ class, 
preferred term, severity, and relationship to the study intervention. Participants will be 
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er with 80% CI and one-sided p-values, will be 
obtained from the model for each visit.
9.4.4.4
Additional Analyses
The incidence rate of positive antibodies to MEDI3506 will be reported by study intervention 
group. If there is a high incidence of ADA, th  association of ADA with MEDI3506 
concentration will be assessed. In addition  the relationship between ADA and PD, efficacy, 
and safety may be evaluated. MEDI3506 serum concentrations will be tabulated along with
descriptive statistics. Mean and individual serum MEDI3506 concentration-time profiles will 
be plotted. Population PK modeling may be performed if data allow. The potential correlation 
between PK exposure and PD biomarkers, and efficacy/safety response may be evaluated.
9.5
Interim Analyses 
The study team may decide to conduct an administrative un-blinded analysis of the study, 
prior to the Primary Analysis, with the intent to trigger internal (AstraZeneca) investment
decisions. The purpose of this interim analysis would be to inform decisions on future 
development options for MEDI3506 or other programs. No termination of this study, or 
adjustments to the study design are planned. Regardless of any interim analysis results, this 
study will be continued and completed. As a result, no alpha will be spent at the interim 
analysis. Additional details on the unblinding for interim analysis are provided in 
Section 6.3.3.1.
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There are 3 planned analyses for this study. The Primary Analysis will occur once all 
participants have either completed the Week 12 assessments or withdrawn from the study. The 
End-of-Treatment analysis will occur once all participants have either completed the Week 28 
assessments or withdrawn from the study. The Final Analysis will occur when all participants 
have completed the safety follow up period. Details relating to the unblinding for the Primary 
Analysis are in Section 6.3.3.1.
9.6
Data Monitoring Committee
An independent unblinded DSMB will perform evaluations of safety data, from this study and 
Studies D9181C00001 (in participants with asthma), D9182C00001 (in participants with 
atopic dermatitis) and D9183C00001 (in participants with diabetic kidney disease). Details of 
the composition of the DSMB, the data to be reviewed, and the frequency of the meetings can 
be found in the DSMB Charter. The DSMB will make any necessary recommendations to the 
sponsor regarding further conduct of the studies bas d on their evaluations of emerging data. 
A blinded study-specific safety committee (or Medical Monitor) will also review SAEs and 
SUSARs. For details on DSMB, refer to Appendix A 5
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
Regulatory and Ethical Considerations
!
This study will be conducted in accordance with the CSP and with the following:
∀
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines
∀
Applicable ICH GCP Guidelines
∀
Applicable laws and regulations
!
The CSP, CSP amendments, ICF, IB, and other relevant documents (eg, advertisements) 
must be submitted to an IRB/IEC by the investigator and reviewed and approved by the 
IRB/IEC before the study is initiated.
!
Any amendments to the CSP 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 Organization but the accountability remains with AstraZeneca.
Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investig tion are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country specific regulatory requirements relating to safety reporting 
to the regulatory authority, IRB/IEC, and investigators.
For all studies except those utilizing medical devices investigator safety reports must be 
prepared for SUSARs according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then 
file it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
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 
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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.
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 will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, 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 requir d to sign a new ICF.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The investigator or authorised 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional 
mples or the future use and may withdraw their consent at any
time and for any reason during the retention period. 
Data Protection
!
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.
!
The participant 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.
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Committees Structure
An independent DSMB will be formed to evaluate safety data from concurrently conducted 
MEDI3506 Phase II clinical studies in other indications. 
Unblinded review of safety data will be required for indications where the potential risks of 
MEDI3506 are high due to the disease under study and the common comorbidities of 
particular participant populations. Safety data from this study will be provided to the DSMB 
for oversight of all safety data. Details of the composition of the DSMB, the data to be 
reviewed, and the frequency of the meetings can be found in the DSMB Charter.
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the main study results when they are 
available. The clinical study and/or summary of main study results may also be available on 
other websites according to the regulations of the countries in which the main study is 
conducted.
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 entri s are accurate and correct by physically or 
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 inspection  and provide direct access to source data documents.
!
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.
!
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
!
The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations).
!
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 CSP and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
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!
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.
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 reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.
!
Definition of what constitutes source data can be found in the monitoring plan.  
Study and Site Start and Closure
The sponsor designee reserves the right to close the study site or terminate the study at any
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
!
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines
!
Inadequate recruitment of participants by the investigator
!
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.
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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
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a participant or clinical 
study participant administered a medicinal product and which does not necessarily have a 
causal relationship with this study intervention. 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.
Definitions of Serious Adverse Event
An SAE is an AE occurring during any study phase (ie, run-in, intervention, washout, 
follow-up), that fulfils one or more of the following riteria:
!
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 anomaly 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 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 hospitalization, may be assessed as Non-Serious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
removed via cone biopsy.
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Life Threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, 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
Severity Rating Scale:
The determination of severity should be made by the investigator based upon medical 
judgment and the severity categories of Grade 1 to 5 (based on the CTCAE criteria; 
NCI 2017) as defined below:
Grade 1
An event of mild intensity that is usually transient and may require only 
minimal treatment or therapeutic intervention. The event does not generally interfere with 
usual activities of daily living.
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Grade 2
An event of moderate intensity that is usually alleviated with additional 
specific therapeutic intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the participant.
Grade 3
A severe event that requires intensive therapeutic intervention. The event 
interrupts usual activities of daily living, or significantly affects the clinical status of the 
participant.
Grade 4
An event, and/or its immediate sequelae, that is associated with an imminent 
risk of death.
Grade 5
Death as a result of an event.
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not an 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 an SAE when it satisfies the criteria 
shown in Appendix B 2.
A Guide to Interpreting the Causality Question
When making an assessment of causali y consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the study intervention.
!
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.
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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 
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.
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 study intervention, but rather a human or 
process related failure while the study intervention 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 study intervention
!
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:
!
Study intervention name confusion
!
Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant
!
Study intervention not administered as indicated, for example, wrong route or wrong site 
of administration
!
Study intervention not taken as indicated eg, tablet dissolved in water when it should be 
taken as a solid tablet 
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!
Study intervention not stored as instructed eg, kept in the fridge when it should be at room 
temperature 
!
Wrong participant received the medication (excluding RTSM system errors)
!
Wrong study intervention administered to participant (excluding RTSM system errors)
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from the RTSM system - including those which lead to one 
of the above listed events that would otherwise have been a medication error 
!
Participant accidentally missed study intervention dose(s) eg, forgot to take medication
!
Accidental overdose (will be captured as an overdose)
!
Participant failed to return unused medication or empty packaging
!
Errors related to background and 
, 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
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 whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
Withdrawal of Informed Consent for Donated Biological Samples 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already
analyzed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:
!
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.
!
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented
!
Ensures that the participant and AstraZeneca are informed about the sample disposal.
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AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented and study site notified.
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association 
(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 e.g., 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 Substa ce, Category B
!
are to be packed in accordance with UN3373 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
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Appendix E
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report PHL cases and HL cases. It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries. 
Specific guidance on managing liver abnormalities can be found in Section 8.3.7 of the CSP.
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets PHL 
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. 
Hy’s law criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury caused by the IMP. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes.
Definitions
Potential Hy’s Law (PHL)
Aspartate aminotransferase or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN at any point
during the study following the start of study medication irrespective of an increase in ALP.
Hy’s Law (HL)
Aspartate aminotransferase or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no 
other reason, other than the IMP, can be found to explain the combination of increases, 
eg, elevated ALP indicating cholestasis, viral hepatitis, another drug. 
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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination:
!
ALT ≥ 3 × ULN
!
AST ≥ 3 × ULN
!
TBL ≥ 2 × ULN
Central Laboratories Being Used:
When a participant meets any of the PHL identification criteria, in isolation or in combination, 
the central laboratory will immediately send an alert to the investigator (also sent to 
AstraZeneca representative). 
The investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the investigator will:
!
Notify the AstraZeneca representa ive
!
Request a repeat of the test (new blood draw) by the central laboratory without delay.
When the identification criteria are met from central or local laboratory results the investigator 
will without delay:
!
Determine whether the participant meets PHL criteria (see Section E 2 for definition) by 
reviewing laboratory reports from all previous visits (including both central and local
laboratory results)
Local Laboratories Being Used:
The investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Notify the AstraZeneca representative
!
Determine whether the participant meets PHL criteria (see Appendix E 2 Definitions 
within this Appendix for definition) by reviewing laboratory reports from all previous 
visits
!
Promptly enter the laboratory data into the laboratory eCRF
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Follow-up
E 4.1
Potential Hy’s Law Criteria Not Met
If the participant does not meet PHL criteria the investigator will:
!
Inform the AstraZeneca representative that the participant has not met PHL criteria.
!
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP.
E 4.2
Potential Hy’s Law Criteria Met
If the participant does meet PHL criteria the investigator will:
!
Determine whether PHL criteria were met at any study visit prior to starting study
intervention
Notify the AstraZeneca representative who will then inform the central Study Team
!
Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; serious criteria ‘Important medical event’ and causality assessment ‘yes/related’ 
according to CSP process for SAE reporting
!
For participants that met PHL criteria pri r to starting IMP, the investigator is not 
required to submit a PHL SAE unless there is a significant change# in the participant’s 
condition
!
The AstraZeneca Study Physician contacts the investigator, to provide guidance, discuss 
and agree an approach for the study participants’ follow-up (including any further 
laboratory testing) and the continuous review of data
!
Subsequent to this contact the investigator will:
∀
Monitor the parti ipant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.
∀
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the AstraZeneca Study Physician.
∀
Complete the three Liver eCRF Modules as information becomes available 
A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the AstraZeneca Study Physician if there is any uncertainty.
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Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the AstraZeneca 
Study Physician contacts the investigator in order to review available data and agree on 
whether there is an alternative explanation for meeting PHL criteria other than drug induced 
liver injury caused by the IMP, to ensure timely analysis and reporting to health authorities 
within 15 calendar days from date PHL criteria was met. The AstraZeneca Global Clinical 
Lead or equivalent and Global Safety Physician will also be involved in this review together 
with other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, 
a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for an SAE:
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF
If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE and 
AE eCRFs accordingly with the new information (reassessing event term; causality and 
seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:
!
Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 
∀
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply
∀
As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:
!
Provides any further update to the previously submitted SAE of PHL, (report term now 
‘Hy’s Law case’) ensuring causality assessment is related to IMP and seriousness criteria 
is medically important, according to CSP process for SAE reporting.
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!
Continue follow-up and review according to agreed plan. Once the necessary
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry
elevations is determined.
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Laboratory tests
Hy’s Law Laboratory Kit for Central Laboratories 
Additional standard chemistry and coagulation tests
GGT
Lactate dehydrogenase
Prothrombin time
International normalized ratio
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA a
IgG anti-HCV
HCV RNA a
IgM anti HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
CD-transferrin b
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin b
Transferrin saturation
a
HCV RNA; HCV DNA are only tested when IgG anti-HCV is positive or inconclusive
b
CD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly
Ab = Antibody; CD-transferrin = Carbohydrate deficient transferrin; CMV = Cytomegalovirus; 
DNA = Deoxyribonucleic acid; EBV = Epstein-Barr virus; GGT = Gamma-glutamyl transferase; 
HAV = Hepatitis A virus; HBc = Hepatitis B core antibody; HBsAg = Hepatitis B surface antigen; 
HBV = Hepatitis B virus; HCV = Hepatitis C virus; HEV = Hepatitis E virus; HSV = Herpes simplex virus; 
Ig = Immunoglobulin; RNA = Ribonucleic acid.
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References
Aithal et al 2011
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case 
Definition and Phenotype Standardization in Drug‐Induced Liver Injury. Clin Pharmacol Ther 
2011;89(6):806-15.
FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from URL: https://www.fda.gov/regulatory-information/search-
fda-guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation.
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Appendix F
Contraception Guidance
Women are considered to be of childbearing potential unless they meet either of the criteria, 
as follows:
!
Surgically sterilized (including bilateral tubal ligation, bilateral oophorectomy, or
!
hysterectomy), or
!
Post-menopausal.
For women aged < 50 years, post-menopausal is defined as having both:
!
A history of ≥ 12 months amenorrhea, without an alternative cause, following cessation of
!
exogenous sex-hormonal treatment and,
!
A follicle-stimulating hormone level in the post-menopausal range.
For women aged ≥ 50 years, post-menopausal is defined as having a history of ≥ 12 months 
amenorrhea, without an alternative cause, following ces ation of exogenous sex-hormonal
treatment.
A highly effective method of contraception is defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly. The acceptable methods of 
contraception are described in Table 10 below.
Periodic abstinence, the rhythm method, and withdrawal are NOT acceptable methods of 
contraception.
Table 10
Highly Effective Methods of Contraception
Barrier Methods
Hormonal Methods
•
Intrauterine device
•
Intrauterine hormone-releasing system (IUS) a
•
Bilateral tubal occlusion
•
Vasectomized partner b
•
Sexual abstinence c 
Combined (estrogen and progestogen containing 
hormonal contraception)
•
Oral (combined pill)
•
Injectable
•
Transdermal (patch)
•
Progestogen-only hormonal contraception
•
Desogestrel
a
This is also considered a hormonal method.
b
With appropriate post-vasectomy medical testing of surgical success (ie, absence of sperm in ejaculate).
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.
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Appendix G
Major and Minor Symptoms of COPD
The following questions and response options (or their translations) will be presented by the 
eDiary device to capture major and minor symptoms of COPD.
Question: How breathless have you been in the last 24 hours?
Response Options:
!
Less breathlessness than usual
!
Usual level of breathlessness
!
More breathless than usual
Question: How much mucus (phlegm) did you have in the last 24 hours?
Response Options:
!
Less than usual or no mucus (phlegm)
!
Usual amount of mucus (phlegm)
!
More mucus (phlegm) than usual
Question: What color was your mucus (phlegm) in the last 24 hours?
Response Options:
!
No mucus (phlegm)
!
Mucus (phlegm) was the usual color
!
Mucus (phlegm) was a darker or a different color than usual
Question: How much have you coughed in the last 24 hours?
Response Options:
!
Less cough than usual
!
Usual level of cough
!
More cough than usual
Question: How much have you wheezed in the last 24 hours?
Response Options:
!
Less wheeze than usual
!
Usual level of wheeze
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!
More wheeze than usual
Question: Have you had a sore throat in the last 24 hours?
Response Options:
!
No
!
Yes, I had a sore throat
Question: Have you had the symptoms of a cold such as a runny nose or nasal congestion in 
the last 24 hours?
Response Options:
!
No symptoms of a cold
!
Yes, I had symptoms of a cold
Question: Have you had a fever in the last 24 hours?
Response Options:
!
No
!
Yes, I had a fever
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Appendix H
National Institute of Allergy and Infectious Diseases and 
Food Allergy and Anaphylaxis Network Guidance for 
Anaphylaxis Diagnosis
National Institute of Allergy and Infectious Diseases and Food Allergy and Anaphylaxis 
Network define anaphylaxis as a serious allergic reaction that is rapid in onset and may cause 
death (Sampson et al 2006). They recognize 3 categories of anaphylaxis, with criteria 
designated to capture from 80% of cases (Category 1) to > 95% of all cases of anaphylaxis 
(for all 3 categories). 
1
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST 1 OF THE FOLLOWING:
(a) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia).
(b) Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence).
2
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
participant (minutes to several hours):
(a) Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula).
(b) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia).
(c) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
(d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting).
3
Reduced BP after exposure to known allergen for that participant (minutes to several 
hours):
(a) Adults: systolic BP of less than 90 mmHg or greater than 30% decrease from that 
person’s baseline.
For the purpose of AE reporting, the above criteria should be used to guide retrospective 
judgment as to whether an event was true anaphylaxis. Guidance on the recognition of 
possible anaphylaxis at the time of the event is provided (Appendix I).
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Appendix I
Signs and Symptoms and Management of Acute Anaphylaxis
Appropriate drugs, such as epinephrine, antihistamines, corticosteroids, etc, and medical
equipment to treat anaphylactic reactions must be immediately available at study sites, and 
study personnel should be trained to recognize and treat anaphylaxis. Local or national 
guidelines for the recognition and management of acute anaphylaxis should be followed 
where available. Where not available, guidance is provided below.
Signs and Symptoms of Acute Anaphylaxis
Anaphylaxis is an acute and potentially lethal multi-system allergic reaction in which some or 
all of the following signs and symptoms occur:
!
Diffuse erythema.
!
Pruritus.
!
Urticaria and/or angioedema.
!
Bronchospasm.
!
Laryngeal edema.
!
Hypotension.
!
Cardiac arrhythmias.
!
Feeling of impending doom.
!
Unconsciousness.
!
Shock.
Other earlier or concomitant signs and symptoms can include:
!
Itchy nose, eyes, pharynx, genitalia, palms, and soles.
!
Rhinorrhea.
!
Change in voice.
!
Metallic taste.
!
Nausea, vomiting, diarrhea, abdominal cramps, and bloating.
!
Light-headedness.
!
Headache.
!
Uterine cramps.
!
Generalized warmth.
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Management of Acute Anaphylaxis
I 2.1
Immediate Intervention
1
Assessment of airway, breathing, circulation, and adequacy of mentation.
2
Administer epinephrine intramuscularly every 5 to 15 minutes, in appropriate doses, as 
necessary, depending on the presenting signs and symptoms of anaphylaxis, to control 
signs and symptoms and prevent progression to more severe symptoms such as 
respiratory distress, hypotension, shock and unconsciousness.
I 2.2
Possibly Appropriate, Subsequent Measures Depending on Response to 
Epinephrine
1
Place participant in recumbent position and elevate lower extremities.
2
Establish and maintain airway.
3
Administer oxygen.
4
Establish venous access.
5
Normal saline IV for fluid replacement.
I 2.3
Specific Measures to Consider after Epinephrine Injections, Where 
Appropriate
1
Consider epinephrine infusion.
2
Consider H1 and H2 antihistamines
3
Consider nebulized beta-2 ag nist [eg, albuterol (salbutamol)] for bronchospasm resistant 
to epinephrine.
4
Consider systemic corticosteroids.
5
Consider vasopressor (eg, dopamine).
6
Consider glucagon for participant taking b-blocker.
7
Consider atropine for symptomatic bradycardia.
8
Consider transportation to an emergency department or an intensive care facility.
9
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and prolonged 
resuscitation efforts are encouraged, if necessary.
If a suspected anaphylactic reaction occurs during or within a 24-hour period after 
administration of study intervention, blood samples for serum tryptase should be collected as 
soon as possible after the event, at 60 ± 30 minutes after the event, at discharge, and between 
2 and 4 weeks post discharge. Immediate care of the participant and treatment of the reaction 
must take priority over collecting blood samples.
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Adapted from Kemp et al 2008.
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Appendix J
Example of Patient COVID-19 Screening Questionnaire
1
Have you experienced unexplained fever, cough, shortness of breath, chills, muscle pain, 
headache, sore throat, and/or new loss of taste or smell within the past 14 days?
2
Have you been in contact with anyone who is sick or with symptoms in the last 14 days? 
Note to site: probe on the same symptoms as Q1.
3
Have you been exposed to someone diagnosed with COVID-19 in the last 14 days?
4
Have you been practicing social distancing over the last 14 days? Note to site: please 
refer to region/city/country regulations.
5
Have you travelled in the last 14 days, if so, where? Note to site: recent travel including 
to countries/regions with Centers for Disease Control and Prevention Level 2 or higher 
travel warning, or equivalent, or known COVID-19 hot spots.
6
Have you been in isolation or quarantine for any reason in the past 14 days?
7
Have you been diagnosed with COVID-19 at any time, if so, where and when?
8
Have you been vaccinated against COVID-19?
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Appendix K
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
notification from the Sponsor, and instructions on how to perform these procedures will be 
provided at the time of implementation.
Reconsent of Study Participants During Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Sections K 2 to K 6. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the participant’s next contact with the study site). Visiting the study sites for the 
sole purpose of obtaining reconsent should be avoided.
Rescreening of Participants To Reconfirm Study Eligibility
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened participants  The investigator should confirm this with the designated 
AstraZeneca Study Physician.
In addition, during study disruption there may be a delay between confirming eligibility of a 
participant and either enrolment into the study or commencing of dosing with IP. If this delay 
is outside the screening window specified in the SoA (see Section 1.3) the participant will 
need to be rescreened to reconfirm eligibility before commencing study procedures. This will 
provide another opportunity to re-screen a participant in addition to that detailed in 
Section 5.4. The procedures detailed in Section 5.1 must be undertaken to confirm eligibility 
using the same randomization number as for the participant.
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Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified HCP from the study site or TPV service will visit the participants home / or other 
remote location as per local SOPs, as applicable. Supplies will be provided for a safe and 
efficient visit. The qualified HCP will be expected to collect information per the CSP.
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the participants
using telecommunications technology including phone calls, virtual or video visits, and 
mobile health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow AEs, concomitant medication, and adherence to the eDiary 
and ePRO measures to be reported and documented.
At-home or Remote Location IP Administration Instructions
If a site visit is not possible, at-home or remote location administration of IP may be 
performed by a qualified HCP, provided this is acceptable within local regulation/guidance, or 
by the participant or his/her caregiver. The option of at-home or remote location IP 
administration ensures participants safety in cases of a pandemic where participants may be at 
increased risk by traveling to the site/clinic. This will also minimize interruption of IP 
administration during other study disruptions, eg, site closures due to natural disaster. 
Section K 5.1 to be used only when applicable for the IP formulation being used, eg, with 
injectable biologics. 
K 5.1
At-home or Rem te Location IP Administration by a Qualified HCP or 
TPV Service
A qualified HCP from the study site or TPV service should administer the IP at the 
participant’s home or other remote location according to the CSP. All necessary supplies and 
instructions for administration and documentation of IP administration will be provided. 
Additional information related to the visit can be obtained via a telemedicine or home visit.
K 5.2
At-home or Remote Location IP Administration by the Participant or 
His/Her Caregiver
Prior to at-home or remote location IP administration the investigator must assess the 
participant or his/her caregiver to determine whether they are appropriate for at-home or 
remote location administration of IP. Once the participant or his/her caregiver is deemed 
appropriate for at-home or remote location administration, he/she must receive appropriate 
training. All necessary supplies and instructions for administration and documentation of IP 
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administration will be provided. More information related to the visit can be obtained via a 
telemedicine or home / remote visit.
Data Capture During Telemedicine or Home / Remote Visits
Data collected during telemedicine or home / remote visits will be captured by the qualified 
HCP from the study site or TPV service, or by the participant themselves by use of the eDiary.
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Appendix L
Abbreviations
Abbreviation or special 
term
Explanation
ACM
Ambulatory Cough Monitoring
ADA
Anti-drug Antibody 
AE
Adverse Event
AECOPD
Acute Exacerbation of Chronic Obstructive Pulmonary Disease
AESI
Adverse Event of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
Anti-HBs
Antibody to hepatitis B core antigen
AO
Airwave Oscillometry
AST
Aspartate Aminotransferase
ATS
American Thoracic Society
AUC
Area under the Concentration Time Curve
AUC0-4 weeks
Area under the Concentration Tim  Curve from Weeks 0 to 4
AX
Area of Reactance
B
Blood
BCSS  
Breathlessness, Cough and Sputum Scale
BD
Bronchodilato
BMI
Body mass ind x
BP
Blood Press re
CAT
COPD Assessment Test
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences 
Cmax,ss
Maximum Concentration at Steady State
COPD
Chronic Obstructive Pulmonary Disease
COPDCompEx
COPD Composite Exacerbations
COVID-19
Coronavirus disease 2019
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computed Tomography 
CTCAE
Common Terminology Criteria for Adverse Events
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G
tration Time Curve
n Time Cur
HG
centration Tim  Curv
ation Tim  
H
e
YH
Y
ness, Cough and Sput
Cough and
R
odilato
UR
y mass ind x
s ind x
SU
lood Press re
ress re
S
SS
$
COPD Assessme
Assessm
$S
$
Confidence In
onfidence In
$S
$
Council fo
Coun
$
CCI
CCI
CCI
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Abbreviation or special 
term
Explanation
d
Day
DBP
Diastolic Blood Pressure
DSMB
Data Safety Monitoring Board
E/A
Exacerbation Assessment
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
E/D
Early Study Intervention Discontinuation Visit
eDiary
Electronic Diary
ePRO
Electronic Patient Reported Outcome
EOT
End of Treatment
E-RS:COPD
Evaluating Respiratory Symptoms of COPD
ERS
European Respiratory Society
EXACT
Exacerbations of Chronic Pulmonary Disease Tool
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in 1 Second
FSH
Follicle Stimulating Hormone
FVC
Forced Vital Capacity
GCP
Good Clinical Prac ice
GGT
Gamma-glutamy  Transferase
Hb
Hemoglobin
HbA1c
Hemoglobin A1c
HBc
He
titis B Core Antibody
HBsAg
Hepatitis B Surface Antigen
HCP
Healthcare Provider
HCV
Hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HL
Hy’s Law
HRT
Hormone Replacement Therapy
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
ICS
Inhaled Corticosteroids
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Vital Capacity
Capacity
UR
Clinical Prac ice
ical Prac ice
U
mma-glutamy  Trans
glutamy  
SU
Hemoglobin
oglobin
SS
Hemoglobin A1c
moglobin 
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He
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He
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Abbreviation or special 
term
Explanation
IEC
Independent Ethics Committee 
Ig
Immunoglobulin
IgG1
Immunoglobulin G1
IGRA
Interferon Gamma Release Assay
IL-33
Interleukin-33
IMP
Investigational Medicinal Product
IP
Investigational Product
IRB
Institutional Review Board 
ITT
Intention-to-Treat
IV
Intravenous
LABA
Long Acting Beta 2 Agonist
LAMA
Long Acting Muscarinic Receptor Antagonist
LTBI
Latent tuberculosis infection
LVEF
Left Ventricular Ejection Fraction
mAb
Monoclonal Antibody
MMP
Matrix Metalloproteinases 
NIMP
Non-investigational Medicinal Product
NT-proBNP
N-terminal pro-brain natriuretic peptide
OCS
Oral Cort osteroids
PD
Pharmacodynamics
PDE4 Inhibitor
Phospohidiesterase-4 Inhibitor
PEF
Pe k Expiratory Flow
PHL
Potential Hy’s Law
PI
Principal Investigator 
PK
Pharmacokinetics
PNV
Predicted Normal Values
Q4W
Every 4 Weeks
R
Randomization
R5/20
Resistance at 5/20 Hz
RBC
Red Blood Cell
RTSM
Randomization and Trial Supply Management
S
Serum
SABA
Short-Acting Beta Agonists
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SS
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Potential
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Abbreviation or special 
term
Explanation
SAE
Serious Adverse Event 
SAMA
Short-Acting Muscarinic Antagonists
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SBP
Systolic Blood Pressure
SC
Subcutaneous
SGRQ
St George’s Respiratory Questionnaire
SID
Subject Identification
SoA
Schedule of Activities
SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
SV
Study Visit
TB
Tuberculosis
TBL
Total Bilirubin
TC
Telephone Contact
TPV
Third party vendor
U
Urine
UK 
United Kingdom
ULN
Up
r Limit of Normal
V
Visit
VAS
Visual Analogue Scale
w/v
Weight per Volume
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Up
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Appendix M Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 4 (23 July 2021)
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 
because it either significantly impacts the safety or physical/mental integrity of participants or 
the scientific value of the study.
Overall Rationale for the Amendment:
To reflect emerging evidence supporting coexistence of significant mucus hypersecretion in all 
extents of emphysema, to adjust for the impact of COVID-19 on exacerbation frequency globally, 
and to clarify wording on various points.
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-
substantial
Section 5.2
(Exclusion criteria)
Section 2.2
(Background) and 
Section 2.3.1
(Risk Assessment)
Section 3
(Objectives)
Section 4.2
(Scientific rationale for 
study design)
Remove exclusion 
criterion 4 (predominant 
emphysema).
Provide rationale for change.
Additional secondary 
 
