Clinical trial NCT05492877
Conditions: Chronic Obstructive Pulmonary Disease (COPD)
Keywords: Mitiperstat AZD4831 Myeloperoxidase MPO Myeloperoxidase inhibitor COPD Chronic Obstructive Pulmonary Disease Lung function
Sponsor: AstraZeneca
Start date: 2022-11-14; Completion date: 2024-08-12
Enrollment: 381 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a research study to evaluate the efficacy and safety of the investigational drug Mitiperstat (AZD4831) in adult patients with chronic obstructive pulmonary disease.

Detailed description:
Study D6582C00001 is a phase IIa randomised, double blind, placebo controlled, parallel arm study to evaluate the efficacy and safety of Mitiperstat (AZD4831) in adult participants with moderate to severe chronic obstructive pulmonary disease.

Approximately 100 sites globally will participate in this study. Approximately 406 participants will be randomised to two treatment groups; Mitiperstat (AZD4831) vs placebo in a 1:1 ratio.

Arms: arm 1: Approximately 203 participants will be randomised to receive placebo. arm 2: Approximately 203 participants will be randomised to receive mitiperstat (AZD4831).
Interventions: intervention 1: Mitiperstat (AZD4831) intervention 2: Placebo
Intervention descriptions: intervention 1: Oral dosage, once daily. intervention 2: Oral dosage, once daily.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
1 of 187
Clinical Study Protocol
Study Intervention
Mitiperstat (AZD4831)
Study Code
D6582C00001
Version
5.0
Date
07 December 2023
A Phase IIa Randomised, Double Blind, Placebo Controlled, Parallel Arm, 
Multi-Centre Study to Evaluate the Efficacy and Safety of Mitiperstat 
(AZD4831), for 12-24 Weeks, in Patients with Moderate to Severe Chronic 
Obstructive Pulmonary Disease (COPD)
Sponsor Name: AstraZeneca AB
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden.
Regulatory Agency Identifier Number(s): 
Registry
ID
EudraCT
2022-002441-18
IND
161799
This protocol has been subject to a peer review according to AstraZeneca Standard 
procedures. The protocol is publicly registered and the results are disclosed and/or published 
according to the AstraZeneca Global Standard - Bioethics and in compliance with prevailing 
laws and regulations.
Version Scope: Global
Brief Title: An Efficacy and Safety Study of Mitiperstat (AZD4831) (MPO Inhibitor) vs 
Placebo in the Treatment of Moderate to Severe COPD
Redacted for Public Disclosure


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
2 of 187
Study Phase: Phase IIa
Acronym: CRESCENDO
Study Physician Name and Contact Information will be provided separately.
The Study Physician is responsible for the clinical integrity of the study.
International Coordinating Investigator
Patient Recruitment Centre
Clinical Research Facility
Bradford Royal Infirmary
Bradford BD9 6RJ
United Kingdom
PPD


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
3 of 187
SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Version 5.0
07 December 2023
Version 4.0
28 April 2023
Version 3.0
13 January 2023
Version 2.0
30 June 2022
Original Protocol
05 May 2022
CSP Version 5.0, 07 December 2023
This modification 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 
and in the EU Clinical Trial Regulation Article 2, 2 (13).
Overall Rationale for the Modification:
The primary rationale for the modifications in this CSP is to increase the sample size, due to 
changes in statistical assumptions, to ensure that the study is adequately powered to assess the 
primary and key secondary endpoints. 
Summary of Changes: 
List of Substantial Modifications
Section Number and 
Name
Description of Change
Brief Rationale
Section 1.1 Synopsis, 
Section 1.2 Schema, 
Section 4.1 Overall 
Design, Section 9.2
Sample Size 
Determination
The estimated study sample size was changed from 
approximately 480 to 677 screened participants. 
The estimated number of participants 
randomised/assigned to the study intervention was 
changed from approximately 288 to 406. 
The estimated number of evaluable participants was 
updated from approximately 288 to 406 (from 144 to 203 
in each arm). 
Due to changes in 
statistical assumptions, 
the sample size was 
modified to ensure 
adequate power to assess 
the primary and key 
secondary endpoints.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
4 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Section 1.1 Synopsis, 
Section 9.2 Sample 
Size Determination
The statistical assumptions were revised based on 
available data. 
The text was amended as follows:
“A total of 113 194 first COPDCompEx events 
(estimated to require 144 203 participants per arm) will 
provide 80% power to detect a 30% decrease between 
the 2 arms at the two-sided 10% level of statistical 
significance to detect a hazard ratio of 0.7 in the 
mitiperstat (AZD3851) 5 mg QD arm based on a 24-
week. A 12-week first COPDCompEx event rate risk of 
55% assumed in the placebo arm of 48%, (constant 
over the course of the study). was assumed.
Available blinded study 
data was used to update 
statistical assumptions 
and study sample size to 
ensure adequate power 
to assess the primary 
and key secondary 
endpoints.
Section 1.1 Synopsis, 
Section 1.2 Schema, 
Section 4.1 Overall 
Design, Section 4.2
Scientific Rationale 
for Study Design, 
Section 7.1.4
Participant 
Discontinuation at 
Study End, 
Section 9.2 Sample 
Size Determination
Section 9.4.2.1
Primary Endpoint
Enrolment will be stopped after at least “194” rather than 
113 first COPDCompEx events have occurred.
Due to the changes in 
statistical assumptions 
and increase in sample 
size, the number of first 
COPDCompEx events 
required before stopping 
enrolment was increased 
to ensure adequate 
power to assess the
primary and key 
secondary endpoints.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
5 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Section 5.2, 
Exclusion Criteria, 
Section 8.2.7
Optional Computer 
Tomography Scan
Exclusion criterion 7 and 7 (g) were amended as follows:
7: “Any other clinically relevant abnormal findings on 
physical examination, laboratory testing including 
haematology, coagulation, serum chemistry, or 
urinalysis; or chest CT scan at screening or recent lung 
imaging prior to randomisation, 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. In
addition, if a participant meets any of the criteria below, 
they will be excluded from the study:...”
7(g): “Recent lung imaging that requires immediate 
diagnostic investigation or follow-up. If initial repeat 
surveillance imaging has been undertaken, and the 
abnormality is considered low risk of malignancy, the 
participant may be eligible for enrolment following 
confirmation with the AstraZeneca medical 
monitor.Chest CT scan findings requiring further 
investigation or repeat CT surveillance scan before 
SV8.”
Additional wording was added in Section 8.2.7 to reflect 
the change to the exclusion criteria.
To ensure that 
appropriate investigation 
of any suspicious lesion 
observed on any 
previous lung imaging 
modality is undertaken 
prior to potential 
enrolment.
Section 5.2, 
Exclusion Criteria
Exclusion criterion 7(f) was amended: “In addition, if a 
participant meets any of the criteria below, they will be 
excluded from the study:…”
“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. Participants with 
atrial fibrillation or flutter and optimally controlled 
ventricular rate at resting < 100 beats per minute 
might be included as judged "by the investigator
Atrial fibrillation is exclusionary.”
To allow participants 
with stable atrial 
fibrillation or atrial 
flutter to be included in 
the study. This is 
supported by lack of 
specific cardiac safety 
signal in previous 
preclinical and clinical 
studies.
Section 5.2, 
Exclusion Criteria
Exclusion criterion 10 was amended: “Use of
domiciliary non-invasive positive pressure ventilation 
device, including BiPAP and CPAP. CPAP for the 
purpose of treating obstructive sleep apnoea is 
allowed.”
To determine that the 
use of BiPAP is 
excluded and reflect the 
change that the use of 
CPAP is acceptable. 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
6 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Section 5.2, 
Exclusion Criteria
Exclusion criterion 12 was amended: “History or 
ongoing allergy/hypersensitivity reactions to drugs 
(including but not limited to rash angioedema, acute 
urticaria) Active drug-induced hypersensitivity skin 
reaction or history of SCARS (including DRESS, 
SJS/TEN, and AGEP).”
To clarify the details of 
the exclusion criteria for 
hypersensitivity skin 
reactions and severe 
cutaneous adverse 
reactions.
Bold signifies added text, strike through signifies deleted text.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
7 of 187
List of Non-Substantial Modifications
Section Number and 
Name
Description of Change
Brief Rationale
Throughout.
Minor changes were made to formatting and wording 
throughout the document for example to fix errors and 
improve grammar and sentence/section structure without 
change of meaning.
To improve clarity and 
readability.
Section 1.1 Synopsis, 
Section 3 Objectives 
and Endpoints
Change to the text for the safety estimand related to 
strategy for intercurrent events. “Primary: while on 
treatment – if an intercurrent event occurs after the safety 
follow-up, any subsequent safety data will not be taken 
into consideration in the safety evaluation.”
To amend an error in the 
previous version of the 
CSP. The text does not 
correspond to the 
estimand while on 
treatment.
Section 1.1 Synopsis, 
Section 4.1 Overall 
Design,Section 9.5
Interim Analysis,
Section 9.6 Data 
Review Committee, 
Appendix A 5
Committees Structure
Sections of text relating to the roles of the URC and 
DRC were updated as follows:
“The DRC will assess safety and will have access to 
interimIA outcome data, if required (including all 
adverse event data).”
“The DRC URC will perform review efficacy data from 
the IA and the DRC will perform periodic safety 
monitoring with a focus on skin reactions and 
pneumonia. See Appendix A 5 for details.”
Text removed from Section 9.6 due to repetition: A URC 
will be embedded in the study to carry out the IA. For 
details on the URC for this study, see Appendix A 5.
“The At the time of the IA, the DRC will assess the
safety profile (ie, all AE data) of mitiperstat 
(AZD4831) and will have access to IA interim analysis
outcome data, if required. This evaluation will be 
performed at the same time as the IA. Additional details 
will be contained in the DRC Charter.”
To clarify the roles of the 
DRC and URC and to 
clarify the extra data the 
DRC will evaluate at the 
time of the IA.
Section 1.1 Synopsis, 
Section 9.5 Interim 
Analysis
Text related to the administrative IA conducted by the 
URC was amended as follows: “An administrative IA 
will be conducted by the URC after 45 136 (40% 70% of 
the required 113 194) first COPDCompEx events have 
occurred.”
Text in the Synopsis was further amended: “It will allow 
an early assessment of efficacy for mitiperstat 
(AZD4831) used for further development of this drug 
programme...”
To update the sample 
size and percentage of 
COPDCompEx events 
required for the 
administrative IA to be 
conducted due to study 
progression and change 
in overall sample size
and to clarify that the 
unblinded IA results will 
not be used to inform 
decisions for the ongoing 
study.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
8 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Section 1.2 Schema, 
Section 1.3 Schedule 
of Activities
The visit day/week window description for SV8 in the 
SoA was amended to +14 days or +2 weeks 
post-SV7/EDV rather than +14 days or +2 weeks post-
treatment.
To amend an error in the 
previous version of the 
CSP.
Section 1.3 Schedule 
of Activities
Change in formatting to show the Q-SAW substudy 
informed consent time between SV1 and SV5. 
Addition of note: Consent can be obtained any time up 
until SV5.
To clarify that consent 
for Q-SAW substudy can 
be obtained any time 
from SV1 to SV5. No 
change to the study 
procedure.
Section 1.3 Schedule 
of Activities
Change in formatting to show the Patient Experience 
Interview substudy informed consent time between SV1 
and SV7. 
Addition of note: Consent can be obtained any time up 
until SV7.
To clarify that consent 
for the Patient 
Experience Interview 
substudy can be obtained 
any time from SV1 to 
SV7. No change to the 
study procedure.
Section 1.3 Schedule 
of Activities, 
Section 5.2 Exclusion 
Criteria, Section 5.4
Screen Failures, 
Section 8.2.7
Optional Computer 
Tomography Scan
Changes to wording to reflect that the CT scan 
assessment is important but optional.
To change and clarify the 
details for the CT scan 
assessment. 
Section 1.3 Schedule 
of Activities, 
Section 8.3.4 Clinical 
Safety Laboratory 
Tests, Section 8.4.9
Adverse Events of 
Special Interest
Removed mandatory ANCA assessment during the study 
and clarified that ANCA sample is optional at the 
discretion of the investigator. 
This assessment is no 
longer mandatory given 
the low prevalence of 
history of ANCA positive 
vasculitis or skin disease. 
Optional ANCA 
assessment is still 
available if needed.
Section 1.3 Schedule 
of Activities, 
Section 8.8.2
Mandatory Genetic 
Analysis Sample 
Collection,
Appendix B 5 Guide 
to Skin Reaction 
Assessment
The mandatory genetic analysis sample collection was 
removed from the schedule of activities and the 
subsection detailing the assessment was deleted. 
Subsequent Section 8.8.3, Optional Cell-free DNA 
Analysis Sample Collection was renumbered as 
Section 8.8.2.
To determine that no 
mandatory genetic 
samples are required in 
the study.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
9 of 187
Section Number and 
Name
Description of Change
Brief Rationale
Section 5.1 Inclusion 
Criteria
Inclusion criterion 5 was amended to ≤100 cells/µL 
rather than ≤100 cells/mL
To amend an error in the 
previous version of the 
CSP.
Section 5.2 Exclusion 
Criteria
Exclusion criterion 19 was amended to “including but 
not limited to TSH ≥10 mIU/L” rather 
than ≥10 mIU/mL.
To amend an error in the 
previous version of the 
CSP.
Section 6.1.1 Medical 
Devices Including 
Combination 
Products with a 
Device Constituent
The following text was added:
ArtiQ.QC will be integrated into ZEPHYRx 
application for an instant artificial intelligence–based 
over-reading of spirometry against ATS/ERS 2019 
standards. Meanwhile ArtiQ.RBM software will also 
be utilised in ZEPHYRx and UNIFY, for risk-based 
quality management analysis of spirometry and 
identification of sites that may require quality 
improvement initiatives.
Both ArtiQ.QC and ArtiQ.RBM are not considered 
to meet the definition of a medical device as it only 
performs quality control and quality management 
functions. It will not be used as the basis for any 
clinical decision making or patient treatment.
To provide details of 
ArtiQ as a vendor for 
quality control 
assessment and ensure 
patient-level data can be 
transferred to ArtiQ for 
risk-based quality 
management purposes.
Section 6.9.1 Rescue 
Medicine
The text was amended as follows: “The following rescue 
medications SABAs, as per local SoC, may be used 
during the study as rescue medication...”
To clarify that SABA 
medication could be used 
as per local SoC.
Section 9.3
Populations for 
Analyses
Full analysis set population description amended: “Will 
include all randomised participants who received at least 
1 dose of study intervention and have post-baseline data 
for COPDCompEx. Participants will be analysed 
according to planned treatment. Efficacy analyses will be 
based on the FAS.
To correct an error from 
the previous version of 
the CSP. Post-baseline 
data for COPDCompEx 
is not required for 
inclusion in the full 
analysis set. 
Bold signifies added text, strike through signifies deleted text.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
10 of 187
TABLE OF CONTENTS
1
PROTOCOL SUMMARY ................................................................................ 18
1.1
Synopsis ........................................................................................................... 18
1.2
Schema............................................................................................................. 27
1.3
Schedule of Activities ....................................................................................... 28
2
INTRODUCTION............................................................................................ 42
2.1
Study Rationale ................................................................................................ 42
2.2
Background ...................................................................................................... 42
2.3
Benefit/Risk Assessment................................................................................... 44
2.3.1
Risk Assessment ............................................................................................... 44
2.3.2
Benefit Assessment........................................................................................... 47
2.3.3
Overall Benefit/Risk Conclusion....................................................................... 48
3
OBJECTIVES AND ENDPOINTS................................................................... 49
4
STUDY DESIGN ............................................................................................. 54
4.1
Overall Design.................................................................................................. 54
4.1.1
Cough Monitoring Substudy............................................................................. 55
4.1.2
Q-SAW Substudy.............................................................................................. 55
4.1.3
SPFQ Substudy................................................................................................. 56
4.1.4
Patient Experience Interview Substudy ............................................................. 56
4.1.5
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 56
4.1.6
Study Conduct Mitigation During SARS-CoV-2 Pandemic ............................... 57
4.2
Scientific Rationale for Study Design ............................................................... 58
4.2.1
Patient Input into Design................................................................................... 58
4.3
Justification for Dose........................................................................................ 59
4.4
End-of-Study Definition ................................................................................... 59
5
STUDY POPULATION.................................................................................... 60
5.1
Inclusion Criteria .............................................................................................. 60
5.2
Exclusion Criteria ............................................................................................. 63
5.3
Lifestyle Considerations ................................................................................... 67
5.3.1
Meals and Dietary Restrictions ......................................................................... 67
5.3.2
Alcohol and Tobacco ........................................................................................ 67
5.4
Screen Failures ................................................................................................. 68
5.5
Criteria 
for 
Temporarily 
Delaying 
Enrolment, 
Randomisation, 
or 
Administration of Study Intervention................................................................ 69
6
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................. 69
6.1
Study Intervention(s) Administered................................................................... 69
6.1.1
Medical Devices Including Combination Products with a Device Constituent... 70
6.2
Preparation, Handling, Storage, and Accountability .......................................... 71


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
11 of 187
6.3
Assignment to Study Intervention ..................................................................... 71
6.4
Blinding............................................................................................................ 72
6.5
Study Intervention Compliance......................................................................... 73
6.6
Dose Modification ............................................................................................ 73
6.7
Continued Access to Study Intervention After the End of the Study .................. 73
6.8
Treatment of Overdose...................................................................................... 73
6.9
Prior and Concomitant Therapy ........................................................................ 74
6.9.1
Rescue Medicine............................................................................................... 75
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 75
7.1
Discontinuation of Study Intervention............................................................... 75
7.1.1
Discontinuation Due to Rash/Skin Reaction...................................................... 76
7.1.2
Temporary Discontinuation............................................................................... 77
7.1.3
Restarting After Temporary Discontinuation ..................................................... 78
7.1.4
Participant Discontinuation at Study End .......................................................... 79
7.2
Participant Discontinuation/Withdrawal from the Study.................................... 79
7.3
Lost to Follow-up ............................................................................................. 80
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 81
8.1
Administrative and General/Baseline Procedures.............................................. 82
8.2
Efficacy Assessments........................................................................................ 82
8.2.1
COPDCompEx ................................................................................................. 82
8.2.2
Chronic Obstructive Pulmonary Disease Exacerbations .................................... 82
8.2.3
Spirometry and Peak Expiratory Flow Measurement......................................... 84
8.2.4
Participant-Reported Outcomes......................................................................... 85
8.2.5
COPD Assessment Test..................................................................................... 86
8.2.6
E-Diary............................................................................................................. 86
8.2.7
Optional Computed Tomography Scan.............................................................. 87
8.2.8
Cough Substudy................................................................................................ 89
8.2.9
Q-SAW Substudy.............................................................................................. 90
8.2.10
SPFQ Substudy................................................................................................. 90
8.2.11
Patient Experience Interview Substudy ............................................................. 91
8.3
Safety Assessments........................................................................................... 91
8.3.1
Physical Examinations...................................................................................... 91
8.3.2
Vital Signs ........................................................................................................ 91
8.3.3
Electrocardiograms........................................................................................... 93
8.3.4
Clinical Safety Laboratory Tests ....................................................................... 93
8.3.5
SARS-CoV-2 Screening.................................................................................... 95
8.4
AEs, SAEs, and Other Safety Reporting............................................................ 95
8.4.1
Time Period and Frequency for Collecting AE and SAE Information................ 96
8.4.2
Follow-up of AEs and SAEs ............................................................................. 96
8.4.3
Causality Collection.......................................................................................... 96
8.4.4
AEs Based on Examinations and Tests.............................................................. 97
8.4.5
AEs Based on Signs and Symptoms.................................................................. 97


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
12 of 187
8.4.6
Hy’s Law.......................................................................................................... 97
8.4.7
Disease Under Study......................................................................................... 98
8.4.8
Reporting of SAEs............................................................................................ 98
8.4.9
Adverse Events of Special Interest.................................................................... 99
8.4.10
Pregnancy......................................................................................................... 99
8.4.11
Medication Error, Drug Abuse, and Drug Misuse............................................ 101
8.4.12
Reporting of Overdose.................................................................................... 101
8.4.13
Medical Device Deficiencies........................................................................... 102
8.5
Pharmacokinetics............................................................................................ 102
8.5.1
Collection of Samples for Pharmacokinetics ................................................... 103
8.5.2
Determination of Drug Concentration ............................................................. 103
8.6
Pharmacodynamics......................................................................................... 104
8.6.1
Collection of Samples for Pharmacodynamics ................................................ 104
8.7
Optional Genomics Initiative Sample.............................................................. 104
8.8
Biomarkers ..................................................................................................... 104
8.8.1
Mandatory Biomarker Sample Collection ....................................................... 104
8.8.2
Optional Cell-free DNA Analysis Sample Collection ...................................... 105
8.9
Medical Resource Utilisation and Health Economics ...................................... 105
9
STATISTICAL CONSIDERATIONS.............................................................. 106
9.1
Statistical Hypotheses..................................................................................... 106
9.2
Sample Size Determination............................................................................. 106
9.3
Populations for Analyses................................................................................. 107
9.4
Statistical Analysis.......................................................................................... 107
9.4.1
General Considerations................................................................................... 107
9.4.2
Efficacy .......................................................................................................... 108
9.4.3
Safety ............................................................................................................. 109
9.5
Interim Analysis.............................................................................................. 110
9.6
Data Review Committee ................................................................................. 110
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ...................................................................................... 110
11
REFERENCES............................................................................................... 185
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 27
LIST OF TABLES
Table 1
Schedule of Activities.............................................................................. 28
Table 2
Risk Assessment...................................................................................... 44


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
13 of 187
Table 3
Objectives and Endpoints......................................................................... 49
Table 4
Study Interventions.................................................................................. 69
Table 5
Orthostatic Blood Pressure Criteria and Management .............................. 93
Table 6
Laboratory Safety Variables..................................................................... 94
Table 7
Populations for Analysis ........................................................................ 107
Table 8
CYP3A-Interacting Medication That Should be Avoided....................... 138
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 111
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 118
Appendix C
Handling of Human Biological Samples ................................................ 128
Appendix D
Optional Genomics Initiative Sample..................................................... 130
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 133
Appendix F
CYP3A-Interacting Medication That Should be Avoided....................... 138
Appendix G
EXACT Questionnaire........................................................................... 139
Appendix H
COPD Assessment Test (CAT).............................................................. 142
Appendix I
Daily e-Diary......................................................................................... 143
Appendix J
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health ...................................... 147
Appendix K
COVID-19 Specifics.............................................................................. 149
Appendix L
Q-SAW Substudy .................................................................................. 153
Appendix M
SPFQ Substudy...................................................................................... 157
Appendix N
Patient Experience Interview Substudy.................................................. 162
Appendix O
Protocol Version History ....................................................................... 166


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
14 of 187
LIST OF ABBREVIATIONS 
Abbreviation or special 
term
Explanation
ACM
Ambulatory cough monitor
ADL
Activities of Daily Living
AE
Adverse event
AECOPD
Acute exacerbation of chronic obstructive pulmonary disease
AESI
Adverse event of special interest
AGEP
Acute generalised exanthematous pustulosis
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase/transaminase
ANCA
Anti-neutrophil cytoplasm antibodies
ATS/ERS
American Thoracic Society/European Respiratory Society
AST
Aspartate aminotransferase/transaminase
AWE
Acute worsening event
BCSS
Breathlessness, Cough, and Sputum Scale
BD
Bronchodilator
BDRM
Blinded data review meeting
BiPAP
Bilevel Positive Airway Pressure
BP
Blood pressure
BSA
Body surface area
CAT
Chronic obstructive pulmonary disease Assessment Test
CFR
Code of Federal Regulations
Cmax
Maximum concentration
COPD
Chronic obstructive pulmonary disease
COPDCompEx
COPD Composite Exacerbations (composite measure of chronic obstructive 
pulmonary disease)
COVID-19
Coronavirus 2019
CPAP
Continuous positive airway pressure
CRO
Contract research organisation
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CV
Coefficient of variation
DILI
Drug Induced Liver Injury


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
15 of 187
Abbreviation or special 
term
Explanation
DNA
Deoxyribonucleic acid 
DRC
Data Review Committee
DRESS
Drug reaction with eosinophilia and systemic symptoms
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
e-Diary
Electronic diary
EDV
Early discontinuation visit
EMA
European Medicines Agency
EU
European Union
EXACT
The Exacerbations of Chronic Pulmonary Disease Tool 
FAS
Full Analysis Set
FDA
United States Food and Drug Administration
FEV1
Forced expiratory volume in 1 second
FSH
Follicle stimulating hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice
GOLD
Global Initiative for Obstructive Lung Disease
GPRI
General Practitioners Research Institute
HbA1c
Glycated haemoglobin
HCP
Healthcare professional
HfpEF
Heart failure with preserved ejection fraction
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
hsCRP
High sensitivity C-reactive protein
IA
Interim analysis
IATA
International Airline Transportation Association
ICF
Informed consent form
ICH
International Council for Harmonisation
ICS
Inhaled corticosteroids
IEC
Independent Ethics Committee
IL-6
Interleukin-6
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IRT
Interactive Response Technology
LABA
Long-acting beta-adrenoceptor agonist


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
16 of 187
Abbreviation or special 
term
Explanation
LAMA
Long-acting muscarinic antagonist
MAD
Multiple ascending dose
MedDRA
Medical Dictionary for Regulatory Activities
MPO
Myeloperoxidase
mRNA
Messenger ribonucleic acid
NIMP
Non Investigational Medicinal Product
NT-proBNP
N-terminal pro B-type natriuretic peptide
OCS
Oral corticosteroids
PCR
Polymerase chain reaction
PD
Pharmacodynamic
PEF
Peak expiratory flow
PI
Principal investigator 
PK
Pharmacokinetic(s)
PP
Per Protocol Set
PRO
Patient reported outcome
QD
Once daily
Q-SAW
Qualitative Study into Acute Worsening Events
RTSM
Randomisation and Trial Supply Management
SABA
Short-acting beta agonist
SAD
Single ascending dose
SAE
Serious adverse event 
SAF
Safety Analysis Set
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SCARS
Severe cutaneous adverse reactions
SD
Standard deviation
SJS
Stevens-Johnson syndrome
SoA
Schedule of Activities
SoC
Standard of care
SPFQ
Study Participant Feedback Questionnaire
SV
Study Visit
TB
Tuberculosis
TBL
Total bilirubin
TEN
Toxic epidermal necrolysis
tmax
Time to reach maximum concentration


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
17 of 187
Abbreviation or special 
term
Explanation
TPV
Third-party vendor
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
URC
Unblinded Review Committee
USA
United States of America
VAS
Visual Analogue Scale


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
18 of 187
1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase IIa Randomised, Double Blind, Placebo Controlled, Parallel Arm, 
Multi-Centre Study to Evaluate the Efficacy and Safety of Mitiperstat (AZD4831), for 
12-24 Weeks, in Patients with Moderate to Severe Chronic Obstructive Pulmonary Disease 
(COPD)
Brief Title: An Efficacy and Safety Study of Mitiperstat (AZD4831) (MPO Inhibitor) vs 
Placebo in the Treatment of Moderate to Severe COPD
Regulatory Agency Identifier Number(s): 
Registry
ID
EudraCT
2022-002441-18
IND
161799
Rationale: This study will evaluate the efficacy and safety of the myeloperoxidase (MPO) 
inhibitor, mitiperstat (AZD4831) in the treatment of moderate to severe COPD. Patients with 
COPD represent a huge unmet medical need: COPD exacerbations are associated with 
accelerated decline in lung function, high mortality, worsening quality of life and 
comorbidities, and high healthcare costs. In addition, COPD is also frequently associated with 
other metabolic or cardiovascular comorbidities, which also contribute to impaired quality of 
life and poorer survival. Furthermore, current COPD therapies, which include combinations of 
inhaled long-acting beta-adrenoceptor agonist (LABA), long-acting muscarinic agonist 
(LAMA), and inhaled corticosteroids (ICS), and add-on anti-inflammatory agents, do not 
eliminate symptoms, disability, exacerbations, or the hospitalisations that are associated with 
COPD, and do not significantly alter the course of COPD.
There is evidence implicating MPO activity in promoting lung inflammation and injury in 
animals exposed to cigarette smoke, and high concentrations of (activated) MPO are 
associated with the progression of COPD in humans. Therefore, this study and the clinical 
development program for mitiperstat (AZD4831) will evaluate whether treating patients with 
COPD with mitiperstat (AZD4831) reduces exacerbations, and improves symptoms, quality of 
life, lung function, and other clinically-relevant outcomes including comorbidities in patients 
with COPD.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
19 of 187
Objectives and Endpoints
Objectives
Estimand Descriptiona
Primary
To evaluate the effect of mitiperstat (AZD4831) 
as compared to placebo on the time to first 
COPDCompEx event in patients with moderate 
to severe COPD.
Population: all participants randomised to either 
active or placebo arm.
Endpoint: time to first COPDCompEx event.
Population level-summary measure: hazard 
ratio.
Strategy for intercurrent events:
Primary estimand: while on treatment – if an 
intercurrent event occurs before first 
COPDCompEx event, the participant will be 
censored at the time of intercurrent event.
Supportive estimand: treatment policy (reflects 
ITT principle) – after intercurrent event 
participants remain in the study so that the 
endpoint can be observed. Treatment policy 
strategy used to estimate the efficacy of 
mitiperstat (AZD4831) in ‘real-world’ 
conditions.
Secondary
To assess the PK of mitiperstat (AZD4831) in 
patients with moderate to severe COPD.
Population: all participants who had received at 
least one dose of mitiperstat (AZD4831), and 
who had at least one measurable PK sample post 
dose.
Endpoint: plasma mitiperstat (AZD4831) 
concentration-time profiles during the 
intervention and follow-up periods, and PK
parameters.
Population level-summary measure: summary 
statistics.
Strategy for intercurrent events: while on 
treatment.
To evaluate the effect of mitiperstat (AZD4831) 
as compared to placebo on the time to first 
moderate or severe COPD exacerbation.
Population: all participants randomised to either 
active or placebo arms.
Endpoint: time to first COPD exacerbation 
eventb
Population level-summary measure: hazard 
ratio.
Strategy for intercurrent events: while on 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
20 of 187
Objectives
Estimand Descriptiona
treatment.
To assess the effects of mitiperstat (AZD4831) 
as compared to placebo on post-BD FEV1 in 
patients with moderate to severe COPD.
Population: all participants randomised to either 
active or placebo arms.
Endpoint: change from baseline in post-BD 
FEV1 after 12 weeks.
Population level-summary measure: the 
difference in mean.
Primary estimand: while on treatment.
Supportive estimand: treatment policy.
To assess the effect of mitiperstat (AZD4831) 
compared with placebo on respiratory 
symptoms in patients with moderate to severe 
COPD.
Population: all participants randomised to either 
active or placebo arms.
Endpoint: change from baseline in EXACT, 
BCSS score, and Cough VAS at Week 12 and 
Week 24
Population level-summary measure: the 
difference in mean.
Strategy for intercurrent events: while on 
treatment.
To assess the effect of mitiperstat (AZD4831) 
compared with placebo on disease impact in 
patients with moderate to severe COPD.
Population: all participants randomised to either 
active or placebo arms.
Endpoint: change from baseline in Total CAT 
measured in clinic at Week 12.
Population level-summary measure: 
The difference in mean. 
Proportion of participants with change from 
baseline of -2 or less.
Strategy for intercurrent events: while on 
treatment.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
21 of 187
Objectives
Estimand Descriptiona
Safety
To assess the safety and tolerability of 
mitiperstat (AZD4831) compared with placebo 
in patients with moderate to severe COPD.
Population: all participants who received at least 
1 dose of study intervention (Safety Analysis 
Set). 
Endpoint: safety and tolerability evaluations 
using AEs, SAEs, AESIs (skin reactions, 
including maculopapular rash, and infections, 
including pneumonia), vital sign measures, 
clinical laboratory assessments (clinical 
chemistry, haematology, and urinalysis), and 
ECG.
Population level-summary measure:
descriptive statistics eg, absolute counts and 
frequencies.
Strategy for intercurrent events: 
Primary: while on treatment – if an intercurrent event 
occurs, any subsequent safety data will not be taken 
into consideration in the safety evaluation.
Supportive: treatment policy – if an intercurrent 
event occurs, participants remain in the study and 
any safety data until Week 12 + safety follow-up 
will be taken into consideration in the safety 
evaluation.
a
An estimand is a precise description of the treatment effect reflecting the clinical question posed by the 
study objective. It summarises at a population-level what the outcomes would be in the same participants 
under different treatment conditions being compared. Definition from FDA E9(R1) Statistical Principles for 
Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials
b
COPD Exacerbation: a worsening in the participant’s usual COPD symptoms that is beyond normal 
day-to-day variation, is acute in onset, lasts 2 or more days (or less if the worsening is so rapid and 
profound that the treating physician judges that intensification of treatment cannot be delayed), may warrant 
a change in regular medication, and leads to any of the following:
•
Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be 
considered equivalent to a 3-day course of systemic corticosteroids.
•
Use of antibiotics to treat COPD exacerbation for at least 3 days.
•
An inpatient hospitalisation due to COPD (defined as an inpatient admission ≥24 hours in the hospital, an 
observation area, the emergency department, or other equivalent healthcare facility depending on the 
country and healthcare system).
•
Admission in emergency department or emergency room due to COPD for < 24 hours requiring intensive 
treatment.
•
An episode of pneumonia.
•
Results in death.
Moderate and severe COPD exacerbations are defined in Section 8.2.2.2.
Intercurrent events are events occurring after treatment initiation (eg, discontinuation of treatment, switching 
treatment, terminal events such as death) that affect either the measurement or interpretation of the summary 
measure (eg, hazard ratio) associated with the clinical question of interest.
This study contains 2 intercurrent events: 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
22 of 187
1
Treatment discontinuation (with the following reasons: SAE, death not due to exacerbation, COVID-19, 
pneumonia, other).
2
Prohibited medication.
AE = adverse event; AESI = adverse event of special interest; BCSS = Breathlessness, cough and sputum scale; 
BD = bronchodilator; CAT = COPD assessment test; COPD = chronic obstructive pulmonary disease; 
COPDCompEx = COPD Composite Exacerbations; ECG = electrocardiogram; EXACT = The Exacerbation of 
Chronic Pulmonary Disease Tool; FEV1 = forced expiratory volume in 1 second; ITT = intent-to-treat; 
PK = pharmacokinetic; SAE = serious adverse event; VAS = visual analogue scale.
For Tertiary/Exploratory objectives and endpoints, see Section 3 of the protocol.
Overall Design Synopsis:
A schematic is provided in Section 1.2 showing the overall study design. 
This is a Phase IIa, randomised, placebo-controlled, double-blind, parallel-arm, event-driven 
study with an up to 24-week treatment time. It will be performed in approximately 100 sites 
across approximately 14 countries.

Participants aged 40 to 80 years inclusive, with confirmed moderate to severe 
symptomatic COPD (forced expiratory volume in 1 second [FEV1]/forced vital capacity 
[FVC] < 0.7, ≥10 pack-years smoking history, and post-BD FEV1 ≥ 25% predicted) who 
are at high risk of exacerbations despite being maintained on optimised standard of care 
(SoC) inhaled therapies (triple inhaled therapy [ICS + LABA + LAMA] or ICS + LABA 
dual therapy or LABA + LAMA dual therapy for participants who are deemed unsuitable 
for ICS) will be enrolled. Being at high risk of exacerbations is defined as participants 
fulfilling one or more of the following criteria:
-
≥1 moderate or severe exacerbation in the last 2 years (defined as requiring systemic 
corticosteroids and/or antibiotics for at least 3 days’ duration [or 1 injection of depot 
formulation], or hospitalisation for reason of acute exacerbation of COPD (AECOPD) 
in the 24 months prior to screening).
-
Frequent productive cough defined as positive answers to both of the following 
2 questions:1
o
Over the past 3 months, I have coughed at least several days a week 
o
Over the past 3 months, I have brought up phlegm (sputum) at least several days 
a week
-
Post-BD FEV1 of < 50% predicted
                                               
1 Used with the permission of the St. George's Respiratory Questionnaire Steering Committee


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
23 of 187

The study will explore an alternative community-based patient recruitment in some 
countries, utilising a network of Primary Care and Community COPD/Pulmonary 
Rehabilitation facilities to boost enrolment. The target countries with established 
Community COPD Clinic/Pulmonary Rehabilitation infrastructure will serve as 
participant recruitment centres or new sites.

To reduce the burden on participants, Visits SV2, SV4, SV7/EDV, and SV8 will have a 
limited number of assessments and shortened duration, and Visit SV6 will be a “virtual 
visit” which will be performed away from the study site. This will be conducted over a 
telemedicine video conferencing facility based on technology provided by Zoom Inc 
(San Jose, California, USA), through the UNIFY platform, using a provisioned handheld 
device. 
Cough Monitoring Substudy
A cough monitoring substudy will be performed alongside this study. In the cough substudy, a 
subset of participants (up to approximately 50 participants from each arm) from selected sites 
will be included. Twenty-four-hour cough frequency monitoring will be conducted at start of 
treatment (Visit SV3) and after 12 weeks of treatment (Visit SV5) using the VitaloJAK®
Cough Monitor device. The substudy will also investigate whether average cough frequency is 
associated with lung function (eg, peak expiratory flow [PEF] or FEV1), cough/COPD 
symptom scores (eg, Breathlessness, Cough and Sputum Scale [BCSS], COPD Assessment 
Test [CAT] and Cough Visual Analogue Scale [VAS]) and sputum/blood biomarkers (eg, MPO 
concentration, neutrophil activation markers).
Q-SAW Substudy
The Q-SAW substudy will be performed alongside this study. In the Q-SAW substudy, a 
subset of approximately 40 participants from selected sites in selected countries will be 
included. Two remote, qualitative, semi-structured interviews will be conducted up to 6 weeks 
apart to provide a deeper understanding of day-to-day variations in symptoms and the impact 
of AWEs on the patient’s life. 
SPFQ Substudy
The SPFQ substudy will be performed alongside this study. Participants from selected sites in 
selected countries will have the option to provide feedback on their clinical study experience. 
Participants will complete the SPFQ in electronic format on the UNIFY platform at SV3, SV5, 
and SV7/EDV, using a provisioned handheld device. The aim of the substudy is to gain an 
understanding of patient experience in clinical studies and identify where improvements can 
be made in the clinical study process. 
Patient Experience Interview Substudy
The patient experience interview substudy will be performed alongside this study and the data 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
24 of 187
from this qualitative substudy will complement the data from the quantitative SPFQ. In the 
patient experience interview substudy approximately 20 participants in total, from selected 
sites in selected countries, will be invited to attend a remote, semi-structured interview. The 
aims of the substudy are to understand how participant experience can be improved and to 
gain further insight into the participant perceptions and experiences of the digital technology 
used, including the virtual spirometry.
Brief Summary:
The purpose of this study is to measure benefit and safety of orally administered mitiperstat 
(AZD4831) as compared to orally administered placebo in participants with COPD. It is 
hypothesised that mitiperstat (AZD4831) will reduce airway inflammation and tissue damage, 
which could potentially lead to an improvement in lung function and/or reduce rate of decline 
in lung function.
Study details include:

The study duration will be up to 30 weeks.

The treatment duration will be up to 24 weeks.
Disclosure Statement: This is a parallel -group treatment study with 2 arms that is participant, 
investigator, and sponsor blinded.

Number of Participants: Approximately 677 participants will be screened to achieve 
406 randomised/assigned to study intervention and 406 evaluable participants.

Participants will be randomised 1:1 to mitiperstat (AZD4831) 5 mg QD or placebo QD.

Randomisation will be stratified by country.

Enrolment will be stopped after at least 194 first COPDCompEx events have occurred. At 
this point, all participants enrolled in the study that have not yet completed SV5 should 
continue in the study to complete 12 weeks of treatment. For these participants SV5 and 
SV7/EDV should be combined into one visit. Participants who have already completed 
12 weeks of treatment when study enrolment is stopped should attend SV7/EDV as soon 
as possible, continuing treatment until they do. All participants should attend 
SV8 14 ± 3 days after SV7/EDV.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
25 of 187
Screened
Estimated 677 participants, assuming a 
screen failure rate of 40%
Randomised/assigned
Estimated 406 participants
Evaluable participants
Estimated 406 participants 
Note: “Screened” means a participant’s, or their legally acceptable representative’s, 
agreement to participate in a clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility for 
the study but are not randomised/assigned in the study, are considered “screen failures”, unless 
otherwise specified by the protocol.
Study Arms and Duration:
The entire study period is planned to take between 18 and 30 weeks for each individual 
participant: a 4-week screening period, minimum 12 weeks to a maximum 24 weeks of 
dosing, and 2 weeks of follow-up. The participant will be randomised into either mitiperstat 
(AZD4831) 5 mg or placebo treatment in the form of an oral tablet, taken once daily. 
Data Monitoring/Other Committees: Yes

Unblinded Review Committee A URC will be set up to perform an administrative IA on 
the primary efficacy endpoint (time to first COPDCompEx event).

Data Review Committee A DRC will be set up to conduct periodic safety monitoring, 
with a focus on skin reactions and pneumonia. The DRC will assess safety and will have 
access to IA outcome data (including all adverse event data). 
Statistical Methods 

The study is powered using COPDCompEx, a composite endpoint used to predict 
treatment effect on moderate and severe exacerbations of COPD. COPDCompEx captures 
clinically relevant deteriorations (diary events [eg, PEF], reliever use, symptoms, 
exacerbation events, and study dropouts resulting from a lack of efficacy) that fulfil 
specific criteria in terms of changes from baseline and deterioration over 5 days, 
combined with exacerbations, and 3-month COPDCompEx treatment effects have been 
shown to reflect treatment effects on exacerbations at 6 to 12 months. 

A total of 194 first COPDCompEx events (estimated to require 203 participants per arm)
will provide 80% power at the two-sided 10% level of statistical significance to detect a 
hazard ratio of 0.70 in the mitiperstat (AZD4831) 5 mg QD arm based on a 24-week first 
COPDCompEx event risk of 55% assumed in the placebo arm (constant over the course 
of the study). 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
26 of 187

The primary objective is to evaluate the effect of mitiperstat (AZD4831) as compared to 
placebo on the time to first COPDCompEx event in participants with moderate to severe 
COPD. The primary endpoint will be time to first COPDCompEx event. A logrank test 
and Cox’s proportional hazards model will be used to analyse the time to first 
COPDCompEx event data. 
A similar approach to that described for the primary efficacy endpoint will be applied to the 
secondary endpoint: time to first exacerbation.

Other secondary assessments of efficacy include: time to first COPD exacerbation event, 
post-BD FEV1 at Week 12 compared to Week 1, MPO level and activity in sputum at 
Week 12 compared to baseline, and symptom scores.

Plasma concentrations will be summarised by timepoint in all participants. 
Pharmacokinetic (PK) data for those participants with additional PK sampling at Visit 
SV5 will be used to derive plasma PK parameters such as maximum concentration (Cmax) 
and time to reach maximum concentration (tmax).

An administrative IA will be conducted by the URC after 136 (70% of the required 194) 
first COPDCompEx events have occurred. It will allow an early assessment of efficacy 
for mitiperstat (AZD4831) used for further development of this drug programme, based 
on the predictive probability of success, according to the decision framework and safety. 
No formal statistical test will be conducted, and no alpha will be spent at the IA.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
27 of 187
1.2
Schema
Figure 1
Study Design
a
SV1 assessments may occur at any time during screening, including SV2, all must occur within the screening window. Informed consent must be obtained 
before any study procedure. Informed consent can be taken prior to SV1.
b
To reduce the burden on participants, Visits SV2, SV4, SV7/EDV, and SV8 will have a limited number of assessments and shortened duration.
c
Visit SV2 should occur 14 to 16 days before SV3 (Day 1).
d
Participants discontinuing study intervention before SV7 should attend site for SV7 assessments as soon as possible as an EDV, then attend for SV8 
assessments 14 (± 3) days later.
Enrolment will be stopped after at least 194 first COPDCompEx events have occurred. At this point, all participants enrolled in the study that have not yet 
completed SV5 should continue in the study to complete 12 weeks of treatment. For these participants SV5 and SV7 should be combined into one visit. 
Participants who have already completed 12 weeks of treatment when study enrolment is stopped should attend SV7 as soon as possible, continuing treatment 
until they do. All participants should attend SV8 14 ± 3 days after SV7/EDV.
EDV = early discontinuation visit; FU = follow-up; SoC = standard of care; SV = Study Visit.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
28 of 187
1.3
Schedule of Activities
Table 1
Schedule of Activities
Procedure
Screening 
(up to 28 days 
before Day 1)
Intervention Period
Follow-up 
Period
Notes
Details in 
protocol 
section or 
appendix
Visit
SV1
SV2
SV3
SV4
SV5
SV6
(VV)a
SV7/
EDV b
SV8
Study procedures should take place prior to 
dosing, unless specified otherwise.
Participants discontinuing study intervention 
before SV7 should attend the site for SV7 
assessments as soon as possible as an EDV.
See Section 7.1.4 for details of study end when 
the last participant has completed 12 weeks of 
treatment.
Visits SV2, SV4, SV7/EDV, and SV8 are visits 
with a reduced number of assessments. SV6 is 
a virtual visit.
Weeks
-4
-2
1
4
12
18
24
+ 2 post-
SV7/EDV
Visit Day (window) (days)
-28 to 
-14
-16 to 
-14
1
28 
(± 3)
84 
(± 3)
126 
(± 3)
168 
(± 3)
+ 14 post-
SV7/EDV 
(± 3)
All Day 1 (SV3) assessments must be collected 
pre-dose unless otherwise stated. SV1 
assessments may occur at any time during 
screening, including SV2, all must occur 
within the screening window. Informed consent 
must be obtained before any study procedure.
Written informed 
consent/assignment of E-code
X
Informed consent can be taken prior to SV1.
Appendix A 3
Written informed consent for 
future use and/or genetic
X
Appendix D
Written informed consent for 
Cough substudy
X
Required only for participants of the cough 
substudy.
Written informed consent for the 
Q-SAW substudy
X
Required only for participants of the Q-SAW 
substudy at selected sites. Consent can be 
obtained any time up until SV5.
Appendix L


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
29 of 187
Procedure
Screening 
(up to 28 days 
before Day 1)
Intervention Period
Follow-up 
Period
Notes
Details in 
protocol 
section or 
appendix
Visit
SV1
SV2
SV3
SV4
SV5
SV6
(VV)a
SV7/
EDV b
SV8
Study procedures should take place prior to 
dosing, unless specified otherwise.
Participants discontinuing study intervention 
before SV7 should attend the site for SV7 
assessments as soon as possible as an EDV.
See Section 7.1.4 for details of study end when 
the last participant has completed 12 weeks of 
treatment.
Visits SV2, SV4, SV7/EDV, and SV8 are visits 
with a reduced number of assessments. SV6 is 
a virtual visit.
Weeks
-4
-2
1
4
12
18
24
+ 2 post-
SV7/EDV
Visit Day (window) (days)
-28 to 
-14
-16 to 
-14
1
28 
(± 3)
84 
(± 3)
126 
(± 3)
168 
(± 3)
+ 14 post-
SV7/EDV 
(± 3)
All Day 1 (SV3) assessments must be collected 
pre-dose unless otherwise stated. SV1 
assessments may occur at any time during 
screening, including SV2, all must occur 
within the screening window. Informed consent 
must be obtained before any study procedure.
Informed consent for SPFQ 
substudy
X
X
X
Required only for participants of the SPFQ 
substudy at selected sites. Informed consent 
given within the UNIFY platform, using a 
provisioned handheld device.
Appendix M
Written Informed consent for the 
Patient Experience Interview 
substudy
X
Required only for participants of the Patient 
Experience Interview substudy at selected 
sites. Consent can be obtained any time up 
until SV7.
Appendix N
Verify eligibility criteria
X
X
X
5
Randomisation
X
6.3


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
30 of 187
Procedure
Screening 
(up to 28 days 
before Day 1)
Intervention Period
Follow-up 
Period
Notes
Details in 
protocol 
section or 
appendix
Visit
SV1
SV2
SV3
SV4
SV5
SV6
(VV)a
SV7/
EDV b
SV8
Study procedures should take place prior to 
dosing, unless specified otherwise.
Participants discontinuing study intervention 
before SV7 should attend the site for SV7 
assessments as soon as possible as an EDV.
See Section 7.1.4 for details of study end when 
the last participant has completed 12 weeks of 
treatment.
Visits SV2, SV4, SV7/EDV, and SV8 are visits 
with a reduced number of assessments. SV6 is 
a virtual visit.
Weeks
-4
-2
1
4
12
18
24
+ 2 post-
SV7/EDV
Visit Day (window) (days)
-28 to 
-14
-16 to 
-14
1
28 
(± 3)
84 
(± 3)
126 
(± 3)
168 
(± 3)
+ 14 post-
SV7/EDV 
(± 3)
All Day 1 (SV3) assessments must be collected 
pre-dose unless otherwise stated. SV1 
assessments may occur at any time during 
screening, including SV2, all must occur 
within the screening window. Informed consent 
must be obtained before any study procedure.
Optional high-resolution CT scan
X
The optional high-resolution CT scan could be 
performed as soon as main eligibility criteria 
are confirmed at SV1 which include blood test 
results, up to randomisation. If a CT scan is 
performed during the study, the local CT scan 
report must be obtained before randomisation.
8.2.7
Demography
X
Medical and COPD history
X
Assessment of COPD 
exacerbations
X
X
X
X
X
X
8.2.2
Smoking history
X
X
Includes e-cigarettes


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
31 of 187
Procedure
Screening 
(up to 28 days 
before Day 1)
Intervention Period
Follow-up 
Period
Notes
Details in 
protocol 
section or 
appendix
Visit
SV1
SV2
SV3
SV4
SV5
SV6
(VV)a
SV7/
EDV b
SV8
Study procedures should take place prior to 
dosing, unless specified otherwise.
Participants discontinuing study intervention 
before SV7 should attend the site for SV7 
assessments as soon as possible as an EDV.
See Section 7.1.4 for details of study end when 
the last participant has completed 12 weeks of 
treatment.
Visits SV2, SV4, SV7/EDV, and SV8 are visits 
with a reduced number of assessments. SV6 is 
a virtual visit.
Weeks
-4
-2
1
4
12
18
24
+ 2 post-
SV7/EDV
Visit Day (window) (days)
-28 to 
-14
-16 to 
-14
1
28 
(± 3)
84 
(± 3)
126 
(± 3)
168 
(± 3)
+ 14 post-
SV7/EDV 
(± 3)
All Day 1 (SV3) assessments must be collected 
pre-dose unless otherwise stated. SV1 
assessments may occur at any time during 
screening, including SV2, all must occur 
within the screening window. Informed consent 
must be obtained before any study procedure.
Physical examination
X
X
X
X
Brief physical examination, except at SV3 
(Day 1) and discontinuation visit, where a full 
physical examination is required.
Additional assessments may be performed as 
clinically indicated.
8.3.1
Weight, height
X
X
ECG
X
X
X
8.3.3
Vital signs
X
X
X
X
X
X
8.3.2
Lying and standing (orthostatic) BP 
test
X
X
Assessed at SV3 and SV5 prior to any required 
blood draw or study intervention. Also to be 
assessed 1 to 2 hours post dose at SV3. 
Orthostatic BP will be measured 1 and 3 
minutes after the participant stands.
8.3.2


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
32 of 187
Procedure
Screening 
(up to 28 days 
before Day 1)
Intervention Period
Follow-up 
Period
Notes
Details in 
protocol 
section or 
appendix
Visit
SV1
SV2
SV3
SV4
SV5
SV6
(VV)a
SV7/
EDV b
SV8
Study procedures should take place prior to 
dosing, unless specified otherwise.
Participants discontinuing study intervention 
before SV7 should attend the site for SV7 
assessments as soon as possible as an EDV.
See Section 7.1.4 for details of study end when 
the last participant has completed 12 weeks of 
treatment.
Visits SV2, SV4, SV7/EDV, and SV8 are visits 
with a reduced number of assessments. SV6 is 
a virtual visit.
Weeks
-4
-2
1
4
12
18
24
+ 2 post-
SV7/EDV
Visit Day (window) (days)
-28 to 
-14
-16 to 
-14
1
28 
(± 3)
84 
(± 3)
126 
(± 3)
168 
(± 3)
+ 14 post-
SV7/EDV 
(± 3)
All Day 1 (SV3) assessments must be collected 
pre-dose unless otherwise stated. SV1 
assessments may occur at any time during 
screening, including SV2, all must occur 
within the screening window. Informed consent 
must be obtained before any study procedure.
Collection of AEs/SAEs
X
X
X
X
X
X
X
X
Participants should be reminded at each visit to 
contact the investigator immediately, if rash or 
skin reaction has developed.
Non-Serious AEs will be collected from the 
first dose of study intervention onwards (see 
Section 8.4.1 for exception for pre-dose 
orthostatic test at SV3). 
SAEs will be collected from signing of the 
ICF.
8.4
Adherence to regular medications 
confirmed
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
6.9


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
33 of 187
Procedure
Screening 
(up to 28 days 
before Day 1)
Intervention Period
Follow-up 
Period
Notes
Details in 
protocol 
section or 
appendix
Visit
SV1
SV2
SV3
SV4
SV5
SV6
(VV)a
SV7/
EDV b
SV8
Study procedures should take place prior to 
dosing, unless specified otherwise.
Participants discontinuing study intervention 
before SV7 should attend the site for SV7 
assessments as soon as possible as an EDV.
See Section 7.1.4 for details of study end when 
the last participant has completed 12 weeks of 
treatment.
Visits SV2, SV4, SV7/EDV, and SV8 are visits 
with a reduced number of assessments. SV6 is 
a virtual visit.
Weeks
-4
-2
1
4
12
18
24
+ 2 post-
SV7/EDV
Visit Day (window) (days)
-28 to 
-14
-16 to 
-14
1
28 
(± 3)
84 
(± 3)
126 
(± 3)
168 
(± 3)
+ 14 post-
SV7/EDV 
(± 3)
All Day 1 (SV3) assessments must be collected 
pre-dose unless otherwise stated. SV1 
assessments may occur at any time during 
screening, including SV2, all must occur 
within the screening window. Informed consent 
must be obtained before any study procedure.
Clinic spirometry (post-BD)
X
X
X
X
X
Participants should bring their spirometer with 
them to all on-site visits. Screening spirometry 
at SV1 will be conducted using the spirometry 
equipment supplied to clinic.
In the event that an adequate quality, maximal 
effort spirometry effort cannot be obtained at 
the first attempt during a study visit, a further 
reattempt is allowed (see Section 8.2.3).
8.2.3
Virtual spirometry (post-BD)
X
X
X
X
8.2.3
Provision and training on use of 
spirometer and e-Diary
X
Compliance to COPDCompEx (e-Diary) 
should be assessed at each study visit. 
Participants must demonstrate a compliance of 
at least 70% during the 14 days preceding SV3 
to be eligible for randomisation.
8.2.3, 8.2.6
Assess adherence to the 
completion of e-Diary entries and 
home device use
X
X
X
X
X


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
34 of 187
e-Diary and PEF 
(2 × daily recording) c
D=distribute, R=Return
D
R
During the study treatment period, daily 
e-Diary compliance is critical for overall 
symptom rating, reliever medication use, and 
change in PEF. The investigator/authorised 
delegate should check the participant’s 
adherence to the daily e-Diary at each visit and 
remotely at any time during the study. If it 
drops below 80% to 85%, sites should take 
steps to ask the participant about the reason 
and to encourage the participant to regularly 
complete the e-Diary.
If compliance does not improve, or there is 
reason why the assessments cannot be 
completed (eg. temporary discontinuation or 
hospitalisation), the AstraZeneca study team 
should be contacted for discussion. 
Participants who fail to meet compliance rate 
may be rescreened once only. 
The baseline for COPDCompEx will be 
estimated during the period between SV2 and 
SV3.
Participants should bring their spirometer and 
the device with the e-Diary on to all on-site 
visits.
e-Diary and PEF will be recorded up until the 
day of SV7 or EDV.
Cough VAS assessment
Cough VAS assessment will be recorded up 
until the day of SV7 or EDV.
8.2.4
CAT
X
X
X
8.2.5
EXACT
X
X
X
8.2.4
BCSS (daily)
BCSS (daily) assessment will be recorded up 
until the day of SV7 or EDV.
Serum chemistry 
X
X
X
X
X
X
8.3.4
T3, T4, TSH
X
X
X
X
X
Systemic biomarkers of 
X
X
X
8.8


