A Randomized, Double-blind, Placebo-controlled, Parallel Group, Multicenter Phase 2a Study to Explore the Efficacy and Safety of Tezepelumab in Patients With Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) (COURSE)
Phase: PHASE2
Conditions: Chronic Obstructive Pulmonary Disease (COPD)
Sponsor: AstraZeneca

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Clinical Study Protocol 
Study Intervention
Tezepelumab
Study Code
D5241C00001
Version
7.0
Date
18-Oct-2022
EudraCT/EU CT 
Number
2019-001363-67
A Randomized, Double-blind, Placebo-controlled, Parallel Group, 
Multicenter, Phase 2a Study to Explore the Efficacy and Safety of 
Tezepelumab in Patients with Moderate to Very Severe Chronic Obstructive 
Pulmonary Disease (COPD) (COURSE)
Sponsor Name: AstraZeneca AB
Legal Registered Address: 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s):
IND number: 103031
EudraCT number: 2019-001363-67
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.
Redacted for Public Disclosure

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Version Scope: Global version 7.0, 18 October 2022
Amendment Number: 6.0
Study Intervention: Tezepelumab
Study Phase: 2a
Short Title: Tezepelumab COPD Exacerbation study
Acronym: COURSE
Study Clinical Lead is responsible for the clinical integrity of the study (for example, the 
study physician or scientist).
Study Physician Name and Contact Information will be provided separately
International Co-ordinating Investigator:
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 6.0
18-Oct-2022
Amendment 5.0 
21-Mar-2022
Amendment 4.0
15-Mar-2021
Amendment 3.0
11-Aug-2020
Amendment 2.0
26-May-2020
Amendment 1.0
16-Dec-2019
Original Protocol
03-May-2019
Amendment 6.0 (18-Oct-2022)
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, 3 (13) because it might impacts the safety of 
participants and the scientific value of the study.
Overall Rationale for the Amendment:
The main reason for this amendment is to update the important potential risks and adverse 
events of special interests (AESI) to align with Investigator’s Brochure (IB) Edition 5.1 (dated 
22 July 2022), as well as, to update the scope of the Independent Adjudication Committee 
assessment.
Other changes are minor and non-substantial, including alignment with regulatory trial 
requirements, correcting typos, among others.
Section # and 
Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
Protocol title and 
Section 1.2
Synopsis 
Added EudraCT/EU CT Number 
to Title and Synopsis page.
To align with regulatory 
requirements related to 
Clinical Trial Transparency 
(CTT) language.
Non-substantial
Section 1.1
Schedule of 
activities, Table 
1 and Section 6.5
Concomitant 
Therapy, Table 6
Restriction for inactive/killed 
vaccinations (e.g. inactive 
influenza vaccine) revised from 
within 7 days to 5 days before or 
after any IP dosing.
To align with IB Edition 5.1.
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
Section 1.2
Synopsis, 
Independent 
Adjudication 
Committee and 
Section 8.4.7
Independent 
Adjudication 
Committee
The scope of the IAC changed.
Added serious cardiac events as 
an event requiring adjudication.
Added that the IAC will assess 
whether there is a causal 
relationship between IP use and 
MACE events, serious cardiac 
events, and deaths.
To update the scope of the 
IAC assessment to align with
IB Edition 5.1.
Substantial
Section 2.3
Benefit/Risk 
Assessment, 
Table 3 – Risk 
Assessment
New Table 3 – Risk Assessment:
“Important potential risks” 
added including serious 
infections, malignancies, and 
serious cardiac events; “Potential 
risks" added including serious 
hypersensitivity reactions, and 
helminth infections; “Study 
procedures” added including 
COVID 19. The rationale for 
risk and mitigation strategy is 
provided for all risks in Table 3.
To align with IB Edition 5.1.
Substantial
Section 4.1
Overall design, 
and Section 9.6
Interim Analyses
Revised data cut off  for the 
second interim analysis from 3 
months to approximately 1 
month after Last Subject 
Randomized.
The second interim analysis 
period was shortened as a 
sufficient amount of data will 
be available 1 month after the 
Last Subject Randomized.
Non-substantial
Section 4.4 End-
of-study
Added the End of Study 
Definition under FDA and EU 
requirements.
To align with regulatory 
requirements related to 
Clinical Trial Transparency 
(CTT) language.
Non-substantial
Section 5.1
Inclusion criteria
Updated Criterion#11: ‘Subjects 
on theophylline or roflumilast 
prior to Visit 1…’ by adding 
“Note”.
To clarify the check of the 
blood concentration levels of 
theophylline is a 
recommendation, not an 
inclusion criterion.
Non-substantial
Section 5.2
Exclusion 
criteria, Section 
8.1.2.1 General 
requirements, 
and section 
8.2.11.2 SARS-
Cov-2 testing
Updated Criterion #39: ‘SARS-
COV-2 test during the study 
conduct’ by adding alternative 
test (approved by local health 
authorities).
Related sections were updated 
for consistency.
To allow alternative tests 
approved by local health 
authorities to confirm SARS-
COV-2 infection.
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
Section 6.5
Concomitant 
Therapy,
Table 6
Added COVID-19 vaccination 
based on the existing section 
8.2.10. The COVID-19 
vaccination restriction has not 
been changed.
To align with section 8.2.10 
where all this information was 
in the previous CSP version.
Non-substantial
Section 8.1.1.1
Severity of 
COPD 
Exacerbation
Severe COPD exacerbation 
definition was clarified. 
Following two bullet points in 
this section… (severe)

“Hospitalization due to the 
COPD exacerbation

The subject been admitted 
for ≥ 24 hours to an 
observation area, the 
emergency department, or 
other equivalent healthcare 
facility (depending on the 
country and healthcare 
system) for the COPD 
exacerbation”
…were merged in a single bullet 
point with the following
wording:

“Hospitalization defined as 
inpatient admission for ≥ 24 
hours to an observation area, 
the emergency department, 
or other equivalent 
healthcare facility 
(depending on the country 
and healthcare system) for 
the COPD exacerbation.”
To clarify the definition of 
severe COPD exacerbation.
Non-substantial
Section 8.3.7.1
Adverse Events 
of Pneumonia 
Requiring a 
Confirmed 
Diagnosis
Amended wording to clarify the 
severe infection pages in eCRFs 
must be completed for infections 
which are defined as SAE, or 
requiring treatment with 
systemic antiviral medications, 
intravenous antibiotics, or 
medications for helminth 
parasitic infection or requiring a 
permanent discontinuation of 
study drug.
To clarify reporting rules for 
pneumonia in eCRFs and align 
with section 8.3.8.
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
Section 8.3.8
Adverse Events 
of Special 
Interest
Added new AESI: ‘Serious 
cardiac events’.
Removed “Injection Site 
reactions”.
Replaced “Anaphylactic 
reactions” and “Immune 
complex disease (Type III 
hypersensitivity reactions)” with 
“Serious hypersensitivity 
reactions”.
Replaced “Severe infections”
and “Opportunistic infections”
with “Serious infections”, and 
added a footnote clarifying when 
to complete the eCRF Severe 
infection pages.
To align with IB Edition 5.1, 
and to ensure consistent 
reporting in the eCRF.
Substantial
Section 8.3.10
Medical Devices 
Deficiencies
Removed “and with third party 
medical devices”.
Replaced bullet points 
- “Device constituent parts of the 
tezepelumab combination 
product
- the AstraZeneca medical 
device complaint report will be 
used to collect the deficiency.’
with ‘The AstraZeneca Clinical 
Study Medical Device/Device 
Constituent Report Form and/or 
Product Complaint Intake Form 
will be used to collect the 
deficiency.”
To clarify that as only device 
constituents of combination 
products are provided for use 
in the study and to align with 
Appendix J.
To clarify the device 
constituent deficiency 
reporting instructions (aligned 
with the Pharmacy Manual).
Non-substantial
Section 8.3.10.3 
Prompt 
Reporting of 
Medical Device 
Deficiencies to 
Sponsor 
Added two bullet points: 
- “The AstraZeneca Clinical 
Study Medical Device/Device 
Constituent Report Form and/or 
Product Complaint Intake Form 
will be sent to AstraZeneca by 
email.”
- “Where an SAE has occurred 
in addition to the malfunction, 
the SAE will be recorded in the 
eCRF as detailed in Section 
8.4.1.”
To clarify the device 
constituent deficiency 
reporting instructions (Aligned 
with the Pharmacy Manual).
To amend instructions on 
reporting to specify use of the 
AstraZeneca Clinical Study 
Medical Device/Device 
Constituent Report Form 
and/or Product Complaint 
Intake Form and to remove 
email addresses.
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
Deleted bullet points:
- “The AstraZeneca Report Form 
will be sent to the sponsor via 
email.
- Medical Device 
Deficiency with an 
associated SAE
-
AEMailboxClinicalTria
lTCS@astrazeneca.com
-
gsqincomingcomplaints
@astrazeneca.com
NOTE: For SAE’s, the eCRF 
must also be populated - see 
Section 8.4.1.
- Medical Device 
Deficiency with an 
associated AE
-
gsqincomingcomplaints
@astrazeneca.com
- Medical Device 
Deficiency without an 
associated adverse or 
serious adverse event
-
GCSCProductComplain
tOriginators@astrazene
ca.com”
Section 8.4.4
Medication 
Error, Drug 
Abuse and Drug
Misuse, and 
Appendix B 8
Added definition and timelines 
for reporting drug abuse and 
drug misuse. Also, added the 
definition of  medication error to 
align with Appendix B.8
To align with EU regulatory 
trials regulations.
Non-substantial
Appendix A 1
Added wording related to 
regulatory requirements for 
Serious Breaches.
To align with EU regulatory 
trials regulations.
Non-substantial
Appendix A 6
Added requirements and 
timelines to submit clinical 
results to EU Clinical Trial 
Information System (CTIS).
To align with regulatory 
requirements related to 
Clinical Trial Transparency 
(CTT) language.
Non-substantial

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TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.................................... 3
TABLE OF CONTENTS...................................................................................................... 8
1.
PROTOCOL SUMMARY................................................................................ 14
1.1
Schedule of Activities (SoA)............................................................................. 14
1.2
Synopsis ........................................................................................................... 20
1.3
Schema............................................................................................................. 28
2.
INTRODUCTION............................................................................................ 29
2.1
Study Rationale ................................................................................................ 29
2.2
Background ...................................................................................................... 29
2.3
Benefit/Risk Assessment................................................................................... 30
3.
OBJECTIVES AND ENDPOINTS................................................................... 35
4.
STUDY DESIGN ............................................................................................. 40
4.1
Overall Design.................................................................................................. 40
4.2
Scientific Rationale for Study Design ............................................................... 44
4.3
Justification for Dose........................................................................................ 45
4.4
End of Study Definition.................................................................................... 45
5.
STUDY POPULATION ................................................................................... 46
5.1
Inclusion Criteria .............................................................................................. 46
5.2
Exclusion Criteria ............................................................................................. 50
5.3
Lifestyle Restrictions ........................................................................................ 55
5.3.1
Meals and Dietary Restrictions ......................................................................... 55
5.3.2
Alcohol, Tobacco and Other ............................................................................. 55
5.3.3
Activity............................................................................................................. 55
5.4
Screen Failures and Re-screening...................................................................... 55
6.
STUDY TREATMENTS.................................................................................. 58
6.1
Treatments Administered.................................................................................. 58
6.1.1
Investigational Products.................................................................................... 58
6.1.2
Medical Devices ............................................................................................... 59
6.2
Preparation/Handling/Storage/Accountability ................................................... 59
6.3
Measures to Minimise Bias: Randomization and Blinding ................................ 63
6.4
Compliance to IP .............................................................................................. 66
6.5
Concomitant Therapy........................................................................................ 66
6.5.1
Background (Maintenance) Medication............................................................. 75
6.5.2
Other Concomitant Treatment........................................................................... 76
6.5.3
Rescue Medication............................................................................................ 76
6.5.4
Allowed Medications to Treat a COPD Exacerbation........................................ 76

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6.5.5
COPD Medication Restrictions on the Days of Scheduled Spirometry and 
FeNO Visits...................................................................................................... 76
6.5.6
COPD Medication Restrictions at Unscheduled and Exacerbation Visits........... 78
6.5.7
COPD Medication Restrictions at Centre Visits with Scheduled ECG 
Assessment....................................................................................................... 78
6.6
Endobronchial Therapy..................................................................................... 78
6.7
Dose Modification ............................................................................................ 78
6.8
Treatment After the End of the Study................................................................ 78
7.
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL . 79
7.1
Discontinuation of Study Treatment.................................................................. 79
7.1.1
Procedures for Discontinuation of Study Treatment .......................................... 80
7.2
Lost to Follow-Up............................................................................................. 81
7.3
Withdrawal from the Study............................................................................... 82
7.3.1
Withdrawal Due to Recruitment Completion..................................................... 82
7.3.2
Discontinuation or Suspension of entire study and Site Closure ........................ 83
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................. 83
8.1
Efficacy Assessments........................................................................................ 84
8.1.1
COPD Exacerbation Definition......................................................................... 84
8.1.1.1
Severity of COPD Exacerbations ...................................................................... 85
8.1.1.2
Duration of COPD Exacerbations ..................................................................... 85
8.1.1.3
Approach for Capturing COPD Exacerbations .................................................. 86
8.1.1.4
Investigator Justified COPD Exacerbations....................................................... 86
8.1.1.5
COPD Exacerbation visit .................................................................................. 87
8.1.2
Spirometry........................................................................................................ 88
8.1.2.1
General Requirements....................................................................................... 88
8.1.2.2
Post-BD Spirometry.......................................................................................... 90
8.1.2.3
Sputum post-BD spirometry.............................................................................. 91
8.1.3
FeNO................................................................................................................ 91
8.1.4
COPDCompEx ................................................................................................. 92
8.1.5
Clinically Important Deterioration (CID) .......................................................... 92
8.1.6
Patient Reported Outcomes............................................................................... 92
8.1.6.1
Major/Minor Symptom Worsening Assessment and Alert System..................... 93
8.1.6.2
Rescue Medication............................................................................................ 93
8.1.6.3
Nocturnal Awakenings...................................................................................... 94
8.1.6.4
Maintenance Medication................................................................................... 94
8.1.6.5
St. George’s Respiratory Questionnaire (SGRQ)............................................... 94
8.1.6.6
COPD Assessment Test (CAT)......................................................................... 94
8.1.6.7
Exacerbations of Chronic Pulmonary Disease Tool– Patient-reported Outcome 
(EXACT-PRO) and Evaluating Respiratory Symptoms in COPD (E-RS™: 
COPD).............................................................................................................. 95
8.2
Safety Assessments........................................................................................... 95
8.2.1
Clinical Safety Laboratory Assessments............................................................ 95
8.2.1.1
Pregnancy Test ................................................................................................. 97
8.2.2
Smoking Status................................................................................................. 98

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8.2.3
Weight and Height............................................................................................ 98
8.2.4
Physical Examinations...................................................................................... 98
8.2.5
Vital Signs........................................................................................................ 98
8.2.6
ECG99
8.2.7
Supplemental Oxygen (O2) ............................................................................... 99
8.2.8
Oxygen Saturation (SpO2)............................................................................... 100
8.2.9
Chest X-ray .................................................................................................... 100
8.2.10
Vaccination Restrictions ................................................................................. 100
8.2.11
Other Safety Assessments............................................................................... 103
8.2.11.1
Serology ......................................................................................................... 103
8.2.11.2
SARS-CoV-2 testing....................................................................................... 103
8.3
Collection of Adverse Events.......................................................................... 104
8.3.1
Method of Detecting AEs and SAEs ............................................................... 104
8.3.2
Time Period and Frequency for Collecting AE and SAE Information.............. 104
8.3.3
Follow-up of AEs and SAEs ........................................................................... 105
8.3.4
Adverse Event Data Collection ....................................................................... 105
8.3.5
Causality Collection........................................................................................ 106
8.3.6
Adverse Events Based on Signs and Symptoms .............................................. 106
8.3.7
Adverse Events Based on Examinations and Tests.......................................... 106
8.3.7.1
Adverse Events of Pneumonia Requiring a Confirmed Diagnosis ................... 107
8.3.8
Adverse Events of Special Interest.................................................................. 107
8.3.9
Hy’s Law........................................................................................................ 108
8.3.10
Medical Device Deficiencies........................................................................... 108
8.3.10.1
Time Period for Detecting Medical Device Deficiencies................................. 108
8.3.10.2
Follow-up of Medical Device Deficiencies ..................................................... 109
8.3.10.3
Prompt Reporting of Medical Device Deficiencies to Sponsor ........................ 109
8.3.10.4
Regulatory Reporting Requirements for Device Deficiencies.......................... 109
8.4
Safety Reporting and Medical Management.................................................... 110
8.4.1
Reporting of Serious Adverse Events.............................................................. 110
8.4.2
Pregnancy....................................................................................................... 110
8.4.2.1
Maternal Exposure.......................................................................................... 111
8.4.2.2
Paternal Exposure........................................................................................... 111
8.4.3
Overdose ........................................................................................................ 111
8.4.4
Medication Error, Drug Abuse and Drug Misuse............................................. 112
8.4.4.1
Timelines........................................................................................................ 112
8.4.4.2
Medication error ............................................................................................. 112
8.4.4.3
Drug Abuse .................................................................................................... 112
8.4.4.4
Drug Misuse ................................................................................................... 113
8.4.5
Management of IP-related Toxicities .............................................................. 113
8.4.6
Independent Data Monitoring Committee ....................................................... 113
8.4.7
Independent Adjudication Committee............................................................. 114
8.5
Pharmacokinetics............................................................................................ 114
8.5.1
Collection of Samples to Measure Drug Concentration ................................... 114
8.5.2
Collection of Samples to Measure for the Presence of ADAs .......................... 115
8.5.3
Storage and Destruction of Pharmacokinetic/Immunogenicity Samples........... 115
8.6
Pharmacodynamics......................................................................................... 115