 objective to 
assess response to 
MEDI3506 by extent of 
emphysema on baseline 
CT scan in main study.
Provide rationale for change.
Emerging evidence supporting 
coexistence of significant mucus 
hypersecretion in all extents of 
emphysema 
(Dunican et al 2021;
Kim et al 2021) and therefore 
amended to investigate impact 
of MEDI3506 in all patients 
regardless 
Substantial
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Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-
substantial
Section 8.1.9
(Chest CT)
Section 9.4.2.2
(Subgroup analyses)
Removal of reference to 
exclusion criteria for extent 
of emphysema.
Addition of emphysema 
subgroup analysis for 
primary endpoint.
Table 2 (Screening 
Procedures) and 
Section 4.1.1 (Study 
[and Sub-Study] 
Conduct and Planned 
Mitigations During 
COVID-19 Pandemic)
PCR analysis changed to 
nucleic acid analysis.
To account for countries that 
use a test equivalent to PCR that 
is not technically PCR.
Non-
substantial 
Section 4.1 (Overall 
Design)
Added information in the 
event that automated 
calculation of emphysema 
percentage is not technically 
possible.
For clarification.
Non-
substantial 
Section 4.2.1
(Rationale for study 
population)
Update to text on h w BCSS 
inclusion criterion helps to 
identify patients most likely 
to respond t  MEDI3506. 
(Criteri n itself unchanged).
For clarification.
Non-
substantial 
Section 5.1
(Inclusion criteria)
Section 4.1
(Overall design)
Section 4.2.1
(Rationale for study 
population)
Chang  t  ≥1 exacerbation 
of COPD in 24 months from 
12 months.
Rationale for change to 
exacerbation inclusion 
criteria.
Impact of COVID-19 on 
exacerbation frequency globally 
due to changed 
behaviour/shielding of 
vulnerable patients with 
respiratory disease.
During the ongoing COVID-19 
pandemic, as a result of changed 
patient behaviour, there has 
been a significant reduction in 
exacerbation frequency 
compared with previous years. 
Data from the UK suggested a 
50% reduction in exacerbation 
related-hospital admissions 
compared with pre-pandemic 
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Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-
substantial
(Alsallakh et al 2021;
Tan et al 2020), and a 39% 
reduction in primary care 
consultations related to COPD. 
This picture is replicated in 
other countries. Leaving the 
requirement for at least one 
moderate or severe exacerbation 
in the previous 12 months 
unchanged would lead to the 
exclusion of patients who in 
previous years would have been 
included.
Section 5.1
(Inclusion criteria)
Change BMI to 18-35 kg/m2
from 19-35 kg/m2.
Correcting error in wording to 
all w all patients of BMI range 
within normal limits to be 
included in study.
Non-
substantial
Section 5.2
(Exclusion criteria)
Clarify wording on lung 
resection exclusion.
To better clarify exclusion for 
lung resection is based upon 
significant resection 
(pneumonectomy) which would 
impact upon lung function or 
where lung volume reduction 
surgery has been carried out 
where COPD was the 
indication. Clarification to allow 
stable patients who have 
previously undergone lobar or 
wedge resection due to causes 
other than COPD.
Non-
substantial
Section 5.2
(Exclusion criteria)
Clarification on testing for 
hepatitis C infection.
Provide greater clarification that 
positive HCV antibodies would 
exclude a participant from the 
study.
Non-
substantial
BCSS = Breathlessness, Cough and Sputum Scale; BMI = Body mass index; COPD = Chronic obstructive 
pulmonary disease; COVID-19 = Coronavirus disease 2019; CT = Computed tomography; HCV = Hepatitis C 
virus; PCR = Polymerase chain reaction; UK = United Kingdom.
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Amendment 3 (01 June 2021)
This amendment is considered to be non-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 because it neither significantly impacts the safety or physical/mental integrity
of participants nor the scientific value of the study.
Overall Rationale for the Amendment:
To clarify wording on various points, to remove unnecessary tests, and add flexibility in 
regard to SARS-CoV-2 testing.
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 1.3
(Schedule of 
Activities)
Section 5.1
(Inclusion Criteria; 
Criterion 14)
Clarification that pregnancy 
tests should be carried out in 
WOCBP only.
Removal of unnecessary testing 
of women not of childbearing 
potential that causes 
inconvenie ce to patients when 
not cli ically relevant or 
appropriate and causes 
co f sion to site staff.
Non-substantial
Section 1.3
(Schedule of 
Activities)
Clarified urine pregnancy tes  
at SV2 is not required if CT 
scan is not performed.
Unnecessary test in that 
circumstance.
Non-substantial
Section 1.3
(Schedule of 
Activities), Section 
4.1.1 and 
Section 8.2.6
(Clinical Safety 
Laboratory
Assessments)
Permitted local laboratories to 
perform SARS-Cov-2 nucleic 
acid testing (nasopharyngeal 
swab), as well as the central 
laboratory and permit less 
frequent testing dependent on 
pr valence of covid infection.
To avoid delays in this result 
and to avoid unnecessary 
duplication where local 
procedures also require local 
testing. To permit less frequent 
testing in areas of low or very 
low incidence after agreement 
with medical monitor.
Non-substantial
Section 5.1
(Inclusion Criteria)
Inclusion Criterion 3: 
Clarification of influenza and 
pneumococcal vaccine 
requirements
To ensure vaccination 
requirements are compatible 
with national practices and 
seasonal vaccine availability.
Non-substantial
Section 5.2
(Exclusion Criteria; 
Criterion 25)
Clarification of a positive 
IGRA test in the context of 
treated latent TB infection.
Participants with a positive 
IGRA test and no active disease, 
who have undergone or who 
undergo full treatment for LTBI 
are not excluded from the study 
by virtue of a positive test 
(which can remain positive 
despite treatment).
Non-substantial
Section 5.2
(Exclusion Criteria)
To remove unnecessary 
effective prohibition on 
Exclusion Criterion 42 serves to 
limit total radiation exposure to 
Non-substantial
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Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 5.4
(Screen Failures)
Section 8.1.9
(Chest CT)
Section 5.4
(Screen Failures)
In the case of re-screening, to 
permit echocardiogram and 
IGRA (TB test) results no 
more than 3 months old, to be 
re-used.
Results are not likely to have 
changed significantly within a 
3 month period unless there has 
been a new significant medical 
event (which would be captured 
within Exclusion Criterion 3). 
These tests are costly and 
time-consuming both for patient 
and/or perator.
Non-substantial
Section 6.3.2
(Methods to Ensure 
Blinding)
Included that the 
randomisation schedule may 
be provided to limited 
personnel.
To facilitate in-stream analysis 
of PK and ADA samples
Non-substantial
Section 6.5.6
(COVID-19 
vaccination)
Clarification of information to 
be recorded in the event of a 
participant receiving a 
COVID-19 vaccine
To ensure necessary data is 
captured.
Non-substantial
Section 8.1.8.8
Clarified that agreement to 
participate in t e Study 
Participant F
dback 
Question aire will be included 
in the ICF
Clarification
Non-substantial
Section 8.3.10
(Pregnancy)
Appendix B
Congenital abnormality 
changed to congenital 
anomaly
To meet regulatory 
requirements on good 
pharmacovigilance practices
Non-substantial
Section 8.5.1
(Pharmacokinetics)
Clarification of processing of 
PK samples from participants 
who received placebo.
Clarification added to avoid 
unnecessary analysis on samples 
where no IMP administered.
Non-substantial
Section 8.5.2
(Immunogenicity 
Assessments)
Included that neutralising 
antibody may also be assessed
To further assess 
immunogenicity
Non-substantial
Throughout
Minor typographical changes
For clarification
Non-substantial
ADA = Anti-drug Antibody; COVID-19 = Coronavirus disease 2019; CT = Computed tomography; 
ICF = Informed Consent Form; IMP = Investigational medicinal product; LTBI = Latent tuberculosis infection; 
PK = Pharmacokinetic; SARS-Cov-2 = Severe acute respiratory syndrome coronavirus 2; SV = Study Visit; 
TB = Tuberculosis; WOCBP = Women of childbearing potential.
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Amendment 2 (08-Feb-2021)
This amendment is considered to be non-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 EU 
because it neither significantly impacts the safety or physical/mental integrity of participants 
nor the scientific value of the study. 
Overall Rationale for the Amendment:
To clarify restrictions applicable to newly available vaccines against COVID-19 and to 
remove the induced sputum and capnography sub-studies.
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.1 Synopsis
1.3 Schedule of Activities
2.3.1 Risk Assessment
3 Objectives and Endpoints
4.1 Overall Design
4.2 Scientific Rationale for 
Study Design
5 Study Population
5.1 Inclusion Criteria
5.2 Exclusion Criteria
8.1.1 Clinic Spirometry
8.6.1.5 Induced Sputum
9.2 Sample Size 
Determination
As a result of the COVID-19 
pandemi  sputum induction and 
required local processes have 
proven not to be feasible at the 
required number of sites. 
Spontaneous sputum sampling 
remains a part of the protocol.
Non-substantial
1.1 Synopsis
1.3 Schedule of Activities
3 Objectives and Endpoints
4.1 Overall Design
4.2 Scientific Rationale for 
Study Design
5 Study Population
5.1 Inclusion Criteria
8.1.12 Capnography Sub-
study
9.2 Sample Size 
Determination
prior to inclusion of any 
participants in that 
sub-study
Given the practical difficulties 
for sites conducting this study 
during the COVID-19 
pandemic, the exploratory sub-
study has been removed to 
reduce site burden.
Non-substantial
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Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.3 Schedule of Activities
Addition of PK and 
immunogenicity 
samples at SV11
To better characterize the PK 
profile
Non-substantial
3 Objectives and Endpoints
Added exploratory 
endpoints 
 