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
35 of 187
Procedure
Screening 
(up to 28 days 
before Day 1)
Intervention Period
Follow-up 
Period
Notes
Details in 
protocol 
section or 
appendix
Visit
SV1
SV2
SV3
SV4
SV5
SV6
(VV)a
SV7/
EDV b
SV8
Study procedures should take place prior to 
dosing, unless specified otherwise.
Participants discontinuing study intervention 
before SV7 should attend the site for SV7 
assessments as soon as possible as an EDV.
See Section 7.1.4 for details of study end when 
the last participant has completed 12 weeks of 
treatment.
Visits SV2, SV4, SV7/EDV, and SV8 are visits 
with a reduced number of assessments. SV6 is 
a virtual visit.
Weeks
-4
-2
1
4
12
18
24
+ 2 post-
SV7/EDV
Visit Day (window) (days)
-28 to 
-14
-16 to 
-14
1
28 
(± 3)
84 
(± 3)
126 
(± 3)
168 
(± 3)
+ 14 post-
SV7/EDV 
(± 3)
All Day 1 (SV3) assessments must be collected 
pre-dose unless otherwise stated. SV1 
assessments may occur at any time during 
screening, including SV2, all must occur 
within the screening window. Informed consent 
must be obtained before any study procedure.
cardiovascular comorbidities
Blood sample for target 
engagement assay
X
X
Performed in a subsample of approximately 60 
participants in selected countries.
8.6
Whole blood RNA PAXgene 
collection for mRNA analyses
X
X
8.8.1
Haematology 
X
X
X
X
X
X
8.3.4
Plasma sample for proteomics
X
X
8.8.1


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
36 of 187
Procedure
Screening 
(up to 28 days 
before Day 1)
Intervention Period
Follow-up 
Period
Notes
Details in 
protocol 
section or 
appendix
Visit
SV1
SV2
SV3
SV4
SV5
SV6
(VV)a
SV7/
EDV b
SV8
Study procedures should take place prior to 
dosing, unless specified otherwise.
Participants discontinuing study intervention 
before SV7 should attend the site for SV7 
assessments as soon as possible as an EDV.
See Section 7.1.4 for details of study end when 
the last participant has completed 12 weeks of 
treatment.
Visits SV2, SV4, SV7/EDV, and SV8 are visits 
with a reduced number of assessments. SV6 is 
a virtual visit.
Weeks
-4
-2
1
4
12
18
24
+ 2 post-
SV7/EDV
Visit Day (window) (days)
-28 to 
-14
-16 to 
-14
1
28 
(± 3)
84 
(± 3)
126 
(± 3)
168 
(± 3)
+ 14 post-
SV7/EDV 
(± 3)
All Day 1 (SV3) assessments must be collected 
pre-dose unless otherwise stated. SV1 
assessments may occur at any time during 
screening, including SV2, all must occur 
within the screening window. Informed consent 
must be obtained before any study procedure.
PK blood sampling for mitiperstat 
(AZD4831)
X
(pre-
dose)
X
(pre-
dose)
EDV 
only
In a subset of participants (approximately 
20%), 2 additional post-dose samples will be 
collected at SV5. SV5 sample collection times 
are: pre-dose, 0.5 to 1.5 h, and 1.5 to 3 h, with 
a minimum of 1 hour between the post-dose 
sampling occasions. Once approximately 20% 
of participants have been tested, no further 
participants need this additional post-dose 
sampling. For participants who are 
discontinued from investigational product due 
to rash, a PK sample should be collected at the 
discontinuation Visit.
8.5.1
Exploratory biomarkers (blood) 
X
X
X
X
8.8
Blood and urine sample for 
exploratory metabolite analysis 
EDV 
only
Participants who discontinue study 
intervention due to rash or skin reaction only, 
at EDV. 
8.8.1


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
37 of 187
Procedure
Screening 
(up to 28 days 
before Day 1)
Intervention Period
Follow-up 
Period
Notes
Details in 
protocol 
section or 
appendix
Visit
SV1
SV2
SV3
SV4
SV5
SV6
(VV)a
SV7/
EDV b
SV8
Study procedures should take place prior to 
dosing, unless specified otherwise.
Participants discontinuing study intervention 
before SV7 should attend the site for SV7 
assessments as soon as possible as an EDV.
See Section 7.1.4 for details of study end when 
the last participant has completed 12 weeks of 
treatment.
Visits SV2, SV4, SV7/EDV, and SV8 are visits 
with a reduced number of assessments. SV6 is 
a virtual visit.
Weeks
-4
-2
1
4
12
18
24
+ 2 post-
SV7/EDV
Visit Day (window) (days)
-28 to 
-14
-16 to 
-14
1
28 
(± 3)
84 
(± 3)
126 
(± 3)
168 
(± 3)
+ 14 post-
SV7/EDV 
(± 3)
All Day 1 (SV3) assessments must be collected 
pre-dose unless otherwise stated. SV1 
assessments may occur at any time during 
screening, including SV2, all must occur 
within the screening window. Informed consent 
must be obtained before any study procedure.
Genomics Initiative optional, 
exploratory genetic sample
X
Sample for genetic analysis can be taken at any 
visit.
8.7, 
Appendix D
Coagulation parameters 
X
8.3.4
Blood sample for cell-free DNA 
analysis (optional)
X
X
8.8.2
Hepatitis B, C; HIV-1; virology 
X
8.3.4
FSH (if needed to confirm 
post-menopausal status in female 
participants aged < 50 years) 
X
8.3.4
Nasal mucosal lining fluid 
X
X
8.8.1


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
38 of 187
Procedure
Screening 
(up to 28 days 
before Day 1)
Intervention Period
Follow-up 
Period
Notes
Details in 
protocol 
section or 
appendix
Visit
SV1
SV2
SV3
SV4
SV5
SV6
(VV)a
SV7/
EDV b
SV8
Study procedures should take place prior to 
dosing, unless specified otherwise.
Participants discontinuing study intervention 
before SV7 should attend the site for SV7 
assessments as soon as possible as an EDV.
See Section 7.1.4 for details of study end when 
the last participant has completed 12 weeks of 
treatment.
Visits SV2, SV4, SV7/EDV, and SV8 are visits 
with a reduced number of assessments. SV6 is 
a virtual visit.
Weeks
-4
-2
1
4
12
18
24
+ 2 post-
SV7/EDV
Visit Day (window) (days)
-28 to 
-14
-16 to 
-14
1
28 
(± 3)
84 
(± 3)
126 
(± 3)
168 
(± 3)
+ 14 post-
SV7/EDV 
(± 3)
All Day 1 (SV3) assessments must be collected 
pre-dose unless otherwise stated. SV1 
assessments may occur at any time during 
screening, including SV2, all must occur 
within the screening window. Informed consent 
must be obtained before any study procedure.
Spontaneous sputum 
X
X
Collect sputum supernatant for target 
engagement and exploratory biomarkers.
Sputum differential cell count should only be 
determined at SV3 (baseline) and only at sites 
with the appropriate equipment.
Participants may use a flutter device (in clinic 
only) during sputum collection to make the 
sputum more accessible when they cough.
8.6, 8.8.1
Urinalysis 
X
X
X
8.3.4
Study intervention dispensation
X
X
X
6
Study intervention dosing

Home administration once daily in 
the morning by the participant

Study intervention can be taken with or 
without food. 
On days with an on-site visit, participant 
should be dosed at the site during the visit.
5.3.1, 6


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
39 of 187
Procedure
Screening 
(up to 28 days 
before Day 1)
Intervention Period
Follow-up 
Period
Notes
Details in 
protocol 
section or 
appendix
Visit
SV1
SV2
SV3
SV4
SV5
SV6
(VV)a
SV7/
EDV b
SV8
Study procedures should take place prior to 
dosing, unless specified otherwise.
Participants discontinuing study intervention 
before SV7 should attend the site for SV7 
assessments as soon as possible as an EDV.
See Section 7.1.4 for details of study end when 
the last participant has completed 12 weeks of 
treatment.
Visits SV2, SV4, SV7/EDV, and SV8 are visits 
with a reduced number of assessments. SV6 is 
a virtual visit.
Weeks
-4
-2
1
4
12
18
24
+ 2 post-
SV7/EDV
Visit Day (window) (days)
-28 to 
-14
-16 to 
-14
1
28 
(± 3)
84 
(± 3)
126 
(± 3)
168 
(± 3)
+ 14 post-
SV7/EDV 
(± 3)
All Day 1 (SV3) assessments must be collected 
pre-dose unless otherwise stated. SV1 
assessments may occur at any time during 
screening, including SV2, all must occur 
within the screening window. Informed consent 
must be obtained before any study procedure.
Assess adherence to study 
intervention
X
X
X
Return of all study supplies to 
clinic
X
Cough Substudy Only
Provision of and training of use of 
VitaloJAK® Cough Monitor device
X
Required only for participants of the cough 
substudy.
8.2.7
VitaloJAK® Cough Monitor 24-
hour cough frequency
X
X


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
40 of 187
Procedure
Screening 
(up to 28 days 
before Day 1)
Intervention Period
Follow-up 
Period
Notes
Details in 
protocol 
section or 
appendix
Visit
SV1
SV2
SV3
SV4
SV5
SV6
(VV)a
SV7/
EDV b
SV8
Study procedures should take place prior to 
dosing, unless specified otherwise.
Participants discontinuing study intervention 
before SV7 should attend the site for SV7 
assessments as soon as possible as an EDV.
See Section 7.1.4 for details of study end when 
the last participant has completed 12 weeks of 
treatment.
Visits SV2, SV4, SV7/EDV, and SV8 are visits 
with a reduced number of assessments. SV6 is 
a virtual visit.
Weeks
-4
-2
1
4
12
18
24
+ 2 post-
SV7/EDV
Visit Day (window) (days)
-28 to 
-14
-16 to 
-14
1
28 
(± 3)
84 
(± 3)
126 
(± 3)
168 
(± 3)
+ 14 post-
SV7/EDV 
(± 3)
All Day 1 (SV3) assessments must be collected 
pre-dose unless otherwise stated. SV1 
assessments may occur at any time during 
screening, including SV2, all must occur 
within the screening window. Informed consent 
must be obtained before any study procedure.
Q-SAW Substudy Only
Qualitative semi-structured 
interviews
X
Two semi-structured interviews may be 
conducted up to 6 weeks apart. Required only 
for participants of the Q-SAW substudy at 
selected sites.
Appendix L
SPFQ Substudy Only
SPFQ 
X
X
X
Required only for participants of the SPFQ 
substudy at selected sites.
Appendix M
Patient Experience Interview Substudy Only


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
41 of 187
Procedure
Screening 
(up to 28 days 
before Day 1)
Intervention Period
Follow-up 
Period
Notes
Details in 
protocol 
section or 
appendix
Visit
SV1
SV2
SV3
SV4
SV5
SV6
(VV)a
SV7/
EDV b
SV8
Study procedures should take place prior to 
dosing, unless specified otherwise.
Participants discontinuing study intervention 
before SV7 should attend the site for SV7 
assessments as soon as possible as an EDV.
See Section 7.1.4 for details of study end when 
the last participant has completed 12 weeks of 
treatment.
Visits SV2, SV4, SV7/EDV, and SV8 are visits 
with a reduced number of assessments. SV6 is 
a virtual visit.
Weeks
-4
-2
1
4
12
18
24
+ 2 post-
SV7/EDV
Visit Day (window) (days)
-28 to 
-14
-16 to 
-14
1
28 
(± 3)
84 
(± 3)
126 
(± 3)
168 
(± 3)
+ 14 post-
SV7/EDV 
(± 3)
All Day 1 (SV3) assessments must be collected 
pre-dose unless otherwise stated. SV1 
assessments may occur at any time during 
screening, including SV2, all must occur 
within the screening window. Informed consent 
must be obtained before any study procedure.
Qualitative semi-structured 
interview
X
A semi-structured interview will be conducted 
in a subsample of participants, stratified over 
the study duration starting after at least 2 study 
visits, ie, after SV4. Required only for 
participants of the patient experience interview 
substudy at selected sites.
Appendix N
a
For virtual visit of SV6, this will be conducted over telemedicine video conferencing facility based on technology provided by Zoom Inc (San Jose, California, USA), 
through the UNIFY platform, using a provisioned handheld device.
b
SV7/EDV timepoint is SV7 or EDV. Participants discontinuing study intervention before SV7 should attend the site for SV7 assessments as soon as possible as an EDV.
c
The morning and evening diaries that include cough VAS and BCSS start the day after SV2.
AE = Adverse event; BCSS = Breathlessness, Cough and Sputum Scale; BD = Bronchodilator; BP = Blood pressure; CAT = COPD Assessment Test; COPD = Chronic obstructive 
pulmonary disease; COPDCompEx = COPD Composite Exacerbations (composite measure of chronic obstructive pulmonary disease); CSP = Clinical Study Protocol; CT = 
Computed tomography; DNA = Deoxyribonucleic acid; ECG = Electrocardiogram; EDV = early discontinuation visit; EXACT = The Exacerbations of Chronic Pulmonary 
Disease Tool; FSH = Follicle stimulating hormone; ICF = Informed consent form; HIV = Human immunodeficiency disease; MPO = Myeloperoxidase; mRNA = Messenger 
ribonucleic acid; PEF = Peak expiratory flow; PK = Pharmacokinetic; Q-SAW = Qualitative; RNA = Ribonucleic acid; SAE = Serious adverse event; SPFQ = Study Participant 
Feedback Questionnaire; SV = Study visit; T3 = Triiodothyronine; T4 = Thyroxine; TSH = Thyroid stimulating hormone; VAS = Visual analogue scale; VV = Virtual visit.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
42 of 187
2
INTRODUCTION
Mitiperstat (AZD4831) is a potent, selective, irreversible, and dose-dependent inhibitor of 
MPO that is being developed for once daily treatment of COPD.
2.1
Study Rationale
This study will evaluate the efficacy and safety of the MPO inhibitor mitiperstat (AZD4831) 
in the treatment of moderate to severe COPD. Patients with COPD represent a huge unmet 
medical need: COPD exacerbations are associated with accelerated decline in lung function, 
high mortality, worsening quality of life and comorbidities, and high healthcare costs. In 
addition, COPD is also frequently associated with other metabolic or cardiovascular 
comorbidities, which also contribute to impaired quality of life and poorer survival. 
Furthermore, current COPD therapies, which include combinations of inhaled LABA, LAMA, 
and ICS, and add-on anti-inflammatory agents, do not eliminate symptoms, disability, 
exacerbations, or the hospitalisations that are associated with COPD, and do not significantly 
alter the course of COPD.
Preclinical smoke exposed animal models have shown that inhibition of MPO can halt the 
progression of emphysema and small airways remodelling (Churg et al 2012). In patients with 
COPD, higher sputum MPO is associated with increased risk of subsequent exacerbation of 
COPD, whilst a meta-analysis showed that sputum MPO levels are higher during 
exacerbation, compared to stable COPD. Persisting elevation of MPO during an exacerbation 
is associated with reduced response to therapy and more prolonged symptoms 
(Zhu et al 2014). Therefore, this study and the clinical development program for mitiperstat 
(AZD4831) will evaluate whether treating patients with COPD with mitiperstat (AZD4831) 
reduces exacerbations, and improves symptoms, quality of life, lung function, and other 
clinically relevant outcomes including comorbidities in patients with COPD.
2.2
Background
Chronic obstructive pulmonary disease is a common, chronic pulmonary disease which is 
characterised by airflow obstruction that is only partly reversible, and usually progressive and 
associated with a decline in lung function (Celli and Wedzicha 2019). Chronic obstructive 
pulmonary disease is now the third most common cause of death worldwide (WHO 2021). It 
is also associated with high morbidity and comorbidity and is currently the fifth leading cause 
of DALYs worldwide. Chronic obstructive pulmonary disease is also associated with an 
enormous economic burden, costing ~$50 billion in direct and indirect healthcare costs in the 
USA alone (Adeloye et al 2015).
Chronic obstructive pulmonary disease is caused by a complex interaction between genetics, 
early life, and ongoing environmental exposure. The major environmental risk factor is 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
43 of 187
inhaling cigarette smoke and/or other pollutants, which trigger a chronic inflammatory 
response in the lung that is associated with increased lung levels of oxidative stress and 
proteolytic injury leading to various pathologic changes in the lung that are heterogeneously 
expressed by patients. Patients with COPD can have varying combinations of destruction of 
the alveolar walls (or emphysema), small airway remodelling, and/or changes in the large 
airway (which manifests clinically as a frequent productive cough characteristic of the chronic 
bronchitis phenotype) that vary in severity between patients. The course of COPD can be 
punctuated by acute exacerbations of COPD which are defined as a sustained worsening of the 
patient’s condition from the stable state, and beyond normal day-to-day variations, that is 
acute in onset and necessitates a change in regular medication in a patient with underlying 
COPD. The initial exacerbation leading to hospitalisation in a patient with COPD is 
considered a seminal event for the patient as it heralds the onset of subsequent exacerbations 
that increase in frequency, and 50% of patients die within 3.6 years of their initial 
exacerbation (Suissa et al 2012).
In addition, COPD is also frequently associated with other metabolic or cardiovascular 
comorbidities, which also contribute to impaired quality of life and poorer survival. There is 
considerable overlap in the patterns of systemic vascular inflammation seen in COPD and that 
of advancing atherosclerotic disease and heart failure.
For these reasons, patients with COPD represent a huge unmet medical need.
Mitiperstat (AZD4831) is a potent, selective, irreversible, and dose-dependent inhibitor of 
MPO. Myeloperoxidase is a heme-containing enzyme that is stored within the granules of 
neutrophils. Myeloperoxidase catalyses the oxidation of halide ions by hydrogen peroxide 
leading to the generation of hypohalous acids which are potent oxidants. Under normal 
conditions, MPO and the hypohalous acids that it generates within neutrophil granules make 
crucial contributions to killing of phagocytosed bacteria. However, during excessive 
inflammation, neutrophil granule contents are extruded, and the extracellular hypohalous acids 
generated by MPO promote lung inflammation and injure the lung. Delivering an MPO 
inhibitor to guinea pigs that were exposed to cigarette smoke for 6 months reduced lung 
oxidative stress levels and lung inflammation and also halted the progression of emphysema 
and small airway fibrosis in the animals (Churg et al 2012) indicating that MPO activity 
contributes significantly to the pathogenesis of COPD-like disease in animals. MPO has also 
been linked to human COPD as MPO levels in sputum are elevated in patients with COPD 
versus controls and increase further during exacerbations (Zhu et al 2014). In addition, 
extracellular MPO serum levels are indirectly related to rate of decline in FEV1 
(Park et al 2013). Finally, preliminary results for mitiperstat (AZD4831) in related 
cardiovascular studies have shown an acceptable benefit/risk profile of this compound and 
suggest potential benefits in comorbid conditions commonly associated with COPD. Thus, the 
clinical development program for mitiperstat (AZD4831) will evaluate whether treating 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
44 of 187
patients with mitiperstat (AZD4831) reduces exacerbations, and improves symptoms, quality 
of life, lung function and other clinically-relevant outcomes and comorbidities in patients with 
COPD.
A detailed description of the chemistry, pharmacology, efficacy, and safety of mitiperstat 
(AZD4831) is provided in the Investigator’s Brochure.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
mitiperstat (AZD4831) may be found in the Investigator’s Brochure. 
2.3.1
Risk Assessment
Identified and potential risks of mitiperstat (AZD4831), along with mitigation strategies, are 
shown in Table 2.
Table 2
Risk Assessment
Potential or identified risk 
of clinical significance
Summary of data/rationale for risk 
Mitigation strategy
Study intervention Mitiperstat (AZD4831)
Identified risk
Maculopapular rash
Generalised maculopapular rash has 
been observed in healthy volunteers in 
completed global SAD/MAD studies at 
single doses of 45 mg and above and at 
repeated doses of 15 mg and above, at 
7 to 10 days post dose. In an MAD study 
in healthy Japanese and Chinese 
participants, maculopapular rash 
CTCAE Grade 1 has been reported in 
one 
 participant (of 6) on 5 mg 
mitiperstat (AZD4831); maculopapular 
rash Grade 2 in 3 
 participants 
(of 6) on 10 mg mitiperstat (AZD4831), 
and maculopapular rash Grade 2 in 1 
 participant (of 6) on 5 mg 
mitiperstat (AZD4831).
One of 27 patients in the HfpEF study 
had generalised maculopapular rash 
CTCAE Grade 3 at 5 mg mitiperstat
(AZD4831) occurring 5 days after up-
titration from 2.5 to 5 mg.
The DRC will evaluate all cases of 
skin reaction/rash.
The protocol clearly states the 
actions that have to be taken by the 
investigator, in case of 
maculopapular rash (see 
Appendix B, B 5).
PPD
PPD
PPD


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
45 of 187
Table 2
Risk Assessment
Potential or identified risk 
of clinical significance
Summary of data/rationale for risk 
Mitigation strategy
Potential risks
Host defence impairment —
infections (including 
pneumonia)
The MPO in neutrophils generates ROS 
that kill microorganisms so there is a 
theoretical risk that treatment with an 
MPO inhibitor could impair 
host-defence mechanisms. 
Kutter et al 2000 reported 
7 life-threatening infections in 
MPO-deficient patients, of whom 3 had 
pneumonia.
Pneumonia occurs commonly in patients
with COPD and COPD is the strongest 
risk factor for development of 
pneumonia (Cavallazzi and Ramirez 
2020).
Humans with total or partial MPO 
deficiency generally do not have an 
increased susceptibility to infections but 
the incidence of Candida infections may 
be increased especially in patients with 
diabetes. Overall, invasive fungal 
infections such as candidaemia, 
disseminated infection, pneumonia, 
osteomyelitis, meningitis or liver abscess 
occur in fewer than 5% of 
MPO-deficient individuals 
(Antachopoulos 2010). 
An increased incidence of infection has 
not been seen with mitiperstat
(AZD4831) in healthy 
volunteers/clinical study participants.
In order to adequately assess and 
characterise the risk of pneumonia 
in participants in a nonbiased 
manner, the DRC will review all 
AEs reported as pneumonia to 
ensure appropriate pre-defined and 
clinically consistent pneumonia 
criteria are met. 
Serious infections, including 
pneumonia, to be considered 
AESI.
Thyroid peroxidase 
inhibition (hypothyroidism)
In the preclinical safety studies in rats 
and dogs, inhibition of thyroid 
peroxidase caused reversible TSH 
increase, decreases in T4 and thyroid 
follicular cell hypertrophy. These effects 
have also been observed preclinically 
and clinically with other compounds of 
the same class and the magnitude of this 
effect is related to the degree of 
selectivity between MPO and TPO. 
Clinically relevant changes in thyroid 
parameters (TSH, T3, T4) have not been 
Monitoring thyroid
parameters (TSH, T3, free T4).
Exclusion criterion 19.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
46 of 187
Table 2
Risk Assessment
Potential or identified risk 
of clinical significance
Summary of data/rationale for risk 
Mitigation strategy
seen in limited clinical data with 
mitiperstat (AZD4831).
Blood pressure reduction 
and heart rate increase
In secondary pharmacology studies, 
mitiperstat (AZD4831) was shown to be 
an inhibitor of α1A adrenoceptors. 
Inhibition of this receptor is known to 
decrease BP and cause reflex 
tachycardia. Clinically relevant changes 
in BP/HR have not been seen in clinical 
study participants on mitiperstat 
(AZD4831).
Monitoring vital signs including 
orthostatic hypotension.
Anaemia and
inflammation
One high-dose (150 mg/kg/day) dog 
developed severe clinical symptoms on 
Day 15 of dosing and did not recover 
sufficiently to allow further dosing. The 
dog was euthanised on Day 22. 
Haematology showed anaemia and 
inflammation. The cause of these 
findings is unknown. No other dogs in 
any studies with mitiperstat (AZD4831) 
showed similar symptoms or 
haematological changes. Clinically 
relevant haematological changes have 
not been seen in healthy 
volunteers/clinical study participants 
with mitiperstat (AZD4831).
Routine haematology
monitoring.
Agranulocytosis and allergic 
reactions
Potential risk based on thiourea motif in 
the mitiperstat (AZD4831) molecule and 
is known liability for antithyroid drugs 
carrying the same motif. No consistent 
findings on haematological or bone 
marrow parameters in rats and dogs. 
Agranulocytosis has not been seen in 
healthy volunteers/clinical study 
participants with mitiperstat (AZD4831).
Routine haematology
monitoring.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
47 of 187
Table 2
Risk Assessment
Potential or identified risk 
of clinical significance
Summary of data/rationale for risk 
Mitigation strategy
Renal toxicity
A renal toxicity finding was found in 
transgenic RasH2 mice in the 1-month 
DRF study.
Kidney findings included increased 
creatinine and BUN. Pathology showed 
discoloration/pale and enlarged kidney, 
increased kidney weight and 
histopathology showed renal 
degeneration/regeneration, tubular 
dilatation and granular casts.
No kidney findings were observed at 
125 mg/kg/day (NOAEL).
Clinically relevant changes in kidney 
function have not been seen in clinical 
studies.
Exclusion criterion for eGFR 
< 30 mL/min/1.73 m2 (exclusion 
criterion 20).
Routine monitoring of renal 
function (creatinine).
AE = adverse event; AESI = adverse event of special interest; BP = blood pressure; BUN = blood urea nitrogen; 
COPD = chronic obstructive pulmonary disease; CTCAE = Common Terminology Criteria for Adverse Events; 
DRC = Data Review Committee; DRF = dose range-finding; eGFR = estimated glomerular filtration rate; 
HfpEF = heart failure with preserved ejection fraction; HR = heart rate; MAD = multiple ascending dose; MPO = 
myeloperoxidase; NOAEL = No-observed-adverse-effect level; ROS = reactive oxygen species; SAD = single 
ascending dose; T3 = triiodothyronine; T4 = thyroxine; TPO = thyroid peroxidase; TSH = thyroid stimulating 
hormone.
Appendix K includes an assessment of risks specific to the COVID-19 pandemic.
2.3.2 Benefit Assessment
Potential reduced hospitalisation
A reduced hospitalisation is considered to be a major potential benefit of the mitiperstat 
(AZD4831) treatment. Hospitalisation is a major challenge for all patients and many times 
patients suffer from life-threatening events, while being in a hospital.
Potential decrease in rate of exacerbations
Acute exacerbations of COPD are responsible for much of the hospitalisation-associated 
morbidity and mortality from COPD (Barnes et al 2015). It has been suggested that the 
mortality increases with the frequency of severe exacerbations (Soler-Cataluña et al 2005).
Potential quality of life improvement
Typical features of COPD include airway closure during expiration, which worsens on 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
48 of 187
exercise resulting in exertional dyspnoea and reduced exercise tolerance, and leads to marked 
impairment in quality of life. By improved lung function with mitiperstat (AZD4831) 
treatment, patients are expected to obtain a beneficial effect in their quality of life. It will be 
assessed in the Phase IIa study by the CAT for patients with COPD. Life expectancy is 
significantly limited in many patients and increased quality of life has a major role in potential 
benefits.
Potential improved symptom control
Symptom control will be evaluated by using the BCSS, EXACT, and cough frequency 
measurement. Improving BCSS and EXACT scores are considered to represent enhancement 
patients’ daily life activities and will affect the quality of life.
Potential improved lung function
It is hypothesised that mitiperstat (AZD4831) will reduce airway inflammation and tissue 
damage. This could potentially lead to an improvement in lung function and/or reduce rate of 
decline in lung function. It would be of great clinical importance to prevent further decrease of 
lung function, especially in patients with severe COPD.
2.3.3 Overall Benefit/Risk Conclusion
COPD is a debilitating disease with high mortality that has a high unmet medical need. 
Therefore, it would be desirable to develop new anti-inflammatory treatments that affect 
chronic symptoms and disease progression in COPD. Exacerbations are major contributors to 
the increased rates of hospitalisation and mortality in patients with COPD. Two of the most 
important potential benefits are therefore decreasing the rate of exacerbations and reducing 
hospitalisation. Further, it is envisaged that mitiperstat (AZD4831) will improve symptom 
control and lung function. As a result of these potential benefits, patients’ quality of life will 
likely be improved. The key risks include maculopapular rash and the potential risks host 
defence impairment-infections (including pneumonia) and thyroid peroxidase inhibition 
(hypothyroidism). Skin reactions (including maculopapular rash) and serious infections 
including pneumonia are AESIs; skin reactions and pneumonia will be evaluated by external 
experts. Given the available data and taking into account both the severity of COPD and that 
the patients to be included in the planned Phase IIa study have an advanced disease, it is 
considered that potential benefits outweigh the risks.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
49 of 187
3
OBJECTIVES AND ENDPOINTS
Table 3
Objectives and Endpoints
Objectives
Estimand descriptiona
Primary
To evaluate the effect of mitiperstat 
(AZD4831) as compared to placebo on the 
time to first COPDCompEx event in patients 
with moderate to severe COPD.
Population: all participants randomised to either 
active or placebo arm.
Endpoint: time to first COPDCompEx event.
Population level-summary measure: hazard 
ratio.
Strategy for intercurrent events:
Primary estimand: while on treatment – if an 
intercurrent event occurs before first 
COPDCompEx event, the participant will be 
censored at the time of intercurrent event.
Supportive estimand: treatment policy (reflects 
ITT principle) – after intercurrent event 
participants remain in the study so that the 
endpoint can be observed. Treatment policy 
strategy used to estimate the efficacy of 
mitiperstat (AZD4831) in ‘real-world’ conditions.
Secondary
To assess the PK of mitiperstat (AZD4831) in 
patients with moderate to severe COPD.
Population: all participants who had received at 
least one dose of mitiperstat (AZD4831), and who 
had at least one measurable PK sample post dose.
Endpoint: plasma mitiperstat (AZD4831) 
concentration-time profiles during the 
intervention and follow-up periods, and PK 
parameters.
Population level-summary measure: summary 
statistics.
Strategy for intercurrent events: while on 
treatment.
To evaluate the effect of mitiperstat 
(AZD4831) as compared to placebo on the 
time to first moderate or severe COPD 
exacerbation.
Population: all participants randomised to either 
active or placebo arms.
Endpoint: time to first COPD exacerbation 
eventb
Population level-summary measure: hazard 
ratio.
Strategy for intercurrent events: while on 
treatment.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
50 of 187
Table 3
Objectives and Endpoints
Objectives
Estimand descriptiona
To assess the effects of mitiperstat (AZD4831) 
as compared to placebo on post-BD FEV1 in 
patients with moderate to severe COPD.
Population: all participants randomised to either 
active or placebo arms.
Endpoint: change from baseline in post-BD 
FEV1 after 12 weeks.
Population level-summary measure: the 
difference in mean.
Primary estimand: while on treatment.
Supportive estimand: treatment policy.
To assess the effect of mitiperstat (AZD4831) 
compared with placebo on respiratory 
symptoms in patients with moderate to severe 
COPD.
Population: all participants randomised to either 
active or placebo arms.
Endpoint: change from baseline in EXACT, 
BCSS score, and Cough VAS at Week 12 and 
Week 24.
Population level-summary measure: the 
difference in mean.
Strategy for intercurrent events: while on 
treatment.
To assess the effect of mitiperstat (AZD4831) 
compared with placebo on disease impact in 
patients with moderate to severe COPD.
Population: all participants randomised to either 
active or placebo arms.
Endpoint: change from baseline in Total CAT 
measured in clinic at Week 12.
Population level-summary measure: 
The difference in mean. 
Proportion of participants with change from 
baseline of -2 or less
Strategy for intercurrent events: while on
treatment.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
51 of 187
Table 3
Objectives and Endpoints
Objectives
Estimand descriptiona
Safety
To assess the safety and tolerability of 
mitiperstat (AZD4831) compared with placebo 
in patients with moderate to severe COPD.
Population: all participants who received at least 
1 dose of study intervention (Safety Analysis Set). 
Endpoint: safety and tolerability evaluations 
using AEs, SAEs, AESIs (skin reactions, 
including maculopapular rash, and serious
infections, including pneumonia), vital sign 
measures, clinical laboratory assessments (clinical 
chemistry, haematology, and urinalysis), and 
ECG.
Population level-summary measure: descriptive 
statistics eg, absolute counts and frequencies.
Strategy for intercurrent events: 
Primary: while on treatment – if an intercurrent event 
occurs, any subsequent safety data will not be taken 
into consideration in the safety evaluation.
Supportive: treatment policy – if an intercurrent 
event occurs, participants remain in the study and 
any safety data until Week 12 + safety follow-up 
will be taken into consideration in the safety 
evaluation.
Tertiary/Exploratory
Objective
Outcome Measure
To assess the effect of mitiperstat (AZD4831) 
compared with placebo on biomarkers related 
to neutrophils and COPD disease activity.
•
Sputum parameters including differential cell 
counts, and markers of neutrophil activation 
and inflammation.
•
MPO- and neutrophil- related circulating and 
nasal mucosal lining fluid biomarkers.
•
Putative biomarkers of lung tissue 
destruction and COPD disease progression.
•
Systemic biomarkers of cardiovascular 
comorbidities — including fibrinogen, 
hsCRP, IL-6, and NT-proBNP.
To assess the effects of mitiperstat (AZD4831) 
as compared to placebo on MPO activity and 
concentration in sputum and blood samples 
from patients with moderate to severe COPD.
Average change from baseline to Week 12 in 
MPO activity normalised to MPO concentration 
in sputum and ex-vivo-stimulated blood.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
52 of 187
Table 3
Objectives and Endpoints
Objectives
Estimand descriptiona
To assess the effects of mitiperstat (AZD4831) 
as compared to placebo on spirometry 
endpoints measured face-to-face and virtually 
in patients with moderate to severe COPD. 
Spirometry endpoints, including but not limited 
to, FEV1, forced vital capacity, forced expiratory 
flow 25% to 75%, inspiratory capacity, and 
reproducibility.
To assess the effect of sputum MPO 
concentration at baseline on primary and 
secondary endpoints in patients with moderate 
to severe COPD.
Time to first COPDCompEx event in participants 
with low MPO concentration at baseline 
compared to high MPO concentration at baseline.
Change from baseline post-BD FEV1 in 
participants with low MPO concentration at 
baseline compared to high MPO concentration at 
baseline.
Tertiary/Exploratory for Cough Substudy only
To assess the effects of mitiperstat (AZD4831) 
compared to placebo on change in cough 
frequency measured over a 24-hour period 
between start of treatment and Week 12.
Change from start of treatment (SV3) in average 
24-hour, waking, and sleeping cough frequency, 
using the VitaloJAK® Cough Monitor device, at 
Week 12.
To investigate whether cough frequency is 
associated with lung function (eg, PEF, 
FEV1), cough/COPD symptom scores (eg, 
BCSS, CAT and Cough VAS) and 
sputum/blood biomarkers (eg, MPO 
concentration, neutrophil activation markers).
Average cough frequency measured over a 
24-hour period as measured at start of treatment 
(Visit SV3) and after 12 weeks treatment 
(Visit SV5) using the VitaloJAK® Cough 
Monitor device.
a
An estimand is a precise description of the treatment effect reflecting the clinical question posed by the 
study objective. It summarises at a population-level what the outcomes would be in the same participants 
under different treatment conditions being compared. Definition from FDA E9(R1) Statistical Principles for 
Clinical Trials: Addendum: Estimands and Sensitivity Analysis in Clinical Trials
b
COPD Exacerbation: a worsening in the participant’s usual COPD symptoms that is beyond normal 
day-to-day variation, is acute in onset, lasts 2 or more days (or less if the worsening is so rapid and 
profound that the treating physician judges that intensification of treatment cannot be delayed), may warrant 
a change in regular medication, and leads to any of the following:
•
Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of corticosteroids will be 
considered equivalent to a 3-day course of systemic corticosteroids.
•
Use of antibiotics to treat COPD exacerbation for at least 3 days.
•
An inpatient hospitalisation due to COPD (defined as an inpatient admission ≥ 24 hours in the hospital, an 
observation area, the emergency department, or other equivalent healthcare facility depending on the 
country and healthcare system).
•
Admission in emergency department or emergency room due to COPD for < 24 hours requiring intensive 
treatment.
•
An episode of pneumonia. 
•
Results in death.
Moderate and severe COPD exacerbations are defined in Section 8.2.2.2.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
53 of 187
Intercurrent events are events occurring after treatment initiation (eg, discontinuation of treatment, switching 
treatment, terminal events such as death) that affect either the measurement or interpretation of the summary 
measure (eg, hazard ratio) associated with the clinical question of interest.
This study contains 2 intercurrent events: 
1
Treatment discontinuation (with the following reasons: SAE, death not due to exacerbation, COVID-19, 
pneumonia, other).
2
Prohibited medication.
-
AE = adverse event; AESI = adverse event of special interest; BCSS = Breathlessness, 
Cough and Sputum scale; BD = bronchodilator; CAT = COPD Assessment Test; 
COPD = chronic obstructive pulmonary disease; COPDCompEx = COPD Composite 
Exacerbations; COVID-19 = Coronavirus disease 2019; ECG = electrocardiogram; 
EXACT = The Exacerbations of Chronic Pulmonary Disease Tool; FDA = Food and 
Drug Administration; FEV1 = forced expiratory volume in 1 second; hsCRP = high 
sensitivity C-Reactive Protein; IL-6 = interleukin-6; ITT = intent-to-treat; 
MPO = myeloperoxidase, NT-proBNP = N-terminal pro-brain natriuretic peptide; 
PEF = peak expiratory flow; PK = pharmacokinetic; SAE = serious adverse event; SV 
= study visit; VAS = visual analogue scale.
-
The objectives of the Q-SAW, SPFQ, and patient experience interview substudies are detailed 
in Appendix L, Appendix M, and Appendix N, respectively. 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
54 of 187
4
STUDY DESIGN
4.1
Overall Design
A schematic is provided in Section 1.2 showing the overall study design. 
This is a Phase IIa, randomised, placebo-controlled, double-blind, parallel-arm, event-driven 
study with an up to 24-week treatment time. It will be performed in approximately 100 sites 
across approximately 14 countries. It is designed to evaluate the efficacy and safety of 
mitiperstat (AZD4831) administered QD using a tablet in adult participants with confirmed 
moderate to severe symptomatic COPD (FEV1/FVC < 0.7, ≥10 pack-years smoking history, 
and post-BD FEV1 ≥ 25% predicted) who are at high risk of exacerbations despite being 
maintained on optimised SoC inhaled therapies — triple inhaled therapy (ICS + LABA 
+ LAMA) or ICS + LABA dual therapy or LABA + LAMA dual therapy for participants who 
are deemed unsuitable for ICS. The treatment will be over a minimum 12-week and maximum 
24-week period.

Approximately 677 participants will be screened and 406 participants randomised into the 
study to evaluate mitiperstat (AZD4831) 5 mg QD versus placebo.

Being at high risk of exacerbations is defined as participants fulfilling one or more of the 
following criteria:
-
≥1 moderate or severe exacerbation in the last 2 years (defined as requiring systemic 
corticosteroids and/or antibiotics for at least 3 days duration [or 1 injection of depot 
formulation], or hospitalisation for reason of AECOPD in the 24 months prior to 
screening; see Section 5.1).
-
Frequent productive cough (see Section 5.1).
-
Post-BD FEV1 of < 50% predicted.

Participants will be randomised 1:1 to mitiperstat (AZD4831) 5 mg QD or placebo QD.

Randomisation will be stratified by country.

The primary objective is to evaluate the effect of mitiperstat (AZD4831) as compared to 
placebo on the time to first COPDCompEx event in patients with moderate to severe 
COPD. The primary endpoint will be time to first COPDCompEx event.

Secondary assessments of efficacy include: time to first COPD exacerbation event, 
post-BD FEV1 at Week 12 compared to Week 1, MPO level and activity in sputum at 
Week 12 compared to baseline, and symptom scores.

The study will explore an alternative community-based patient recruitment in some 
countries, utilising a network of Primary Care and Community COPD/Pulmonary 
Rehabilitation facilities to boost enrolment. The target countries with established 
Community COPD Clinic/Pulmonary Rehabilitation infrastructure will serve as 
participant recruitment centres or new sites.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
55 of 187

Enrolment will be stopped after at least 194 first COPDCompEx events have occurred. At 
this point, all participants enrolled in the study that have not yet completed SV5 should 
continue in the study to complete 12 weeks of treatment. For these participants SV5 and 
SV7 should be combined into one visit. Participants who have already completed 12 
weeks of treatment when study enrolment is stopped should attend SV7 as soon as 
possible, continuing treatment until they do. All participants should attend 
SV8 14 ± 3 days after SV7/EDV.

The URC will review efficacy data from the IA and the DRC will perform periodic
safety monitoring with a focus on skin reactions and pneumonia. See Appendix A 5 for 
details.

To reduce the burden on participants, Visits SV2, SV4, SV7, and SV8 will have a 
limited number of assessments and shortened duration, and Visit SV6 will be a “virtual 
visit” which will be performed away from the study site. This will be conducted over the 
same telemedicine video conferencing facility that is being used for the virtual spirometry 
during other visits in the study and is based on technology provided by Zoom Inc (San 
Jose, California, USA), through the UNIFY platform, using a provisioned handheld 
device.

The entire study period is planned to take between 18 and 30 weeks for each individual 
participant: a 4-week screening period, minimum 12 weeks to a maximum 24 weeks of 
dosing and 2 weeks of follow-up.
4.1.1
Cough Monitoring Substudy
A cough monitoring substudy will be performed alongside this study. In the cough substudy, a 
subset of participants (up to approximately 50 participants from each arm) from selected sites 
will be included. Twenty-four-hour cough frequency monitoring will be conducted at 
Visit SV3 (start of treatment) and Visit SV5 (after 12 weeks of treatment) using the 
VitaloJAK® Cough Monitor device. The main objective of the substudy is to explore the 
effect of mitiperstat (AZD4831) compared with placebo on change in average 24-hour, awake, 
and sleeping cough frequency between baseline and Week 12. The substudy will also 
investigate whether average cough frequency is associated with lung function (eg, PEF or 
FEV1), cough/COPD symptom scores (eg, BCSS, CAT, and cough VAS) and sputum/blood 
biomarkers (eg, MPO concentration, neutrophil activation markers).
4.1.2
Q-SAW Substudy
The Q-SAW substudy will be performed alongside this study. A subset of approximately 
40 participants in total, from selected sites in selected countries will be included.
COPDCompEx captures AWEs ie, clinically relevant deteriorations of PEF, reliever use or 
symptoms that fulfil specific criteria in terms of reaching thresholds or slopes. The Q-SAW 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
56 of 187
substudy aims to provide a deeper understanding of day-to-day variations in symptoms and 
the impact of AWEs on the patient’s life.
Participants may be invited to 2 semi-structured interviews: an initial interview and a second 
interview up to 6 weeks later, each conducted over video or telephone call.
For further details on the Q-SAW substudy, refer to Appendix L. 
4.1.3
SPFQ Substudy
The SPFQ substudy will be performed alongside this study. Participants from selected sites in 
selected countries will have the option to provide feedback on their clinical study experience. 
Participants will complete the SPFQ in electronic format on the UNIFY platform at SV3, SV5, 
and SV7, using a provisioned handheld device. The aim of the substudy is to gain an 
understanding of patient experience in clinical studies and identify where improvements can 
be made in the clinical study process. 
For further details on the SPFQ substudy, refer to Appendix M.
4.1.4
Patient Experience Interview Substudy
The patient experience interview substudy will be performed alongside this study and the data 
from this qualitative substudy will complement the data from the quantitative SPFQ 
(Section 4.1.3). In the patient experience interview substudy, approximately 20 participants in 
total, from selected sites in selected countries will be invited to attend a remote, 
semi-structured interview conducted over video call or telephone call. The aims of the 
substudy are to understand how participant experience can be improved and to gain further 
insight into the participant perceptions and experiences of the digital technology used, 
including the virtual spirometry. 
For further details on the patient experience interview substudy, refer to Appendix N.
4.1.5
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 CSP and should 
be implemented only 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 personnel or study participants become infected with SARS-CoV-2 or 
similar pandemic infection) which would prevent the conduct of study-related activities at 
study sites, thereby compromising the study site staff or the participant’s ability to conduct the 
study. The investigator or designee should contact AstraZeneca to discuss whether the 
mitigation plans below should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
57 of 187
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with GCP, and minimise risks to study integrity.
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options:

Obtaining consent or reconsent for the mitigation procedures (note, in the case of verbal 
consent or reconsent, the ICF should be signed at the participant’s next contact with the 
study site).

Home or Remote visit: Performed by a site qualified HCP or HCP provided by a TPV.

Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.

At-home study procedure: Performed by a qualified HCP from the study site or TPV 
service.

Additional information that cannot be obtained via a site visit can be obtained via 
telemedicine.
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix J.
4.1.6
Study Conduct Mitigation During SARS-CoV-2 Pandemic
In case of local or global SARS-CoV-2 outbreaks, appropriate risk assessments and mitigation 
measures will need to be taken into consideration to protect participants and HCPs involved in 
the clinical study and ensure data quality as per regulatory agencies and local guidelines. 
If, for reasons related to the COVID-19 pandemic (eg, local lockdown, self-isolation 
requirements), a participant is not able to attend their scheduled visit within the visit window, 
they can have their visit rescheduled as per agreement with the AstraZeneca Study Physician. 
Where visits cannot be rescheduled, participants should continue at the next scheduled visit. 
Additionally, 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 
collection of data for AEs, concomitant medications, adherence to the e-Diary, and PRO 
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.
Applicable measures for source data verification, if on-site monitoring at the study sites is not 
indicated due to the COVID-19 pandemic, should be implemented.
For further details on study conduct during SARS-CoV-2 or similar pandemic refer to 
Appendix K.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
58 of 187
4.2
Scientific Rationale for Study Design
This Phase IIa study has 2 treatment arms (mitiperstat [AZD4831] and placebo) to allow the 
efficacy and safety of mitiperstat (AZD4831) to be assessed. Participants will remain on their 
SoC treatment (triple or dual therapy) during the study.
A placebo controlled, double-blind design has been chosen to limit the occurrence of
conscious and unconscious bias in the conduct and interpretation of the clinical study arising 
from the influence that the knowledge of treatment may have on the recruitment and 
allocation of participants. It is considered the optimal approach according to ICH E9 
“Statistical principles in clinical studies” (ICH 1998). The inclusion of a placebo arm is also 
recommended by the EMA guideline EMA/CHMP/483572/2012 “Clinical investigation of 
medicinal products in the treatment of chronic obstructive pulmonary disease (COPD)” (EMA 
2012) for drugs to be used as add-on therapy, providing that all participants receive optimised 
background therapy; participants in both groups will remain on SoC inhaled therapies (triple 
inhaled therapy [ICS + LABA + LAMA] or ICS + LABA dual therapy or LABA + LAMA 
dual therapy for participants who are deemed unsuitable for ICS).
The primary endpoint, time to COPDCompEx event, is a novel, surrogate, composite endpoint 
that captures clinically relevant deteriorations (diary events [eg, PEF], reliever use, symptoms, 
exacerbation events, and study dropouts resulting from a lack of efficacy) that fulfil specific 
criteria in terms of changes from baseline and deterioration over 5 days, combined with 
exacerbations. Three-month COPDCompEx treatment effects have been shown to reflect 
treatment effects on exacerbations at 6 to 12 months (Vogelmeier et al 2020). 
The participants anticipated to be most likely to benefit from mitiperstat (AZD4831) treatment 
are those at high risk of exacerbations. Therefore, participants will be at high risk of 
exacerbations as defined by the criteria in Section 4.1.
The study is event-driven: once at least 194 COPDCompEx first events have occurred, 
enrolment will stop (see Section 7.1.4).
The study design includes several outcome assessments that will be performed remotely by 
participants. The purpose of this is to enable more frequent measurement and to minimise the 
burden of attending on-site visits. Several of these measurements will undergo further 
validation during the course of the study to ensure equivalence with site-based assessments 
where appropriate.
4.2.1 Patient Input into Design
Two patient experts with COPD have been engaged to provide input into the study objectives 
and design. Their advice has been actively considered and incorporated where appropriate. In 
particular they have influenced the duration, acceptability, and burden of study visits; the 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
59 of 187
devices and setting for clinical outcome assessments; and practical aspects of safety 
monitoring.
Their input and advice will continue during the course of the study setup, providing further 
feedback and perspectives on protocol implementation.
In addition, a wider group of volunteer patients will be engaged to pilot the usability and 
acceptability of the planned digital health devices prior to study initiation.
4.3
Justification for Dose
The dose selection is based on target engagement (MPO inhibition) data from the Phase I 
MAD study (D6580C00004), the Phase IIa study (D6580C00003), and data from the MAD 
study in Japanese and Chinese healthy participants (Study D6580C00008). One dose level is 
being proposed (5 mg) based on expected efficacy and safety. The 5 mg dose is predicted to be 
a clinically relevant dose in COPD, resulting in approximately 56% MPO inhibition, based on 
PK/PD data from the Phase I and Phase II studies.
Four Phase I clinical studies have been completed in which a total of 36 healthy subjects have 
been exposed to mitiperstat (AZD4831) at doses 5 to 405 mg as single doses and 53 healthy 
subjects (including 24 Japanese and Chinese participants) at doses 2.5 to 45 mg as multiple 
doses. 
In these healthy subjects, mitiperstat (AZD4831) was generally well tolerated with the 
exception of generalised maculopapular rash seen around 7 to 10 days after the first dose. 
Maculopapular rash CTCAE Grade 1 was reported in 1 of 6 
 participants on 5 mg 
mitiperstat (AZD4831); Grade 2 maculopapular rash was reported in 1 of 6 
 
participants on 5 mg mitiperstat (AZD4831). 
A Phase IIa study in participants with HfpEF was prematurely terminated during the 
COVID-19 pandemic after meeting pre-defined target engagement, safety, and tolerability 
criteria (Study D6580C00003). One of 27 participants receiving 5 mg mitiperstat (AZD4831) 
was discontinued from study treatment due to CTCAE Grade 3 generalised maculopapular 
rash.
4.4
End-of-Study Definition
For the purpose of Clinical Trial Transparency (CTT) the definition of the end of the study 
differs under FDA and EU regulatory requirements:
European Union requirements define study completion as the last visit of the last subject for 
any protocol related activity.
Food and Drug Administration requirements defines two completion dates:
PPD
PPD


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
60 of 187
Primary Completion Date – the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure with 
different completion dates, this term refers to the date on which data collection is completed 
for all of the primary outcomes.
Study Completion Date – the date the final participant is examined or receives an intervention 
for purposes of final collection of data for the primary and secondary outcome measures and 
AEs (for example, last participant’s last visit), whether the clinical study concludes according 
to the pre-specified protocol or is terminated.
A participant is considered to have completed the study if they have completed all phases of 
the study including SV8.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1
Participant must be 40 to 80 years of age inclusive, at the time of signing the ICF.
Type of Participant and Disease Characteristics
2
Participants who have a confirmed primary diagnosis of moderate to severe COPD as per 
GOLD criteria (FEV1/FVC < 0.7, and post-BD FEV1 ≥25% predicted) (Global Initiative 
for Chronic Obstructive Lung Disease 2022).
3
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.
4
Participants must be deemed at high risk of exacerbations as defined by any one of the 
following:
(a) 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 hospitalisation for reason of AECOPD in the 24 months prior to 
screening. A verbal history from the participant of AECOPD is not sufficient. 
Acceptable documentation is:


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
61 of 187

Clinic visit or consultation (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 an 
AECOPD event. In participants with an established self-management plan, 
documented filling of a prescription to replace an above course of therapy will be 
considered as adequate

Discharge summaries from a hospital, emergency room, or an urgent care facility 
indicating that a participant was hospitalised or treated with systemic 
corticosteroids or antibiotics for a COPD exacerbation, or
(b) Frequent productive cough, defined as a positive response to both of the following 
questions:*

Over the past 3 months, I have coughed at least several days a week 

Over the past 3 months, I have brought up phlegm (sputum) at least several days 
a week, or
(c) Post-BD FEV1 < 50% predicted. 
5
Participants who have a documented stable regimen of triple therapy or dual therapy for 
≥3 months prior to enrolment (change of inhaler device or change of medication in the 
same drug class is allowed). Triple therapy may consist of an appropriate combination of 
ICS + LABA + LAMA. Dual therapy consists of either inhaled ICS + LABA or 
LABA + LAMA where the treating physician deems the participant unsuitable for ICS 
(eg, blood eosinophil count ≤100 cells/µL on 2 separate occasions, or on the basis of 
previous or perceived risk of significant AEs from ICS-based therapy, such as previous 
episodes of pneumonia or significant oral candidiasis).
-
Both dual and triple therapy may be in the form of separate inhalers or fixed dose 
combination inhalers but may not be in nebulised form. Documented evidence of 
prescription for these medications must be provided. A verbal history from the 
participant is not considered sufficient.
-
Acceptable documentation includes:
                                               
* Used with the permission of the St. George's Respiratory Questionnaire Steering Committee.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
62 of 187
o
Recent, active medication list as per HCP note
o
Filled prescriptions based on a pharmacy record
o
Another acceptable medical record as per local clinical practice
6
Participants who are clinically stable and free from an exacerbation of COPD for 1 month 
prior to SV1 (screening) and prior to Day 1.
7
Participants who are at least 70% compliant with each of the following: morning e-Diary, 
evening e-Diary, and PEF measurements during the 14 days preceding SV3 based on the 
e-Diary. This is defined as completing the daily diary for any 10 mornings, any 10 
evenings, and performing PEF for any 10 morning and any 10 evenings.
8
Participants who are able to read, write, and use electronic devices.
Weight
9
Body mass index within the range 18 to 40 kg/m2 (inclusive).
Sex and Contraceptive/Barrier Requirements
10 Male or female of non-childbearing potential.
Contraceptive use by males or females should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
(a) Male participants:

Male participants must be surgically sterile (eg, vasectomy with confirmed 
azoospermia) or using an acceptable method of contraception (defined as barrier 
methods in conjunction with spermicides if available) during treatment and until 
the end of relevant systemic exposure in the male participant, plus a further 
105 day period. Male study participants must not donate or bank sperm during 
this same time period.

For a non-pregnant woman of childbearing potential partner, contraception 
recommendations should also be considered. Acceptable methods of 
contraception are birth control pills, injections, implants, or patches, intrauterine 
devices, and tubal ligation/occlusion. A barrier method is not necessary if the 
female partner is sterilised. All other contraceptive methods are considered 
unacceptable.
(b) Female participants must not be lactating and must be of nonchild-bearing potential. 
Women not of childbearing potential are defined as women who are either 
permanently sterilised (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy [but not tubal ligation]), or who are postmenopausal. Women will be 
considered postmenopausal if they have been amenorrhoeic for 12 months prior to 
the planned date of randomisation without an alternative medical cause. The 
following age-specific requirements apply:


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
63 of 187

Women < 50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatment and follicle stimulating hormone levels in the postmenopausal range.