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8.7
Genetics.......................................................................................................... 115
8.7.1
Optional Exploratory Genetic Sample............................................................. 115
8.7.2
Storage and Destruction of Genetic Samples................................................... 116
8.8
Biomarkers ..................................................................................................... 116
8.8.1
Storage, Re-use and Destruction of Biomarker Samples.................................. 116
8.8.2
Total Serum Immunoglobulin ......................................................................... 117
8.8.3
Transcriptomics .............................................................................................. 117
8.8.4
Nasal Epithelial Cell and Sputum Cell Transcriptomics .................................. 117
8.8.5
Sputum Induction ........................................................................................... 118
8.8.6
Nasal Lining Fluid .......................................................................................... 119
8.8.7
Urine Biomarkers ........................................................................................... 120
8.9
Healthcare Resource Utilization and Health Economics.................................. 120
9.
STATISTICAL CONSIDERATIONS............................................................. 120
9.1
Statistical Hypothesis...................................................................................... 120
9.2
Sample Size Determination............................................................................. 120
9.2.1
Estimands ....................................................................................................... 121
9.3
Populations for Analyses ................................................................................ 122
9.4
Outcome Measures for Analyses..................................................................... 123
9.4.1
Definition of Baseline and Subject Baseline Analyses..................................... 123
9.4.2
Calculation or Derivation of Efficacy Variables.............................................. 124
9.4.2.1
Exacerbation Rate........................................................................................... 124
9.4.2.2
Proportion of Subjects with ≥ 1 COPD Exacerbation ...................................... 125
9.4.2.3
Time to First Exacerbation.............................................................................. 125
9.4.2.4
Annual Rate of Severe COPD Exacerbations .................................................. 126
9.4.2.5
Forced Expiratory Volume in 1 Second........................................................... 126
9.4.3
Calculation or Derivation of Safety Variables ................................................. 126
9.4.3.1
Safety Variables.............................................................................................. 126
9.4.3.2
Adverse Events............................................................................................... 126
9.4.3.3
Other Significant Adverse Events ................................................................... 127
9.4.3.4
Laboratory Variables ...................................................................................... 127
9.4.3.5
ECGs.............................................................................................................. 128
9.4.3.6
Physical Examination...................................................................................... 128
9.4.3.7
Vital signs....................................................................................................... 129
9.4.4
Calculation or Derivation of PRO variables .................................................... 129
9.4.4.1
SGRQ............................................................................................................. 129
9.4.5
Calculation or Derivation of Pharmacokinetic Variables ................................. 129
9.4.6
Calculation or Derivation of Immunogenicity Variables.................................. 129
9.5
Statistical Analyses......................................................................................... 130
9.5.1
Multiple Testing Procedure............................................................................. 130
9.5.2
Efficacy Analyses........................................................................................... 130
9.5.2.1
Primary Analysis Methods.............................................................................. 130
9.5.2.2
Secondary Analysis Methods.......................................................................... 131
9.5.3
Subgroup Analyses ......................................................................................... 132
9.5.4
Safety Analyses .............................................................................................. 133
9.5.5
Pharmacokinetic and Immunogenicity Analyses ............................................. 133

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9.5.6
Biomarker Analyses........................................................................................ 133
9.6
Interim Analyses............................................................................................. 133
9.6.1
Independent Data Monitoring Committee (IDMC).......................................... 134
10.
REFERENCES............................................................................................... 135
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...................................................................................... 139
APPENDIX A REGULATORY, ETHICAL AND STUDY OVERSIGHT 
CONSIDERATIONS...................................................................................... 139
APPENDIX B ADVERSE EVENT DEFINITIONS AND ADDITIONAL SAFETY 
INFORMATION ............................................................................................ 146
APPENDIX C HANDLING OF HUMAN BIOLOGICAL SAMPLES ............................ 151
APPENDIX D GENETICS.............................................................................................. 154
APPENDIX E ACTIONS REQUIRED IN CASES OF INCREASES IN LIVER 
BIOCHEMISTRY AND EVALUATION OF HY’S LAW.............................. 158
APPENDIX F MAINTENANCE THERAPY EQUIVALENCE TABLE ........................ 163
APPENDIX G ANAPHYLAXIS: SIGNS AND SYMPTOMS, MANAGEMENT........... 164
APPENDIX H ABBREVIATIONS.................................................................................. 168
APPENDIX I
CORONAVIRUS (COVID-19) PANDEMIC GUIDANCE...................... 175
APPENDIX J
MEDICAL DEVICE AES, ADES, SAES, SADES, USADES AND 
MEDICAL DEVICE DEFICIENCIES: DEFINITIONS AND PROCEDURES 
FOR RECORDING, EVALUATING AND FOLLOW-UP............................. 180
APPENDIX K PROTOCOL AMENDMENT HISTORY................................................. 185
LIST OF TABLES
Table 1 – Screening Period – Enrolment, Run-in................................................................. 14
Table 2 – Treatment Period - Randomization, Treatment and Follow-Up ............................ 16
Table 3 – Risk Assessment.................................................................................................. 31
Table 4 - Study Objectives .................................................................................................. 35
Table 5 - Study Treatments ................................................................................................. 58
Table 6 - Allowed, Restricted and Prohibited Medications .................................................. 67
Table 7 - Laboratory Safety Variables................................................................................. 97
Table 8 - COVID-19 Vaccination Guidance...................................................................... 101

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LIST OF FIGURES
Figure 1 - Study Flow Chart................................................................................................ 28
Figure 2 - Suggested Schema of Rotation of Injection Sites................................................. 62
Figure 3 - COVID-19 Vaccination between IP Dosing ...................................................... 102

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1.
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)
Table 1 – Screening Period – Enrolment, Run-in 
Assessment/Activity
Screening
Details in CSP Section or 
Appendix
Enrolment
Run-in
Visit
1a
2a
Day
-42 to -35
-35
Visit Window (days)
0
+/- 4b
Pre-visit Assessments 
Telephone assessment of possible COVID-19  
symptoms k
X
X
Section 4.1 and Appendix I
Study Procedures
Informed Consent Form (ICF) and addendum to ICF 
(sputum/nasal sub-studies) (if applicable)
X
Section 5.1
COVID-19 addendum to ICF (if applicable) m
X
Appendix A 3 and Appendix I
Inclusion/exclusion criteria
X
X
Section 5.1 and 5.2
Demography
X
Section 5.1
Medical, Surgical and COPD history
X
Section 5.1
Concomitant medication
X
X
Section 6.5
Adverse events
X
X
Section 8.3 and Appendix B
Assessment of COPD exacerbation
X
X
Section 8.1.1
Smoking status
X
X
Section 8.2.2
Fractional Exhaled Nitric Oxide (FeNO) c
X
Section 8.1.3
Patient Reported Outcome Assessments at Visit
COPD Assessment Test (CAT)
X
Section 8.1.6.6
Site assigns electronic Patient Reported Outcome 
(ePRO) device and trains subject per the training 
guidelines
X
Section 8.1.6
Patient Reported Outcome Assessments at Home
Home ePRO daily completion d
X
Section 8.1.6.1
EXACT-PRO/E-RS™: COPD d
X
Section 8.1.6.7
Clinical Lung Function Assessments
Pre-BD spirometry l
X
X
Section 8.1.2
Post-BD spirometry
X
Section 8.1.2.2
Routine Safety Procedures f
Complete physical examination e
X
Section 8.2.4
Weight, Height e
X
Section 8.2.3
Vital Signs e
X
Section 8.2.5
Supplemental oxygen (O2) status e
X
Section 8.2.7
Oxygen saturation (SpO2) e
X
Section 8.2.8
Chest x-ray eg
X
Section 8.2.9
12-Lead digital Electrocardiogram (dECG)
X
Section 8.2.6
Laboratory Assessments
Clinical chemistry
X
Section 8.2.1
Hematology h
X
Section 8.2.1
Urinalysis
X
Section 8.2.1
Serology (Hepatitis B, C; HIV-1; HIV-2)
X
Section 8.2.11.1
Serum pregnancy test
X
Section 8.2.1.1
FSH i
X
Section 8.2.1.1
TB Test (if applicable) e
X
Section 5.2

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Pneumococcal and annual influenza vaccination, if 
applicable
Xj
Section 8.2.10
SARS-CoV-2 naso/oropharyngeal swab test (or rapid 
test) l
X
Section 8.2.11.2
a
Screening lung function assessments and ECG can only be done when there are no restrictions to medications (refer to Section 6.5.5 
and 8.1.3) and Visit 1 SARS-CoV-2 naso/oropharyngeal swab test (or rapid test) result is negative. If the SARS-CoV-2 
naso/oropharyngeal swab test (or rapid test) result will not be available on the day of Visit 1, the screening lung function assessments 
and ECG must be postponed until next visit, the postponed Visit 1, after the SARS-CoV-2 naso/oropharyngeal swab test (or rapid test) 
result is confirmed negative. At a minimum, the following assessments/activities must be performed at Visit 1: obtain informed 
consent, temperature measurement, enrolment of subject in IWRS and SARS-CoV-2 naso/oropharyngeal swab test. The remaining 
Visit 1 assessments can be postponed together with the screening lung function assessments and ECG. At the postponed Visit 1, the 
spirometry equipment will allow pre-BD, post-BD spirometry, FeNO and ECG (combined Visit 1 and Visit 2) to be performed. Visit 2 
should be scheduled, if the Visit 2 post-BD spirometry and FeNO were not done at the postponed Visit 1. Preferably, Visit 2 should be 
scheduled no later than 1 week after Visit 1 but the enrolment can be extended to accommodate additional waiting time required to 
obtain Visit 1 SARS-CoV-2 naso/oropharyngeal swab test result. 
b
The run-in phase (35 days) can be shortened by 4 days (to 31 days) or extended by 4 days (to 39 days). In case of a COPD 
exacerbation or respiratory infection (excluding pneumonia) during the screening phase, the screening period may be extended up to 
14 days (including the 4 days i.e., to 49 days) to allow for the completion of the course of systemic corticosteroids and/or antibiotics or 
antiviral medication or to meet FeNO restrictions (Refer to section 5.4).
c
The sponsor will be blinded to the FeNO values except at screening visit, at any repeat testing that is performed during the screening 
period and prior to Investigational Product (IP) administration. The sites will be blinded to the FeNO values for the whole study 
duration.
d
Daily Morning Diary: Nocturnal awakening and items related to: rescue medication use, major/minor symptoms; Daily Evening Diary: 
EXACT-PRO/E-RS™: COPD and items related to: rescue medication and maintenance medication.
e
These Visit 1 procedures can be performed at any time between Visit 1 and Visit 2 inclusive.
f
The suggested order of assessments: ePRO, vital signs, ECG, FeNO, spirometry and blood draws.
IMPORTANT: Applicable during COVID-19 pandemic: the suggested order of assessments: Vital signs, ePRO, blood draws and 
SARS-CoV-2 naso/oropharyngeal swab testing. The lung function assessments and ECG can only be done after Visit 1 SARS-CoV-2 
naso/oropharyngeal swab test (or rapid test) result is negative. 
g
A chest X-ray must be done at Visit 1, or at any time that allows the chest X-ray assessment prior to randomization. Under special 
circumstances, a recently done historical chest X-ray (anterior-posterior and lateral)/CT/MRI for other reasons (not study related) 
might be acceptable. The outcome of the X-ray/CT/MRI must be documented in the patients’ medical records. Study Physician 
approval of historical chest X-ray must be obtained prior to randomization.
h
The sponsor and site will be blinded to the immunoglobulin, eosinophil, basophil and monocyte counts from the central laboratory 
reports except screening visits (Visit 1 and Visit 2), any repeat testing that is performed during the screening period and prior to first 
Investigational Product (IP) administration.
i
FSH test done only for female subjects to confirm postmenopausal status in women <50 years who have been amenorrheic for >12 
month.
j
Pneumococcal vaccination can be done at Visit 1 or at any time prior to first IP administration. Annual influenza vaccination can be 
done at any other time throughout the study (except for within ±5 days of IP administration) at the discretion of Investigator. 
Inactive/killed vaccinations e.g. influenzae should be withheld 3 weeks prior to EOT for patients in the sub study (if no safety 
concerns) as it might influence exploratory sputum analysis. Refer to Section 8.2.10.
k
During the COVID-19 pandemic, subjects must be contacted by telephone for COVID-19 screening assessments within 72 hours prior 
to every study visit (except remote visits). Refer to Appendix I for details.
l 
Central laboratory SARS-CoV-2 nasopharyngeal or locally performed SARS-CoV-2 naso/oropharyngeal swab test result (or rapid test 
result) must be available and negative prior to performing screening lung function assessments and ECG (refer to footnote a under 
Table 1, section 1.1).
m
During re-consenting of subjects during the COVID-19 pandemic, local and regional guidelines must be followed. Refer to Appendix I
for further details.

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Table 2 – Treatment Period - Randomization, Treatment and Follow-Up
Assessment/
Activity
Treatment Period
Follow-up
IPD
UNS a
EXA b
Details in CSP Section or 
Appendix
Visit
3
4
5
6
7
8
9
10
11
12
13
14
15
EOT/
16
17
18
Week
0
4
8
12
16
20
24
28
32
36
40
44
48
52
58
64
Visit Window (days)
0
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
±5  
N/A
N/A
Pre-visit Assessments 
Telephone assessment of possible 
COVID-19 symptoms p
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Appendix I
Study Procedures
COVID-19 addendum to ICF 
(if applicable) m
X
Appendix A 3 and 
Appendix I
Inclusion/exclusion criteria
X
Section 5.1 and 5.2
Concomitant medication n, o
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 6.5
Adverse events n, o
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.3 and 
Appendix B
Assessment of COPD exacerbation n, o
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.1.1
Smoking status n, o
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.2
Healthcare resource utilization n, o
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.9
FeNO c
X
X
X
X
X
X
X
Section 8.1.3
Patient Reported Outcome Assessments at Visit d
CAT n, o
X
X
X
X
X
X
Section 8.1.6.6
SGRQ n, o
X
X
X
X
X
X
X
Section 8.1.6.5
ePRO compliance check n, o
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.1.6
Patient Reported Outcome Assessments at Home d
Home ePRO daily completion
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.1.6.1
EXACT-PRO/E-RS™: COPD
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.1.6.7
Routine Safety Procedures
Brief physical examination n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.4

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Assessment/
Activity
Treatment Period
Follow-up
IPD
UNS a
EXA b
Details in CSP Section or 
Appendix
Visit
3
4
5
6
7
8
9
10
11
12
13
14
15
EOT/
16
17
18
Week
0
4
8
12
16
20
24
28
32
36
40
44
48
52
58
64
Visit Window (days)
0
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
±5  
N/A
N/A
Complete physical examination n
X
X
X
Section 8.2.4
Weight
X
X
Section 8.2.3
Vital Signs n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.5
Supplemental O2 status n
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.7
Oxygen saturation (SpO2) n
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.8
12-lead digital Electrocardiogram (ECG)
X
X
X
X
X
X
X
Section 8.2.6
Lung Function Assessments e
Pre-BD spirometry
X
X
X
X
X
X
X
X f
Section 8.1.2
Post-BD spirometry 
X
X
X
X
Section 8.1.2.2
Laboratory Assessments 
Clinical chemistry n
X
X
X
X
X
X
X
X
Section 8.2.1
Hematology g n
X
X
X
X
X
X
X
X
X
X
Section 8.2.1
Total Serum Immunoglobulin g 
X
X
X
X
X
X
X
Section 8.8.2
Urinalysis n
X
X
X
X
X
X
X
Section 8.2.1
Urine pregnancy test (dipstick)h n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.1.1
Serum for Pharmacokinetics (PK)
X
X
X
X
X
X
X
X
Section 8.5
Serum for Immunogenicity i
X
X
X
X
X
X
X
X
Section 8.5.2
Serum/Plasma Biomarkers
X
X
X
X
X
X
X
X
Section 8.8
Urine Biomarkers
X
X
X
X
X
X
X
X
Section 8.8
Blood RNA transcript profiling 
(PAXgene® tube)
X
X
X
X
X
X
X
X
Section 8.8.3
AstraZeneca (AZ) genetics blood sample 
(optional)j
X
Section 8.7.1 and 
Appendix D
SARS-CoV-2 serology test q
X
Section8.2.11.2

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Assessment/
Activity
Treatment Period
Follow-up
IPD
UNS a
EXA b
Details in CSP Section or 
Appendix
Visit
3
4
5
6
7
8
9
10
11
12
13
14
15
EOT/
16
17
18
Week
0
4
8
12
16
20
24
28
32
36
40
44
48
52
58
64
Visit Window (days)
0
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
±5  
N/A
N/A
Subset of Subjects Participating in Sputum and Nasal Lining Fluid/Epithelial Cells Sub Studies Only k
Sputum post-BD spirometry
X
X
X
X
Section 8.1.2.3
Sputum microbiome
X
X
X
X
Section 8.8.5
Sputum biomarkers and Exploratory PK 
X
X
X
X
Section 8.8.5
Sputum cell pellet – cell counts and/or 
RNA transcriptomic profiling 
X
X
X
X
Section 8.8.5
Nasal lining fluid (nasal biomarkers and 
Exploratory PK)
X
X
X
X
X
X
X
X
Section 8.8.6
Nasal epithelial cells (RNA 
transcriptome)
X
X
X
Section 8.8.4
Study treatment administration
Randomization r
X
Section 6.1
Administration of IP l n
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 6.1.2
NOTE: The suggested order of assessments to be completed prior IP administration: ePRO, Vital signs, ECG, FeNO, spirometry and blood draws. Applicable during COVID-19 pandemic: Vital signs, 
ePRO, ECG, FeNO, spirometry and blood draws.
a
Unscheduled visits may be initiated as needed and additional assessments can be performed at the discretion of the PI.
b
EXA visit is an optional visit and may be initiated when patient experiences COPD exacerbation. Additional assessments can be performed at the discretion of the PI. If the EXA visit falls within 
+/- 5 days of the scheduled treatment visit window, the laboratory assessments do not need to be repeated at the next scheduled visit if the same laboratory assessments were already completed at 
EXA visit, unless at the PI’s discretion. Refer to Section 8.1.1.5.
c
The sponsor will be blinded to the FeNO values except at screening visit, at any repeat testing that is performed during the screening period and prior to Investigational Product (IP) 
administration.. The sites will be blinded to FeNO values for the whole study duration.
d
Daily Morning Diary: Nocturnal awakening and items related to: Rescue medication use, major/minor symptoms; Daily Evening Diary: EXACT-PRO/E-RS™: COPD and items related to: rescue 
medication and maintenance medication. EXACT-PRO/E-RS™: COPD is completed daily via e-diary and checked at visits.
e
Visit 3 spirometry must be performed on the day of randomization prior to IP administration after appropriate restriction are met as per Section 8.1.2. For every other visit, pre-BD spirometry 
assessments must be performed only after appropriate restrictions are met as per Section 8.1.2, if not this should be rescheduled to the earliest opportunity within the allowed visit window. 
Applicable for the COVID-19 pandemic: Spirometry should be performed if allowed and according to local regulations and guidance. 
f
Pre-BD spirometry (according to separate instruction manual) will be performed at EXA visit as part of induced sputum procedures during treatment phase if subject is participating in the sputum 
sub study.
g
The sponsor and site will be blinded to the immunoglobulin, eosinophil, basophil and monocyte counts from the central laboratory reports except screening visits (Visit 1 and 2), any repeat testing 
that is performed during the screen visits, and prior to IP administration.
h
For WOCBP only, urine HCG test to be done at study site at each treatment visit before the IP administration.