Correction of erroneous 
omission in protocol (data was 
collected in previous version)
Non-substantial
4.1.1.1 Vaccination Against 
COVID-19
5.2 Exclusion Criteria
6.5.5 Restricted and 
Prohibited Medications
Addition of instructions 
on when COVID-19 
vaccination should be 
given to study 
participants
To respond to recent emergency 
use authorizations of COVID-19 
vaccines and mitigate any 
potential risks
Non-substantial
4.4.1 Study Stopping 
Criteria
Addition of specific 
study stopping criteria 
(individual IP 
discontinuation criteria 
already present)
To comply with a request from 
the FDA
Non-substantial
5.2 Exclusion Criteria
Exclusion Criterion 15:
Addition of clarification
To comply with a request from 
n Ethics Committee
Non-substantial
5.2 Exclusion Criteria
Exclusion Criterion 
9(g): Removing 
requirement for 
surveillan
 CT s ans 
as exclusion for main 
study
Exclusion Criterion 43:
Adding need for future 
CT scans (eg, 
surveillance scans) as 
exclusion for CT sub-
study
Given available scientific 
literature on natural history of 
chest CT findings requiring CT 
scan, and lack of relationship to 
mechanism of action, it was 
considered that exclusion was 
unnecessary. However, it was 
recognized that the total 
radiation burden of surveillance 
scans should not be added to by 
end of study scans.
Non-substantial
5.2 Exclusion Criteria 6.5.5 
Restricted and Prohibited 
Medications
Exclusion 
Criterion 34(d): Added 
clarification for 
vaccines with 
adenoviral vectors that 
are unable to replicate
To clarify that these are not 
considered live or attenuated
Non-substantial
6.5.6 COVID-19 
Vaccination 
8.2.1 Medical, Surgical and 
COPD History
Added clarification on 
recording of COVID-19 
vaccination
To ensure this information is 
accurately recorded
Non-substantial
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Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Appendix J Example of 
Patient COVID-19 
Screening Questionnaire
New question added for 
COVID-19 vaccination
To provide an example question 
for sites on COVID-19 
vaccination
Non-substantial
COPD = Chronic Obstructive Pulmonary Disease; COVID-19 = Coronavirus disease 2019; CT = Computed 
Tomography; FDA = Food and Drug Administration; PK = Pharmacokinetics; SV = Study Visit.
Amendment 1 (01-Oct-2020)
This amendment is considered to be non-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 because it neither significantly impacts the safety or physical/mental integrity
of participants nor the scientific value of the study.
Overall Rationale for the Amendment:
The FDA recommended changes to the protocol, including amending the study intervention 
discontinuation criteria and using a standardized toxicity grading scale.
Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.3 Schedule of 
Activities
Adjustment of footnotes 
regarding timing of repeat 
attempts in case of failure to 
successfully obtain 
spontaneous and induced 
sputum samples
To improve flexibility for sites 
and thereby minimise the 
chance of failure to obtain a 
sample.
Non-substantial
5 Study Population
Addition of ext regarding 
par i ipants who meet 
eligibility criteria for main 
study but not sub-study.
To clarify that participants 
found to be ineligible for the 
sub-study should not 
automatically be discontinued 
from the main study.
Non-substantial
5.1 Inclusion Criteria
Correction of typographical 
error in Inclusion Criterion 6
-
Non-substantial
5.2 Exclusion Criteria
Addition of clarification 
regarding quantitative 
assessment of CT scan 
showing emphysema in 
Exclusion Criterion 4 (c).
To avoid confusion with other 
quantitative assessments of 
CT scan.
Non-substantial
5.2 Exclusion Criteria
Correction of typographical 
error in Exclusion Criterion 34 
(h)
-
Non-substantial
6.2.2 Dose 
Preparation Steps
Correction of a typographical 
error
-
Non-substantial
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Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
7.1 Discontinuation 
of Study Intervention
Criteria for discontinuation 
amended.
To address recommendations 
from the FDA.
Non-substantial
8.2.5 
Echocardiogram
Addition of detail regarding 
how the echocardiogram 
should be performed.
To ensure consistency 
between sites.
Non-substantial
8.2.6 Clinical Safety 
Laboratory
Assessments
Addition of urine specific 
gravity to Table 8 (Laboratory 
Safety Variables)
Correction of omission in 
original protocol.
Non-substantial
8.2.6 Clinical Safety 
Laboratory
Assessments
Removal of ‘Hepatitis A’ 
from other safety tests.
Correction of erroneous 
inclusion in original protocol.
Non-substantial
Appendix B Adverse 
Events: Definitions 
and Procedures for 
Recording, 
Evaluating, 
Follow-up, and 
Reporting
Replacement of Intensity 
Rating Scale with Severity 
Rating Scale based on the 
CTCAE criteria.
To address recommendations 
from the FDA
Non-substantial
CT = computed tomography; CTCAE = Common Termin logy Criteria for Adverse Events; FDA = Food and 
Drug Administration.
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11
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$SSURYHG
elel of
l
, Vasileiou E, Lyo
asileiou E
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en WH and Kline
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Clinical Study Protocol – Amendment Number 5.0
AstraZeneca
MEDI3506 - D9180C00002
CONFIDENTIAL AND PROPRIETARY
155 of 155
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SAP_001.pdf: 
Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 1 of 167 
 
 
Statistical Analysis Plan 
Study Code 
D9180C00002 
Edition Number 
2.0 
Date 
11 May 2023 
A Phase II, Randomized, Double-blind, Placebo-controlled Study 
to Assess the Efficacy, Safety and Tolerability of MEDI3506 in 
Participants with Moderate to Severe Chronic Obstructive 
Pulmonary Disease and Chronic Bronchitis (FRONTIER 4) 
 
 


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Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 5 of 167 
 
 
4.2.10.6 
Other safety tests................................................................................................... 82 
5 
INTERIM ANALYSES ........................................................................................ 83 
6 
CHANGES OF ANALYSIS FROM PROTOCOL .............................................. 83 
7 
REFERENCES ..................................................................................................... 84 
8 
APPENDIX .......................................................................................................... 85 
 
 
 


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Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 7 of 167 
 
 
Table 29 
BCSS© scoring ......................................................................................... 167 
 
LIST OF APPENDICES 
APPENDIX A TABLE OF CONTENTS ............................................................................ 86 
APPENDIX B EPRO SCORING ...................................................................................... 157 
 


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Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 17 of 167 
 
 
instead of eosinophil strata (Change from 
the CSP). 
Other 
11May2023 
Appendix A list of outputs have been updated 
Following the above update, the list of 
outputs have been evolved. 
* Pre-specified categories are  
Primary or secondary endpoints; Statistical analysis method for the primary or secondary endpoints; Derivation of primary or secondary endpoints; Multiple 
Testing Procedure; Data presentations; Other 
 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 18 of 167 
 
 
1 
STUDY DETAILS 
1.1 
Study objectives 
Table 1 
Primary objective and associated endpoint 
Objective 
Endpoint 
To assess the effects of MEDI3506 compared with 
placebo on pulmonary function in participants with 
COPD and chronic bronchitis. 
Change from baseline to Week 12 in pre-BD FEV1 
measured in clinic. 
BD = Bronchodilator; COPD = Chronic obstructive pulmonary disease; FEV1 = Forced expiratory volume 1 
second. 
 
Table 2 
Secondary objectives and associated endpoints 
Objectives 
Endpoints 
To assess the PK of MEDI3506 in participants with 
COPD and chronic bronchitis. 
Serum MEDI3506 concentration-time profiles during 
the intervention and follow-up periods. 
To assess the immunogenicity of MEDI3506 
compared with placebo in participants with COPD 
and chronic bronchitis. 
Anti-drug antibodies during the intervention and 
follow-up periods. 
To assess the effect of MEDI3506 on COPDCompEx 
event in participants with COPD and chronic 
bronchitis. 
Time to first COPDCompEx event based on the 
period from baseline to 4 weeks after last dose 
(Week 28) 
To assess the effect of MEDI3506 compared with 
placebo on respiratory symptoms in participants with 
COPD and chronic bronchitis. 
Change from baseline to Week 12 in: 
• 
E-RS:COPD 
• 
Mean BCSS score (over the previous 4 weeks) 
• 
Cough VAS item 
To assess the effect of MEDI3506 compared with 
placebo on disease impact in participants with COPD 
and chronic bronchitis.  
• 
Change from baseline to Week 12 in SGRQ 
total score 
• 
Proportion of participants with a decrease in 
SGRQ total score of ≥ 4 points from baseline to 
Week 12 
To assess the effect of MEDI3506 compared with 
placebo on airway resistance and reactance in 
participants with COPD and chronic bronchitis. 
Change from baseline to Week 12 in AO parameters: 
• 
R5-R20 
• 
R5 
• 
R20 
• 
AX 
To evaluate the effect of MEDI3506 compared with 
placebo on objective cough measures in participants 
with COPD and chronic bronchitis. 
At Week 12, ratio to baseline in: 
• 
Daily (ie, 24 hour) cough frequency 
• 
Night time cough frequency 
• 
Awake time cough frequency 
To evaluate the effect of MEDI3506 or placebo on 
lung function by extent of baseline emphysema on 
CT scan. 
• 
Change from baseline in pre-BD and post-BD 
FEV1 through Week 28 
• 
Change from baseline in pre-BD and post BD 
FVC through Week 28 


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Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 27 of 167 
 
 
• 
At a time point where more than 50% (but not all) of the values are NQ, the gmean, 
gmean ± gSD and gCV% will be set to NR. The maximum value will be reported from 
the individual data, and the minimum and median will be set to NQ. 
• 
If all concentrations are NQ at a time point, no descriptive statistics will be calculated for 
that time point. The gmean, minimum, median and maximum will be reported as NQ and 
the gCV% and gmean ± gSD as NR. 
• 
The number of values below LLOQ (n < LLOQ) will be reported for each time point 
together with the total number of collected values (n). 
 
Three observations > LLOQ are required as a minimum for a PK serum concentration to be 
summarised. Two observations > LLOQ are presented as minimum and maximum with the 
other summary statistics as NC. 
3.1.4.1 
Imputation of partial missing AE dates 
Date and time of AE are mandatory eCRF fields. In the rare cases of missing date, following 
rules will be applied. Completely missing AE dates are not imputed. 
Partial missing AE end dates are imputed as below:  
• 
If the AE is ongoing, the end date is stated to missing.  
• 
If the AE is not ongoing, and: 
− 
If only the day is missing: Assume the last day of the collected month. 
− 
If the month is missing: Assume 31-DEC of the collected year. 
 
After applying these rules, if the imputed AE end date is after the end of study date, set the AE 
end date to end of study date. 
Before proceeding with the AE start date imputation, the AE end date is imputed as described 
above, if necessary.  
Only partial AE start dates are imputed. Dates which are completely missing are not imputed. 
Partial dates are imputed as described below:  
• 
If the day is missing and:  
− 
If the month and year are different from the month and year of the first dose of IP, 
assume 01-MMM-YYYY.  
− 
If the month and year are the same as the first dose of IP month and year and the end 
date is on or after (including ongoing / missing) the first dose of IP, then assume the 
date of the first dose of IP.  
− 
If the month and year are the same as the first dose of IP month and year and the end 
date is prior to the first dose of IP, then assume the end date.  


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 28 of 167 
 
 
• 
If the month is missing and:  
− 
If the year is different from the year of first dose of IP, assume 01-JAN-YYYY of the 
collected year.  
− 
If the year is the same as the first dose of IP year and the end date is on or after 
(including ongoing / missing) the first dose of IP, then assume the date of the first 
dose of IP.  
− 
If the year is the same as the first dose of IP and the end date is prior to the first dose 
of IP, then assume the end date.  
 
After applying these rules, if the imputed AE start date is after a complete AE end date then 
assume the same date as the complete AE end date; if the end date is missing and the imputed 
AE start date is after the end of study date then assume the same date as the study end date. 
3.1.4.2 
Imputation of partial missing medication dates 
Both, completely missing and partially missing concomitant medication start dates are not 
imputed. 
Completely missing medication end dates are not imputed. Partial missing concomitant 
medication end dates are imputed as below:  
• 
If the medication is ongoing, the end date is set to missing.  
• 
If the medication is not ongoing, and: 
− 
If only the day is missing: Impute with the last day of the collected month.  
− 
If the month is missing: Impute with 31st of December of the collected year. 
 
3.1.4.3 
Imputation of partial missing COPD history dates 
Only partial COPD history dates will be imputed. Dates which are completely missing will not 
be imputed.  
Partial start dates will be imputed as described below: 
• 
If only day is missing, then impute the first day of the month; 
• 
If the month is missing, then impute 1st of January of the collected year. 
 
Partial end dates will be imputed as described below: 
• 
If only day is missing, then impute the last day of the month; 
• 
If the month is missing, then impute 31st of December of the collected year. 
 
 


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Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 31 of 167 
 
 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled Study 
Day 
Visit Window for Analysis 
(Days) 
SV6 
Week 4 
Visit 6, Week 4 
29 
23 to 57 
SV8 
Week 12 
Visit 8, Week 12 
85 
58 to 113 
SV10 
Week 20 
Visit 10, Week 20 
141 
114 to 155 
SV11 
Week 24 
Visit 11, Week 24 
169 
156 to 183 
SV12  
Week 28 
Visit 12, Week 28 
197 
184 to 211 
SV13 
Week 32 
Visit 13, Week 32 
225 
212 to 239 
SV14 
Week 36 
Visit 14, Week 36 
253 
≥240 
SV = Study Visit. 
Table 10 
Analysis visit windows for ECGs 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled Study 
Day 
Visit Window for Analysis 
(Days) 
SV3 
Week 0 
Baseline 
1 
All assessments prior to the first 
administration of 
investigational product 
SV8 
Week 12 
Visit 8, Week 12 
85 
All assessments on or after the 
first administration of 
investigational product to 141 
SV12 
Week 28 
Visit 12, Week 28 
197 
142 to 225 
SV14 
Week 36 
Visit 14, Week 36 
253 
≥226 
ECG = Electrocardiogram; SV = Study Visit. 
 