Women ≥ 50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous 
hormonal treatment.
Informed Consent
11 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 protocol.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
This criterion has been removed. 
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.
(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 SV1 [screening] through to 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 (ie, HbA1c < 10%).
(b) History of left heart failure (left ventricular ejection fraction < 40% on 
echocardiogram or Cardiac magnetic resonance imaging).
(c) Unstable angina, acute coronary syndrome/acute myocardial infarction or coronary 
intervention with percutaneous coronary intervention/coronary artery bypass graft 
within 6 months, arrhythmia requiring treatment, or cardiomyopathy.
(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.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
64 of 187
(f) Pulmonary arterial hypertension, either idiopathic or due to connective tissue or 
thromboembolic disease. Participants with cor pulmonale (with or without long term 
oxygen supplementation) secondary to severe COPD are allowed.
(g) History of another underlying condition that predisposes the participant to infections. 
This includes but not limited to history of splenectomy, history of previous systemic 
fungal infection or known primary or secondary immune deficiency syndromes 
(including but not limited to chronic granulomatous disease, severe combined 
immunodeficiency, chronic mucocutaneous candidiasis, hyper-IgE syndrome, 
myeloperoxidase deficiency, leukocyte adhesion deficiency, DiGeorge syndrome, 
X-linked hyper-IgM syndrome, Wiskott-Aldrich syndrome and common variable 
immunodeficiency).
(h) History of ulcerative colitis, Crohn’s disease, or microscopic colitis diagnosed by 
either a gastroenterologist or by histopathology.
4
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 of COPD, 
determined to be a misdiagnosis by the physician treating at the time.
(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 participant was aged ≥ 40 years, confirmed by 
the investigator to be a misdiagnosis on the basis of objective testing.
5
Clinically important pulmonary disease other than COPD (eg, active lung infection, 
clinically significant bronchiectasis where bronchiectasis is the predominant diagnosis, 
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), radiological findings, and/or laboratory 
findings suggestive of a respiratory disease other than COPD that is contributing to the 
participant’s respiratory symptoms.
6
Known history of allergy or reaction to any component of the study intervention 
formulation, including hereditary fructose intolerance.
7
Any other clinically relevant abnormal findings on physical examination, laboratory 
testing including haematology, coagulation, serum chemistry, or urinalysis; or recent lung 
imaging prior to randomisation, 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. In addition, if a participant meets any of the criteria below, they will be excluded 
from the study:


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
65 of 187
(a) ALT or AST > 2 × ULN.
(b) TBL > 2 × ULN (unless due to Gilbert’s disease).
(c) Evidence of chronic liver disease on previous hepatic imaging or pathological 
sampling.
(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 < 90 mmHg or ≥ 160 mmHg.
(ii) Diastolic BP < 50 mmHg or ≥ 95 mmHg.
(iii) Pulse < 45 or > 100 beats per minute.
(e) Signs of pulmonary oedema or volume overload.
(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. Participants with atrial fibrillation or flutter and 
optimally controlled ventricular rate at resting < 100 beats per minute might be 
included as judged by the investigator.
(g) Recent lung imaging that requires immediate diagnostic investigation or follow-up. If 
initial repeat surveillance imaging has been undertaken, and the abnormality is 
considered low risk of malignancy, the participant may be eligible for enrolment 
following confirmation with the AstraZeneca medical monitor. 
8
History of a clinically significant infection (viral, bacterial, or fungal; defined as requiring 
systemic antibiotics, antiviral, or antifungal medication for > 7 days) within 4 weeks prior 
to SV3 (Day 1) (including unexplained diarrhoea) or clinical suspicion of infection at 
time of dosing.
9
Any history of lung volume reduction surgery, including endoscopic lung volume 
reduction procedure with endobronchial valves.
10 Use of domiciliary non-invasive positive pressure ventilation device, including BiPAP. 
CPAP for the purpose of treating obstructive sleep apnoea is allowed.
11 Active malignancy requiring treatment (with the exception of basal cell or squamous cell 
carcinomas of the skin and stable prostate cancer)
12 Active drug-induced hypersensitivity skin reaction or history of SCARS (including 
DRESS, SJS/TEN, and AGEP). 
13 History of ANCA positive vasculitis or ANCA positive skin disease.
14 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.
15 Positive hepatitis C antibody, hepatitis B virus surface antigen, or hepatitis B virus core 
antibody, at screening.
16 Known to have tested positive for HIV, including at screening.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
66 of 187
17 Evidence of untreated active TB:
-
Participants currently receiving treatment for active TB may be considered after 
completion of an appropriate course of therapy.
18 Change in smoking status in 12 weeks prior to enrolment or intention to change smoking 
status between enrolment and end of follow-up.
19 Current diagnosis of hyperthyroidism, uncontrolled hypothyroidism (including but not 
limited to TSH ≥10 mIU/L), or any clinically significant thyroid disease.
20 Estimated glomerular filtration rate < 30 mL/min/1.73 m2 by Chronic Kidney Disease 
Epidemiology Collaboration formula at screening.
Prior/Concomitant Therapy
21 Participants currently receiving background therapy for COPD that is not approved by 
regulatory authorities in the country of study (with the exception of nicotine vaping 
products, long-term azithromycin, erythromycin and/or ICS standalone inhaler [as part of 
triple or dual therapy] of at least 3 months’ duration) are not eligible for the study.
22 This criterion has been removed.
23 Major surgery within 8 weeks prior to screening or planned inpatient surgery or 
hospitalisation during the study period. 
24 Treatment with broad spectrum antibiotic (excluding long-term azithromycin or 
erythromycin as mentioned in exclusion criterion 21) within 4 weeks prior to 
randomisation (Day 1).
25 Donation of blood or blood products in excess of 500 mL within 3 months prior to 
screening.
26 History of allogeneic bone marrow transplant.
27 Participant who is going to start or finish intensive COPD rehabilitation program at any 
time during study period. Participants can be recruited immediately following the 
completion of their COPD rehabilitation program.
28 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) Chronic oral steroids within 6 months of SV1.
(c) Any other immunosuppressive therapy (including methotrexate, cyclosporine, 
tacrolimus, or maintenance systemic steroid treatment) within 3 months of 
randomisation.
(d) Immunoglobulin or blood products within 4 weeks of SV1.
(e) Live, attenuated, or mRNA vaccines within 2 weeks prior to SV1 only.
(f) Interferon gamma within 3 months of randomisation.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
67 of 187
(g) Investigational products within 4 months or 5 half-lives of randomisation, whichever 
is longer.
(h) Marketed biologics within 4 months or 5 half-lives of randomisation, whichever is 
longer.
(i)
Sulfamethoxazole, sulfadiazine, and dapsone, from 14 days before randomisation 
until 14 days after last dose of study treatment.
(j)
Propylthiouracil, carbimazole, and methimazole.
29 Any concomitant medications known to be potent CYP3A4 inducers or inhibitors from 
14 days before randomisation until 2 days after the last dose of study treatment (see 
Table 8), eg, itraconazole, rifampicin, or clarithromycin.
30 Initiation within 2 months prior to study start or during the study initiation of a new 
treatment by allopurinol, lamotrigine, and phenytoin. All of them commonly cause rash. 
Prior/Concurrent Clinical Study Experience
31 Concurrent enrolment in another clinical study involving an investigational treatment.
Other Exclusions
32 Participant is an investigator, sub-investigator, study coordinator, or employee of the 
participating site or AstraZeneca, or is a first-degree relative of the aforementioned. 
33 Inability to perform technically acceptable spirometry.
34 Randomisation of participant is not permitted due to closure of stratum.
35 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
1
Participants should avoid eating a large meal for at least 1 hour prior to all scheduled 
supervised spirometry assessments.
2
Participants should refrain from consumption of grapefruit juice and St John’s wort from 
the start of study intervention until the final dose. Study intervention can be taken with or 
without food.
5.3.2
Alcohol and Tobacco
1
Chronic alcohol or drug abuse within 2 years (at the investigator’s discretion) is restricted 
prior to SV1 and throughout the conduct of the study. 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
68 of 187
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 the 
12 weeks prior to enrolment or intention to change smoking status between enrolment 
and the end of follow-up will result in a screen failure. However, following change in 
smoking status, they will be eligible for rescreening. Smoking status changes during the 
study will be captured on the eCRF but the participant will be permitted to continue in 
the study.
5.4
Screen Failures
A screen failure occurs when a participant who has consented to participate in the clinical 
study is not subsequently assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened, if one or more of the following occurs:

There is reason to believe the reason for ineligibility was temporary (eg, exacerbation 
and/or background medication stability periods).

Failure to achieve the required 70% compliance on any of the following: morning 
e-Diary, evening e-Diary, and PEF measurements during the 14 days preceding SV3.

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 a change in smoking status, participants will be eligible for 
rescreening.
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. Rescreened participants should be assigned the same 
participant number as for the initial screening.
Where an appropriate chest CT scan was performed within the last 6 months, such as for part 
of the previous screening process, this CT scan may be used for the study. This scan should be 
submitted at the time of screening, but can be repeated if the quality is not adequate for 
analysis.
If previously performed as part of the previous screening process, a second FSH test does not 
need to be performed. All other tests must be performed as per the SoA (Table 1).


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
69 of 187
5.5
Criteria for Temporarily Delaying Enrolment, Randomisation, or 
Administration of Study Intervention 
6
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all pre-specified, IMPs and NIMPs, medical devices and other 
interventions (eg, surgical and behavioural) intended to be administered to the study 
participants during the study conduct.
6.1
Study Intervention(s) Administered
Table 4
Study Interventions
Arm name
Mitiperstat (AZD4831)
Placebo
Intervention 
name
Mitiperstat (AZD4831)
Placebo
Type 
Drug
Placebo
Dose 
formulation
Film-coated tablet
Film-coated tablet
Unit dose 
strength
5 mg
N/A
Dosage level
5 mg once daily
Home administration by the 
participant should be in the morning.
On days with an on-site visit, 
participant should be dosed at the site 
during the visit.
Once daily
Home administration by the 
participant should be in the morning.
On days with an on-site visit, 
participant should be dosed at the site 
during the visit.
Route of 
administration
Oral
Oral
Use
Experimental
Placebo-comparator
IMP or NIMP
IMP
IMP
Sourcing
Provided centrally by AstraZeneca
Provided centrally by AstraZeneca
Packaging and 
labelling
Study Intervention will be provided in 
bottles. Each bottle will be labelled in 
accordance with GMP and country 
regulatory requirements for labelling.
Study Intervention will be provided in 
bottles. Each bottle will be labelled in 
accordance with GMP and country
regulatory requirements for labelling.
Current/former 
name(s) or 
alias(es)
N/A
N/A
GMP = Good manufacturing practice; IMP = Investigational Medicinal Product; N/A = not applicable; 
NIMP = Non-Investigational Medicinal Product


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
70 of 187
6.1.1
Medical Devices Including Combination Products with a Device 
Constituent
1)
Medical devices (not manufactured by or for AstraZeneca) provided for use in this study 
are:

MIR Spirobank Smart spirometer (available in each study region)

MIR Spirobank II Smart (available in each study region) (SV1 screening visit 
only)

VitaloJAK® Cough Monitor (available in each study region where the cough 
substudy will be performed)
2)
Instructions for medical device use are provided.
3)
All medical device deficiencies (including malfunction, use error and inadequate 
labelling) shall be documented and reported by the investigator throughout the clinical 
investigation (see Section 8.4.13) and appropriately managed by AstraZeneca.
In addition to the medical devices described above, an e-Diary (a handheld device) will be 
used to complete the assessments described in Section 8.2.6. AstraZeneca’s UNIFY 
application will be used on the handheld device for collection of e-Diary, PEF, and virtual 
spirometry data. The Medidata application for image handling is installed on the handheld 
device. A tablet installed with ZEPHYRx’s application will display the data from the MIR 
Spirobank II Smart.
ArtiQ.QC will be integrated into ZEPHYRx application for an instant artificial 
intelligence-based over-reading of spirometry against ATS/ERS 2019 standards. Meanwhile 
ArtiQ.RBM software will also be utilised in ZEPHYRx and UNIFY, for risk-based quality 
management analysis of spirometry and identification of sites that may require quality 
improvement initiatives.
Both ArtiQ.QC and ArtiQ.RBM are not considered to meet the definition of a medical device 
as it only performs quality control and quality management functions. It will not be used as 
the basis for any clinical decision making or patient treatment.
The UNIFY application is not considered to meet the definition of a medical device as it 
performs only administrative study functions and collects and displays medical information. It 
does not process or analyse medical information for the purposes of treating or diagnosing 
participants.
The ZEPHYRx application is not considered to meet the definition of a medical device as it 
does not modify or alter the medical device data coming from the spirometer. The application 
will only be used for assessing if the participant meets the screening criteria for the study. It 
will not be used as the basis for any clinical decision making or patient treatment.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
71 of 187
The Medidata application is not considered to meet the definition of a medical device as it 
only acts as a file transfer mechanism. The images captured in the application are not used for 
clinical decision making or patient treatment.
6.2
Preparation, Handling, Storage, and Accountability

The investigator or designee (eg, pharmacist or study coordinator) must confirm 
appropriate conditions (eg, temperature) have been maintained during transit for all study 
intervention received at the site and throughout the entire study until authorisation is 
provided for on-site destruction or removal of the IMP, reflecting completion of the study. 
In the event of a temperature excursion detected at any time during the study, sites will 
follow the reporting procedures for notifying AstraZeneca (or designated party); release 
of IMP for clinical use can only occur once the event has been reviewed and approval is 
provided by AstraZeneca (or designated party).

Only participants randomised 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.

The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).

Study medication will be dispensed to participants in bottles. Participants will be 
instructed to take one tablet per day in the morning.

Further guidance and information for the final disposition of unused study interventions 
are provided in the pharmacy manual.
6.3
Assignment to Study Intervention
All participants will be centrally assigned to randomised study intervention, and have an 
E-code assigned, using an Interactive Response Technology/Randomisation and Trial Supply 
Management (IRT/RTSM) system. Before the study is initiated, the log in information and 
directions for the IRT/RTSM will be provided to each site. 
Participants will be randomised 1:1 to mitiperstat (AZD4831) 5 mg or placebo at SV3 
(Table 1). Randomisation will be stratified by country.
Study intervention will be dispensed at the study visits summarised in the SoA (Table 1). 
Returned study intervention should not be re-dispensed to the participants.
The IRT/RTSM will provide to the investigator(s) or pharmacists the kit identification number 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
72 of 187
to be allocated to the participant at the dispensing visit.
Routines for this will be described in the IRT/RTSM user manual that will be provided to each 
centre.
6.4
Blinding
The study will be blinded to both participants and investigators/site staff as well as to 
AstraZeneca staff. With the formation of the URC and DRC (see Appendix A 5) the study will 
become unblinded to the AstraZeneca staff assigned to these committees (including those with 
clinical, medical, statistical, and programming expertise) who will form a firewalled URC for 
administrative purposes and will all be independent from the study team (see Appendix A 5). 
The URC will be responsible for conducting the administrative IA whereas the DRC will be 
responsible for safety monitoring.
The randomisation list should be sent to the personnel analysing the PK samples. 
Pharmacokinetic samples will be analysed by the bioanalytical laboratory performing the 
bioanalyses only for participants on active treatment, as referenced in Section 8.5.2. To allow 
for the appropriate selection of samples, the bioanalytical laboratory will, therefore, have 
access to the treatment codes but will not share the codes with AstraZeneca or others involved 
in the study until the blinding is broken for the study.
The randomisation code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment randomisation. 
The investigator documents and reports the action to AstraZeneca, without revealing the 
treatment given to the participant to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product and that potentially require 
expedited reporting to regulatory authorities. Randomisation codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
participant have been made and documented.
The IRT/RTSM will be programmed with blind-breaking instructions. In case of an 
emergency, in which the knowledge of the specific blinded study intervention will affect the 
immediate management of the participant’s condition (eg, antidote available), the investigator 
has the sole responsibility for determining if unblinding of a participant’s 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, AstraZeneca
must be notified within 24 hours after breaking the blind. 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
73 of 187
6.5
Study Intervention Compliance
The first dose of study intervention will be administered in clinic on the day of randomisation. 
Participants will receive study intervention at the site on visit days and at home between visits.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of dose administered in 
the clinic will be recorded in the source documents and recorded in the eCRF. The dose of 
study intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff other than the person administering the study intervention. 
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by counting returned 
tablets during the site visits and comparison of this data to e-Diary self-administration data, 
and/or direct questioning can be used to confirm details. Compliance will be documented in 
the source documents and eCRF. Deviation(s) from the prescribed dosage regimen should be 
recorded in the eCRF.
A record of the number of the mitiperstat (AZD4831)/placebo tablets dispensed to and taken 
by each participant must be maintained and reconciled with study intervention and compliance 
records. Intervention start and stop dates, including dates for intervention delays will also be 
recorded in the eCRF.
6.6
Dose Modification
No dose modifications are allowed during the study.
6.7
Continued Access to Study Intervention After the End of the 
Study
There is no planned intervention following the end of the study.
6.8
Treatment of Overdose 
For this study, any dose of mitiperstat (AZD4831) greater than those specified in this protocol
within the same day will be considered an overdose.
Should an overdose occur, the patient should be treated symptomatically, and supportive 
measures instituted.
In the event of an overdose, the investigator should:

Evaluate the participant to determine, in consultation with the Study Physician, if 
possible, whether study intervention should be interrupted.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
74 of 187

Closely monitor the participant for any AE/SAE and laboratory abnormalities as 
medically appropriate and at least until the next scheduled follow-up. Refer to 
Section 8.4.12 for details of AE/SAE reporting related to overdose.

Document the quantity of the excess dose as well as the duration of the overdose.
6.9
Prior and Concomitant Therapy
Any medication or vaccine (including over the counter or prescription medicines, vitamins, 
and/or herbal supplements), or other specific categories of interest that the participant is 
receiving at the time of enrolment or receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
If and when a participant received 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, second, or booster dose

Dose

Anatomical site/region of administration (eg, left deltoid)

Lot number
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
The following medications are prohibited (see Section 5.2 for details of duration of 
prohibition): 

Potent inhibitors or inducers of CYP3A: mitiperstat (AZD4831) is metabolised via 
CYP3A4 and hence strong inhibitors or inducers of CYP3A should not be administered 
from 14 days before randomisation until 2 days after the last dose of study treatment since 
that will affect the plasma concentration of mitiperstat (AZD4831). For guidance 
regarding potential interactions with concomitant medications that are inhibitors or 
inducers of CYP3A4, see Appendix F, Table 8.

Treatment with allopurinol, lamotrigine, and phenytoin should not be initiated within 
2 months prior to study start or during the screening and treatment period. All of them 
commonly cause rash. They were also recently shown (in a large population database) to 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
75 of 187
be associated with the highest absolute risk for life-threatening SJS and TEN among 
various culprit drugs (Gronich et al 2022).

Acute or chronic systemic (oral or injectable) corticosteroids (see exclusion criterion 28)

Any other immunosuppressive therapy (including methotrexate, cyclosporine, tacrolimus, 
or maintenance systemic steroid treatment).

Immunoglobulin or blood products.

Live, attenuated, or mRNA vaccines if within 2 weeks prior to SV1 only.

Interferon gamma.

Other investigational products.

Marketed biologics.

Sulfamethoxazole

Sulfadiazine

Dapsone

Propylthiouracil

Carbimazole

Methimazole
6.9.1 Rescue Medicine
The following SABAs, as per local SoC, may be used during the study as rescue medication:
1
Salbutamol/albuterol inhalation aerosol, powder, or nebuliser.
2
Terbutaline inhalation aerosol, powder, or nebuliser.
The study site will not supply SABA rescue medication. 
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. 
Participants will be discontinued from IP in the following situations:
1
Withdrawal of consent to further treatment with study intervention.
2
Lost to follow-up.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
76 of 187
3
Adverse event or other safety reasons as judged by the investigator and/or AstraZeneca 
where continued treatment may put the participant at undue risk.
4
Pregnancy.
5
If it is found that, following randomisation, the participant met ≥ 1 of the exclusion 
criteria or failed to meet all the inclusion criteria for study participation at or before 
randomisation, unless the PI and medical monitor agree the participant may continue 
receiving study intervention.
6
Severe non-compliance to study protocol.
7
Development of uncontrolled and clinically significant thyroid dysfunction as judged by 
the investigator.
8
Maculopapular rash CTCAE Grades 1, 2, or 3.
9
Any rash or skin reaction that is considered to be an SAE.
10 Generalised rash/skin reaction without an alternative suspect COPD medication (see 
Section 7.1.1 for details).
If study intervention is permanently discontinued, the participant will remain in the study to be 
evaluated for assessments at end of treatment and during follow-up, including follow-up of 
any AEs unless consent is withdrawn from further study participation, the participant is lost to 
follow-up, or the participant is enrolled in another clinical study.
Participants discontinuing study intervention before SV7 should attend the study site for SV7 
assessments (as an early treatment discontinuation visit), then attend for SV8 assessments 
14 (± 3) days later. In the event a participant is permanently discontinued from further receipt 
of study intervention, it should be recorded in the IRT/RTMS.
Note that discontinuation from study intervention is not the same thing as a discontinuation or 
withdrawal from the study (see Section 7.2).
If study intervention is permanently discontinued, the participant should, if at all possible, 
remain in the study. See the SoA (Table 1) 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.
7.1.1
Discontinuation Due to Rash/Skin Reaction
At each visit, participants will be instructed to contact the investigator immediately, if rash or 
skin reaction has developed. If maculopapular rash CTCAE Grade 1, 2, or 3 has developed, 
the participant must be permanently discontinued from the study intervention and AstraZeneca 
medical staff should be informed.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
77 of 187

Grade 1: Macules/papules covering < 10% BSA with or without symptoms (eg, pruritus, 
burning, tightness).

Grade 2: Macules/papules covering 10% to 30% BSA, with or without symptoms (eg, 
pruritus, burning, tightness); limiting Instrumental ADL (refer to preparing meals, 
shopping for groceries or clothes, using the telephone, managing money, etc); rash 
covering > 30% BSA with or without mild symptoms.

Grade 3: Macules/papules covering > 30% BSA, with moderate or severe symptoms; 
limiting Self-care ADL (refer to bathing, dressing and undressing, feeding self, using the 
toilet, taking medications, and not bedridden).
If the participant develops a rash or skin reaction that is not considered a maculopapular rash, 
but is considered to be an SAE, the participant must be permanently discontinued from the 
study intervention and AstraZeneca medical staff should be informed.
If the participant develops a generalised rash or skin reaction that is not considered a 
maculopapular rash or SAE, the participant may continue dosing if the generalised rash/skin 
reaction occurs following the initiation of another COPD therapy (eg, antibiotics), and in the 
opinion of the investigator the rash/skin reaction is more likely to have been as a result of this 
COPD therapy. The suspect COPD therapy must be stopped and the participant must be 
monitored by the site on a daily basis until the rash/skin reaction has resolved. If, in the 
opinion of the investigator, the generalised rash/skin reaction does not resolve, worsens, or 
becomes maculopapular in appearance despite stopping the suspect COPD therapy, the 
participant must permanently discontinue the study medication. Also, if the participant 
develops a generalised rash or skin reaction in the absence of alternative suspect COPD 
medications, the participant must permanently discontinue the study medication. AstraZeneca 
medical staff should be informed in the event of either occurrence.
For further information and rash/skin reaction evaluation guidance, see Appendix B, B 5.
7.1.2
Temporary Discontinuation
Every attempt should be made to maintain participants on the study intervention during the 
course of the study. If the study intervention has been interrupted, it should be re-introduced as 
soon as, in the opinion of the investigator and the participant wishes to resume, the participant 
is able to re-start study treatment. The treatment period will not be extended to compensate for 
the temporary discontinuation. Note related to AESI skin reactions (including maculopapular 
rash): In the occurrence of maculopapular rash CTCAE Grade 1, 2, and 3, or generalised 
rash/skin reaction without an alternative suspect COPD medication (per Section 7.1.1), or 
serious rash/skin reaction, study intervention should be permanently discontinued.
At each visit, participants will be instructed to stop the study intervention and contact the 
investigator immediately if rash or skin reaction has developed. If, after the participant has 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
78 of 187
been seen by the study doctor or designee, the skin reaction does not meet permanent 
discontinuation criteria per Section 7.1, the study treatment can be restarted.
In the event that a participant develops symptoms suggestive of COVID-19 infection, the 
participant should undergo confirmatory rapid screening test for SARS-CoV-2 or PCR testing 
as soon as possible. Rapid screening test could be either lateral flow test/antigen test or 
molecular test. If the rapid screening test or PCR test confirms COVID-19 infection, the study 
intervention should be immediately discontinued on a temporary basis, unless any permanent 
discontinuation criteria are met (Section 7.1). After discontinuation of study intervention, any 
appropriate treatment is allowed if conditions presented in Section 6.9 are met.
In the event that a participant develops symptoms suggestive of pneumonia, the participant 
should undergo confirmatory chest x-ray and appropriate blood testing (eg, hsCRP, 
complete/full blood count, procalcitonin as deemed appropriate by the investigator) as soon as 
possible. If chest x-ray confirms the presence of consolidation and clinical markers are 
consistent with acute infection, the study intervention should be immediately discontinued on 
a temporary basis, unless any permanent discontinuation criteria are met (Section 7.1). After 
discontinuation of study intervention, any appropriate treatment is allowed if conditions 
presented in Section 6.9 are met.
In cases of ‘unconfirmed pneumonia’, if the participant is not hospitalised and/or does not 
have a chest x-ray confirming diagnosis of pneumonia, this should generally be considered an 
infective exacerbation of COPD rather than pneumonia. In this scenario, study intervention 
can continue. If the investigator still considers this to be pneumonia, then discussion with the 
AstraZeneca medical monitor would be needed regarding continuation/discontinuation of 
study intervention.
In case of serious infection, the study intervention should be immediately discontinued on a 
temporary basis, unless any permanent discontinuation criteria are met (Section 7.1). After 
discontinuation of study intervention, any appropriate treatment is allowed if conditions 
presented in Section 6.9 are met.
Study intervention does not need to be stopped for antibiotic treatment of non-serious 
infection.
If a participant does not receive study intervention for ≥28 days continuously, they should be 
permanently withdrawn from the study intervention.
7.1.3
Restarting After Temporary Discontinuation
Participants who have temporarily discontinued study intervention can resume treatment as 
soon as, in the opinion of the investigator, the participant is able to re-start study treatment and 
the participant wishes to resume. No minimum time period is necessary before treatment can 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
79 of 187
resume, with the exception of participants who temporarily discontinued due to COVID-19, 
pneumonia or serious infection:

If the study intervention has been temporarily discontinued due to confirmed COVID19 
infection, it may be possible to resume the study intervention at least 7 days after the 
confirmatory rapid screening test or PCR test if, in the opinion of the investigator, the 
symptoms related to COVID19 were mild and have resolved.

If the study intervention has been temporarily discontinued due to confirmed pneumonia 
or serious infection, it may be possible to resume the study intervention at least 7 days 
after completion of anti-microbial therapy if, in the opinion of the investigator, the 
symptoms related to pneumonia or serious infection were not severe and have resolved.
If the participant misses a scheduled visit during temporary discontinuation of study 
intervention, the missed visit should be recorded as “not done”, unless:

SV5 is missed, in which case it should be performed as soon as possible (eg, when the 
investigator believes an episode of serious infection, pneumonia or COVID19 has 
resolved).

SV7 is missed, in which case it should be performed as soon as possible (eg, when the 
investigator believes an episode of serious infection, pneumonia or COVID-19 has 
resolved). The participant should not be re-dosed, but should complete all assessments as 
per the visit and continue in follow-up (this will ensure data are available at SV7 for the 
analysis).
7.1.4
Participant Discontinuation at Study End
Enrolment will be stopped after at least 194 first COPDCompEx events have occurred. At this 
point, all participants enrolled in the study that have not yet completed SV5 should continue in 
the study to complete 12 weeks of treatment. For these participants SV5 and SV7 should be 
combined into one visit. Participants who have already completed 12 weeks of treatment when 
study enrolment is stopped should attend SV7 as soon as possible, continuing treatment until 
they do. All participants should attend SV8 14 ± 3 days after SV7/EDV.
7.2
Participant Discontinuation/Withdrawal from the Study
Discontinuation of the participant from the study by the investigator:

A participant may be discontinued from the study at any time at the discretion of the 
investigator for behavioural or compliance reasons.

At the time of discontinuing from the study, if the participant has not been discontinued 
from the study intervention, see Section 7.1.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
80 of 187

At the time of discontinuation from the study, if possible, SV7, as an EDV should be 
conducted as shown in the SoA (Table 1). See the SoA for data to be collected at the time 
of study withdrawal and follow-up and for any further evaluations that need to be 
completed. The participant will discontinue the study intervention and be withdrawn from 
the study at that time.
Voluntary withdrawal from the study by the participant:

A participant may withdraw from the study at any time at the participant’s own request 
for any reason (or without providing any reason). 

A participant who wishes to withdraw from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).

At the time of withdrawal from the study, if possible, SV7, as an EDV , should be 
conducted, as shown in the SoA (Table 1). See the SoA for data to be collected at the time 
of study withdrawal and follow-up and for any further evaluations that need to be 
completed. 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, AstraZeneca may retain and continue to use any data collected before such a 
withdrawal of consent.

If the participant withdraws from the study, AstraZeneca may retain and continue to use 
any samples collected before such a withdrawal of consent for the purposes the 
participant originally consented unless the participant withdraws consent for use of 
samples already collected. If the participant specifically withdraws consent for use of 
samples, it must be documented in the site study records by the investigator and the 
investigator must inform the Local and Global Study Team. Destruction of any samples 
taken and not yet tested should be carried out in line with documented sample withdrawal 
wishes in conjunction with what was stated in the informed consent and local regulation. 
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if the participant 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 study site for a 
required study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible. The participant should be counselled on the importance of maintaining the 
assigned visit schedule. At this time, ascertain whether the participant should or wishes to 
continue in the study.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
81 of 187

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, texts, 
emails, 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.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarised in the SoA (Table 1). Protocol waivers 
or exemptions are not allowed.

Urgent safety concerns should be discussed with AstraZeneca 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.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.

Instructions for the collection and handling of human biological samples will be provided 
in the study-specific laboratory manual. Samples should be stored in a secure storage 
space with adequate measures to protect confidentiality. For further details on handling of 
human biological samples see Appendix C.

In the event of a significant study-continuity issue (eg, caused by a pandemic), alternate 
strategies for participant visits, assessments, medication distribution and monitoring may 
be implemented by AstraZeneca or the investigator, as per local health authority/ethics 
requirements. Analyte results that could unblind the study will not be reported to 
investigative sites or other blinded personnel.

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 250 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
82 of 187
8.1
Administrative and General/Baseline Procedures
The following administrative and general/baseline procedures will be performed:

Demography

Medical, COPD, and smoking history

Assessment of COPD exacerbations

Physical examination

Weight and height

ECG

Vital signs

Procedures conducted as part of the participant’s routine clinical management (serum 
chemistry, haematology, urinalysis
8.2
Efficacy Assessments
Planned timepoints for all efficacy assessments are provided in the SoA (Section 1.3).
8.2.1
COPDCompEx
A COPDCompEx event is a composite endpoint developed to reproduce the treatment effect 
on COPD exacerbations (52 weeks) in a 12-week study (Vogelmeier et al 2020). 
COPDCompEx incorporates changes in symptoms, reliever use and PEF obtained from a daily 
diary, with confirmed exacerbations or study dropouts resulting from a lack of efficacy. The 
definition of an event is one of the following criteria:

Moderate or severe exacerbations: episodes leading to one or more of the following: 
hospitalisation, emergency room visit, an episode of pneumonia, treatment with OCS, 
corticosteroid injection, or treatment with antibiotics. 

Diary events: defined by threshold and slope criteria using the following diary and home 
spirometry variables: overall symptom rating, reliever medication use, and change in 
PEF. 

Study dropouts: withdrawal from a study as a result of a lack of efficacy.
The baseline for COPDCompEx will be estimated during the period between SV2 and SV3. 
More details on the derivation and analysis of this variable will be given in the SAP.
8.2.2
Chronic Obstructive Pulmonary Disease Exacerbations
8.2.2.1
Assessment of COPD Exacerbation
For the purpose of the protocol, a moderate or severe COPD exacerbation will be defined as a 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
83 of 187
worsening in the participant’s usual COPD symptoms that is beyond normal day-to-day 
variation, is acute in onset, lasts 2 or more days (or less if the worsening is so rapid and 
profound that the treating physician judges that intensification of treatment cannot be 
delayed), may warrant a change in regular medication, and leads to any of the following:

Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of 
corticosteroids will be considered equivalent to a 3-day course of systemic 
corticosteroids.

Use of antibiotics to treat COPD exacerbation for at least 3 days.

An inpatient hospitalisation due to COPD (defined as an inpatient admission ≥24 hours 
in the hospital, an observation area, the emergency department, or other equivalent 
healthcare facility depending on the country and healthcare system).

Admission in emergency department or emergency room due to COPD for < 24 hours 
requiring intensive treatment.

An episode of pneumonia.

Results in death.
8.2.2.2
Severity of Chronic Obstructive Pulmonary Disease Exacerbations
A COPD exacerbation will be considered moderate if it requires treatment with systemic 
corticosteroids and/or antibiotics for at least 3 days or resulted in emergency room visit 
< 24 hours requiring intensive treatment; and does not result in hospitalisation or death.
A COPD exacerbation will be considered severe if it results in hospitalisation (defined as an 
inpatient admission ≥24 hours in the hospital, an observation area, the emergency department, 
or other equivalent healthcare facility depending on the country and healthcare system) or 
death due to COPD.
8.2.2.3
Duration of AECOPD
The start and stop dates of COPD exacerbations will be 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

Date of hospital admission due to AECOPD


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
84 of 187
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.
8.2.3
Spirometry and Peak Expiratory Flow Measurement
At SV1, on-site spirometry will be performed to confirm eligibility for the study using an 
accredited diagnostic spirometer conforming to ATS/ERS 2019 Spirometry Standards with 
independent over-reading. Where sites do not have access to such a device, they will be 
provided with an MIR Spirobank II Smart and android tablet with ZEPHYRx KIOSK mode 
application. This device and application shall only be used for screening spirometry performed 
at SV1. Subsequently, a spirometer (MIR Spirobank Smart) will be provided to the 
participant, paired to a smartphone with the AstraZeneca UNIFY application (also used for the 
e-Diary and PROs, see Sections 8.2.4 and 8.2.6) at SV2. Spirometry data collection and 
processing is completed exclusively on the MIR Spirobank Smart device. The MIR Spirobank 
Smart is regulated as a medical device and is approved for use in all study countries. The 
UNIFY application will receive spirometry data from the device and acts as an interface to 
communicate quality of reading and other pertinent information concerning the act of 
spirometry data collection. The UNIFY application will also send the spirometry data to 
investigator telemedicine interfaces and study databases. 
Full spirometry will be performed at the times indicated in the SoA (Table 1). Data collected 
will include, but are not limited to, absolute and % predicted (as applicable) PEF, FEV1, FVC, 
FEV1/FVC, forced mid-expiratory flow (FEF25-75%), and inspiratory capacity.
All spirometry will be performed post-BD, which includes the participant’s regular triple or 
dual (ICS + LABA or LAMA + LABA) therapy. Administration of a SABA should only be 
necessary if the participant has failed to take their regular inhaled therapy as prescribed in the 
last 24 hours. In this circumstance, spirometry should be performed at least 15 minutes after 
the administration of salbutamol 400 mcg, albuterol 360 mcg or terbutaline 500 mcg, or 
equivalent.
In the event that an adequate quality, maximal effort spirometry effort cannot be obtained at 
the first attempt during a study visit, a further reattempt is allowed. The participant should be 
rested for a period of time deemed appropriate by the investigator and have recovered 
sufficiently for the procedure to be completed safely. This will not be considered rescreening 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
85 of 187
if undertaken on the same day as the first attempt.
At SV3 and SV5, face-to-face spirometry will be undertaken at the site, followed by virtual 
spirometry over video link with the participant in a different room from the healthcare 
professional. Face-to-face spirometry will take the form of supervised, coached measurement 
by a trained healthcare professional performed in person at the site. Feedback to the 
participant and session quality assessment will be provided by the healthcare professional in 
real-time and in adherence with American Thoracic Society 2019 Spirometry criteria (Graham 
et al 2019). Only measurements obtained by face-to-face spirometry will be utilised for the 
secondary outcome of post-BD FEV1.
At SV4 and SV7/EDV, virtual spirometry will be performed away from the study site prior to 
attendance at the site. Virtual Spirometry will take the form of supervised, coached 
measurement by a trained healthcare professional over a video link (AstraZeneca UNIFY 
application) with the participant. The healthcare professional will be able to visualise the 
participant and the spirometry data (including flow-volume loop) over the video link. 
Feedback to the participant and session quality assessment will be provided by the healthcare 
professional in real-time and in adherence with American Thoracic Society 2019 Spirometry 
criteria (Graham et al 2019). Measurements obtained by virtual spirometry will be part of the 
exploratory analysis only. Face-to-face spirometry, as detailed above, will be performed 
subsequently once the participant has attended the site.
The same MIR Spirobank Smart spirometer will be used for both forms of spirometry 
assessment. This is to ensure consistency and comparability of the results and that adequate 
training and technical setup has occurred. Participants will be asked to bring their spirometer 
with them to all on-site visits; a “back-up” will be available on-site in case this does not occur. 
In addition to the use of face-to-face and virtual spirometry data collection, the patient will use 
the MIR Spirobank Smart and UNIFY application to undertake twice daily, unsupervised 
PEF-only measurements, which will form part of the COPD CompEx assessment. The patient 
will be suitably trained on how to use the MIR Spirobank Smart and UNIFY application to 
record PEF measurements.
8.2.4
Participant-Reported Outcomes
The following assessments will be performed to evaluate respiratory symptoms at the times 
indicated in the SoA (Table 1). Participants should complete on-site PRO assessments before 
all other scheduled assessments in a quiet area. The appointed site personnel should also stress 
that the information is confidential. Therefore, if the participant has any medical problems, he 
or she should discuss them with the doctor or study nurse separately from the PRO 
assessments.
All PROs will be completed on the e-Diary. The participant will be asked to bring the device 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
86 of 187
with the e-Diary on with them to all on-site visits.

Exacerbations of Chronic Pulmonary Disease Tool– Patient-reported Outcome (EXACT)
The EXACT 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 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 defined exacerbation event. In 
identifying event onset and recovery, the EXACT can provide information on event frequency 
and duration as well as event severity.
The EXACT will be performed at on-site visits using the e-Diary. The EXACT questionnaire 
is presented in Appendix G.

Breathlessness, Cough and Sputum Scale (BCSS)
The BCSS is a 3-item questionnaire rating breathlessness, sputum, and cough on a 5-point 
Likert scale from 0 (no symptoms) to 4 (severe symptoms) (Leidy et al 2003). Item scores can 
be reported as domains scores and are summed to yield a total score. The BCSS will be 
captured each evening via the e-Diary over the period indicated in the SoA (Table 1). The 
recall period for the BCSS is “today”. 

Cough Visual Analogue Scale (Cough VAS)
Participants will be asked to complete a cough severity VAS (100-point linear scale marked 
with a horizontal or vertical line by the participant, with 0 representing ‘‘no cough’’ and 
100 representing “worst cough”) measuring subjective assessment by the participant of the 
prior 24 hours for severity of cough symptoms (Smith et al 2006). The Cough VAS will be 
completed each morning in the e-Diary over the period indicated in the SoA (Table 1). The 
Cough VAS is presented in Appendix I.
8.2.5
COPD Assessment Test 
The CAT is designed to measure how COPD impacts on a participant’s daily life and how this 
might change over time (Jones et al 2009). It consists of 8 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 5-point Likert scale from 0 (no symptoms/no impact) 
to 5 (severe symptoms/impact). The CAT will be completed by participants at on-site visits 
using the e-Diary as indicated in the SoA (Table 1). The CAT is presented in Appendix H.
8.2.6
E-Diary
The e-Diary will be provided to participants at Visit SV2, at which point they will receive 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
87 of 187
training on its use. 
Participants will record information in their e-Diary twice a day. 
The participant will be asked to bring the e-Diary on with them to all on-site visits.
The following parameters will be reported by participants according to the SoA (Table 1):

COPDCompEx parameters

BCSS

OCS use, antibiotic use, and hospitalisation

Cough VAS

Study intervention administration at home

EXACT

CAT

Self-photos of skin affected with rash/skin reaction
Participants must demonstrate a compliance of at least 70% during the 14 days preceding SV3 
to be eligible for randomisation (defined as completing the daily diary for any 10 mornings, 
any 10 evenings, and performing PEF for any 10 morning and any 10 evenings).
During the study treatment period, daily eDiary compliance is critical for overall symptom 
rating, reliever medication use, and change in PEF. The investigator/authorised delegate 
should check the participant’s adherence to the daily eDiary at each visit during the study and 
at any time during the study. If it drops below 80% to 85%, sites should take steps to ask the 
participant about the reason and to encourage the participant to regularly complete the eDiary.
See Appendix I for the BCSS and Cough VAS assessments to be completed.
If technical or other issues prohibit completion, an appropriate back-up option may be 
considered with prior approval from AstraZeneca.
8.2.7
Optional Computed Tomography Scan
The purpose of the optional CT scan is to characterise and assess the severity of COPD at 
baseline by, among other approaches, evaluation of the distribution of emphysema and 
visualisation of small airways disease, mucous plugging, and/or bronchiectasis. It is 
anticipated that a more detailed analysis of responders to treatment will be done on the basis 
of pre-existing emphysema severity and the presence of mucous plugging in particular. This 
may guide the inclusion of patients in the subsequent development program and will also be 
used to explore the association with the other biomarkers of disease progression from both 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
88 of 187
blood and sputum biomarker sampling. To support this analysis it is preferred that the majority 
of participants within the study should have a CT scan undertaken or results of a historical CT 
scan available, where feasible.
Where an inspiratory and expiratory chest CT scan has been performed within 6 months of 
informed consent and can be obtained and is adequate for quantitative assessment, it can serve 
as the baseline scan. Otherwise, an optional CT scan can be performed, per Table 1, to serve as 
the baseline scan. The high resolution CT could be performed as soon as main eligibility 
criteria are confirmed at SV1 which include blood test results, up to randomisation. If a CT 
scan is performed during the study, the local CT scan report must be obtained before 
randomisation.
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 does not meet Exclusion Criterion 7(g) (given available clinical, 
radiological and other data),

The participant has not had an inspiratory and/or expiratory 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 had recent lung imaging either in 
the study or before the screening that requires immediate diagnostic investigation or 
follow-up, they must not be randomised. If initial repeat surveillance imaging has been 
undertaken, and the abnormality is considered low risk of malignancy, the participant may be 
eligible for enrolment following confirmation with the AstraZeneca medical monitor. 
(Exclusion Criterion 7(g)).


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
89 of 187
New (optional) CT scans must be performed in a standardised way:

All new CT scans should be performed post-BD which includes the participant’s regular 
triple or dual (ICS + LABA or LAMA + LABA) therapy. When these are undertaken at 
the same visit as spirometry, the CT should be performed after these assessments.

Both full inspiration and end expiration sequences should be obtained.
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 optimised CT protocol will also be provided to the sites that includes all required 
scan parameters. Full compliance with the imaging vendor protocol is preferred, but where 
this is not possible, an adapted clinical protocol which is adherent to the above principles may 
be acceptable after discussion with AstraZeneca.
Any clinical findings from historical CT should be recorded on the specific imaging eCRF 
page for SV3. Any findings based on the local assessment of a new CT scan performed during 
screening must be recorded in the corresponding eCRF section.
All CT images submitted to the imaging vendor (VIDA, Iowa, US) 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.
8.2.8
Cough Substudy
The assessments described in Section 8.2.8.1 are only applicable to participants of the cough 
substudy.
8.2.8.1
VitaloJAK® Cough Monitor Device
Twenty-four-hour ambulatory monitoring of coughing will be performed at timepoints as 
specified in the SoA (Table 1). The assessment of 24-hour coughs per hour (ie, average hourly 
cough frequency based on 24-hour sound recordings) will be evaluated using the VitaloJAK® 
Ambulatory Cough Monitor (ACM) (Vitalograph, Buckinghamshire, UK), which has been 
implemented successfully in clinical studies of potential cough therapies. Participants will be 
provided with the device and appropriate training for its use. The participants will be able to 
manually mute the recordings. Data from the device will be filtered for voice frequencies, and 
speech will not be analysed. If the first recording is successful but the Week 12 recordings are 
not usable, the Week 12 assessment can be repeated as soon as possible but no later than 
Week 18. If the first recording at start of treatment is unsuccessful, the Week 12 recording can 
be omitted. The participants will be asked to return the device to site after completion of 
recording as soon as feasible. At some sites, the participants will also have the option of 
having the device collected, eg, by courier. This data will not be used for any safety 
assessments. The VitaloJAK® Cough Monitor is regulated as a medical device and has import 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
90 of 187
approval in each study region where the cough substudy will be performed.
The VitaloJAK® Cough Monitor will be fitted and worn by the participants for approximately 
24 hours after the visits detailed in the SoA (Table 1). 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 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. The data digitally recorded on the ACM will be sent to 
Vitalograph who will undertake cough counting for all participants using a standardised 
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 analysing 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.
8.2.9
Q-SAW Substudy
Participants from selected sites in selected countries, who provide written informed consent, 
will be eligible to participate in the Q-SAW substudy. Not all participants that provide consent 
will be interviewed.
Participants may be invited to 2 semi-structured interviews: an initial interview and a second 
interview up to 6 weeks later. Each interview will take approximately 30 minutes and will be 
conducted over video call or telephone call. A topic list and interview guide with example 
questions will be used as a framework for the interviews (Appendix L 3).
This substudy will be conducted by an external vendor, GPRI (Groningen, Netherlands). 
Results of this substudy will be reported separately from the CSR.
Further details of the Q-SAW substudy are described in Appendix L.
8.2.10
SPFQ Substudy
Participants at selected sites will be eligible to complete the SPFQ, which will give 
participants the opportunity to provide feedback on their clinical study experience. Informed 
consent will be given via the UNIFY platform immediately prior to completing the 
questionnaire.
Participants will be asked to complete the questionnaire at the beginning, middle and end of 
the study in electronic format via the UNIFY platform as specified in the SoA (Table 1).


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
91 of 187
Results of this substudy will be reported separately from the CSR.
Further details of the SPFQ Substudy and a copy of the SPFQ are shown in Appendix M.
8.2.11
Patient Experience Interview Substudy
A subsample of participants from selected sites in selected countries will be invited to take 
part in a semi-structured interview. The interview will take approximately 60 minutes and will 
be conducted video or telephone call via Zoom. The timepoints of the interviews will be 
stratified over the study duration, starting after at least 2 study visits. A topic list and interview 
guide will be used as a framework for the interviews (Appendix N 2).
This substudy will be conducted by an external vendor, GPRI (Groningen, Netherlands). 
Results of this substudy will be reported separately from the CSR.
Further details of the Patient Experience Interview Substudy are described in Appendix N.
8.3
Safety Assessments
Planned timepoints for all safety assessments are provided in the SoA (Table 1).
8.3.1
Physical Examinations

A complete physical examination will be performed and include assessments of the 
following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose, and throat), lymph nodes, thyroid, muscular-skeletal 
(including spine and extremities) and neurological systems. 

A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
Physical examination will be performed at timepoints as specified in the SoA (Table 1). 
8.3.2
Vital Signs
Vital signs (supine BP [average of 3 measurements], respiratory rate, pulse rate, and body 
temperature) will be performed in-clinic at timelines as specified in the SoA (Table 1).
Vital sign assessments are to be collected using equipment supplied by the investigator.
At Visits SV3 and SV5, the vital signs BP measurements can be used for the pre-dose supine 
measurements for the orthostatic test, if taken after being supine for at least 10 minutes and as 
long as the standing BP measurements are taken after these supine measurements at the time 
intervals described below for the orthostatic blood pressure measurement.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
92 of 187
The measurements should be done before any blood sampling. The measurements should be 
preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions.
Orthostatic Blood Pressure Measurements and Follow-up of Confirmed Orthostatic 
Hypotension 
Orthostatic BP measurements will be obtained using a standard sphygmomanometer after 
scheduled supine measurements (1 and 3 minutes after the participant stands) and prior to any 
required blood draw:

At SV3 (baseline; Day 1), orthostatic BP should be measured pre-dose and 1 to 2 hours 
post dose.

At SV5 (Week 12), orthostatic BP should be measured pre-dose.
To minimise chances of orthostatic hypotension related to volume depletion, participants 
should be well hydrated when they come to the clinic for study visits. Supine BP measures 
will be collected after participants have been lying down for at least 10 minutes. To ensure 
that a stable supine BP is obtained, at least 2 systolic and 2 diastolic BP measurements will be 
obtained. If the replicate measurements differ by no more than 10 mmHg and 5 mmHg, 
respectively, the supine BP will be considered stable. The mean value of each replicate (mean 
systolic and mean diastolic value) will represent the baseline BP for that visit. After stable BP 
is achieved, the participant will stand, and BP measurements will be taken at 1 and 3 minutes 
after the participant stands. If the BP measurements do not meet the criteria for orthostatic 
hypotension, no additional measurement is needed. If the BP measurement meets the criteria 
shown in Table 5, investigators will repeat the supine and standing measurements up to 
2 additional times. The exception is for participants with orthostatic hypotension symptoms: in 
this situation, the orthostatic hypotension AE should be reported based on a single orthostatic 
test sequence.
When evaluating orthostatic vital signs, any symptoms of dizziness or light headedness should 
be recorded on the AE page in the eCRF. At Visit SV3, if orthostatic hypotension is confirmed 
pre-dose and post-dose, the orthostatic hypotension AE should be reported twice (pre-dose and 
post-dose). The same applies to symptoms related to the measurement of orthostatic vitals: if 
present pre-dose and post-dose, it should also be reported as an AE twice (pre-dose and post-
dose).


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
93 of 187
Table 5
Orthostatic Blood Pressure Criteria and Management
Decrease in BP indicative of 
orthostatic hypotension 
Actions
≥ 20 mmHg systolic or 
≥ 10 mmHg diastolic 
Repeat the BP measurements (supine and standing) up to 2 additional 
times, unless orthostatic hypotension is present in association with 
symptoms related to the measurement of orthostatic vitals: in such a case 
the test does not need to be repeated and the orthostatic hypotension AE 
and symptoms related to the measurement of orthostatic vitals AE should 
be reported based on a single sequence.
If either the 1-minute or 3-minute standing BP meets the orthostatic 
(postural) hypotension criteria, then the sequence is considered indicative 
of orthostatic hypotension. 
If 2 of 2 or 2 of 3 sequences are positive, then orthostatic hypotension is 
confirmed, and an AE of orthostatic hypotension will be reported. 
AE = adverse event; BP = blood pressure.
For participants with orthostatic hypotension, individualised treatment should be prescribed at 
the investigator’s discretion following local guidelines, including pharmacological (eg, down 
titration of nitrates) or non-pharmacological (eg, hydration) treatments.
8.3.3
Electrocardiograms
12-lead ECG will be performed in-clinic at timepoints as specified in the SoA (Table 1).
Single 12-lead ECG (standard ECG with a paper speed of 25 to 50 mm/second covering at 
least 6 sequential beats) will be obtained after the participant has been resting in a supine 
position for at least 5 minutes, at the visits outlined in the SoA (Table 1). An ECG machine 
that automatically calculates the heart rate and RR interval and measures PR, QRS, QT, and 
QTcF (Fridericia) intervals will be used. Interpretation of the clinical safety ECG findings will 
be reviewed and confirmed by the investigator and recorded in the eCRF.
Electrocardiogram assessments are to be collected using equipment supplied by the 
investigator.
8.3.4
Clinical Safety Laboratory Tests
Blood and urine samples for determination of clinical chemistry, haematology, coagulation, 
and urinalysis will be taken in-clinic or at a designated phlebotomy service location at the 
visits indicated in the SoA (Table 1).
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 at the 
central laboratory, except for tests completed using urine dipstick tests, which will be done 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
94 of 187
locally (see Table 6 for details of these tests). Abnormal clinically significant laboratory 
results should be repeated as soon as possible (preferably within 24 hours). 
Additional safety samples, including ANCA samples, may be collected, if clinically indicated, 
at the discretion of the investigator. The date, time of collection, and results (values, units, and 
reference ranges) will be recorded on the appropriate eCRF.
The laboratory variables to be measured are presented in Table 6.
Table 6
Laboratory Safety Variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin (Hb)
S/P-Creatinine
B-Leukocyte count
S/P-Bilirubin, total
B-Leukocyte differential count (absolute count)
S/P-Alkaline phosphatise (ALP)
B-Platelet count
S/P-Aspartate transaminase (AST)
Urinalysis (dipstick) 
S/P-Alanine transaminase (ALT)
Leukocytes
S/P-Albumin
Nitrite
S/P-Potassium
Urobilinogen
S/P-Calcium, total
Protein
S/P-Sodium
Blood
S/P-Creatine kinase (CK)
Ketone
Thyroid tests
Bilirubin
Free T4 and total T4
Glucose
T3
Other
Thyroid stimulating hormone (TSH)
FSH (screening only, if needed to confirm post-
menopausal status in female participants aged < 50 
years only)
Coagulation parameters (screening only)
ANCA (optional if rash AE occurs, at the discretion 
of investigator) 
Prothrombin time (PT)
Viral serology (screening only):
Activated partial thromboplastin time (aPTT)
Hepatitis B
International normalised ratio (INR)
Hepatitis C
Fibrinogen
HIV-1
-
NB. 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 Hy’s Law, for further instructions.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
95 of 187
8.3.5
SARS-CoV-2 Screening
A SARS-CoV-2 (COVID-19) screening test can be performed at the time of study visits if 
required by local clinical guidelines for the safety of site staff and other site attendees but 
otherwise is not mandated in the study.
8.4
AEs, SAEs, and Other Safety Reporting 
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.
Participants (or, when appropriate, a caregiver, surrogate, or the participant’s legally
authorised representative) will notify the investigator or designees of symptoms. These must 
then be assessed by the investigator and if considered an AE it will be reported by the 
investigator.
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
AE variables
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

Maximum intensity

Maximum CTCAE grade for maculopapular rash and non-maculopapular rash

Whether the AE is serious or not

Investigator causality rating against the IMP (yes or no)

Action taken with regard to IMP

Whether the event is a serious infection including pneumonia or skin reaction including 
maculopapular rash

AE caused participant’s withdrawal from the study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date investigator became aware of SAE


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
96 of 187

AE description

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
8.4.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events will be collected from the time of first dose of study intervention throughout 
the treatment and the follow-up periods (SV8; Table 1). The only exception is related to the 
pre-dose orthostatic test at Visit SV3: if orthostatic hypotension is confirmed, it should be 
reported as an AE, and symptoms related to the measurement of orthostatic vital signs if 
present should also be reported as an AE.
Serious adverse events will be recorded from the time of signing of the ICF.
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 treated participant, the investigator shall, 
without undue delay, report the SAE to AstraZeneca.
Participants should be reminded at each visit to contact the investigator immediately, if rash or 
skin reaction has developed.
8.4.2
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.
8.4.3 Causality Collection
The investigator should assess causal relationship between IMP and each AE, and answer 
‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that the 
event may have been caused by the IMP?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
97 of 187
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B.
8.4.4 AEs Based on Examinations and Tests
Deterioration as compared to baseline in protocol-mandated measurements should only be 
reported as AEs if they meet any of the following:

fulfil any of the SAE criteria 

are the reason for discontinuation of the IMP

are clinically relevant as judged by the investigator (which may include but not be limited 
to consideration as to whether treatment or non-planned visits were required or other 
action was taken with the IMP, eg, dose adjustment or drug interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in 
non-mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study.
The results from the protocol mandated laboratory tests and vital signs will be summarised in 
the CSR.
8.4.5 AEs Based on Signs and Symptoms
All signs or symptoms spontaneously reported by the participant or reported in response to the 
open question from the study site staff: ‘Have you had any health problems since the previous 
visit/you were last asked?’ or revealed by observation will be collected and recorded in the 
eCRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms. However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately.
8.4.6 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 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
98 of 187
need to be reported as SAEs. Please refer to Appendix E for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law.
8.4.7 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 AEs during the study unless they meet SAE criteria or lead to discontinuation of the IMP.
8.4.8
Reporting of SAEs
All SAEs must be reported, whether or not considered causally related to the IMP. All SAEs 
will be recorded in the eCRF.
If any SAE occurs during the study, investigators or other site personnel will inform the 
appropriate AstraZeneca representatives within one day ie, immediately but no later than 24 
hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day, ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the investigators or other site personnel indicate an AE is serious in the eCRF, an 
automated email alert is sent to the designated AstraZeneca representative.
If the eCRF is not available, then the investigator or other study site staff reports the SAE via 
secure method to the appropriate AstraZeneca representative.
When the eCRF is temporarily not accessible, the AstraZeneca Study Representative should 
confirm that the investigator/site staff enters the SAE in the AstraZeneca eCRF when access 
resumes. 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
99 of 187
8.4.9
Adverse Events of Special Interest
The following events are defined as AESI for mitiperstat (AZD4831) in this study:
Skin reactions, including maculopapular rash
To ensure that data are collected systematically, any skin reaction will be recorded on a special 
eCRF page. All skin reactions should be recorded in the eCRF as an AE or SAE. If the rash is 
considered maculopapular, it will be evaluated using CTCAE Grades 1 to 3 for maculopapular 
rash; if not considered maculopapular, severity will be captured as mild/moderate/severe, 
along with data element components generally used for CTCAE grading of other skin 
reactions, given that CTCAE grading is specific to the particular type of skin lesion. For all 
rashes, various aspects of the rash will be documented, including start/end date, morphology 
of lesions (maculopapular vs other morphologies), BSA impacted, anatomical site(s), 
symptoms, effect on participant (including ADL impacted), concomitant medications, 
medication administered, and specific rash diagnosis, if available. Photos (overview and 
detailed) should be taken. Please refer to Appendix B, B 5 for further guidance in rash 
assessment and reporting.
At all visits, participants will be instructed to contact the investigator immediately if rash or 
skin reaction has developed at any timepoint during the study. Participants will be 
recommended to make an acceptable quality self-photo of skin affected with rash/skin 
reaction.
Participants who develop skin reactions, including rash, will be asked to return to the clinic for 
an additional visit that will include a full physical examination and blood samples for safety, 
hsCRP, and PK. If a participant is discontinued from investigational product and proceeds to 
the EDV (SV7/EDV; see Table 1), an exploratory biomarker sample and blood and urine 
samples for exploratory metabolite analysis will also be collected. It is suggested to start 
treatment for maculopapular rash, per local standard treatment guidelines (which may include, 
but not be limited to, a topical steroid and/or oral antihistamine). The treatment should be 
individualised per participant and based on PI discretion. Upon PI discretion, a clinical 
dermatologist can be consulted, and a skin biopsy considered. The participant can be provided 
with a treatment for the skin rash, according to clinical management standard. Blood samples 
should be drawn prior to treatment, if possible, and without delaying treatment.
Serious infections, including pneumonia
Local laboratory testing for microorganisms per local guidelines is requested for serious 
infections (those that meet SAE criteria) and results documented. Any imaging reports and 
scans should be uploaded to the Medidata imaging portal and included in source documents. 
8.4.10
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
100 of 187

If the pregnancy is discovered before the study participant has received any study 
intervention.
8.4.10.1
Maternal Exposure
Females of childbearing potential are not allowed to be included in this study. Should a 
pregnancy still occur, the study intervention should be discontinued immediately, and the 
pregnancy reported to AstraZeneca.
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 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital anomaly/birth defect) should be followed up and documented even if the 
participant was discontinued from the study.
If any pregnancy occurs during the study, then the investigator or other site personnel informs 
the appropriate AstraZeneca representatives immediately but no later than 24 hours after he 
or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 
or 5 calendar days for pregnancies associated with SAEs (see Section 8.4.8) and within 
30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module is used to report the outcome of the pregnancy.
8.4.10.2
Paternal Exposure 
Male participants should refrain from fathering a child or donating sperm from Day 1 until the 
end of relevant systemic exposure in the male participant, plus a further 105 day period.
In case of pregnancy in the partner of a male participant, the partner’s pregnancy should be 
reported on the pregnancy form (consent from the partner must be obtained before the 
pregnancy form is completed) following the same timeframe and routing as described for any 
participant’s pregnancy. Pregnancy of the participant’s partner is not considered to be an AE. 
These pregnancies will also be followed up, and the outcome of the pregnancy (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital anomaly) 
should, if possible, be obtained and documented.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
101 of 187
8.4.11
Medication Error, Drug Abuse, and Drug Misuse
8.4.11.1
Timelines
If an event of medication error, drug abuse, or drug misuse occurs during the study, then the 
investigator or other site personnel informs the appropriate AstraZeneca representatives within 
one calendar day, ie, immediately but no later than 24 hours of when they become aware of 
it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within one (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 event of medication error, drug abuse or misuse (see Section 8.4.8) 
and within 30 days for all other events.
8.4.11.2
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant. 
The full definition and examples of medication error can be found in Appendix B 4.
8.4.11.3
Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix B 4.
8.4.11.4
Drug Misuse 
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route.
The full definition and examples of drug misuse can be found in Appendix B 4.
8.4.12
Reporting of Overdose
Refer to Section 6.8 for definition and treatment of overdose.