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i
In case of anaphylaxis additional samples will be taken for serum for immunogenicity.
j
The ICF must be signed by the subject prior to the collection of optional pharmacogenetic sample. 
k
Induced sputum and nasal sampling will be performed in a subset of subjects only and selected sites that are participating in the sub-study will consent subjects to participate in both induced 
sputum and nasal sample collection. Induced sputum is preferred however spontaneous sputum is acceptable if subjects that cannot induce sputum. If sputum and nasal collections occur at the 
same visit, nasal sampling should occur before spontaneous/induced sputum collection. If patient is not able to produce sputum (spontaneous or induced) at Visit 3, the patient should then be 
withdrawn from the sub-study, but can continue in the main study, and the nasal samples should be discarded. Sputum sampling at IPD visit and at EOT visit can be performed up to 5 days after 
the IPD visit and EOT visit. During the COVID-19 pandemic, sputum and nasal samples will only be collected if allowed per local Health and Safety regulations or guidance and if sub-study 
laboratory test kits are available.
l
IP must be administered only after all other assessments have been completed on a scheduled visit. During the COVID-19 pandemic, IP administration can be performed at the subject’s home or 
alternative location. Also, laboratory assessments can be completed post IP administration. Please refer to Appendix I.
m
During re-consenting of subjects during the COVID-19 pandemic, local and regional guidelines must be followed with regard to verbal informed consent. Refer to Appendix I for further details.  
n
During the COVID-19 pandemic for at home IP administration visits, where possible study assessments should be conducted according to the SoA 1.1. However, the qualified HCP is expected to 
collect this information as a minimum. If possible, it is preferred that the HCP collects urine samples, safety and other blood samples as well. For further details, please refer to Appendix I.
o
These assessments can be replaced by a phone visit during COVID-19 pandemic. Please refer to Appendix I.
p
During the COVID-19 pandemic, subject must be contacted by telephone for COVID-19 screening assessment within 72 hours prior to every study visit (except remote visits). Refer to Appendix I
for details.
q
SARS-CoV-2 serology test at Visit 3 is applicable for newly enrolled subjects. For remaining ongoing active subjects (in treatment or in follow-up), the test should be done as soon as possible but 
preferably at the next site visit.
r
Randomization transaction in IWRS should be completed after confirmation of subject eligibility.
(EOT) - End of treatment; (EXA) - COPD exacerbation visit; (FU) - Follow-up; (IPD) - IP discontinuation visit; (UNS) - Unscheduled visit

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1.2
Synopsis
Protocol Title: A Randomized, Double-blind, Placebo-controlled, Parallel Group, 
Multicenter, Phase 2a Study to Explore the Efficacy and Safety of Tezepelumab in Patients 
with Moderate to Very Severe Chronic Obstructive Pulmonary Disease (COPD) (COURSE)
Brief Title: Tezepelumab COPD Exacerbation study
Regulatory Agency Identifying Number(s):
IND number: 103031
EudraCT number: 2019-001363-67
Rationale: The purpose of this global study is to evaluate the efficacy and safety of 
tezepelumab 420 mg administered by subcutaneous (SC) injection every 4 weeks (Q4W) in 
adults with moderate to very severe COPD receiving triple inhaled maintenance therapy 
(inhaled corticosteroid/long-acting β2 agonist and long acting muscarinic antagonist 
[ICS/LABA/LAMA]) who have had ≥2 documented COPD exacerbations in the 12 months 
prior to study start. The study will evaluate the incidence of COPD exacerbations and other 
efficacy parameters such as lung function and quality of life and will provide adequate safety 
information in order to characterize the benefit-risk profile of tezepelumab treatment in 
subjects with COPD.
Primary Objective
Outcome Measure
To evaluate the effect of tezepelumab as 
compared with placebo on COPD 
exacerbations in subjects with moderate to 
very severe COPD
Primary endpoint: Rate of moderate or severe 
COPD exacerbations
Primary outcome measure: Moderate or 
severe COPD exacerbation rate ratio 
(tezepelumab vs placebo) 
Supportive endpoint: Rate of moderate 
(excluding exacerbations treated only with 
antibiotics) or severe COPD exacerbations 
Supportive Measure: Moderate (excluding 
exacerbations treated only with antibiotics) or 
severe COPD exacerbation rate ratio 
(tezepelumab vs placebo) 

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Secondary Objectives
Outcome measure
To evaluate the effect of tezepelumab 
compared with placebo on time to first 
moderate/severe exacerbation
Outcome variables:

Time to first moderate or severe COPD 
exacerbation 

Proportion of subjects with ≥1 
moderate or severe COPD exacerbation 
Outcome Measures:

Hazard Ratio (tezepelumab vs placebo)

Odds Ratio (tezepelumab vs placebo)
To evaluate the effect of tezepelumab as 
compared with placebo on severe COPD 
exacerbations
Secondary outcome variable: Rate of severe 
COPD exacerbations
Outcome measure: Rate ratio (tezepelumab 
vs placebo) 
Supportive outcome variables: 

Time to first severe COPD 
exacerbation

Proportions of patients experiencing a 
severe COPD exacerbation
Supportive outcome measures:

Hazard ratio (tezepelumab vs placebo)

Odds ratio (tezepelumab vs placebo)
To evaluate the effect of tezepelumab as 
compared with placebo on pre-
bronchodilator (BD) lung function
Outcome variable: Change from baseline in 
pre-BD forced expiratory volume in 1 second 
(FEV1) at Week 52
Outcome measure: Mean difference in 
change from baseline (tezepelumab vs 
placebo) at Week 52

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To evaluate the effect of tezepelumab as 
compared with placebo on respiratory 
health status/health-related quality of life 
Outcome variables:

Proportion of subjects achieving an 
MCID of 4 units or more in SGRQ total 
score at Week 52

Change from baseline in SGRQ at 
Week 52 

Change from baseline in COPD 
assessment tool (CAT) at Week 52
Outcome Measures:

Odds Ratio (tezepelumab vs placebo)

Mean difference in change from 
baseline (tezepelumab vs placebo) at 
Week 52
To evaluate the pharmacokinetics (PK) 
and immunogenicity of tezepelumab
PK: Serum trough concentration 
Immunogenicity: Incidence of anti-drug 
antibodies (ADA)
Safety Objectives:
Safety Variables:
To assess the safety and tolerability of 
tezepelumab as compared with placebo in 
subjects with moderate to very severe 
COPD
Adverse events/serious adverse events 
(AEs/SAEs)
Vital signs
Laboratory assessments
Electrocardiograms (ECG)
Exploratory Objectives:
Exploratory Variables:

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To explore the effect of tezepelumab on 
COPD Composite Exacerbations 
(COPDCompEx) event
Outcome variable: 

Time to COPDCompEx event

Rate of COPDCompEx events 
Outcome Measure: 

Hazard Ratio (tezepelumab vs placebo)

Rate ratio (tezepelumab vs placebo) 
over first 12 weeks treatment period
To explore the effect of tezepelumab on 
time to a Clinically Important 
Deterioration (CID) event
Outcome variable: Time to CID event
Outcome Measure: Hazard Ratio 
(tezepelumab vs placebo)
To explore the impact of tezepelumab on 
blood eosinophil and neutrophil levels
Outcome variable: Change from baseline in 
blood eosinophil and neutrophil levels 
Outcome measure: Change from baseline at 
Week 52
To explore the effect of tezepelumab on 
post-BD lung function (FEV1)
Outcome variable: Change from baseline in 
post-BD forced expiratory volume in 1 second 
(FEV1) 
Outcome measure: Mean difference in 
change from baseline (tezepelumab vs 
placebo) at Week 52

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To evaluate the effect of tezepelumab on 
respiratory symptoms and on the 
frequency, duration and severity of 
EXACT-PRO defined events
Outcome variable:

Change from baseline in Exacerbations 
of Chronic Pulmonary Disease Tool-
Respiratory Symptoms (EXACT-
PRO/E-RS™: COPD)

Rate of EXACT-PRO defined 
exacerbations
Outcome measure:

Mean difference in change from 
baseline (tezepelumab vs placebo) at 
Week 52

EXACT-PRO defined exacerbation rate 
ratio (tezepelumab vs placebo)
To evaluate tezepelumab’s effect on 
COPD-related healthcare resource 
utilization
Outcome variable:
Rate of COPD-specific resource utilization 
(e.g., unscheduled physician visits, 
unscheduled phone calls to physicians, use of 
other COPD medications)
Outcome measure:
Difference in rate of COPD-specific resource 
utilizations (tezepelumab vs placebo) over 52 
weeks
To assess the effect of tezepelumab on 
airway inflammation
Outcome variable: Fractional exhaled nitric 
oxide (FeNO)
Outcome measure: Mean difference in 
change from baseline (tezepelumab vs 
placebo) at Week 52
To assess the effect of tezepelumab on 
total serum immunoglobulins
Outcome variable: Total Immunoglobulins 
(IgE, IgA, IgM, IgG)
Outcome measure: Mean difference in 
change from baseline (tezepelumab vs 
placebo) at Week 52

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To assess the effect of tezepelumab on 
blood biomarkers 
Serum and plasma biomarkers including 
markers of remodeling and inflammation
To evaluate the effect of tezepelumab on 
sputum biomarkers, sputum cell counts 
and sputum microbiome, in subjects 
participating in sub-study, at baseline, end 
of treatment, and at the start of all 
exacerbations during treatment phase

Sputum biomarkers of inflammation 
and remodeling   

Sputum cell counts and cell 
differentials from cytospins 

Sputum microbiome
To explore the effect of tezepelumab on 
the blood and/or nasal epithelial cell 
and/or sputum cell transcriptome for 
pharmacodynamic (PD) markers of 
exposure or response to tezepelumab and 
pre-and post-dose predictive markers of 
clinical response
Transcriptomic biomarkers (may include but 
not limited to): RNA-Seq and RNA microarray 
profiling and microbiome profiling. 
Transcriptomics analysis may be carried out on 
blood cells, and/or nasal epithelial cells and/or 
sputum cells 
To evaluate the effect of tezepelumab on 
nasal lining fluid biomarkers
Nasal biomarkers including but not limited to 
inflammation and remodeling
To evaluate the effect of tezepelumab on 
urine biomarkers
Urine biomarkers including but not limited to 
inflammation and remodeling
To explore the relationships between 
pharmacogenomic DNA markers and 
response/exposure to tezepelumab
Optional AZ genomics blood sample. 
Pharmacogenomic biomarkers may include 
(but not limited to): SNP and epigenetic 
To explore the PK of tezepelumab in 
respiratory tract fluid
Tezepelumab concentrations in nasal lining 
fluid and/or sputum
Note: Some exploratory analyses may be reported separately from the CSR.
Overall design:
This is a Phase 2a, multicenter, randomized, double-blind, placebo-controlled, parallel group 
study to evaluate the efficacy and safety of tezepelumab 420 mg administered by SC injection 
Q4W in subjects with moderate to very severe COPD receiving triple inhaled maintenance 
therapy (ICS, LABA and LAMA), and having had ≥2 documented COPD exacerbations in the 
12 months prior to visit 1. Approximately 40% of subjects will have had ≥3 exacerbations in 
the 12 months prior to Visit 1 and approximately 30% of subjects will have had at least 1 

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severe exacerbation (an exacerbation resulting in hospitalization) in the 12 months prior to 
Visit 1. 
The study will randomize approximately 338 subjects 1:1 to either tezepelumab or placebo, 
stratified by region, and number of prior exacerbations. Approximately 20% of the subjects 
will be targeted to have ≥300 eosinophils/μL, 40% of the subjects between ≥150 to <300 
eosinophils/μL and a maximum of approximately 40% of the subjects with <150 
eosinophils/μL at enrolment.
Induced sputum analyses will be performed in a subset of subjects and in a limited number of 
sites globally. The aim of the induced sputum subset analysis is to explore the mechanisms by 
which tezepelumab might reduce COPD exacerbations. In these same selected subjects, 
analysis of nasal lining fluid and epithelial transcriptomics will also be performed. 
The screening period which consist of enrolment and run-in, will be approximately 6 weeks to 
allow adequate time for all the eligibility criteria to be evaluated. At the end of the run-in 
period, subjects must continue to have a CAT score ≥15 and 70% compliance with the 
maintenance therapy and acceptable compliance with the eDiary to be randomized. Subjects 
who meet the eligibility criteria will be randomized to treatment.
After randomization subjects will be treated at monthly intervals with the last treatment 
administered at Week 48. The end-of-treatment (EOT) visit (Week 52) will occur at 4 weeks 
after last treatment administered at Week 48 and follow-up visits will occur at Week 58 and 
Week 64. Subjects will be maintained on their currently prescribed maintenance therapies 
from enrolment throughout the run-in and treatment period. 
Study Period:
Estimated date of first patient enrolled Q3 2019.
Estimated date of last patient completed Q1 2024.
Number of Subjects:
Approximately 338 subjects will be randomized to either tezepelumab or placebo (1:1) 
globally from at least 90 sites. The subjects will be stratified by region and prior number of 
exacerbations (2 vs ≥3). Since the primary analysis of the primary endpoint will include all 
available data, including after treatment discontinuation, no need is envisaged to adjust the 
number of subjects planned to be randomized to obtain a number of evaluable subjects.
Treatments and Treatment Duration:
The study will consist of a screening period for approximately 6 weeks, a treatment period of 
52 weeks and a post-treatment follow-up period of 12 weeks. Subjects will be randomized in a 

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1:1 ratio to either 420 mg of tezepelumab or matching placebo both administered Q4W SC. 
During the treatment period, IP will be administered from Day 0 until Week 48. No IP will be 
administered at Week 52. Subjects that complete the 52-week study visit will complete a 12 
week off-treatment follow-up period for assessments. Subjects who discontinue IP during the 
study will be encouraged to undergo appropriate study visits/procedures for the full 52-week 
period (see Section 7.1.1). 
Independent Adjudication Committee:
An Independent Adjudication Committee (IAC) will assess blinded data to confirm the 
diagnosis and causality of major adverse cardiac events (MACE; defined in the IAC charter), 
serious cardiac events, and deaths, as well as the diagnosis of malignancies, that occur from 
randomisation until the end of the follow-up period.
The IAC will also assess whether cases of ER or urgent care visits and hospitalizations, that 
occur from randomisation until the end of the follow-up period, are due to a worsening of 
COPD. 
Details on the adjudication process, including scope of adjudication and the committee 
membership, will be included in the Adjudication Committee Charter/Manual of Operations.
Independent Data Monitoring:
An Independent Data Monitoring Committee (IDMC) will be tasked with two major 
responsibilities.  First, it will be responsible for assessing all safety related data collected 
during the study, including serious adverse events (including deaths and all hospitalizations), 
non-serious adverse events and laboratory values. The IDMC will periodically review 
unblinded safety summary tables and listings and evaluate for subject safety and make 
appropriate recommendations. The committee will operate in accordance with an IDMC 
Charter.
Second, the IDMC will be responsible for overseeing the two unblinded interim analyses 
based on the primary endpoint that will be conducted in this study (see Section 4.1).  
Statistical Methods:
Efficacy analyses will be performed using the full analysis set (FAS), which consists of all 
subjects randomized and receiving any dose of IP. All subjects in the FAS will be included in 
the main efficacy analyses, including subjects who discontinue IP prior to Week 52 (for which 
every attempt will be made to collect data after discontinuation of IP up until Week 52). 
The primary efficacy variable is the annual COPD exacerbation rate.  The exacerbation rate in 
the tezepelumab dose group will be compared to the exacerbation rate in the placebo group 