Table 11 
Analysis visit windows for urinalysis and SGRQ assessments 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled Study 
Day 
Visit Window for Analysis 
(Days) 
SV3 
Week 0 
Baseline 
1 
All assessments prior to the first 
administration of 
investigational product 
SV6 
Week 4 
Visit 6, Week 4 
29 
All assessments on or after the 
first administration of 
investigational product to 57 
SV8 
Week 12 
Visit 8, Week 12 
85 
58 to 141 
SV12 
Week 28 
Visit 12, Week 28 
197 
≥142 
SGRQ = St George’s respiratory questionnaire; SV = Study Visit. 
 




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Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 34 of 167 
 
 
4-weekly period 
Label 
Period 6: Evening of Day 141 – Morning of Day 169 
Day 141 – 169 (Week 24) 
Period 7: Evening of Day 169 – Morning of Day 197 
Day 169 – 197 (Week 28) 
Period 8: Evening of Day 197 – Morning of Day 225 
Day 197 – 225 (Week 32) 
Period 9: Evening of Day 225 – Morning of Day 253 
Day 225 – 253 (Week 36) 
For all other assessments, there will be no analysis visit windows, the data will be reported 
according to CRF visit. 
For variables analysed using a 4-weekly period, all the days should be considered. 
3.1.6 
Analysis timepoints for vital signs 
For reporting of analysis timepoints in vital signs summaries and listings, the next time 
windows will be applied: 
Table 19 
Vital signs timepoint labelling  
Visit 
Analysis Visit 
Planned timepoint 
Screening (SV1), SV5, Follow-up 1 
(SV13), Follow-up 2 (SV14) 
Baseline / Visit 5, Week 2 / 
Visit 13, Week 32/ Visit 14, 
Week 36 
NA 
First 2 doses of study intervention (SV3 
and SV6) 
Baseline / Visit Y, Week X 
Pre-dose 
Visit Y, Week X 
Post-dose 
Visit Y, Week X 
30 min Post-dose 
Visit Y, Week X 
60 min Post-dose 
Visit Y, Week X 
120 min Post-dose 
SV7 – SV11 
Visit Y, Week X 
Pre-dose 
Visit Y, Week X 
Post-dose 
Visit Y, Week X 
30 min Post-dose 
Visit Y, Week X 
60 min Post-dose 
SV12 
Visit 12, Week 28 
NA 
NA = Not Applicable, SV = study visit. 
To be noted, that assessment that was done at SV3 pre-dose will be labelled “Baseline – Pre-
dose”, and the following post-dose assessments at SV3, eg Post-dose, 30 min Post-dose, will 
have analysis visit label “Day 1”. 
In case of early discontinuation visit, if the visit falls during an on-treatment visit, the 
corresponding visit will be assigned for the analysis visit with Pre-dose as timepoint.  


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Daily cough frequency as full average hourly cough of the full duration of recording, night 
time cough frequency as sleep average hourly cough of the duration of recording at night, and 
awake time cough frequency as awake average hourly cough of the full duration of recording 
minus sleep recording will be derived from the recording. All frequency data will be recorded 
to 2 decimal places. The minimum recording time for the measurement to be ‘done’ is one 
hour, however the minimum recording time required for analysis is 18 hours within the 24-
hour interval, and participants’ data with recording time < 18 hours will be excluded from 
analysis.  
3.3.4 
COPDCompEx events 
The COPDCompEx is a composite endpoint for exacerbations in COPD. The COPDCompEx 
combines exacerbations with events defined from participant e-Diaries and PEF.  
Note the COPDCompEx definition typically includes dropout due to lack of efficacy as a 
CompEx event. However, since ‘lack of efficacy’ is not listed as a reason for drop out in this 
study, we will not include the drop out criterion for COPD CompEx in this study. 
A participant will be considered to have a CompEx event during the planned Intervention 
Period if the participant has one or more of the following: 
• 
COPDCompEx defined exacerbation, those collected in eCRF with at least one of the 
following criteria met: 
− 
Associated Hospitalizations = Yes; 
− 
Systemic Corticosteroids (injected and/or oral) = Yes; 
− 
Antibiotics = Yes; 
− 
Any emergency room visit due to COPD exacerbation? = Yes. 
 
• 
A diary event - An objective deterioration, which is defined as either the threshold 
criterion or the slope criterion (or both), being met for ≥2 consecutive days. See 
derivation below. 
 
For this purpose, “2 consecutive days” means strictly the same 2 consecutive days when 
assessing multiple requirements within those days. For the eDiary data (which is captured 
twice during the day), one day will be defined by the evening/morning pairing as the other 
eDiary endpoints in this trial. Diary data recorded in the evening of day n and in the morning 
of day n+1 will belong to study day n. 
 
 


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Derivation of Diary Events:  
The fulfilment of objective deterioration criteria will be calculated for each (single) diary 
variable for thresholds and slopes: 
Threshold criterion: 
The threshold assessment in each 2-day rolling period: 
(a) ≥ 12% decrease from baseline in morning PEF.  
(b) ≥ 1.75 doses increase from baseline in daily total rescue medication (one day is 
defined as evening/morning pairing. The number of doses of rescue medication is 
defined as the number of puffs of inhaler recorded in the evening and morning, 
respectively.) If either the evening or morning result is missing then the single non-
missing result will be used. 
(c) ≥ 0.75 increase from baseline or having maximal symptom score 4 in at least one of 
the symptom scores: breathlessness, cough, sputum. To be specific: 
(i) ≥ 0.75 increase from baseline or having maximal symptom score 4 in 
breathlessness daily score 
or 
(ii) ≥ 0.75 increase from baseline or having maximal symptom score 4 in cough 
daily score 
or 
(iii) ≥ 0.75 increase from baseline or having maximal symptom score 4 in sputum 
daily score. 
The threshold criterion is met if [(a) or (b)] and at least one of (c) are met on 2 consecutive 
days.  
Slope criterion: 
The regression slope assessment in each preceding 5-day rolling period:  
(d) Morning PEF slopes ≤ -3%/day.  
(e) Daily total rescue medication slope ≥ 0.4 doses/day 
(f) Slope ≥ 0.2/day in all of symptom scores breathlessness, cough, sputum.  
The slope criterion is met if [(d), (e) and (f)] are all met, and at least one of [(a), (b) or (c)] is 
met.   
In all of the above cases, the regression slope is the point estimate of the slope obtained from a 
linear regression of the absolute values of each of the variables separately against day number, 
with no other variables included in the regression model. 




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3.4 
Patient reported outcome variables 
3.4.1 
Evaluating Respiratory Symptoms in COPD (E-RS™: COPD) 
Change from baseline to Week 12 in 4-weekly mean ER-S: COPD is a secondary endpoint of 
this study. 
The E-RS™: COPD is an 11-item PRO developed to evaluate the severity of respiratory 
symptoms of COPD. Summation of E-RS™: COPD item responses produces a total score 
ranging from 0 to 40, with higher scores indicating greater severity. In addition to the total 
score, symptom domain scores can be calculated for breathlessness (5 items; score range: 
0 to 17), cough and sputum (3 items; score range: 0 to 11) and chest symptoms (3 items; score 
range: 0 to 12) by summing the responses of items within a respective domain. As with the 
total score, higher domain scores indicate greater severity (see Appendix B 1). 
Scoring instructions: 
Convert each original item response code to an item-level raw score, by matching the 
responses in Appendix B 1. A daily RS-Total score is derived by summing across all 11 item-
level scores. Subscale scores are computed as sum of item-level scores for each subscale 
(domain): 
• 
RS-Breathlessness score will be calculated as the sum of items 7, 8, 9, 10, 11. 
• 
RS-Cough & Sputum score will be calculated as the sum of items 2, 3, 4. 
• 
RS-Chest symptoms score will be calculated as the sum of items 1, 5, 6. 
 
Domain and total scores will not be calculated if at least one item response is missing. 
The 4-weekly mean will be calculated as the sum of all non-missing daily scores over the 28-
day evaluation period, as described in Table 18, divided by the number of non-missing daily 
scores. The 4-weekly mean will be calculated if there are at least 14 completed days during 
the 28-day evaluation period, where a day = evening + following morning. 
3.4.2 
Cough Visual Analogue Scale 
Change from baseline to Week 12 in average Cough VAS score over the previous 4 weeks is a 
secondary endpoint of this study. 
Participants will be asked to complete a cough severity VAS (100 mm linear scale marked 
with a horizontal line by the participant, with 0 mm representing ‘‘no cough’’ and 100 mm 
representing “worst cough”) measuring subjective assessment by the participant of the prior 
24 hrs for severity of cough symptoms (Smith et al 2006). The cough VAS will be completed 
each evening in the eDiary. 


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The 4-weekly mean cough VAS score will be calculated as the sum of all non-missing daily 
scores over the 28-day evaluation period, as described in Table 18, divided by the number of 
non-missing daily scores. The 4-weekly mean will be calculated if there are at least 14 
completed days during the 28-day evaluation period, where a day = evening + following 
morning. 
3.4.3 
Breathlessness, Cough and Sputum Scale  
Change from baseline to Week 12 in the average BCSS score over the previous 4 weeks is a 
secondary endpoint of this study. 
The BCSS© is a 3-item daily diary that assesses the severity of the 3 symptoms: 
breathlessness, sputum, and cough, each on a 5-point scale (see Appendix B 4). Item scores 
will be reported as domains scores and are summed to yield a total score. Higher scores for 
each domain, and thus for total score, indicate more severe symptoms. The BCSS will be 
captured each evening via the eDiary. 
The 4-weekly mean BCSS score will be calculated as the sum of all non-missing daily scores 
over the 28-day evaluation period, as described in Table 18, divided by the number of non-
missing daily scores. The 4-weekly mean will be calculated if there are at least 14 completed 
days during the 28-day evaluation period, where a day = evening + following morning. 
3.4.4 
St George’s Respiratory Questionnaire  
The SGRQ is a 50-item PRO instrument developed to measure the health status of patients 
with airway obstruction diseases (Jones et al 1991). The SGRQ yields a total score and three 
domain scores (symptoms, activity, and impacts). The total score indicates the impact of 
disease on overall health status. This total score is expressed as a percentage of overall 
impairment, in which 100 represents the worst possible health status and 0 indicates the best 
possible health status. Likewise, the domain scores range from 0 to 100, with higher scores 
indicative of greater impairment. Specific details on the scoring algorithms are provided by 
the developer in a user manual (Jones and Forde 2009). The principle of calculation of total 
score and domain scores in accordance with the abovementioned user manual are provided in 
Appendix B 3. 
The SGRQ will be completed using the eDiary in accordance with the SoA (CSP Section 1.3), 
and a 4-week recall version will be used. 
The key outcome variable for the SGRQ will be the change in total SGRQ score from baseline 
to Week 12, but the change in total score from baseline to Week 4 and Week 28 will also be 
derived (see Section 3.1.3). Change in the domain score from baseline to Week 4, Week 12 
and Week 28 will also be derived. 
Other variables based on SGRQ to report include: 


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Non-Treatment-emergent ADA positive (non-TE-ADA+) is defined as ADA positive but not 
fulfilling the definition of TE-ADA positive.  
ADA incidence is the proportion of TE-ADA+ participants in a population. 
ADA persistently positive is defined as ADA negative at baseline and positive at ≥ 2 post-
baseline assessments (with ≥ 16 weeks between first and last positive) or ADA positive at last 
post-baseline assessment. ADA transiently positive is defined as ADA negative at baseline 
and at least one post- baseline ADA positive measurement and not fulfilling the conditions for 
persistently positive. 
The median of maximum titres is calculated based on the maximum titre for each ADA 
positive participant within each study intervention group (including both baseline and post-
baseline measurements). 
3.6.2 
Categories of ADA responses 
Numbers and proportions of: 
• 
Participants who are ADA positive at any time during the study, including baseline and/or 
post-baseline (also generally referred to as ADA positive).  
• 
Participants who are ADA negative at all assessments, including baseline and post-
baseline (also generally referred to as ADA negative). 
• 
Participants who are ADA positive at baseline only. 
• 
Participants who are ADA positive at baseline and at least one post-baseline assessment. 
• 
Participants who are treatment-emergent ADA positive (see definition in Section 3.6.1), 
reported overall and separately as treatment-induced and treatment-boosted participants.  
• 
Participants who are non treatment-emergent ADA positive (see definition in Section 
3.6.1). 
• 
Participants who are persistently ADA positive, which is defined in Section 3.6.1. 
• 
Participants who are transiently ADA positive, defined in Section 3.6.1. 
• 
Participants who are ADA positive with maximum titre > median of maximum titres. 
 
3.7 
Exposure to study intervention 
Duration of exposure 
Exposure duration (days) is calculated only for participants in the As-treated population as the 
total number of days on study drug. Exposure is calculated as (the study drug application last 
date plus 28 days) minus study drug application first date plus one. If any of the first or last 
dates are missing or partially missing, then imputed dates will not be used, and study drug 
exposure is set to missing. 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
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Number of doses received 
Full dose of study drug is administered in 2 injections. The date and time of the first injection 
will be recorded in eCRF. 
Total number of doses received will be calculated as number of study visits where at least one 
injection with dose level >0 is administered. The first dose of the intervention period intended 
to be the SV3 dose and the intended last dose of the intervention period is SV11 dose. 
Treatment interruptions 
Study intervention is interrupted when at least one of the following events occur:  
• 
Checkbox with action taken with study intervention = “Drug Interrupted” is ticked on 
EX eCRF; 
• 
There is no dosing (dose recorded as ‘0’ in eCRF) however visit has been performed; 
• 
There is a dose < 4 ml recorded in eCRF (only one syringe has been administered or the 
volume of 2 syringes is less than intended);  
• 
There are less than 4 kits dispensed and less than 4 kit numbers recorded in eCRF.   
Permanent drug withdrawal is not considered an interruption. 
3.8 
Safety outcome variables 
The following safety data will be collected: 
• 
AEs, SAEs, AESI; 
• 
Vital signs; 
• 
Clinical chemistry, haematology, and urinalysis; 
• 
ECGs; 
• 
LVEF as measured by echocardiogram; 
• 
NT-proBNP; 
• 
SARS-CoV-2 tests. 
 
3.8.1 
Adverse events 
Adverse events and SAEs on this study will be collected from informed consent throughout 
the intervention period and including the follow-up period. AEs will be coded with 
MedDRA version 25.1 or higher.  
AE data will be allocated to the study phase (as defined in section 3.1.7) according to their 
onset date. 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 51 of 167 
 
 
AEs will be defined as treatment emergent adverse events (TEAEs) if they have an onset, 
during the on-treatment phase. AEs with a missing start date will be considered as on-
treatment.  
Adverse events of special interest 
The following AESIs will be particularly monitored in this study: 
• 
Hepatic function abnormality meeting the definition of HL as described in CSP Section 
8.3.7. 
• 
Serious hypersensitivity (including Type 1 to 4 hypersensitivity reactions), for example 
anaphylaxis and severe allergic reactions, and immune complex disease. 
• 
Injection site reactions (ISR). 
• 
Cardiac events (including angina or myocardial infarction, congestive heart failure, 
symptomatic atherosclerotic vascular disease, cor pulmonale, or arrhythmia). 
• 
Serious infections (including opportunistic infections and viral reactivations), for example 
herpes simplex virus/varicella zoster virus, Epstein Barr virus/cytomegalovirus, TB, and 
all other opportunistic infections listed in the Guidelines for the Prevention and Treatment 
of Opportunistic Infections in HIV Infected Adults and Adolescents: Recommendations 
from the Centers for Disease Control and Prevention, the National Institutes of Health, 
and the HIV Medicine Association of the Infectious Diseases Society of America (NIH 
2019). 
• 
Gastrointestinal AEs 
• 
Malignancy 
 
AEs will be assigned to a specific category based on investigator’s judgement, using a 
checkbox on the AE CRF page. In addition, standardized MedDRA queries (SMQs) will be 
used when possible, and a selection of HLTs, SOCs and/or PTs will be used to represent other 
situations, to perform a cross-check with eCRF categories.  A comprehensive list will be 
provided by the patient safety team prior to any study delivery. 
 
COVID-19 related AEs and SAEs 
AE or SAE will be considered as related to COVID-19 if a participant has been tested positive 
for SARS-CoV-2 (by nucleic acid or serology test), during the intervention and follow-up 
periods and had an AE or SAE associated with COVID-19 based on the COVID-19 SMQ.  
3.8.2 
Laboratory variables 
Following haematology, clinical chemistry, urinalysis and coagulation parameters will be 
assessed: 


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Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 53 of 167 
 
 
3.8.3 
Vital signs 
The following vital signs parameters are collected as per SoA (CSP Section 1.3): 
• 
Oral or tympanic temperature (collected in ℃ or ℉) 
• 
Diastolic blood pressure (collected in mmHg) 
• 
Systolic blood pressure (collected in mmHg) 
• 
Pulse rate (collected in beats/min) 
• 
Respiratory rate (collected in breaths/min) 
 
Body mass index at baseline will be calculated from the height (in meters) and weight (in 
kilograms) as follows: BMI = weight / (height^2). 
Additionally, vital signs values will be classified as normal (if value is between lower and 
upper limit), low (if value is below the lower limit), high (if value is above the upper limit), 
and high change (if increase from baseline is greater than prespecified criterion) and low 
change (if decrease from baseline is greater than prespecified criterion) according to the 
following normal reference ranges: 
Table 23 
Vital sign reference ranges 
Parameter 
Standard Unit 
Lower limit 
Upper limit 
Change Criteria 
Body temperature 
(oral, tympanic) 
°C 
 
>37 
±1 
DBP 
mmHg 
<60 
>100 
±15 
SBP 
mmHg 
<90 
>160 
±30 
Heart (pulse) rate 
beats/min 
<50 
>100 
±20 
Respiratory rate 
breath/min 
<12 
>24 
±4 
DBP = Diastolic Blood Pressure; SBP = Systolic Blood Pressure. 
High value (H) is defined as upper reference limit. High change (HC) is defined as increase 
from baseline greater than prespecified criterion. Low value (L) is defined as below lower 
reference limit. Low change (LC) is defined as decrease from baseline greater than 
prespecified criterion. 
3.8.4 
Electrocardiogram 
Electrocardiograms will be performed at timelines as specified in the SoA. Electrocardiogram 
variables will be collected, as follows: 
• 
Heart rate (beats/min); 
• 
RR interval (msec); 
• 
QRS interval (msec); 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 54 of 167 
 
 
• 
PR interval (msec); 
• 
QT interval (msec). 
 