An overdose with associated AEs is recorded as the AE diagnoses/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
102 of 187

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study intervention occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 
or 5 calendar days for overdoses associated with an SAE (see Section 8.4.8) and within 
30 days for all other overdoses.
8.4.13
Medical Device Deficiencies
In this study any deficiency observed with a third-party medical device will be reported 
directly to the third-party manufacturer by the study site staff according to the contact details 
in the device Instructions For Use.
A medical device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. Medical device deficiencies include 
malfunctions, use errors, and information supplied by the manufacturer.
The manufacturer’s medical device complaint report will be used to collect the deficiency.
8.5
Pharmacokinetics

Blood samples will be collected for measurement of plasma concentrations of mitiperstat 
(AZD4831) as specified in the SoA (Table 1). Pharmacokinetic samples will be collected 
pre-dose; thus, participants should be reminded not to take their study medication at home 
on the day of their clinic visit as they will receive study medication in clinic on these 
days.

In a subset of approximately 20% of participants, 2 additional (post-dose) samples will be 
taken at SV5. Once approximately 20% of participants have been tested, no further 
participants need this additional post-dose sampling.

For participants who are discontinued from investigational product due to rash, a PK 
sample should be collected at the discontinuation visit.

Samples may be collected at additional timepoints during the study if warranted and 
agreed upon between the investigator and AstraZeneca, eg, for urgent safety reasons, and 
this may be reflected as a protocol deviation. 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
103 of 187

The timing of sampling may be altered during 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. 

Plasma samples will be used to analyse the PK of mitiperstat (AZD4831). Samples 
collected for analyses of mitiperstat (AZD4831) plasma concentration may also be used 
to evaluate safety or efficacy aspects related to concerns arising during or after the study.

Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory 
Manual.

For storage, re-use, and destruction of samples for PK see Appendix C. 

Pharmacokinetics samples will be disposed of after the Bioanalytical Report finalisation 
or 6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
consented for future analyses. 

Only samples from participants on active treatment will be analysed (Section 6.3), unless 
there is a need to confirm that correct treatment has been given to study participants.

Additional analyses may be conducted on the anonymised, pooled, or individual PK 
samples to further evaluate and validate the analytical method. Any results from such 
analyses may be reported separately from the CSR.
8.5.1
Collection of Samples for Pharmacokinetics
Blood samples will be collected for measurement of mitiperstat (AZD4831) as specified in the 
SoA (Table 1). 
Blood and urine samples will be collected for exploratory metabolite analysis as specified in 
the SoA (Table 1).
8.5.2
Determination of Drug Concentration
Samples for determination of drug concentration in plasma 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.
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.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
104 of 187
8.6
Pharmacodynamics
8.6.1
Collection of Samples for Pharmacodynamics
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
Blood and sputum samples will be collected for PD assessments as specified in the SoA 
(Table 1).
Pharmacodynamic blood samples to assess:

Systemic target engagement: blood samples will be taken to assess MPO activity and 
concentration in a subsample of approximately 60 participants in selected countries.
Pharmacodynamic sputum samples to assess:

Target engagement: sputum samples will be taken to assess MPO activity and 
concentration in sputum supernatant.
For storage, re-use and destruction of samples for PD see Appendix C.
8.7
Optional Genomics Initiative Sample
Collection of optional samples for Genomics Initiative research is also part of this study as 
specified in the SoA and is subject to agreement in the ICF addendum.
A blood sample for DNA isolation will be collected from participants who have consented to 
participate in the genetic analysis component of the study (see SoA; Section 1.3). Participation 
is optional. Participants who do not wish to participate in the genetic research may still 
participate in the study.
See Appendix D for information regarding the Genomics Initiative genetic sample. Details on 
processes for collection and shipment and destruction of these samples can be found either in 
the appendices of this protocol or in the Laboratory Manual.
For storage and destruction of genetic samples see Appendix D.
8.8
Biomarkers
8.8.1
Mandatory Biomarker Sample Collection

Samples for biomarker research are required and will be collected from all participants in 
this study as specified in the SoA (Table 1).

Samples will be tested for biomarkers related to cardiovascular comorbidities, 
neutrophils, lung tissue destruction, the development of skin reactions, and COPD disease 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
105 of 187
activity to evaluate their association with the observed clinical responses to 
mitiperstat (AZD4831) compared with placebo.
Blood samples to assess:

Systemic biomarkers of cardiovascular comorbidities: NT-proBNP, hsCRP, IL-6, and 
plasma fibrinogen. *

Putative biomarkers of lung tissue destruction and COPD disease progression. *

Putative circulating markers of airway MPO as assessed by proteomics. *

Gene expression as assessed by transcriptomic analysis of mRNA. *
Sputum samples to assess: 

MPO concentration and activity.

Other markers of inflammation and neutrophil activation. *

Putative biomarkers of lung tissue destruction and COPD disease progression. *

Differential cell counts (at SV3 only, where local equipment for analysis is available).*
Nasal mucosal lining fluid samples to assess:

MPO concentration and markers of lung tissue destruction. *
* will not be delivered prior to database lock and will not be part of the CSR. 
For participants who discontinue investigational product due to rash or skin reaction, blood 
and urine will be collected at the EDV for exploratory biomarker analysis in blood and 
analysis of mitiperstat (AZD4831) metabolites in urine and plasma. Samples will be collected, 
handled, labelled, stored, and shipped as detailed in the Laboratory Manual. For storage, 
re-use and destruction of exploratory samples, see Appendix C.
8.8.2
Optional Cell-free DNA Analysis Sample Collection
Two blood samples for cell-free DNA analysis (see SoA; Table 1) will be collected from 
participants who have consented to participate in the genomic analysis component of the 
study. Participation is optional. Participants who do not wish to participate in the genetic 
research may still participate in the study.
8.9
Medical Resource Utilisation and Health Economics
Health economics/Medical resource utilisation and health economics parameters are not 
evaluated in this study. 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
106 of 187
9
STATISTICAL CONSIDERATIONS
The SAP will be finalised prior to database lock and it will include a more technical and 
detailed description of the planned statistical analyses. This section is a summary of the 
planned statistical analyses of the most important endpoints including primary and key 
secondary endpoints.
9.1
Statistical Hypotheses
Null hypothesis that there is no difference in the time to first COPDCompEx event in 
mitiperstat (AZD4831) 5 mg QD vs placebo with an alternative hypothesis that there is a 
difference in the time to first COPDCompEx event. As a single logrank test, adjustment for 
multiple testing will not be required.
9.2
Sample Size Determination
The study is powered using COPDCompEx, a composite endpoint used to predict treatment 
effect on moderate and severe exacerbations of COPD (see Section 8.2.1).
The time to first COPDCompEx event will be compared between mitiperstat (AZD4831) 5 mg 
QD vs placebo arms using a logrank test. A total of 194 first COPDCompEx events (estimated 
to require 203 participants per arm) will provide 80% power at the two-sided 10% level of 
statistical significance to detect a hazard ratio of 0.70 in the mitiperstat (AZD4831) 5 mg QD 
arm based on a 24-week first COPDCompEx event risk of 55% assumed in the placebo arm 
(constant over the course of the study). 
A screen failure rate of 40% is assumed, therefore approximately 677 participants will be 
screened to achieve randomisation of 406 participants.
For all other secondary or exploratory endpoints, no formal sample size calculation was 
performed. Further information is available in the SAP.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
107 of 187
9.3
Populations for Analyses
The following populations are defined:
Table 7
Populations for Analysis
Population/Analysis set
Description
Full Analysis Set (FAS) 
Will include all randomised participants who received at least 1 dose of 
study intervention. Participants will be analysed according to planned 
treatment. Efficacy analyses will be based on the FAS.
Safety Analysis Set (SAF) 
Will include all participants who received at least 1 dose of study 
intervention. Participants will be analysed according to actual treatment. 
Safety analyses will be based on the SAF.
Per Protocol Set (PP)
Will include all participants in the FAS who have no important protocol 
deviations thought to affect the analysis of COPDCompEx and FEV1 data.
PK Analysis Set
Will include all participants who received mitiperstat (AZD4831) and who 
have evaluable PK data for mitiperstat (AZD4831), with no important 
protocol deviations thought to impact on the analysis of the PK data.
Randomised Set
Will include all participants who have been randomised.
Cough subset
Will include the subset of FAS who consented to the cough substudy.
Participants will be analysed according to their randomised study intervention arm.
9.4
Statistical Analysis
9.4.1
General Considerations
The statistical methodology below describes the high-level statistical analysis as it is foreseen 
when the study is being planned.
All original and derived parameters as well as demographic and disposition data will be listed 
and described using summary statistics. Continuous data will be summarised using descriptive 
statistics (number of observations, mean, SD, median, 25th and 75th percentiles [where 
appropriate], minimum and maximum). In the case of log-transformed data, the geometric 
mean, CV% of geometric mean, median, minimum, and maximum will be presented. 
Frequencies and percentages will be used to summarise categorical data. Only the minimum, 
median, and maximum will be presented for time parameters such as tmax.
Deviations from the protocol will be assessed as “important” or “not-important” by blinded 
members of the study team.
Deviations will be defined before database hard lock and unblinding. Important deviations 
will include the following:

Violation of inclusion and/or exclusion criteria


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
108 of 187

Participants who developed withdrawal criteria during the study but were not withdrawn

Wrong study intervention or incorrect dose administered

Administration of prohibited concomitant medications that are expected to influence the 
measurement of the primary endpoint
A BDRM will be held before database hard lock and unblinding. The reasons for excluding 
participants or data from the study will be defined in the SAP and documented in the BDRM 
report.
9.4.2
Efficacy
9.4.2.1
Primary Endpoint
The primary endpoint to evaluate the clinical efficacy of mitiperstat (AZD4831) 5 mg 
compared with placebo is time to first COPDCompEx event. After at least 194 first 
COPDCompEx events have occurred, enrolment will be stopped and when the last participant 
completes 12 weeks of treatment, the study will stop (see Section 7.1.4). A logrank test and 
Cox's proportional hazards model will be used to analyse the time to first COPDCompEx 
event data. Survival probabilities will be presented as survival curves estimated using the 
Kaplan-Meier method. A two-sided logrank test P-value ≤ 0.10 is required to provide evidence 
of efficacy.
The primary estimand strategy for intercurrent events will be while on treatment and the 
supportive estimand strategy will be treatment policy (see Table 3). Model assumptions will 
be checked and mitigations for possible non-proportionality will be described in the SAP.
9.4.2.2
Secondary Endpoints
A similar approach to that described for the primary efficacy endpoint will be applied to the 
secondary endpoint: time to first exacerbation.
In order to ensure that the same event is not counted twice, concurrent moderate or severe 
COPD exacerbations with start and stop dates ≤7 days apart will be considered the same 
event and assigned the maximum severity between the two. Time during an exacerbation or in 
the 7 days following an exacerbation will not be included in the calculation of time at risk. 
However, the start day of a COPD exacerbation will not be excluded from the time at risk.
Any COPD exacerbation that occurs within 7 days of the last dose of systemic corticosteroids 
(oral, intramuscular, intravenous) or antibiotics or the last day of hospitalisation or emergency 
room visit for a prior COPD exacerbation will be combined and counted as a single 
exacerbation event and as the maximum severity between the individual events. Further 
details on combining exacerbation events will be provided in the SAP. Consistent criteria will 
be applied to all exacerbation endpoints.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
109 of 187
Plasma concentrations will be summarised by timepoint in all participants. Pharmacokinetic 
data for those participants with additional PK sampling at Visit SV5 will be used to derive 
plasma PK parameters such as Cmax and tmax.
9.4.2.3
Tertiary/Exploratory Endpoints
Details for the analyses of exploratory efficacy endpoints will be included in the SAP.
9.4.3
Safety
Adverse Events
Adverse events will be coded using the most recent version of MedDRA that will have been 
released for execution at AstraZeneca. Adverse events will be presented for each treatment 
group by system organ class and/or preferred term covering number and percentage of 
participants reporting at least one event and number of events where appropriate. An overview 
of AEs will be presented for each treatment group the number and percentage of participants 
with any AE, AEs with outcome of death, SAEs, and AEs leading to discontinuation of IP.
Separate AE tables will be provided taking into consideration seriousness, death, and events 
leading to discontinuation of IMP. An additional table will present number and percentage of 
participants with most common AEs. Most common (eg, frequency of > x%, ≥x%) will be 
defined in the SAP. In accordance with the requirements of the FDA, a separate table will 
present non-serious AEs occurring in more than 5% of participants in any treatment group. 
Key participants information will be presented for participants with AEs with outcome of 
death, SAEs, and AEs leading to discontinuation of IMP. An AE listing for the SAF will cover 
details for each individual AE. AESIs related to skin reactions, including maculopapular rash, 
and infection, including pneumonia, will be presented. Full details of AE analyses will be 
provided in the SAP.
Vital Signs
Vital sign parameters will be presented for each treatment group. Summary statistics for 
continuous variables cover n, mean, SD, min, Q1, median, Q3, and max. For each scheduled 
post-baseline visit, descriptive statistics for all vital sign parameters will be presented for 
observed values and change from baseline. Details of vital sign analyses will be provided in 
the SAP.
Laboratory Parameters
Laboratory parameters will be presented for each treatment group. Summary statistics for 
continuous variables cover n, mean, SD, minimum, Q1, median, Q3, and maximum. For each 
scheduled post-baseline visit, descriptive statistics for all clinical chemistry and haematology 
parameters will be presented for observed values and change from baseline. A frequency table 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
110 of 187
presents the number of participants reporting at least one abnormality in selected laboratory 
parameters. Details of laboratory analyses will be provided in the SAP.
Electrocardiogram
Electrocardiogram parameters will be presented for each treatment group. Summary statistics 
for continuous variables cover n, mean, SD, minimum, Q1, median, Q3, and maximum. For 
each scheduled post-baseline assessment, descriptive statistics for all ECG parameters will be 
presented for observed values and change from baseline. Supportive ECG listings will cover 
observed values for each individual participant. Details of ECG analyses will be provided in 
the SAP.
9.5
Interim Analysis
An administrative IA will be conducted after 136 (70% of the required 194) first 
COPDCompEx events have occurred. It will allow an early assessment of efficacy for 
mitiperstat (AZD4831), according to the decision framework (Frewer et al 2016). No formal 
statistical test will be conducted. The IA assessment will be used to guide internal 
(AstraZeneca) decision-making regarding further development of the mitiperstat (AZD4831) 
programme. As a result, no alpha will be spent at the IA. A URC will be set up to review data 
from this administrative IA on the primary efficacy endpoint. (see Appendix A 5 for further 
details).
The URC charter will describe the planned administrative IA in greater detail.
9.6
Data Review Committee 
The DRC members will be notified on an ongoing basis of all skin reaction and pneumonia 
events and can call a meeting at any time to discuss the event frequency. Although not part of 
the IA, the DRC will conduct an evaluation of safety at the time of the administrative IA, to 
allow efficacy IA outcome data to be considered should it be required. For details on the DRC 
for this study, see Appendix A 5.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
111 of 187
Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:
-
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki as amended at 64th WMA General Assembly, Fortaleza, 
Brazil, October 2013 and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines
-
Applicable ICH GCP Guidelines
-
Applicable laws and regulations

The protocol, revised protocol, ICF, Investigator’s Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.

Any revised protocol will require IRB/IEC and applicable Regulatory Authority approval 
before implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with AstraZeneca.

The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to AstraZeneca 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 investigation are met.

AstraZeneca 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. AstraZeneca will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and AstraZeneca policy 
and forwarded to investigators as necessary.

Adherence to European Medical Device Regulation 2017/745 for clinical device research 
(if applicable), and all other applicable local regulations


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
112 of 187

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from AstraZeneca will 
review and then file it along with the Investigator’s Brochure and other relevant 
documents and will notify the IRB/IEC, if appropriate according to local requirements.
Regulatory Reporting Requirements for Serious Breaches

Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met.

A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a participant or the reliability and robustness of the data generated in the 
clinical study.

If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
he or she becomes aware of it.

In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.

AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If EU 
Clinical Trials Regulation 536/2014 applies, AstraZeneca is required to enter details 
of serious breaches into the European Medicines Agency (EMA) Clinical Trial 
Information System (CTIS). It is important to note that redacted versions of serious 
breach reports will be available to the public via CTIS.

The investigator should have a process in place to ensure that:
o
The site staff or service providers delegated by the investigator/institution are 
able to identify the occurrence of a (potential) serious breach

A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by AstraZeneca.
A 2
Financial Disclosure
Investigators and sub-investigators will provide AstraZeneca with sufficient, accurate 
financial information as requested to allow AstraZeneca to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the study 
and for 1 year after completion of the study.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
113 of 187
A 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorised representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, privacy and data protection 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.

If new information requires changes to the ICF, consider if participants must be re-
consented and if so, this must be to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative.
Participants who are rescreened are required to sign a new ICF.
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 samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period.
A 4
Data Protection

Participants will be assigned a unique identifier by AstraZeneca. Any participant records 
or datasets that are transferred to AstraZeneca 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 
AstraZeneca 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 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
114 of 187
AstraZeneca, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.

The participant must be informed that data will be collected only for the business needs. 
We will only collect and use the minimum amount of personal data to support our 
business activities and will not make personal data available to anyone (including internal 
staff) who is not authorised or does not have a business need to know the information. 

The participant must be informed that in some cases their data may be pseudonymised. 
The General Data Protection Regulation (GDPR) defines pseudonymisation as the 
processing of personal data in such a way that the personal data can no longer be 
attributed to a specific individual without the use of additional information, provided that 
such additional information is kept separately and protected by technical and 
organisational measures to ensure that the personal data are not attributed to an identified 
or identifiable natural person.
A 5
Committees Structure

A URC consisting only of AstraZeneca personnel will require unblinding and will be 
independent from the study team. The URC will ensure that the IA is performed in a way 
that maintains the integrity of the study and in accordance with the IA unblinding plan. 
The URC will communicate to the study team as specified in the URC charter.

A DRC consisting of AstraZeneca personnel, an external dermatologist, and an external 
pulmonologist will be set up for periodic safety monitoring, with a focus on skin 
reactions and pneumonia. The AstraZeneca personnel in the DRC will be independent 
from the study team. At the time of the IA, the DRC will assess the safety profile (ie, all 
AE data) of mitiperstat (AZD4831) and will have access to IA outcome data, if required. 
Additional details will be contained in the DRC Charter.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the 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 CRESCENDO study is conducted.
A 7
Data Quality Assurance 

All participant data relating to the study will be recorded on eCRF unless transmitted to 
AstraZeneca or designee electronically (eg, laboratory data). The investigator is 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
115 of 187
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy, including definition of study-critical data items 
and processes (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 included in the 
Monitoring Plan.

AstraZeneca or designee is responsible for medical oversight throughout the conduct of 
the study which includes clinical reviews of study data in accordance with the currently 
approved protocol. Monitoring details describing clinical reviews of study data from a 
medical perspective are included in more detail in the Monitoring Plan(s).

AstraZeneca or designee is responsible for the data management of this study including 
quality checking of the data.

AstraZeneca assumes accountability for actions delegated to other individuals 
(eg, CROs).

Study monitors will perform ongoing source data verification as per the 
Monitoring Plan(s) to confirm that data entered into the eCRF by authorised site 
personnel are accurate, complete, and verifiable from source documents; that the safety 
and rights of participants are being protected; and that the study is being conducted in 
accordance with the currently approved protocol and any other study agreements, ICH 
GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 25 years after study archiving or as required by 
local regulations, according to the AstraZeneca Global Retention and Disposal (GRAD) 
Schedule. No records may be destroyed during the retention period without the written 
approval of AstraZeneca. No records may be transferred to another location or party 
without written notification to AstraZeneca.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
116 of 187

Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available.

Definition of what constitutes source data can be found in the source data verification 
plan.
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first site open and will be the study start date.
AstraZeneca designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of AstraZeneca. 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 AstraZeneca 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, AstraZeneca’s procedures, or GCP guidelines.

Inadequate recruitment of participants by the investigator.

Discontinuation of further study intervention development.
Reasons for the early termination of the study by AstraZeneca may include but are not 
limited to:

The incidence, frequency, duration or severity of AEs in this or other studies exposing 
participants to undue harm.

Participant enrolment is unsatisfactory.

Non-compliance that might significantly jeopardise the validity or integrity of the study.

AstraZeneca decision to terminate development of the investigational product for this 
indication.

Unjustifiable risk resultant from the risk-benefit assessment conducted at the IA.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
117 of 187
If the study is prematurely terminated or suspended, AstraZeneca shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study. 
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to AstraZeneca 
before submission. This allows AstraZeneca to protect proprietary information and to 
provide comments.

AstraZeneca will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, AstraZeneca 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.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
118 of 187
Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether considered related to the 
medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered.
B 2
Definition of Serious Adverse Events
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, 
follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient 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 SAEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should 
be used. In certain situations, however, medical judgement on an individual event basis should 
be applied to clarify that the malignant tumour event should be assessed and reported as a 
non-SAE. For example, if the tumour is included as medical history and progression occurs 
during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumour, the AE may not fulfil the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumour as an AE is valid and should occur. Also, 
some types of malignant tumours, which do not spread remotely after a routine treatment that 
does not require hospitalisation, may be assessed as non-serious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
119 of 187
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 medicinal product would result in 
the participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more 
severe form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself an SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the participant was enrolled in the study, provided that it did not deteriorate in an unexpected 
way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
Intensity Rating Scale:

Mild (awareness of sign or symptom, but easily tolerated)

Moderate (discomfort sufficient to cause interference with normal activities)

Severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs. Severity is a measure of 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
120 of 187
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.
B 3
A Guide to Interpreting the Causality Question
When assessing causality consider the following factors when deciding if there is a 
‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host, or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
rechallenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest a 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
121 of 187
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 4
Medication Error, Drug Abuse, and Drug Misuse
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error: 

Occurred

Was identified and intercepted before the participant received the drug

Did not occur, but circumstances were recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, eg, wrong route or wrong site of administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed, eg, kept in the fridge when it should be at room temperature 

Wrong participant received the medication (excluding IRT/RTSM errors)

Wrong drug administered to participant (excluding IRT/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT/RTSM - including those which lead to one of the 
above listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose)


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
122 of 187

Participant failed to return unused medication or empty packaging
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the Data Entry Site (DES) using the Drug Abuse Report Form. This form should be used both 
if the drug abuse happened in a study participant or if the drug abuse regards a person not 
enrolled in the study (such as a relative of the study participant).
Examples of drug abuse include but are not limited to:

The drug is used with the intent of getting a perceived reward (by the study participant or 
a person not enrolled in the study)

The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or 
for unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study participant or if the drug misuse regards a person not enrolled in 
the study (such as a relative of the study participant).
Examples of drug misuse include but are not limited to:

The drug is used with the intention to cause an effect in another person

The drug is sold to other people for recreational purposes

The drug is used to facilitate assault in another person

The drug is deliberately administered by the wrong route


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
123 of 187

The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole

Only half the dose is taken because the study participant feels that he/she is feeling better 
when not taking the whole dose

Someone who is not enrolled in the study intentionally takes the drug
B 5
Guide to Skin Reaction Assessment
This Appendix describes the process to be followed to appropriately identify, assess, and 
report cases of skin reactions. Skin reactions, including maculopapular rash, will be 
considered AESIs in this study. To ensure that data are collected systematically, any skin 
reaction will be recorded on a special eCRF page. All skin reactions should be recorded and 
reported as AEs or SAEs.
If the rash is considered maculopapular, it will be evaluated using CTCAE Grades 1 to 3 for 
maculopapular rash; if not considered maculopapular, severity will be captured as 
mild/moderate/severe, along with data element components generally used for CTCAE 
grading of other skin reactions, given that CTCAE grading is specific to the particular type of 
skin lesion. For all rashes, various aspects of the rash will be documented, including start/end 
date, morphology of lesions (maculopapular vs other morphologies), BSA impacted, 
anatomical site(s), symptoms, effect on participant (including ADL impacted), concomitant 
medications, medication administered, and specific rash diagnosis, if available. 
If maculopapular rash Grade 1, 2, or 3 has developed, participant must be permanently 
discontinued from IP, and AstraZeneca medical staff should be informed. 
If the participant develops a rash or skin reaction that is not considered a maculopapular rash, 
but is considered to be an SAE, the participant must be permanently discontinued from the 
study intervention and AstraZeneca medical staff should be informed.
If the participant develops a generalised rash or skin reaction that is not considered a 
maculopapular rash or SAE, the participant may continue dosing if the generalised rash/skin 
reaction occurs following the initiation of another COPD therapy (eg, antibiotics), and in the 
opinion of the investigator the rash/skin reaction is more likely to have been as a result of this 
COPD therapy. The suspect COPD therapy must be stopped and the participant must be 
monitored by the site on a daily basis until the rash/skin reaction has resolved. If, in the 
opinion of the investigator, the generalised rash/skin reaction does not resolve, worsens, or 
becomes maculopapular in appearance despite stopping the suspect COPD therapy, the 
participant must permanently discontinue the study medication. Also, if the participant 
develops a generalised rash or skin reaction in the absence of alternative suspect COPD 
medications, the participant must permanently discontinue the study medication. AstraZeneca 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
124 of 187
medical staff should be informed in the event of either occurrence.
At all visits, participants will be instructed to contact the investigator immediately if rash has 
developed at any timepoint during the study. Participants will be recommended to make an 
acceptable quality self-photo of skin affected with rash using the provisioned handheld device.
Participants who develop skin reactions, including rash, will be asked to return to the clinic for 
an additional visit that will include a full physical examination and blood samples for safety, 
hsCRP, and PK. If a participant is discontinued from investigational product and proceeds to 
the EDV (SV7/EDV; see Table 1), an exploratory biomarker sample and blood and urine 
samples for exploratory metabolite analysis will also be collected. It is suggested to start 
treatment for maculopapular rash, per local standard treatment guidelines (which may include 
but not be limited to a topical steroid and/or oral antihistamine). 
The treatment should be individualised per participant and based on PI discretion. Upon PI 
discretion, a clinical dermatologist can be consulted, and a skin biopsy considered. The 
participant can be provided with a treatment for the skin rash, according to clinical 
management standard. Blood samples should be drawn prior to treatment, if possible, and 
without delaying treatment. 
The investigator should make quality photo(s) of the participant’s skin affected with rash 
using the Medidata imaging application, that will allow the evaluation of rash according to the 
guidance given in this section. 
The Common Terminology Criteria for AEs is a descriptive terminology that can be used for 
AE reporting.
In general, CTCAE Guideline describes the Grades of AE severity from 1 to 5: 
Grade 1:  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
Grade 2:  
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL* 
Grade 3:  
Severe or medically significant, but not immediately life-threatening; 
hospitalisation or prolongation of hospitalisation indicated; disabling; limiting 
self-care ADL** 
Grade 4:  
Life-threatening consequences; urgent intervention indicated
Grade 5: 
Death related to AE


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
125 of 187
*Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc.
**Self-care Activities of Daily Living (ADL) refer to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden.
Note: for Maculo-papular rash, only 3 CTC Grades exist:
Maculo-Papular Rash
Definition: A disorder characterised by the presence of macules (flat) and papules (elevated). Also 
known as morbilliform rash, it is one of the most common cutaneous adverse events, frequently 
affecting the upper trunk, spreading centripetally and associated with pruritis.
Grade 1
Macules/papules covering < 10% BSA with or without symptoms (eg, pruritus, burning, tightness)
Grade 2
Macules/papules covering 10 to 30% BSA, with or without symptoms (eg, pruritus, burning, 
tightness); limiting Instrumental Activities of Daily Living*; rash covering > 30% BSA with or 
without mild symptoms
Grade 3
Macules/papules covering > 30% BSA, with moderate or severe symptoms; limiting Self-care 
Activities of Daily Living **
NCI 2017
To assess the BSA affected by rash, please follow the algorithm described below:
Area
Number of palms
Percent area
Whole body
100
100%
Head and Neck
10
10%
Upper extremities
20
20%
Trunk
30
30%
Lower extremities
40
40%
The participant’s palm is defined as ”1”, representing 1% of total BSA. 
Total BSA = 100% (100 palms). 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
126 of 187


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
127 of 187


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
128 of 187
Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples 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.
C 2
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 
analysed, 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.
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented, and study site is notified.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
129 of 187
C 3
International Air Transport Association Guidance Document 62nd
edition
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Air Transport Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A Pathogens are, eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900.
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN 3373 and IATA 650
Exempt Substances are 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


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
130 of 187
Appendix D
Optional Genomics Initiative Sample
D 1
Use/Analysis of DNA

AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response 
to medications. 

This genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care, and to the discovery of new diagnostics, 
treatments or medications. Therefore, where local regulations and IRB/IEC allow, a blood 
sample will be collected for DNA analysis from consenting participants.

This optional genetic research may consist of the analysis of the structure of the 
participant’s DNA, ie, the entire genome. 

The results of genetic analyses may be reported in a separate study summary.

AstraZeneca will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.
D 2
Genetic Research Plan and Procedures
Selection of Genetic Research Population
All participants will be asked to participate in this genetic research. Participation is voluntary 
and if a participant declines to participate there will be no penalty or loss of benefit. The 
participant will not be excluded from any aspect of the main study.
Inclusion Criteria
For inclusion in this genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the CSP and provide informed consent for the Genomics 
Initiative sampling and analyses.
Exclusion Criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Non-leukocyte depleted whole blood transfusion within 120 days of optional genetic 
sample collection.
Withdrawal of Consent for Genetic Research

Participants may withdraw from this genetic research at any time, independent of any 
decision concerning participation in other aspects of the main study. Voluntary 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
131 of 187
withdrawal will not prejudice further treatment. Procedures for withdrawal are outlined in 
Section 7.2 of the main protocol.
Collection of Samples for Genetic Research

One blood sample for DNA isolation will be obtained from the participants at Visit SV3 
after randomisation. Although DNA is stable, early sample collection is preferred to avoid 
introducing bias through excluding participants who may withdraw due to an AE. If for 
any reason the sample is not drawn at Visit SV3, it may be taken at any visit until the last 
study visit. Only one sample should be collected per participant for genetics during the 
study.
Coding and Storage of DNA Samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum of 15 
years, from the date of last subject last visit, after which they will be destroyed. DNA is a 
finite resource that is used up during analyses. Samples will be stored and used until no further 
analyses are possible or the maximum storage time has been reached.

An additional second code will be assigned to the sample either before or at the time of 
sample processing replacing the information on the sample tube. Thereafter, the sample 
will be identifiable only by the second, unique number. This number is used to identify 
the sample and corresponding data at the AstraZeneca genetics laboratories, or at the 
designated organisation. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organisations working with the DNA or 
blood derivatives).

The link between the participant enrolment/randomisation code and the second number 
will be maintained and stored in a secure environment, with restricted access at 
AstraZeneca or designated organisations. The link will be used to identify the relevant 
samples for analysis, facilitate correlation of genotypic, or multi-omics results with 
clinical data, allow regulatory audit, and permit tracing of samples for destruction in the 
case of withdrawal of consent.
Ethical and Regulatory Requirements

The principles for ethical and regulatory requirements for the study, including this 
genomics and multi-omics research component, are outlined in Appendix A.
Informed Consent

The genomic and multi-omics component of this study are optional and the participant 
may participate in other components of the main study without participating in this 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
132 of 187
genetic component. To participate in the genetic component of the study the participant 
must sign and date both the consent form for the main study and the addendum for the 
Genomics Initiative component of the study. Copies of both signed and dated consent 
forms must be given to the participant and the original filed at the study centre. The PI(s) 
is responsible for ensuring that consent is given freely, and that the participant 
understands that they may freely withdrawal from the genetic aspect of the study at any 
time.
Participant Data Protection

AstraZeneca will not provide individual genotype results to participants, any insurance 
company, any employer, their family members, general physician unless required to do so 
by law. Extra precautions are taken to preserve confidentiality and prevent genetic data 
being linked to the identity of the participant. In exceptional circumstances, however, 
certain individuals might see both the genetic data and the personal identifiers of a 
participant. For example, in the case of a medical emergency, an AstraZeneca Physician 
or an investigator might know a participant’s identity and also have access to his or her 
genetic data. Regulatory authorities may require access to the relevant files, though the 
participant’s medical information and the genetic files would remain physically separate.
Data Management

Any genetic data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organisations to analyse the samples.

AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with 
other researchers, such as hospitals, academic organisations or health insurance 
companies. This can be done by placing the results in scientific databases, where they can 
be combined with the results of similar studies to learn even more about health and 
disease. The researchers can only use this information for health-related research 
purposes. Researchers may see summary results, but they will not be able to see 
individual participant data or any personal identifiers. 

Some or all of the clinical datasets from the main study may be merged with the genetic 
data in a suitable secure environment separate from the clinical database.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
133 of 187
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report potential Hy’s Law cases and Hy’s Law cases. It is not intended to be a comprehensive 
guide to the management of elevated liver biochemistries. 
During the study the investigator will remain vigilant for increases in liver biochemistry. The 
investigator is responsible for determining whether a participant meets potential Hy’s Law 
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of potential Hy’s Law and 
Hy’s Law 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, potential Hy’s Law 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 potential Hy’s Law events.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting potential Hy’s Law criteria to agree whether Hy’s 
Law 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 (DILI) caused by the 
IMP. 
The investigator is responsible for recording data pertaining to potential Hy’s Law/Hy’s Law 
cases and for reporting SAEs and AEs according to the outcome of the review and assessment 
in line with standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3 × Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).
Hy’s Law
AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
134 of 187
For potential Hy’s Law and Hy’s Law 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.
E 3
Identification of Potential Hy’s Law Cases
In order to identify cases of potential Hy’s Law 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
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 potential Hy’s Law criteria (see Section 
E 2 for definition) by reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory eCRF
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria not met
If the participant does not meet potential Hy’s Law criteria the investigator will:

Inform the AstraZeneca representative that the participant has not met potential 
Hy’s Law criteria. 

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the protocol.
E 4.2
Potential Hy’s Law Criteria met
If the participant does meet potential Hy’s Law criteria the investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
135 of 187

Within 1 day of potential Hy’s Law criteria being met, the investigator will report the 
case as an SAE of Potential Hy’s Law; serious criteria ‘Important medical event’ and 
causality assessment ‘yes/related’ according to protocol process for SAE reporting.

For participants that met potential Hy’s Law criteria prior to starting IMP, the investigator 
is not required to submit a potential Hy’s Law SAE unless there is a significant change# in 
the participant’s condition

The Study Physician will contact the investigator, to provide guidance, discuss and agree 
an approach for the study participants’ follow-up (including any further laboratory 
testing) and the continuous review of data

Subsequent to this contact the investigator will:
-
Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.
-
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which the tests available in 
the Hy’s Law laboratory kit should be used. 
-
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 Study Physician if there is any uncertainty.
E 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this appendix should be followed for all cases where potential Hy’s Law 
criteria are met.
As soon as possible after the biochemistry abnormality is initially detected, the Study 
Physician will contact the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting potential Hy’s Law criteria other than DILI 
caused by the IMP, to ensure timely analysis and reporting to health authorities within 15 
calendar days from date potential Hy’s Law criteria was met. The AstraZeneca Global Study 
Physician 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.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
136 of 187
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 Potential 
Hy’s Law SAE and AE eCRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 
-
The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply
-
As there is no alternative explanation for the Hy’s Law 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 the case meets the criteria for Hy’s Law, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:

Provide any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to protocol process for SAE 
reporting.

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether Hy’s Law criteria are still met. Update the previously submitted potential Hy’s 
Law SAE report following protocol 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.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
137 of 187
E 6
Laboratory Tests
Hy’s Law Laboratory Kit for Central Laboratories 
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
HBsAg
IgM and IgG anti-HBc
HBV DNA a
IgG anti-HCV
HCV RNA b
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-
transferrin) c
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin c
Transferrin saturation
aHBV DNA is only recommended when IgG anti-HBc is positive
bHCV RNA is only recommended when IgG anti-HCV is positive or inconclusive 
cCD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly
E 7
References
FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
138 of 187
Appendix F
CYP3A-Interacting Medication That Should be Avoided
Potent inhibitors and potent inducers of CYP3A4 should not be combined with mitiperstat 
(AZD4831) and should be stopped at least 14 days before the first dose of study intervention 
until 2 days after the last dose of study intervention.
The following are drugs known to be potent inhibitors and inducers of CYP3A4 (Table 8).
Table 8 is not intended to be exhaustive, and a similar restriction will apply to other agents 
that are known to strongly modulate CYP3A4. For an updated list, please refer to the links 
below Table 8. 
Appropriate medical judgment is required. The Study Physician should be contacted if there 
are any questions regarding concomitant or prior therapy.
Table 8
CYP3A-Interacting Medication That Should be Avoided
Medication
Recommendation
Rationale
Potent CYP3A4 inhibitors:
Grapefruit juice
Should be avoided for 14 days 
prior to randomisation and for 
2 days following discontinuation 
of mitiperstat (AZD4831) 
Potent CYP3A inhibitors, which 
may increase mitiperstat 
(AZD4831) exposure 
Macrolide antibiotics:
clarithromycin, telithromycin, 
troleandomycin
Azole antifungals: itraconazole, 
ketoconazole, voriconazole, 
posaconazole
Antibiotics: chloramphenicol
Nefazodone
Potent CYP3A4 inducers:
Carbamazepine 
Should be avoided for 14 days 
prior to randomisation and for 
2 days following discontinuation 
of mitiperstat (AZD4831)
Potent CYP3A inducers that can 
decrease mitiperstat (AZD4831) 
exposure
Fosphenytoin
Rifapentine
Phenytoin
Primidone
Rifampicin
St. John’s wort
Macrolide antibiotics can be used to treat pneumonia as soon as needed during study period, following temporary 
or permanent discontinuation of mitiperstat (AZD4831).
References:
FDA list of CYP3A inhibitors and inducers: https://www.fda.gov/drugs/drug-interactions-labeling/drug-
development-and-drug-interactions-table-substrates-inhibitors-and-inducers
Flockhart Table: https://drug-interactions.medicine.iu.edu/MainTable.aspx
Metabolism & Transport Drug interaction database (DIDB) - Washington University:
www.druginteractionsolutions.org


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
139 of 187
Appendix G
EXACT Questionnaire


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
140 of 187


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
141 of 187


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
142 of 187
Appendix H
COPD Assessment Test (CAT)
Patient Reported Outcome Questionnaire was removed due to copyrights.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
143 of 187
Appendix I
Daily e-Diary 
Patient Reported Outcome Questionnaire was removed due to copyrights.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
144 of 187
Patient Reported Outcome Questionnaire was removed due to copyrights.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
145 of 187
Patient Reported Outcome Questionnaire was removed due to copyrights.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
146 of 187
Patient Reported Outcome Questionnaire was removed due to copyrights.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
147 of 187
Appendix J
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health
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 
agreement from AstraZeneca.
J 1
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 where applicable, and where 
consent has not already been provided for the alternative means of carrying out visits and 
assessments. 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.
J 2
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified HCP from the study site or TPV service may visit the participants home/or other 
remote location as per local Standard Operating Procedures/local regulations, as applicable. 
Supplies will be provided for a safe and efficient visit. The qualified HCP will be expected to 
collect information per the CSP. Home visits may be combined with telemedicine visits.
J 3
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 and where a home or remote visit 
is not possible. Having a telemedicine contact with the participants will allow collection of 
AEs, concomitant medication, adherence to the e-Diary and PRO measures to be reported and 
documented, and any information that may be possible to collect virtually.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
148 of 187
J 4
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 in the source documents, or by the participant 
themselves.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
149 of 187
Appendix K
COVID-19 Specifics
K 1
Background to COVID-19
There is currently an outbreak of respiratory disease (COVID-19) caused by a novel 
SARS-CoV-2 that was first detected in Wuhan City, Hubei Province, China in 2019. This new 
virus has rapidly spread across the globe causing the WHO to declare a pandemic situation on 
12 March 2020. The countermeasures initiated by national and local governments worldwide 
and the recommendations issued by the health authorities have impacted current and new 
clinical studies. As the threat of pandemic burden including new outbreaks, locally or globally, 
will impact the further conduct of clinical studies, appropriate risk assessments and mitigation 
measures will need to be taken into consideration in all clinical studies to protect participants, 
site staff, and society as a whole.
Both the EMA and FDA as well as national health authorities in Europe have issued new 
guidelines that aim to provide recommendations for actions for conduct of clinical studies of 
medical products during COVID-19 pandemic. Since the pandemic situation is evolving, 
guidelines, recommendations, national laws, and local restrictions may change at high pace. 
Given the circumstances of potentially relapsing pandemic or epidemic situation with regard 
to the spread of COVID-19 in future, special attention will be paid to protect participants 
participating in the study and site staff involved in the investigations against infection with 
SARS-CoV-2 as requested by the newly issued EMA guideline.
K 2
Risk Assessment for COVID-19 Pandemic
While there is a theoretical risk that treatment with an MPO inhibitor could impair 
host-defence mechanisms, an increased incidence of infection has not been seen in limited 
clinical data with mitiperstat (AZD4831). Therefore, the risk to participants exposed to SARS-
CoV-2 or to those who suffer from COVID-19 is expected to be similar to the background 
population with the same comorbidities as those in the study. The risk of exposure to infected 
people cannot be completely excluded as the participants may need to expose themselves to 
public areas (eg, commute to the site) and have additional human contact (eg, with site staff 
and other participants of the clinical study).
AstraZeneca has no data on the co-administration of mitiperstat (AZD4831) and COVID-19 
vaccines being approved. Potential mitiperstat (AZD4831) vaccine interactions affecting 
participant safety or IMP and vaccine efficacy are therefore unclear.
Measures to mitigate the additional risks caused by COVID-19 are:
-
Exclusion of participants with a significant COVID-19 illness within 6 months of 
enrolment defined as:


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
150 of 187
(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.

This study is going to start enrolling only when AstraZeneca deems it is safe to start the 
study. In addition, the study will not start until the local confinement measures or other 
safety restrictions linked to the COVID-19 pandemic imposed by the local authorities are 
compatible with safe conduct of the study.

Current national laws and local recommendations for prevention of pandemic will be 
strictly adhered to.

Participants will be closely monitored for any signs and symptoms of COVID-19, 
including fever, dry cough, dyspnoea, sore throat and fatigue throughout the study during 
the pandemic. Once clinical signs of infection are reported by participants, the 
investigator needs to determine whether samples can be collected, and safety data can be 
recorded on site. If not, AEs and concomitant medications will be obtained via phone 
calls. The decision to continue with dosing the participant with the study interventions in 
the event of him/her showing symptoms of COVID-19 infection will be per investigator’s 
discretion.

The probability of virus transmission will be controlled as much as possible by:
-
Advice for participant to adhere to local requirements for reduction of the public 
exposure while ambulatory.
-
Confirmation of COVID-19 infection by optional laboratory assessment will be 
conducted based on availability (test capacity and turnaround time) of approved tests 
and on investigator’s discretion.
-
Requesting all participants to be contacted by phone 1 day prior to every visit for 
assessing COVID-19 symptoms and signs and participants are asked not to attend the 
site in case of suspected reports (if appropriate, in accordance with local clinical 
guidelines). In addition, participants are asked for any contact with a person who has 
tested positive for SARS-CoV-2 (if appropriate, in accordance with local clinical 
guidelines). If applicable, participants will be referred to the local health care system 
for further follow-up and treatment.
-
Physical distancing and person-to-person contact restrictions will be applied during 
site visits. 
-
Where physical distancing is not possible, personal protective equipment will be used 
by study participants (surgical face mask, gloves) and staff (for example but not 
limited to masks, gloves, protectors, medical suits) if deemed appropriate by the 
investigators and site staff and guided by local requirements.
-
If, for reasons related to the COVID-19 pandemic (eg, local lockdown, self-isolation 
requirements), a participant is not able to attend their scheduled visit within the visit 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
151 of 187
window, they can have their visit rescheduled as detailed in the study reference 
manual/as per agreement with AstraZeneca Study Physician. Where visits cannot be 
rescheduled, participants should continue at the next scheduled visit. Additionally, 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 collection of 
data for AEs, concomitant medications, adherence to the e-Diary and PRO 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.
-
Logistical improvements of the site and structural measures of the study site building 
will be implemented to further improve physical distancing.

If site visits are not possible due to local restrictions, home nursing visits may be 
considered after discussion with and approval by AstraZeneca. Study intervention may be 
delivered direct to participant if appropriate and via AstraZeneca approved courier 
service.
K 3
Restrictions Related to COVID-19
During the COVID-19 pandemic, participants are advised to adhere to local requirements for 
reduction of the public SARS-CoV-2 exposure while ambulatory. If applicable, according to 
local clinical guidelines prior to SV1 (screening), potential participants should be called to 
confirm they are not experiencing any COVID-19 symptoms and signs and are asked not to 
attend the site in case of suspected infection. If appropriate, participants will be referred to the 
local health care system. Physical distancing and person-to-person contact restrictions will be 
applied and explained to participants while staying at the study site. Where physical 
distancing is not possible, study participants will be asked to use surgical face masks and/or 
gloves if deemed appropriate by the investigator and site staff and guided by local 
requirements.
K 4
Data Quality Assurance Related to COVID-19
Monitoring visits at site will be limited to a minimum required as deemed appropriate during 
COVID-19 pandemic, per local regulations.
In addition, where possible, other measures for carrying out protocol related activities, such as 
but not limited to home nursing, may be employed as required.
K 5
References
Guidance on the Management of Clinical Trials during the COVID 19 (Coronavirus) 
pandemic, EMA, Version 5 (10/02/2022). 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
152 of 187
FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 Public 
Health Emergency, August 2021, Updated on January 27, 2021 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-guidance-
conduct-clinical-trials-medical-products-during-covid-19-public-health-emergency


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
153 of 187
Appendix L
Q-SAW Substudy
L 1
Substudy Synopsis
Background: A composite endpoint (COPDCompEx) for exacerbations is a novel endpoint 
that is being used as a surrogate efficacy endpoint for exacerbation risk reduction in 
randomised controlled trials. COPDCompEx captures AWEs, ie, clinically relevant 
deteriorations of PEF, reliever use or symptoms that fulfil specific criteria in terms of reaching 
thresholds or slopes. The Q-SAW substudy aims to provide a deeper understanding of 
day-to-day variations in symptoms and the impact of AWEs on the participant’s life.
Objectives:
1
To evaluate the impact of an AWE on daily lives of patients with COPD
2
To identify and explain the AWE associated behaviours
Methods: A qualitative substudy will be conducted using a grounded theory approach 
(Strauss and Corbin 1994). Two semi-structured individual interviews will be conducted by 
video call or telephone call using open-ended questions, each of 30-minute duration. A topic 
list and interview guide with example questions will be used as a framework for the interviews 
(Appendix L 3).
Participant selection: Participants from selected sites in selected countries may be eligible 
for participation. 
Participants who provided informed consent for this substudy may be invited for the initial 
interview after occurrence of an AWE. Study site personnel and interviewers will be instructed 
to avoid sharing information on the full study objectives and the procedure by which the 
participant will be selected for the interview in order not to influence the participant’s 
recognition of having an AWE upon which any follow-up actions would be expected. Instead, 
participants will be informed that the aim of this substudy is to learn more about the impact of 
COPD on daily life. A second interview will be scheduled up to 6 weeks after the first 
interview when most participants are expected to have recovered from the AWE (Wageck et al 
2019). 
Selection of participants will continue until saturation in topics is achieved, which is expected 
to occur within a total of approximately 40 participants.
Methods of Analysis: Audio recordings of interviews will be transcribed and analysed with 
qualitative content analysis. Data will be coded and analysed by 2 researchers and consensus 
will be reached about potential discrepancies. Results will be systematically discussed with 
experts in the field. To achieve saturation in interview topics, data collection and coding will 
be done in an iterative manner. This allows for adaptation of the interview guide based on new 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
154 of 187
insights. The method of ‘constant comparison’ will be used for coding thereby expanding an 
initially defined coding tree (ie, according to the interview guide) with superordinate and 
subordinate themes.
L 2
Collection of Adverse Events During Participant Interviews
If a participant during the interview reports an AE, which occurred at any time, this will be 
recorded by the interviewer. For each AE the following variables will be collected: 

Participant details: Patient Ecode, Gender, Age. 

Treatment details: AstraZeneca product, Dose regimen, Date when treatment received.

AE details: Description of AE (what experience), Date when the AE started and stopped, 
Whether the AE required any medical intervention (eg, hospitalization, medical treatment 
etc), Causality, Action taken with regard to medicinal product, Outcome.

If follow-up is consented by the participant (Yes/No)

Reporter information (name and contact information) 

Date/time of AE reporting 

Causality collection 

Causality assessment will be done by the participant. The interviewer will ask about 
causality during the interview (“Do you consider that there is a reasonable possibility that 
the event may have been caused by drug X?”).
L 2.1
Reporting of Adverse Events During the Interviews
Participants will be encouraged to contact the clinical study team when AE or product 
complaints come up during the interview. The interviewer will ensure that all the necessary 
information is provided to the PI of the CRESCENDO study site. The PI will prompt GPRI if 
important or relevant information is missing. Follow-up is undertaken only if the participant 
has consented to be followed-up. If so, GPRI informs the PI of any follow-up information 
within the same timeframe as the original report. 
In the event that GPRI and its Employees, during the course of performing the Services, 
become aware of an AE or other reportable safety information with or without an associated 
AE, (as defined by AstraZeneca’s policies and the AE and other safety reporting training 
program) involving any AstraZeneca Group company product that is the subject of this 
Agreement, GPRI and its Employees are required to collect and submit within one business 
day from becoming aware, the appropriate information to AstraZeneca in accordance with 
AstraZeneca’s policies, procedures, and any training provided by AstraZeneca. AstraZeneca is 
responsible for reporting AEs and other safety information to regulatory and government 
authorities. 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
155 of 187
L 3
Topics of Interview Guide
The interviews with participants will be centred around the following topics. Each interview 
will end with a reflection on discussed issues and potential omissions. 
Topics First Interview
Current health status

Symptoms

Comorbidities

Management of COPD

Impact on daily task / responsibilities

Impact on relationships with family /friends
Perception of COPD symptoms and exacerbations

Variation in symptoms

Understanding the difference between typical and bad days in:
Mood
Daily activities and tasks
Duration relative to one another
Participant’s perceived reasons
Reflection
Topics second interview
Current health status

Symptoms

Comorbidities

Management of COPD

Impact on daily task / responsibilities

Impact on relationships with family /friends
Health behaviour

Anticipation of exacerbations

Actions to control exacerbations
Barriers to reaching out


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
156 of 187
L 4
References
Strauss and Corbin 1994
Strauss A and Corbin J. Grounded Theory Methodology: An Overview. in Handbook of
Qualitative Research. 1994;273–285.
Wageck et al 2019
Wageck B, Cox NS, Holland AE. Recovery Following Acute Exacerbations of Chronic 
Obstructive Pulmonary Disease - A Review. COPD. 2019;16,93–103.

Personal history with health care (in general)

Participant’s opinion about health care
Reflection


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
157 of 187
Appendix M SPFQ Substudy
M 1
Study Synopsis
This study will include an option for participants to complete a questionnaire, the SPFQ, 
which will give participants the opportunity to provide feedback on their clinical study 
experience. Participants will be asked to complete the questionnaire at the beginning, middle 
and end of the study in electronic format. Individual participant level responses will be 
anonymous to the investigator and site staff and so will not be reviewed by investigators. 
Coded responses will be used by the sponsor to understand participant experience on clinical 
studies and to identify where improvements can be made in the clinical study process. To do 
this, responses will be combined across studies and with data collected as part of the study, 
such as gender, ethnicity, and trial duration, to investigate correlations with the participant 
experience. Aggregated data may be shared, maintaining individuals’ anonymity, with site 
staff so they can take steps to understand and improve the participant experience at their site. 
Data may also be compared with responses from other research partners/sponsors to better 
understand participant experience in clinical studies across the biopharmaceutical industry. 
This questionnaire does not collect data about the participant’s disease, symptoms, treatment 
effect or adverse events and therefore would not be study data. Consequently, these data do 
not contribute to any endpoints on the study and will be analysed and reported separately from 
the clinical study data. The results of this participant experience analysis may be published or 
presented at scientific meetings, with the sponsor complying with the requirements for 
publication.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
158 of 187
M 2
Study Participant Feedback Questionnaire 
Patient Experience Initiative
Study Participant Feedback 
Questionnaire (SPFQ)
Version 1.0
Prepared by:
TransCelerate Patient Experience Initiative Team 
This deliverable prepared by TransCelerate BioPharma can be adopted by member companies and 
others, but all adoption is purely voluntary and based solely on the particular company’s unilateral 
decision. TransCelerate has provided this Study Participant Feedback Questionnaire (“SPFQ”) and the 
corresponding User Guide (collectively the “Work Product”) for informational purposes only.  By 
using the Work Product, you manifest your assent to the terms of use set out in this paragraph.  The 
Work Product are not tailored to any particular factual situation and are provided ‘AS IS’ WITHOUT 
WARRANTY OF ANY KIND, EITHER EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, THE 
IMPLIED WARRANTIES OF FITNESS FOR A PARTICULAR PURPOSE, NON-INFRINGEMENT, OR 
MERCHANTABILITY.  TransCelerate and its members do not accept any responsibility for any loss of 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
159 of 187
any kind including loss of revenue, business, anticipated savings or profits, loss of goodwill or data, or 
for any indirect or consequential loss whatsoever to any person using the Work Product.  Any party 
using the Work Product bears sole and complete responsibility for ensuring that the Work Product, 
whether modified or not, are suitable for the particular clinical trial, accurate, current, commercially 
reasonable under the circumstances, and comply with all applicable laws and regulations.
Section A: Your experience before you started the study <to be completed within 1 
month of study enrollment>
Thank you for your participation. Your experiences in this trial are important to us and we would like 
to hear about them. Your answers will help us improve future trials. There are no right or wrong 
answers, and it will take approximately 5 minutes to complete. Your answers will be kept anonymous 
and will not impact your participation in this trial. 
1
2
3
4


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
160 of 187
Section B: Your experience during the trial <to be completed during trial progress>
Thank you for your participation. Your experiences in this trial are important to us and we would like 
to hear about them. Your answers will help us improve future trials. There are no right or wrong 
answers, and it will take approximately 5 minutes to complete. Your answers will be kept anonymous 
and will not impact your participation in this trial. 
1
2
3
4
5
6
7
8


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
161 of 187
Section C: Your experience at the end of the trial <to be completed at last trial 
visit>
Thank you for your participation. Your experiences in this trial are important to us and we would like 
to hear about them. Your answers will help us improve future trials. There are no right or wrong 
answers, and it will take approximately 5 minutes to complete. Your answers will be kept anonymous 
and will not impact your participation in this trial. 
1
2
3
4
5


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
162 of 187
Appendix N
Patient Experience Interview Substudy
N 1
Synopsis
Background and Objectives: This substudy has two aims. First, to get more in-depth insight 
into the perceptions and experiences of participants on this study. This substudy complements 
the data of the quantitative SPFQ (Appendix M) and will be used to understand how 
participant experience can be improved in this study and in future studies. Secondly, it aims to 
gain further insight into the participant perceptions and experiences of the digital technology 
used in the study, including virtual spirometry. 
Methods: Approximately 20 participants from selected sites will be invited to take part in a 
remote, semi-structured interview conducted over video call or telephone call. Overlap with 
Q-SAW substudy sites or participants will be avoided. The duration of the remote, 
semi-structured interview will be approximately 60 minutes. The timepoints of the interviews 
will be stratified over the study duration, starting after at least 2 study visits. 
Methods of Analysis: The interviews will be recorded, transcribed, translated if applicable, 
and analysed with qualitative content analysis.
Please see Appendix L 2.1 for Adverse Event Reporting requirements for this substudy.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
163 of 187
N 2
Interview Guide Themes
CRESCENDO-specific themes / topics
Themes
Example topics for each theme
Spirometry / FEV1

Usability/ease of use of virtual spirometry device

Experience connecting the device

The overall experience of virtual versus face-to-face 
spirometry

Acceptability of this data collection method

Acceptability of time taken to collect data
Digital patient solutions

Unify usability/ease of use

Unify perceived value as a whole and perceived value of 
the specific features (e.g., notifications/reminders)

Attitude of using provisioned device versus using your own 
device 

Acceptability of time taken to collect data

ePRO completion via smartphone (daily diary)
Visits

Experience of preparing for and attending a
o
face-to-face visit
o
virtual visit

Perceived value of a 
o
face-to-face visit
o
virtual visit

Attitudes and perceptions related to communication, 
comfort, trust
Non-financial impact

Expected and actual time commitment 

Impact on usual daily activities (eg work)

Impact on level of energy

Overall satisfaction
Motivation to 
participate 

What motivated the participant to enter the study?