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using a negative binomial model including covariates of treatment group, region and the 
number of exacerbations in the year before the study (2 vs ≥3). The logarithm of the follow-up 
time will be used as an offset variable in the model. 
Secondary efficacy variables include the time to first COPD exacerbation, proportion of 
subjects with at least one COPD exacerbation, annual rate of severe COPD exacerbations, 
change from baseline in Pre-BD FEV1 and SGRQ, and proportion of subjects with at least 4 
units decrease in SGRQ.  These endpoints will be compared to the placebo group using 
appropriate models (Cox proportional hazards for time to event endpoint, logistic regression 
for proportion endpoints, Negative Binomial regression for annual rate endpoints, Mixed 
effect Model Repeated Measures (MMRM) for change from baseline endpoints.)
All safety parameters will be analyzed descriptively. Safety analyses will be based on the 
safety analysis set, defined as all subjects who received at least 1 dose of IP.
1.3
Schema
The general study design is summarised in Figure 1.
Figure 1 - Study Flow Chart
V1
V2
R/V3
V4-V15
EOT/V16
V17, V18
Week
-6
Week
-5
Week 
0
Week 
4-48
Week 
52
Week 
58, 64
Enrolment
Run-in
Treatment Phase
Follow-up
Screening
Screening Period
(Enrolment, Run-in)
Tezepelumab 420 mg, SC every 4 weeks (n=169)
Placebo, SC every 4 weeks (n=169)
V: Visit, R: Randomization
1:1
Randomization
1:1

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2.
INTRODUCTION
2.1
Study Rationale
2.2
Background
Chronic obstructive pulmonary disease (COPD) is a progressive disease and a significant 
cause of morbidity and mortality worldwide.  In contrast to other chronic diseases, COPD is 
increasing in prevalence and is projected to be the third leading cause of death and disability 
worldwide by 2020 (Global Initiative for Chronic Obstructive Lung Disease [GOLD 2019]). 
Acute exacerbations of COPD (AECOPD) are responsible for a large portion of the economic 
burden of COPD. In addition to a substantial economic burden, AECOPDs are also 
responsible for much of the morbidity and mortality from COPD.  Patients with frequent 
AECOPD show associated increased airway inflammation and accelerated decline in lung 
function compared with patients with infrequent exacerbations (Donaldson et al 2002). 
Thymic stromal lymphopoietin (TSLP) is an upstream pleiotropic cytokine which is released 
by airway epithelial cells in response to either allergens or non-specific stimuli such as 
viruses, bacteria, and cigarette smoke, all of which are known to be associated with COPD 
exacerbations (Ziegler et al 2013). In response to an allergen or non-specific stimuli, TSLP 
activates dendritic cells, which stimulate Type 2 helper T (Th2) cells to differentiate and 
produce the Type 2 cytokines interleukin (IL)-4, IL-5, and IL-13 (Watson and Gauvreau 
2014). TSLP can also drive Th17 cell expansion through activation of dendritic cells, which 
will increase neutrophil recruitment (Ziegler et al 2013).
TSLP, along with the other epithelial “alarmins”, IL-25 and IL-33, activates Type 2 innate 
lymphoid cells (ILC2) and other inflammatory cell (including mast cells, basophils, and 
macrophages), thus promoting T2 inflammation by up-regulating Type 2 cytokines in 
response to an epithelial insult (e.g., pollutants, microbes, cigarette smoke, bacterial and viral 
infections, mechanical injury, trauma and pro-inflammatory cytokines etc.) (Camelo et al 
2017). 
TSLP protein is released from COPD epithelium following toll-like receptor (TLR) viral 
(Calvern et al 2012) and pro-inflammatory cytokine stimulation (Kato et al 2007, Lee and 
Ziegler 2007). TSLP protein has been detected in nasal secretions from healthy subjects 
undergoing natural rhinovirus infection (Perez et al 2014) as well as in the bronchoalveolar 
lavage (BAL) fluid and sputum of non-exacerbating COPD subjects (Ying et al 2008), and 
sputum (Anzalone et al 2018). TSLP mRNA expression is seen in airway epithelial cells in 
patients with COPD (Ying et al 2008).

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Tezepelumab is a fully human immunoglobulin G (IgG) monoclonal antibody (mAb) directed 
against TSLP.  Tezepelumab binds to human TSLP and prevents its interaction with the TSLP 
receptor (TSLPR). The hypothesis for the mechanism of action of tezepelumab in COPD is 
two-fold. First, because TSLP is one of the earliest responses to airway damage caused by a 
range of stimuli, inhibition of TSLP is expected to prevent the acute response to epithelial 
damage and prevent COPD exacerbations.  Secondly, given that TSLP is an upstream and 
pleiotropic cytokine, the blockade of TSLP is anticipated to have broad impact on the 
spectrum of acute and chronic airway inflammatory responses seen in COPD. Both effects are 
expected to reduce COPD exacerbations and improve COPD symptoms (Camelo et al 2017).  
Thus, it is hypothesized that inhibition of upstream TSLP by tezepelumab will be effective in 
reducing airway inflammation in patients with COPD and reducing annualized COPD 
exacerbation rates.  The purpose of the present study is to investigate the ability of 
tezepelumab versus placebo to enable reduction of the annualized COPD exacerbation rate in 
subjects with moderate to very severe COPD receiving standard maintenance therapy.  
2.3
Benefit/Risk Assessment
COPD is a progressive disease which is characterized by exacerbations and health related 
quality of life loss (GOLD 2019). Despite being treated with double and triple inhaled 
therapy, many COPD patients continue to have exacerbations (Wedzicha et al 2013).  
It has been shown that tezepelumab, as add-on therapy to standard-of-care (SoC), significantly 
reduces asthma exacerbations, including exacerbations associated with hospitalization or ER 
visit, and improves lung function, asthma control, and quality of life in patients with severe 
uncontrolled asthma. Moreover, clinical improvements were seen irrespective of patient 
phenotype or biomarker status (Corren et al 2017). In the same study, tezepelumab was shown 
to decrease blood eosinophil counts, FeNO, and IgE levels, suggesting that multiple pathways 
are being impacted by blocking TSLP. 
No clinical data are available to show the effect of tezepelumab in COPD.  However, efficacy 
and safety data obtained in asthma supports clinical development of tezepelumab in COPD.
Use of tezepelumab has been demonstrated to show an important benefit in asthma in a phase 
2b and phase 3 study. Tezepelumab has been well tolerated with an acceptable safety profile 
and no safety signals in subjects with severe, uncontrolled asthma identified in the completed 
studies to date. No serious allergic reactions or anaphylactic reactions considered related to 
tezepelumab were reported in the Phase 3 program. To date there has been a low incidence of 
ADA and neutralising antibodies (nAb) reported with tezepelumab treatment in the Phase 2 or 
Phase 3 studies. Although TSLP suppression could theoretically have unanticipated immune-
related side effects impairing host defense against certain infections, there is no clear 
preclinical or clinical evidence supporting such a role, and no safety concerns related to 

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serious infections, severe infections or helminth infections have been detected in the 
completed studies to date. 
Risk mitigation measures for important potential risks will be in place during the conduct of 
this study (refer to Table 3), in conjunction with the performance of the AstraZeneca’s routine 
pharmacovigilance activities.
A detailed assessment of the overall risk/benefit of tezepelumab in patients with COPD is 
given in the Investigator’s Brochure.
Table 3 – Risk Assessment
Important 
potential Risk
Summary of data/rationale 
for risk
Mitigation strategy
Study intervention
Serious infections
are defined as 
infections fulfilling 
criteria for 
regulatory reporting
The mechanism of action of 
tezepelumab suggests potential 
inhibitory effects on immune 
responses mediated by Th2 
cells, leading to the possibility 
of diminution of the host’s 
protective response to 
infection. Although there is a 
theoretical risk of serious 
infections with tezepelumab 
treatment, there is no data to 
support this potential risk. 
There is also no evidence for 
causal relationship with 
tezepelumab.
Vulnerable participants will be 
excluded based on eligibility 
criteria, and randomised 
participants will be monitored by 
safety blood work throughout the 
study; and through standard 
AE/SAE reporting. 
Participants will be excluded if they 
received systemic 
immunosuppressive or 
immunomodulating drugs within 3 
months prior to Visit 1; or if they 
have a history of a known 
immunodeficiency disorder; or 
have a history of clinically 
significant infection requiring 
treatment with systemic antibiotics 
or antiviral medications finalised < 
2 weeks before Visit 1 or during the 
run-in period or at randomisation; 
or who have evidence of active 
coronavirus disease 2019 (COVID-
19) infection during the run-in 
period; or have had tuberculosis
requiring treatment.
Serious infections are an AESI and 
participants who develop serious 

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infection will be followed up 
closely throughout study.
Malignancies
Given the potential theoretical 
risk due to the mechanism of 
action of tezepelumab, the 
long-term treatment intended 
for a chronic disease and the 
nature of malignancy 
development, malignancy is 
included as an important 
potential risk.
There is no evidence to suggest 
an increase in malignancies in 
the tezepelumab data to-date in 
either pre-clinical or clinical 
studies. No causal relationship 
with tezepelumab could be 
established for cases reported. 
Participants with current 
malignancy or whose curative 
therapy was completed recently will 
be excluded from participation 
based on eligibility criteria. All 
participants will be closely 
followed during the study for any 
adverse events/serious adverse 
event, including malignancies that 
are considered AESI.
Serious cardiac 
events
A numerical imbalance in 
cardiac disorder SAEs was 
observed in the 
DESTINATION Long Term 
Extension study (see 
Investigator’s Brochure) with 
more events in participants 
treated with tezepelumab 
versus participants treated with 
placebo. None of the cardiac 
disorder SAEs was considered 
causally related to tezepelumab 
by investigators or 
Independent Adjudication 
Committee. There is no known 
mechanism by which blocking 
TSLP would lead to cardiac 
pathophysiology.
Participants with cardiac disorders 
that are not stable in the opinion of 
the investigator or who present 
meaningful abnormal findings in 
examination, lab assessments or 
ECG will be excluded based on 
eligibility criteria. 
All participants will be closely 
followed during the study for any 
adverse events, including serious 
cardiac events that are considered 
AESI.
Potential risks
Summary of data/rationale 
for risk
Mitigation strategy
Study intervention
Serious 
hypersensitivity 
reactions
Systemic reactions to large 
therapeutic molecules can be 
IgE or non-IgE-mediated and 
are generally characterised by 
To mitigate the potential risk of 
serious hypersensitivity reactions 
during and after administration of 
tezepelumab, specific requirements 

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signs and symptoms such as 
skin rash, urticaria, pruritus, 
local or diffuse erythema, 
angioedema, fever, chills, 
cough, dyspnoea, wheezing, 
bronchospasm, 
nausea/vomiting, diaphoresis, 
chest pain, tachycardia or 
bradycardia, and/or 
hypotension, which can all be 
severe or life-threatening. 
Effects typically occur during 
or within several hours after 
study intervention but may be 
delayed.
The administration of a 
monoclonal antibody can result 
in the formation of ADA. The 
occurrence of ADA could 
result in immune complex 
disease (Type 3 
hypersensitivity reactions) 
with manifestations such as 
serum sickness, nephritis, and 
vasculitis, or altered 
tezepelumab levels or activity. 
for observing participants for 
AEs/SAEs and for monitoring vital 
signs are included in this CSP. In 
addition, medical equipment to treat 
acute anaphylactic reactions will be 
immediately available and site staff 
will be trained to recognise and 
treat anaphylaxis.
To mitigate the potential risk of 
immune complex disease 
participants will be monitored for 
confirmed immune complex disease 
through routine monitoring of 
AEs/SAEs.
Participants with sensitivity to any 
component of the study intervention 
or a history of drug or other allergy 
that, in the opinion of the 
investigator or medical monitor, 
contraindicates their participation 
will be excluded. Participants who 
have a history of anaphylaxis or 
documented immune complex 
disease following any biologic 
therapy will also be excluded.
Serious hypersensitivity reactions 
are an AESI and these events will 
be monitored closely throughout the 
study.
Helminth 
infections
Potential inhibitory effects on 
immune responses mediated by 
Th2 cells, leading to the 
possibility of diminution of the 
host’s protective response to 
parasitic infestation/infection.
Participants with a helminth 
infection diagnosed within 6 
months prior to Visit 1 that has not 
been treated with, or has failed to 
respond to, standard of care therapy 
will be excluded.
Helminth infections are an AESI. 
Participants who develop such 
infections will be monitored closely 
throughout the study.
Study procedures

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COVID-19 
Pandemic, risk of 
COVID-19 
infection
There is the risk of exposure to 
COVID-19 to participants 
during site visits
Local guidelines will be followed to 
mitigate risk of participant’s 
exposure to COVID-19.
To identify potential COVID-19 
infection during the study a 
COVID-19-related questionnaire is 
recommended prior to every visit. 
Visits will be deferred if 
abnormalities noted.
Sites are recommended to follow 
local severe acute respiratory 
coronavirus 2 (SARS-CoV-2) 
testing guidelines, if applicable.
COVID-19 vaccination is allowed 
during the study (see Table 6).
Refer to Appendix I Coronavirus 
(COVID 19) Pandemic Guidance.

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3.
OBJECTIVES AND ENDPOINTS
Table 4 - Study Objectives
Primary Objective
Outcome Measure
To evaluate the effect of tezepelumab as 
compared with placebo on COPD 
exacerbations in subjects with moderate to 
very severe COPD
Primary endpoint: Rate of moderate or severe 
COPD exacerbations
Primary outcome measure: Moderate or 
severe COPD exacerbation rate ratio 
(tezepelumab vs placebo) 
Supportive endpoint: Rate of moderate 
(excluding exacerbations treated only with 
antibiotics) or severe COPD exacerbations 
Supportive Measure: Moderate (excluding 
exacerbations treated only with antibiotics) or 
severe COPD exacerbation rate ratio 
(tezepelumab vs placebo) 
Secondary Objectives
Outcome measure
To evaluate the effect of tezepelumab 
compared with placebo on time to first 
moderate/severe exacerbation
Outcome variables:

Time to first moderate or severe COPD 
exacerbation 

Proportion of subjects with ≥1 
moderate or severe COPD exacerbation 
Outcome Measures:

Hazard Ratio (tezepelumab vs placebo)

Odds Ratio (tezepelumab vs placebo)
To evaluate the effect of tezepelumab as 
compared with placebo on severe COPD 
exacerbations
Secondary outcome variable: Rate of severe 
COPD exacerbations

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Outcome measure: Rate ratio (tezepelumab 
vs placebo) 
Supportive outcome variables: 

Time to first severe COPD 
exacerbation

Proportions of patients experiencing a 
severe COPD exacerbation
Supportive outcome measures:

Hazard ratio (tezepelumab vs placebo)

Odds ratio (tezepelumab vs placebo)
To evaluate the effect of tezepelumab as 
compared with placebo on pre-
bronchodilator (BD) lung function
Outcome variable: Change from baseline in 
pre-BD forced expiratory volume in 1 second 
(FEV1) at Week 52
Outcome measure: Mean difference in 
change from baseline (tezepelumab vs 
placebo) at Week 52
To evaluate the effect of tezepelumab as 
compared with placebo on respiratory 
health status/health-related quality of life 
Outcome variables:

Proportion of subjects achieving an 
MCID of 4 units or more in SGRQ total 
score at Week 52

Change from baseline in SGRQ at 
Week 52 

Change from baseline in COPD 
assessment tool (CAT) at Week 52
Outcome Measures:

Odds Ratio (tezepelumab vs placebo)

Mean difference in change from 
baseline (tezepelumab vs placebo) at 
Week 52

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To evaluate the pharmacokinetics (PK) 
and immunogenicity of tezepelumab
PK: Serum trough concentration 
Immunogenicity: Incidence of anti-drug 
antibodies (ADA)
Safety Objectives:
Safety Variables:
To assess the safety and tolerability of 
tezepelumab as compared with placebo in 
subjects with moderate to very severe 
COPD
Adverse events/serious adverse events 
(AEs/SAEs)
Vital signs
Laboratory assessments
Electrocardiograms (ECG)
Exploratory Objectives:
Exploratory Variables:
To explore the effect of tezepelumab on 
COPD Composite Exacerbations 
(COPDCompEx) event
Outcome variable: 

Time to COPDCompEx event

Rate of COPDCompEx events 
Outcome Measure: 

Hazard Ratio (tezepelumab vs placebo)

Rate ratio (tezepelumab vs placebo) 
over first 12 weeks treatment period
To explore the effect of tezepelumab on 
time to a Clinically Important 
Deterioration (CID) event
Outcome variable: Time to CID event
Outcome Measure: Hazard Ratio 
(tezepelumab vs placebo)
To explore the impact of tezepelumab on 
blood eosinophil and neutrophil levels
Outcome variable: Change from baseline in 
blood eosinophil and neutrophil levels 
Outcome measure: Change from baseline at 
Week 52

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To explore the effect of tezepelumab on 
post-BD lung function (FEV1)
Outcome variable: Change from baseline in 
post-BD forced expiratory volume in 1 second 
(FEV1) 
Outcome measure: Mean difference in 
change from baseline (tezepelumab vs 
placebo) at Week 52
To evaluate the effect of tezepelumab on 
respiratory symptoms and on the 
frequency, duration, and severity of 
EXACT-PRO defined events
Outcome variable:

Change from baseline in Exacerbations 
of Chronic Pulmonary Disease Tool-
Respiratory Symptoms (EXACT-
PRO/E-RS™: COPD)

Rate of EXACT-PRO defined 
exacerbations
Outcome measure:

Mean difference in change from 
baseline (tezepelumab vs placebo) at 
Week 52

EXACT-PRO defined exacerbation rate 
ratio (tezepelumab vs placebo)
To evaluate tezepelumab’ s effect on 
COPD-related healthcare resource 
utilization
Outcome variable: Rate of COPD-specific 
resource utilization (e.g., unscheduled 
physician visits, unscheduled phone calls to 
physicians, use of other COPD medications)
Outcome measure: Difference in rate of 
COPD-specific resource utilizations 
(tezepelumab vs placebo) over 52 weeks
To assess the effect of tezepelumab on 
airway inflammation
Outcome variable: Fractional exhaled nitric 
oxide (FeNO)
Outcome measure: Mean difference in 
change from baseline (tezepelumab vs 
placebo) at Week 52

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To assess the effect of tezepelumab on 
total serum immunoglobulins
Outcome variable: Total Immunoglobulins 
(IgE, IgA, IgM, IgG)
Outcome measure: Mean difference in 
change from baseline (tezepelumab vs 
placebo) at Week 52
To assess the effect of tezepelumab on 
blood biomarkers 
Serum and plasma biomarkers including 
markers of remodeling and inflammation
To evaluate the effect of tezepelumab on 
sputum biomarkers, sputum cell counts 
and sputum microbiome, in subjects 
participating in sub-study, at baseline, end 
of treatment, and at the start of all 
exacerbations during treatment phase

Sputum biomarkers of inflammation 
and remodeling   

Sputum cell counts and cell 
differentials from cytospins 

Sputum microbiome
To explore the effect of tezepelumab on 
the blood and/or nasal epithelial cell 
and/or sputum cell transcriptome for 
pharmacodynamic (PD) markers of 
exposure or response to tezepelumab and 
pre-and post-dose predictive markers of 
clinical response
Transcriptomic biomarkers (may include but 
not limited to): RNA-Seq and RNA microarray 
profiling and microbiome profiling. 
Transcriptomics analysis may be carried out on 
blood cells, and/or nasal epithelial cells and/or 
sputum cells 
To evaluate the effect of tezepelumab on 
nasal lining fluid biomarkers
Nasal biomarkers including but not limited to 
inflammation and remodeling
To evaluate the effect of tezepelumab on 
urine biomarkers
Urine biomarkers including but not limited to 
inflammation and remodeling
To explore the relationships between 
pharmacogenomic DNA markers and 
response/exposure to tezepelumab
Optional AZ genomics blood sample. 
Pharmacogenomic biomarkers may include 
(but not limited to): SNP and epigenetic 
To explore the PK of tezepelumab in 
respiratory tract fluid
Tezepelumab concentrations in nasal lining 
fluid and/or sputum
Note: Some exploratory analyses may be reported separately from the CSR

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4.
STUDY DESIGN
4.1
Overall Design
For an overview of the study design see Figure 1. For details on treatments given during the 
study, see Section 6.1.  
For details on what is included in the efficacy and safety endpoints, see Section 3 Objectives 
and Endpoints.  
This is a Phase 2a, multicenter, randomized, double-blind, placebo-controlled, parallel group 
study to evaluate the efficacy and safety of tezepelumab 420 mg administered by SC injection 
Q4W in subjects with moderate to very severe COPD receiving triple inhaled maintenance 
therapy (ICS, LABA and LAMA), and having had ≥2 documented COPD exacerbations in the 
12 months prior to visit 1. Approximately 30% of subjects will have had at least 1 severe 
exacerbation (an exacerbation resulting in hospitalization) within the 12 months prior to Visit 
1. Approximately 40% of subjects will have had ≥3 exacerbations within the 12 months prior 
to Visit 1. 
The study will randomize approximately 338 subjects 1:1 to the treatment arms, stratified by 
region, and number of prior exacerbations. Approximately 20% of the subjects will be 
targeted to have ≥300 eosinophils/μL, 40% of the subjects between ≥150 to <300
eosinophils/μL and a maximum of approximately 40% of the subjects with <150 
eosinophils/μL at enrolment. When the target percentage of subjects for the prior 
exacerbations or eosinophil subgroup in a region or overall is reached, consideration will be 
given to closing the Interactive Web Response System (IWRS) randomization for that 
subgroup [by region or overall]. Once a subgroup is closed, subjects in the screening period in 
the closed subgroup will not be allowed to be randomized and will be screen failed.
Induced sputum analysis will be performed in a subset of subjects and in a limited number of 
sites globally. The aim of the induced sputum subset analysis is to explore the mechanisms by 
which tezepelumab might reduce COPD exacerbations. In these same selected subjects, 
analysis of nasal lining fluid and epithelial transcriptomics will also be performed. 
Pre-visit assessment during COVID-19 pandemic
Subjects must be contacted by telephone for assessment of possible COVID-19 symptoms 
within 72 hours prior to every study visit (except remote visits). Please refer to Appendix I for 
details.
Screening Period (Enrolment and Run-in)

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After the initial enrolment period and confirmation of the eligibility criteria at Visit 1, subjects 
will proceed to the run-in period at Visit 2 for approximately 5 weeks to allow adequate time 
for all the eligibility criteria to be evaluated, refer to Table 1. Visit 1 and Visit 2 assessments 
can be combined. 
Screening lung function assessments and ECG can only be done when there are no restrictions 
to medications (refer to Section 6.5.5 and 8.1.3) and Visit 1 SARS-CoV-2 naso/oropharyngeal 
swab test (or rapid test) result is negative. If the SARS-CoV-2 naso/oropharyngeal swab test 
(or rapid test) result will not be available on the day of Visit 1, the screening lung function 
assessments and ECG must be postponed until next visit, the postponed Visit 1, after the 
SARS-CoV-2 naso/oropharyngeal swab test (or rapid test) result is confirmed negative.
At a minimum, the following assessments/activities must be performed at Visit 1: obtain 
informed consent, temperature measurement, enrolment of subject in IWRS and SARS-CoV-2 
naso/oropharyngeal swab test. The remaining Visit 1 assessments can be postponed together 
with the screening lung function assessments and ECG. At the postponed Visit 1, the 
spirometry equipment will allow pre-BD, post-BD spirometry, FeNO and ECG (combined 
Visit 1 and Visit 2) to be performed. 
Visit 2 should be scheduled, if the Visit 2 post-BD spirometry and FeNO were not done at the 
postponed Visit 1. Preferably, Visit 2 should be scheduled no later than 1 week after Visit 1 
but the enrolment can be extended to accommodate additional waiting time required to obtain 
Visit 1 SARS-CoV-2 naso/oropharyngeal swab test result.
Subjects who have a blood eosinophil count <300 at enrolment Visit 1 can be re-tested at an 
unscheduled visit, upon approval of the AstraZeneca Study Physician. It is recommended that 
any re-test for blood eosinophils is performed not earlier than 4 weeks from the previous 
testing. In case of recent treatment with systemic corticosteroids, an interval of ≥6 weeks from 
the last dose is recommended.
The 35 day run-in can be extended by:

4 days for all patients (maximum run-in duration is then 39 days) or

14 days (including 4 days for all patients) for patients with exacerbation or respiratory 
infection (excluding pneumonia) during screening (maximum run-in duration is then 
49 days) (Refer to section 5.4).

waiting time required to obtain Visit 1 SARS-CoV-2 naso/oropharyngeal swab test 
result

28 days for patients receiving COVID-19 vaccine during screening

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
28 days for waiting time required to receive central lab kits  

Extension of the screening/run-in for any other reason will be allowed only upon 
approval of the AstraZeneca Study Physician (Refer to section 5.4).
The 35 day run-in can be shortened by:

4 days for all patients (run-in duration is then 31 days)
At the end of the run-in period, subjects must continue to have a CAT score ≥15, 70% 
compliance with maintenance therapy and acceptable compliance with the eDiary in order to 
be randomized. Subjects who meet the eligibility criteria will be randomized to treatment. 
Acceptable Documentation for COPD disease state and Historical COPD Exacerbations 
and Background Therapy 
A patient's verbal history suggestive of COPD symptoms and/or COPD exacerbation(s) in the 
previous year, but without supporting documentation, is not sufficient to satisfy these 
inclusion criteria. The below defines what is acceptable documentation for COPD disease and 
historical COPD exacerbations (inclusion criterion 6) in this program:

COPD disease state and COPD exacerbation(s) in the previous year:

Clinic visit (primary or specialist healthcare provider [HCP]) notes or emergency 
room/hospital records listing COPD as a current diagnosis and providing evidence 
of ≥2 moderate or severe exacerbations in the previous year (52 weeks prior to 
enrolment)

Documented prescription of systemic corticosteroids of at least 3 days duration (or 
1 injection of depot formulation) and/or antibiotics for treatment of exacerbation

Discharge summaries from a hospital, emergency room, or an urgent care facility
indicating that a subject was hospitalized or treated with systemic corticosteroids 
for a COPD exacerbation
NOTE: In case of re-screening, moderate to severe COPD exacerbations from screening 
period are considered as historical COPD exacerbations within 2 to 52 weeks prior to re 
screening Visit 1 (Inclusion 6) and should be entered in eCRF module COPDEXH and 
included in total number of historical COPD exacerbation during IWRS stratification 
transition at re-screening visit. Refer to section 5.4
The below defines what is acceptable documentation for background COPD therapy 
(inclusion criterion 7) in this program:

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
Use of triple (ICS/LABA/LAMA) background therapy for COPD throughout the previous 
year (52 weeks prior to enrolment), including assessment of patient’s compliance and any 
identified gaps in treatment or periods of double/monotherapy during the previous year:

Recent, active medication list as per HCP note

Filled prescriptions based on a pharmacy record

Another acceptable medical record as per local clinical practice
During the screening period the subject must undergo all assessments per Table 1. 
Randomization, Treatment and Follow-up
After randomization subjects will be treated at monthly intervals with the last treatment 
administered at Week 48. The end-of-treatment (EOT) visit (Week 52) will occur at 4 weeks 
after last treatment administered at Week 48. Follow-up visits will occur at Week 58 and 
Week 64 to allow for determination of immunogenicity and evaluation of safety. Subjects will 
be maintained on their currently prescribed maintenance therapies from enrolment throughout 
the run-in and treatment period. During the treatment period the subject must undergo all 
assessments per Table 2. 
During the COVID-19 pandemic, a phone call visit can replace an on-site visit and on-site IP 
administration can be replaced with home/alternative location IP administration. Patient must 
sign the COVID-19 addendum to informed consent prior to starting the alternative options of 
on-site IP administration. If obtaining signed addendum is not feasible, patient can follow 
alternative options after verbal consenting. Please refer to Appendix I for details.
The subject will enter the optional COPD exacerbation visit (EXA) and complete the 
assessments according to Table 2 if he/she experiences a COPD exacerbation during the 
treatment period, if deemed necessary by Investigator (refer to Section 8.1.1.5). 
The subject can also return to the site to complete an unscheduled visit (UNS) for the 
following reasons but not limited to, missed assessment(s) at last scheduled visit, safety follow 
up, issues with equipment, or other reasons that the site deems necessary. The UNS visit 
should not be used for a COPD exacerbation as there is an EXA visit for this reason. In 
addition to the assessments listed in Table 2, other assessments may be performed at the PI’s 
discretion. 
Section 6.5 (Table 6) provides a list of medication restrictions and prohibitions to be followed 
throughout the conduct of the clinical trial.
Interim Analyses

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Two interim analyses will be performed. The first interim analysis will occur when subjects 
with at least 3 months of follow-up represent approximately 30% of all potential follow-up 
data and will be a futility analysis to potentially stop the study early if lack of efficacy 
observed.  
The second interim analysis will be conducted approximately 1 month after all subjects have 
been randomized. This interim analysis will be used to guide an ‘Early Go’ decision by the 
sponsor to begin planning activities for the next stage of development.  Both interim analyses 
will be carried out using pre-defined rules by the IDMC while the study team remains blinded 
to ensure the integrity and blinded nature of the study. After the second interim analysis, the 
study will continue, regardless of whether the criteria for 'Early Go' was met.
4.2
Scientific Rationale for Study Design
The purpose of this global study is to provide evidence of the efficacy and safety of a 420 mg 
dose of tezepelumab administered Q4W SC in adults with a history of COPD exacerbations 
and moderate to very severe COPD receiving triple inhaled maintenance therapy with 
ICS/LABA/LAMA. 
The primary endpoint (COPD exacerbation) is a well-accepted measure for a study in COPD. 
In order to avoid bias the study will be randomized and double blinded. Subject entry will be 
stratified by region and prior number of exacerbations (2 vs ≥3) to ensure equitable 
distribution for analysis.
Given that TSLP is an upstream and pleiotropic cytokine, the blockade of TSLP is anticipated 
to have impact on the broad spectrum of inflammatory responses seen in COPD. Subject entry 
into the study will be monitored to ensure that there are adequate numbers of patients within 
different phenotypes (level of blood eosinophils and number of exacerbations in the previous 
year) for analysis.
Induced sputum analysis will be performed in a selected group of sites. The aim of this subset 
analysis is to further help to answer mechanistic and conceptual questions regarding the effect 
of tezepelumab in COPD exacerbations. Sputum biomarkers may be measured to evaluate the 
pharmacology of tezepelumab, exploratory PK, airway microbiome and biomarkers related to 
COPD, inflammation and the TSLP pathway. Key understandings are believed to come from 
sputum samples obtained at the time of COPD exacerbation. In these same subjects, analyses 
of nasal lining fluid and nasal epithelial transcriptomics will be performed to complement the 
sputum analyses.

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4.3
Justification for Dose
A 420 mg Q4W dosing regimen was selected for this Phase 2a study in COPD based on the 
efficacy, safety, and exposure-response relationships found with tezepelumab treatment in 
patients with severe asthma, as well as safety data from the Phase 1 studies.
Based on the efficacy and safety data, as well as exposure-response analysis, of the Phase 2b 
asthma study CD-RI-MEDI9929-1146, 210 mg Q4W SC was selected as the optimal dose of 
tezepelumab for adult and adolescent patients with severe asthma and is  confirmed in the 
Phase 3 studies in severe asthma. Given the uncertainty in the exposure-response relationship 
in COPD compared to asthma patients, a higher dose of 420 mg Q4W was selected to ensure 
maximum efficacy in this proof-of-concept study in COPD patients.
The safety of 420 mg SC dose has been demonstrated in the Phase 1 single ascending dose 
study 20070620, in which doses up to 420 mg SC and 700 mg IV were evaluated in healthy 
subjects and subjects with AD and well tolerated. In addition, repeated doses up to 700 mg 
Q4W IV have been evaluated and well tolerated in healthy subjects in the Phase 1 multiple 
ascending dose study 20080390 as well as the allergen challenge study 20101183 in patients 
with mild asthma. Further, in study CD-RI-MEDI9929-1146, repeated dosing at 70 mg Q4W, 
210 mg Q4W, and 280 mg Q2W SC for 52 weeks were well tolerated in subjects with severe 
asthma, and the safety profile was well balanced between the tezepelumab and placebo groups 
with no evidence of a dose relationship in treatment-emergent adverse events. Based on 
population PK model simulation, the predicted area under the concentration-time curve 
(AUC) of serum tezepelumab concentration at steady state was 
 lower and the predicted 
maximum concentration (Cmax) at steady state was 
 lower at 420 mg Q4W compared to 
280 mg Q2W SC. Therefore, the dose of 420 mg Q4W SC
 
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:
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 
CCI
CCI
CCI

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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 subject is considered to have completed the study when he/she has completed his/her last 
scheduled contact.
See Appendix A 6 for guidelines for the dissemination of study results.
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each subject should meet all the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomized to the study intervention. Under no circumstances 
can there be exceptions to this rule. Subjects who do not meet the eligibility requirements are 
screen failures (refer to Section 5.4).
In this protocol, “enrolled” subjects are defined as those who sign the informed consent.  
“Randomized” subjects are defined as those who undergo randomization and receive a 
randomization number. 
5.1
Inclusion Criteria
Subjects are eligible to be included in the study only if all the following inclusion criteria and 
none of the exclusion criteria apply:
Informed consent:
1.
Provision of signed and dated, written informed consent form prior to any 
mandatory study specific procedures, sampling, and analyses. 
2.
Provision of signed and dated written addendum to informed consent form for 
sputum/nasal sub studies prior to collection of sputum/nasal samples (if applicable). 
3.
Provision of signed and dated written genetic informed consent prior to collection 
of optional samples for genetic analysis (if applicable). 
The ICF process is described in Appendix A 3.

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Age:
4.
Female or male subjects aged ≥40 to 80 years inclusive at the time of enrolment 
(Visit 1). 
Type of subject and disease characteristics:
5.
History of moderate to very severe documented physician-diagnosed COPD for at 
least 12 months prior to enrolment with a post-bronchodilator FEV1/FVC<0.70 and 
a post-bronchodilator FEV1 ≥20% and ≤80% of predicted normal value at Visit 2 
(or Visit 1 if Visit 1 and 2 are combined). 
6.
History of at least 2 documented moderate to severe COPD exacerbations, within 2 
to 52 weeks prior to enrolment (Visit 1) or re-screening Visit 1.  See Section 4.1 for 
required source documentation for this inclusion.

A moderate COPD exacerbation is defined as an exacerbation that required 
treatment with systemic corticosteroids for at least 3 days duration (or 1 
injection of depot formulation) and/or antibiotics.

A severe COPD exacerbation is defined as an exacerbation that required 
hospitalization (defined as an inpatient admission ≥24 hours in the hospital, 
in an observation area, the emergency department or other equivalent 
healthcare facility depending on the country and healthcare system).  

Prior use of antibiotics alone does not qualify as a moderate exacerbation 
unless the antibiotic was specifically prescribed for the treatment of 
worsening COPD symptoms.