Additionally, QTc interval corrected for heart rate will be calculated directly from the CRF for 
Fridericia’s correction and derived for Bazett’s correction using  
Fridericia’s correction: QTcF[msec] = QT[msec]/(RR[sec]1/3)  
Bazett’s correction: QTcB[msec] = QT[msec]/(RR[sec]1/2) 
At baseline, pre-dose of study intervention at SV3 (Day 1), triplicate ECGs will be performed 
(all 3 ECGs within a 5-minute time period, at least 1 minute apart). Electrocardiograms taken 
at all other times will be single assessments. The outcome of overall evaluation will be 
recorded as normal/abnormal in CRF, with abnormalities being recorded as clinically 
significant or not clinically significant and reason for abnormal evaluation being provided. 
Additionally, ECG values will be classified as normal (if observed value is within normal 
reference ranges), low (if observed value is below lower limit of normal range) and high (if 
observed value is above upper limit of normal range) according to normal reference ranges 
(Table 24). 
Table 24 
ECG normal reference ranges 
Parameter (standard unit) 
Lower limit 
Upper limit 
Change criteria 
Heart rate (beats/min) 
<60 
>100 
 
RR interval (msec) 
<600 
>1200 
 
QRS interval (msec) 
<80 
>120 
 
PR interval (msec) 
<120 
>200 
 
QT interval (msec) 
N/A 
>420 male >440 female 
+30 
QTcB (msec) 
N/A 
>450  
+30 
QTcF (msec) 
N/A 
>450  
+30 
 
3.8.5 
Echocardiogram 
A transthoracic echocardiogram to assess LVEF will be performed at timelines as specified in 
SoA (CSP Section 1.3). 
3.8.6 
Other safety variables 
NT-proBNP 
NT-proBNP samples will be collected at SV1, SV8, SV12 and at Early discontinuation visit. 


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Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
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At the time of both, the primary and the end of treatment analyses, all data collected on and 
prior to data cut-off dates (i.e. respectively Week 12 and Week 28 visit dates for the last 
subjects) will be cleaned. For the purpose of the statistical analysis, data cut-off rules might be 
implemented and described in a separate document. All data collected until the time of the 
final DBL will be included in the final analysis. No cut-off rules will be implemented for the 
final analysis. 
 
For subjects whose IXRS strata does not match with data collected on the CRF, the IXRS 
strata will be used in the analyses 
4.1.1 
Statistical hypotheses 
The primary efficacy endpoint is the change from baseline in pre-BD FEV1 at Week 12. A 
treatment policy estimand will be applied whereby all available data are included in the 
analysis, irrespective of whether a participant remains on study intervention or not.   
The null hypothesis is that the change from baseline in FEV1 at Week 12 on MEDI3506 is 
equal to the change from baseline in FEV1 at Week 12 on placebo. The alternative hypothesis 
is that the change from baseline in FEV1 at Week 12 on MEDI3506 is greater than the change 
from baseline in FEV1 at Week 12 on placebo, ie: 
H0: Change from Baseline in FEV1 at Week 12 (MEDI3506-placebo) = 0. 
HA: Change from Baseline in FEV1 at Week 12 (MEDI3506-placebo) > 0.  
Hypothesis testing will be performed at the one-sided 10% level. If the p-value is < 0.1, reject 
H0 and accept HA. 
The primary analysis will act as a gate-keeper for hypothesis testing of secondary endpoints. 
Should the primary analysis hypothesis H0 be rejected, then multiplicity will be controlled for 
a subset of key secondary endpoints using the Hochberg procedure.  
Hypothesis testing of secondary endpoints 
To account for multiplicity to test the primary endpoint (change from baseline in pre-BD 
FEV1 at Week 12) and key secondary endpoints, the Hochberg procedure will be used to 
control the overall type I error rate.  
Let H0 denote a null hypothesis as stated above, and H1, H2, H3, H4 denote null hypotheses 
tested on key secondary endpoints:  
H1: Difference in time to first COPDCompEx event at Week 28 (MEDI3506-placebo) = 0. 
H2: Change from Baseline in daily cough frequency at Week 12 (MEDI3506-placebo) = 0. 


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H3: Change from Baseline in R5-R20 at Week 12 (MEDI3506-placebo) = 0. 
H4: Change from Baseline in mean BCSS score (over the previous 4 weeks) at Week 12 
(MEDI3506-placebo) = 0. 
Let pi denote the p-value for the hypothesis Hi, where 𝑖𝑖= 1. . .4. Let p(1), p(2), p(3), p(4) denote 
ordered p-values starting from the largest, and the ordered hypotheses H(1), H(2), H(3), H(4) 
corresponding to them.  
The testing strategy will be as following: 
The procedure begins with testing of the H0 null hypothesis is tested at the full alpha level 
of 0.1. If the one-sided p-value is less than 0.1, then null hypothesis will be rejected, and the 
procedure go to Step 1. 
• 
Step 1. The largest p-value p(1) is compared to its alpha critical value, 𝛼𝛼1  =  0.1. If 
𝑝𝑝(1) > 𝛼𝛼1, then accept and declare non-significant the hypothesis H(1) and go to the 
Step 2. Otherwise testing stops and all remaining hypotheses are rejected and declared 
significant. 
• 
Step 2. Calculate new 𝛼𝛼2  =  0.1/2. If 𝑝𝑝(2) > 𝛼𝛼2, then accept and declare non-significant 
the hypothesis H(2) and go to the Step 3. Otherwise testing stops and all remaining 
hypotheses (which have smaller p-values) are rejected and declared significant. 
• 
Step 3. Calculate new 𝛼𝛼3  =  0.1/3. If 𝑝𝑝(3) > 𝛼𝛼3, then accept and declare non-significant 
the hypothesis H(3) and go to the Step 4. Otherwise testing stops and all remaining 
hypotheses (which have smaller p-values) are rejected and declared significant. 
• 
Step 4. Reject H(4) if 𝑝𝑝(4) ≤0.1/4. 
 
The Hochberg procedure is available in PROC MULTTEST (specifying the HOCHBERG 
option). 
4.1.2 
Repeated measures mixed effects analysis of covariance model  
The repeated measures mixed effects analysis of covariance model (MMRM) will be used to 
fit change from baseline for continuous endpoints at each visit, for the ITT population. For 
Primary Analysis, the model will include all available data from all visits up to and including 
Week 12, irrespective of whether the participant discontinued study intervention. Since a 
repeated measures model is being applied, no imputation will be made for missing data. The 
model will include fixed effects for baseline, log-transformed eosinophil value, background 
medication strata, geographical region, number of exacerbations during the previous 12 
months (≤1 vs 2 or more), visit, study intervention and the baseline by visit and study 
intervention by visit interactions. An unstructured covariance matrix will be used to describe 
the correlations between observations on a participant between visits, and Kenward-Roger 
correction will be used for degrees of freedom approximation in the generation of model. In 


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the event that the model with unstructured covariance matrix fails to converge, and alternative 
such as autoregressive or compound symmetry will be used instead. Estimates of the least 
square mean change from baseline in FEV1 for each study intervention, and the difference 
between them (MEDI3506-placebo), together with two-sided 80% CI, will be obtained from 
the model for each visit. The significance of the study intervention effect will be tested at a 
10% one-sided level of significance. 
The reportable results from the model will be: 
• 
The least-square means (LSMeans) change from baseline at each visit and their standard 
errors for each study intervention group 
• 
The difference in change from baseline at certain visit between MEDI3506 and placebo 
(LSMeans difference) together with its two-sided 80% confidence interval (CI) 
• 
The one-sided p-value for the difference in change from baseline at each visit between 
MEDI3506 and placebo 
 
If the parameter is log-normally distributed, the variable fitted in the model will be the change 
from baseline in logarithmical scale, with the logarithm of the baseline value as a covariate. 
Change from baseline in logarithmical scale is defined as the log-transformation of the post-
baseline visit value minus the log-transformation of the baseline value. 
The MMRM will be as described above but the reportable results from the model will be: 
• 
Back transformed LSmeans for each group, which correspond to the estimated ratio to  
baseline; back transformed LSmeans is derived as EXP(LSMean);  
• 
The two-sided 80% CI of the back transformed LSmeans for each group; 80% CI of the 
back transformed LSmeans is derived as  EXP(Lower limit of the 80% CI of the 
LSmean); EXP(Upper limit of the 80% CI of the LSmean); 
• 
The ratio between MEDI3506 and placebo; the ratio is calculated as EXP(LSMean 
difference); 
• 
The two-sided 80% CI of the ratio; the 80% CI of the ratio is calculated as EXP(Lower 
limit of the 80% CI of the LSmean difference); EXP(Upper limit of the 80% CI of the 
LSmean difference); 
• 
One-sided p-value. 
 
Note that a ratio lower than 1 means that the active study intervention group shows a higher 
decrease (or a lower increase) compared to the placebo group. On the other hand, a ratio 
greater than 1 means that the active study intervention group shows a lower decrease (or a 
higher increase) compared to the placebo group. 


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Statistical Analysis Plan  
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4.2.2 
Important protocol deviations 
The number and percentage of participants with at least one IPD, including COVID-19 related 
IPD, will be summarised following the PDP categories, for each study intervention group and 
overall.  
All IPDs will be also listed for all participants included in the ITT population. All issues 
reported due to COVID-19 pandemic, regardless of whether the type of issue is considered a 
protocol deviation or not, will be listed separately. 
4.2.3 
Baseline assessments and other participant-specific characteristics 
4.2.3.1 
Demographics and participant-specific characteristics 
All demographic and participant-specific characteristics reported in section 3.2.1 will be 
presented in summary tables for each study intervention group and overall; age, height, weight 
and BMI will be summarised descriptively. Only the baseline measurement for height, weight 
and BMI will be considered. All the other demographic and participant-specific characteristics 
will be summarised as categorical variables with the number and percentages of participants 
by categories. Participants recruitment by geographical region and country will be 
summarised. 
All demographic and participant-specific characteristics will be also provided in listings. The 
tables and the listings will be based on the ITT population. 
4.2.3.2 
Medical history 
Medical history as described in section 3.2.2 will be presented in summary tables as number 
and percentages of participants by System Organ Class (SOC) and Preferred Term (PT) for 
each study intervention group and overall. Participants with multiple events in the same 
SOC/PT will be counted only once in that SOC/PT. Participants with events in more than one 
SOC/PT will be counted once in each of those SOC/PT. Tables will be sorted alphabetically 
by SOC and PT. The tables will be based on the ITT population. 
4.2.3.3 
Prior and concomitant medication 
The number and percentage of participants receiving prior or concomitant medication (by 
ATC4 classification system codes and generic name) will be presented by treatment in 
separate tables for the ITT population. 
A separate table will be presented for participants who take disallowed prior or concomitant 
medications. Percentages will be calculated relative to the number of participants in the ITT 
population. 
All medications will also be listed by participant for the ITT population. 


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Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 78 of 167 
 
 
Number and percentage of participants who received initial dose, who had no interruption, 
who had any interruption or 1, 2, 3, etc. interruption will be summarised by study intervention 
group for the As-treated population. 
Exposure details, such as duration of exposure, date of each treatment administration and dose 
per administration, will be listed for As-treated population. 
4.2.10 
Safety data 
4.2.10.1 
Adverse events 
All AE summary tables and listings will be created by study intervention group for the As-
treated population, unless otherwise specified. AEs occurred during study intervention and 
follow-up period (both periods are defined in section 3.1.7) will be reported in summary 
tables. All AEs, including AEs for enrolled but not randomized participants and for 
participants who were not exposed to treatment, will be listed.  
Overview tables will contain number and percentages of participants and number of episodes 
in following categories: 
• 
Any AEs 
• 
Any AE with toxicity grade 4 or 5 
• 
Any AEs with outcome = death 
• 
Any SAEs (including events with outcome = death) 
• 
Any AEs leading to discontinuation of IP 
• 
Any AEs leading to dose interruption 
• 
Any AEs leading to withdrawal from study 
• 
Any AESI 
 
Number and percentage of participants with at least one AE by SOC term will be produced by 
study intervention group.  
Number and percentage of participants with AE by SOC and PT term will be summarised by 
study intervention group. Total number of AEs by SOC and PT term will be summarised by 
study intervention group. 
The number and percentages of participants with AEs occurring in >5% of participants in 
Total study intervention group will be summarised by PT and study intervention group. Non-
serious adverse events occurring in greater than 5% of participants (including number and 
percentages of participants and number of events) in any study intervention group by SOC and 
PT term will be summarised by study intervention group. 


Statistical Analysis Plan  
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11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
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The number and percentages of participants with AEs by maximum reported toxicity grade by 
PT term will be summarised by study intervention group. 
The number and percentages of participants with AEs by relationship as assessed by 
investigator will be summarised by PT term and study intervention group. 
Number and percentage of participants with AE leading to dose interruption of IP by SOC and 
PT term will be summarised by study intervention group. 
The number and percentages of participants with AEs with outcome of death by SOC and PT 
term will be summarised by study intervention group. Key participant information for 
participants experienced AEs with outcome of death will be produced for each study 
intervention group using following information: 
• 
Study intervention group 
• 
Participant identifier 
• 
Sex 
• 
Age (years) 
• 
Event term as reported by the investigator 
• 
PT term 
• 
Time from first IP administration to onset of AE (days) as derived in Section 3.1.8.6 
• 
Treatment period 
• 
Time from last IP administration to death (days) as derived in Section 3.1.8.8 
• 
Time from first IP administration to death (days) as derived in Section 3.1.8.9 
• 
Received treatment for AE 
• 
Reasonable possibility AE caused by IP 
 
The number of SAEs by SOC and PT term will be summarised by study intervention group. 
The number and percentages of participants with SAEs by SOC and PT term will be 
summarised by study intervention group. Key participant information for participants 
experienced SAEs will be produced using following information: 
• 
Study intervention group 
• 
Participant identifier 
• 
Sex 
• 
Age (years) 
• 
Event term as reported by the investigator 
• 
PT term 
• 
Time from first IP administration to onset of AE (days) as derived in Section 3.1.8.6 


Statistical Analysis Plan  
AstraZeneca 
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11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
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• 
Time from last IP administration prior to AE start date, calculated for AEs starting after 
the discontinuation of the IP. 
• 
Time from start of IP administration to becoming serious 
• 
Outcome 
• 
Action taken with IP 
• 
Reasonable AE caused by IP 
 
The number and percentages of participants with AEs leading to discontinuation of 
investigational product by SOC and PT term will be summarised by study intervention group. 
Key participant information for participants experienced AEs leading to discontinuation of IP 
will be produced using following information: 
• 
Study intervention group 
• 
Participant identifier  
• 
Sex 
• 
Age 
• 
AE as reported by the investigator 
• 
PT term 
• 
Time from first IP administration to AE onset 
• 
Time from first IP administration to discontinuation of IP 
• 
Seriousness 
• 
Outcome  
• 
Reasonable possibility AE caused by IP 
 
Number and percentage of participants with AE of special interest by maximum reported 
toxicity grade will be summarised by study intervention group. A list of PT terms for AEs of 
special interest will be produced. Number of participants with AE for each medical concept 
(injection site reaction (ISR), serious hypersensitivity, serious infection, progression of heart 
failure, gastrointestinal adverse reactions, COVID-19) by maximum reported toxicity grade 
will be summarised by study intervention group. 
Number of subjects with COVID-19 related AEs of special interest by SOC and PT will be 
summarised by treatment group and for total MEDI3506. Similar table will be repeated for the 
number of subjects with COVID-19 related serious AEs of special interest. 
All AEs will be listed as well as AEs among ADA positive participants. 
 