What motivated the participant to continue with/complete 
the study?


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
164 of 187
General participant experiences themes / topics
Themes
Example topics for each theme
Communication

Experience with finding the study and getting the questions 
answered

Quality and clarity of communication from Sponsor and 
Site 

Quality and sufficiency of the information provided to 
outline all the procedures and set the right expectations

Frequency of the communication

Acceptability of the channels used for communication

Ease of understanding the information provided, eg the ICF
Interactions with Staff

Availability of staff

Perceived trust, respect, comfort with staff

Knowledgeability of staff
Study Site

Location: ease of access, parking

Waiting room experience

Treatment area experience (e.g., comfort and privacy)
Financial impact

Costs associated with participation in this study

Speed and sufficiency of the reimbursement of study-related 
expenses

Acceptability of the method of delivery of the 
reimbursement
Appreciation/Gratitude 
Did the participant receive any gratitude/appreciation?

(If yes) How was it? Did it make participants feel 
appreciated?
Experience joining the 
trial
Previous trial 
experience vs 
Crescendo (If 
applicable)
How does this experience compare to the experience in other 
studies they may have participated in?


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
165 of 187
Open-ended questions 
about their experience
Anything else that they want to share related to their experience 
in this study (like/dislike/want to improve/remove)


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
166 of 187
Appendix O
Protocol Version History
The Summary of Changes Table for the current revision is located directly before the Table of 
Contents. 
CSP Version 4.0, 28 April 2023 
This modification 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 
and in the EU Clinical Trial Regulation Article 2, 2 (13). 
Overall Rationale for the Modification:
The primary rationale for the modifications in this CSP is to add the optional Q-SAW, SPFQ 
and patient experience interview substudies which affect only selected sites in selected 
countries where the substudies will be conducted. A substantial change was made to remove 
history of treatment with cardiotoxic medications from the list of exclusion criteria. 
Summary of Changes: 
List of Substantial Modifications
Section Number and Name
Description of Change
Brief Rationale
Section 5.2 Exclusion 
Criteria.
Exclusion criterion 22 “History of 
treatment with cardiotoxic medications (eg, 
as part of cancer therapy) including 
thiazolidinediones such as rosiglitazone and 
pioglitazone” was removed and replaced 
with text: This criterion has been 
removed.
Previously included in error. 
List of Non-Substantial Modifications
Section Number and Name
Description of Change
Brief Rationale
Throughout.
Minor changes were made to formatting
and wording throughout the document for 
example to fix errors and improve 
grammar and sentence/section structure 
without change of meaning.
To improve clarity and 
readability.
Throughout.
AZD4831 was changed to 
mitiperstat (AZD4831) throughout. 
To align with other study 
regulatory documents. 
Title page, Section 1.1
Synopsis.
The protocol title was changed: A 
Phase IIa Randomised, Double Blind, 
Placebo Controlled, Parallel Arm, 
Multi-Centre Study to Evaluate the 
Efficacy and Safety of Mitiperstat 
(AZD4831), for 12-24 Weeks, in Patients
To include mitiperstat name and 
more accurately reflect the 
study objectives. 
The title change was considered 
to be a non-substantial change 
as it was not considered to have 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
167 of 187
Section Number and Name
Description of Change
Brief Rationale
with Moderate to Severe Chronic 
Obstructive Pulmonary Disease (COPD).
a significant impact on the 
safety or physical or mental 
integrity of the clinical trial 
participants or the scientific 
value of the trial. 
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints.
“Participants” was amended to “patients” 
as appropriate.
To clarify that the study 
participants included in this 
study are patients with moderate 
to severe COPD. 
Section 1.1 Synopsis, 
Section 1.3 Schedule of 
Activities, Section 3
Objectives and Endpoints, 
Section 4.1.2 Q-SAW 
Substudy, Section 8.2.9
Q-SAW Substudy, 
Appendix L Q-SAW 
Substudy.
Details of the optional Q-SAW substudy
were added throughout the protocol.
New sections: Section 4.1.2, Section 8.2.9, 
and Appendix L were added.
To briefly outline the 
assessments and procedures for 
the optional Q-SAW substudy. 
The substudy affects only 
selected sites in selected 
countries where the substudy 
will be conducted.
This is a non-interventional 
study and therefore considered 
to be a non-substantial change. 
Section 1.1 Synopsis, 
Section 1.3 Schedule of 
Activities, Section 3
Objectives and Endpoints, 
Section 4.1.3 SPFQ 
Substudy, Section 8.2.10
SPFQ, Appendix M SPFQ 
Substudy.
Details of the optional Study Participant 
Feedback Questionnaire (SPFQ) were 
added throughout the protocol.
New sections: Section 4.1.3, 
Section 8.2.10, and Appendix M were 
added.
To briefly outline assessment 
and procedures for the optional 
SPFQ substudy. The substudy 
affects only selected sites in 
selected countries where the 
substudy will be conducted.
This is a non-interventional 
study and therefore considered 
to be a non-substantial change.
Section 1.1 Synopsis, 
Section 1.3 Schedule of 
Activities, Section 3
Objectives and Endpoints, 
Section 4.1.4 Patient 
Experience Interview 
Substudy, Section 8.2.11
Patient Experience Interview 
Substudy, Appendix N
Patient Experience Interview 
Substudy.
Details of the optional patient experience 
interview substudy were added throughout 
the protocol.
New sections: Section 4.1.4, 
Section 8.2.11, and Appendix N were 
added.
To briefly outline the 
assessments and procedures for 
the optional patient experience 
interview substudy. The 
substudy affects only selected 
sites in selected countries where 
the substudy will be conducted.
This is a non-interventional 
study and therefore considered 
to be a non-substantial change.
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints.
Alteration to primary objective: “To 
evaluate the effect of AZD4831 as 
compared to placebo on the time to first 
COPDCompEx event in participants with 
moderate to severe COPD.”
To be consistent with the style 
of the other objectives. 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
168 of 187
Section Number and Name
Description of Change
Brief Rationale
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints.
For secondary objective: To assess the 
effect of AZD4831 compared with placebo 
on post-BD FEV1 in participants with 
moderate to severe COPD, the estimand 
text was amended: 
“Strategy for intercurrent events Primary 
estimand: while on treatment.
Supportive estimand: treatment policy.”
For secondary objective: To assess the 
effect of AZD4831 compared with placebo 
on respiratory symptoms in participants 
with moderate to severe COPD, the 
estimand text was amended: 
“Strategy for intercurrent events: while on
treatment policy.”
For the secondary objective: To assess the 
effect of AZD4831 compared with placebo 
on disease impact in participants with 
moderate to severe COPD, the estimand 
text was amended: 
“Strategy for intercurrent events: while on
treatment policy.”
To clarify the wording of the 
estimands for the secondary 
objectives. 
Section 1.1 Synopsis, 
Section 3 Objectives and 
Endpoints, Section 8.2.1
COPDCompEx and 
Section 8.2.2.1 Assessment 
of COPD Exacerbation.
“An episode of pneumonia” added to list 
as an exacerbation. 
To align with the revised 
COPDCompEx Business Rules 
(dated 13 April 2023), where an 
episode of pneumonia is now 
included as an exacerbation, not 
a dropout due to efficacy.
Section 1.1 Synopsis, 
Section 4.1 Overall Design.
Text amended “It will be performed in 
approximately 100 101 sites...”
Wording change to show a more 
approximate number. This is not 
a change to study design. 
Section 1.1 Synopsis, 
Section 1.2 Schema, 
Section 4.1 Overall Design, 
Section 4.2 Scientific 
Rationale for Study Design, 
Section 7.1.4 Participant 
Discontinuation at Study 
End, Section 9.4.2.1 Primary 
Endpoint. 
Text relating to the end of study in 
Sections 1.1, 1.2, 4.1, and 7.1.4 was 
changed: Once the last participant has 
completed 12 weeks of treatment, the study 
can stop. At this point, all participants still 
receiving treatment should attend Study 
Visit SV7 as soon as possible, continuing 
treatment until they do. They should then 
attend SV8 14 ± 3 days later. These SV7 
visits can be planned in anticipation of the 
last participant completing 12 weeks of 
treatment, but must not be performed 
To clarify the study 
discontinuation process.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
169 of 187
Section Number and Name
Description of Change
Brief Rationale
before that date. The last participant can 
combine SV5 and SV7 in one visit, then 
attend SV8 14 ± 3 days later.
Enrolment will be stopped after at least 
113 first COPDCompEx events have 
occurred. At this point, all participants 
enrolled in the study that have not yet 
completed SV5 should continue in the 
study to complete 12 weeks of treatment. 
For these participants SV5 and SV7 
should be combined into one visit. 
Participants who have already 
completed 12 weeks of treatment when 
study enrolment is stopped should 
attend SV7 as soon as possible, 
continuing treatment until they do. All 
participants should attend SV8 14 ± 3 
days after SV7.
Minor changes were made to the text in 
Sections 4.2 and 9.4.2.1 to reflect this 
change. 
Section 1.3 Schedule of 
Activities.
Visit timepoint SV7 changed to SV7/EDV 
and associated footnote added for 
explanation. 
To clarify that this timepoint 
could be SV7 or EDV. No 
change to the study procedure.
Section 1.3 Schedule of 
Activities, Section 8.2.7
Computed Tomography 
Scan.
Details for high resolution CT scan 
amended: The high resolution CT can could be 
performed within ± 2 weeks of SV3 as soon as 
main eligibility criteria are confirmed at SV1 
which include blood test result, up to 
randomisation. The local CT scan report 
must be obtained before randomisation.
These details were also added to 
Section 8.2.7.
To clarify the timing of the 
study procedure.
Section 1.3 Schedule of
Activities.
The R denoting the timepoint at which the 
device for e-Diary should be returned was 
moved from SV8 to SV7. A footnote was 
added to explain that the morning and 
evening diaries that include cough VAS 
and BCSS start the day after SV2. 
Notes were added to explain that e-Diary 
and PEF, Cough VAS assessment and 
BCSS (daily) will be recorded up until the 
day of SV7 or EDV.
To clarify the timing of the 
study procedures.
Section 5.2 Exclusion 
criteria.
Exclusion criteria 3(e) amended: Systemic 
hypertension, except if well controlled 
using 2 or fewer medications and stable for 
To clarify the details of the 
exclusion criteria related to 
systemic hypertension. 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
170 of 187
Section Number and Name
Description of Change
Brief Rationale
at least 6 months and stable for at least 3 
months in the opinion of the 
investigator.
Section 5.2 Exclusion 
criteria.
Exclusion criteria 9 amended: Any history 
of lung volume reduction surgery, 
including endoscopic lung volume 
reduction procedure with endobronchial 
valves.
To clarify lung volume 
reduction procedure that would 
exclude participant from the 
study.
Section 6.1 Study 
Intervention(s) 
Administered.
Dose formulation for AZD4831 and 
placebo changed from tablet to film-coated 
tablet.
For accuracy and consistency 
with other study documentation. 
Section 7.2 Participant 
Discontinuation/Withdrawal 
from the Study, B 5 Guide to 
Skin Reaction Assessment.
The wording “early treatment 
discontinuation visit” was changed to 
“early discontinuation visit.”
For document consistency. 
There is no change to the 
meaning. 
Section 8.2.7 Computed 
Tomography Scan.
The Computed Tomography Scan section 
was moved from Section 8.3.5 to 
Section 8.2.7. As a result, Section 8.2.7 
Cough Substudy and Section 8.2.7.1 
VitaloJAK® Cough Monitor Device were 
moved to Section 8.2.8 and 
Section Section 8.2.8.1 respectively. 
Section 8.3.6 SARS-CoV-2 Screening was 
moved to Section 8.3.5.
The assessment is considered to 
relate to efficacy rather than 
safety. 
Section 8.2.7 Computed 
Tomography Scan.
Addition of text: The CT scan will be 
performed to characterise and assess the 
severity of COPD at baseline by, among 
other approaches, evaluation of the 
distribution of emphysema and 
visualisation of small airways disease, 
mucous plugging and/or bronchiectasis. 
It is anticipated that a more detailed 
analysis of responders to treatment will 
be done on the basis of pre-existing 
emphysema severity and the presence of 
mucous plugging in particular. This may 
guide the inclusion of patients in the 
subsequent development program and 
will also be used to explore the 
association with the other biomarkers of 
disease progression from both blood and 
sputum biomarker sampling.
To justify the CT scan 
assessment. 
Section 8.8.1 Mandatory 
Biomarker Sample 
Collection.
Footnote added to note that each of the 
applicable blood sample assessments “Will 
To specify and clarify the 
biomarker samples and 
assessments and to clarify that 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
171 of 187
Section Number and Name
Description of Change
Brief Rationale
not be delivered prior to database lock and 
will not be part of the CSR.”
Specification that sputum samples will be 
collected to assess “MPO concentration 
and activity” and “other” markers of 
inflammation and neutrophil activation.
some sample assessments will 
not be included in the CSR.
Section 9.3 Populations for
Analysis.
The description of the cough subset 
population for analysis was amended “Will 
include the subset of PP set FAS who 
consented to the cough substudy.”
A new analysis set “Randomised Set” was 
added to the populations for analysis table 
with the description “Will include all 
participants who have been randomised.”
To outline the populations for 
analysis.
Section 9.4.3 Safety.
Treatment emergent heading and text 
removed from safety statistical analysis 
section. 
The definition for treatment emergent 
events will be provided in the SAP.
This was included in the 
previous version in error. This 
is not detailed in the SAP.
Section 9.4.3 Safety.
Text in laboratory parameters statistical 
safety section amended: “A frequency table 
presents the number of participants 
reporting at least one abnormality 
treatment emergent change in selected 
laboratory parameters.”
To correct inaccuracies in the 
statistical analysis procedures.
Bold signifies added text, strike through signifies deleted text.
CSP Version 3.0, 13 January 2023
This modification 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 
and in the EU Clinical Trial Regulation Article 2, 2 (13). 
Overall Rationale for the Modification:
The primary rationale for the modifications in this CSP is to add clarity and detail to the study 
procedures and avoid ambiguity. Changes were also made in response to the requirements of 
various health authorities. A substantial change was made to adapt to changes in SARS-CoV-2 
screening requirements.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
172 of 187
Summary of Changes: 
List of Substantial Modifications
Section Number and Name
Description of Change
Brief Rationale
5.2 Exclusion Criteria
Exclusion criteria 1 removed and replaced 
with text: “This criterion has been 
removed.” Participants with a positive 
diagnostic lateral flow test for SARS-CoV-2 
at SV1 or SV3. Participants will be eligible 
for rescreening ≥ 2 weeks after a positive 
SARS-CoV-2 lateral flow test once COVID-
19 symptoms have resolved, at the 
investigator’s discretion (see Section 5.4).”
To confirm the change in 
requirement for SARS-CoV-2 
screening during the study. 
Positive SARS-CoV-2 test at 
SV1 and SV3 is no longer an 
exclusion criterion. This is to 
be in line with local 
requirements in most 
countries in which 
SARS-CoV-2 screening is no 
longer mandatory.
List of Non-Substantial Modifications
Section Number and Name
Description of Change
Brief Rationale
Throughout
CSP template updates were amended 
throughout except for Objectives and 
Endpoints (Synopsis and Section 3).
Amendments included changing wording of 
“Sponsor” to “AstraZeneca” and “patient” 
or “subject” to “participant”. 
Sections were added, removed, or amended 
in accordance with template updates. 
New section headings in this version 
compared with the previous CSP version 
include:
5.5 Criteria for Temporarily Delaying 
Enrolment, Randomisation, or 
Administration of Study Intervention
6.1.1 Medical Devices Including 
Combination Products with a Device 
Constituent
6.3 Assignment to Study Intervention
6.4 Blinding
6.8 Treatment of Overdose
8.1 Administrative and General/Baseline 
Procedures
8.2.2.3 Duration of AECOPD
8.3.6 SARS-CoV-2 Screening
8.4.12 Reporting of Overdose
8.10 Study Participant Feedback 
Questionnaire
The CSP was updated in line 
with the latest AstraZeneca 
CSP protocol template v7.0, 
Doc ID TMP-0010225 (dated 
November 2022) which is 
based on the TransCelerate 
Common Protocol Template 
v9.0.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
173 of 187
Section Number and Name
Description of Change
Brief Rationale
In addition, several section numbers have 
changed, particularly from Section 6 
onwards. 
Throughout
Minor changes were made to formatting and 
wording throughout the document for 
example to fix errors and to improve 
grammar and sentence/section structure 
without change of meaning.
To improve clarity and 
readability.
Title page
“Short Title” changed to “Brief Title” and 
changed from “12 to 24 weeks of 
AZD4831versus placebo for treatment of 
moderate to severe chronic obstructive 
pulmonary disease” to “An Efficacy and 
Safety Study of AZD4831 (MPO 
Inhibitor) vs Placebo in the Treatment of 
Moderate to Severe COPD”
To align with the brief title 
used on ClinicalTrials.gov, 
which is also in accordance 
with AstraZeneca CSP 
protocol template v7.0, Doc ID 
TMP-0010225 (dated 
November 2022) which is 
based on the TransCelerate 
Common Protocol Template 
v9.0. 
1.3 Schedule of Activities, 
5.4 Screen Failures
Since exclusion criteria 1 has been 
removed, 
SARS-CoV-2 test (at SV1 and SV3) 
removed from SoA.
Text removed from Section 5.4 as Screen 
Failures as no longer relevant: “A positive
SARS-CoV-2 lateral flow test. Participants 
will be eligible for rescreening ≥2 weeks 
after a positive SARS-CoV-2 lateral flow 
test once COVID-19 symptoms have 
resolved, at the investigator’s discretion.”
To confirm and clarify the 
change in requirement for 
SARS-CoV-2 screening during 
the study. Positive SARS-
CoV-2 test at SV1 and SV3 is 
no longer an exclusion 
criterion. This is to be in line 
with local requirement in most 
countries in which SARS-
CoV-2 screening is no longer 
mandatory.
1.1 Synopsis, 
3 Objectives and Endpoints
Secondary objective for cough substudy: 
“To assess the effects of AZD4831 
compared to placebo on change in cough 
frequency measured over a 24-hour period 
between start of treatment and Week 12” 
corrected to exploratory objective. 
Due to template update, only primary and 
secondary objectives and endpoints are 
included in synopsis; therefore, removed 
from synopsis. 
The wording of “baseline” changed to 
“start of treatment”.
Correction of endpoint of the 
cough substudy from 
secondary to exploratory, as 
the substudy is an exploratory 
study and hence the endpoints 
would not be considered 
secondary. This does not 
impact the scientific value of 
the main study or the substudy. 
Start of treatment is used in 
place of baseline to clarify the 
time of study measure.
1.1 Synopsis, 3 Objectives 
and Endpoints 
Text moved from table to footnotes: 
“Intercurrent events are events occurring 
after treatment initiation (eg, 
Clarification of intercurrent 
events in the study.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
174 of 187
Section Number and Name
Description of Change
Brief Rationale
discontinuation of treatment, switching 
treatment, terminal events such as death) 
that affect either the measurement or 
interpretation of the summary measure 
(eg, hazard ratio) associated with the 
clinical question of interest.
Addition of text: “This study contains 2 
intercurrent events: 
1) Treatment discontinuation (with the 
following reasons: SAE, death not due to 
exacerbation, COVID-19, pneumonia, 
other). 
2) Prohibited medication.”
1.1 Synopsis, 4.1 Overall 
Design
Update to the approximate number of study 
sites (from 143 to 101) and countries (from 
12 to 14). 
Text amended in Section 4.1: “This is a 
Phase IIa, randomised, placebo-controlled, 
double-blind, parallel-arm, event-driven 
study with an up to 24-week treatment time. 
It will be performed in approximately 
101 sites across approximately 14 
countries. It is designed…”
Update to study logistics. This 
does not impact number of 
participants and does not have 
a significant impact on safety 
or scientific value of the study.
1.1 Synopsis, 1.3 Schedule of 
Activities, 2.3.2 Benefit 
Assessment, 3 Objectives 
and Endpoints, 8.2.4 
Participant-Reported 
Outcomes, 8.2.6 E-Diary, 
Appendix G EXACT 
Questionnaire
Patient reported outcome questionnaire 
changed from E-RS:COPD to EXACT 
throughout and copy of EXACT added in 
Appendix G.
Due to requirement to use the 
full 14-question EXACT Scale 
by the license holder. 
ERS:COPD is similar to 
EXACT, therefore this change 
would not affect the safety and 
scientific value of the study. 
1.1 Synopsis, 9.5 Interim 
Analysis, 9.6 Data Review 
Committee Appendix A5 
Committees Structure
Updates to clarify that the URC will be 
responsible for conducting the 
administrative IA and the DRC will be 
responsible for safety monitoring.
To simplify/clarify the roles of 
the URC/DRC. 
1.1 Synopsis, 4.1 Overall 
Design
Change of wording related to SV6 (virtual 
visit) from “will be performed at the 
participant’s home” to “will be performed 
away from the study site.”
Clarification of acceptable 
locations for study virtual visit.
1.2 Schema, 1.3 Schedule of 
Activities
Change to the wording for SV1 and SV2. 
SV1 wording amended from “Day -28 to -
1” to “Day -28 to -14.” 
SV2 wording amended from “Day -14 (-2)” 
to “Day -16 to -14.”
To clarify the study visit 
window wording and ensure 
compliance according to 
inclusion criterion 7 (SV2 
must be completed 14 days 
preceding SV3 to ensure 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
175 of 187
Section Number and Name
Description of Change
Brief Rationale
eDiary/PEF compliance 
according to inclusion criterion 
7, therefore SV1 required to be 
completed by Day -14).
1.3 Schedule of Activities, 
4.1 Overall Design
Footnote (a) added for SV6 (virtual visit) in 
SoA: “For virtual visit of SV6, this will be 
conducted over telemedicine video 
conferencing facility based on technology 
provided by Zoom Inc (San Jose, 
California, USA), through the UNIFY 
platform, using a provisioned handheld 
device.”
Text added to overall design: “This will be 
conducted over the same telemedicine 
video conferencing facility that is being 
used for the virtual spirometry during 
other visits in the study and is based on 
technology provided by Zoom Inc (San 
Jose, California, USA), through the 
UNIFY platform, using a provisioned 
handheld device.”
Detail to clarify how the SV6 
virtual visit will be performed.
1.1 Synopsis, 4.1 Overall 
Design
Text amended: “MPO level and activity in 
sputum at Week 12 compared to Week 1
baseline, and symptom scores.”
Clarification of secondary 
efficacy assessment timepoint 
(not a change of timepoint).
1.3 Schedule of Activities
Clinical spirometry (post-BD) site 
measurement added at SV4.
To align with other site visits.
1.3 Schedule of Activities
Text added to notes for clinical spirometry 
(post-BD) procedure: “Screening 
spirometry at SV1 will be conducted 
using the spirometry equipment supplied 
to clinic.
In the event that an adequate quality, 
maximal effort spirometry effort cannot 
be obtained at the first attempt during a 
study visit, a further reattempt is allowed 
(see Section 8.2.3).”
To clarify the clinical 
spirometry (post-BD) 
procedure and to determine the 
criteria for when reattempt is 
permitted at SV1.
1.3 Schedule of Activities, 
5.1 Inclusion Criteria, 
8.2.6 E-Diary
Text added to e-Diary and PEF procedure 
notes (Schedule of Activities), inclusion 
criterion 7 and e-Diary section to define 
compliance and to detail the steps to take 
should adherence drop below 80% to 85%. 
To clarify the compliance 
procedures in the study.
1.3 Schedule of Activities, 
8.6.1 Collection of Samples 
for Pharmacodynamics
Added text to both sections related to blood 
sample for target engagement assay: “In a 
subsample of approximately 60 
participants in selected countries.” 
To clarify that systemic target 
engagement assay is not 
required for all participants. 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
176 of 187
Section Number and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities
Text: “EDV only” added for PK blood 
sampling for AZD4831 procedure at SV7.
To clarify timing of PK blood 
sampling for AZD4831 at 
early discontinuation visit.
2.3.1 Risk Assessment, 
2.3.3 Overall Benefit/Risk 
Conclusion, 3 Objectives and 
Endpoints, 7.1.2 Temporary 
Discontinuation, 
7.1.3 Restarting After 
Temporary Discontinuation, 
8.4 Events, AEs, SAEs, and 
Other Safety Reporting, 
8.4.9 Adverse Events of 
Special Interest
Text amended to “serious infection” where 
appropriate.
To clarify serious infection 
rather than any infection.
3 Objectives and Endpoints
Text added: “MPO- and neutrophil- related 
circulating and nasal mucosal lining fluid
biomarkers.”
To clarify that nasal lining 
fluid biomarkers will be one of 
the exploratory endpoints as 
the samples will be collected 
from the participants as per 
SoA.
3 Objectives and Endpoints
Exploratory spirometry objective and 
endpoints added to Table 3:
Objective: To assess the effects of 
AZD4831 as compared to placebo on 
spirometry endpoints measured face-to-face 
and virtually in participants with moderate 
to severe COPD endpoints: spirometry 
endpoints, including but not limited to, 
FEV1, forced vital capacity, forced 
expiratory flow 25% to 75%, inspiratory 
capacity, and reproducibility
These spirometry endpoints 
are being collected in the 
previous version of protocol. 
The objectives and endpoints 
were added to clarify the 
intention to analyse these data, 
in an exploratory manner. This 
does not have a significant 
impact on safety and scientific 
value of the study.
3 Objectives and Endpoints
Exploratory objective and endpoints added 
to measure effect of sputum MPO 
concentration:
Objective: To assess the effect of sputum 
MPO concentration at baseline on 
primary and secondary endpoints in 
participants with moderate to severe 
COPD.
Endpoints:
Time to first COPD CompEx event in 
participants with low MPO concentration 
at baseline compared to high MPO 
concentration at baseline.
To clarify intended exploratory 
analysis for sputum MPO 
concentration. This does not 
have a significant impact on 
safety and scientific value of 
the study.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
177 of 187
Section Number and Name
Description of Change
Brief Rationale
Change from baseline post-BD FEV1 in 
participants with low MPO concentration 
at baseline compared to high MPO 
concentration at baseline.
5.1 Inclusion Criteria
Added text to inclusion criterion 5: 
“Participants who have a documented stable 
regimen of triple therapy or dual therapy for 
≥3 months prior to enrolment (change of 
inhaler device or change of medication in 
the same drug class is allowed).”
To clarify the details of the 
inclusion criterion related to 
therapy.
5.1 Inclusion Criteria, 
8.4.10.2 Paternal Exposure
Contraceptive period for males updated 
from 90 to 105 days and text amended for 
inclusion criterion 10a: “Male patients must 
be surgically sterile (eg, vasectomy with 
confirmed azoospermia)…”
To ensure the global protocol 
is suitable for all 
country-specific requirements 
and to clarify specific detail. 
5.1 Inclusion Criteria
Inclusion criterion 10a amended: “For a 
non-pregnant woman of childbearing 
potential partner, contraception 
recommendations should also be 
considered. Acceptable methods of 
contraception include are birth control pills, 
injections, implants, or patches, intrauterine 
devices, and tubal ligation/occlusion. A 
barrier method is not necessary if the 
female partner is sterilised. All other 
contraceptive methods are considered 
unacceptable.”
To clarify specific details of 
inclusion criterion 10a as per 
request from Spanish Health 
Authority to ensure the global 
protocol is suitable for all 
country-specific requirements.
5.2 Exclusion Criteria
Exclusion criterion 3 updated to “SV1 
[screening] and through to SV3 
[pre-dose]”
To clarify that SV2 is also 
included since it is part of the 
screening period. 
5.2 Exclusion Criteria
Exclusion criterion 4c wording amended: 
“A diagnosis of asthma made when the 
participant was aged ≥ 40 years, confirmed 
by the investigator to be a misdiagnosis on 
the basis of objective testing after 
discussion with and agreement of the 
AstraZeneca Study Physician.”
Exclusion criterion 23 wording amended: 
“Major surgery within 8 weeks prior to 
screening or planned inpatient surgery or 
hospitalisation during the study period. 
Elective hospitalisations that cannot be 
delayed until after the end of the study need 
to be discussed with the sponsor’s medical 
monitor.”
Exclusion criteria 4c and 23 
were updated to remove the 
need for Sponsor involvement 
in eligibility determination, as 
per Good Clinical Practice 
ICH E6(R2), Section 4.3.1, as 
per request from the UK 
Health Authority.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
178 of 187
Section Number and Name
Description of Change
Brief Rationale
5.2 Exclusion Criteria
Exclusion criterion 7 wording updated to 
add that any of the criteria listed would lead 
to exclusion from the study, including 
previous hepatic imaging or pathological 
sampling. 
To clarify exclusion criterion 7 
and to ensure further guidance 
is given to the investigator, as 
per request from German 
Health Authority.
5.2 Exclusion Criteria
Exclusion criterion 7(g) updated to “Chest 
CT scan findings requiring further 
investigation other than surveillance 
CT scan(s) or repeat CT surveillance scan 
before SV8.”
For consistency with 
Section 8.3.5 Computed 
Tomography Scan. 
5.2 Exclusion Criteria
Exclusion criterion 21 wording amended: 
“Participants currently receiving 
background therapy for COPD that is not 
approved by regulatory authorities in the 
country of study (with the exception of 
nicotine vaping products, long-term 
azithromycin, erythromycin and/or ICS 
monotherapy standalone inhaler [as part 
of triple or dual therapy] of at least 3 
months' duration).”
To clarify acceptable ICS 
therapy.
5.2 Exclusion Criteria
Exclusion criterion 21 wording amended: 
“Treatment with broad spectrum antibiotic 
(excluding long-term azithromycin or 
erythromycin as mentioned in exclusion 
criterion 21) within 4 weeks prior to 
randomisation (Day 1).”
To clarify exceptions to the 
excluded antibiotic treatment.
5.2 Exclusion Criteria, 6.9 
Prior and Concomitant 
Therapy
Exclusion criterion 28(e) wording amended: 
“Live, attenuated, or mRNA vaccines 
within 2 weeks prior to of SV1 only.”
Addition of text relating to vaccines in 
section 6.9: “Live, attenuated, or mRNA 
vaccines if within 2 weeks prior to SV1 
only.”
To clarify that live, attenuated 
or mRNA vaccines are not 
permitted only within the 
2-week period prior to SV1.
5.2 Exclusion Criteria, 6.9 
Prior and Concomitant 
Therapy
Addition of carbimazole and methimazole 
to prohibited medications listed in exclusion 
criterion 28(e) and Section 6.9. 
To clarify further drugs (for 
hyperthyroidism) which are 
prohibited from the study. 
5.3.1 Meals and Dietary 
Restrictions
St John’s wort added to list of restrictions.
To clarify that participants 
should not consume St John’s 
wort during study.
6.1.1 Medical Devices 
Including Combination 
Products with a Device 
Constituent, Appendix B 5, 
Inclusion of text defining the use of 
ZEPHYRx and/or Medidata as appropriate. 
To clarify the applications 
used. 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
179 of 187
Section Number and Name
Description of Change
Brief Rationale
Guide to Skin Reaction 
Assessment
6.1.1 Medical Devices 
Including Combination 
Products with a Device 
Constituent 
Addition of the type of spirometer: MIR 
Spirobank II Smart for SV1 screening only. 
Addition of text “(available in each study 
region)” for medical devices: MIR 
Spirobank Smart spirometer, MIR 
Spirobank II Smart spirometer and 
VitaloJAK® cough monitor.
To specify the medical devices 
used in the study and their 
availability.
6.3 Assignment to Study 
Intervention
Text amended: Before the study is initiated, 
the telephone number and call in directions 
for the IRT and/or the log in information 
and directions for the IRT/RTSM will be 
provided to each site.
Telephone number and call in 
details removed as not 
relevant. 
6.4 Blinding
Creation of new section 6.4, ‘Blinding’ and 
text added: “The study will be blinded to 
both participants and investigators/site 
staff as well as to AstraZeneca staff. With 
the formation of the URC and DRC (see 
Appendix A 5) the study will become 
unblinded to the AstraZeneca staff 
assigned to these committees (including 
those with clinical, medical, statistical, 
and programming expertise) who will 
form a firewalled URC for 
administrative purposes and will all be 
independent from the study team (see 
Appendix A 5). The URC will be 
responsible for conducting the 
administrative IA whereas the DRC will 
be responsible for safety monitoring.”
In accordance with 
AstraZeneca CSP protocol 
template v7.0, Doc ID TMP-
0010225 (dated November 
2022) which is based on the 
TransCelerate Common 
Protocol Template v9.0 and to 
simplify/clarify the roles of the 
URC/DRC.
6.8 Treatment of Overdose
Text added to new section including: 
“Should an overdose occur, the patient 
should be treated symptomatically and 
supportive measures instituted.” 
In accordance with 
AstraZeneca CSP protocol 
template v7.0, Doc ID TMP-
0010225 (dated November 
2022) which is based on the 
TransCelerate Common 
Protocol Template v9.0 and to 
clarify the study procedure.
7.1.2 Temporary 
Discontinuation
Text added: “The treatment period will 
not be extended to compensate for the 
temporary discontinuation.”
To clarify the study procedure.
7.1.2 Temporary 
Discontinuation
New text added: “In case of ‘unconfirmed 
pneumonia’, if the participant is not 
hospitalised and/or does not have a chest 
To clarify the study procedure.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
180 of 187
Section Number and Name
Description of Change
Brief Rationale
x-ray confirming diagnosis of 
pneumonia, this should generally be 
considered an infective exacerbation of 
COPD rather than pneumonia. In this 
scenario, study intervention can continue. 
If the investigator still considers this to 
be pneumonia, then discussion with the 
AstraZeneca medical monitor would be 
needed regarding 
continuation/discontinuation of study 
intervention.
In case of serious infection, the study 
intervention should be immediately 
discontinued on a temporary basis, unless 
any permanent discontinuation criteria 
are met (Section 7.1). After 
discontinuation of study intervention, 
any appropriate treatment is allowed if 
conditions presented in Section 6.9 are 
met. 
Study intervention does not need to be 
stopped for antibiotic treatment of non-
serious infection.”
7.2 Participant 
Discontinuation/Withdrawal 
from the Study
Text added to discontinuation section: “At 
the time of discontinuation from the 
study, if possible, SV7, as an early 
treatment discontinuation visit, should be 
conducted, as shown in the SoA 
(Table 1). See the SoA for data to be 
collected at the time of study withdrawal 
and follow-up and for any further 
evaluations that need to be completed. 
The participant will discontinue the 
study intervention and be withdrawn 
from the study at that time.
To clarify the study procedure 
and to be consistent with 
paragraph below regarding 
participant withdrawal.
8.2.1 COPDCompEx
The COPDCompEx definition was updated 
to include corticosteroid injection.
To clarify that corticosteroid 
injection is defined as a 
COPDCompEx event.
8.2.2.3 Duration of AECOPD
Section added to this version of the protocol 
in line with template.
In accordance with 
AstraZeneca CSP protocol 
template v7.0, Doc ID TMP-
0010225 (dated November 
2022) which is based on the 
TransCelerate Common 
Protocol Template v9.0 and to 


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
181 of 187
Section Number and Name
Description of Change
Brief Rationale
define the start and stop dates 
of AECOPD.
8.2.3 Spirometry and Peak 
Expiratory Flow 
Measurement
Amendment of text: “Where sites do not 
have access to such device, they will be 
provided with an MIR Spirobank II 
Smart and android tablet with 
ZEPHYRx KIOSK mode application. 
This device and application shall only be 
used for screening spirometry performed 
at SV1, an appropriate spirometer will be 
provided.”
To clarify the study procedure 
and devices.
8.2.3 Spirometry and Peak 
Expiratory Flow 
Measurement
Text added: “In the event that an 
adequate quality, maximal effort 
spirometry effort cannot be obtained at 
the first attempt during a study visit, a 
further reattempt is allowed. The 
participant should be rested for a period 
of time deemed appropriate by the 
investigator and have recovered 
sufficiently for the procedure to be 
completed safely. This will not be 
considered rescreening if undertaken on 
the same day as the first attempt.”
To clarify that reattempt of 
spirometry assessment at 
screening visit is permitted for 
borderline results. 
8.2.3 Spirometry and Peak 
Expiratory Flow 
Measurement
Change of wording related to SV3, SV4, 
SV5 and SV7 to make it clearer where and 
when virtual and face-to-face spirometry 
assessments will be performed. 
To clarify acceptable locations 
for study virtual spirometry 
assessments and to clarify the 
study procedure for face-to-
face and virtual spirometry 
assessments.
8.2.7.1 VitaloJAK® Cough 
Monitor Device
Text added “The participants will be 
asked to return the device to site after 
completion of recording as soon as 
feasible. At some sites, the participants 
will also have the option of having the 
device collected, eg, by courier.”
To clarify study procedures.
8.3.2 Vital Signs
Removed the text stating the orthostatic BP 
measured at SV3 will be reviewed by the 
unblinded DRC.
Included in error in previous 
version.
8.3.4 Clinical Safety 
Laboratory Tests
“Thyroid stimulating hormone (TSH)” 
added to Table 6 under “Thyroid Tests” 
heading.
Missing from previous 
protocol version in error. 
8.3.5 Computed Tomography 
Scan
Text amended: “All new CT scans should 
be performed post-BD, ie, within 60 
minutes of using up to 4 inhalations of 
albuterol or salbutamol which includes the 
To clarify the procedure for 
CT scans and for consistency 
with Section 8.2.3 Spirometry 
and Peak Flow Measurement.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
182 of 187
Section Number and Name
Description of Change
Brief Rationale
participant’s regular triple or dual 
(ICS + LABA or LAMA + LABA) 
therapy. When these are undertaken at the 
same visit as spirometry and small airway 
measurements, the 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.”
8.3.5 Computed Tomography 
Scan
Addition of “/or” to text: “The participant 
has not had an inspiratory and/or expiratory 
chest CT scan within 6 months of informed 
consent”
To add clarification.
8.3.6 SARS-CoV-2 
Screening
New section with text: “A SARS-CoV-2 
(COVID-19) screening test can be 
performed at the time of study visits if 
required by local clinical guidelines for 
the safety of site staff and other site 
attendees but otherwise is not mandated 
in the study.”
Following removal of SARS-
CoV-2 screening test 
Exclusion Criteria 1, this is 
added to accommodate those 
countries which still need the 
test as per local clinical 
guidelines.
8.4 AEs, SAEs, and Other 
Safety
Addition of AE variable for maximum 
CTCAE grade for non-maculopapular rash 
(in addition to maculopapular rash) and 
clarification of wording that CTCAE 
Grades for maculopapular and non-
maculopapular rash will be captured.
To align with the eCRF and 
clarify that CTCAE Grade will 
be collected for maculopapular 
and non-maculopapular rashes.
8.4.9 Adverse Events of 
Special Interest
Text amended: “It is suggested to start the 
treatment with for maculopapular rash, 
per local standard treatment guidelines 
(which may include, but not be limited to, 
a topical steroid and/or oral antihistamine)”
Addition of text: … should be uploaded to 
the Medidata imaging portal… “
To clarify the study procedure 
and application used.
8.4.10.2 Paternal Exposure
Text added: “In case of pregnancy in the 
partner of a male participant, the 
partner’s pregnancy should be reported 
on the pregnancy form (consent from the 
partner must be obtained before the 
pregnancy form is completed) following 
the same timeframe and routing as 
described for any participant’s 
pregnancy. Pregnancy of the 
participant’s partner is not considered to 
To clarify the study procedure.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
183 of 187
Section Number and Name
Description of Change
Brief Rationale
be an AE. These pregnancies will also be 
followed up, and the outcome of the 
pregnancy (spontaneous miscarriage, 
elective termination, ectopic pregnancy, 
normal birth or congenital anomaly) 
should, if possible, be obtained and 
documented.”
8.4.13 Medical Device 
Deficiencies
Text amended from “In this study any 
deficiency observed with a third-party 
medical device will be collected and 
reported to the manufacturer.” to “In this 
study any deficiency observed with a 
third-party medical device will be 
reported directly to the third-party 
manufacturer by the study site staff 
according to the contact details in the 
device Instructions For Use”
To clarify the procedure in the 
event of a deficiency with a 
third-party medical device.
8.5 Pharmacokinetics
Removal of US and UK wording related to 
20% of patients to have additional post-dose 
PK samples.
To clarify this may not be 
limited to patients in the US 
and UK.
8.8.1 Mandatory Biomarker 
Sample Collection
Sputum colour removed.
Not required as part of sputum 
sample assessment. 
8.8.2 Mandatory Genetic 
Analysis Sample Collection
Text amended: “Genotyping will include, 
but will not be limited to an assessment of 
the HLA genes. The genetic research may 
involve the genotyping of selected genes or 
the analysis of the whole genome sequence.
The sample will only be used for these 
purposes as outlined.”
To clarify the study procedure.
Appendix A 1 Regulatory 
and Ethical Considerations
Addition of section “Regulatory Reporting 
Requirements for Serious Breaches” in line 
with template.
In accordance with 
AstraZeneca CSP protocol 
template v7.0, Doc ID TMP-
0010225 (dated November 
2022) which is based on the 
TransCelerate Common 
Protocol Template v9.0.
Appendix A 7 Data Quality 
Assurance
Storage of records and documents, 
including signed ICFs, pertaining to the 
conduct of the study updated from 15 years 
to 25 years.
To align with wording in the 
ICF and in accordance with 
AstraZeneca CSP protocol 
template v7.0, Doc ID TMP-
0010225 (dated November 
2022) which is based on the 
TransCelerate Common 
Protocol Template v9.0.


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
184 of 187
Section Number and Name
Description of Change
Brief Rationale
Appendix A 9 Study and Site 
Start and Closure
Examples of reasons for early termination 
of the study by AstraZeneca were added.
To clarify the possible reasons 
for the early termination of the 
study.
Version 2.0, 30 June 2022
Version 1.0 of the protocol was not published or used; therefore, there is no history of 
amendments to include for version 2.0 of the protocol. Version 2.0 was the first version to 
be submitted to any Health Authority/Ethics committee.
Version 1.0, 05 May 2022
INITIAL CREATION


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
185 of 187
11
REFERENCES
Adeloye et al 2015
Adeloye D, Chua S, Lee C, Basquill C, Papana A, Theodoratou E, et al. Global and regional 
estimates of COPD prevalence: Systematic review and meta-analysis. J Glob Health. 
2015;5(2):020415.
Antachopoulos 2010
Antachopoulos C. Invasive fungal infections in congenital immunodeficiencies. Clin 
Microbiol Infect. 2010;16(9):1335-1342.
Barnes et al 2015
Barnes PJ, Burney PG, Silverman EK, Celli BR, Vestbo J, Wedzicha JA, et al. Chronic 
obstructive pulmonary disease. Nat Rev Dis Primers. 2015;1:15076.
Cavallazzi and Ramirez 2020
Cavallazzi R and Ramirez J. Community-acquired pneumonia in chronic obstructive 
pulmonary disease. Curr Opin Infect Dis. 2020;33(2):173-181.
Celli and Wedzicha 2019
Celli BR, Wedzicha JA. Update on clinical aspects of chronic obstructive pulmonary disease. 
N Engl J Med. 2019;381(13):1257-1266.
Churg et al 2012
Churg A, Marshall CV, Sin DD, Bolton S, Zhou S, Thain K, et al. Late intervention with a 
myeloperoxidase inhibitor stops progression of experimental chronic obstructive pulmonary 
disease. Am J Respir Crit Care Med. 2012;185(1):34-43.
EMA 2012
EMA 2012. Guideline on clinical investigation of medicinal products in the treatment of 
chronic obstructive pulmonary disease (COPD). 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-
medicinal-products-treatment-chronic-obstructive-pulmonary-disease_en.pdf. Accessed May 
31 2022.
Frewer et al 2016
Frewer P, Mitchell P, Watkins C, Matcham J. Decision-making in early clinical drug 
development. Pharm Stat. 2016;15(3):255-63.
Global Initiative for Chronic Obstructive Lung Disease 2022
Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global strategy for the 
diagnosis, management, and prevention of chronic obstructive pulmonary disease: 2022 
report. https://goldcopd.org/2022-gold-reports-2/


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
186 of 187
Graham et al 2019
Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, et al. 
Standardisation of Spirometry 2019 Update. An Official American Thoracic Society and 
European Respiratory Society Technical Statement. Am J Respir Crit Care Med. 
2019;200(8):e70-e88.
Gronich et al 2022
Gronich N, Maman D, Stein N, Saliba W. Culprit medications and risk factors associated with 
Stevens-Johnson syndrome and toxic epidermal necrolysis: population-based nested case-
control study. Am J Clin Dermatol. 2022;23(2):257-266
ICH 1998
ICH. Guidance for Industry. E9 Statistical Principles for Clinical Trials. 1998. 
https://www.fda.gov/media/71336/download. Accessed 07 June 2022
Jones et al 2009
Jones PW, Harding G, Berry P, Wiklund I, Chen WH, Kline Leidy N. Development and first 
validation of the COPD Assessment Test. Eur Respir J. 2009;34(3):648-654.
Jones et al 2011
Jones PW, Chen WH, Wilcox TK, Sethi S, Leidy NK and EXACT-PRO Study Group. 
Characterizing and quantifying the symptomatic features of COPD exacerbations. Chest 
2011;139(6):1388–94.
Kutter et al 2000
Kutter D, Devaquet P, Vanderstocken G, Paulus JM, Marchal V, Gothot A. Consequences of 
total and subtotal myeloperoxidase deficiency: risk or benefit? Acta Haematol. 
2000;104(1):10-15.
Leidy et al 2003
Leidy NK, Schmier JK, Jones MK, Lloyd J, Rocchiccioli K. Evaluating symptoms in chronic 
obstructive pulmonary disease: validation of the Breathlessness, Cough and Sputum Scale. 
Respir Med. 2003;97 Suppl A:S59-70.
Leidy et al 2011
Leidy NK, Wilcox TK, Jones PW, Roberts L, Powers JH, Sethi S, et al. Standardizing 
measurement of chronic obstructive pulmonary disease exacerbations. Reliability and validity 
of a patient-reported diary. Am J Respir Crit Care Med 2011;183(3):323–9.
NCI 2017
NCI. Common Terminology Criteria for Adverse Events (CTCAE) v5.0. 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick


Clinical Study Protocol - 5.0
AstraZeneca
Mitiperstat (AZD4831) - D6582C00001
CONFIDENTIAL AND PROPRIETARY
187 of 187
_Reference_5x7.pdf. Published 2017. Accessed 01 March 2022.
Park et al 2013
Park HY, Man SF, Tashkin D, Wise RA, Connett JE, Anthonisen NA, Sin DD. The relation of 
serum myeloperoxidase to disease progression and mortality in patients with chronic 
obstructive pulmonary disease (COPD). PLoS One. 2013;8(4):e61315.
Smith et al 2006
Smith JA, Owen EC, Jones AM, Dodd ME, Webb AK, Woodcock A. Objective measurement 
of cough during pulmonary exacerbations in adults with cystic fibrosis. Thorax. 
2006;61(5):425-429.
Soler-Cataluña et al 2005
Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, Salcedo E, Navarro M, Ochando 
R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary 
disease. Thorax. 2005;60(11):925-931.
Suissa et al 2012
Suissa S, Dell'Aniello S, Ernst P. Long-term natural history of chronic obstructive pulmonary 
disease: severe exacerbations and mortality. Thorax. 2012 Nov;67(11):957-963.
Vandenberk et al 2016
Vandenberk B, Vandael E, Robyns T, Vandenberghe J, Garweg C, Foulon V, et al. Which QT 
correction formulae to use for QT monitoring? J Am Heart Assoc. 2016;5(6):e003264.
Vogelmeier et al 2020
Vogelmeier CF, Fuhlbrigge A, Jauhiainen A, Scheepers LEJM, Bengtsson T, Peterson S, et al. 
COPDCompEx: A novel composite endpoint for COPD exacerbations to enable faster clinical 
development. Respir Med. 2020;173:106175.
WHO 2021
World Health Organization 2021. Chronic obstructive pulmonary disease (COPD). 
https://www.who.int/news-room/fact-sheets/detail/chronic-obstructive-pulmonary-disease-
(copd)#:~:text=Chronic%20Obstructive%20Pulmonary%20Disease%20(COPD)%20is%20the
%20third%20leading%20cause,%2Dincome%20countries%20(LMIC). Accessed 
April 01 2022.
Zhu et al 2014
Zhu A, Ge D, Zhang J, Teng Y, Yuan C, Huang M, et al. Sputum myeloperoxidase in chronic 
obstructive pulmonary disease. Eur J Med Res. 2014;19(1):12.