Previous exacerbations should be confirmed to have occurred while patient 
was on stable triple (ICS/LABA/LAMA) background therapy for COPD and 
not as a result of a step down in therapy, i.e. change from triple to dual 
therapy.
NOTE: In case of re-screening, moderate to severe COPD exacerbations 
from screening period are considered as historical COPD exacerbations 
within 2 to 52 weeks prior to re-screening visit and should be included in 
total number of historical COPD exacerbations. Refer to section 5.4
7.
Documented treatment with medium or high dose ICS at a total daily dose 
corresponding to >250μg fluticasone propionate dry powder formulation equivalent 
and LABA and LAMA for COPD throughout the year prior to enrolment (Visit 1). 
The dose of ICS should be stable for 3 months prior to Visit 1. See Section 4.1 for 
required source documentation for this inclusion criterion. See Appendix F for ICS 
dose conversion table. 

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
Patient could have switched therapies during the previous year and/or 
stepped down for short periods of time, although the total cumulative 
duration that the patient was not using triple (ICS/LABA/LAMA) 
background therapy must not exceed 2 months.

If an Investigator decides to switch a subject who is on an ICS in a separate 
single device to a fixed-dose combination device therapy, this should be done 
at Visit 1 and the ICS component must remain at the same dose and schedule 
as used in the 3 months prior to Visit 1 (provided dose and regimen are 
locally approved for COPD).
8.
CAT score ≥15 at Visit 1 (only based on ePRO questionnaire).
9.
Current smoker or ex-smoker with a tobacco history of ≥10 pack-years (1 pack year 
= 20 cigarettes smoked per day for 1 year). Never smokers are not eligible for study 
entry.
10.
If on allergen-specific immunotherapy, subjects must be on a maintenance dose and 
schedule for at least 2 months prior to Visit 1. 
11.
If on theophylline or roflumilast, subjects must be on maintenance treatment for at 
least 12 months prior to Visit 1 and on stable dose 3 months prior to Visit 1. 
Note: Subjects on maintenance treatment with theophylline should have blood 
concentration levels within the therapeutic range documented within 8 weeks prior 
to Visit 1. If this is not documented before signing the informed consent, it can be 
obtained after informed consent has been given or as part of the Visit 1 procedures 
(see Section 6.3 and Table 6.
12.
Inclusion criterion 12 removed with version 4.0 of Clinical Study Protocol and 
replaced with Exclusion criterion 40.
Weight:
13.
Weight ≥40 kg at Visit 1.
Reproduction:
14.
Negative serum pregnancy test for female subjects of childbearing potential.
15.
Women of childbearing potential (WOCBP) who are sexually active must use a 
highly effective form of birth control from enrolment and must agree to continue 
using such precautions for 16 weeks after the final dose of IP. Cessation of 
contraception after this point should be discussed with a responsible physician. 
Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception. 

An effective method of contraception is defined as one that results in a low 

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failure rate (i.e., less than 1% per year) when used consistently and correctly. 
Highly effective birth control methods include: sexual abstinence [periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of exposure to IMP, and withdrawal 
are not acceptable methods of contraception], a vasectomized partner, 
Implanon®, bilateral tubal occlusion, intrauterine device/levonorgestrel 
intrauterine system, Depo-Provera™ injections, oral contraceptive, and Evra 
Patch™, Xulane™, or NuvaRing®.

Women not of childbearing potential are defined as women who are either 
permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy), or who are postmenopausal. Women will be considered 
postmenopausal if they have been amenorrhoeic for 12 months prior to the 
planned date of randomization without an alternative medical cause. The 
following age-specific requirements apply:
(a) 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 (FSH) levels in the 
postmenopausal range. Until FSH is documented to be within menopausal 
range, treat the subject as WoCBP.                                                                                           
(b) 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. 
Additional criteria to be checked prior to randomization (Visit 3): 
16.
Compliance with the eDiary completion during the run-in period defined as 
completing at least 8 EXACT-PRO/E-RS assessments in the 12-day period prior to 
Visit 3.
17.
At least 70% compliance with the subject’s maintenance therapy (defined as taking 
all maintenance medication as scheduled for the day) during the run-in period from 
Visit 2 (or Visit 1 if Visit 1 and 2 are combined) to Visit 3 based on the eDiary.
18.
A CAT score of ≥15 (only based on ePRO questionnaire).
19.
Stable FEV1 during the screening period, defined as a change in pre-BD FEV1 ≤400 
mL and/or ≤25% compared to baseline pre-BD (Visit 1) assessment. If a patient 
demonstrates significant change (>400 mL and/or >25% in either direction) in pre-
BD FEV1 during the screening period, the AZ study physician must be consulted to 
determine the patient's disposition; randomization may not occur without 
consultation and agreement with AZ study physician/delegate.

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20.
Acceptable inhaler and spirometry techniques according to the American Thoracic 
Society/European Respiratory Society (ATS/ERS) guidelines (Miller et al 2005) 
during the run-in period. 
5.2
Exclusion Criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled:
Medical conditions:
1.
Clinically important pulmonary disease other than COPD, as judged by 
Investigator, (e.g., active lung infection, main clinical feature is bronchiectasis or 
emphysema, 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 (e.g., allergic 
bronchopulmonary aspergillosis (ABPA)/mycosis, eosinophilic granulomatosis with 
polyangiitis (EGPA), hypereosinophilic syndrome) and/ or radiological and/or 
laboratory findings suggestive of a respiratory disease other than COPD that is 
contributing to the subject’s respiratory symptoms.  
2.
Current asthma diagnosis according to the Global Initiative for Asthma (GINA) 
guidelines (GINA 2018) or other accepted guidelines. Patients with a history of 
asthma, including paediatric asthma or asthma-COPD Overlap Syndrome (ACOS), 
are not eligible for the study.  
3.
Any disorder, including, but not limited to, cardiovascular, gastrointestinal, hepatic, 
renal, neurological, musculoskeletal, infectious (including risk factors for 
pneumonia), endocrine, metabolic, haematological, immune, psychiatric, or major 
physical impairment that is not stable in the opinion of the Investigator and/or 
could:
(a) Affect the safety of the subject throughout the study
(b) Influence the findings of the study or their interpretation
(c) Impede the subject’s ability to complete the entire duration of study
Note: Subjects who have epilepsy must be on a stable dose of medication for 28 days 
prior to randomization.
4.
Unstable ischemic heart disease, arrhythmia, cardiomyopathy, heart failure, renal 
failure, uncontrolled hypertension as defined by the Investigator, or any other 
relevant cardiovascular disorder as judged by the Investigator or any ECG 
abnormality obtained during the screening period that in Investigator’s judgement 
may put the patient at risk or negatively affect the outcome of the study.

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5.
Treatment with systemic corticosteroids and/or antibiotics, and/or hospitalization 
for a COPD exacerbation within 14 days prior to enrolment (Visit 1), based on last 
dose of corticosteroids or last date of hospitalization, whichever occurred later.
Note: Refer to Exclusion criteria 19 for restriction with maintenance systemic 
steroid treatment.
6.
History of clinically significant infection (excluding pneumonia), acute upper or 
lower respiratory infection, requiring antibiotics or antiviral medication within 14 
days prior to enrolment (Visit 1) based on the last day of antibiotic/antiviral 
treatment or hospitalization date, whatever occurred later.  
7.
History of pneumonia requiring antibiotics or antiviral medication within 28 days 
prior to enrolment (Visit 1) or during the screening period, based on the last day of 
antibiotics or hospitalization date, whatever occurred later or during the enrolment 
and screening period. 
8.
Known history of allergy or reaction to any component of the investigational 
product formulation.
9.
History of anaphylaxis to any other biologic therapy.
10.
Donation of blood, plasma, or platelets within the past 90 days prior to Visit 1.
11.
A helminth parasitic infection diagnosed within 24 weeks prior to Visit 1 that has 
not been treated with, or has failed to respond to, standard of care therapy.
12.
History of alcohol or drug abuse within the past year, which may compromise the 
study data interpretation as judged by Investigator or Study Physician.
13.
History of cancer: 

Subjects who have had basal cell carcinoma, localized squamous cell 
carcinoma of the skin or in situ carcinoma of the cervix are eligible to 
participate in the study provided that curative therapy was completed at least 12 
months prior to Visit 1. 

Subjects who have had other malignancies are eligible provided that curative 
therapy was completed at least 5 years prior to Visit 1.
14.
Subjects who in the opinion of the Investigator have evidence of active tuberculosis 
(TB), either treated or untreated, or latent TB without completion of an appropriate 
course of treatment. Evaluation will be according to the local standard of care as 
determined by local guidelines and may consist of medical history and physical 
examinations, chest x-ray, sputum stain and/or culture, and/or TB test (e.g., purified 
protein derivative or QuantiFeron test). 
15.
Major surgery within 8 weeks prior to Visit 1 or planned surgical procedures 

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requiring general anaesthesia or in-patient status for >1 day during the conduct of 
the study.
Prior/concomitant therapy:
16.
Subjects currently receiving background therapy that is not locally approved for 
COPD are not eligible for the study (refer to Section 6.5.1)
17.
Long term oxygen therapy (LTOT) with signs and/or symptoms of cor pulmonale 
and/or right ventricular failure, or subjects receiving LTOT >4.0 litres/minute 
(L/min), or saturation <89% despite LTOT. 
18.
Use of any non-invasive positive pressure ventilation device (NIPPV).  Note: 
Subjects using continuous positive airway pressure (CPAP) or bilevel positive 
airway pressure (BiPAP) for Sleep Apnea Syndrome are allowed in the study.
19.
Use of systemic immunosuppressive medication (including but not limited to 
methotrexate, cyclosporine, maintenance systemic steroid treatment, any 
experimental anti-inflammatory therapy) within 3 months prior to enrolment (Visit 
1) or throughout the screening period. Use of systemic steroids for treatment of 
exacerbations is allowed (see exclusion criterion 5). 
20.
Receipt of immunoglobulin or blood products within 30 days prior to enrolment 
(Visit 1).
21.
Receipt of any investigational non-biologic product within 30 days or 5 half-lives 
whichever is longer, prior to Visit 1.
22.
Receipt of any marketed (e.g., omalizumab) or any investigational monoclonal or 
polyclonal antibody therapy (e.g., gamma globulin) taken for any reason within 4 
months or 5 half-lives prior to Visit 1, whichever is longer.
23.
Receipt of live attenuated vaccines 30 days prior to first IP administration.
24.
Chronic use of macrolide or other antibiotics for prophylactic use of COPD 
exacerbation if duration of treatment is < 9 months prior to enrolment (Visit 1) or 
re-screening visit. If the patient was previously on prophylactic treatment but is no 
longer taking it, the patient cannot be randomized until 6 weeks after the last dose.
Chronic macrolide or other antibiotic therapy is allowed provided the patient has 
been on a stable dose/regimen for ≥ 9 months prior to enrolment (Visit 1) or re-
screening visit and have had at least 2 historical COPD exacerbations while on 
prophylactic treatment.
Note: Patients who received ≥6 months of antibiotics treatment in the previous year 
must have a hearing assessment performed as per local standard of care within 3 
months prior to randomization. These patients must be interviewed for potential 

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hearing issues/tinnitus at enrolment; any reported issues will be recorded as part of 
medical history.  
25.
Influenza vaccination within 3 weeks before sputum collection (Visit 3) for subset 
of subjects only. Vaccination prior to that or after that time is acceptable.
26.
Subjects with lung volume reduction surgery within the 6 months prior to Visit 1.  
Subjects with history of partial or total lung resection (single lobe or 
segmentectomy is acceptable).
27.
Subjects that have been treated with bronchial thermoplasty or received 
endobronchial valves in the last 12 months prior to Visit 1. 
Prior/concurrent clinical study experience: 
28.
Subjects participating in, or scheduled for, an intensive (active) COPD 
rehabilitation program (however subjects who are in the maintenance phase of a 
rehabilitation program are eligible to take part).
29.
Employees of the clinical study centre or family members (first-degree relatives) of 
such individuals or anyone involved in the planning and/or conduct of the study.
30.
Previous treatment with tezepelumab (MEDI9929/AMG157).
Diagnostic assessments:
31.
Any clinically significant abnormal findings in physical examination, vital signs, 
hematology, clinical chemistry, or urinalysis during screening period, which in the 
opinion of the Investigator, may put the subject at risk because of his/her 
participation in the study, or may influence the results of the study, or the subject’s 
ability to complete entire duration of the study.
32.
Evidence of active liver disease (with or without ongoing treatment), including 
jaundice or aspartate transaminase (AST), alanine transaminase (ALT), or alkaline 
phosphatase (ALP) > 2 times the upper limit of normal (ULN) at Visit 1.
33.
Subjects are excluded if they have any of the following:

A history of known immunodeficiency disorder including a positive test for 
human immunodeficiency virus, HIV-1 or HIV-2 at Visit 1.

Positive hepatitis B surface antigen, or positive hepatitis C virus antibody 
serology, or a positive medical history for hepatitis B or C at Visit 1.  Patients 
with a history of hepatitis B vaccination without history of hepatitis B are 
allowed to enrol.
Other exclusions:

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34.
Pregnant, breastfeeding, or lactating women.

A serum β-HCG pregnancy test must be drawn for women of childbearing 
potential at the screening visit. If test result is positive, the subject should be 
excluded. Since urine and serum tests may miss a pregnancy in the first days 
after conception, relevant menstrual history and sexual history, including 
methods of contraception, should be considered. Any subject whose 
menstrual and/or sexual history suggests the possibility of early pregnancy 
should be excluded. 
35.
Judgment by the Investigator that the subject should not participate in the study if 
the subject is unlikely to comply with study procedures, restrictions and 
requirements or for safety reasons.
Genetic Research exclusion criteria:
36.
Previous allogeneic bone marrow transplant.
37.
Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample 
collection.
COVID-19 pandemic exclusion criteria:
38.
Judgment by the Investigator that the subject should not participate in the study 
based on assessment of COVID-19 symptoms for active COVID-19 infection or is 
febrile (≥ 38°C; ≥ 100.4°F) suspected due to COVID-19 infection. 
39.
Positive SARS-CoV-2 naso/oropharyngeal swab test, positive rapid antigen test or  
positive alternative test (approved by local health authorities) for active infection at 
Visit 1. 
40.
Chest X-ray performed during the screening period which shows abnormalities or 
evidence of  COVID-19 pneumonia that precludes the patient’s ability to complete 
the study. 
Note: Under special circumstances, a recently done historical chest X-ray (anterior-
posterior and lateral)/CT/MRI for other reasons (not study related) might be 
acceptable. The outcome of the X-ray/CT/MRI must be documented in the patients’ 
medical records. Study Physician approval of historical chest X-ray must be 
obtained prior to randomization.
41.
Receipt of any COVID-19 vaccine within 28 days prior to date of randomization.

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5.3
Lifestyle Restrictions
Subjects must abstain from donating blood and plasma from the time of informed consent, and 
for 16 weeks (5 half-lives) after last dose of IP.
5.3.1
Meals and Dietary Restrictions
Subjects should avoid eating a large meal for at least 2 hours prior to all lung function 
assessments at the site.
Subjects should not eat or drink 1 hour prior to having FeNO assessment.
5.3.2
Alcohol, Tobacco and Other
Chronic alcohol or drug abuse within 12 months is restricted prior to Visit 1 and throughout 
the conduct of the study.
Current tobacco smokers or subjects with smoking history ≥ 10 pack-years (1 pack year = 20 
cigarettes smoked per day for 1 year) at Visit 1 are allowed. Never smokers are not allowed to 
enter the study. Smoking status will be captured on the eCRF throughout the study. See 
Section 8.2.2.
The use of e-cigarettes (e.g., JUUL) is allowed during the course of the study. 
Subjects should not smoke on the assessment day prior to all lung function assessments at the 
site.
5.3.3
Activity
Subjects should avoid engaging in strenuous exertion for at least 30 minutes prior to all lung 
function assessments at the site.
5.4
Screen Failures and Re-screening
Screen failures are defined as subjects who signed the informed consent form to participate in 
the clinical study but are not subsequently randomized. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects 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 serious adverse event (SAE).
These subjects should have the reason for study withdrawal recorded as ‘Screen Failure’ (i.e., 
subject does not meet the required inclusion/exclusion criteria) in the electronic case report 

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form (eCRF). This reason for study withdrawal is only valid for screen failures, and not 
randomized subjects. 
In following situations, the screening may be extended without prior approval from 
AstraZeneca Study Physician:

Subjects that experience a COPD exacerbation during the screening period: May 
remain in screening and the screening period may be extended up to 14 days to allow 
for the completion of the course of systemic corticosteroids and/or antibiotics if 
deemed suitable by the Investigator.
Note: Enrolment: Subjects treated with systemic corticosteroids and/or antibiotics 
and/or hospitalization for a COPD exacerbation within 14 days prior to enrolment 
(Visit 1 or re-screening Visit 1), should be delayed allowing patient to be eligible for 
the study (exclusion criterion 5).

Subjects with respiratory infection (excluding pneumonia) requiring antibiotics or 
antiviral medication within 14 days prior to Visit 1 or during the screening period:
May remain in screening and the screening period may be extended up to 14 days to 
allow for the completion of therapy if deemed suitable by the Investigator.
Note: Subjects treated with antibiotics or antiviral medications for respiratory infection 
within 14 days prior to enrolment (Visit 1 or re-screening Visit 1) should be delayed 
allowing patient to be eligible for the study (exclusion criterion 6).