Statistical Analysis Plan  
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11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 81 of 167 
 
 
4.2.10.2 
Analysis of vital signs 
Observed values and change from baseline in vital signs will be summarised by study 
intervention group and visit. Key participant information will be produced for vital sign 
parameters treatment-emergent changes outside predefined criteria (Table 23). All vital signs 
will be listed. 
4.2.10.3 
Analysis of laboratory measurements 
Laboratory evaluations (continuous haematology, clinical chemistry, urinalysis and 
coagulation results as per Table 22) will be summarised with descriptive statistics at each visit 
and change from baseline summarised for each post-baseline visit. Categorical urinalysis 
results will be summarised in shift tables comparing maximum value during treatment to 
baseline value. Shifts from baseline to maximum value during treatment in haematology, 
clinical chemistry, urinalysis and coagulation results will be presented using low, normal and 
high categories. Laboratory measurements will also be summarised based on the number and 
percentage of participants above or below a pre-specified threshold for each test, and a listing 
on key participant information supporting the summary will be provided.  
Continuous haematology, clinical chemistry, urinalysis and coagulation results baseline versus 
maximum observation on treatment will be presented in figures using shift plots.  
In addition to the summaries above also the maximum on-treatment ALT and AST by 
maximum total bilirubin for assessing Hy’s law criteria will be presented using the following 
categories: 
Table 25 
Category for Liver Function parameters 
Liver Function Parameters 
Category 
ALT 
• 
≥3 × – <5 × ULN  
• 
≥5 × – <10 × ULN 
• 
≥10 × ULN 
AST 
• 
≥3 × – <5 × ULN  
• 
≥5 × – <10 × ULN 
• 
≥10 × ULN 
Total bilirubin 
• 
<2 × ULN 
• 
≥2 × ULN 
Potential Hy’s law 
• 
(AST ≥ 3 × ULN or ALT ≥ 3 × ULN) and (Total 
Bilirubin ≥ 2×ULN)a  
ULN:  upper limit of normal range. 
a: It includes all subjects who have ALT or AST≥3xULN and total bilirubin ≥2xULN, and in 
which the elevation in transaminases precede or coincide with (that is, on the same day as) the 
elevation in total bilirubin.  


Statistical Analysis Plan  
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11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 82 of 167 
 
 
ALT or AST versus total bilirubin, expressed as multiples of ULN as well as liver 
biochemistry test results over time – participants with elevated ALT or AST, and elevated 
total bilirubin will be presented in figures. Liver biochemistry results over time will be 
presented in figures for participants with elevated AST or ALT, and elevated total bilirubin. A 
separate listing of key information for participants with potential Hy’s law will be produced.  
All laboratory results will be listed. 
4.2.10.4 
Analysis of ECG 
Observed values and change from baseline in ECG variables will be summarised by visit 
using descriptive statistics. Key participant information will be produced for ECG parameter 
values outside predefined criteria (Table 24). 
A shift table of categorical ECG interpretation (from best to worst: normal, abnormal - not 
clinically significant, abnormal - clinically significant) at baseline versus maximum (worst) 
observation on treatment will be provided. Abnormalities in ECG will be listed. 
In addition, the number and percentage of participants with QTcF (derived as described in 
Section 3.8.4) changes from baseline will be presented by QTcF values >450 ms, >480 ms, 
>500 ms and QTcF increase from baseline >30 ms, >60 ms, >90 ms, and combination of both. 
4.2.10.5 
Analysis of echocardiogram 
Observed values and change from baseline in LVEF will be summarised by visit using 
descriptive summary statistics. Echocardiogram data and abnormalities in echocardiogram 
will be listed. 
4.2.10.6 
Other safety tests 
NT-proBNP results will be summarised with descriptive statistics at each visit and change 
from baseline summarised for each post-baseline visit. The summary based on the number and 
percentage of participants above or below a pre-specified threshold will be produced. NT-
proBNP results will be also summarised in shift table comparing maximum value during 
treatment to baseline value. NT-proBNP results will be listed. 
Number and proportion of participants with a negative or positive SARS-Cov-2 serology 
result at the end of study, who were seronegative at baseline, will be summarised. Number and 
proportion of participants who received a COVID-19 vaccine during the study will be 
included in the summary. All SARS-Cov-2 tests results (both PCR and serology) by visit will 
be listed for As-treated population. 


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Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 85 of 167 
 
 
Jones et al 1991 
Jones PW, Quirk FH and Baveystock CM. The St George's Respiratory Questionnaire. Respir 
Med 1991;85 Suppl B:25-31. 
Jones and Forde 2009 
Jones PW and Forde Y. St George’s respiratory questionnaire manual. 2009. Version 2.3. 
Available from URL: 
http://www.healthstatus.sgul.ac.uk/SGRQ_download/SGRQ%20Manual%20June%202009.pd
f. 
Jones et al 2009 
Jones PW, Harding G, Berry P, Wiklund I, Chen WH and Kline Leidy N. Development and 
first validation of the COPD Assessment Test. Eur Respir J. 2009;34(3):648-54. 
 
8 
APPENDIX  
 
 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 86 of 167 
 
 
Appendix A Table of contents 
Table 26 
Used versions of reference documents for standard mock shells and SAP 
Reference document for standard mock shells and SAP 
Version 
Date created 
AstraZeneca Authoring Style Guide 
2.0 
May, 2020 
AZ Corporate CSRHLD Tables Templates 
3.3 
July, 2020  
AZ Corporate CSRHLD Figures Templates 
3.2 
July, 2020 
AZ Corporate CSRHLD Listings Templates 
1.2 
July, 2020 
AZ Respiratory CSRHLD Table and Figure Templates 
1.0 
May 14, 2019 
ADA Stats Guidance 
1.0  
 July 5, 2016 
AZ Corporate CSRHLD ADA Standards 
3.0 
April 29, 2019 
AZ Corporate CSRHLD Reporting Standards  
3.2 
January 31, 2020 
AZ Corporate Pandemic CSRHLD Table and Listing Templates 
1.0 
July, 2020 
AZ Oncology TA TFL Templates 
3.0 
April 9, 2020 
 
 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 87 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 
14.1.1.1 
Subject disposition (All 
subjects) 
AZ Corporate 
CSRHLD Table 
Template 
COVID-
summary1 
(based on AZ 
Corporate 
CSR/HLD 
Table Template 
SP1) 
Include Total column. Percentage for all categories are based on the 
number of subjects randomized  
Present rows relating to: 
• 
Subjects enrolled [a] 
• 
Subjects run-in 
• 
Subjects who were not run-in 
<<INSERT REASONS>> from CRF in sentence case 
• 
Subjects randomized 
• 
Subjects who were not randomized 
<<INSERT REASONS>> from CRF in sentence case 
• 
Subjects who received treatment 
• 
Subjects who did not receive treatment 
<<INSERT REASONS>> from CRF in sentence case 
• 
Subjects who completed treatment 
• 
Subjects who discontinued treatment  
<<INSERT REASONS>> from CRF in sentence case: Adverse 
event; Death; Lost to follow up; Non-compliance with study 
drug; Physician decision; Pregnancy; Protocol deviation; Site 
terminated by sponsor; Study terminated by sponsor; 
Withdrawal by subject; Other; add “Due to COVID-19 
pandemic” 
• 
Subjects who completed study 
• 
Subjects withdrawn from study  
<<INSERT REASONS>> from CRF in sentence case: Adverse 
event; Death; Lost to follow up; Non-compliance with study 
drug; Physician decision; Pregnancy; Protocol deviation; 
Screen failure; Site terminated by sponsor; Study terminated by 
sponsor; Withdrawal by subject; Other; add “Due to COVID-
19 pandemic” 
Include the needed footnotes for explaining terms used in the table 
X  
X 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 88 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 
14.1.1.2 
Subject disposition (ITT 
population) 
AZ Corporate 
CSRHLD Table 
Template 
COVID-
summary1 
(based on AZ 
Corporate 
CSR/HLD 
Table Template 
SP1) 
Include Total column. 
Categorise subjects into dose groups based on planned treatment. 
Percentage for all categories should be based on the number of 
subjects randomized  
Present rows relating to: 
• 
Subjects who received treatment 
• 
Subjects who completed treatment 
• 
Subjects who discontinued treatment  
<<INSERT REASONS>> e.g. the following: Adverse event, Death, 
Lost to follow up, Non-compliance with study drug, Physician 
decision, Pregnancy, Protocol deviation, Site terminated by 
sponsor, Study terminated by sponsor, Withdrawal by subjects, 
Due to COVID-19 pandemic, Other 
• 
Subjects who completed study 
• 
Subjects withdrawn from study  
<<INSERT REASONS>> from CRF in sentence case: Adverse 
event; Death; Lost to follow up; Non-compliance with study 
drug; Physician decision; Pregnancy; Protocol deviation; 
Screen failure; Site terminated by sponsor; Study terminated by 
sponsor; Withdrawal by subject; Other; add “Due to COVID-
19 pandemic” 
Include the needed footnotes for explaining terms used in the table 
X  
X 
X 


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Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 90 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 14.1.3 
Analysis sets (All subjects) 
AZ Corporate 
CSR/HLD 
Table Template 
SP3  
 
Each summary of an analysis set will account for all subjects 
assigned to treatment. 
Reasons for exclusion from safety analysis set will include “Did not 
receive treatment”. 
At the end of each row label “Subjects excluded from <<…>> 
analysis set”, include “[a]”, and include footnote [a] if there is 
potentially more than 1 reason to exclude a subject from an analysis 
set. 
The table contains the following: 
• 
Subjects randomized  
• 
Subjects included in ITT population  
• 
Subjects excluded from ITT population[a]  
Did not receive treatment  
• 
Subjects included in As-treated population 
• 
Subjects excluded from As-treated population[a] 
Did not receive treatment 
• 
Subjects included in PK population 
• 
Subjects excluded from PK population[a]  
Subject did not receive any dose of MEDI3506 
Missing PK measurements  
Non-quantifiable post-dose samples 
Update footnotes to include analysis set definitions to reflect SAP 
and protocol. 
X  
X 
X 
Table 14.1.4 
Demographic characteristics 
(ITT population) 
AZ Corporate 
CSR/HLD 
Table Template 
SP4 
Include Total column. 
Include summaries of ethnic group. 
Age group categories of ≥18 - <50, ≥50 - <65, ≥65 will be modified 
to project-specific categories (“>=40-<65” and “>=65-75”). 
Include age group categories for ≥18 - <65 and ≥65 for EudraCT 
reporting purposes. 
X  
 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 91 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 14.1.5 
Subject characteristics (ITT 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
SP8 (with 
characteristics 
and categories 
specified) 
Include Total column. 
Include height, weight and body mass index (BMI) at baseline.  
Weight group and BMI group are optional. 
Use project specific ranges for BMI group: <19, ≥19 to <25, ≥25 to 
<30, ≥30. 
X  
 
X 
Table 14.1.6 
Subject recruitment by 
region and country (ITT 
population). 
AZ Corporate 
CSR/HLD 
Table Template 
ASP6 (with 
examples for 
stratification 
factors) 
Include Total column. 
Categories, i.e. countries based on IWRS or CRF. 
Proposed region/countries:  
• 
North America: 
Canada  
United States  
• 
Eastern Europe: 
Hungary  
Poland  
Czech Republic 
• 
Western Europe: 
Spain  
Netherlands  
United Kingdom  
Germany  
Denmark  
• 
Rest of the world: 
Israel 
South Africa  
Australia 
New Zealand 
 
X  
 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 92 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 14.1.7 
COPD treatments at 
randomization (ITT 
population)  
AZ Respiratory 
CSR/HLD 
Table Template 
SP_T7 
Include Total column. 
Non-indented row labels defined per the CSP Sn 6.5.1: 
• 
ICS + LABA, n (%) 
• 
LABA + LAMA, n (%)  
• 
ICS + LABA + LAMA, n (%) 
(Rows are mutually exclusive) 
Insert footnote(s) to define abbreviations, ICS, LABA, LAMA.  
Insert footnote(s) to define previous treatment/timeperiod for which 
treatments are collected  
Title should include either "previous" or "at timepoint", never both. 
X  
X 
X 
Table 14.1.8 
Medical history (ITT 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
SP7(i)  
Include Total column. 
To include any past or current medical history data (MH page from 
CRF). 
Add a footnote: Number (%) of subjects are sorted alphabetically by 
SOC and PT. A subject can have one or more PTs reported under a 
given SOC. 
Add a footnote to define the dictionary used within the table. 
X  
X 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 93 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 14.1.9 
COPD characteristics at 
study entry (ITT population) 
AZ Respiratory 
CSR/HLD 
Table Template 
SP_T14 
(Customization 
of AZ Corporate 
table template 
SP4, as both 
continuous and 
categorical 
variables are 
presented) 
Include Total column. 
<< Time unit>> can be "months" or "days" or "years" 
• 
Time since COPD diagnosis (years) 
• 
Time since COPD symptoms started (years)  
• 
Time since last exacerbation (months) 
• 
Total number of exacerbations within previous 12 months prior 
to screening (0, 1, 2, >2.) 
• 
Total number of exacerbations resulted in antibiotic treatment 
within previous 12 months prior to screening (0, 1, 2, >2.) 
• 
Total number of exacerbations resulted in oral steroid treatment 
within previous 12 months prior to screening (0, 1, 2, >2.) 
• 
Total number of exacerbations resulted in hospitalization 
within previous 12 months prior to screening (0, 1, 2, >2.) 
• 
Diagnosis of chronic airway obstruction (n [%]) 
• 
Diagnosis of emphysema (n [%]) 
• 
Diagnosis of obstructive chronic bronchitis (n [%]) 
• 
Chronic symptoms (n [%]) 
• 
Respiratory failure (n [%]) 
• 
Previous diagnosis of asthma (n [%]) 
• 
Diagnosis of rhinitis (n [%]) 
• 
CAT (COPD Assessment test) score. 
 
X  
 
X 
Table 
14.1.10 
Diary data at baseline 
AZ Respiratory 
CSR/HLD 
Table Template 
SP_T13 
 
X 
 
X 


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Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 99 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 
14.2.1.3.8 
Change from baseline to 
Week 12 in pre-BD FEV1 
(as measured in the clinic), 
including eosinophil strata, 
treatment comparisons, 
MMRM - sensitivity 
analysis 1 (ITT population) 
AZ Respiratory 
CSR/HLD 
Table Template 
EF_T2a 
(Customization 
of AZ Corporate 
table template 
E7) 
Sensitivity analysis – adding eosinophil strata instead of log-
transformed eosinophil value. 
X 
 
X 
Table 
14.2.1.3.9 
Change from baseline to 
Week 12 in pre-BD FEV1 
(as measured in the clinic), 
excluding eosinophil data, 
treatment comparisons, 
MMRM - sensitivity 
analysis 2 (ITT population) 
AZ Respiratory 
CSR/HLD 
Table Template 
EF_T2a 
(Customization 
of AZ Corporate 
table template 
E7) 
Sensitivity analysis – excluding eosinophil value. 
X 
 
X 
Table 
14.2.1.3.10 
Change from baseline to 
Week 12 in pre-BD FEV1 
(as measured in the clinic), 
excluding implausible data, 
treatment comparisons, 
MMRM - sensitivity 
analysis 3 (ITT population) 
AZ Respiratory 
CSR/HLD 
Table Template 
EF_T2a 
(Customization 
of AZ Corporate 
table template 
E7) 
Sensitivity analysis – excluding implausible data. 
X 
 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 100 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 
14.2.1.3.11 
Change from baseline in pre-
BD FEV1 (L) through Week 
28 (as measured in the 
clinic) treatment 
comparisons by extent of 
emphysema, MMRM (ITT 
population) 
AZ Respiratory 
CSR/HLD 
Table Template 
EF_T2a 
(Customization 
of AZ Corporate 
table template 
E7) 
Comparison by extent of emphysema subgroup. 
X 
X 
X 
Table 
14.2.1.3.12 
Change from baseline in pre-
BD FEV1 (L) through Week 
28 (as measured in the 
clinic) treatment 
comparisons by extent of 
emphysema, MMRM (ITT 
population) 
AZ Respiratory 
CSR/HLD 
Table Template 
EF_T2a 
(Customization 
of AZ Corporate 
table template 
E7) 
Comparison by extent of emphysema subgroup. 
X 
X 
X 
Table 
14.2.1.3.13 
Change from baseline in pre-
BD FVC (L) through Week 
28 (as measured in the 
clinic) treatment 
comparisons by extent of 
emphysema, MMRM (ITT 
population) 
AZ Respiratory 
CSR/HLD 
Table Template 
EF_T2a 
(Customization 
of AZ Corporate 
table template 
E7) 
Comparison by extent of emphysema subgroup. 
X 
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Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 109 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 
14.2.1.16 
Relative change from 
baseline to Week 12 in 
objective cough measures 
treatment comparisons, 
ANCOVA (ITT population) 
AZ Respiratory 
CSR/HLD 
Table Template 
EF_T2b 
(Customization 
of AZ Corporate 
table template 
E7) 
“Page-by” presentation for difference in mean change from baseline 
in:  
• 
Daily (ie, 24 hour) cough frequency 
• 
Night time cough frequency 
• 
Awake time cough frequency 
At Week 12 (MEDI3506 vs. placebo). Results are based on 
ANCOVA on log-transformed variable (calculated as visit value in 
log minus baseline value in log), with log(baseline value) as a 
covariate and study intervention, log-transformed eosinophil value, 
background medication strata, geographical region and number of 
exacerbations during the previous 12 months (1 vs 2 or more) as 
factors. Back-transformed results to be reported. 
X  
  
 X 
Figure 
14.2.1.1 
Change in pre-BD FEV1 
measured in the clinic at 
Week 12, MMRM - forest 
plot by subgroups (ITT 
population) 
AZ Corporate 
CSR/HLD 
Figure Template 
E5 
 
X 
 
X 
Figure 
14.2.1.2.1 
Change from baseline to 
Week 12 in pre-BD FEV1 
measured in the clinic, 
LSMeans (80% CI) (ITT 
population) 
AZ Corporate 
CSR/HLD 
Figure Template 
E4 
 
X  
 
X  
Figure 
14.2.1.2.2 
Change from baseline to 
Week 12 in pre-BD FEV1 
measured in the clinic, 
excluding data after subjects 
discontinued IP, LSMeans 
(80% CI) - supportive 
analysis (ITT population) 
AZ Corporate 
CSR/HLD 
Figure Template 
E4 
 
X  
 
X  


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Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 135 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 
14.3.2.1 
Number of subjects with 
adverse events in any 
category (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
S5 
Specify the period/periods which AE will be reported for, in the 
footnote. 
Include the following AE categories: 
• 
Any AE 
• 
Any AE of toxicity grade 4 or 5 
• 
Any AE with outcome = death 
• 
Any SAE (including events with outcome = death) 
• 
Any AE leading to discontinuation of IP 
• 
Any AE leading to dose interruption 
• 
Any AE leading to withdrawal from study 
• 
Any AESI 
 
X  
X 
X 
Table 
14.3.2.2 
Adverse events in any 
category - event counts (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S6 
Present the same categories of AE as in S5 
X 
X 
X 
Table 
14.3.2.3 
Number of subjects with 
adverse events, by system 
organ class (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
S7 
<<event rate>> will not be included. 
X 
X 
X 
Table 
14.3.2.4 
Number of subjects with 
adverse events by system 
organ class and preferred 
term (As-treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S9(i) 
Specify the period/periods which AE will be reported for, in the 
footnote 
[a] Number (%) of subjects with AEs, sorted on international order 
for system organ class and alphabetical order for preferred term. 
Subjects with multiple events in the same preferred term are counted 
only once in that preferred term. Subjects with events in more than 1 
preferred term are counted once in each of those preferred terms. 
 