6,*1$785(3$*(
7KLVLVDUHSUHVHQWDWLRQRIDQHOHFWURQLFUHFRUGWKDWZDVVLJQHG
HOHFWURQLFDOO\DQGWKLVSDJHLVWKHPDQLIHVWDWLRQRIWKHHOHFWURQLFVLJQDWXUH
'RFXPHQW1DPHGFFVSY
'RFXPHQW7LWOH
'&&OLQLFDO6WXG\3URWRFROYHUVLRQ
'RFXPHQW,'
'RF,'
9HUVLRQ/DEHO
&855(17/$7(67$33529('
6HUYHU'DWH
GG000\\\\++PPµ87&¶=
6LJQHGE\
0HDQLQJRI6LJQDWXUH
'HF87&
&RQWHQW$SSURYDO
'HF87&
&RQWHQW$SSURYDO
'HF87&
&RQWHQW$SSURYDO
1RWHV'RFXPHQWGHWDLOVDVVWRUHGLQ$1*(/DQ$VWUD=HQHFDGRFXPHQWPDQDJHPHQWV\VWHP
PPD
PPD
PPD

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
1 of 112 
 
STATISTICAL ANALYSIS PLAN 
Study Code 
D6582C00001 
Edition Number 
5.0 
Date 
4-Oct-2024 
A Phase IIa Randomised, Double Blind, Placebo Controlled, 
Parallel Arm, Multi-Centre Study to Evaluate the Efficacy and 
Safety of Mitiperstat (AZD4831), for 12-24 Weeks, in Patients 
with Moderate to Severe Chronic Obstructive Pulmonary 
Disease (COPD) 
 
 
 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
2 of 112 
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................... 1 
TABLE OF CONTENTS ................................................................................................. 2 
LIST OF ABBREVIATIONS .......................................................................................... 6 
AMENDMENT HISTORY ............................................................................................ 11 
1 
INTRODUCTION ....................................................................................... 15 
2 
CHANGES TO PROTOCOL PLANNED ANALYSES ............................ 15 
3 
DATA ANALYSIS CONSIDERATIONS .................................................. 16 
3.1 
Timing of Analyses ...................................................................................... 16 
3.2 
Analysis Populations ................................................................................... 16 
3.3 
General Considerations ................................................................................ 17 
3.3.1 
General Study Level Definitions ................................................................. 18 
3.3.1.1 
Study Day and Baseline ............................................................................... 18 
3.3.1.2 
Derivations ................................................................................................... 20 
3.3.1.3 
Handling of missing data ............................................................................. 22 
3.3.1.4 
Dates Imputation .......................................................................................... 23 
3.3.2 
Periods ......................................................................................................... 24 
3.3.3 
Visit Window ............................................................................................... 25 
3.3.4 
Handling of Unscheduled Visits .................................................................. 30 
3.3.5 
Multiplicity/Multiple Comparisons ............................................................. 30 
3.3.6 
Handling of Protocol Deviations in Study Analysis .................................... 30 
3.4 
General Principles and Analysis Methods ................................................... 31 
3.4.1 
Time to event analysis ................................................................................. 32 
3.4.2 
Analysis of Covariance (ANCOVA) ........................................................... 32 
3.4.3 
Mixed Model Repeated Measures (MMRM) .............................................. 33 
3.4.4 
Negative binomial regression ...................................................................... 34 
4 
STATISTICAL ANALYSIS ....................................................................... 34 
4.1 
Study Population .......................................................................................... 34 
4.1.1 
Patient Disposition and Completion Status ................................................. 34 
4.1.1.1 
Definitions and Derivations ......................................................................... 34 
4.1.1.2 
Presentation .................................................................................................. 35 
4.1.2 
Analysis Sets ................................................................................................ 36 
4.1.2.1 
Definitions and Derivations ......................................................................... 36 
4.1.2.2 
Presentation .................................................................................................. 36 
4.1.3 
Protocol Deviations ..................................................................................... 36 
4.1.3.1 
Definitions and Derivations ......................................................................... 36 
4.1.3.2 
Presentation .................................................................................................. 36 
4.1.4 
Demographics .............................................................................................. 36 
4.1.4.1 
Definitions and Derivations ......................................................................... 36 
4.1.4.2 
Presentation .................................................................................................. 37 
4.1.5 
Baseline Characteristics ............................................................................... 37 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
3 of 112 
4.1.5.1 
Definitions and Derivations ......................................................................... 37 
4.1.5.2 
Presentation .................................................................................................. 37 
4.1.6 
Disease Characteristics ................................................................................ 38 
4.1.6.1 
Definitions and Derivations ......................................................................... 38 
4.1.6.2 
Presentation .................................................................................................. 38 
4.1.7 
Medical History and Concomitant Disease ................................................. 38 
4.1.7.1 
Definitions and Derivations ......................................................................... 38 
4.1.7.2 
Presentation .................................................................................................. 38 
4.1.8 
Prior and Concomitant Medications ............................................................ 39 
4.1.8.1 
Definitions and Derivations ......................................................................... 39 
4.1.8.2 
Presentation .................................................................................................. 39 
4.1.9 
Substance usage – Inhaled Tobacco ............................................................ 40 
4.1.9.1 
Definitions and Derivations ......................................................................... 40 
4.1.9.2 
Presentation .................................................................................................. 40 
4.1.10 
Study Drug Compliance .............................................................................. 40 
4.1.10.1 
Definitions and Derivations ......................................................................... 40 
4.1.10.2 
Presentation .................................................................................................. 41 
4.2 
Endpoint Analyses ....................................................................................... 41 
4.2.1 
Primary Endpoint – Time to First COPDCompEx Event ............................ 45 
4.2.1.1 
Definition ..................................................................................................... 45 
4.2.1.2 
Derivations ................................................................................................... 45 
4.2.1.3 
Handling of Dropouts and Missing Data ..................................................... 45 
4.2.1.4 
Primary Analysis of Primary Endpoint ........................................................ 46 
4.2.1.5 
Sensitivity Analyses of the Primary Endpoint ............................................. 46 
4.2.1.6 
Supplementary Analyses of the Primary Endpoint ...................................... 46 
4.2.1.7 
Subgroup Analyses ...................................................................................... 47 
4.2.2 
Secondary Endpoint – Time to First Moderate or Severe COPD 
Exacerbation Event ...................................................................................... 48 
4.2.2.1 
Definition ..................................................................................................... 48 
4.2.2.2 
Derivations ................................................................................................... 49 
4.2.2.3 
Handling of Dropouts and Missing Data ..................................................... 49 
4.2.2.4 
Primary Analysis of Secondary Endpoint .................................................... 49 
4.2.2.5 
Sensitivity Analyses of the Secondary Endpoint ......................................... 50 
4.2.2.6 
Supplementary Analyses of the Secondary Endpoint .................................. 50 
4.2.2.7 
Subgroup Analyses ...................................................................................... 50 
4.2.3 
Secondary Endpoint – post-BD FEV1 ......................................................... 50 
4.2.3.1 
Definition ..................................................................................................... 50 
4.2.3.2 
Derivations ................................................................................................... 50 
4.2.3.3 
Handling of Dropouts .................................................................................. 50 
4.2.3.4 
Primary Analysis of Secondary Endpoint .................................................... 50 
4.2.3.5 
Sensitivity Analyses of the Secondary Endpoint ......................................... 51 
4.2.3.6 
Supplementary Analyses of the Secondary Endpoint .................................. 51 
4.2.3.7 
Subgroup Analyses ...................................................................................... 51 
4.2.4 
Secondary Endpoint – EXACT score .......................................................... 52 
4.2.4.1 
Definition ..................................................................................................... 52 
4.2.4.2 
Derivations ................................................................................................... 52 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
4 of 112 
4.2.4.3 
Handling of Dropouts .................................................................................. 52 
4.2.4.4 
Primary Analysis of Secondary Endpoint .................................................... 52 
4.2.4.5 
Sensitivity Analyses of the Secondary Endpoint ......................................... 53 
4.2.4.6 
Supplementary Analyses of the Secondary Endpoint .................................. 53 
4.2.4.7 
Subgroup Analyses ...................................................................................... 53 
4.2.5 
Secondary Endpoint – BCSS score .............................................................. 53 
4.2.5.1 
Definition ..................................................................................................... 53 
4.2.5.2 
Derivations ................................................................................................... 53 
4.2.5.3 
Handling of Dropouts .................................................................................. 53 
4.2.5.4 
Primary Analysis of Secondary Endpoint .................................................... 53 
4.2.5.5 
Sensitivity Analyses of the Secondary Endpoint ......................................... 54 
4.2.5.6 
Supplementary Analyses of the Secondary Endpoint .................................. 54 
4.2.5.7 
Subgroup Analyses ...................................................................................... 54 
4.2.6 
Secondary Endpoint – Cough VAS ............................................................. 54 
4.2.6.1 
Definition ..................................................................................................... 54 
4.2.6.2 
Derivations ................................................................................................... 54 
4.2.6.3 
Handling of Dropouts .................................................................................. 54 
4.2.6.4 
Primary Analysis of Secondary Endpoint .................................................... 54 
4.2.6.5 
Sensitivity Analyses of the Secondary Endpoint ......................................... 55 
4.2.6.6 
Supplementary Analyses of the Secondary Endpoint .................................. 55 
4.2.6.7 
Subgroup Analyses ...................................................................................... 55 
4.2.7 
Secondary Endpoint – Total CAT measured in clinic ................................. 55 
4.2.7.1 
Definition ..................................................................................................... 55 
4.2.7.2 
Derivations ................................................................................................... 55 
4.2.7.3 
Handling of Dropouts .................................................................................. 55 
4.2.7.4 
Primary Analysis of Secondary Endpoint .................................................... 55 
4.2.7.5 
Sensitivity Analyses of the Secondary Endpoint ......................................... 56 
4.2.7.6 
Supplementary Analyses of the Secondary Endpoint .................................. 56 
4.2.7.7 
Subgroup Analyses ...................................................................................... 56 
4.2.8 
Tertiary/Exploratory Endpoint – Cough frequency ..................................... 56 
4.2.8.1 
Definition ..................................................................................................... 56 
4.2.8.2 
Derivations ................................................................................................... 56 
4.2.8.3 
Handling of Dropouts .................................................................................. 56 
4.2.8.4 
Primary Analysis of Tertiary/Exploratory Endpoint ................................... 57 
4.2.8.5 
Sensitivity Analyses of the Tertiary/Exploratory Endpoint......................... 57 
4.2.8.6 
Supplementary Analyses of the Tertiary/Exploratory Endpoint ................. 57 
4.2.8.7 
Subgroup Analyses ...................................................................................... 57 
4.2.9 
Tertiary/Exploratory Endpoint – Change from baseline in spirometry 
endpoints measured face to face .................................................................. 57 
4.2.9.1 
Definition ..................................................................................................... 57 
4.2.9.2 
Derivations ................................................................................................... 58 
4.2.9.3 
Handling of Dropouts .................................................................................. 58 
4.2.9.4 
Primary Analysis of Tertiary/Exploratory Endpoint ................................... 58 
4.2.9.5 
Sensitivity Analyses of the Tertiary/Exploratory Endpoint......................... 58 
4.2.9.6 
Supplementary Analyses of the Tertiary/Exploratory Endpoint ................. 58 
4.2.9.7 
Subgroup Analyses ...................................................................................... 58 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
5 of 112 
4.2.10 
Tertiary/Exploratory Endpoint – Annualised rate of COPDCompEx Event58 
4.2.10.1 
Definition ..................................................................................................... 58 
4.2.10.2 
Derivations ................................................................................................... 59 
4.2.10.3 
Handling of Dropouts .................................................................................. 59 
4.2.10.4 
Primary Analysis of Tertiary/Exploratory Endpoint ................................... 59 
4.2.10.5 
Sensitivity Analyses of the Tertiary/Exploratory Endpoint......................... 59 
4.2.10.6 
Supplementary Analyses of the Tertiary/ Exploratory Endpoint ................ 60 
4.2.10.7 
Subgroup Analyses ...................................................................................... 60 
4.2.11 
Tertiary/Exploratory Endpoint – Annualised rate of moderate or severe 
COPD exacerbations .................................................................................... 60 
4.2.11.1 
Definition ..................................................................................................... 60 
4.2.11.2 
Derivations ................................................................................................... 60 
4.2.11.3 
Handling of Dropouts .................................................................................. 60 
4.2.11.4 
Primary Analysis of Tertiary/Exploratory Endpoint ................................... 60 
4.2.11.5 
Sensitivity Analyses of the Tertiary/Exploratory Endpoint......................... 61 
4.2.11.6 
Supplementary Analyses of the Tertiary/ Exploratory Endpoint ................ 61 
4.2.11.7 
Subgroup Analyses ...................................................................................... 61 
4.3 
Pharmacodynamic Endpoint(s) .................................................................... 61 
4.3.1.1 
Definitions and Derivations ......................................................................... 61 
4.3.1.2 
Presentation .................................................................................................. 61 
4.4 
Pharmacokinetics ......................................................................................... 62 
4.4.1 
Definitions and Derivations ......................................................................... 62 
4.4.2 
Presentation .................................................................................................. 63 
4.5 
Immunogenicity ........................................................................................... 63 
4.6 
Genetics ....................................................................................................... 63 
4.7 
Safety Analyses ........................................................................................... 63 
4.7.1 
Exposure ...................................................................................................... 64 
4.7.1.1 
Definitions and Derivations ......................................................................... 64 
4.7.1.2 
Presentation .................................................................................................. 64 
4.7.2 
Adverse Events ............................................................................................ 65 
4.7.2.1 
Definitions and Derivations ......................................................................... 65 
Any AE ............................................................................................................................ 65 
Any SAE .......................................................................................................................... 65 
SAEs with outcome death ............................................................................................... 65 
AEs leading to discontinuation of IP .............................................................................. 65 
AEs possibly related to IP .............................................................................................. 66 
AEs by maximum intensity .............................................................................................. 66 
Adverse events of special interest ................................................................................... 66 
4.7.2.2 
Presentation .................................................................................................. 66 
4.7.3 
Clinical Laboratory, Blood Sample ............................................................. 70 
4.7.3.1 
Definitions and Derivations ......................................................................... 70 
4.7.3.2 
Presentations ................................................................................................ 71 
4.7.4 
Clinical Laboratory, Urinalysis ................................................................... 72 
4.7.4.1 
Definitions and Derivations ......................................................................... 72 
4.7.4.2 
Presentations ................................................................................................ 73 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
6 of 112 
4.7.5 
Other Laboratory Evaluations ...................................................................... 73 
4.7.5.1 
Definitions and Derivations ......................................................................... 73 
4.7.5.2 
Presentations ................................................................................................ 73 
4.7.6 
Vital Signs ................................................................................................... 73 
4.7.6.1 
Definitions and Derivations ......................................................................... 73 
4.7.6.2 
Presentations ................................................................................................ 75 
4.7.7 
Electrocardiogram ........................................................................................ 76 
4.7.7.1 
Definitions and Derivations ......................................................................... 76 
4.7.7.2 
Presentations ................................................................................................ 77 
4.7.8 
Other Safety Assessments ............................................................................ 77 
4.7.8.1 
Definitions and Derivations ......................................................................... 77 
4.7.8.2 
Presentations ................................................................................................ 77 
5 
INTERIM ANALYSIS ................................................................................ 78 
6 
REFERENCES ............................................................................................ 78 
7 
APPENDIX.................................................................................................. 78 
Appendix A Orthostatic Blood Pressure ........................................................................ 78 
Appendix B Table of contents ........................................................................................ 80 
 
LIST OF ABBREVIATIONS  
List abbreviations and definitions of specialized or unusual terms, measurements, or units. 
Examples are provided below. These can be modified at study level. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
7 of 112 
Abbreviation or 
Specialized 
Term 
Definition 
AE 
Adverse Event 
AECOPD 
Acute Exacerbation of Chronic Obstructive Pulmonary Disease 
AESI 
Adverse Event of Special Interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase/transaminase 
ANCA 
Anti-neutrophil cytoplasm antibodies 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase/transaminase 
ATC 
Anatomical Therapeutic Chemical 
ATP 
According to Protocol 
AWE 
Acute worsening event 
B 
Blood 
BCSS 
Breathlessness, Cough and Sputum scale 
BD 
Bronchodilator 
BDRM 
Blinded data review meeting 
BMI 
Body Mass Index 
BP 
Blood pressure 
BSR 
Baseline Scaled Ratio 
CAT 
COPD Assessment Test 
CI 
Confidence interval 
Cmax 
Maximum concentration 
COPD 
Chronic Obstructive Pulmonary Disease 
COPDCompEx 
COPD Composite Exacerbations (composite measure of chronic obstructive 
pulmonary disease) 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV% 
Coefficient of variation 
d 
Day 
DBP 
Diastolic Blood Pressure 
DNA 
Deoxyribonucleic acid 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
8 of 112 
Abbreviation or 
Specialized 
Term 
Definition 
DILI 
Drug Induced Liver Injury 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eDiary 
Electronic diary 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials Database 
EXACT 
EXAcerbations of Chronic pulmonary disease Tool 
FAS 
Full Analysis Set 
FDA 
United States Food and Drug Administration 
FEV1 
Forced Expiratory Volume in 1 second 
FSH 
Follicle stimulating hormone 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
gCV% 
Geometric coefficient of variation 
GOLD 
Global Initiative for Obstructive Lung Disease 
Hb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HL 
Hy’s Law 
hsCRP 
High sensitivity C-reactive protein 
IA 
Interim Analysis 
ICF 
Informed consent form 
ICH 
International Conference on Harmonization 
ICS 
Inhaled Corticosteroids 
Ig 
Immunoglobulin 
IL-6 
Interleukin-6 
IMP 
Investigational Medicinal Product 
IP 
Investigational Product 
IPD 
Important Protocol Deviation 
ITT 
Intent-to-Treat 
IXRS 
Interactive voice/web response system 
LABA 
Long-acting beta-adrenoceptor agonist 
LAMA 
Long-acting muscarinic antagonist 
LLOQ 
Lower Limit Of Quantification 
LSMean 
Least square mean 
LSMD 
Least Squares Mean Difference 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
9 of 112 
Abbreviation or 
Specialized 
Term 
Definition 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures  
MPO 
Myeloperoxidase 
mRNA 
Messenger ribonucleic acid 
NQ 
Not Quantifiable 
NR 
Not Reportable 
NS 
No Sample 
NT-proBNP 
N-terminal pro B-type natriuretic peptide 
OCS 
Oral corticosteroids 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PDP 
Protocol Deviation Plan 
PEF 
Peak Expiratory Flow 
PHL 
Potential Hy’s Law 
PI 
Principal investigator 
PK 
Pharmacokinetics 
PRO 
Patient reported outcome 
PT 
Preferred Term 
QD 
Quaque Die (every day) 
RDMS 
Regulatory Document Management System 
REML 
REstricted Maximum Likelihood 
SAE 
Serious adverse event 
SS 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SBP 
Systolic Blood Pressure 
SD 
Standard deviation 
SID 
Patient ID 
SMQ 
Standardised MedDRA Query 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
SoC 
Standard of care 
SV 
Study Visit 
TA 
Therapeutic Area 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
10 of 112 
Abbreviation or 
Specialized 
Term 
Definition 
TBL 
Total bilirubin 
TFL 
Tables, Figures and Listings 
Tmax 
Time to reach maximum concentration 
TSH 
Thyroid stimulating hormone 
U 
Urine 
ULN 
Upper limit of normal 
URC 
Unblinded Review Committee 
VAS 
Visual Analogue Scale 
 
 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
11 of 112 
AMENDMENT HISTORY  
CATEGORY 
Change refers to: 
Date 
Description of change 
In line 
with CSP? 
Rationale 
N/A 
10/27/2022 
Initial approved SAP 
N/A 
N/A 
Data presentation 
2/6/2023 
The wording of “baseline” changed to “start of 
treatment” for cough frequency endpoint. 
yes 
Start of treatment is used in place of 
baseline to clarify the time of study 
measure. 
Data presentation 
2/6/2023 
Text moved from Table 9 to footnotes: 
“Intercurrent events are events occurring after 
treatment initiation (eg, premature treatment 
discontinuation, switching treatment, terminal 
events such as death) that affect either the 
measurement or interpretation of the summary 
measure (eg, hazard ratio) associated with the 
clinical question of interest. 
yes 
Clarification of intercurrent events in the 
study. 
 
Secondary 
endpoint(s) 
2/6/2023 
Patient reported outcome questionnaire changed from 
E-RS:COPD to EXACT throughout and copy of 
EXACT added in Appendix G of the CSP. 
yes 
Due to requirement to use the full 
14-question EXACT Scale by the 
license holder. ERS:COPD is similar to 
EXACT, therefore this change would 
not affect the safety and scientific value 
of the study. 
Derivation of 
secondary endpoint(s) 
2/6/2023 
Clinical spirometry (post-BD) site measurement 
added at SV4. 
yes 
To align with other site visits. 
Secondary 
endpoint(s) 
2/6/2023 
Exploratory spirometry objective and endpoints 
added. 
yes 
These spirometry endpoints are being 
collected in the previous version of 
protocol. The objectives and endpoints 
were added to clarify the intention to 
analyse these data, in an exploratory 
manner (Section 4.2.9).  
Data presentation 
2/6/2023 
Exploratory objective and endpoints added to 
measure effect of sputum MPO concentration (added 
as subgroup analysis) 
yes 
To clarify intended exploratory analysis 
for sputum MPO concentration. This 
does not have a significant impact on 
safety and scientific value of the study. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
12 of 112 
CATEGORY 
Change refers to: 
Date 
Description of change 
In line 
with CSP? 
Rationale 
Data presentation 
2/6/2023 
Creation of new CSP section 6.4, ‘Blinding’ and text 
added: “The study will be blinded to both 
participants and investigators/site staff as well as 
to AstraZeneca staff. With the formation of the 
URC and DRC (see Appendix A 5) the study will 
become unblinded to the AstraZeneca staff 
assigned to these committees (including those with 
clinical, medical, statistical, and programming 
expertise) who will form a firewalled URC for 
administrative purposes and will all be 
independent from the study team (see Appendix 
A 5). The URC will be responsible for conducting 
the administrative IA whereas the DRC will be 
responsible for safety monitoring.” Updated 
Section 5 Interim Analysis  
yes 
In accordance with AstraZeneca CSP 
protocol template v7.0, Doc ID TMP-
0010225 (dated November 2022) which 
is based on the TransCelerate Common 
Protocol Template v9.0 and to 
simplify/clarify the roles of the 
URC/DRC. 
Derivation of 
secondary endpoint(s) 
2/6/2023 
AECOPD definition, start and stop dates added. 
yes 
In accordance with AstraZeneca CSP 
protocol template v7.0, Doc ID TMP-
0010225 (dated November 2022) which 
is based on the TransCelerate Common 
Protocol Template v9.0 and to define the 
start and stop dates of AECOPD. 
Derivation of 
secondary endpoint(s) 
2/6/2023 
Change of wording related to SV3, SV4, SV5 and 
SV7 to make it clearer where and when virtual and 
face-to-face spirometry assessments will be 
performed (Section 4.2.9). 
yes 
To clarify acceptable locations for study 
virtual spirometry assessments and to 
clarify the study procedure for face-to-
face and virtual spirometry assessments. 
Secondary 
endpoint(s) 
2/22/2023 
Daily assessments of BCSS and Cough VAS will be 
analysed as 2-weekly means according to periods 
defined in Section 3.3.3. 
no 
 
Data presentation 
12/27/2023 
An administrative IA will be conducted after 136 
(70% of the required 194) first 
COPDCompEx events have occurred 
yes 
To align with CSP v5.0 
Data presentation 
12/27/2023 
Added Recurrent Rate analysis for both CompEx and 
Exacerbations 
no 
 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
13 of 112 
CATEGORY 
Change refers to: 
Date 
Description of change 
In line 
with CSP? 
Rationale 
Derivation of 
secondary endpoint(s) 
5/10/2024 
Added visits SV4 and SV7 to make it clearer when 
virtual and face-to-face spirometry assessments will 
be performed. 
yes 
To clarify the visits for face-to-face and 
spirometry assessments. 
Secondary 
endpoint(s) 
5/10/2024 
Text updated in section 4.2.3.4 to add Week 4 and 
Week 12 for change from baseline analysis. 
yes 
To be consistent across SAP. 
Statistical analysis 
method for secondary 
endpoint(s) 
5/10/2024 
Updated to use Region will be added as a random 
effect 
NA 
To correct an error from 
the previous version of 
the SAP. 
Data presentation 
5/10/2024 
Time at risk calculation updated. For the IA a NTF 
was filed 
NA 
In case subjects have CompEx or 
exacerbation from start to end of 
treatment 
Data presentation 
5/10/2024 
The analysis windows for Table 4 updated 
yes 
To include maximum records for 
analysis 
Data presentation 
5/20/2024 
Remove the entire Section 4.2.10 
Tertiary/Exploratory Endpoint – Systemic 
Biomarkers of Cardiovascular Comorbidities and all 
the subsections. 
yes 
This is not a part of CSR as per the 
protocol 
Data presentation 
5/23/2024 
Updated text in section 4.7.1.2 “Duration of exposure 
and total dose will be presented categorically by 
categories by every 28th day from Day 1 to Day 172, 
with 141-172 as the final category” 
NA 
To correct an error from 
the previous version of 
the SAP. 
Data presentation 
5/23/2024 
Updated text in section 4.2.1.7 to clarify the estimates 
required for analysis 
NA 
To add clarity 
Data presentation 
5/23/2024 
Updated text in section 4.2.3.7 to specify how the 
forest plot should be presented 
NA 
To add clarity 
Data presentation 
6/12/2024 
Updated Table 10 to remove the abnormality criteria 
not required. 
NA 
To correct an error from 
the previous version of 
the SAP. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
14 of 112 
CATEGORY 
Change refers to: 
Date 
Description of change 
In line 
with CSP? 
Rationale 
Data presentation 
6/12/2024 
Removed text in section 3.3 – “This will not be part 
of the main analyses produced for the CSR” 
Yes 
To include Cough substudy outputs in 
CSR 
Data presentation 
6/17/2024 
Added calculation rule for cough frequency 
parameters 
NA 
To handle log transformed values 
Data presentation 
9/25/2024 
Safety analysis will not use estimand policy and will 
include all on study data 
No 
 
Data presentation 
9/25/2024 
Updates in handling spirometry screening and 
baseline data 
No 
To handle missing/implausible values 
Data presentation 
10/3/2024 
Updated compliance calculation 
NA 
To handle data issues 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
15 of 112 
1 
INTRODUCTION  
The purpose of this document is to give details for the statistical analysis of study 
D6582C00001 supporting the clinical study report. The reader is referred to the Clinical 
Study Protocol (CSP) version 5.0 and the Case report Form (CRF) for details of study conduct 
and data collection. 
2 
CHANGES TO PROTOCOL PLANNED ANALYSES  
• The Per-Protocol Set defined in the protocol will not be used for the analysis. 
• The Cough subset will then be defined as a subset of the Full Analysis Set. 
• The randomized Set is added to this analysis.  
• The following biomarkers will not be delivered prior to DBL and will not be part of 
the CSR:  
o Sputum parameters including differential cell counts, and markers of 
neutrophil activation and inflammation; 
o neutrophil- related circulating biomarkers; 
o Putative biomarkers of lung tissue destruction and COPD disease progression; 
o nasal lining fluid biomarkers. 
• Daily assessments of BCSS and Cough VAS will be analysed as 2-weekly means 
according to periods defined in Section 3.3.3. 
• Laboratory safety analysis will be based on abnormality and not on treatment 
emergent change. 
• Safety analysis will not use either the While on Treatment or Treatment policy estimand 
policy, and will simply include all on study data. 
• Screening spirometry values will be used at Baseline if the Baseline results are missing. 
For % predicted FEV1 and FVC, implausible values due to data issues will be excluded 
from statistical analysis 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
16 of 112 
3 
DATA ANALYSIS CONSIDERATIONS  
3.1 
Timing of Analyses  
The present study is aimed to evaluate the efficacy and safety of the myeloperoxidase (MPO) 
inhibitor AZD4831 in the treatment of moderate to severe COPD compared to placebo.  
The study will be event-driven thus the enrolment will be stopped after approximately 
194 participants have had a COPDCompEx event; when the last enrolled patient completes 
12 weeks of treatment, the study will stop, thus the treatment will be over a minimum 12-
week and maximum 24-week period followed by 2 weeks of follow-up. 
An administrative Interim Analysis (IA) will be conducted after the 136 first COPDCompEx 
events (70% of the required 194 events) have occurred. It will allow an early assessment of 
efficacy for AZD4831 according to the decision framework (Frewer et al 2016) and safety. 
No formal statistical test will be conducted. The IA assessment will be used to guide internal 
(AstraZeneca) decision-making regarding further development of the AZD4831 program. As 
a result, no alpha will be spent at the IA.Analysis Populations   
The following populations are defined for the analysis: 
• All Patients (Screened set) 
Will include all the participants who have signed the informed consent form during the 
screening period and have been screened. Participants who have been randomised will be 
analysed according to their planned study intervention group. Participants not randomised 
will be summarised only in Total column. 
• Randomised set  
Will include all the participants who have signed the informed consent form during the 
screening period and have been randomised. Participants will be analysed according to their 
planned study intervention group. 
• Full Analysis Set (FAS) 
Will include all randomised participants who received at least one dose of study intervention. 
Participants will be analysed according to planned study intervention. Efficacy analyses will 
be based on the FAS. 
• Safety Analysis Set (SS) 
Will include all participants who received at least 1 dose of study intervention. Participants 
will be analysed according to actual treatment. Safety analyses will be based on the SS. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
17 of 112 
• PK set 
Will include all participants who received AZD4831 and who have evaluable PK data for 
AZD4831, with no important protocol deviations thought to impact on the analysis of the PK 
data. 
• Cough subset 
Will include the subset of FAS set who consented to the cough substudy. 
‘All Patients’ population will be used to summarise all participants disposition. The FAS 
population will be used to summarise all demographic and baseline characteristics, 
concomitant medications, and efficacy measures. The Safety set will be used to summarise 
all safety measures (AEs, laboratory tests, ECG, and vital signs). The PK population will be 
used to summarise PK measures. The Cough substudy population will be used to summarise 
substudy specific efficacy measures. 
3.3 
General Considerations  
Study design 
This is a Phase IIa, randomised, placebo-controlled, double-blind, parallel-arm, event-driven 
study with an up to 24-week treatment time designed to evaluate the efficacy and safety of 
AZD4831 administered QD using a tablet in adult patients with confirmed moderate to severe 
symptomatic COPD (FEV1/FVC < 0.7, ≥ 10 pack-years smoking history, and post-BD FEV1 
≥ 25% predicted) who are at high risk of exacerbations despite being maintained on optimised 
SoC inhaled therapies - triple inhaled therapy (ICS/LABA/LAMA) or ICS/LABA dual 
therapy or LABA/LAMA dual therapy (for participants with a history of pneumonia or who 
are otherwise deemed unsuitable for ICS). The treatment will be over a minimum 12-week 
and maximum 24-week period. Further details about inclusion and exclusion criteria are 
available in Section 5 – Study population in the CSP. 
Approximately 406 participants will be randomised 1:1 to AZD4831 QD or placebo QD. The 
randomisation will be stratified by country. The study will be blinded to both participants 
and investigators/site staff as well as to the sponsor. 
The entire study period is planned to take between 18 and 30 weeks for each individual 
patient: a 4-week screening period, minimum 12 weeks to a maximum 24 weeks of dosing 
and 2 weeks of follow-up. The enrolment will be stopped after approximately 194 
COPDCompEx events have occurred, and when the last enrolled patient completes 12 weeks 
of treatment, the study will stop. At the point the study ends due to the required number of 
COPDCompEx events occurring, participants who are receiving study intervention between 
Weeks 12 and 24 at the time the last patient completes Week 12 should attend SV7 as soon 
as possible, continuing treatment until they do. They should then attend SV8 14 ± 3 days 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
18 of 112 
later. For further details and the Schedule of Activities, refer to Table 1 – Schedule of 
Activities in the CSP. 
Study product 
The study product is AZD4831 and it will be administered orally once a day as tablet 
containing 5 mg of investigational product (IP). The first dose of study intervention will be 
administered in clinic on the day of randomisation. Participants will receive study 
intervention at the site on visit days and at home between visits. No dose modification is 
allowed during the study. 
Sample size determination 
The study is powered using COPDCompEx, a composite endpoint used to estimate the 
magnitude of treatment effect on moderate and severe exacerbations of COPD. The time to 
first COPDCompEx event will be compared between AZD4831 QD vs placebo arms using a 
logrank test. A total of 194 first COPDCompEx events (estimated to require 203 participants 
per arm) will provide 80% power at the two-sided 10% level of statistical significance to 
detect a hazard ratio of 0.70 in the AZD4831 5 mg QD arm based on a 24-week first 
COPDCompEx event risk of 55% assumed in the placebo arm (constant over the course of 
the study). A screen failure rate of 40% is assumed, therefore approximately 677 participants 
will be screened to achieve the randomisation of 406 participants. 
Cough Monitoring Substudy  
A cough monitoring substudy will be performed alongside this study, where a subset of 
participants (maximum of 50 participants from each arm) from selected sites will be included. 
Twenty-four-hour cough frequency monitoring will be conducted at Visit SV3 (start of 
treatment) and Visit SV5 (after 12 weeks of treatment) using the VitaloJAK® Cough Monitor 
device. The main objective of the substudy is to explore the effect of AZD4831 compared 
with placebo on change in average 24-hour, awake, and sleeping cough frequency between 
baseline and Week 12. The substudy will also investigate whether average cough frequency 
is associated with lung function (e.g., PEF or FEV1), cough/COPD symptom scores (e.g., 
BCSS, CAT, and cough VAS) and sputum/blood biomarkers (e.g., MPO concentration). 
3.3.1 
General Study Level Definitions  
3.3.1.1 
Study Day and Baseline  
Whenever data is summarised over time, study day will be calculated based on the actual 
assessment date. All data will be summarised in relation to date of first IP administration. 
If actual assessment date is prior to the first IP administration, then study day will be: 
Study day = Actual assessment date – first IP administration date. 
If actual assessment date is on or after the first IP administration, then study day will be: 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
19 of 112 
Study day = Actual assessment date – first IP administration date + 1. 
In general, the last non-missing measurement prior to first application of IP will serve as 
the baseline measurement for efficacy and safety endpoints. 
If multiple visits are equally eligible to assess patient status at baseline (for example 
assessments both on the same date prior to first dose of IP administration), the average (for 
numeric values)/worst (for categorical values) of the measurements will be taken as the 
baseline value. If several assessments are performed on the same day as first dose of IP 
administration, only those with time recorded prior to IP time of administration will be used 
to assess patient status at baseline (i.e. if time of assessment on the same day as IP 
administration is missing, the assessment will be assumed to be collected after 
administration). 
If no value exists before the first dose of any study drug, then the baseline value will be 
treated as missing. 
 
Orthostatic blood pressure measurements, even if assessed prior to IP administration, will not 
be used as baseline; they will be summarised and listed separately. 
For daily PEF, Cough VAS Assessment and BCSS, baseline will be defined as the average 
from last 2 weeks (14 days) results prior to first dose of investigational product, i.e. from 
evening of Study Day -14 to the morning of Study Day 1. If there are fewer than 7 completed 
days in the 14-day baseline period (where a complete day = entry from the evening AND the 
following morning, i.e. one day will include all the data performed at or after 12.00 in the 
afternoon up to 12.00 the following morning) then baseline will be set to missing.  
The baseline value of each CompEx variable will be defined as the average of all available 
measurements during the baseline period. There must be at least 50% of non-missing daily 
assessments for a variable in order for baselines to be calculated. Daily assessments could be 
made up of a single assessment in either the morning or evening, or two assessments daily, 
depending on the variable. For a baseline window of 14 days and for variables where 
assessments are available morning and evening, there should be at least 7 days of non-missing 
morning assessments and 7 days of non-missing evening assessments. For variables using 
once daily assessment, 7 days of non-missing assessments (from either morning or evening, 
depending on when the variable is captured) should be used. 
The baseline cough frequency is derived from the cough monitoring performed at Visit 3 (or 
Revisit 3 for rescreened participants). For cough frequency, a baseline value will be defined 
for 24h, waking and sleeping.  


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
20 of 112 
For spirometry, if multiple assessments have been collected during the same day, the ’best 
result’ flag out of all measurements per timepoint (including baseline) will be used in the 
analysis. 
3.3.1.2 
Derivations  
Absolute change from baseline 
Absolute change from baseline will be derived as follows: 
Absolute change from baseline = (post-randomisation value – baseline value). 
Time since COPD diagnosis (years) 
Time from COPD first diagnosis date to randomization will be calculated as (date 
randomized minus date of first diagnosis of COPD plus one) divided by 365.25. If date of 
first diagnosis of COPD is partially missing, then imputed date will be used. 
Time since COPD symptoms started (years) 
Time from COPD first symptoms date to randomization will be calculated as (date 
randomized minus date of first symptoms of COPD plus one) divided by 365.25. If date of 
first symptoms of COPD is partially missing then imputed date will be used. 
Time since last exacerbation (months) 
Time since last COPD exacerbation date to randomization will be calculated as (date 
randomized minus date of most recent exacerbation plus one) divided by 365.25 and 
multiplied by 12. If date of first symptoms of COPD is partially missing then imputed date 
will be used. 
Total number of COPD exacerbations within previous 24 months prior to screening 
This number is derived by counting the number of events occurring prior the screening. 
Duration of AECOPD 
The start and stop dates of COPD exacerbations will be 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 
• 
Date of hospital admission due to AECOPD 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
21 of 112 
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. 
Time from first IP administration to AE onset (days) 
Time from first IP administration to AE onset will be calculated as date of AE onset minus 
date of first IP administration plus one. 
Time from latest IP administration to AE onset (days) 
Time from latest IP administration to AE onset will be calculated as date of AE onset minus 
date of last IP administration plus one. 
Time from first IP administration to death (days) 
Time from first IP administration to death will be calculated as date of death minus date of 
first IP administration plus one. 
Time from latest IP administration to death (days) 
Time from latest IP administration to death will be calculated as date of death minus date of 
latest IP administration plus one. 
Duration of AE (days) 
Duration of AE will be calculated as stop date of AE minus start date of AE plus one. 
Duration of acute worsening events (days) 
Duration of acute worsening events (AWE) will be calculated as stop date of AWE minus 
start date of AWE plus one. If two or more AWEs overlap then the duration of worsening 
will be calculated as stop date of latest AWE minus start date of first AWE plus one. 
Duration of Interruptions 
Duration of interruption will be calculated as the end date of dose interruption minus the start 
date of dose interruption plus one. 
The start date of dose interruption is the day when drug was interrupted and the treatment 
was not administered. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
22 of 112 
3.3.1.3 
Handling of missing data  
No imputation for missing efficacy endpoints will be done. 
Missing safety data will generally not be imputed. However, safety assessment values of the 
form of “< x” (i.e., below the lower limit of quantification) will be imputed as “0.5x LLOQ” 
in the calculation of summary statistics but displayed as “< x” in the listings. No imputation 
will be done for laboratory values of the form “>x” (i.e., above the upper limit of 
quantification) and the value “>x” will be displayed in the listings. Note that 0 should not be 
used as an imputed value in case the endpoint requires a log transformation. 
Additionally, adverse events (AEs) that have missing causality (after data querying) will be 
assumed to be causally related to study drug. 
Plasma concentrations below the lower limit of quantification will be reported as NQ (Not 
Quantifiable) in the listings with the LLOQ defined in the footnotes of the relevant TFLs. 
Individual plasma concentrations that are Not Reportable will be reported as NR and those 
that are missing will be reported as NS (No Sample) in the listings. Plasma concentrations 
that are NQ, NR or NS will be handled as follows for the provision of descriptive statistics: 
• 
 Any values reported as NR or NS will be excluded from the summary tables and 
corresponding figures. 
• 
At a time point where less than or equal to 50% of the concentration values are NQ, all 
NQ values will be set to the LLOQ, and all descriptive statistics will be calculated 
accordingly. 
• 
At a time point where more than 50% (but not all) of the values are NQ, the gmean, 
gmean ± gSD and gCV% will be set to NC (as Not Calculated). The maximum value 
will be reported from the individual data, and the minimum and median will be set to 
NQ. 
• 
If all concentrations are NQ at a time point, no descriptive statistics will be calculated 
for that time point. The gmean, minimum, median and maximum will be reported as 
NQ and the gCV% and gmean ± gSD as NC. 
• 
The number of values below LLOQ (n < LLOQ) will be reported for each time point 
together with the total number of collected values (n). 
Three observations > LLOQ are required as a minimum for a plasma concentration to be 
summarised. Two observations > LLOQ are presented as minimum and maximum with the 
other summary statistics as NC. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
23 of 112 
3.3.1.4 
Dates Imputation  
Imputation of partial missing AE dates 
Date and time of AE are mandatory eCRF fields. In the rare cases of missing AE 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: 
o If only the day is missing: Assume the last day of the collected month. 
o 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:  
o If the month and year are different from the month and year of the first dose 
of IP, assume 01-MMM-YYYY.  
o 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.  
o 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.  
• If the month is missing and:  
o If the year is different from the year of first dose of IP, assume 01-JAN-YYYY 
of the collected year.  
o 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.  


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
24 of 112 
o 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. 
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: 
o If only the day is missing: Impute with the last day of the collected month.  
o If the month is missing: Impute with 31-DEC of the collected year. 
In case the medication end date is after the end of study date after applying the above rules, 
the concomitant medication end date should be set to end of study date. 
Imputation of partial missing COPD/Medical history dates 
Only partial COPD/medical 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 JAN 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 month is missing, then impute 31st DEC of the collected year. 
3.3.2 
Periods  
Pre-treatment period 
The pre-treatment period starts at the date of signed informed consent and ends before the 
date and timepoint of first dose of Investigational Product (IP). 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
25 of 112 
On-treatment period 
The on-treatment period will be calculated from the date and timepoint (as in time of day) of 
the first dose of IP to the earliest of date of last dose, date of withdrawal of consent or date 
of death. If withdrawal of consent or death did not occur, it will be calculated from the time 
of the first dose of IP to the earliest of date of last dose of study drug or the last study visit. 
If the timepoint of first dose of IP is missing, only the day of first dose of IP will be used. 
Follow-up period 
The follow-up period will be calculated from the date of last dose of IP + 1 day to the date of 
last visit.  
3.3.3 
Visit Window  
For COPDCompEx and the exacerbation related analyses no analysis visit windows will be 
applied. 
For PK related analyses no analysis visit windows will be applied and the actual visits/time 
points will be used instead. 
With the exception of the above, visit windows will be used for all scheduled assessments to 
allow for by-visit analyses, since not all assessments are performed on the scheduled day. 
Unless specified otherwise, all efficacy and safety analyses will be based on the analysis visit 
windows. The actual assessment day will be mapped to the planned study visit following the 
analysis visit windowing rules below:  
• If screening and re-screening visits have same date and time then the re-screening 
assessment will be used in the analysis. 
• If more than one assessment falls within a visit window, the closest non-missing 
assessment to the scheduled day will be used in the analysis. 
• If more than one non-missing assessment actual dates are equidistant from the target 
day, the earlier assessment will be used in the analysis.  
Table 1 
Analysis visit windows for CAT and EXACT 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled Study 
Day 
Visit Window for Analysis 
(Days) 
SV1 
Week -4 
Screening 
-28 
All assessments up to and 
including Day -1 
SV3 
Week 1 
Day 1 Pre-dose  
1 
All assessments on Day 1prior 
to the first administration of 
investigational product 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
26 of 112 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled Study 
Day 
Visit Window for Analysis 
(Days) 
SV5 
Week 12 
Week 12 
84 
All assessments on or after the 
first administration of 
investigational product to 127 
SV7 
Week 24 
Week 24 
168 
≥128 
SV = Study Visit. 
 
Table 2 
Analysis visit windows for serum chemistry, haematology, vital signs 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled Study 
Day 
Visit Window for Analysis 
(Days) 
SV1 
Week -4 
Screening 
-28 
All assessments up to and 
including Day -1 
SV3 
Week 1 
 Day 1 Pre-dose 
1 
All assessments on Day 1 prior 
to the first administration of 
investigational product 
SV4 
Week 4 
Week 4 
28 
All assessments on or after the 
first administration of 
investigational product to 56 
SV5 
Week 12 
Week 12 
84 
57 to 127 
SV7* 
Week 24 
EOT [a] 
• 
For completed 
participant who 
performed Week 24: 
168 
For completed 
participant who 
performed Week 12 
only: 84 
• 
For completed participant 
who performed Week 24:  
128 to 176 
For completed participant who 
performed Week 12 only:  
57 to 127 
SV8† 
End of 
safety 
period 
14 days post treatment 
 
Treatment end date + 14 (+/-3) 
days 
[a] EOT may occur from Week 12 onwards.  
Which means that the Week 12 assessment may need to be duplicated for EOT using the Penultimate 
Observation Carried Forward Imputation Technique, ensuring EOT assessment will also contribute to the Week 
12 summary statistics  
     
*If a subject’s visit is marked with EOT it is automatically allocated to Protocol Visit SV7. If a subject's SV5 
occurs after End of Enrolment, then this visit is also duplicated as SV7. 
†If a subject’s visit is marked as ‘14 days post treatment’, it is automatically allocated to Protocol Visit SV8 
SV = Study Visit. 
 
For vital signs, the analysis visit will be "Day 1" for the post-dose assessment done the day 
of the first administration. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
27 of 112 
Table 3 
Analysis visit windows for exploratory biomarkers (blood) and clinic 
spirometry (post-BD) 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled Study 
Day 
Visit Window for Analysis 
(Days) 
SV1 
Week -4 
Screening 
-28 
All assessments up to and 
including Day -1 
SV3 
Week 1 
 Day 1 Pre-dose 
1 
All assessments on Day 1 prior 
to the first administration of 
investigational product 
SV4 
Week 4 
Week 4 
28 
All assessments on or after the 
first administration of 
investigational product to 56 
SV5 
Week 12 
Week 12 
84 
57 to 127 
SV7 
Week 24 
Week 24 
168 
≥128 
BD = Bronchodilator; SV = Study Visit. 
For Spirometry assessment at screening, the maximum reading from each series will be used in the analysis. For 
subjects who have two series of Spiroload screening data, the maximum reading from the latter series will be 
used for analysis. 
 
Table 4 
Analysis visit windows for Thyroid test 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled Study 
Day 
Visit Window for Analysis 
(Days) 
SV1 
Week -4 
Screening 
-28 
All assessments up to and 
including Day -1 
SV3 
Week 1 
 Day 1 Pre-dose 
1 
All assessments on Day 1 prior 
to the first administration of 
investigational product 
SV5 
Week 12 
Week 12 
84 
All assessments on or after the 
first administration of 
investigational product to 127 
SV7* 
Week 24 
EOT[a] 
For completed 
participant who 
performed Week 24: 
168 
For completed 
participant who 
performed Week 12 
only: 
84 
For completed participant who 
performed Week 24: 
128 to 176 
For completed participant who 
performed Week 12 only: 
all assessments on or after the 
first administration of 
investigational product to 127 
SV8† 
End of 
safety 
period 
14 days post treatment 
 
Treatment end date + 14 (+/-3) 
days 
[a] EOT may occur from Week 12 onwards. Which means that the Week 12 assessment may need to be 
duplicated for EOT using the Penultimate Observation Carried Forward Imputation Technique, ensuring EOT 
assessment will also contribute to the Week 12 summary statistics  
 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
28 of 112 
 * If a subject’s visit is marked with EOT it is automatically allocated to Protocol Visit SV7 
† If a subject’s visit is marked as ‘14 days post treatment’, it is automatically allocated to Protocol Visit SV8 
SV = Study Visit. 
 
Table 5 
Analysis visit windows for Urinalysis 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled Study 
Day 
Visit Window for Analysis 
(Days) 
SV1 
Week -4 
Screening 
-28 
All assessments up to and 
including Day -1 
SV3 
Week 1 
 Day 1 Pre-dose 
1 
All assessments on Day 1 prior 
to the first administration of 
investigational product 
SV8 
End of 
safety 
period 
14 days post treatment 
> Date of last IP 
intake 
All assessments after the last 
administration of 
investigational product 
SV = Study Visit. 
 
Table 6 
Analysis visit windows for ECGs, Blood sample for target 
engagement assay, Whole blood RNA PAXgene collection form 
mRNA analyses, Plasma sample for proteomics, Blood sample for 
cell-free DNA analysis, Nasal mucosal lining fluid, Spontaneous 
sputum 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled Study 
Day 
Visit Window for Analysis 
(Days) 
SV1 
Week -4 
Screening 
-28 
All assessments up to and 
including Day -1 
SV3 
Week 1 
 Day 1 Pre-dose 
1 
All assessments on Day 1 prior 
to the first administration of 
investigational product 
SV5 
Week 12 
Week 12 
84 
All assessments on or after the 
first administration of 
investigational product  
ECG = Electrocardiogram; SV = Study Visit. 
For all other assessments (e.g., cough monitoring), there will be no analysis visit windows, 
the 
data 
will 
be 
reported 
according 
to 
CRF 
visit. 
 
Table 7 Analysis visit windows for Lying and Standing (orthostatic) BP 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled Study 
Day 
Visit Window for Analysis 
(Days) 
SV3 
Week 1 
Day 1 Pre-dose 
1 
All assessments on Day 1 prior 
to the first administration of 
investigational product 
SV3 
Week 1 
 Day 1 Post-dose 
1 
All assessments on Day 1 post 
the first administration of 
investigational product 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
29 of 112 
Protocol 
Visit 
Week 
Analysis Visit 
Scheduled Study 
Day 
Visit Window for Analysis 
(Days) 
SV5 
Week 12 
Week 12 
84 
All assessments before the 
administration of 
investigational product from 
Day 81-Day 87 
SV = Study Visit. 
 
Daily assessments from eDiary (PEF, BCSS, cough VAS) will primarily be summarised and 
analysed as 2-weekly averages, separately. The assessment period of visit windows will be 
defined in Table 8. 
Table 8 
Labelling of 2-weekly periods for daily PEF, BCSS, cough VAS 
2-weekly period 
Adjusted defined 
windows visit 
Scheduled day 
Baseline: as defined in Section 3.3.1.1 
Baseline 
1 
Period 1: Evening of Day 1 – Morning of Day 15 
Week 2 
15 
Period 2: Evening of Day 15 – Morning of Day 29 
Week 4 
29 
Period 3: Evening of Day 29 – Morning of Day 43 
Week 6 
43 
Period 4: Evening of Day 43 – Morning of Day 57 
Week 8 
57 
Period 5: Evening of Day 57 – Morning of Day 71 
Week 10 
71 
Period 6: Evening of Day 71 – Morning of Day 85 
Week 12 
85 
Period 7: Evening of Day 85 – Morning of Day 99 
Week 14 
99 
Period 8: Evening of Day 99 – Morning of Day 113 
Week 16 
113 
Period 9: Evening of Day 113 – Morning of Day 127 
Week 18 
127 
Period 10: Evening of Day 127 – Morning of Day 141 
Week 20 
141 
Period 11: Evening of Day 141 – Morning of Day 155 
Week 22 
155 
Period 12: Evening of Day 155 – Morning of Day 172* 
Week 24 
169 
*the 2-weekly period for Period 12 is extended to "Morning of Day 172", to allow for the +3 day window. 
The Early Discontinuation and unscheduled visits will be included when applying the visit 
windows to ensure that all available data are used in the analysis.  
For 2-weekly summaries, the mean of all non-missing observations within an assigned 
window is calculated. If there are fewer than 7 completed days in the 14 day period (where a 
complete day = entry from the evening AND the following morning) then the analysis value 
will be set to missing. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
30 of 112 
3.3.4 
Handling of Unscheduled Visits  
Any data collected at early discontinuation and unscheduled visits will be listed and included 
in the definition of maximum/minimum value. The Early Discontinuation and Unscheduled 
visits will be included when applying the visit windows to ensure that all available data are 
used in the analysis.  
3.3.5 
Multiplicity/Multiple Comparisons  
No multiplicity/multiple comparison are planned for this study. 
3.3.6 
Handling of Protocol Deviations in Study Analysis  
The deviations from the protocol will be classified as important or non-important by blinded 
members of the study team.  
The list of study specific IPDs is provided in the AstraZeneca Protocol Deviations Plan 
(PDP). Refer to the PDP for all details of IPDs. Important deviations will include the 
following: 
• Inclusion criteria deviations 
• Exclusion criteria deviations 
• Discontinuation criteria for study treatment met but participant not withdrawn from 
study treatment 
• Discontinuation criteria for overall study withdrawal met but participant not 
withdrawn from study 
• Investigational product deviation 
• Excluded medications taken 
• Deviations to study procedure 
• Other important protocol deviations 
Additionally, all protocol deviations and major issues related to COVID-19 (such as missed 
visit, procedure not performed at visit etc.) will be captured with the prefix “COVID19” for 
CSR reporting. 
All important protocol deviations except for dosing error will be identified and documented 
by the study team prior to unblinding of the trial. 
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
31 of 112 
3.4 
General Principles and Analysis Methods  
Efficacy analyses will be performed using the FAS. Demography and baseline characteristics 
will be summarised by study intervention group for the FAS. Safety analyses will be 
performed on SS. 
Study intervention groups will be displayed as follows: 
• 
AZD4831 
• 
Placebo 
A column reflecting all participants (“Total”) will be included in tables that summarise study 
population data. 
The below mentioned general principles will be followed throughout the study: 
• 
Descriptive statistics will be used for all variables, as appropriate. Continuous variables 
will be summarised by the number of observations, mean, SD, median, upper and lower 
quartiles, minimum, and maximum. For log-transformed data geometric mean, CV%, 
median, minimum and maximum will be presented. Categorical variables will be 
summarised by frequency counts and percentages for each category. 
• 
Concentration data will be summarised using descriptive statistics, including n, 
n<LLOQ, geometric mean, CV%, arithmetic mean, SD, minimum, median, and 
maximum values. The geometric mean is calculated as the exponential of the arithmetic 
mean calculated from data on a log scale. 
• 
Unless otherwise stated, percentages will be calculated out of the population total for the 
corresponding study intervention group. Overall totals will be calculated for baseline 
summaries only.  
• 
For continuous data, the mean and median will be rounded to 1 additional decimal place 
compared to the original data. The SD will be rounded to 2 additional decimal places 
compared to the original data. Minimum and maximum will be displayed with the same 
accuracy as the original data. CV%, where reported, will always be reported to 1 decimal 
place. 
• 
PK concentration data will be presented in the listings to the same number of significant 
digits as the data received from the bioanalytical laboratory (usually to 3 significant 
figures) and against the same units as received. PK concentration descriptive statistics 
will all be presented to 1 additional significant figure than original data. Min, max will 
be presented as original data, n and n<LLOQ which will be presented as integers. 
• 
For categorical data, percentages will be rounded to 1 decimal place. 
• 
SAS® version 9.3 (as a minimum) will be used for all analyses. 
 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
32 of 112 
3.4.1 
Time to event analysis  
Time to event endpoints will be analysed using Kaplan-Meier survival analysis (PROC 
LIFETEST). 
The following results at Weeks 4, 12, 18 and 24 will be reported by study intervention: 
• The number of participants at risk 
• the number of censored participants 
• the number of events  
• Kaplan-Meier estimates and CI 
The Kaplan-Meier curves (active versus placebo) will be compared with a two-sided 
logrank test stratified by region. 
Time to event endpoint will be displayed graphically using a Kaplan-Meier plot. 
A Cox proportional hazard model stratified by region will be fitted with study intervention 
as covariate. If any regions have very few events (i.e. <10) the regions can be collapsed as 
appropriate. The Efron approximation will be used for any tied data. The hazards 
proportionality assumption of the model will be examined graphically using plots of 
complementary log-log (event times) versus log (time). If these raise concerns, the variation 
in treatment effect will be described by presenting piecewise hazard ratios calculated over 
distinct time-periods. The HR from the primary analysis will then represent the average HR, 
which can be potentially misleading and should be interpreted with caution (ref: Bartlett et 
al, 2020). Alternative analysis methods not assuming proportional hazard could also be 
considered, for example landmark analysis comparing Kaplan-Meier curves at a particular 
time point. 
The reportable results for this model will be:  
• hazard ratio estimate for the study intervention 
• hazard ratio two-sided CI for the study intervention 
• two-sided Wald test p-value for the hazard ratio 
3.4.2 
Analysis of Covariance (ANCOVA)  
The ANCOVA model will be used to fit change from baseline for continuous endpoints 
collected at only one post-baseline visit. The response variable is the value of the variable of 
interest at the scheduled post-baseline visit. Region will be added as a random covariate. The 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
33 of 112 
study intervention will be the fixed effect with the baseline value of the variable of interest 
as covariate. Comparisons of AZD4831 versus placebo will be assessed. The restricted 
maximum likelihood (REML) approach will be used for the estimation of the variance and 
covariance parameters of the linear mixed model; two-sided difference test, with alpha level 
at 10% will be used to compare the difference in means and for the confidence interval 
calculation. No imputation will be made for missing data. 
The reportable results from the model will be: 
• 
The least-squares means (LSmeans) and their standard errors for each study 
intervention group; 
• 
The difference between AZD4831 and placebo (LSmeans difference) together with its 
two-sided 90% CI; 
• 
The two-sided p-value for the difference between AZD4831 and placebo. 
3.4.3 
Mixed Model Repeated Measures (MMRM)  
The MMRM model will be used to fit change from baseline for continuous endpoints that 
have data at several post-baseline visits. The model will include all available data from all 
visits, irrespective of whether the patient discontinued study intervention. Since a repeated 
measures model is being applied, no imputation will be made for missing data. Region will 
be added as a random effect. The model will include fixed effects for baseline, 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 on a patient between 
visits, and the Kenward-Roger correction will be used for degree of freedom approximation 
in the generation of the model. In the event that the model with unstructured covariance 
matrix fails to converge, an alternative such as autoregressive or compound symmetry will 
be used instead. Estimates of the least square (LS) mean change from baseline for each study 
intervention, and the difference between them (AZD4831-placebo), together with two-sided 
90% CI, will be obtained from the model for each visit. The study intervention effect will be 
tested at the 10% two-sided level of significance. 
The reportable results from the model are: 
• 
The LSmeans change from baseline at each visit and their standard errors for each 
study intervention group. 
• 
The difference in change from baseline at each visit between AZD4831 and placebo 
(LSmeans difference) together with its two-sided 90% confidence interval (CI). 
• 
The two-sided p-value for the difference in change from baseline at each visit between 
AZD4831 and placebo. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
34 of 112 
3.4.4 
Negative binomial regression  
Negative binomial regression will be used for the analysis of event rates. In this study the 
response variable in the model will be either the number of COPDCompEx event or the 
number of moderate or severe AECOPD exacerbations experienced by a participant. The 
model will include study intervention group as a fixed effect and logarithm of the 
participant’s corresponding 'at risk' time will be used as an offset variable in the model to 
adjust for participants having different exposure times during which the events occur. All 
available data from participants will be included, irrespective of whether they discontinued 
study intervention. 
The model will include study intervention group and geographical region as fixed effects.  
The standard parameterization approach (NB2) of the negative binomial model will be 
applied using PROC GENMOD (SAS procedure).  
The estimated annual event rate (AER) for each treatment, the treatment effect (ie, the rate 
ratio of actual study intervention group versus placebo), corresponding two-sided 90% CI, 
and two-sided p-value for the rate ratio will be presented. The estimate of the negative 
binomial overdispersion parameter will also be reported. 
4 
STATISTICAL ANALYSIS  
This section provides information on definitions, derivation and analysis/data presentation 
per domain. 
4.1 
Study Population  
The domain study population covers patient disposition, analysis sets, protocol deviations, 
demographics, baseline characteristics, medical history, prior and concomitant medication 
and study drug compliance.  
4.1.1 
Patient Disposition and Completion Status  
4.1.1.1 
Definitions and Derivations  
Participants screened are those who were enrolled, i.e., participants who agreed/whose 
legally acceptable representatives agreed to participate in a clinical study following 
completion of the informed consent process. 
Screening failures/participants not randomised are those potential participants who are 
screened for the purpose of determining eligibility for the study but are not randomly assigned 
in the study. 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. 
Participants randomized are defined in Section 3.2. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
35 of 112 
Participants started treatment are all randomised participants who reported at least one 
administration of the study drug. 
Participants completed treatment are participants who completed at least 12 weeks of 
treatment. Participants who are receiving study intervention between Weeks 12 and 24 at the 
time the last patient completes Week 12 should attend Study Visit (SV)7 as soon as possible, 
continuing treatment until they do. They should then attend SV8 14 ± 3 days later.  
Participants discontinued treatment are participants who did not complete 12 weeks of 
treatment due to a permanent discontinuation of the study drug administration.  
4.1.1.2 
Presentation  
Patient dispositions (number and percentage) of subjects enrolled, subjects not randomised 
(incl. reasons), subjects randomised, subjects randomised and who did not receive treatment, 
subjects who started treatment, subjects who completed the treatment, subjects who 
discontinued treatment (incl. reasons), subjects included in the cough substudy, subjects who 
completed the study and subjects withdrawn from study (incl. reasons) will be presented in a 
summary table for each study intervention group and overall. A listing including all 
standardised disposition terms will also be provided for all discontinued subjects and subjects 
completing the study. Both the table and the listings will be based on the screened set. 
To demonstrate balance in stratification factor categories (i.e. countries), the number and 
percentage of participants in each category will be summarised by study intervention group 
and overall focusing on the randomised set. 
The recruitment per country and site will be provided based on the screened set, while the 
global/country situation study disruption will be summarised on the full analysis set. 
The number and percentage of participants with one or more disruption due to COVID-19 
pandemic will be presented by study intervention group considering the participants valid for 
the full analysis set. A listing of all the participants affected by COVID-19 related study 
disruption will be produced by unique patient number identifier, investigational site, and a 
description of how the individual’s participation was altered. COVID-19 related study 
disruptions can be: 
• Visit related (if visit is impacted by global/country situation, then contact mode will 
be specified); 
• Study drug related (if study drug action taken (except “Drug Withdrawn”) was 
impacted by global/country situation; study drug administration or location was 
impacted by global/country situation; who performed a study drug administration); 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
36 of 112 
• Discontinuation of study drug due to COVID-19 pandemic (if study drug action taken 
“Drug Withdrawn” was impacted by global/country situation); 
• Withdrawal from study (if primary reason for ending study is related to 
global/country situation). 
Randomisation scheme and codes as well as participants receiving the various batch of 
investigational product will also be listed for all randomised participants. 
4.1.2 
Analysis Sets  
4.1.2.1 
Definitions and Derivations  
The analysis populations used in the analysis have been described in Section 3.2. 
4.1.2.2 
Presentation  
The number of participants belonging to each analysis population will be presented in a 
summary table for each study intervention group on the Screened set. 
A listing of all participants excluded from any population will also be provided. The listing 
will include reason for exclusion from respective population and will be based on the 
screened set. 
4.1.3 
Protocol Deviations  
4.1.3.1 
Definitions and Derivations  
The definition of IPD is available in Section 3.3.6. Deviations from the protocol will be 
assessed as important or non-important by blinded members of the study team before 
database hard lock and unblinding. A blind data review meeting will be held. 
4.1.3.2 
Presentation  
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 also be listed for all participants included in the FAS 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. 
4.1.4 
Demographics  
4.1.4.1 
Definitions and Derivations  
Demographics are collected pre-treatment as per schedule of activities (CSP Section 1.3). 
they include age, age group (≥ 40 – < 65; ≥ 65 - ≤ 80), sex, race, ethnic group, region and 
country. Age is the age at screening as reported in the eCRF. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
37 of 112 
4.1.4.2 
Presentation  
All demographics will be presented in summary tables for each study intervention group and 
overall. Age will be described as a continuous variable; all the other demographics (i.e., age 
group, gender, race, and ethnicity) will be summarised as categorical variables with the 
number and percentage of participants by categories. 
All demographics will also be provided in listings.  
The tables and the listings will be based on the FAS. 
4.1.5 
Baseline Characteristics  
4.1.5.1 
Definitions and Derivations  
Patient characteristics are collected pre-treatment as per schedule of activities (CSP Section 
1.3). They include height (cm) and weight (kg) at baseline. 
Body Mass Index (BMI) (kg/m²) is calculated at baseline from the height (m) and weight 
(kg) as follows: BMI = weight / (height2). Only the baseline measurement for height, weight 
and BMI will be considered.  
The lung function variables from spirometry collected at baseline/screening are: absolute and 
% predicted (as applicable) PEF, FEV1, FVC, FEV1/FVC, forced mid-expiratory flow 
(FEF25-75%), and forced inspiratory vital capacity. Screening spirometry data will be used 
for any subjects with missing baseline spirometry data. 
For patients with missing Baseline spirometry results, screening results will be used, with 
ZephyrX results prioritised over Unify if both are available. 
In case data issues for % predicted FEV1 and FVC are not resolved for database lock, any 
implausible values (i.e. <1% or >500%) will be set to missing, and consequently excluded 
from analysis. 
4.1.5.2 
Presentation  
All patient-specific characteristics will be presented in summary tables for each study 
intervention group and overall. Height, weight, and BMI will be summarised as a continuous 
variable. BMI categories (<18, ≥ 18 to < 25, ≥ 25 to < 30, ≥ 30 (kg/m²) will be summarised 
as a categorical variable. 
Lung function parameters will be summarised in a separate table as continuous variables. 
Lung function parameters (FEV1, FVC, FEV1/FVC and FEV1% predicted) at screening will 
be summarised in a separate table as continuous variables. 
All patient-specific characteristics will also be provided in listings.  