Subjects with respiratory infection (excluding pneumonia) NOT requiring antibiotics 
or antiviral medication during the screening period:
May remain in screening and the screening period may be extended up to 14 days to 
allow subject to meet FeNO restrictions.
Note: Subjects without antibiotics or antiviral medications for respiratory infection 
within 14 days prior to enrolment (Visit 1 or re-screening Visit 1) should be delayed 
allowing patient to meet FeNO restrictions.
Extension of the screening period for any other reason will be allowed only upon approval of 
the AstraZeneca Study Physician. 
In following situation, subject must be screen failed:

Subjects who experience pneumonia during the screening period should be screen 
failed. They may be re-screened but no sooner than 28 days after the last day of 
antibiotic treatment or the last date of hospitalization, whatever occurred later 
(exclusion criterion 7).

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
Judgment by the Investigator that the subject should not participate in the study based 
on assessment of COVID-19 signs and symptoms for active infection. Subject can 
be re-screened within 2 to 4 weeks, upon approval of the AZ Study Physician 
(exclusion criterion 38).

Subject who had positive SARS-CoV-2 naso/oropharyngeal test (or rapid test) at 
Visit 1 for active infection during screening should be screen failed. They may be re-
screened once recovered from the infection, upon approval of the AZ Study Physician 
(exclusion criterion 39).
Re-screening:
If the reason for screen failure was transient (including but not limited to study-supplied 
equipment failure, unforeseen personal events that mandate missed screening visits, etc), 
subjects may potentially be re-screened. These cases should be discussed with the 
AstraZeneca study physician and documented in the Investigator Study File (ISF).
Re-screening for subjects who have screen-failed due to ePRO criteria (e.g., did not meet 
minimum EXACT-PRO/E-RS™: COPD requirement or did not report adequate compliance 
with maintenance medications) is not allowed. 
Re-screening of a subject for any reason will be allowed only upon approval of the
AstraZeneca Study Physician. A documented approval for re-screening should be filed in the 
Investigator Study File (ISF).
Any re-screened subject will be re-enrolled and reassigned their originally assigned subject 
number after signing a new ICF and addendum to ICF (if applicable) and after all Visit 1 
assessments have been performed as listed in Table 1 (with the exception of testing for HIV-1 
and HIV-2, hepatitis B and C, and FSH). If the timeframe between Screening and Re-
screening is more than 30 days, then all Visit 1 assessments should be repeated.
In case of re-screening, moderate to severe COPD exacerbations from screening period are 
considered as historical COPD exacerbations within 2 to 52 weeks prior to re-screening Visit 
1 (Inclusion 6) and should be entered in eCRF module COPDEXH and included in total 
number of historical COPD exacerbation during IWRS stratification transition at re-screening 
Visit 1.
Rescreened subjects should be assigned the same subject number as for the initial screening. 
However, rescreening should be documented so that its effect on study results, if any, can be 
assessed. 
Subjects who were screen failed when the recruitment was temporarily paused due to the 
COVID-19 pandemic may be allowed to re-screen even if the subjects have already been re-

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screened once before. A documented approval for re-screening due to COVID-19 should be 
filed in the Investigator Study File (ISF).
6.
STUDY TREATMENTS
Study treatment is defined as an IP (including placebo) intended to be administered to a study 
participant according to the study protocol. Study treatment in this study refers to tezepelumab 
or placebo.
6.1
Treatments Administered
6.1.1
Investigational Products
All investigational products will be manufactured in accordance with Good Manufacturing 
Practice (GMP).
Each subject will receive two SC injections at each dosing interval to receive a total dose of 
420 mg tezepelumab, or placebo.
Table 5 - Study Treatments
Treatment 1
Treatment 2
Study treatment name:
Tezepelumab
Placebo
Dosage formulation:
0.7% (w/v) sodium carboxy 
methyl cellulose in 10 mM 
acetate, 250 mM L-proline, 
0.01% (w/v) polysorbate 80, 
pH 5.0
Route of administration 
Subcutaneous
Subcutaneous
Dosing instructions:
Refer to Section 6.1.2
Refer to Section 6.1.2
Packaging and labelling
Study treatment will be
provided in an APFS with
1.91 mL fill volume. Each
APFS will be labelled in
accordance with GMP
Annex 13 per country
regulatory requirement. The 
labels will be translated into
local language where
applicable.
Study treatment will be
provided in an APFS with
1.91 mL fill volume. Each
APFS will be labelled in
accordance with GMP
Annex 13 per country
regulatory requirement. The 
labels will be translated into
local language where
applicable.
APFS – Accessorised Pre-Filled Syringe
CCI

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The accessorized pre-filled syringe (APFS) is a single use, disposable system that is designed
to deliver the labelled dose to the subcutaneous space during one injection and automatically 
provide a safety mechanism to reduce the occurrence of accidental needle sticks during 
disposal of the system.
The APFS consists of a pre-filled syringe sub-assembly (PFS-SA; 1 mL long prefilled syringe
barrel with a 1/2-inch 27-gauge thin wall staked in needle, rigid needle shield, plunger 
stopper) and a safety device.
6.1.2
Medical Devices
The sponsor manufactured medical device, which forms part of the combination product and
is referred to as a device constituent part, provided for use in this study is:

Accessorised pre-filled syringe (APFS)
Instructions for medical device use are provided in IP Handling Instructions and Pharmacy 
Manual.
All medical device deficiencies (including malfunction, use error and inadequate labelling) 
shall be documented and reported by the Investigator throughout the study (see Section 
8.3.10) and appropriately managed by the manufacturer.
6.2
Preparation/Handling/Storage/Accountability
IP will be supplied to the site in a kit containing APFS tezepelumab or matching placebo. 
Each kit has a unique number that is printed on all labels within the kit (i.e., the outer carton 
label and the label of each APFS within the carton).
The Investigator or designee must confirm appropriate temperature conditions have been
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the IP. 
The IP is to be stored at the study centre in a secured facility with limited access and 
controlled temperature. The temperature should be monitored on a daily basis and documented 
in the temperature monitoring log while IP is stored at the study centre. The IP must be kept in 
the original outer container and under conditions specified on the label (between 2°C to 8°C 
[36°F to 46°F], protected from light). Only subjects randomized in the study may receive 
study treatment. Only authorized site staff may supply or administer study treatment. 

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The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records). 
The centre staff should not administer the affected IP and should immediately contact an 
AstraZeneca representative for further guidance if the following cases are met:

Temperature excursion upon receipt or during storage at the study centre

Storage conditions were not met (e.g., frozen) or cannot be confirmed

Damaged kit upon receipt

Damaged APFS device

Security seal on the carton has been broken

The expiration date has passed

Other reason(s) that may have affected the IP
Damaged IP should be documented via IWRS (please refer to IWRS manual for further 
details).
Please Note: If allowed by local and regional guidelines, IP preparation and administration 
may be performed at the subject’s home/alternative location by a qualified HCP. Before 
initiating consent for home IP administration visit, the subject must have received at least the 
first 2 IP administrations at the site. Please refer to Appendix I for further details.
Dose preparation 
Each APFS should be visually inspected prior to dose preparation. The IP will be provided to 
the study sites as a clear to slightly opalescent, colorless to slightly yellow clear solution 
contained in a pre-filled syringe to be stored between 2°C to 8°C [36°F to 46°F] until used.
If defects are noted with the IP, the Investigator and site monitor should be notified 
immediately. Preparation of IP must be performed by a qualified person (e.g., pharmacist, 
Investigator, or nurse) at the site.
The IP does not contain preservatives and any unused portion must be discarded. Preparation 
of the IP is to be performed aseptically. Total in-use storage time from removal of the IP from 
the refrigerator to start of administration should not exceed 8 hours. If storage time exceeds 
this limit, a new dose must be prepared with a new IP kit.
To prepare the subject’s dose, two IP kits will be selected for administration according to the 
kit identification numbers assigned by IWRS.  

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Dose preparation steps:
1. Allow the IP to equilibrate to room temperature 68°F to 77°F (20°C to 25°C) for at 
least 60 minutes prior to dose administration. Ensure that the APFS is adequately 
protected from light during the warming process. 
2. To prepare IP for administration remove the syringe from the carton by holding the 
middle of the syringe body.
3. Unwrap, but do not detach, the wrap-around label attached to syringe body to view the 
syringe contents.
4. Look at the liquid through the viewing window. The liquid should be clear and 
colorless to slightly yellow. Do not inject IP if the liquid is cloudy, discolored, or 
contains large particles.
5. Re-wrap the label around the syringe body.
Unused product in opened and dispensed IP kits should not be used for subsequent dosing and 
should be stored for IP accountability. If the opened and dispensed IP kits must be discarded 
immediately after dose preparation as per site’s Standard Operating Procedures (SOP), the 
syringe labels along with the kit boxes must be retained for IP accountability.
Dose administration
The IP will be administered by the Investigator/authorized delegate. Two injections are 
required and will be administered at the same anatomical site with a distance of at least 1 inch 
(3 cm) between the two injections. The injection site must be recorded in the source 
documents at each treatment visit and recorded in the eCRF.
The person administering the dose will wipe the skin surface of the upper arm, anterior thigh
or abdomen with alcohol and allow to air dry. The skin will be pinched to isolate the SC
tissue from the muscle. The needle will be fully inserted at a 45-degree angle approximately
into the SC tissue. The injection site should not be rubbed after each injection. The second 
injection should be administered immediately after the first one.
It is advised that the site of injection of IP be rotated such that the subject receives IP at a 
different anatomical site at each treatment visit. Injection site must be documented on the 
eCRF and in the source documents at each treatment visit. In cases when rotation of the 
injection site is not feasible, and/or the subject prefers not to rotate injection sites, the reason 
for not rotating the injection site should be documented in the source documents. The 
suggested injection site rotation sequence is presented below in Figure 2.

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Figure 2 - Suggested Schema of Rotation of Injection Sites
Further details on IP administration are provided in the IP Handling Instructions document. IP 
administration must be carried out according to these instructions.
Subjects should be observed for a minimum of 2 hours after administration of the first two IP 
dosing visits for the appearance of any acute drug reactions. For the remaining doses, subjects 
will be observed for a minimum of 1 hour after IP administration for any such reaction.
If any of the following should occur, the IP should not be administered: 

The subject received allergen immunotherapy injection on the same day as scheduled 
IP administration. 

The subject has an intercurrent illness that in the opinion of the Investigator and/or 
medical monitor may compromise the safety of the subject in the study (e.g., viral 
illnesses). 

The subject is febrile (≥ 38°C; ≥ 100.4°F) within 72 hours prior to IP administration. 

The subject is confirmed to have an active COVID-19 infection based on positive 
SARS-CoV-2 test results.

The subject is suspected to have an active COVID-19 infection based on assessment of 
COVID-19 symptoms.

The subject received COVID-19 vaccination or is planning to receive COVID-19 
vaccination where the required time interval between IP dosing and COVID-19 
vaccination as specified in section 8.2.10, Table 8 cannot be followed.
The visit should be rescheduled within the allowed visit window and IP should be 
administered at that visit. If this is not possible the IP administration should be skipped. 
If the subject is suspected to have an active COVID-19 infection or fever (≥ 38°C; ≥ 100.4°F) 
suspected due to COVID-19 infection, the visit should be rescheduled (and IP administration 

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deferred) and subject should be re-assessed for symptoms of COVID-19 prior to re-scheduled 
visit. 
AZ Study Physician should be contacted to discuss further subject participation in the 
following situations:

The subject has been diagnosed with an active COVID-19 infection.

The subject skips 2 consecutive IP administrations.
If the subject reports an injection site reaction, the Investigator or qualified designee will 
complete the AE eCRF page and an additional eCRF page with questions about the injection 
site reaction.
The subject may remain in the study after an exacerbation and continue to receive IP if the 
investigator judges that it is medically appropriate for the subject to do so.
6.3
Measures to Minimise Bias: Randomization and Blinding
The Investigator(s) will:
1. Obtain signed informed consent from the potential subject before any study specific 
procedures are performed.
2. Assign the potential subject a unique enrolment number (which begins with an ‘E’) via 
IWRS.
3. Determine subject eligibility. 
4. Assign the eligible subject unique randomization code via IWRS.
5. Subjects will be allocated to receive tezepelumab or placebo in a 1:1 ratio and 
according to the stratification factors listed in Section 4.1. Randomization numbers 
will be grouped in blocks. If a subject withdraws from the study, then his/her 
enrolment/randomization code cannot be reused. Withdrawn subjects will not be 
replaced.
Specific information concerning the use of the IWRS will be provided in a separate manual.
Procedures for handling incorrectly enrolled or randomized subjects
Subjects who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive study medication. There can be no exceptions to this rule. Subjects who 
are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomized or initiated on treatment and must be withdrawn from the study.

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Where a subject does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca study 
physician immediately, and a discussion should occur between the AstraZeneca study 
physician and the Investigator regarding whether to continue or discontinue the subject from 
treatment. Study treatment must be discontinued in all cases where continued treatment is 
deemed to pose a safety risk to the patient and AstraZeneca study physician must ensure the 
decision is appropriately documented. Subjects that are discontinued from treatment should be 
followed up according to the options described in Section 7.1.1.
In those cases where continuation of the study therapy is judged not to present a concern 
related to safety and disease management, the rationale for continuing study therapy must also 
be clearly documented.
Methods for assigning treatment groups
Randomization codes will be assigned strictly sequentially in each stratum as subjects become 
eligible for randomization.
The randomization code will be assigned from a randomization list prepared by a 
computerized system provided by 
 on behalf of AZ (AZRand). All subjects will be 
stratified at randomization by region and number of exacerbations in the 12 months prior to 
Visit 1 (or re-screening Visit 1) (2 vs ≥ 3).
In order to achieve the assumed exacerbation rates used to determine sample size, it is 
expected that approximately 30% of subjects will have had at least 1 severe exacerbation (an 
exacerbation resulting in hospitalization) within 12 months prior to Visit 1 (or re-screening 
Visit 1) and approximately 40% of subjects will have had ≥3 exacerbations within 12 months 
prior to Visit 1 (or re-screening Visit 1). (Refer to Section 4.1)  
Consideration will be given to closing the Interactive Web Response System (IWRS) 
randomization for a subgroup [by region or overall] to ensure that approximately 20% of the 
subjects will be targeted to have ≥300 eosinophils/μL, 40% of the subjects between ≥150 to 
<300 eosinophils/μL and a maximum of approximately 40% of the subjects with <150 
eosinophils/μL at enrolment.
Ensuring blinding 
This is a double-blind study in which tezepelumab and placebo are not visually distinct from 
each other. All packaging and labelling of IP will be done in such way as to ensure blinding 
for all sponsor and investigational site staff. Neither the subject nor any of the Investigators or 
sponsor staff who are involved in the treatment or clinical evaluation and monitoring of the 
subjects will be aware of the treatment received. Since tezepelumab and placebo are not 
PPD

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visually distinct, IP will be handled by a qualified person (e.g., pharmacist or study nurse) at 
the site. 
An AstraZeneca site monitor will perform IP accountability. In the event that the treatment 
allocation for a subject becomes known to the Investigator or other study staff involved in the 
management of study subjects or needs to be known to treat an individual subject for an AE, 
the sponsor must be notified immediately by the Investigator and, if possible, before 
unblinding.
The following personnel will have access to the randomization list:

Those carrying out the packaging and labelling of IP

Those generating the randomization list

Personnel at the IWRS company

Supply Chain Management department

Patient Safety department at AstraZeneca

Bioanalytical lab performing the PK sample analysis

Those involved in the reporting and reviewing the unblinded IDMC presentations
The information in the randomization list will be kept from other personnel involved in the 
conduct of the study and in a secure location until the end of the study.
No other member of the extended study team at AstraZeneca, or any Contract Research 
Organization (CRO) handling data, will have access to the randomization scheme during the 
conduct of the study until after the primary database lock.
Methods for unblinding
Individual treatment codes, indicating the treatment randomization for each randomized 
subject, will be available to the Investigator(s) and delegate(s) at the study sites from the 
IWRS. Routines for this will be described in the IWRS user manual that will be provided to 
each site.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the subject requires knowledge of the treatment randomization. The 
Investigator should document and report the action to AstraZeneca, without revealing the 
treatment given to subject 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 IP and that potentially require expedited reporting to 
regulatory authorities. Treatment codes will not be broken for the planned analyses of data 
until all decisions on the evaluability of the data from each individual subject have been made 
and documented and until primary database lock after last subject completes week 52 has been 
documented.