X 
X 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 136 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 
14.3.2.5 
Number of adverse events, 
by system organ class and 
preferred term (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
S16(i) 
 
X 
X 
X 
Table 
14.3.2.6 
Number of subjects with 
adverse events, most 
common (frequency of 
>5%), by preferred term 
(As-treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S8 
Specify the period/periods which AE will be reported for, in the 
footnote 
Number (%) of subjects with AEs, sorted in decreasing frequency 
for preferred term (sorted by MEDI3506 treatment group) 
The cut off used is to be clearly stated in the title and footnote. 
The difference between S8 and FDAAA1 is – in S8 most common 
are defined as % in Total group, not individual treatment groups – 
and in FDAAA1 it is % in any treatment group. 
X 
X 
X 
Table 
14.3.2.7 
Non-serious adverse events 
occurring in greater than 5% 
of subjects (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
FDAAA1 
 
X 
X 
X 
Table 
14.3.2.8 
Number of subjects with 
adverse events, by preferred 
term and maximum reported 
toxicity grade (As-treated 
population) 
AZ Oncology 
CSR/HLD 
Table Template 
TAE050 - TA 
specific version 
of AZ Corporate 
CSR/HLD 
Table Template 
S10 
Specify the period/periods which AE will be reported for, in the 
footnote 
Each subject has only been represented with the maximum reported 
toxicity grade for each preferred term. Subjects with events in more 
than 1 preferred term are counted once in each of those preferred 
terms. 
Each subject is counted only once (by their maximum reported 
toxicity grade) within a treatment group in this overall summary. 
 
 
 
X 
X 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 137 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 
14.3.2.9 
Number of subjects with 
adverse events, by preferred 
term and relationship as 
assessed by investigator (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S11 
<<event rate>> will not be included. 
X 
X 
X 
Table 
14.3.2.10 
Number of subjects with 
adverse events, leading to 
dose interruption of IP, by 
system organ class and 
preferred term (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
S_T1 
 
X 
X 
X 
Table 
14.3.2.11 
Number of subjects with 
COVID-19 related adverse 
events by system organ class 
and preferred term (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S9(i) 
 
X 
X 
X 
Table 
14.3.3.1 
Number of subjects with 
adverse events with outcome 
of death, by system organ 
class and preferred term (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S13(i) 
Specify the period/periods which AE will be reported for, in the 
footnote 
Percentages are based on the total numbers of subjects in the 
treatment group (N). 
MedDRA version 25.1 or higher used 
X 
X 
X 
Table 
14.3.3.2 
Adverse Events with 
outcome of death - key 
subject information (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S14 
Specify the period/periods which AE will be reported for, in the 
footnote 
 
X 
X 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 138 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 
14.3.4.1.1 
Number of serious adverse 
events, by system organ 
class and preferred term (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S16(ii) 
Specify the period/periods which AE will be reported for, in the 
footnote 
 
X 
X 
X 
Table 
14.3.4.1.2 
Number of subjects with 
serious adverse events, by 
system organ class and 
preferred term (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
S17(i) 
 
X 
X 
X 
Table 
14.3.4.1.3 
Number of subjects with 
COVID-19 related serious 
adverse events, by system 
organ class and preferred 
term (As-treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S17(i) 
 
X  
X  
X  
Table 
14.3.4.2 
Serious adverse events - key 
subject information (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S18 
 
X 
X 
X 
Table 
14.3.5.1 
Number of subjects with 
adverse events leading to 
discontinuation of 
investigational product, by 
system organ class and 
preferred term (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
S19(i) 
Specify the period/periods which AE will be reported for, in the 
footnote 
MedDRA version 25.1 or higher used 
X 
X 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 139 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 
14.3.5.2 
Adverse events leading to 
discontinuation of 
investigational product - key 
subject information (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S20 
MedDRA version 25.1 or higher used 
X 
X 
X 
Table 
14.3.6.1 
Adverse events of special 
interest - list of preferred 
terms 
AZ Corporate 
CSR/HLD 
Table Template 
AS9 
 
X  
X 
X 
Table 
14.3.6.2 
Number of subjects with 
adverse events of special 
interest, by maximum 
reported toxicity grade (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
AS8 
 
X  
X 
X 
Table 
14.3.6.3 
Number of subjects with 
adverse events of ISR, by 
maximum reported toxicity 
grade (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
AS8 
 
X  
X 
X 
Table 
14.3.6.4 
Number of subjects with 
adverse events of serious 
hypersensitivity, by 
maximum reported toxicity 
grade (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
AS8 
 
X  
X 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 140 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 
14.3.6.5 
Number of subjects with 
adverse events of serious 
infection, by maximum 
reported toxicity grade (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
AS8 
 
X  
X 
X 
Table 
14.3.6.6 
Number of subjects with 
adverse events of 
progression of heart failure, 
by maximum reported 
toxicity grade (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
AS8 
 
X  
X 
X 
Table 
14.3.6.7 
Number of subjects with 
adverse events of 
gastrointestinal adverse 
reactions, by maximum 
reported toxicity grade (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
AS8 
 
X  
X 
X 
Table 
14.3.6.8 
Number of subjects with 
adverse events of COVID-
19, by maximum reported 
toxicity grade (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
AS8 
 
X  
X 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 141 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 
14.3.7.1.1 
Haematology laboratory 
variables over time (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S25 (applied to 
Laboratory 
Data) 
Choose timepoints relevant to the study: 
SV1, SV3, SV5, SV6, SV8, SV10, SV12, SV13, SV14, E/D 
Labels as per SAP Analysis Visit Windows. 
Report summary statistics 
Include Q1 and Q3 
Include in the summary all haematology and clinical chemistry 
parameters listed in the protocol. 
X  
X 
X 
Table 
14.3.7.1.2 
Clinical chemistry 
laboratory variables over 
time (As-treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S25 (applied to 
Laboratory 
Data) 
Choose timepoints relevant to the study: 
SV1, SV3, SV5, SV6, SV8, SV10, SV12, SV13, SV14, E/D 
Labels as per SAP Analysis Visit Windows. 
Report summary statistics 
Include Q1 and Q3 
Include in the summary all clinical chemistry parameters listed in 
the protocol. 
X  
X 
X 
Table 
14.3.7.1.3 
Urinalysis laboratory 
variables over time (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S25 (applied to 
Laboratory 
Data) 
Choose timepoints relevant to the study: 
SV1, SV3, SV5, SV6, SV8, SV10, SV12, SV13, SV14, E/D 
Labels as per SAP Analysis Visit Windows. 
Report summary statistics 
Include Q1 and Q3 
Include in the summary all clinical chemistry parameters listed in 
the protocol. 
X  
X 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 142 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 
14.3.7.1.4 
Coagulation laboratory 
variables over time (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S25 (applied to 
Laboratory 
Data) 
Choose timepoints relevant to the study: 
SV1, SV3, SV5, SV6, SV8, SV10, SV12, SV13, SV14, E/D 
Labels as per SAP Analysis Visit Windows. 
Report summary statistics 
Include Q1 and Q3 
Include in the summary all clinical chemistry parameters listed in 
the protocol. 
X  
X 
X 
Table 
14.3.7.2.1 
Haematology laboratory 
variables, baseline versus 
maximum observation on 
treatment (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
S27 
Define baseline measurement in the footnotes 
X  
X 
X 
Table 
14.3.7.2.2 
Clinical chemistry 
laboratory variables, 
baseline versus maximum 
observation on treatment 
(As-treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S27 
Define baseline measurement in the footnotes 
X  
X 
X 
Table 
14.3.7.2.3 
Urinalysis laboratory 
variables, baseline versus 
maximum observation on 
treatment (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
S27 
Define baseline measurement in the footnotes 
X  
X 
X 
Table 
14.3.7.2.4 
Coagulation laboratory 
variables, baseline versus 
maximum observation on 
treatment (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
S27 
Define baseline measurement in the footnotes 
X  
X 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 143 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 
14.3.7.4 
Maximum on-treatment 
ALT and AST by maximum 
total bilirubin for assessing 
Hy's Law criteria (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
AS14 
 
X  
X 
X 
Table 
14.3.7.5 
Subjects with potential Hy's 
Law - individual subject data 
(As-treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S32 
"If there are subjects who met the criteria specified. A potential Hy’s 
Law case is defined as any situation where a study subject has an 
increase in both AST or ALT ≥ 3×ULN and TBL ≥ 2×ULN, 
irrespective of ALP, at any point during the study. " 
Multiple of ULN is defined as value divided by ULN, i.e. if the ALT 
value was X (ULN = Y) then the multiple would be X/Y.  
X  
X 
X 
Table 
14.3.7.6 
Urinalysis, baseline versus 
maximum observation on 
treatment, shift table (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S33 
Define baseline measurement in the footnotes 
X  
X 
X 
Figure 
14.3.7.1 
Haematology laboratory 
variables, baseline versus 
maximum observation on 
treatment – shift plot (As-
treated population) 
AZ Corporate 
CSR/HLD 
Figure Template 
S8 
 
 
X 
X 
Figure 
14.3.7.2 
Clinical chemistry 
laboratory variables, 
baseline versus maximum 
observation on treatment – 
shift plot (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Figure Template 
S8 
 
 
X 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 144 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Figure 
14.3.7.3 
Urinalysis laboratory 
variables, baseline versus 
maximum observation on 
treatment – shift plot (As-
treated population) 
AZ Corporate 
CSR/HLD 
Figure Template 
S8 
 
 
X 
X 
Figure 
14.3.7.4 
Coagulation laboratory 
variables, baseline versus 
maximum observation on 
treatment – shift plot (As-
treated population) 
AZ Corporate 
CSR/HLD 
Figure Template 
S8 
 
 
X 
X 
Figure 
14.3.7.5 
ALT versus total bilirubin, 
expressed as multiples of 
ULN (As-treated population) 
 
AZ Corporate 
CSR/HLD 
Figure Template 
S9 
This must be produced for both ALT and AST.  Also, that the 
preferred approach for the plot is that it should be produced on the 
log scale, and reference lines must be included at 2xULN for total 
bilirubin and at 3xULN for ALT/AST.   
Reference lines at 3*ULN of ALT /AST and 2*ULN for total 
bilirubin are compulsory 
Multiple of ULN is defined as value divided by ULN, i.e. if the ALT 
value was X (ULN = Y) then the multiple would be X/Y.  
Additional reference lines may be added, if so, please ensure 
compulsory reference lines must be easily identified 
X 
X 
X 
Figure 
14.3.7.6 
AST versus total bilirubin, 
expressed as multiples of 
ULN (As-treated population) 
AZ Corporate 
CSR/HLD 
Figure Template 
S9 
This must be produced for both ALT and AST.  Also, that the 
preferred approach for the plot is that it should be produced on the 
log scale, and reference lines must be included at 2xULN for total 
bilirubin and at 3xULN for ALT/AST.   
Reference lines at 3*ULN of ALT /AST and 2*ULN for total 
bilirubin are compulsory 
Multiple of ULN is defined as value divided by ULN, i.e. if the ALT 
value was X (ULN = Y) then the multiple would be X/Y.  
X 
X 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 145 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Figure 
14.3.7.7 
Liver biochemistry test 
results over time – subjects 
with elevated ALT or AST, 
and elevated total bilirubin, 
at any time (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Figure Template 
S10 
 
 X 
X 
X 
Table 
14.3.8.1.1 
Vital signs variables over 
time (As-treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S25(vital) 
(applied to Vital 
Signs data). 
Use relevant timepoints for the study: 
SV3, SV5, SV6, SV7, SV8, SV9, SV10, SV11, SV12, SV13, SV14, 
E/D at timepoints Pre-Dose; Post-Dose; 0.5H Post-Dose; 1H Post-
Dose; 2H Post-Dose. Labels as per SAP Analysis Visit Windows 
and Timepoints. 
Define baseline measurement in the footnotes 
Vital signs variables (temperature; DBP; SBP; Heart rate; 
Respiratory rate) should be presented in same way for Lab data. 
(incl. Q1 and Q3) 
 
X  
X 
X 
Table 
14.3.8.1.2 
Vital signs, treatment-
emergent changes outside 
predefined criteria – key 
subject information (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
AS3 
Use relevant timepoints for the study: 
SV3, SV5, SV6, SV7, SV8, SV9, SV10, SV11, SV12, SV13, SV14, 
E/D at timepoints Pre-Dose; Post-Dose; 0.5H Post-Dose; 1H Post-
Dose; 2H Post-Dose. Labels as per SAP Analysis Visit Windows 
and Timepoints. 
Define baseline measurement in the footnotes 
Vital signs variables (temperature; DBP; SBP; Heart rate; 
Respiratory rate) should be presented in same way for Lab data. 
 
 
 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 146 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 
14.3.8.2.1 
ECG variables, over time 
(As-treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S25(ecg). 
Use relevant timepoints for the study: 
SV1, SV3, SV8, SV12, SV14, E/D 
Labels as per SAP Analysis Visit Windows 
Report summary statistics (incl. Q1 and Q3) 
X  
X 
X 
Table 
14.3.8.2.2 
QTcF intervals, change from 
baseline to any postbaseline 
observation (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
S35 
(transposed) 
Title and column headers should indicate which formula is being 
used and this should then be footnoted e.g., “QTcB calculated using 
Bazett’s formula” or; “QTcF calculated using Fridericia’s formula” 
or “QTc‘X’ calculated using <<>> formula”. 
Define baseline measurement in the footnotes 
X  
X  
X  
Table 
14.3.8.2.3 
ECG values outside 
predefined criteria – key 
subject information (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
AS4 
 
 
 
X 
Table 
14.3.8.2.4 
ECG, baseline versus 
maximum observation on 
treatment (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
S41 (applied to 
ECG data). 
Update column header from “Assessment at end of treatment” to 
“Maximum value during treatment” 
X  
X  
X  
Table 
14.3.8.3.1 
Left ventricular ejection 
fraction (%), over time (As-
treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S25(echoc) 
 
X  
X  
X 
Table 
14.3.8.3.2 
NT-proBNP data over time 
(As-treated population) 
AZ Corporate 
CSR/HLD 
Table Template 
S25 (applied to 
Laboratory 
Data) 
 
X  
X  
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 147 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Table 
14.3.8.3.3 
NT-proBNP baseline to 
maximum value during 
treatment (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Table Template 
S27 
 
X  
X  
X 
Table 
14.3.8.3.5 
Other safety tests – COVID-
19 related (As-treated 
population) 
NEW1 
Number of participants seropositive for SARS-CoV-2 at end of 
study who were seronegative at randomization visit. 
X  
X  
X  
Appendix 
16.1.6 
Subjects receiving the 
various batches of 
investigational products (All 
randomized subjects) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL22 
  
  
X 
Appendix 
16.1.7 
Randomization scheme and 
codes (All randomized 
subjects) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL23 
 
  
  
X 
Appendix 
16.2.1.1 
Discontinued subjects (All 
subjects) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL01 
Provide definition of exposure in the footnote 
Actual exposure is optional 
If the race Other was collected in the study, a separate column may 
be added after the Age/Sex/Race column. 
Sort this listing by: Short subject identifier, Description of planned 
arm, Start date/Time of disposition event. 
Standardised disposition terms should include: 
• 
Informed consent obtained  
• 
Randomization 
• 
Study discontinued due to <<insert reason for discontinuation 
from EOS form in lower case, e.g. adverse event >> 
X  
X 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 148 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Appendix 
16.2.1.2 
Subjects completing the 
study (All subjects) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL02 
Optional. 
Standardised disposition terms should include: 
• 
Informed consent obtained  
• 
Randomization 
• 
Study completed 
 X 
X 
X 
Appendix 
16.2.1.3 
Subjects affected by the 
COVID-19 pandemic (ITT 
population) 
AZ Corporate 
CSR/HLD 
Listing 
Template APL-
COVID1 
This listing is to satisfy the FDA Guidance which requires A listing 
of all participants affected by the COVID-19 related study 
disruption by unique subject number identifier and by 
investigational site, and a description of how the individual’s 
participation was altered. 
X  
X  
X 
Appendix 
16.2.2.1 
Subjects with important 
protocol deviations (ITT 
population) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL03 
Sort this listing by: Short subject identifier, Description of planned 
arm, Date/Time of collection. 
 X 
X 
X 
Appendix 
16.2.2.2 
Subjects with reported issues 
in the Clinical Trial 
Management System due to 
COVID-19 pandemic (ITT 
population) 
AZ Corporate 
CSR/HLD 
Listing 
Template APL-
COVID2 
This listing is to satisfy the AZ Data Integrity document requirement 
Please note that important Protocol Deviations and COVID-19 
related non-important PDs and issues will be part of the CSR. 
X  
X  
X 
Appendix 
16.2.3.1 
Subjects excluded from any 
analysis set (All subjects) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL04 
Sort this listing by: Short subject identifier, Description of planned 
arm. Add column for Description of Actual arm. 
 