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
38 of 112 
The tables and the listings will be based on the FAS population. 
4.1.6 
Disease Characteristics  
4.1.6.1 
Definitions and Derivations  
The patient’s COPD history will be collected and will include questions related to the: 
• 
COPD first diagnosed date 
• 
First appearance of COPD symptoms date 
• 
GOLD Classification 
• 
Occurrence of previous admission to ICU for COPD in past 24 months 
• 
Required mechanical ventilation for COPD 
• 
Occurrence of Cough at least several days/week over past 3 months 
Brought up phlegm at least several days/week over past 3 months 
4.1.6.2 
Presentation  
The following variables will be summarised by intervention group and overall for FAS: 
• Time since COPD diagnosis (years) 
• Time COPD symptoms started (years) 
• GOLD Classification 
• Occurrence of previous admission to ICU for COPD in past 24 months 
• Number of moderate and severe exacerbation within 24 months prior enrolment 
• Frequent productive cough 
• Use of disease-related medications (ICS + LABA + LAMA or ICS + LABA or LABA 
+ LAMA) 
4.1.7 
Medical History and Concomitant Disease  
4.1.7.1 
Definitions and Derivations  
Complete medical and surgical history will be collected as per SoA (CSP Section 1.3). 
Medical history will be coded in Medical Dictionary for Regulatory Activities (MedDRA) 
version 24.1 or higher. 
4.1.7.2 
Presentation  
Medical history will be presented in summary tables as number and percentage 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 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
39 of 112 
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 FAS population. 
4.1.8 
Prior and Concomitant Medications  
4.1.8.1 
Definitions and Derivations  
Any prior and concomitant medication(s), including herbal preparations, taken during the 
study will be recorded in the eCRF. The WHO-DD March 2022 B3 Global or higher will be 
used to classify medications by WHO ATC classification of ingredients. The imputation 
method described in Section 3.3.1.4 will be used in case of medication stop date partially 
missing. Completely missing stop date will not be imputed. Completely missing or partially 
missing concomitant medication start dates will not be imputed. 
After the end date imputation, the medications will be classified as either prior or concomitant 
(but not both) according to its stop date: 
• Prior medication is defined as any medication with a stop date prior to the first dose 
of IP (exclusive). 
• Concomitant medication is defined as any medication with a stop date on or after the 
first dose of study drug, or any medication taken prior to study drug and that is 
ongoing. 
Medications with completely missing stop date are classified as concomitant. 
Disallowed medications will include medications defined as prohibited according to CSP 
Section 6.5. They will be defined following a physician review (prior to database lock) of the 
unique combinations of ATC code classifications and generic terms captured and detailed in 
the Integrated Data Review Plan. 
COVID-19 vaccine information will be recorded and summarised as part of concomitant 
medication. For reporting purposes, COVID-19 vaccines will be selected using ATC code 
J07BX. 
4.1.8.2 
Presentation  
The number and percentage of participants receiving prior or concomitant medication (by 
ATC4 classification system codes and generic name) will be presented by study intervention 
in separate tables for the FAS population. The number and percentage of participants 
receiving prior disease related medication will be presented by study intervention group for 
the FAS population by study intervention. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
40 of 112 
A separate table will be presented for participants who take restricted prior or concomitant 
medications. The numbers and percentages will be calculated relative to the number of 
participants in the FAS population by intervention group and overall. 
All medications will also be listed by patient for the FAS population. 
4.1.9 
Substance usage – Inhaled Tobacco  
4.1.9.1 
Definitions and Derivations  
Smoking status (cigarettes, cigars, pipes, smokeless tobacco and electronic nicotine delivery 
systems) together with the consumption of cigarettes in pack-years will be collected.  
4.1.9.2 
Presentation  
All substance usage will be presented in summary tables for each study intervention group 
and overall. Smoking amount consumed in pack-years will be summarised descriptively as a 
continuous variable; all the other substance usage variables (i.e., substance type, substance 
usage) will be summarised as categorical variables with the number and percentage of 
participants by categories.  
All substance usage will also be provided in listings.  
The tables and the listings will be based on the FAS population. 
4.1.10 
Study Drug Compliance  
4.1.10.1 
Definitions and Derivations  
Compliance with investigational product (IP) will be calculated using the following equation:  
𝐼𝑃 𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 (%) = 
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑑𝑜𝑠𝑒𝑠 𝑡𝑎𝑘𝑒𝑛
𝑁𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑖𝑛𝑡𝑒𝑛𝑑𝑒𝑑 𝑑𝑜𝑠𝑒𝑠 𝑥 100 
The number of intended doses is equal to one tablet per day throughout the duration of the 
study for each patient, and thus it is approximated by treatment start date minus treatment 
end date + 1, i.e. independent of any dose interruptions. 
The number of doses taken is  the “actual exposure” from section 4.7.1.1, i.e. the difference 
between dispensed and returned tablets as recorded in eCRF. If any ‘Amount Returned’ field 
in the Drug Accountability CRF page is blank, then the Number of Doses taken – and 
therefore IP Compliance – is not calculated. 
Participants’ IP compliance will be categorized in <80%, from 80% (included) to 120% 
(included), >120%. Participants having IP compliance between 80% to 120% inclusive will 
be defined as treatment compliant. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
41 of 112 
4.1.10.2 
Presentation  
The compliance with IP will be presented in a summary table for each study intervention 
group and overall. 
The number and percentage of participants by each compliance category will also be 
provided. 
The tables will be based on the FAS population. 
4.2 
Endpoint Analyses  
This section covers details related to the endpoint analyses such as primary, secondary, other 
endpoints including sensitivity and supportive analyses. 
All endpoint analyses will include data reported up to end of treatment (EOT) visit. 
Table 9 
Analyses of primary, secondary and tertiary/exploratory endpoints 
Objectives 
Estimand description / Outcome 
Measure 
Population 
Primary 
 
To evaluate the effect of 
AZD4831 as compared to 
placebo on the time to first 
COPDCompEx event in 
participants with moderate to 
severe COPD. 
Endpoint: time to first COPDCompEx 
event. 
Population level-summary measure: 
hazard ratio. 
Strategy for intercurrent events: 
Primary estimand: while on treatment. 
Supportive estimand: treatment policy. 
FAS 
Secondary 
 
To assess the PK of 
AZD4831 in participants with 
moderate to severe COPD. 
Endpoint: plasma AZD4831 
concentration-time profiles during the 
intervention and follow-up periods, and 
PK parameters. 
Population level-summary measure: 
summary statistics. 
Strategy for intercurrent events: while 
on treatment. 
PK set 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
42 of 112 
Objectives 
Estimand description / Outcome 
Measure 
Population 
To evaluate the effect of 
AZD4831 as compared to 
placebo on the time to first 
moderate or severe COPD 
exacerbation. 
Endpoint: time to first COPD 
exacerbation eventa 
Population level-summary measure: 
hazard ratio. 
Strategy for intercurrent events: while 
on treatment. 
FAS 
To assess the effects of 
AZD4831 as compared to 
placebo on post-BD FEV1 in 
participants with moderate to 
severe COPD. 
Endpoint: change from baseline in post-
BD FEV1 after 12 weeks. 
Population level-summary measure: the 
difference in mean. 
Primary 
estimand: while on treatment. 
Supportive estimand: treatment policy. 
FAS 
To assess the effect of 
AZD4831 compared with 
placebo on respiratory 
symptoms in participants with 
moderate to severe COPD.  
Endpoint: change from baseline in 
EXACT, BCSS average score, and Cough 
VAS average score at Week 12 and Week 
24. 
Population level-summary measure: the 
difference in mean. 
Strategy for intercurrent events: while 
on treatment. 
FAS 
To assess the effect of 
AZD4831 compared with 
placebo on disease impact in 
participants with moderate to 
severe COPD. 
Endpoint: change from baseline in Total 
CAT measured in clinic at Week 12. 
Population level-summary measure:  
The difference in mean.  
Proportion of participants with change 
from baseline of -2 or less 
Strategy for intercurrent events: while 
on treatment. 
FAS 
Safety 
 
To assess the safety and 
tolerability of AZD4831 
compared with placebo in 
participants with moderate to 
severe COPD. 
Endpoint: safety and tolerability 
evaluations using AEs, SAEs, AESIs (skin 
reactions, including maculopapular rash, 
and serious infections, including 
pneumonia), vital sign measures, clinical 
SS 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
43 of 112 
Objectives 
Estimand description / Outcome 
Measure 
Population 
laboratory assessments (clinical chemistry, 
haematology, and urinalysis), and ECG. 
Population level-summary measure: 
descriptive statistics eg, absolute counts 
and frequencies. 
Tertiary/Exploratory 
 
To assess the effect of 
AZD4831 compared with 
placebo on biomarkers related 
to COPD disease activity. 
Systemic biomarkers of cardiovascular 
comorbidities - including fibrinogen, 
hsCRP, IL-6, and NT-proBNP. 
FAS 
To assess the effects of 
AZD4831 as compared to 
placebo on MPO activity and 
concentration in sputum 
samples from participants 
with moderate to severe 
COPD. 
Average change from baseline to Week 12 
in MPO activity normalised to MPO 
concentration in sputum. 
FAS 
To assess the effects of 
AZD4831 as compared to 
placebo on spirometry 
endpoints measured face-to-
face in participants with 
moderate to severe COPD.  
Spirometry endpoints, including but not 
limited to, FEV1, forced vital capacity, 
forced expiratory flow 25% to 75%, 
inspiratory capacity, and reproducibility. 
FAS 
To assess the effect of sputum 
MPO concentration at 
baseline on primary and 
secondary endpoints in 
participants with moderate to 
severe COPD. 
Time to first COPDCompEx event in 
participants with low MPO concentration 
at baseline compared to high MPO 
concentration at baseline. 
 
Change from baseline post-BD FEV1 in 
participants with low MPO concentration 
at baseline compared to high MPO 
concentration at baseline. 
FAS 
To assess the effects of 
AZD4831 compared to 
placebo on change in cough 
frequency measured over a 
Change from start of treatment in average 
24-hour, waking, and sleeping cough 
frequency, using the VitaloJAK® Cough 
Monitor device, at Week 12. 
Cough 
subset 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
44 of 112 
Objectives 
Estimand description / Outcome 
Measure 
Population 
24-hour period between start 
of treatment and Week 12. 
To investigate whether cough 
frequency is associated with 
lung function (eg, PEF, 
FEV1), cough/COPD 
symptom scores (eg, BCSS, 
CAT and Cough VAS) and 
blood biomarkers (eg, MPO 
concentration). 
Average cough frequency measured over a 
24-hour period as measured at start of 
treatment (Visit SV3) and after 12 weeks 
treatment (Visit SV5) using the VitaloJAK 
Cough® Monitor device. 
Cough 
subset 
To assess the effects of 
AZD4831 as compared to 
placebo on COPDCompEx in 
participants with moderate to 
severe COPD. 
Annualised rate of COPDCompEx events, 
based on the period from baseline to the 
last dose 
Strategy for intercurrent events: while 
on treatment. 
FAS 
To assess the effect of 
AZD4831 compared with 
placebo on moderate to 
severe COPD exacerbation. 
Annualised rate of moderate or severe 
COPD exacerbations based on the period 
during the intervention from baseline to 
the last dose 
Strategy for intercurrent events: while 
on treatment. 
FAS 
a 
COPD Exacerbation: a worsening in the participant’s usual COPD symptoms that is beyond normal 
day-to-day variation, is acute in onset, lasts 2 or more days (or less if the worsening is so rapid and 
profound that the treating physician judges that intensification of treatment cannot be delayed), may 
warrant a change in regular medication, and leads to any of the following: 
• 
Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of 
corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids. 
• 
Use of antibiotics to treat COPD exacerbation for at least 3 days. 
• 
An inpatient hospitalisation due to COPD (defined as an inpatient admission ≥ 24 hours in the 
hospital, an observation area, the emergency department, or other equivalent healthcare facility 
depending on the country and healthcare system). 
• 
Admission in emergency department or emergency room due to COPD for < 24 hours requiring 
intensive treatment. 
• 
Results in death. 
Intercurrent events are events occurring after treatment initiation (eg, premature treatment discontinuation, 
switching treatment, terminal events such as death) that affect either the measurement or interpretation of the 
summary measure (eg, hazard ratio) associated with the clinical question of interest. This study contains 2 
intercurrent events: 
1  Premature treatment discontinuation (with the following reasons: SAE, death not due to exacerbation, 
COVID-19, pneumonia, other). 
2  Prohibited medication. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
45 of 112 
4.2.1 
Primary Endpoint – Time to First COPDCompEx Event  
4.2.1.1 
Definition  
The COPDCompEx is a composite endpoint developed to estimate the magnitude of 
treatment effect on COPD exacerbations over 52 weeks, in a 12-week study. It incorporates 
change in symptoms, reliever use and PEF obtained from daily diary, with confirmed 
exacerbations and/or study drop-outs. 
The definition of the event is one of the following criteria: 
• Moderate or severe exacerbations: episodes leading to one or more of the following: 
hospitalization, emergency room visit, an episode of pneumonia, treatment with OCS 
or corticosteroid depot injection, or treatment with antibiotics.  
• Diary events: defined by threshold and slope criteria using the following diary and 
home spirometry variables: overall symptom rating, reliever medication use, and 
change in PEF. 
• Study dropouts: early treatment discontinuation due to lack of efficacy. 
The COPDCompEx definition and derivation are detailed in AZ Business Rules. 
Time to first COPDCompEx event is defined as time elapsed from the start of study treatment 
to the occurrence of the first COPDCompEx event. 
4.2.1.2 
Derivations  
Time to first COPDCompEx event will be calculated as: 
Time to first COPDCompEx event (days) = [Start date of first event/censoring – date of the 
first dose of study intervention+ 1]. 
For participants who do not experience an on-treatment COPDCompEx event, date of 
censoring will be the last dose date or last date of eDiary recording – whichever is earlier.  
4.2.1.3 
Handling of Dropouts and Missing Data  
The “while on treatment” strategy will be used for the primary estimand: if an intercurrent 
event occurs before first COPDCompEx event, the patient will be censored at the time of 
intercurrent event. 
For participants who do not experience an on-treatment COPDCompEx event, 
• If intercurrent event is earlier than date of last dose or the last eDiary date, the 
participant will be censored at intercurrent event date. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
46 of 112 
• If the intercurrent event is after the last eDiary date, but earlier than date of last dose, 
participants who do not experience an on-treatment COPDCompEx event, date of 
censoring will be last day of eDiary recording. 
Intercurrent events are events occurring after treatment initiation (eg, premature treatment 
discontinuation, switching treatment, terminal events such as death) that affect either the 
measurement or interpretation of the summary measure (eg, hazard ratio) associated with the 
clinical question of interest. This study contains 2 intercurrent events:  
1. 
Treatment discontinuation (with the following reasons: SAE, death not due to 
exacerbation, COVID-19, pneumonia, other). 
2. 
Prohibited medication. 
4.2.1.4 
Primary Analysis of Primary Endpoint  
Kaplan-Meier curves, region-stratified logrank test and region stratified Cox proportional 
hazard (PH) model results, will be provided for time to first COPDCompEx event as specified 
in Section 3.4.1. 
The evidence of efficacy requires a two-sided region-stratified logrank test p-value ≤ 0.10. 
Kaplan-Meier curve estimates will be provided with a 90% CI. 
Survival probabilities will be presented as survival curves estimated using the Kaplan-Meier 
method. 
Diagnostic plot (log-log) will be presented to assess proportional hazard assumption. 
The hazard ratio estimate from the Cox PH model will be provided with a 90% CI. 
COPDCompEx data will be listed. 
The analyses will be focused on the FAS population, including only those subjects with post-
baseline eDiary data. 
4.2.1.5 
Sensitivity Analyses of the Primary Endpoint  
Not applicable.
4.2.1.6 
Supplementary Analyses of the Primary Endpoint   
The analysis described above (Section 4.2.1.4) will be repeated applying the “treatment 
policy” estimand strategy as supportive. The events that occurred after intercurrent events 
will not be censored (i.e. will be treated as events). The treatment policy strategy used to 
estimate the efficacy of AZD4831 in ‘real-world’ conditions. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
47 of 112 
4.2.1.7 
Subgroup Analyses  
The subgroup analysis will be conducted for exploratory purposes. 
The Cox proportional hazards model specified above would also be run separately with the 
“while on treatment” strategy for the following subgroups: 
• Frequent Productive Cough (Yes; No) 
• Gender (Male; Female) 
• Age (≥40 – <65; ≥65 - ≤80) 
• Race (as collected in CRF) 
• BMI (<18; ≥18 to <25; ≥25 to <30; ≥30) 
• Geographic region (North America (Canada, United States of America), Eastern 
Europe (Bulgaria, Poland, Turkey), Western Europe (Denmark, Germany, Italy, 
Netherlands, Spain, United Kingdom), Rest of the world (Argentina, Mexico, South 
Africa).  
• Baseline FEV1 as percent of predicted (<50%; ≥50%) 
• Maintenance medications: 
o ICS; no ICS 
o LABA/ICS; LABA/LAMA/ICS; LABA/LAMA 
• Number of COPD exacerbations in last 24 months (<2; ≥2) 
• Type of site of recruitment (primary care site; specialist care site) 
• Smoking status (Current smokers; Ex-smokers)  
• MPO concentration at baseline (upper tertile; middle tertile; lower tertile) 
The hazard ratio estimate from the Cox PH model will be provided with a 90% CI only for 
subgroup categories that contain at least 20% of the total participants. 
 
 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
48 of 112 
4.2.2 
Secondary Endpoint – Time to First Moderate or Severe 
COPD Exacerbation Event  
4.2.2.1 
Definition  
A moderate or severe AECOPD may leads to any of the following:  
• Use of systemic corticosteroids for at least 3 days; a single depot injectable dose of 
corticosteroids will be considered equivalent to a 3-day course of systemic 
corticosteroids. 
• Use of antibiotics to treat COPD exacerbation for at least 3 days. 
• An inpatient hospitalization due to COPD (defined as an inpatient admission ≥ 24 
hours in the hospital, an observation area, the emergency department, or other 
equivalent healthcare facility depending on the country and healthcare system). 
• Admission in emergency department or emergency room due to COPD for < 24 
hours requiring intensive treatment. 
• An episode of pneumonia. 
• Results in death. 
The start and stop of a moderate or severe exacerbation is defined as: 
• The start date of systemic corticosteroids or antibiotic treatment or 
hospital/emergency admission, whichever occurs earlier, and the stop date is 
defined as the last day of systemic corticosteroids or antibiotic treatment or 
hospital/emergency discharge, whichever occurs later. 
• A single depot injectable dose of corticosteroids will be considered equivalent to a 
3-day course of systemic corticosteroids. The corresponding stop date for this 
treatment will consequently be determined as the date of administration plus 2 days. 
• If multiple treatments are prescribed for the same exacerbation, the earliest start date 
and the latest stop date will be used. 
For a severe COPD exacerbation with no documented corticosteroid or antibiotics treatment, 
hospitalization admission/discharge dates, or emergency visit date will be used as start/stop 
dates 
A COPD exacerbation will be considered moderate if it requires treatment with systemic 
corticosteroids and/or antibiotics for at least 3 days or resulted in emergency room visit< 24 
hours requiring intensive treatment; and does not result in hospitalization or death. 
A COPD exacerbation will be considered severe if it results in hospitalization (defined as an 
inpatient admission ≥ 24 hours in the hospital, an observation area, the emergency department, 
or other equivalent healthcare facility depending on the country and healthcare system) or 
death due to COPD. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
49 of 112 
Time to first moderate or severe COPD exacerbation event is defined as time elapsed from 
the start of study treatment to the occurrence of the first moderate or severe COPD 
exacerbation event.  
4.2.2.2 
Derivations  
Time to first moderate or severe COPD exacerbation event will be calculated as: 
Time to first moderate or severe COPD exacerbation event (days) = [Start date of first 
event/censoring – date of the first dose of study intervention+ 1]. 
The date of first moderate or severe COPD exacerbation event will be the first start date of a 
moderate or severe COPD exacerbation event, i.e. the earliest of the exacerbation which 
meets the definition of moderate or severe COPD exacerbation. 
For participants who do not experience an on-treatment moderate or severe COPD 
exacerbation event, date of censoring will be the date of last dose. 
4.2.2.3 
Handling of Dropouts and Missing Data  
The “while on treatment” strategy will be used: if an intercurrent event occurs before first 
moderate or severe exacerbation, the patient will be censored at the time of intercurrent event. 
For participants who do not experience an on-treatment moderate or severe COPD 
exacerbation event, 
• If intercurrent event is earlier than date of last dose, the participant will be censored 
at intercurrent event date. 
4.2.2.4 
Primary Analysis of Secondary Endpoint  
Kaplan-Meier curves, region-stratified logrank test and region stratified Cox proportional 
hazard model results, will be provided for time to first moderate or severe exacerbation as 
specified in Section 3.4.1. 
A two-sided region-stratified logrank test p-value ≤ 0.10 is required to provide evidence of 
efficacy. Kaplan-Meier curve estimates will be provided with a 90% CI. 
Survival probabilities will be presented as survival curves estimated using the Kaplan-Meier 
method. 
Diagnostic plot (log-log) will be presented to assess proportional hazard assumption. 
The hazard ratio estimate from the Cox PH model will be provided with a 90% CI. 
Exacerbations data will be listed. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
50 of 112 
The analysis will be focused on the FAS population. 
4.2.2.5 
Sensitivity Analyses of the Secondary Endpoint  
Not applicable. 
4.2.2.6 
Supplementary Analyses of the Secondary Endpoint  
Not applicable. 
4.2.2.7 
Subgroup Analyses  
Not Applicable. 
4.2.3 
Secondary Endpoint – post-BD FEV1  
4.2.3.1 
Definition  
All spirometry will be performed post-BD, which includes the patient’s regular triple or dual 
(ICS + LABA or LAMA + LABA) therapy. Data collected will include absolute and % 
predicted (as applicable) PEF, FEV1, FVC, FEV1/FVC, forced mid-expiratory flow (FEF25-
75%), and forced inspiratory vital capacity. At SV3, SV4, SV5 and SV7, face-to-face (clinic) 
spirometry will be undertaken at the site. Face-to-face spirometry will take the form of 
supervised, coached measurement by a trained healthcare professional performed in person 
at the site. Only measurements obtained by face-to-face spirometry will be utilized for the 
secondary outcome of post-BD FEV1. 
For daily spirometry, if multiple assessments have been collected during the same day, the 
maximum value out of all measurements per timepoint (including baseline) will be used in 
the analysis. 
4.2.3.2 
Derivations  
Change from baseline in post-BD FEV1 to Weeks 4, 12 and 24 will be calculated as specified 
in Section 3.3.1.2. 
4.2.3.3 
Handling of Dropouts  
The 'while-on treatment' strategy will be used: which means that if an intercurrent event 
occurs all subsequent data for that participant are excluded from the evaluation. 
4.2.3.4 
Primary Analysis of Secondary Endpoint  
Observed values and absolute change from baseline up to Weeks 4, 12 and 24 in post-BD 
FEV1 will be summarised by each intervention group for the FAS population. 
Change from baseline to Week 4, Week 12 and Week 24 in post-BD FEV1 for participants 
with moderate to severe COPD will be analysed using MMRM as described in Section 3.4.3. 
The analysis will be focused on the FAS population. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
51 of 112 
4.2.3.5 
Sensitivity Analyses of the Secondary Endpoint  
Not applicable. 
4.2.3.6 
Supplementary Analyses of the Secondary Endpoint  
The analysis described above (Section 4.2.3.4) will be repeated applying the “treatment 
policy” estimand strategy as supportive. This means if an intercurrent event occurs all 
subsequent data for that participant up to last dose are included in the evaluation. 
4.2.3.7 
Subgroup Analyses  
The subgroup analysis will be conducted for exploratory purposes. 
For subgroup categories that contain at least 20% of the total participants a single forest plot 
including all subgroups will display graphically the mean difference (AZD4831 - Placebo) 
in change from baseline in post-BD FEV1 at Week 12, together with the two-sided 90% CI 
and reference line at zero. In addition, the following statistical parameters will be displayed: 
total number of subjects, mean change from baseline and its standard error for each study 
intervention, as well as the mean difference (AZD4831 - Placebo) from baseline, together 
with the two-sided 90% CI. 
For subgroup categories that contain less than 20% of the total participants, only the total 
number of subjects in each arm will be presented. 
Following are the subgroups: 
• Frequent Productive Cough (Yes; No) 
• Gender (Male; Female) 
• Age (≥40 – <65; ≥65 - ≤80) 
• Race (as collected in CRF) 
• BMI (<18; ≥18 to <25; ≥25 to <30; ≥30) 
• Geographic region (North America (Canada, United States of America), Eastern 
Europe (Bulgaria, Poland, Turkey), Western Europe (Denmark, Germany, Italy, 
Netherlands, Spain, United Kingdom), Rest of the world (Argentina, Mexico, South 
Africa)) 
• Baseline FEV1 as percent of predicted (<50%; ≥50%) 
• Maintenance medications: 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
52 of 112 
o ICS; no ICS 
o LABA/ICS; LABA/LAMA/ICS; LABA/LAMA 
• Number of COPD exacerbations in last 24 months (<2; ≥2) 
• Type of site of recruitment (primary care site; specialist care site) 
• Smoking status (Current smokers; Ex-smokers)  
• MPO concentration at baseline (upper tertile; middle tertile; lower tertile) 
4.2.4 
Secondary Endpoint – EXACT score  
4.2.4.1 
Definition  
The exacerbations of chronic pulmonary disease tool (EXACT) is a PRO measure designed 
to standardize the method for evaluating the frequency, severity, and duration of both 
reported and unreported acute exacerbations of COPD and chronic bronchitis in clinical trials.  
The EXACT total score is computed across 14 items and has a theoretical range of 0 to 100, 
with higher values indicating a more severe condition. Additional information regarding the 
patient´s condition can be obtained through 3 domain scores embedded in the measure: 
Breathlessness, Cough & Sputum, and Chest Symptoms. These scores also range from 0 to 
100, with higher scores indicating more severe symptoms. The EXACT will be performed at 
on-site visits using the e-Diary. 
4.2.4.2 
Derivations  
The derivation of the EXACT total and 3 domain scores can be found in EXACT user manual 
v8.0. Change from baseline in EXACT total and domains scores to Weeks 12 and 24 will be 
calculated as specified in Section 3.3.1.2. 
4.2.4.3 
Handling of Dropouts  
The 'while-on treatment' strategy will be used: which means that if an intercurrent event 
occurs all subsequent data for that participant are excluded from the evaluation. 
4.2.4.4 
Primary Analysis of Secondary Endpoint  
Observed values and absolute change from baseline up to Weeks 12 and 24 in EXACT total 
and domain scores will be summarised by each intervention group for the FAS population. 
Change from baseline to Weeks 12 and 24 in EXACT (total and domain scores) will be 
analysed using MMRM as described in Section 3.4.3. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
53 of 112 
LSMean change from baseline and two-sided 90% CI up to Weeks 12 and 24 in EXACT total 
and domain scores will be presented in figures. For primary analysis, LSMean change from 
baseline through Weeks 12 and 24 in EXACT total and domain scores will be presented. 
A listing including results from each of the domain and the total EXACT score will be 
produced for the FAS population. 
4.2.4.5 
Sensitivity Analyses of the Secondary Endpoint  
Not applicable 
4.2.4.6 
Supplementary Analyses of the Secondary Endpoint  
Not applicable 
4.2.4.7 
Subgroup Analyses  
Not Applicable 
4.2.5 
Secondary Endpoint – BCSS score  
4.2.5.1 
Definition  
Breathlessness, Cough and Sputum Scale (BCSS) is a 3-item questionnaire rating 
breathlessness, sputum, and cough on a 5-point Likert scale from 0 (no symptoms) to 4 
(severe symptoms). Item scores can be reported as domains scores and are summed to yield 
a total score. The BCSS will be captured each evening via the e-Diary. If there are repeated 
measurements in a day (evening), then the first measurement will be used in the analysis. 
4.2.5.2 
Derivations  
Change from baseline in BCSS average score to Weeks 12 and 24 will be calculated as 
specified in Section 3.3.1.2. 
4.2.5.3 
Handling of Dropouts  
The 'while-on treatment' strategy will be used: which means that if an intercurrent event 
occurs all subsequent data for that participant are excluded from the evaluation.  
4.2.5.4 
Primary Analysis of Secondary Endpoint  
Observed values and absolute change from baseline to Weeks 12 and 24 in BCSS average 
total and domain scores will be summarised by each intervention group for the FAS 
population. 
Change from baseline to Weeks 12 and 24 in BCSS average total and domain scores will be 
analysed using MMRM as described in Section 3.4.3. 
LSMean change from baseline and two-sided 90% CI up to Weeks 12 and 24 in BCSS 
average total and domain scores will be presented in figures. For primary analysis, LSMean 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
54 of 112 
change from baseline through Weeks 12 and 24 in BCSS average domain and total scores 
will be presented. 
A listing including results from each of the domain and the total BCSS average score will be 
produced for the FAS population. 
4.2.5.5 
Sensitivity Analyses of the Secondary Endpoint  
Not applicable. 
4.2.5.6 
Supplementary Analyses of the Secondary Endpoint  
Not applicable. 
4.2.5.7 
Subgroup Analyses  
Not Applicable 
 
4.2.6 
Secondary Endpoint – Cough VAS  
4.2.6.1 
Definition  
Participants will be asked to complete a cough severity VAS (100-point linear scale marked 
with a horizontal or vertical line by the patient, with 0 representing “no cough” and 100 
representing “worst cough”) measuring subjective assessment by the patient of the prior 24 
hours for severity of cough symptoms. 
The Cough VAS will be completed each morning in the e-Diary until Week 24. 
4.2.6.2 
Derivations  
Change from baseline in Cough VAS average score to Weeks 12 and 24 will be calculated 
as specified in Section 3.3.1.2. 
4.2.6.3 
Handling of Dropouts  
The 'while-on treatment' strategy will be used: which means that if an intercurrent event 
occurs all subsequent data for that participant are excluded from the evaluation. 
4.2.6.4 
Primary Analysis of Secondary Endpoint  
Observed values and absolute change from baseline up to Weeks 12 and 24 in Cough VAS 
average score will be summarised by each intervention group for the FAS population. 
Change from baseline to Weeks 12 and 24 in Cough VAS average score will be analysed 
using a MMRM as described in Section 3.4.3. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
55 of 112 
LSMean change from baseline and two-sided 90% CI up to Weeks 12 and 24 in Cough VAS 
average scores will be presented in figures. For primary analysis, LSMean change from 
baseline through Weeks 12 and 24 in Cough VAS average score will be presented. 
A listing including results from the Cough VAS average score will be produced for the FAS 
population. 
4.2.6.5 
Sensitivity Analyses of the Secondary Endpoint  
Not applicable. 
4.2.6.6 
Supplementary Analyses of the Secondary Endpoint  
Not applicable. 
4.2.6.7 
Subgroup Analyses  
Not Applicable. 
4.2.7 
Secondary Endpoint – Total CAT measured in clinic  
4.2.7.1 
Definition  
COPD Assessment Test (CAT) is designed to measure how COPD impacts on a patient’s 
daily life and how this might change over time. It consists of 8 questions that ask the patient 
to rate items relating to symptoms and impact on quality of life (such as normal activity and 
sleep). Each question is performed on a 5-point Likert scale from 0 (no symptoms/no impact) 
to 5 (severe symptoms/impact). The CAT will be completed by participants at on-site visits 
using the e-Diary. 
4.2.7.2 
Derivations  
Change from baseline in total CAT score to Week 12 and Week 24 will be calculated as 
specified in Section 3.3.1.2. 
4.2.7.3 
Handling of Dropouts  
The 'while-on treatment' strategy will be used: which means that if an intercurrent event 
occurs all subsequent data for that participant are excluded from the evaluation. 
4.2.7.4 
Primary Analysis of Secondary Endpoint  
Observed values and absolute change from baseline up to Weeks 12 and Week 24 in CAT 
score will be summarised by each intervention group for the FAS population. 
Change from baseline through Weeks 12 and 24 in total CAT score will be analysed using 
MMRM (see details in Section 3.4.3). 
LSMean change from baseline and two-sided 90% CI for Weeks 12 and 24 in total CAT 
score will be presented in figure. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
56 of 112 
The number and percentage of participants with a change from baseline of -2 or less will be 
summarised by intervention group. 
The total CAT score will be listed by patient for the FAS population. 
The analysis will be focused on the FAS population. 
4.2.7.5 
Sensitivity Analyses of the Secondary Endpoint  
Not applicable 
4.2.7.6 
Supplementary Analyses of the Secondary Endpoint  
Not applicable 
4.2.7.7 
Subgroup Analyses  
Not Applicable 
4.2.8 
Tertiary/Exploratory Endpoint – Cough frequency  
4.2.8.1 
Definition  
The assessment of 24-hour coughs per hour (i.e., average hourly cough frequency based on 
24-hour sound recordings) will be evaluated at Visit SV3 (start of treatment) and Visit SV5 
(after 12 weeks of treatment) using the VitaloJAK® Cough Monitor device for a subset of 
participants (up to approximately 50 participants from each arm) from selected sites enrolled 
in the cough substudy. Data from the device will be filtered for voice frequencies, and speech 
will not be analysed. If the first recording is successful but the Week 12 recordings are not 
usable, the Week 12 assessment can be repeated as soon as possible but no later than Week 
18. If the first recording at baseline is unsuccessful, the Week 12 recording can be omitted. 
More details about VitaloJAK® Cough Monitor device can be found in the Objective 
Cough Endpoint documentation. 
4.2.8.2 
Derivations  
Change from start of treatment in cough frequency to Week 12 will be expressed as 
baseline scale ratio (BSR) due to the log-normality of the data. 
𝐵𝑆𝑅= exp (ln 𝑃𝑜𝑠𝑡 𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒−ln 𝐵𝑎𝑠𝑒𝑙𝑖𝑛𝑒) 
4.2.8.3 
Handling of Dropouts  
Participants who drop out study early or had intercurrent events will be included for analysis 
using treatment policy strategy. 
Treatment policy strategy means if an intercurrent event occurs all subsequent data for that 
participant up to last dose are included in the evaluation. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
57 of 112 
4.2.8.4 
Primary Analysis of Tertiary/Exploratory Endpoint  
Observed values and BSR cough frequency will be summarised with the statistics planned 
for log-normal data for 24h, waking and sleeping. For cough frequency parameters (24-
hour, waking and sleeping) the values will be log-transformed (to base e) after adding an 
offset of 0.005 to bring all data above zero. 
BSR cough frequency at Week 12 will be analysed using ANCOVA model for 24-hour, 
waking and sleeping. The response variable will be the ln(BSR cough frequency) at Week 
12 with study intervention as factor for comparison of AZD4831 and placebo, ln(baseline 
value) as a covariate, and region will be added as a random covariate. 
The reportable results from the ANCOVA are the ones described in Section 3.4.2, by back-
transforming all the results (i.e. LSMean, CI), except the p-value. 
Distributions of 24-hour, waking and sleeping cough frequency at baseline and Week 12 will 
be displayed by study intervention group with box-plots. 
The average 24-hour, waking and sleeping cough frequency will also be listed by patient. 
All these analyses will be based on the cough subset population. 
4.2.8.5 
Sensitivity Analyses of the Tertiary/Exploratory Endpoint  
Not applicable 
4.2.8.6 
Supplementary Analyses of the Tertiary/Exploratory 
Endpoint  
Not applicable 
4.2.8.7 
Subgroup Analyses  
Not Applicable 
4.2.9 
Tertiary/Exploratory Endpoint – Change from baseline in 
spirometry endpoints measured face to face   
4.2.9.1 
Definition  
Data collected will include, but are not limited to, absolute and % predicted (as applicable) 
PEF, FEV1, FVC, FEV1/FVC, forced mid-expiratory flow (FEF25-75%), and inspiratory 
capacity. The following parameters will be included in the analysis PEF, FEV1, FVC, FEV1 
and FVC % predicted, FEV1/FVC, forced mid-expiratory flow (FEF25-75%) and forced 
inspiratory vital capacity. At SV3 and SV5, face-to-face spirometry will be undertaken at the 
site, followed by virtual spirometry. At SV4 and SV7, virtual spirometry will be performed 
away from the study site prior to attendance at the site and then face-to-face spirometry will 
be performed subsequently once the participant has attended the site. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
58 of 112 
4.2.9.2 
Derivations  
Change from baseline in spirometry endpoints to Weeks 4, 12 and 24 will be calculated as 
specified in Section 3.3.1.2. 
4.2.9.3 
Handling of Dropouts  
Participants who had intercurrent events will be included for analysis using “treatment 
policy” strategy.  
4.2.9.4 
Primary Analysis of Tertiary/Exploratory Endpoint  
Observed values and absolute change from baseline up to Weeks 4, 12 and 24 in spirometry 
endpoints will be summarised by each intervention group for the FAS population. 
Change from baseline through Week 24 in spirometry endpoints for participants with 
moderate to severe COPD will be analysed using MMRM as described in Section 3.4.3.  
Spirometry endpoints measured face to face will be summarised. 
Spirometry assessments measured face to face will be listed. 
The analysis will be focused on the FAS population. 
4.2.9.5 
Sensitivity Analyses of the Tertiary/Exploratory Endpoint  
Not applicable. 
4.2.9.6 
Supplementary Analyses of the Tertiary/Exploratory 
Endpoint  
Not applicable. 
4.2.9.7 
Subgroup Analyses  
Not applicable. 
4.2.10 
Tertiary/Exploratory Endpoint – Annualised rate of 
COPDCompEx Event  
4.2.10.1 
Definition  
The COPDCompEx definition and derivation are detailed in AZ Business Rules. 
 
Events regardless of what type (i.e., acute worsening or exacerbation) must be separated by 
at least 14 days in order to count as separate events (i.e., there must be at least 14 days 
during which no criteria for events are fulfilled). 
 
The time during the event and the 14 days after each event will not be considered when 
defining time at risk for the COPDCompEx event rate. Time at risk (days) will be defined as 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
59 of 112 
[Date of last dose of study intervention – date of the first dose of study intervention] + 2 – 
recovery time. 
Where recovery time is defined as: 
∑[𝑚𝑖𝑛(𝑖𝑡ℎ 𝑒𝑣𝑒𝑛𝑡 𝑒𝑛𝑑 𝑑𝑎𝑡𝑒+ 14, 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑠𝑡𝑢𝑑𝑦 𝑖𝑛𝑡𝑒𝑟𝑣𝑒𝑛𝑡𝑖𝑜𝑛)
𝑘
𝑖=1
− 𝑖𝑡ℎ 𝑒𝑣𝑒𝑛𝑡 𝑠𝑡𝑎𝑟𝑡 𝑑𝑎𝑡𝑒+ 1] 
 
4.2.10.2 
Derivations  
Annualised rate of COPDCompEx events, based on the period from baseline to last dose, 
will be calculated as: 
Annualised rate of COPDCompEx events 
= 
Total number of COPDCompEx events 
(Date of last dose of IP –  Date of the first dose of IP −recovery time +  2)/365.25 
For participants who do not experience an on-treatment COPDCompEx event, date of 
censoring will be the last dose date or last date of eDiary recording whichever is earlier. 
For CompEx analyses, only on-treatment events (i.e., events occurring from randomisation 
up to and including the last dose day) will be considered. 
4.2.10.3 
Handling of Dropouts  
The “while on treatment” strategy, same as defined in section 4.2.1.3. 
4.2.10.4 
Primary Analysis of Tertiary/Exploratory Endpoint  
Number of COPDCompEx events, total follow-up time and annualised exacerbation rate 
including the two-sided 90% CI will be summarised by study intervention group. 
The COPDCompEx event rate based on the period during the intervention from baseline 
through the last dose will be analysed using negative binomial regression (see Section 3.4.4). 
Rate ratio from AZD4831 compared to placebo will be displayed. 
The analyses will be focused on the FAS population, including only those subjects with post-
baseline eDiary data. 
4.2.10.5 
Sensitivity Analyses of the Tertiary/Exploratory Endpoint  
Not applicable 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
60 of 112 
4.2.10.6 
Supplementary Analyses of the Tertiary/ Exploratory 
Endpoint  
Not applicable 
4.2.10.7 
Subgroup Analyses  
Not Applicable 
4.2.11 
Tertiary/Exploratory Endpoint – Annualised rate of 
moderate or severe COPD exacerbations  
4.2.11.1 
Definition  
Defined in section 4.2.2.1. Events must be separated by at least 7 days in order to count as 
separate events. 
4.2.11.2 
Derivations  
Annualised rate of moderate or severe COPD exacerbations based on the period during the 
intervention from baseline through the last dose will be calculated as follows: 
Annualised rate of moderate or severe COPD exacerbations 
= 
Total number of moderate or severe COPD exacerbations
(Date of last dose of IP –  Date of the first dose of IP −recovery time +  2)/365.25 
Where recovery time is defined as: 
∑[𝑚𝑖𝑛(𝑖𝑡ℎ 𝑒𝑥𝑎𝑐𝑒𝑟𝑏𝑎𝑡𝑖𝑜𝑛 𝑒𝑛𝑑 𝑑𝑎𝑡𝑒+ 7, 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 𝑜𝑓 𝑠𝑡𝑢𝑑𝑦 𝑖𝑛𝑡𝑒𝑟𝑣𝑒𝑛𝑡𝑖𝑜𝑛)
𝑘
𝑖=1
− 𝑖𝑡ℎ 𝑒𝑥𝑎𝑐𝑒𝑟𝑏𝑎𝑡𝑖𝑜𝑛 𝑠𝑡𝑎𝑟𝑡 𝑑𝑎𝑡𝑒+ 1] 
For participants who do not experience an on-treatment moderate or severe COPD 
exacerbation event, date of censoring will be the date of last dose. 
4.2.11.3 
Handling of Dropouts  
The “while on treatment” strategy, same as defined in section 4.2.2.3 
4.2.11.4 
Primary Analysis of Tertiary/Exploratory Endpoint  
Number of moderate or severe AECOPD events, total follow-up time and annualised 
exacerbation rate including the two-sided 90% CI will be summarised by study intervention 
group. 
Number of participants with at least one moderate or severe AECOPD, total number of days 
of exacerbations, total number of days of exacerbations per participant and total number of 
exacerbations per participant-treatment year will be summarised by study intervention group. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
61 of 112 
Annualised rate of moderate or severe COPD exacerbations based on the period during the 
intervention from baseline through the last dose will be analysed using negative binomial 
regression (see Section 3.4.4). Rate ratio from AZD4831 compared to placebo will be 
displayed. 
The analyses will be focused on the FAS population. 
4.2.11.5 
Sensitivity Analyses of the Tertiary/Exploratory Endpoint  
Not applicable 
4.2.11.6 
Supplementary Analyses of the Tertiary/ Exploratory 
Endpoint  
Not applicable 
4.2.11.7 
Subgroup Analyses  
Not Applicable 
 
4.3 
Pharmacodynamic Endpoint(s)  
4.3.1.1 
Definitions and Derivations  
Sputum samples will be collected for pharmacodynamic assessments at SV3(Baseline) and 
SV5(Week 12). 
The target engagement will be defined as: 
100 × 
𝑀𝑃𝑂 𝐴𝑐𝑡𝑖𝑣𝑖𝑡𝑦
𝑀𝑃𝑂 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 
Change from baseline in target engagement to Weeks 12 will be calculated as specified in 
Section 3.3.1.2. 
4.3.1.2 
Presentation  
The normalised MPO activity and its change from baseline will be summarised using 
descriptive statistics. 
Change from baseline to Weeks 12 in normalised MPO activity will be analysed using a 
ANCOVA as described in Section 3.4.2. 
LSMean change from baseline and two-sided 90% CI to Weeks 12 in normalised MPO 
activity will be presented. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
62 of 112 
Participants who had intercurrent events will be included for analysis using treatment policy 
strategy. 
Treatment policy strategy means if an intercurrent event occurs all subsequent data for that 
participant up to last dose are included in the evaluation. 
4.4 
Pharmacokinetics  
4.4.1 
Definitions and Derivations  
Blood samples will be collected for measurement of plasma concentrations of AZD4831 at 
the following timepoints: 
• Day 1 Pre-dose 
• Week 12: 
o Pre-dose 
o Post-dose (for approximately 20% of participants) 
0.5h to 1.5h post-dose and 1.5h to 3h post, with a minimum of 1h between 
the post-dose sampling occasions. 
Plasma samples will be used to analyse the PK of AZD4831. Samples collected for analyses 
of AZD4831 concentration may also be used to evaluate safety or efficacy aspects related to 
concerns arising during or after the study. 
Pharmacokinetic data for those participants with additional PK sampling at Week 12 will be 
used to derive plasma PK parameters. 
Cmax 
Maximum observed plasma concentration 
Tmax 
Time to reach peak or maximum observed concentration following 
drug administration 
Ctrough 
Observed lowest concentration before the next dose is administered 
Additional PK parameters may be determined where appropriate.  
The derivation of PK parameters from the plasma concentration for AZD4831 will be 
performed by AstraZeneca CPK scientist team, in accordance with AZ Global Guidance for 
Non-Compartmental Pharmacokinetic Evaluations in Clinical Studies. 
Pharmacokinetic analysis will, where possible, be carried out using actual times determined 
from the PK sampling and dosing times recorded in the raw data. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
63 of 112 
4.4.2 
Presentation  
The PK concentrations and PK parameters will be listed and presented in tabular and 
graphical form, as appropriate, according to the version of the AstraZeneca Corporate 
templates and reporting standards as documented in the TFL shells, that include applicable 
descriptive statistics, defined handling of individual concentrations BLQ and 
precision/rounding rules for PK concentration and parameter data. 
Plasma AZD4831 concentrations will be summarised using descriptive statistics (including 
geometric mean, CV%) for all timepoints at each visit by study intervention group on PK set 
and will be listed for each patient from the SS. 
Geometric mean (together with gSD) serum AZD4831 concentration over time will be 
plotted on both linear and semi-logarithmic scales for Week 12 based on PK set. For the 0.5h 
to 1.5h sample and 1.5h to 3h sample, the geometric mean will be plotted at the midpoint of 
the collection window (ie 1h and 2.25h respectively). 
Individual and combined individual serum AZD4831 concentration vs actual time plots will 
be provided for the 20% of participants with post-dose PK sampling at Week 12 on both the 
linear and semi-logarithmic scale. 
4.5 
Immunogenicity  
Not applicable 
4.6 
Genetics  
Not applicable. 
4.7 
Safety Analyses  
The domain safety covers exposure, adverse events, clinical laboratory, vital signs, ECG and 
physical examination.  
Tables are provided for the safety set; listings are provided for All participants or the safety 
set depending on the availability of data. 
The safety analysis will not be performed as planned in the CSP using estimand strategy. The 
analyses of adverse events will include all data reported, which includes all data up to the 
end of the study period including the treatment and follow-up periods, starting from date of 
the first dose of IP and ending on the earliest date of withdrawal of consent or date of death 
or last study visit (SV8). For other safety analysis (ie, labs, vital signs), all data up to the end 
of the study period including the treatment and follow-up periods starting from baseline or 
screening data and ending on the earliest date of withdrawal of consent or date of death or 
last study visit (SV8). 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
64 of 112 
 
4.7.1 
Exposure  
4.7.1.1 
Definitions and Derivations  
Exposure duration is calculated only for participants in the Safety population as the total 
number of days on study drug and is calculated as: 
𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛 (𝑑𝑎𝑦𝑠) = 𝐿𝑎𝑠𝑡 𝑑𝑟𝑢𝑔 𝑎𝑝𝑝𝑙𝑖𝑐𝑎𝑡𝑖𝑜𝑛 𝑑𝑎𝑡𝑒−
𝐹𝑖𝑟𝑠𝑡 𝑑𝑟𝑢𝑔 𝑎𝑝𝑝𝑙𝑖𝑐𝑎𝑡𝑖𝑜𝑛 𝑑𝑎𝑡𝑒+ 1 – (𝑡𝑟𝑒𝑎𝑡𝑚𝑒𝑛𝑡 𝑖𝑛𝑡𝑒𝑟𝑟𝑢𝑝𝑡𝑖𝑜𝑛 𝑝𝑒𝑟𝑖𝑜𝑑)  
The date from end of treatment phase is to be used for last drug application date. 
Exposure as measured by amount tablets administered calculated as: 
𝐴𝑐𝑡𝑢𝑎𝑙 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒 (𝑡𝑎𝑏𝑙𝑒𝑡𝑠) = 𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑑𝑖𝑠𝑝𝑒𝑛𝑠𝑒𝑑−𝑡𝑎𝑏𝑙𝑒𝑡𝑠 𝑟𝑒𝑡𝑢𝑟𝑛𝑒𝑑 
Note that if any ‘Amount Returned’ field in the Drug Accountability CRF page is blank, then 
this formula will not be calculated. 
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. 
Total amounts of doses received will be calculated as number of days where at least one dose 
amount of >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 SV7 dose. 
Total time of exposure (patients-years) is calculated as: 
𝑇𝑜𝑡𝑎𝑙 𝑡𝑖𝑚𝑒 𝑜𝑓 𝑒𝑥𝑝𝑜𝑠𝑢𝑟𝑒 (𝑝𝑎𝑡𝑖𝑒𝑛𝑡𝑠−𝑦𝑒𝑎𝑟𝑠) = 
1
365.25 × ∑
𝐸𝑥𝑝𝑜𝑠𝑢𝑟𝑒 𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛
𝑃𝑎𝑡𝑖𝑒𝑛𝑡
 
4.7.1.2 
Presentation  
The duration of exposure and total amount of dose received will be summarised using 
descriptive statistics for each study intervention group and overall. 
Duration of exposure and total dose will be presented by category, with categories being 
Days 1-28, 29-56, 57-84, 85-112, 113-140 and 141-172. 
The total time of exposure will be displayed by intervention and overall. 
In addition, a figure of exposure over time will be presented, with one line for each study 
intervention group, and percentage of participants still exposed on the y-axis and time from 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
65 of 112 
first dose on the x-axis. At a given time t, the curve will show the percentage of participants 
with exposure time >t. 
The total amount of dose will be summarised by intervention group and overall. 
These outputs will be based on the SS.  
Exposure details, such as duration of exposure, date of each treatment administration and 
dose per administration, will be listed for the Safety population. 
4.7.2 
Adverse Events  
4.7.2.1 
Definitions and Derivations  
Adverse events (AEs) will be collected from the time of first dose of study intervention 
throughout the treatment and the follow-up periods (SV8). The only exception is related to 
the pre-dose orthostatic test at Visit SV3: if orthostatic hypotension is confirmed, it should 
be reported as an AE, and symptoms related to the measurement of orthostatic vital signs if 
present should also be reported as an AE. 
Serious adverse events (SAEs) will be recorded from the time of signing of the ICF. AEs will 
be coded with MedDRA version 25.1 or higher and will be classified by SOC and PT. For 
any additional details on AE reporting please refer to the CSP.  
AEs will be defined as treatment emergent adverse events (TEAEs) if they have an onset date 
on or after first dose date of study intervention until safety follow-up. AEs with a missing 
start date will be considered as TEAEs.  
Any AE  
Defined as an AE reported with an onset date within the defined period. 
Any SAE  
Defined as an AE reported as serious, irrespective of outcome. 
SAEs with outcome death  
Defined as an AE with reported outcome as ‘Fatal’, there may be more than one AE with 
outcome death for a patient. The onset date of the AE determines the analysis period, 
irrespective of date of death. 
AEs leading to discontinuation of IP  
Defined as an AE with action taken IP reported as drug permanently discontinued. The onset 
date of the AE determines the analysis period, irrespective of date of discontinuation of IP.  


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
66 of 112 
AEs possibly related to IP  
Defined as an AE that is reported as “reasonable possibility AE caused by IP”. If this 
evaluation is missing, it will be counted as an AE possibly related to IP. 
AEs by maximum intensity  
AEs will be classified by the reported maximum intensity, “Mild”, “Moderate” and “Severe”. 
If this maximum intensity evaluation is missing, it will be counted as “Severe”. 
Adverse events of special interest  
The following AESIs will be particularly monitored in this study: 
Skin reactions, including maculopapular rash: 
− 
Skin reactions/rashes considered maculopapular (described as macules/papules 
under the morphology/appearance question). 
− 
Skin reactions/rashes not considered maculopapular (not described as 
macules/papules under the morphology/appearance question).  
Infections, including pneumonia will be defined by the SOC “Infections and infestations” 
or the pathogen specific High level group term (HLGT) “Fungal infectious disorders” 
AEs will be assigned to a specific category based on investigator’s judgement, using a 
checkbox on the AE CRF page. 
4.7.2.2 
Presentation  
All AE summary tables and listings will be created by study intervention group for the SS, 
unless otherwise specified. TEAEs occurring during study intervention and follow-up period 
will be reported in summary tables including any related to the pre-dose orthostatic test at 
Visit SV3. All AEs will be listed in key subject information tables and listings. 
Overview tables will contain number and percentage of participants and number of episodes 
in following categories: 
Any AEs 
Any AEs with outcome = death 
Any SAEs (including events with outcome = death) 
Any AE related to IP (as assessed by the Investigator) 
Any AEs leading to discontinuation of IP 
Any AEs leading to dose interruption 
Any AEs leading to withdrawal from study 
Any AESI 
Any pneumonia or other serious infection 
Any skin reaction 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
67 of 112 
Any maculopapular rash 
Any non-maculopapular rash 
Any maculopapular rash leading to IP discontinuation, by maximum of CTCAE grade and 
overall 
Any non-maculopapular rash leading to IP discontinuation, by maximum of CTCAE grade 
and overall 
 
The number and percentage of participants with AE by SOC and PT will be summarised by 
study intervention group. 
The number and percentage of participants with AEs occurring in >5% of participants in any 
study intervention group will be summarised by PT and study intervention group. 
The number and percentage of participants with AEs by maximum reported intensity by SOC 
and PT will be summarised by study intervention group. 
The number and percentage of participants with possibly-related AEs as assessed by 
investigator will be summarised by: 
• SOC, PT and study intervention group 
• SOC, PT, maximum grade of severity and study intervention group. 
The number and percentage of participants with AEs with outcome of death by SOC and PT 
will be summarised by study intervention group. Key patient information for participants 
who experienced AEs with outcome of death will be produced for each study intervention 
group using following information: 
Patient identifier 
Sex 
Age (years) 
Race 
Event term as reported by the investigator 
PT 
Time from first IP administration (days) 
Time from last IP administration (days) 
Time from last IP administration to death (days)  
Time from first IP administration to death (days)  
Reasonable possibility AE caused by IP 
 
The number and percentage of participants with SAEs by SOC and PT will be summarised 
by study intervention group, the summary will be repeated to present number and percentage 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
68 of 112 
of participants with related SAEs. Key patient information for participants who experienced 
SAEs will be produced using following information: 
Study intervention group 
Patient identifier 
Sex 
Age (years) 
Race 
Event term as reported by the investigator 
PT 
Time from first IP administration to onset of AE (days)  
Time from last IP administration prior to onset of AE (days) 
Time from start of IP administration to becoming serious 
Outcome 
Action taken with IP 
Reasonable AE caused by IP 
 
The number and percentage of participants with AEs leading to discontinuation of 
investigational product by SOC and PT will be summarised by study intervention group. Key 
patient information for participants who experienced AEs leading to discontinuation of IP 
will be produced using following information: 
Study intervention group 
Patient identifier  
Sex 
Age 
Race 
AE as reported by the investigator 
PT term  
Time from first IP administration to onset of AE (days)  
Time from last IP administration prior to onset of AE (days) 
Seriousness 
Outcome  
Reasonable possibility AE caused by IP 
 
A list of PTs for AESIs will be produced. 
Number and percentage of participants with AESIs will be summarised by category and PT 
for each study intervention group. Number and percentage of participants with serious AESIs 
will be summarised by category and PT for each study intervention group. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
69 of 112 
Number and percentage of participants with skin reactions will be summarised by category, 
PT and maximum CTCAE grade for each study intervention group. Number and percentage 
of participants with serious skin reactions will be summarised by category, PT and maximum 
CTCAE grade for each study intervention group. Additionally to the all AE listing, all skin 
reactions will be listed separately.  
Number and percentage of participants with AESIs will be summarised by category, PT and 
maximum intensity for each study intervention group. Number and percentage of participants 
with serious AESIs will be summarised by category, PT and maximum intensity for each 
study intervention group. 
Key patient information for participants who experienced AESI will be produced using 
following information: 
Study intervention group 
Patient identifier  
Sex 
Age 
Race 
AE Category 
AE as reported by the investigator 
PT term  
Time from first IP administration to onset of AE (days)  
Time from last IP administration prior to onset of AE (days) 
Seriousness 
Maximum Intensity (mild, moderate, severe) 
Outcome  
Reasonable possibility AE caused by IP 
 
Key patient information for participants who experienced at least one positive sequence 
suggesting orthostatic hypotension (more details in Section 4.7.6) will be produced using 
following information: 
Study intervention group 
Patient identifier  
Sex 
Age 
Race 
AE as reported by the investigator 
PT term  


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
70 of 112 
Time from first IP administration to onset of AE (days)  
Time from last IP administration prior to onset of AE (days) 
Seriousness 
Maximum Intensity (mild, moderate, severe) 
Outcome  
Reasonable possibility AE caused by IP 
Flag for event occurring within 3 hours after first dose of IP for baseline 
BP values from VS 
Key patient information for participants who experienced at least two positive sequence 
suggesting orthostatic hypotension (more details in Section 4.7.6) will be produced using 
same information as above. 
Time to onset to maculopapular rash and grade 3 maculopapular rash will be summarised and  
time to onset to maculopapular rash will be displayed with box plots. 
Narratives will be generated for all deaths, AEs leading to discontinuation of IP, AEs of 
Special interest and SAEs. 
4.7.3 
Clinical Laboratory, Blood Sample  
4.7.3.1 
Definitions and Derivations  
Following haematology, clinical chemistry, and coagulation parameters will be assessed: 
Abnormalities in selected parameters for haematology and chemistry laboratory 
measurements are defined as post-baseline measurements meeting the pre-defined criteria for 
abnormality below and is more extreme than the non-missing baseline value for a patient. 
Thus, if the baseline value met the criteria for marked abnormality and the post-baseline value 
is equal to or less extreme than the baseline value, this is not considered as abnormal. Low 
and high ranges are derived based on reference ranges provided by the central laboratory, if 
available. 
Table 10 
Laboratory Blood Safety Variables and criterion for abnormality 
Parameter 
Selected parameters and their criterion for 
abnormality 
Haematology/haemostasis (whole blood) 
 
B-Haemoglobin (Hb) 
• 
< 100 g/L 
• 
< 80 g/L 
Eosinophils  
• 
≥ 0.7 x 109/L 
• 
≥1.5 x109/L 
Neutrophils  
• 
< 1.5 x 109/L 
• 
< 1.0 x 109/L 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
71 of 112 
Parameter 
Selected parameters and their criterion for 
abnormality 
Haematology/haemostasis (whole blood) 
 
B-Leukocyte count 
• 
< 3.0 x 109/L 
• 
< 2.0 x 109/L 
B-Platelet count 
• 
  < 100 x109/L 
Clinical chemistry (serum) 
 
S/P-Creatinine 
• 
 ≥ 1.5x baseline creatinine 
• 
 ≥ 2x baseline creatine 
S/P-Bilirubin, total  
• 
≥2 × ULN 
S/P-Aspartate transaminase (AST) 
• 
≥3 × – <5 × ULN  
• 
≥5 × – <10 × ULN 
• 
≥10 × ULN 
S/P-Alanine transaminase (ALT) 
• 
≥3 × – <5 × ULN  
• 
≥5 × – <10 × ULN 
• 
≥10 × ULN 
S/P-Potassium 
• 
≥ 5.5 mmol/L 
• 
≥ 6.0 mmol/L 
• 
≥ 6.5 mmol/L 
S/P-Sodium 
• 
< 135 mmol/L 
• 
>145 mmol/L 
Coagulation parameters (screening only) 
 
Prothrombin time (PT) 
 
Activated partial thromboplastin time (aPTT) 
 
International normalised ratio (INR) 
 
Fibrinogen 
 
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; aPTT= Activated partial thromboplastin time; 
AST = Aspartate aminotransferase; B = Blood; CK = Creatine kinase; FSH = Follicle stimulating hormone; 
Hb = Haemoglobin; INR = International normalised ratio; PT = Prothrombin time; S/P = Serum/Plasma;  
4.7.3.2 
Presentations  
Laboratory evaluations (continuous haematology and clinical chemistry as per Precision tab 
in mock shells) will be summarised using descriptive statistics at each visit and change from 
baseline summarised for each post-baseline visit, if available. Haematology and clinical 
chemistry abnormalities by predefined criteria will also be summarised, and a listing on key 
patient information supporting the summary will be provided. Coagulation results will be 
summarized for screening only. 
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: 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
72 of 112 
Table 11 
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 
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 participants 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.  
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.  
A listing of individual laboratory measurements, including reference range indicator will be 
presented. 
The analysis will be focused on the SS. 
4.7.4 
Clinical Laboratory, Urinalysis  
4.7.4.1 
Definitions and Derivations  
Following urinalysis parameters will be assessed via dipsticks:  
Table 12 
Laboratory Urinalysis Safety Variables 
Urinalysis (dipstick) 
U - Leukocytes 
U - Nitrite 
U- Urobilinogen 
U- Protein 
U- Blood  
U-Ketones 
U-Bilirubin 
U-Glucose 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
73 of 112 
4.7.4.2 
Presentations  
Urinalysis results will be summarised in tables by intervention group. A urinalysis listing on 
key patient information supporting the summary will be provided for patient with urinalysis 
abnormalities.  
The analysis will be focused on the SS. 
4.7.5 
Other Laboratory Evaluations  
4.7.5.1 
Definitions and Derivations  
Other laboratory tests assessed include FSH (screening only, if needed to confirm 
postmenopausal status in female participants aged < 50 years only), ANCA, Viral serology 
at screening only (Hepatitis B, Hepatitis C, HIV-1) and thyroid test (Free T4, T3, Total T4 
and TSH). 
Table 13 
Thyroid criterion for abnormality 
Parameter 
Selected parameters and their criterion for abnormality 
TSH 
• 
>6 mIU/L 
• 
≥10 mIU/L 
TSH and free T4 
• 
TSH > 6mIU/L and free T4 < Lower limit normal 
(LLN) 
• 
TSH ≥10mIU/L and free T4 < LLN 
 
4.7.5.2 
Presentations  
Thyroid functions parameters will be summarised at each visit. Thyroid abnormalities by 
predefined criteria will also be summarised. 
A listing with key patient information will be provided for each other laboratory test for the 
safety population. 
The analysis will be focused on the SS. 
4.7.6 
Vital Signs   
4.7.6.1 
Definitions and Derivations  
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) 
 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
74 of 112 
Multiple blood pressure and heart rate measurements will be performed and the average of 
the measurements will be used for analysis in case the measurements are valid. Valid blood 
pressure measurements are defined as 2 or more measurements with a maximum difference 
of 10 mmHg whatever the position (supine/standing/sitting). Valid heart rate measurements 
are defined as 2 or more measurements with a maximum difference of 10 bpm whatever the 
position (supine/standing/sitting). All measurements will be considered within a visit in case 
the measurements are within the range pairwise.  
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) and high (if value is above the upper 
limit) according to the normal reference ranges (Table 14): 
Table 14 
Vital sign reference ranges 
Parameter 
Standard Unit 
Lower limit 
Upper limit 
Body temperature (oral, tympanic) 
°C 
 
≥37.5 
DBP 
mmHg 
<50 
≥95 
SBP 
mmHg 
<90 
≥160 
Heart (pulse) rate 
beats/min 
<45 
>100 
Respiratory rate 
breath/min 
<12 
≥25 
DBP = Diastolic Blood Pressure; SBP = Systolic Blood Pressure. 
High value (H) is defined as upper reference limit. Low value (L) is defined as below lower 
reference limit. 
Orthostatic BP measurements 
Orthostatic BP measurements are obtained using a standard sphygmomanometer after 
scheduled supine measurements (1 and 3 minutes after the patient stands) and prior to any 
required blood draw: 
• At SV3 (baseline; Day 1), orthostatic BP should be measured pre-dose and 1 to 2 
hours post-dose. 
• At SV5 (Week 12), orthostatic BP should be measured pre-dose. 
For each visit/timepoint, up to 2 additional orthostatic blood pressure sequences may be 
performed. For each sequence, the orthostatic hypotension is defined by a decrease (between 
supine value and values at 1 or 3 minutes after standing) of ≥20 mmHg for SBP or ≥10 mmHg 
for DBP. The orthostatic hypotension for the visit/timepoint is confirmed if 2 of 2 or 2 of 3 
sequences have demonstrated hypotension or if symptoms are reported to have occurred at 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
75 of 112 
any of the sequences. When orthostatic hypotension is confirmed, the investigator reports an 
“Orthostatic Hypotension” adverse event specifying the date and time. 
Details about the orthostatic blood pressure assessment are described in Appendix A. 
The following definitions will be applied:  
• BP decrease: orthostatic hypotension derived from orthostatic BP data with at least 2 
positive sequences (ie. 2 of 2 or 2 of 3). 
• BP decrease reported as AE: “Orthostatic Hypotension” AE starting the same day on 
Day 1 Pre-dose, Day 1 Post-dose or within the same day of the 12 weeks 
measurement. 
The three following timepoints will be considered:  
• Day 1 pre-dose 
• Day 1 post-dose 
• Week 12 
For BP decrease, the CRF visit/timepoint variables will be used. For BP decreased reported 
as AE, these timepoints should be derived from exposure dates and times, and “Orthostatic 
Hypotension” start dates and times. 
4.7.6.2 
Presentations  
Observed values and change from baseline in vital signs (excluding the orthostatic 
assessments) will be summarised by study intervention group and visit with descriptive 
statistics. 
The number and percentage of participants with at least one vital sign abnormalities 
(Low/High values) will be summarised by abnormality criteria and intervention group. 
Shift from baseline to maximum on-treatment value in vital signs will be presented by 
intervention group (using the categories from Table 14). 
Key patient information will be produced for vital sign parameters treatment-emergent 
changes outside predefined criteria (Table 14). All vital signs will be listed.  
The number and percentage of participants with orthostatic hypotension (BP decreased and 
BP decreased reported as an AE) will be summarised by intervention group and 
visit/timepoint. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
76 of 112 
Key patient information of participants with at least one positive sequence for orthostatic 
blood pressure (ie. at least one sequence proving a blood pressure decrease) will be presented. 
This listing will present the following variables: 
• Age, gender, race 
• The number of positive sequences at the following timepoints: 
o Day 1 Pre-dose 
o Day 1 Post-dose 
o Week 12 
The analysis will be focused on the SS. 
4.7.7 
Electrocardiogram  
4.7.7.1 
Definitions and Derivations  
Electrocardiograms (ECGs) will be performed at screening visit, SV3 (Day 1) and SV5 
(Week 12). ECG variables will be collected, as follows: 
Heart rate (beats/min); 
RR interval (msec); 
QRS interval (msec); 
PR interval (msec); 
QT interval (msec); 
QTcF (msec). 
Additionally, QTc interval corrected for heart rate will be calculated directly from the CRF 
using  
Bazett´s correction: QTcB[msec]=QT[msec]/(RR[sec]1/2) 
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 15). 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
77 of 112 
Table 15 
ECG normal reference ranges 
Parameter (standard unit) 
Lower limit 
Upper limit 
Heart rate (beats/min) 
<45 
>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 
QTcB (msec) 
N/A 
>450  
QTcF (msec) 
N/A 
>450  
 
4.7.7.2 
Presentations  
Observed values and change from baseline in ECG variables will be summarised by visit 
using descriptive statistics.  
ECG data and ECG abnormalities will be listed. 
The analysis will be focused on the SS. 
4.7.8 
Other Safety Assessments  
4.7.8.1 
Definitions and Derivations  
Physical Examination 
A complete physical examination will be performed at Visit SV3 (Day 1) and at 
Discontinuation visit, including assessments of the following: general appearance, 
respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose, and 
throat), lymph nodes, thyroid, muscular-skeletal (including spine and extremities) and 
neurological systems. 
A brief physical examination performed at Screening (SV1),Visit SV5 and SV7 will include, 
at a minimum, assessments of the skin, lungs, cardiovascular system, and abdomen (liver and 
spleen). 
The CRF page for physical examination is designed in a way to collect whether the 
examination was performed, and if so, the date of the examination. Any post-baseline 
abnormalities in physical examination will be recorded on the AE form. 
4.7.8.2 
Presentations  
As every abnormality in physical examination will recorded on the AE form, the physical 
examination data will not be reported. 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
78 of 112 
5 
INTERIM ANALYSIS  
An administrative IA will be conducted after the first 136 COPDCompEx events (70% of the 
required total 194 events) have occurred. It will allow an early assessment of efficacy for 
AZD4831 according to the decision framework. No formal statistical test will be conducted. 
The IA assessment will be used to guide internal (AstraZeneca) decision-making regarding 
further development of the AZD4831 program. As a result, no alpha will be spent at the IA. 
A URC will be set up to perform this administrative IA on the primary efficacy endpoint. 
Details about the execution of the IA will be provided in the URC charter. This will ensure 
that the study team remains blinded throughout the study conduct and guarantee the integrity 
and avoid any conscious or unconscious biases.  
A subset of TFLs from CSR TFLs will be generated for IA. IA TFLs are indicated in TOC 
(7 Appendix B). 
In addition, the IA results will be used for the evaluation of the safety profile of the drug, 
by the DRC - see section 9.6 of the CSP. 
6 
REFERENCES  
Bartlett JW, Morris TP, Stensrud MJ, Daniel R. The Hazards of Period Specific and 
Weighted Hazard Ratios. Statistics in Biopharmaceutical Research June 2020; 12(4):1-2 
 
Frewer, P., Mitchell, P., Watkins, C. and Matcham, J. Decision-making in early clinical 
drug development. Pharmaceutical Statistics 2016;15(3): 255-263 
Objective Cough Endpoint: Standards for Analyzing Cough Data from the VitaloJak 
Monitoring System, 15th September 2022EXACT user manual v8.0 
 
7 
APPENDIX  
Appendix A Orthostatic Blood Pressure  
To minimise chances of orthostatic hypotension related to volume depletion, participants 
should be well hydrated when they come to the clinic for study visits. Supine BP measures 
will be collected after participants have been lying down for at least 10 minutes. To ensure 
that a stable supine BP is obtained, at least 2 systolic and 2 diastolic BP measurements will 
be obtained. If the replicate measurements differ by no more than 10 mmHg and 5 mmHg, 
respectively, the supine BP will be considered stable. The mean value of each replicate (mean 
systolic and mean diastolic value) will represent the baseline BP for that visit. After stable 
BP is achieved, the patient will stand, and BP measurements will be taken at 1 and 3 minutes 
after the patient stands. If the BP measurements do not meet the criteria for orthostatic 
hypotension, no additional measurement is needed. If the BP measurement meets the criteria 
shown in Table 16, investigators will repeat the supine and standing measurements up to 2 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
79 of 112 
additional times. The exception is for participants with orthostatic hypotension symptoms: in 
this situation, the orthostatic hypotension AE should be reported based on a single orthostatic 
test sequence. 
When evaluating orthostatic vital signs, any symptoms of dizziness or light headedness 
should be recorded on the AE page in the eCRF. At Visit SV3, if orthostatic hypotension is 
confirmed pre-dose and post-dose, the orthostatic hypotension AE should be reported twice 
(pre-dose and post-dose). The same applies to symptoms related to the measurement of 
orthostatic vitals: if present pre-dose and post-dose, it should also be reported as an AE twice 
(pre-dose and post-dose). 
Table 16 : Orthostatic Blood Pressure Criteria and Management 
Decrease in BP indicative of 
orthostatic hypotension  
Actions 
≥ 20 mmHg systolic or  
≥ 10 mmHg diastolic  
Repeat the BP measurements (supine and standing) up to 2 additional 
times, unless orthostatic hypotension is present in association with 
symptoms related to the measurement of orthostatic vitals: in such a case 
the test does not need to be repeated and the orthostatic hypotension AE 
and symptoms related to the measurement of orthostatic vitals AE should 
be reported based on a single sequence. 
If either the 1-minute or 3-minute standing BP meets the orthostatic 
(postural) hypotension criteria, then the sequence is considered 
indicative of orthostatic hypotension.  
If 2 of 2 or 2 of 3 sequences are positive, then orthostatic hypotension is 
confirmed, and an AE of orthostatic hypotension will be reported.  


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
80 of 112 
Appendix B Table of contents  
Table 17: Used versions of reference documents for standard mock shells and SAP 
Reference document for standard mock shells and SAP 
Version 
Date created 
AZ Early-Phase Biometrics Content Guidance for RIA SAP 
 
 
AZ Corporate CSRHLD Figure Templates v3.2 
3.2 
30Jun2020 
AZ Corporate CSRHLD Listing Templates v1.5 
1.5 
31Mar2021 
AZ Corporate Pandemic CSRHLD Table and Listing Templates v1.3 
1.3 
31Mar2022 
AZ Oncology TA TFL Templates v3.1 
3.1 
18Dec2020 
AZ Respiratory CSRHLD Table and Figure Templates v1.3 
1.3 
Mar2022 
AZ Respiratory Pandemic CSRHLD Table and Listing Templates v1.0 
1.0 
01Oct2020 
AZ_Corporate_Table_Templates_20220408 
20220408 
08Apr2022 
AZ_Respiratory_Immunology_Table_Templates_20220405 
20220405 
05Apr2022 
AZ_Standard_Output_general_principles_20220930_v1 
v1 
30Sep2022 
AZ Corporate CSR/HLD Table Templates 
2.0 
May2020 
 
 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
81 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
14.1 - STUDY POPULATION 
Table 14.1.1 
Disposition  
AZ_Corporate_Table_Templates_20220408 AZTSP01 
Include: 
• subjects enrolled,  
• subjects not 
randomised (incl. 
reasons),  
• subjects randomised,  
    o   subjects 
randomised, not treated,  
    o   subjects started 
treatment,  
    o   subjects 
completed the 
treatment,  
    o   subjects 
discontinued treatment 
(incl. reasons),  
• subjects included in 
the cough substudy,  
• subjects completed the 
study and  
• subjects withdrawn 
from study (incl. 
reasons)  
 
Add a "Total" column. 
no 
Table 14.1.2 
Recruitment per country 
and site 
AZ_Corporate_Table_Templates_20220408 AZTSP02 
A column is added for 
each analysis set 
no 
Table 14.1.3 
Stratification at 
randomisation 
(Randomised set) 
AZ_Corporate_Table_Templates_20220408 AZTSP03 
To be revised with the 
stratification factor of 
the study. 
 
Add a "Total" column.  
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
82 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.1.4 
Disposition due 
to global/country 
situation (Full analysis 
set) 
AZ_Corporate_Table_Templates_20220408 AZTSP04 
To be revised with 
study-specific reasons 
no 
Table 14.1.5 
Global/country 
situation study 
disruptions (Full analysis 
set) 
AZ_Corporate_Table_Templates_20220408 AZTSP05 
To be revised with 
study design 
no 
Table 14.1.6 
Important protocol 
deviations (Full analysis 
set) 
AZ_Corporate_Table_Templates_20220408 AZTSP06 
The categories are 
revised according to 
Protocol Deviations 
Plan 
no 
Table 14.1.7 
Analysis sets  
AZ_Corporate_Table_Templates_20220408 AZTSP07 
For each analysis set, 
include reasons for 
exclusion. 
no 
Table 14.1.8 
Demographics (Full 
analysis set) 
AZ_Corporate_Table_Templates_20220408 AZTSP08 
Include age, gender, 
race and ethnicity 
Yes 
Table 14.1.9 
Baseline characteristics 
(Full analysis set) 
AZ_Corporate_Table_Templates_20220408 AZTSP09 
Include: 
 - height, weight and 
BMI 
Yes 
Table 14.1.10 
Lung function data at 
screening (Full analysis 
set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRISP03 
Include:- FEV1, FVC, 
FEV1/FVC and 
FEV1% predicted 
no 
Table 14.1.11 
Lung function data at 
baseline (Full analysis 
set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRISP03 
Include:- Lung 
functions PEF, FEV1, 
FVC, FEV1/FVC 
FEF25-75%, FEV1 and 
FVC % predicted,and 
forced inspiratory vital 
capacity 
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
83 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.1.12 
COPD characteristics at 
randomisation (Full 
analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRISP04 
Include : 
  - Time since COPD 
diagnosis 
  - Time to first 
appearance of COPD 
symptoms 
  - GOLD Classification 
  - Occurrence of 
previous admission to 
ICU for COPD in past 
24 months 
  - Number of moderate 
and severe exacerbation 
within 24 months prior 
enrolment 
  - Frequent productive 
cough 
  - Use of disease-
related medications 
(ICS + LABA + LAMA 
or ICS + LABA or 
LABA + LAMA) 
no 
Table 14.1.13 
Medical history by 
system organ class and 
preferred term (Full 
analysis set) 
AZ_Corporate_Table_Templates_20220408 AZTSP13 
  
no 
Table 14.1.14 
Prior medication by ATC 
classification and generic 
drug name (Full analysis 
set) 
AZ_Corporate_Table_Templates_20220408 AZTSP14 
  
no 
Table 14.1.15 
Prior disease-related 
medications (Full 
analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRISP05 
Revise column with the 
disease-related 
medication. 
Add a "Total" column.  
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
84 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.1.16 
Concomitant medication 
by ATC classification 
and generic drug name 
(Full analysis set) 
AZ_Corporate_Table_Templates_20220408 AZTSP15 
  
no 
Table 14.1.17 
Intercurrent event of 
restricted medication use 
(Full analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRISP07 
  
no 
Table 14.1.18 
Study treatment 
compliance (Full analysis 
set) 
AZ_Corporate_Table_Templates_20220408 AZTSP17 
Revise footnotes 
no 
Table 14.1.19 
Inhaled tobacco usage 
characteristics at baseline 
(Full analysis set) 
AZ Corporate CSRHLD Table Templates v3.4 ASP2 
  
no 
14.2 - EFFICACY 
14.2.1 - Primary efficacy 
Table 14.2.1.1 
Summary for time to first 
COPDCompEx event: 
while on treatment (Full 
analysis set) 
AZ_Corporate_Table_Templates_20220408 AZTEF06 
The following results 
will be displayed at 
Weeks 4, 12, 18 and 24:  
- The number of 
patients at risk  - the 
number of censored 
patients  - the number 
of events   - Kaplan-
Meier estimates and 
CIAdd the log-rank test. 
Yes 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
85 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.2.1.2 
Summary for time to first 
COPDCompEx event: 
treatment policy - 
Supportive analysis (Full 
analysis set) 
AZ_Corporate_Table_Templates_20220408 AZTEF06 
The following results 
will be displayed at 
Weeks 4, 12, 18 and 24: 
  - The number of 
patients at risk 
  - the number of 
censored patients 
  - the number of events  
  - Kaplan-Meier 
estimates and CI 
 
Add the log-rank test. 
no 
Table 14.2.1.3 
Hazard ratio for time to 
first COPDCompEx 
event: while on treatment 
(Full analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF10 
Remove the following 
columns: 
  - Median time to event 
  - Time to percentile 
  - P-value 
Yes 
Table 14.2.1.4 
Hazard ratio for time to 
first COPDCompEx 
event: treatment policy - 
Supportive analysis (Full 
analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF10 
Remove the following 
columns: 
  - Median time to event 
  - Time to percentile 
  - P-value 
no 
Table 14.2.1.5 
Subgroup Analysis: 
Hazard ratio for time to 
first COPDCompEx 
event by Frequent 
Productive Cough: while 
on treatment (Full 
analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF10 
Remove the following 
columns: 
  - Median time to event 
  - Time to percentile 
  - P-value 
 
To be repeated for each 
category 
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
86 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.2.1.6 
Subgroup Analysis: 
Hazard ratio for time to 
first COPDCompEx 
event by Gender: while 
on treatment (Full 
analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF10 
Remove the following 
columns: 
  - Median time to event 
  - Time to percentile 
  - P-value 
 
To be repeated for each 
category 
no 
Table 14.2.1.7 
Subgroup Analysis: 
Hazard ratio for time to 
first COPDCompEx 
event by Age: while on 
treatment (Full analysis 
set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF10 
Remove the following 
columns:  - Median 
time to event  - Time to 
percentile  - P-valueTo 
be repeated for each 
category 
no 
Table 14.2.1.8 
Subgroup Analysis: 
Hazard ratio for time to 
first COPDCompEx 
event by Race: while on 
treatment (Full analysis 
set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF10 
Remove the following 
columns: 
  - Median time to event 
  - Time to percentile 
  - P-value 
 
To be repeated for each 
category 
no 
Table 14.2.1.9 
Subgroup Analysis: 
Hazard ratio for time to 
first COPDCompEx 
event by BMI: while on 
treatment (Full analysis 
set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF10 
Remove the following 
columns: 
  - Median time to event 
  - Time to percentile 
  - P-value 
 
To be repeated for each 
category 
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
87 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.2.1.10 
Subgroup Analysis: 
Hazard ratio for time to 
first COPDCompEx 
event by Geographic 
Region: while on 
treatment (Full analysis 
set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF10 
Remove the following 
columns: 
  - Median time to event 
  - Time to percentile 
  - P-value 
 
To be repeated for each 
category 
no 
Table 14.2.1.11 
Subgroup Analysis: 
Hazard ratio for time to 
first COPDCompEx 
event by Baseline FEV1 
as percent of predicted: 
while on treatment (Full 
analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF10 
Remove the following 
columns: 
  - Median time to event 
  - Time to percentile 
  - P-value 
 
To be repeated for each 
category 
no 
Table 14.2.1.12 
Subgroup Analysis: 
Hazard ratio for time to 
first COPDCompEx 
event by Maintenance 
medications (ICS): while 
on treatment (Full 
analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF10 
Remove the following 
columns: 
  - Median time to event 
  - Time to percentile 
  - P-value 
 
To be repeated for each 
category 
no 
Table 14.2.1.13 
Subgroup Analysis: 
Hazard ratio for time to 
first COPDCompEx 
event by Maintenance 
medications 
(LABA/LAMA/ICS): 
while on treatment (Full 
analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF10 
Remove the following 
columns:  - Median 
time to event  - Time to 
percentile  - P-valueTo 
be repeated for each 
category 
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
88 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.2.1.14 
Subgroup Analysis: 
Hazard ratio for time to 
first COPDCompEx 
event by Number of 
COPD exacerbations in 
last 24 months: while on 
treatment (Full analysis 
set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF10 
Remove the following 
columns: 
  - Median time to event 
  - Time to percentile 
  - P-value 
 
To be repeated for each 
category 
no 
Table 14.2.1.15 
Subgroup Analysis: 
Hazard ratio for time to 
first COPDCompEx 
event by Type of site of 
recruitment: while on 
treatment (Full analysis 
set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF10 
Remove the following 
columns: 
  - Median time to event 
  - Time to percentile 
  - P-value 
 
To be repeated for each 
category 
no 
Table 14.2.1.16 
Subgroup Analysis: 
Hazard ratio for time to 
first COPDCompEx 
event by Smoking status: 
while on treatment (Full 
analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF10 
Remove the following 
columns: 
  - Median time to event 
  - Time to percentile 
  - P-value 
 
To be repeated for each 
category 
no 
Table 14.2.1.17 
Subgroup Analysis: 
Hazard ratio for time to 
first COPDCompEx 
event by MPO 
concentration at baseline: 
while on treatment (Full 
analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF10 
  
no 
Figure 14.2.1.1 
Time to first 
COPDCompEx event 
(days), Kaplan-Meier 
AZ Corporate CSRHLD Figure Templates v3.2 E1 
  
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
89 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
plot: while on treatment 
(Full analysis set) 
Figure 14.2.1.2 
Time to first 
COPDCompEx event 
(days), Kaplan-Meier 
plot: treatment policy – 
Supportive analysis (Full 
analysis set) 
AZ Corporate CSRHLD Figure Templates v3.2 E1 
  
no 
Figure 14.2.1.3 
Time to first 
COPDCompEx event 
(days), diagnostic plot 
(log-log): while on 
treatment (Full analysis 
set) 
AZ Corporate CSRHLD Figure Templates v3.2 E1 
  
no 
Figure 14.2.1.4 
Time to first 
COPDCompEx event 
(days), diagnostic plot 
(log-log): treatment 
policy – Supportive 
analysis (Full analysis 
set) 
AZ Corporate CSRHLD Figure Templates v3.2 E1 
  
no 
14.2.2 - Secondary efficacy 
Table 14.2.2.1 
Summary for time to first 
COPD exacerbation 
event: while on treatment 
(Full analysis set) 
AZ_Corporate_Table_Templates_20220408 AZTEF06 
The following results 
will be displayed at 
Weeks 4, 12, 18 and 24: 
  - The number of 
patients at risk 
  - the number of 
censored patients 
  - the number of events  
  - Kaplan-Meier 
estimates and CI 
 
Add the log-rank test. 
Yes 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
90 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.2.2.2 
Hazard ratio for time to 
first COPD exacerbation 
event: while on treatment 
(Full analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF10 
Remove the following 
columns: 
  - Median time to event 
  - Time to percentile 
  - P-value 
Yes 
Table 14.2.2.3 
Summary by visit for 
post-BD FEV1: while on 
treatment (Full analysis 
set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF06 
  
no 
Table 14.2.2.4 
Mean change from 
baseline in post-BD 
FEV1 through Week 24: 
while on treatment (Full 
analysis set) 
AZ_Corporate_Table_Templates_20220408 AZTEF01 
Remove the following 
<<Variables>> columns 
no 
Table 14.2.2.5 
Summary by visit for 
respiratory symptoms: 
while on treatment (Full 
analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF06 
Include in "Page by 
values" the following 
parameters: 
EXACT - total 
EXACT - 
breathlessness 
EXACT - cough & 
sputum 
EXACT - chest 
symptoms 
BCSS - total 
BCSS - breathlessness 
BCSS - sputum 
BCSS - cough 
Cough VAS 
no 
Table 14.2.2.6 
Mean change from 
baseline in respiratory 
symptoms through Week 
24: while on treatment 
(Full analysis set) 
AZ_Corporate_Table_Templates_20220408 AZTEF01 
  
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
91 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.2.2.7 
Summary by visit for 
total CAT measured in 
clinic: while on treatment 
(Full analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF06 
  
no 
Table 14.2.2.8 
Mean change from 
baseline in total CAT 
measured in clinic at 
Week 12 and Week 24: 
while on treatment (Full 
analysis set) 
AZ_Corporate_Table_Templates_20220408 AZTEF01 
Remove the following 
<<Variables>> columns 
no 
Table 14.2.2.9 
Proportion of participants 
with change from 
baseline of -2 or less total 
CAT measured in clinic 
at week 12: while on 
treatment (Full analysis 
set) 
AZ_Corporate_Table_Templates_20220408 AZTBL1b 
  
no 
Table 14.2.2.10 
Summary by visit for 
post-BD FEV1: treatment 
policy - Supportive 
analysis (Full analysis 
set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF06 
  
no 
Table 14.2.2.11 
Mean change from 
baseline in post-BD 
FEV1 through Week 24: 
treatment policy - 
Supportive analysis (Full 
analysis set) 
AZ_Corporate_Table_Templates_20220408 AZTEF01 
Remove the following 
<<Variables>> columns 
no 
Figure 14.2.2.1 
Time to first moderate or 
severe COPD 
exacerbation (days), 
Kaplan- Meier plot: 
while on treatment (Full 
analysis set) 
AZ Corporate CSRHLD Figure Templates v3.2 E1 
  
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
92 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Figure 14.2.2.2 
Time to first COPD 
exacerbation event 
(days), diagnostic plot 
(log-log): while on 
treatment (Full analysis 
set) 
AZ Corporate CSRHLD Figure Templates v3.2 E1 
  
no 
Figure 14.2.2.3 
Change from Baseline in 
post-BD FEV1 measured 
in the clinic through 
Week 12, MMRM - 
forest plot by subgroup: 
while on treatment (Full 
analysis set) 
AZ Corporate CSRHLD Figure Templates v3.2 E5 
Use the subgroups 
defined in the SAP. 
no 
Figure 14.2.2.4 
Change from Baseline in 
EXACT (total and 
domain scores) through 
Week 24, LSMeans: 
while on treatment (Full 
analysis set) 
AZ Corporate CSRHLD Figure Templates v3.2 E6 
  
no 
Figure 14.2.2.5 
Change from Baseline in 
BCSS (total and domain 
scores) through Week 24, 
LSMeans: while on 
treatment (Full analysis 
set) 
AZ Corporate CSRHLD Figure Templates v3.2 E6 
  
no 
Figure 14.2.2.6 
Change from Baseline in 
cough VAS through 
Week 24, LSMeans: 
while on treatment (Full 
analysis set) 
AZ Corporate CSRHLD Figure Templates v3.2 E6 
  
no 
Figure 14.2.2.7 
Change from Baseline in 
total CAT measured in 
clinic through Week 12, 
LSMeans: while on 
AZ Corporate CSRHLD Figure Templates v3.2 E6 
  
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
93 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
treatment (Full analysis 
set) 
14.2.3 - Secondary efficacy, PK 
Table 14.2.3.1 
Plasma concentrations 
(nmol/L) of 
AZD4831 over time (PK 
analysis set) 
AZ_Corporate_Table_Templates_20220408 AZTPK02 
  
Yes 
Table 14.2.3.2 
Pharmacokinetic 
parameters of AZD4831 
(PK analysis set) 
AZ_Corporate_Table_Templates_20220408 AZTPK03 
Keep only one column 
for IP. 
Include only the 
parameters provided by 
PK team. 
No 
Figure 14.2.3.1 
Geometric mean (gSD) 
plasma concentration 
(nmol/L) of AZD4831 
versus time (Linear 
scale) (PK analysis set) 
AZ Corporate CSRHLD Figure Templates v3.2 PK2(i) 
  
no 
Figure 14.2.3.2 
Geometric mean (gSD) 
plasma concentration 
(nmol/L) of AZD4831 
versus time (Semi-
logarithmic scale) (PK 
analysis set) 
AZ Corporate CSRHLD Figure Templates v3.2 PK2(i) 
  
no 
Figure 14.2.3.3 
Combined individual 
plasma concentrations 
(nmol/L) of AZD4831 
versus time (Linear 
scale) (PK analysis set) 
AZ Corporate CSRHLD Figure Templates v3.2 PK3 
Individual --> 
Combined (in order to 
have several patient on a 
same plot)Added to 
cover the semi-
logarithmic scale 
no 
Figure 14.2.3.4 
Combined individual 
plasma concentrations 
(nmol/L) of AZD4831 
versus time (Semi-
AZ Corporate CSRHLD Figure Templates v3.2 PK3 
Individual --> 
Combined (in order to 
have several patient on a 
same plot) 
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
94 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
logarithmic scale) (PK 
analysis set) 
Added to cover the 
semi-logarithmic scale 
Figure 14.2.3.5 
Individual plasma 
concentrations (nmol/L) 
of AZD4831 versus time 
(Linear scale) (PK 
analysis set) 
AZ Corporate CSRHLD Figure Templates v3.2 PK1 
  
no 
Figure 14.2.3.6 
Individual plasma 
concentrations (nmol/L) 
of AZD4831 versus time 
(Semi-logarithmic scale) 
(PK analysis set) 
AZ Corporate CSRHLD Figure Templates v3.2 PK1 
  
no 
14.2.4 - Tertiary/exploratory efficacy 
Table 14.2.4.1 
Summary by visit for 
average cough frequency: 
treatment policy (Cough 
subset) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF06 
Include in "Page by 
values" the following 
parameters: 
  - waking 
  - sleeping 
  - 24h 
no 
Table 14.2.4.2 
Mean change from start 
of study treatment in 
average cough frequency 
after Week 12: treatment 
policy (Cough subset) 
AZ_Corporate_Table_Templates_20220408 AZTEF01 
Include in "Page by 
values" the following 
parameters: 
  - waking 
  - sleeping 
  - 24h 
no 
Table 14.2.4.3 
Summary by visit for 
spirometry: treatment 
policy (Full analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF06 
  
no 
Table 14.2.4.4 
Mean change from 
baseline in spirometry 
through Week 24: 
AZ_Corporate_Table_Templates_20220408 AZTEF01 
Remove the following 
<<Variables>> columns 
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
95 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
treatment policy (Full 
analysis set) 
Table 14.2.4.5 
Summary of sputum 
MPO activity normalised 
to sputum MPO 
concentration: treatment 
policy (Full analysis set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF06 
Only one variable to be 
analyzed.  
no 
Table 14.2.4.6 
Mean change from 
baseline in sputum MPO 
activity normalised to 
sputum MPO 
concentration to Week 
12: treatment policy (Full 
analysis set) 
AZ_Corporate_Table_Templates_20220408 AZTEF01 
Only one variable to be 
analyzed.  
no 
Table 14.2.4.7 
COPDCompEx recurrent 
event rates over the 
period from baseline , 
negative binomial 
regression: while on 
treatment (Full analysis 
set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF03 
 
Yes 
Table 14.2.4.8 
COPD exacerbation 
recurrent event rates over 
the period from baseline , 
negative binomial 
regression: while on 
treatment (Full analysis 
set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIEF03 
 
Yes 
Figure 14.2.4.1 
Box-plot of waking 
cough frequency by 
study intervention group 
and timepoint (Cough 
subset) 
AZ Corporate CSRHLD Figure Templates v3.2 PK5 
4 boxplots in total:  - 2 
arms  - 2 timepoints 
(Baseline + Week 12) 
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
96 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Figure 14.2.4.2 
Box-plot of sleeping 
cough frequency by 
study intervention group 
and timepoint (Cough 
subset) 
AZ Corporate CSRHLD Figure Templates v3.2 PK5 
4 boxplots in total: 
  - 2 arms 
  - 2 timepoints 
(Baseline + Week 12) 
no 
Figure 14.2.4.3 
Box-plot of 24h cough 
frequency by study 
intervention group and 
timepoint (Cough subset) 
AZ Corporate CSRHLD Figure Templates v3.2 PK5 
4 boxplots in total: 
  - 2 arms 
  - 2 timepoints 
(Baseline + Week 12) 
no 
14.3 - SAFETY 
14.3.1 - Drug exposure 
Table 14.3.1.1 
Duration of exposure 
(Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTEX01 
To be included:  - 
Duration in days  - 
Cumulative categories 
by every 28th day, from 
Day 1 to Day 168  - 
Total time of exposure 
Yes 
Table 14.3.1.2 
Exposure as measured by 
amount administered 
(Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTEX02 
Include the Total 
amount of doses 
received. 
no 
Figure 14.3.1.1 
Exposure over time 
(Safety Set) 
AZ Corporate CSRHLD Figure Templates v3.2 S1 
  
no 
14.3.2 - Adverse events 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
97 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.3.2.1 
Overall summary of 
adverse events (Safety 
set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIAE01 
Include: 
 
  - Any AEs 
  - Any AEs with 
outcome = death 
  - Any SAEs (including 
events with outcome = 
death) 
  - Any AE related to IP 
(as assessed by the 
Investigator) 
  - Any AEs leading to 
discontinuation of IP 
  - Any AEs leading to 
dose interruption 
  - Any AEs leading to 
withdrawal from study 
  - Any AESI 
  - Any pneumonia or 
other serious infection 
  - Any skin reaction 
  - Any maculopapular 
rash 
  - Any non-
maculopapular rash 
  - Any maculopapular 
rash leading to IP 
discontinuation, by 
maximum of CTCAE 
grade and overall 
  - Any non-
maculopapular rash 
leading to IP 
discontinuation, by 
maximum of CTCAE 
grade and overall 
Yes 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
98 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.3.2.2 
Adverse events by 
system organ class and 
preferred term (Safety 
set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIAE02 
Remove: 
  - "n per 100 subject 
years" column 
  - AE row category 
 
Footnote to be updated. 
Yes 
Table 14.3.2.3 
Adverse events sorted by 
decreasing frequency on 
preferred term level in 
AZ total treatment arm 
(frequency of > 5%) 
(Safety set) 
AZ_Corporate_Table_Templates_20220408 AZTAE03 
Preferred terms are 
selected if frequency 
>5% in at least one 
treatment arm. 
no 
Table 14.3.2.4 
Adverse events by 
maximum reported 
intensity on system organ 
class and preferred term 
(Safety set) 
AZ_Corporate_Table_Templates_20220408 AZTAE04 
Remove:  - "n per 100 
subject years" 
columnUse category 
column for maximum 
reported 
intensityFootnote to be 
updated. 
no 
Table 14.3.2.5 
Possibly related adverse 
events by system organ 
class and preferred term 
(Safety set) 
AZ_Corporate_Table_Templates_20220408 AZTAE07 
Remove: 
  - "n per 100 subject 
years" column 
  - AE row category 
 
Footnote to be updated. 
no 
Table 14.3.2.6 
Possibly related adverse 
events by maximum 
intensity and system 
organ class and preferred 
term (Safety set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIAE04 
Remove: 
  - "n per 100 subject 
years" column 
 
Use category column 
for maximum reported 
intensity 
 
Footnote to be updated. 
no 
14.3.3 - Deaths 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
99 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.3.3.1 
Serious adverse 
events with outcome 
death by system organ 
class and preferred term 
(Safety set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIAE02 
Remove: 
  - "n per 100 subject 
years" column 
  - AE row category 
 
Footnote to be updated. 
Yes 
Table 14.3.3.2 
Serious adverse events 
with outcome death – 
Key subject information 
(Safety set) 
AZ_Corporate_Table_Templates_20220408 AZTAE13 
  
Yes 
14.3.4 - Serious adverse events 
Table 14.3.4.1 
Serious adverse 
events by system organ 
class and preferred term 
(Safety set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIAE02 
Remove: 
  - "n per 100 subject 
years" column 
  - AE row category 
 
Footnote to be updated. 
Yes 
Table 14.3.4.2 
Possibly related serious 
adverse events by system 
organ class and preferred 
term (Safety set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIAE02 
Remove: 
  - "n per 100 subject 
years" column 
  - AE row category 
 
Footnote to be updated. 
no 
Table 14.3.4.3 
Serious adverse events – 
Key subject information 
(Safety set) 
AZ_Corporate_Table_Templates_20220408 AZTAE17 
  
Yes 
14.3.5 - Discontinuation of investigational product due to adverse events 
Table 14.3.5.1 
Adverse events leading 
to discontinuation of 
investigational 
product by system organ 
class and preferred term 
(Safety set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIAE02 
Remove:  - "n per 100 
subject years" column  - 
AE row 
categoryFootnote to be 
updated. 
Yes 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
100 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.3.5.2 
Adverse events leading 
to discontinuation of 
investigational product - 
Key subject information 
(Safety set) 
AZ_Corporate_Table_Templates_20220408 AZTAE19 
  
Yes 
14.3.6 - Other significant adverse events 
Table 14.3.6.1 
Adverse events of special 
interest - mapping  
AZ_Corporate_Table_Templates_20220408 AZTAE20 
  
no 
Table 14.3.6.2 
Adverse events of special 
interest by category and 
preferred term (Safety 
Set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIAE03 
  
Yes 
Table 14.3.6.3 
Adverse events of special 
interest – Key subject 
information (Safety Set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIAE06 
  
Yes 
Table 14.3.6.4 
Serious adverse events of 
special interest by 
category and preferred 
term (Safety Set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIAE03 
  
no 
Table 14.3.6.5 
Adverse events of special 
interest by maximum 
intensity grade on 
category class and 
preferred term (Safety 
Set) 
AZ_Corporate_Table_Templates_20220408 AZTAE04 
  
no 
Table 14.3.6.6 
Serious adverse events of 
special interest by 
maximum reported 
intensity on category 
class and preferred term 
(Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTAE04 
  
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
101 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.3.6.7 
Skin reactions by 
CTCAE grade on 
category class and 
preferred term (Safety 
Set) 
AZ_Corporate_Table_Templates_20220408 AZTAE04 
  
Yes 
Table 14.3.6.8 
Serious skin reactions by 
CTCAE grade on 
category class and 
preferred term (Safety 
Set) 
AZ_Corporate_Table_Templates_20220408 AZTAE04 
  
no 
Table 14.3.6.9 
Time to onset to First 
Maculopapular rash 
(Safety Set) 
AZ Oncology TA TFL Templates v3.1 TAE300 
  
no 
Table 14.3.6.10 
Adverse events – Key 
subject information - 
Patients with at least one 
test sequence suggestive 
of Orthostatic 
hypotension (Safety Set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIAE06 
  
no 
Table 14.3.6.11 
Adverse events – Key 
subject information - 
Patients with at least two 
test sequence suggestive 
of Orthostatic 
hypotension (Safety Set) 
AZ_Respiratory_Immunology_Table_Templates_20220405 
AZTRIAE06 
  
no 
Figure 14.3.6.1 
Box-plot of Time to 
onset to First 
Maculopapular rash 
(Safety Set) 
AZ Corporate CSRHLD Figure Templates v3.2 PK5 
  
no 
14.3.7 - Laboratory 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
102 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.3.7.1 
Haematology results over 
time (Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTLB01 
Include: 
  - Q1 and Q3 
  - Change from baseline 
 
Use <<Page by 
values>> for each 
parameter 
no 
Table 14.3.7.2 
Haematology 
abnormalities by 
predefined criteria 
(Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTLB03 
See Table 10 for 
parameters to be 
included and 
abnormality criteria 
Yes 
Table 14.3.7.3 
Haematology 
abnormalities by 
predefined criteria - Key 
subject information 
(Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTLB04 
  
no 
Table 14.3.7.4 
Chemistry results over 
time (Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTLB06 
Include:  - Q1 and Q3  - 
Change from 
baselineUse <<Page by 
values>> for each 
parameter 
no 
Table 14.3.7.5 
Chemistry abnormalities 
by predefined criteria 
(Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTLB08 
See Table 10 for 
parameters to be 
included and 
abnormality criteria 
Yes 
Table 14.3.7.6 
Chemistry abnormalities 
by predefined criteria - 
Key subject information 
(Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTLB09 
  
no 
Table 14.3.7.7 
Coagulation results at 
Screening (Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTLB06 
Include: 
  - Q1 and Q3 
 
Use <<Page by 
values>> for each 
parameter 
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
103 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.3.7.8 
Maximum on-treatment 
ALT and AST versus 
maximum on-treatment 
total bilirubin (Safety 
Set) 
AZ_Corporate_Table_Templates_20220408 AZTLB11 
  
no 
Table 14.3.7.9 
Potential Hy’s law – Key 
subject information 
(Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTLB12 
  
no 
Table 14.3.7.10 
Thyroid function results 
over time (Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTLB06 
Include: 
  - Q1 and Q3 
  - Change from baseline 
 
Use <<Page by 
values>> for each 
parameter 
no 
Table 14.3.7.11 
Thyroid abnormalities by 
predefined criteria 
(Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTLB08 
See Table 11 for 
parameters to be 
included and 
abnormality criteria 
Yes 
Table 14.3.7.12 
Thyroid abnormalities by 
predefined criteria - Key 
subject information 
(Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTLB09 
  
no 
Figure 14.3.7.1 
ALT versus total 
bilirubin, expressed as 
multiples of ULN (Safety 
Set) 
AZ Corporate CSRHLD Figure Templates v3.2 S9 
  
no 
Figure 14.3.7.2 
AST versus total 
bilirubin, expressed as 
multiples of ULN (Safety 
Set) 
AZ Corporate CSRHLD Figure Templates v3.2 S9 
  
no 
Figure 14.3.7.3 
Liver biochemistry test 
results over time - 
subjects with elevated 
ALT or AST, and 
AZ Corporate CSRHLD Figure Templates v3.2 S10 
  
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
104 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
elevated total bilirubin 
(Safety Set) 
14.3.8 - Vital signs 
Table 14.3.8.1 
Vital sign results over 
time (Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTVS01 
Include: 
  - Q1 and Q3 
  - Change from baseline 
 
Use <<Page by 
values>> for each 
parameter 
no 
Table 14.3.8.2 
Vital sign abnormalities 
by predefined criteria 
(Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTVS03 
Abnormality criteria are 
defined by Low and 
High, based on Lower 
and Higher limits values 
for each parameter. 
Yes 
Table 14.3.8.3 
Vital sign shift from 
baseline to maximum on-
treatment value (Safety 
Set) 
AZ_Corporate_Table_Templates_20220408 AZTVS05 
The categories are:Low 
< Normal < High 
no 
Table 14.3.8.4 
Vital sign abnormalities 
by predefined criteria - 
Key subject information 
(Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTVS04 
  
no 
Table 14.3.8.5 
Summary of orthostatic 
hypotension related 
measurements (Safety 
Set) 
AZ_Corporate_Table_Templates_20220408 AZTVS03 
For parameter/Criteria 
are : 
  - BP decrease 
  - BP decrease reported 
as an AE 
 
Add a column for the 
timepoints : 
  - Post first dose 
  - Only post first dose 
  - Week 12 
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
105 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Table 14.3.8.6 
Orthostatic blood 
pressure decrease - Key 
subject information 
(Safety set) 
AZ_Corporate_Table_Templates_20220408 AZTVS04 
This listing will include 
: 
  - Age, gender, race 
  - The number of 
positive sequences at 
the following 
timepoints: 
    - Day 1 pre-dose 
    - Day 1 post-dose 
    - Week 12 
no 
14.3.9 - ECG 
Table 14.3.9.1 
Electrocardiogram results 
over time (Safety Set) 
AZ_Corporate_Table_Templates_20220408 AZTEC01 
Include: 
  - Q1 and Q3 
  - Change from baseline 
 
Use <<Page by 
values>> for each 
parameter 
Yes 
APPENDIX 
Appendix 16.1.1 
Subjects receiving the 
various batches of 
investigational products  
AZ Corporate CSRHLD Listing Templates v1.5 APL22 
  
no 
Appendix 16.1.2 
Randomisation scheme 
and codes (Randomised 
set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL23 
  
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
106 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Appendix 16.2.1.1 
Discontinued subjects 
(Randomised set) 
AZ Corporate CSRHLD Listing Templates v1.5 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 
• Randomisation 
• Study discontinued 
due to <<insert reason 
for discontinuation from 
EOS form in lower case, 
e.g. adverse event >> 
no 
Appendix 16.2.1.2 
Subjects completing the 
study (Randomised set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL02 
Optional.Standardised 
disposition terms should 
include:• Informed 
consent obtained• 
Randomisation• Study 
completed 
no 
Appendix 16.2.1.3 
Subjects affected by the 
COVID-19 pandemic 
(Screened set) 
AZ Corporate Pandemic CSRHLD Table and Listing 
Templates v1.3 APL-COVID1 
This listing is to satisfy 
the FDA Guidance 
which requires A listing 
of all participants 
affected by the COVID-
19 related study 
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
107 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
disruption by unique 
subject number 
identifier and by 
investigational site, and 
a description of how the 
individual’s 
participation was 
altered. 
Appendix 16.2.1.4 
Adverse events in 
patients reporting 
COVID-19 AEs (Safety 
set) 
AZ Respiratory Pandemic CSRHLD Table and Listing 
Templates v1.0 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. 
no 
Appendix 16.2.1.5 
Subjects affected by the 
global/country situation  
AZ Corporate CSRHLD Listing Templates v1.5 APL24 
  
no 
Appendix 16.2.1.6 
Subjects affected by the 
global/country situation - 
details  
AZ Corporate CSRHLD Listing Templates v1.5 APL25 
  
no 
Appendix 16.2.2 
Subjects with important 
protocol deviations (Full 
analysis set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL03 
Sort this listing by: 
Short subject identifier, 
Description of planned 
arm, Date/Time of 
collection. 
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
108 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Appendix 16.2.3 
Subjects excluded from 
any analysis set 
(Screened set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL04 
Sort this listing by: 
Short subject identifier, 
Description of planned 
arm. Add column for 
Description of Actual 
arm. 
no 
Appendix 16.2.4 
Demographic and 
baseline characteristics 
(Full analysis set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL06 
Sort this listing by: 
Short subject identifier, 
Description of planned 
arm. Add column for 
Description of Actual 
arm. 
no 
Appendix 16.2.4.2.1 
Lung function data at 
screening (Full analysis 
set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL07 
 
no 
Appendix 16.2.4.2.2 
Lung function data at 
baseline (Full analysis 
set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL07 
  
no 
Appendix 16.2.4.2.3 
Inhaled tobacco usage 
(Full analysis set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL07 
  
no 
Appendix 16.2.4.3 
Concomitant medication 
on entry and during the 
study (Randomised set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL08 
  
no 
Appendix 16.2.5 
Administration of 
investigational product 
(Safety set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL09 
Sort this listing by: 
Short subject identifier, 
Description of planned 
arm, Date first dose 
(and/or Administration 
time, if relevant). 
Columns in the example 
listing presenting data 
that are not collected or 
derived can be 
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
109 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
excluded. The listing 
should be adjusted 
according to the 
administration data 
collected and the type of 
study/treatment. 
Appendix 16.2.6.1.1 
Individual efficacy 
response data - 
COPDCompEx events 
(Full analysis set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL10 
Sort this listing by: 
Short subject identifier, 
Description of planned 
arm. Add column for 
Description of Actual 
arm. 
no 
Appendix 16.2.6.1.2 
Individual efficacy 
response data - COPD 
exacerbations (Full 
analysis set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL10 
Sort this listing by: 
Short subject identifier, 
Description of planned 
arm. Add column for 
Description of Actual 
arm. 
no 
Appendix 16.2.6.1.3 
Efficacy assessment(s) - 
Spirometry measured 
face to face (Full analysis 
set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL11 
Drop “Site of 
assessment” and 
“Method of assessment” 
columns. 
“Parameter” are: 
  - absolute and % 
predicted (as applicable) 
PEF 
  - FEV1 
  - FVC 
  - FEV1/FVC 
  - forced mid-expiratory 
flow (FEF25-75%) 
  - FEV1 and FVC % 
predicted, 
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
110 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
  - forced inspiratory 
vital capacity 
Appendix 16.2.6.1.4 
Efficacy assessment(s) - 
Respiratory symptoms 
(Full analysis set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL11 
Drop “Site of 
assessment” and 
“Method of assessment” 
columns.“Parameter” 
are: EXACT - 
totalEXACT - 
breathlessnessEXACT - 
cough & 
sputumEXACT - chest 
symptomsBCSS - 
totalBCSS - 
breathlessnessBCSS - 
sputumBCSS - 
coughCough VAS 
no 
Appendix 16.2.6.1.5 
Efficacy assessment(s) - 
CAT (Full analysis set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL11 
  
no 
Appendix 16.2.6.1.6 
Efficacy assessment(s) - 
Cough measures (Cough 
subset) 
AZ Corporate CSRHLD Listing Templates v1.5 APL11 
Include 24h, waking and 
sleeping cough 
frequencies 
no 
Appendix 16.2.6.1.7 
Efficacy assessment(s) - 
Sputum MPO activity 
normalised to sputum 
MPO concentration (Full 
analysis set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL11 
Sort this listing by: 
Short subject identifier, 
date/time and test. 
no 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
111 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Appendix 16.2.6.2.1 
Individual plasma 
AZD4831 concentrations 
(<UNIT>) (PK analysis 
set)  
AZ Corporate CSRHLD Listing Templates v1.5 APL30 
Sort this listing by: 
Short subject identifier 
and date/time. 
Yes 
Appendix 16.2.6.2.2 
Individual AZD4831 
pharmacokinetic 
parameters for each study 
intervention group (PK 
analysis set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL28 
Sort this listing by: 
Short subject identifier, 
date/time and 
parameter. 
no 
Appendix 16.2.7.1 
Adverse events (Safety 
set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL14 
Include all AEs 
Sort this listing by: 
Short subject identifier, 
AE start date. 
Yes 
Appendix 16.2.7.2 
Adverse events, skin 
reaction/rash (Safety set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL14 
Sort this listing by: 
Short subject identifier, 
AE start date. 
Yes 
Appendix 16.2.8 
Individual laboratory 
measurement (Safety set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL16 
Sort this listing by: 
Short subject identifier, 
Lab test, Analysis visit, 
planned time point 
name. 
Yes 
Appendix 16.2.9 
Individual vital signs 
data (Safety set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL18 
Sort this listing by: 
Short subject identifier, 
test, Analysis visit, 
planned time point 
name. 
Yes 
Appendix 16.2.10.1 
Electrocardiogram data 
(Safety set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL19 
Sort this listing by: 
Short subject identifier, 
test, Analysis visit, 
planned time point 
name. 
Yes 
Appendix 16.2.10.2 
Abnormalities in 
electrocardiogram 
(Safety set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL20 
  
Yes 


STATISTICAL ANALYSIS PLAN 
AstraZeneca 
D6582C00001 –5.0 04Oct2024 
CONFIDENTIAL AND PROPRIETARY 
112 of 112 
TFL number 
Title 
Standard mock shell reference 
Additional 
Information 
IA 
Appendix 16.2.11 
Weight, Height and BMI 
(Safety set) 
AZ Corporate CSRHLD Listing Templates v1.5 APL21 
  
Yes