X  
X 
X 


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Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 153 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Appendix 
16.2.6.2.1 
Drug concentration data (PK 
population) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL13 
 
X  
X 
X 
Appendix 
16.2.6.3.1 
Anti-Drug Antibody results 
(As-treated population)  
SPADA1 
Sort this listing by: Subject identifier within treatment group.  
ADA study status provided may include ADA negative, treatment-
induced ADA positive, treatment-boosted ADA positive, TE-ADA 
negative, persistently positive, transiently positive, ADA positive at 
baseline only, etc.... The goal is to ensure that all applicable ADA 
categories are listed for each subject in the listing. If a subject is 
included in more than one category, they should all be listed. For 
example, a subject may be persistently positive and treatment-
induced ADA positive. 
 X 
X 
X 
Appendix 
16.2.6.3.2 
Listing of ADA positive 
subjects, key subject 
information (As-treated 
population)  
SPADA3 
Sort by treatment group and subject identifier. Include all subjects 
with a positive ADA result at baseline and/or post-baseline. 
 X 
X 
X 
Appendix 
16.2.7.1.1 
Adverse events (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL14 
Mention the used Med dictionary (MedDRA v25.1 or higher), in the 
footnotes. 
Sort this listing by: Short subject identifier, Treatment/Period, and 
Preferred term. Note that it may be more applicable to sort by 
Treatment start date and AE start date than Treatment/Period (ie, 
alphabetically), although these data are not presented in the listing. 
 
X  
X 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 154 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Appendix 
16.2.7.1.2 
Adverse events among Anti-
Drug Antibody positive 
subjects (As-treated 
population)  
SADA1 
 
X 
X 
X 
Appendix 
16.2.7.2 
Adverse events for enrolled 
but not randomized subjects 
and for subjects who were 
not exposed to treatment 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL15 
 
 
 
 X 
Appendix 
16.2.8.1.1 
Individual laboratory 
measurement - Haematology 
(As-treated population) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL16 
Sort this listing by: Short subject identifier, Description of actual 
arm, Lab test or examination name, Analysis visit, planned time 
point name. 
The study team will decide about which lab variables to include in 
this listing 
Unique values used for analysis will be flagged with asterisk (*) (i.e. 
repeated measurements outside visit windows will not be flagged) 
 
X 
X 
Appendix 
16.2.8.1.2 
Individual laboratory 
measurement – Clinical 
chemistry (As-treated 
population) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL16 
Sort this listing by: Short subject identifier, Description of actual 
arm, Lab test or examination name, Analysis visit, planned time 
point name. 
The study team will decide about which lab variables to include in 
this listing 
Unique values used for analysis will be flagged with asterisk (*) (i.e. 
repeated measurements outside visit windows will not be flagged) 
 
X 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 155 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Appendix 
16.2.8.1.3 
Individual laboratory 
measurement – Coagulation 
(As-treated population) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL16 
Sort this listing by: Short subject identifier, Description of actual 
arm, Lab test or examination name, Analysis visit, planned time 
point name. 
The study team will decide about which lab variables to include in 
this listing 
Unique values used for analysis will be flagged with asterisk (*) (i.e. 
repeated measurements outside visit windows will not be flagged) 
 
X 
X 
Appendix 
16.2.8.1.4 
Individual laboratory 
measurement - Urinalysis 
(As-treated population) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL16 
Sort this listing by: Short subject identifier, Description of actual 
arm, Lab test or examination name, Analysis visit, planned time 
point name. 
The study team will decide about which lab variables to include in 
this listing 
Unique values used for analysis will be flagged with asterisk (*) (i.e. 
repeated measurements outside visit windows will not be flagged) 
 
X 
X 
Appendix 
16.2.8.2 
Laboratory safety variables 
(As-treated population) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL17 
Sort this listing by: Short subject identifier, Description of actual 
arm, Lab test or examination name, Analysis visit. 
The listing will present results from the following tests: 
• 
SARS-CoV-2 (serology and nucleic acid test) 
 
X 
X 
Appendix 
16.2.9.1 
Individual vital signs data 
(As-treated population) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL18 
Unique values used for analysis will be flagged with asterisk (*) 
 
X 
X 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 156 of 167 
 
 
TLF 
number 
Title 
Standard mock 
shell reference 
Additional Information 
Analysis1 
(Week 
12) 
Analysis2 
(Week 
28) 
Final 
Analysis 
Appendix 
16.2.10.1 
Electrocardiogram data (As-
treated population) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL19 
Unique values used for analysis will be flagged with asterisk (*) 
 
X 
X 
Appendix 
16.2.10.2 
Abnormalities in 
electrocardiogram (As-
treated population) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL20 
Rename columns to match with CRF content: 
Specification of ECG finding -> Reason, abnormal overall ECG 
evaluation 
 
X 
X 
Appendix 
16.2.10.3 
Echocardiogram data (As-
treated population) 
NEW2 
 
 X 
X 
 X 
Appendix 
16.2.10.4 
Individual NT-proBNP data 
(As-treated population) 
AZ Corporate 
CSR/HLD 
Listing 
Template 
APL16 
Similar to Laboratory data listing, rename columns: 
Lab test or examination name -> Test or examination name (use NT-
proBNP as default) 
Remove Category for lab test column 
 
 X 
X 
 X 
 
 
 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 157 of 167 
 
 
Appendix B ePRO scoring 
B 1 
Calculation of E-RS™: COPD scores 
Table 27 
E-RS™: COPD scoring 
Domain 
Item (number) 
Patient’s Response / Score 
Breathlessness 
Breathless today (7): 
Were you breathless today? 
Not at all = 0 
Slightly = 1 
Moderately = 2 
Severely = 3 
Extremely = 4 
Breathless with activity (8): 
Describe how breathless 
you were today: 
Unaware of breathlessness = 0 
Breathless during strenuous activity = 1 
Breathless during light activity = 2 
Breathless when washing or dressing = 3 
Present when resting = 3 
Short of breath – personal 
care (9): 
Were you short of breath 
today when performing your 
usual personal care 
activities like washing or 
dressing? 
Not at all = 0 
Slightly = 1 
Moderately = 2 
Severely = 3 
Extremely = 3 
Too breathless to do this = 4 
Short of breath – indoor 
activity (10): 
Were you short of breath 
today when performing your 
usual indoor activities like 
cleaning or household 
work? 
Not at all = 0 
Slightly = 1 
Moderately = 2 
Severely = 3 
Extremely = 3 
Too breathless to do this = 3 
Short of breath – outdoor 
activity (11): 
Were you short of breath 
today when performing your 
usual activities outside the 
home such as yard work or 
errands? 
Not at all = 0 
Slightly = 1 
Moderately = 2 
Severely = 3 
Extremely = 3 
Too breathless to do this = 3 
Cough and Sputum 
Cough frequency (2): 
How often did you cough 
today? 
Not at all = 0 
Rarely = 1 
Occasionally = 2 
Frequently = 3 
Almost constantly = 4 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 158 of 167 
 
 
Domain 
Item (number) 
Patient’s Response / Score 
Mucus quantity (3): 
How much mucus (phlegm) 
did you bring up when 
coughing today? 
None at all = 0 
A little = 1 
Some = 1 
A great deal = 2 
A very great deal = 3 
Difficulty with mucus (4): 
How difficult was it to bring 
up mucus (phlegm) today? 
Not at all = 0 
Slightly = 1 
Moderately = 2 
Severely = 3 
Extremely = 4 
Chest symptoms 
Congestion (1): 
Did your chest feel 
congested today? 
Not at all = 0 
Slightly = 1 
Moderately = 2 
Severely = 3 
Extremely = 4 
Discomfort (5): 
Did you have chest 
discomfort today? 
Not at all = 0 
Slight = 1 
Moderate = 2 
Severe = 3 
Extreme = 4 
Tightness (6): 
Did your chest feel tight 
today? 
Not at all = 0 
Slightly = 1 
Moderately = 2 
Severely = 3 
Extremely = 4 
 
 
 


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Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 162 of 167 
 
 
B 3 
Calculation of SGRQ scores 
Each questionnaire response has a unique empirically derived 'weight'. The lowest possible 
weight is zero and the highest is 100. 
Each component of the questionnaire is scored separately in three steps: 
1 
The weights for all items with positive responses are summed. 
2 
The weights for missed items are deducted from the maximum possible weight for each 
component. The weights for all missed items are deducted from the maximum possible 
weight for the Total score. 
3 
The score is calculated by dividing the summed weights by the adjusted maximum 
possible weight for that component and expressing the result as a percentage: 
Score =  100 × Summed weights from positive items in that component
Sum of weights for all items in that component
  
The Total score is calculated in similar way: 
Score =  100 × Summed weights from positive items in the questionnaire
Sum of weights for all items in the questionnaire
 
The Symptoms component is calculated from the summed weights for the positive responses 
to questions 1-8. 
The Activity component is calculated from the summed weights for the positive responses to 
questions 11 and 15. 
The Impacts component is calculated from the summed weights for the positive responses to 
questions 9-10, 12-14 and 16-17.  
The questionnaire requests a single response to questions 1-17. If multiple responses are given 
to one of these questions then averaging the weights for the positive responses for that 
question will be done. 
The Total score is calculated by summing all positive responses in the questionnaire and 
expressing the result as a percentage of the total weight for the questionnaire. 
Item weights 
The wording of the item may not correspond exactly with the wording in the current version 
of the questionnaire. 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 163 of 167 
 
 
PART 1 
Response 
Response weight 
1) Over the past 4 weeks, I have coughed: 
Almost every day  
80.6 
Several days a week  
63.2 
A few days a month 
29.3 
Only with respiratory infections 
28.1 
Not at all 
0.0 
2) Over the past 4 weeks, I have brought up phlegm (sputum): 
Almost every day  
76.8 
Several days a week  
60.0 
A few days a month 
34.0 
Only with respiratory infections 
30.2 
Not at all 
0.0 
3) Over the past 4 weeks, I have had shortness of breath: 
Almost every day  
87.2 
Several days a week  
71.4 
A few days a month 
43.7 
Only with respiratory infections 
35.7 
Not at all 
0.0 
4) Over the past 4 weeks, I have had wheezing attacks:  
Almost every day  
86.2 
Several days a week  
71.0 
A few days a month 
45.6 
Only with respiratory infections 
36.4 
Not at all 
0.0 
5) How many times during the past 4 weeks have you suffered from severe or very unpleasant respiratory 
attacks? 
More than three times 
86.7 
3 times  
73.5 
2 times  
60.3 
1 time  
44.2 
None of the time 
0.0 
6) How long did the worst respiratory attack last? 
A week or more  
89.7 
3 or more days  
73.5 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 164 of 167 
 
 
Response 
Response weight 
1 or 2 days  
58.8 
Less than a day  
41.9 
7) Over the past 4 weeks, in a typical week, how many good days (with few respiratory problems) have you 
had? 
None of the days 
93.3 
1 or 2 days 
76.6 
3 or 4 days 
61.5 
Nearly every day was good 
15.4 
Every day was good 
0.0 
8) If you wheeze, is it worse when you get up in the morning? 
No  
0.0 
Yes  
62.0 
PART 2 
Response 
Response weight 
9) How would you describe your respiratory condition? 
The most important problem I have  
83.2 
Causes me quite a lot of problems  
82.5 
Causes me a few problems  
34.6 
Causes no problem  
0.0 
10) If you have ever held a job: 
My respiratory problems made me stop working altogether 
88.9 
My respiratory problems interfere with my job or 
made me change my job 
77.6 
My respiratory problems do not affect my job 
0.0 
Not applicable 
0.0 
11) These are questions about what activities usually make you feel short of breath these days. 
Sitting or lying still = TRUE 
90.6 
Washing or dressing yourself = TRUE 
82.8 
Walking around the house = TRUE 
80.2 
Walking outside on level ground = TRUE 
81.4 
Walking up a flight of stairs = TRUE 
76.1 
Walking up hills = TRUE 
75.1 
Playing sports or other physical activities = TRUE 
72.1 
12) These are more questions about your cough and shortness of breath these days. 
Coughing hurts = TRUE 
81.1 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 165 of 167 
 
 
Response 
Response weight 
Coughing makes me tired = TRUE 
79.1 
I am short of breath when I talk = TRUE 
84.5 
I am short of breath when I bend over = TRUE 
76.8 
My coughing or breathing disturbs my sleep = TRUE 
87.9 
I get exhausted easily = TRUE 
84.0 
13) Questions about other effects your chest trouble may have on you. 
My cough or breathing is embarrassing in public = TRUE 
74.1 
My respiratory problems are a nuisance to my family, friends 
or neighbors = TRUE 
79.1 
I get afraid or panic when I cannot catch my breath = TRUE 
87.7 
I feel that I am not in control of my respiratory problems = 
TRUE 
90.1 
I do not expect my respiratory problems to get any better = 
TRUE 
82.3 
I have become frail or an invalid because of my respiratory 
problems = TRUE 
89.9 
Exercise is not safe for me = TRUE 
75.7 
Everything seems too much of an effort = TRUE 
84.5 
14) These are questions about your respiratory treatment. 
My treatment does not help me very much = TRUE 
88.2 
I get embarrassed using my medication in public = TRUE 
53.9 
I have unpleasant side effects from my medication = TRUE 
81.1 
My treatment interferes with my life a lot = TRUE 
70.3 
15) These are questions about how your activities might be affected by your respiratory problems. 
I take a long time to get washed or dressed = TRUE 
74.2 
I cannot take a bath or shower, or I take a long time to do it = 
TRUE 
81.0 
I walk slower than other people my age, or I stop to rest = 
TRUE 
71.7 
Jobs such as household chores take a long time, or I have to 
stop to rest = TRUE 
70.6 
If I walk up one flight of stairs, I have to go slowly or stop = 
TRUE 
71.6 
If I hurry or walk fast, I have to stop or slow down = TRUE 
72.3 
My breathing makes it difficult to do things such as walk up 
hills, carry things up stairs, light gardening such as weeding, 
dance, bowl or play golf = TRUE 
74.5 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 166 of 167 
 
 
Response 
Response weight 
My breathing makes it difficult to do things such as carry 
heavy loads, dig in the garden or shovel snow, jog or walk 
briskly (5 miles per hour), play tennis or swim = TRUE 
71.4 
My breathing makes it difficult to do things such as very 
heavy manual work, ride a bike, run, swim fast, or play 
competitive sports = TRUE 
63.5 
16) We would like to know how your respiratory problems usually affect your daily life. 
I cannot play sports or do other physical activities = TRUE 
64.8 
I cannot go out for entertainment or recreation = TRUE 
79.8 
I cannot go out of the house to do the shopping = TRUE 
81.0 
I cannot do household chores = TRUE 
79.1 
I cannot move far from my bed or chair = TRUE 
94.0 
17) Now please select the response (one only) that you think best describes how your respiratory problems 
affect you: 
It does not stop me from doing anything I would like to do 
0.0  
It stops me from doing one or two things I would like to do 
42.0 
It stops me from doing most of the things I would like to do 
84.2 
It stops me from doing everything I would like to do 
96.7 
 
 
Handling of missing items 
The Symptoms component will tolerate a maximum of 2 missed items. The Activity 
component will tolerate a maximum of 4 missed items. The Impacts component will tolerate a 
maximum of 6 missed items. Domain score will be set to missing if there are more than 
tolerated number of items missing. 


Statistical Analysis Plan  
AstraZeneca 
D9180C00002 - 2.0 
11 May 2023 
CONFIDENTIAL AND PROPRIETARY 
 167 of 167 
 
 
B 4 
Calculation of BCSS scores 
Table 29 
BCSS© scoring 
Item 
Question 
Score 
Breathlessness 
How much difficulty did you have breathing 
today? 
0 – None 
1 – Mild 
2 – Moderate  
3 – Marked  
4 – Severe  
Cough 
How was your cough today? 
0 – None  
1 – Rare  
2 – Occasional  
3 – Frequent  
4 – Almost constant 
Sputum 
How much trouble was your sputum today? 
0 – None 
1 – Mild 
2 – Moderate  
3 – Marked  
4 – Severe 
 
 
 


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