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6.4
Compliance to IP
Any change from the dosing schedule or dose discontinuations should be recorded in the 
eCRF.
The IP Storage Manager is responsible for managing the IP from receipt by the study site until 
the destruction or return of all unused IP. The date and time of all IP administrations, as well 
as any missed doses with the reason for drug interruption, should be recorded in the 
appropriate section of the eCRF.
6.5
Concomitant Therapy
Information about all COPD medications given within the 12 months prior to Visit 1, all 
medications for other indications given in the 3 months prior to Visit 1, COVID-19 vaccine 
given at any time, and all concomitant medications given during the study, with reason for the 
treatment, will be collected by the Investigator/authorized delegate at each visit (as shown in 
Table 1 and Table 2) and recorded in the eCRF.
The subject’s usual pre-study triple inhaled therapy (medium to high dose ICS/LABA/LAMA) 
formulation, dose and regimen, and any other additional allowed COPD medications that may 
have been taken prior to enrolment, should be continued without any change throughout the 
enrolment, run-in, treatment and follow-up period as outlined below. 
As theophylline has a narrow therapeutic window, please note that subjects on maintenance 
treatment with theophylline should have blood concentration levels within therapeutic range 
documented within 8 weeks prior to Visit 1 (see Table 6). If this is not documented before 
signing the informed consent, it can be obtained after informed consent has been given or as 
part of the Visit 1 procedures. The sample can be analyzed at the central or local lab as 
applicable. Theophylline blood levels greater than 12mg/dl should be managed according to 
local standards of care and the Investigator’s judgment and discussed with AZ study physician 
prior to randomization. It is recommended that additional increments in dose are evaluated 
with blood levels. Investigator can use their clinical judgement about the therapeutic range of 
theophylline levels on the basis of sampling time and other factors that may impact the results.
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the subject 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

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Table 6 - Allowed, Restricted and Prohibited Medications
Medication
Allowed/ 
Restricted/ 
Prohibited
Details
Background 
(maintenance) COPD 
medication 
(ICS/LABA/LAMA) 
Allowed
Documented treatment with medium or high 
dose ICS at a total daily dose corresponding to 
>250μg fluticasone propionate dry powder 
formulation equivalent and a LABA and 
LAMA for COPD throughout the year prior to 
enrolment (Visit 1) and throughout the study. 
The dose of ICS should be stable 3 months 
prior to V1 and throughout the study. See 
inclusion criterion 7. 
ICS in a separate, single device is permitted if 
all the following criteria are met:
- it is administered at the same dose and 
schedule as in the fixed dose combination 
product; 
- it is not given in combination with a LAMA 
alone. 
If an Investigator decides to switch a subject 
who is on an ICS in a separate single device to 
a fixed-dose combination device therapy, this 
should be done at Visit 1 and the ICS 
component must remain at the same dose and 
schedule as used in the 3 months prior to Visit 
1 (provided dose and regimen are locally 
approved for COPD).
Nebulized budesonide is accepted as part of 
maintenance therapy if the dosing regimen is 
equivalent to that of budesonide approved as 
part of a combination product for COPD (e.g., 
for budesonide/formoterol combination 
320mcg/9mcg BID equivalent dose of 
nebulized budesonide is 0.5mg BID [GOLD 
2019]

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Medication
Allowed/ 
Restricted/ 
Prohibited
Details
Nebulized LABA is accepted as part of 
maintenance therapy.
Twice daily triple inhaled 
(ICS/LABA/LAMA) medications should be 
withheld at least 12 hours prior to scheduled 
spirometry at site.
Once daily triple inhaled (ICS/LABA/LAMA) 
medications should be withheld at least 24 
hours prior to scheduled spirometry at site
Twice daily LABA or LAMA-containing 
therapies should be withheld for at least 12 
hours prior to scheduled spirometry at site.
Once daily LABA or LAMA-containing 
therapies should be withheld for at least 24 
hours prior to scheduled spirometry at site.
Additional ICS on top of 
COPD ICS maintenance 
medication
Restricted
Can only be given concomitantly with 
systemic steroids during acute COPD 
exacerbation treatment while at site or other 
health care provider. Additional use of ICS 
outside of this is not allowed.
Systemic corticosteroids 
(tablets or injections)
Restricted
Prohibited as maintenance treatment within 3 
months prior to Visit 1 and throughout the 
study. 
Allowed to treat a COPD exacerbation or an 
AE where there is no alternative treatment 
available, for no more than 14 days. 
If treatment duration is expected to exceed 14 
days, the AstraZeneca study physician must 
be contacted.
Maintenance SABA 
(short-acting β2-
Prohibited if 
Please see below. Use on their own, or for 

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Medication
Allowed/ 
Restricted/ 
Prohibited
Details
agonists) administered by 
either MDI or nebulizer
administered 
as part of 
maintenance 
double/triple 
therapy.
step-up or step-down are not allowed.
SABA (short-acting β2-
agonists administered by 
an MDI or nebulizer)
Allowed as 
rescue 
medication and
for treatment 
of acute COPD 
exacerbation.
Prohibited if 
administered 
as maintenance 
medication or 
in a scheduled 
dose.
Prophylactic use of SABA in the absence of 
symptoms is discouraged. However, if 
deemed necessary by the subject and 
Investigator (e.g., prior to planned exercise), it 
can be used, but such use of prophylactic 
inhalations should be documented in the 
medical notes and recorded in the eCRF.
Use of SABA is to be avoided 6 hours before 
a scheduled ECG, FeNO and spirometry 
assessment.
Occasions (# of times used) where SABA was 
administered via an MDI will be recorded 
separately from the nebulized inhalations in 
the eDiary.
Maintenance SAMA
(short acting muscarinic 
antagonists = short acting 
anticholinergics 
administered by MDI or 
nebulizer)
Prohibited if 
administered 
as part of 
maintenance 
double/triple 
therapy.
Please see below. Use on their own, or for 
step-up or step-down is not allowed.
SAMA (short acting 
muscarinic antagonists = 
short acting 
anticholinergics 
administered by MDI or 
nebulizer)
Allowed as 
rescue 
medication and 
for treatment 
of acute COPD 
exacerbation.
Prohibited if 
Prophylactic use of SAMA in the absence of 
symptoms is discouraged. However, if 
deemed necessary by the subject and 
Investigator (e.g., prior to planned exercise), it 
can be used, but such use of prophylactic 
inhalations should be documented in the 
medical notes and recorded in the eCRF.

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Medication
Allowed/ 
Restricted/ 
Prohibited
Details
administered 
as maintenance 
medication or 
in a scheduled 
dose.
Use of SAMA is to be avoided 6 hours before 
a scheduled ECG, FeNO and spirometry 
assessment.
Occasions (# of times used) where SAMA 
was administered via MDI will be recorded 
separately from the nebulized inhalations in 
the eDiary.
SABA and SAMA 
combination products
Allowed as 
rescue 
medication and 
for treatment 
of acute COPD 
exacerbation.
Prohibited if 
administered 
as maintenance 
medication or 
in a scheduled 
dose.
Prophylactic use of SABA and SAMA 
combination product in the absence of 
symptoms is discouraged. However, if 
deemed necessary by the subject and 
Investigator (e.g., prior to planned exercise), it 
can be used, but such use of prophylactic 
inhalations should be documented in the 
medical notes and recorded in the eCRF.
Use of SABA and SAMA combination 
product is to be avoided 6 hours before a 
scheduled ECG, FeNO and spirometry 
assessment.
Occasions (# of times used) where SABA and 
SAMA combination product was administered 
via MDI will be recorded separately from the 
nebulized inhalations in the eDiary.
Antitussives prn 
Allowed
Mucolytics 
Allowed
Antihistamines prn 
Allowed
Dermal topical steroids, 
intra-articular, nasal 
steroids, topical 
ophthalmic and otic 
Allowed

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Medication
Allowed/ 
Restricted/ 
Prohibited
Details
corticosteroids
Xanthines
Restricted
Allowed only if on maintenance treatment for 
12 months and on a stable dose for 3 months 
prior to enrolment (Visit 1).
Allowed in a dose equivalent to theophylline 
≤400mg q day. For doses greater than 400 mg, 
the dose must be stable and theophylline 
blood levels should be confirmed to be equal 
to or below 12 mg/dl, within 8 weeks prior to 
Visit 1 or during the screening period.
Theophylline blood levels greater than 
12mg/dl should be managed according to 
local standards of care and the Investigator’s 
judgment and discussed with AZ study 
physician. It is recommended that additional 
increments in dose are evaluated with blood 
levels.
Twice daily xanthines should be withheld for 
at least 12 hours prior to scheduled spirometry 
at site.
Once daily xanthines for at least 24 hours 
prior to scheduled spirometry at site. 
Antibiotics
Restricted
Allowed to treat COPD exacerbations and/or 
AEs. 
Antibiotics to treat a COPD exacerbation 
should not be used for more than 14 days. If 
treatment duration is expected to exceed 14 
days, the AstraZeneca study physician must 
be contacted.
Chronic use (>3wks) and use for the 
prevention of COPD exacerbations is 

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Medication
Allowed/ 
Restricted/ 
Prohibited
Details
disallowed, unless the patient is on stable dose 
and regimen for ≥9 months prior to 
randomization and has had ≥2 COPD 
exacerbations while on stable therapy (see 
exclusion criterion 24, Section 5.2). In all 
other cases of chronic use, ≥6 weeks wash-out 
period should be in place after the last dose of 
antibiotic and prior to randomization.
Allergen immunotherapy
Restricted
Allowed, if on stable therapy for at least 2 
months prior to date of Visit 1 with no 
anticipated change during the screening and 
the treatment period. 
These should not be administered on the same 
day as IP administration.
Inactive/killed 
vaccinations (e.g., 
inactive influenza)
Restricted
Allowed, except
- within 5 days before or after any IP dosing 
visit
- within 3 weeks before sputum collection 
(Visit 3) for subset of subjects only.
- 3 weeks prior to EOT visit for sub-study 
subjects only
COVID-19 vaccinations
Restricted
COVID-19 vaccination is allowed, provided  
it is not administered within 28 days before 
and 14 days after IP administration. 
Administration timing of COVID-19 
vaccination should be discussed with the 
AstraZeneca Study Physician.
If participant receives COVID-19 vaccine less 
than 14 days before the next scheduled dose 
of study intervention, the study intervention 
administration should be rescheduled or 
skipped to ensure the next study intervention 
dose is at least 28 days after the vaccine 

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Medication
Allowed/ 
Restricted/ 
Prohibited
Details
administration.
COVID-19 vaccination schedule should 
follow country-specific health authority 
guidelines. Vaccination against COVID-19 
should be planned in advance to ensure the 
study intervention dosing/COVID-19 
vaccination intervals are maintained. 
At every study visit during the treatment 
period, the investigator must ask if the 
participant has received or is planning to 
receive a COVID-19 vaccination. This is to 
ensure that the required time interval for study 
intervention dosing (mentioned above) is 
maintained.
As these intervals might change, please 
discuss with AstraZeneca Study Physician for 
the most current recommended time interval 
prior to any vaccine dose
Refer to section 8.2.10
Roflumilast (Daxas®, 
Daliresp®)
Restricted
Allowed only if on maintenance treatment for 
12 months, on a stable dose for 3 months prior 
to enrolment (Visit 1), and only if locally 
approved for COPD.
If roflumilast is discontinued at Visit 1, 
approximately 7 days must elapse before 
performing spirometry testing at Visit 2.
Leukotrienes (LTRA) 
Restricted
Restricted for at least 24 hours prior to 
scheduled spirometry at site.
Immunoglobulin and 
Blood products
Prohibited
Prohibited within 30 days prior to enrolment 
(Visit 1) and throughout the treatment period.

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Medication
Allowed/ 
Restricted/ 
Prohibited
Details
Medications containing 
ephedrine
Prohibited
From Visit 3 and throughout the treatment 
period.
Live attenuated vaccines 
Prohibited
Prohibited within 30 days prior to Visit 3, 
during the treatment period and for 16 weeks 
(5 half-lives) after the last dose of IP.
Omalizumab, denosumab 
or any other monoclonal 
or polyclonal antibody 
therapy (e.g., gamma 
globulin)
Prohibited
Prohibited if taken for any reason within 4 
months or 5 half-lives (whichever is longer) 
prior to Visit 1 and during the study (even if 
the subject has discontinued IP).
Systemic 
immunomodulators and 
immunosuppressive 
medication (including 
but not limited to 
methotrexate, 
cyclosporine, any 
experimental anti-
inflammatory therapy
Prohibited
Prohibited within 3 months prior to Visit 1 
and throughout the study or 4 weeks after the 
last dose of IP.
Refer to Systemic corticosteroids (tablets or 
injections) for further restrictions.
Long term oxygen 
therapy (LTOT)
Restricted
Prohibited with signs and/or symptoms of cor 
pulmonale and/or right ventricular failure or 
receiving LTOT >4.0 litres/minute (L/min), or 
saturation <89% despite LTOT.
During the treatment phase, any increase in 
maintenance oxygen therapy up to 4 L/min is 
allowed, based on investigator’s judgement.
Investigational non-
biologic products
Prohibited
Prohibited within 30 days or 5 half-lives 
whichever is longer prior to Visit 1 and during 
the study.

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6.5.1
Background (Maintenance) Medication
All subjects are required to be treated with maintenance locally approved triple inhaled 
therapy (ICS/LABA/LAMA) for COPD for at least 12 months prior to enrolment (Visit 1) 
with a stable dose of ICS for the 3 months prior to Visit 1. 
The aim of this study is to establish the treatment effect of tezepelumab as add-on therapy.  
Therefore, the background medications should be maintained at the same dose and schedule 
from Visit 1 until the end of the study, i.e., when the subject has completed his/her last 
scheduled contact. 
Subjects currently receiving background therapy that is not approved for COPD are not 
eligible for the study. However, for individual cases when subjects are treated with 
background therapy that is not approved for COPD, the subject may be considered for 
enrolment and maintain their maintenance medication during the study if the following criteria 
are met:

Current treatment regimen is considered the best option for the subject by the treating 
physician/Investigator without acceptable alternative;

Medication/dose/device is approved for COPD in other countries or contains 
components and doses equivalent to those in approved medication/combination 
therapy.
These cases should always be consulted with the AZ Study Physician prior to the decision to 
enrol the patient into the study.
Changes to the subject’s maintenance therapy are discouraged during the treatment period, 
unless judged medically necessary by the Investigator. Any changes should be discussed with 
the AstraZeneca Study Physician and the justification for treatment changes should be 
documented in the source notes along with the rationale for the change. Changes should be 
recorded in the eCRF.
During the study, inhaled background medications that are given once daily should be 
administered in the morning to conform with spirometry measurements requirements. 
Recommended background medication compliance during the treatment period is ≥70%. It is 
recommended that compliance levels below 70% prompt the site/investigator to evaluate the 
reasons for low compliance and to provide re-education to the patient in regard to the 
importance of compliance. It is strongly recommended that when compliance level falls below 
50%, the site contacts the AZ study physician in order to discuss the potential safety 
implications for the patient and future decisions. 

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Background medication adherence will be assessed daily via the eDiary. The patient will be 
asked if they took their regularly scheduled COPD medicine (yes/no) and instructed not to 
consider instances of rescue inhaler usage when answering this question.
6.5.2
Other Concomitant Treatment
Other medication other than that described above, which is considered necessary for the 
subject’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF.
6.5.3
Rescue Medication
SABA (short-acting β2-agonists) and/or SAMA (short acting muscarinic antagonists = short 
acting anticholinergics) or SABA/SAMA combinations may be used as rescue medication 
during the study in the event of a worsening of COPD symptoms (see Table 6). 
6.5.4
Allowed Medications to Treat a COPD Exacerbation
Medications to treat an exacerbation should not be used for more than 14 days.  
The restrictions that apply during the study are summarized in Table 6.
If the Investigator makes the clinical decision that a subject needs treatment with any 
disallowed medication, e.g., “step up” or treatment for an exacerbation for more than 14 days, 
the Investigator must contact the AstraZeneca Study Physician to discuss justification for 
disallowed medication use and/or prolonged oral corticosteroid treatment. The Investigator 
must document outcome of discussion in the source documentation.
6.5.5
COPD Medication Restrictions on the Days of Scheduled Spirometry 
and FeNO Visits 
Spirometry assessments will be performed at the site at scheduled visits (see Table 1 and 
Table 2). There are restrictions regarding the subject’s COPD medications prior to the 
spirometry assessments. Please see Section 8.1.2.1.
NOTE: Screening (Visit 1 and Visit 2) and Randomization spirometry and FeNO are not 
allowed without proper medication wash out.
Screening Visit 1 and Visit 2
Screening lung function assessments can only be done when there are no restrictions to 
medications (also refer to Section 8.1.3) and Visit 1 SARS-CoV-2 naso/oropharyngeal swab 
test (or rapid test) result is negative. If the SARS-CoV-2 naso/oropharyngeal swab test (or 
rapid test) result will not be available on the day of Visit 1, the screening lung function 

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assessments must be postponed until next visit, the postponed Visit 1, after the SARS-CoV-2 
naso/oropharyngeal) swab test (or rapid test) result is confirmed negative. 
At the postponed Visit 1, the spirometry equipment will allow pre-BD, post-BD spirometry, 
FeNO and ECG (combined Visit 1 and Visit 2) to be performed. Visit 2 should be scheduled, 
if the Visit 2 post-BD spirometry and FeNO were not done at the postponed Visit 
1. Preferably, Visit 2 should be scheduled no later than 1 week after Visit 1 but the enrolment 
can be extended to accommodate additional waiting time required to obtain Visit 1 SARS-
CoV-2 naso/oropharyngeal swab test result. The subject must meet the COPD medications 
restrictions in order to perform the lung assessments. 
Subjects will be asked to withhold their triple inhaled (ICS/LABA/LAMA) medications on the 
morning of the screening pre-BD and post-BD spirometry and FeNO (should be at least 12 
hours prior to the assessment for twice daily medication and for 24 hours prior to the 
assessment for once daily medications) for the eligibility assessment (see Section 5.1, 
inclusion criterion 7). In addition, SABA and SAMA should not be used within 6 hours of this 
spirometry and FeNO assessment. The subject’s usual COPD medications may be 
administered following completion of the screening lung function procedures.
Treatment Visits 3-15
Subjects will be asked to withhold their usual triple inhaled (ICS/LABA/LAMA) medications 
on the mornings of the scheduled spirometry and FeNO visits and preferably for at least 12 
hours prior to the spirometry and FeNO assessment (for medications that are administered 
twice daily)/24 hours prior to the assessment (for once daily medications). This is especially 
important prior to scheduled spirometry and FeNO assessments (see Table 1 and Table 2) in 
order to maintain the integrity of planned efficacy analyses around lung function 
improvement. In addition, SABA and SAMA should not be used within 6 hours prior to the 
spirometry assessments. The subject’s usual COPD medications may be administered 
following completion of the post-BD spirograms or sputum post-BD spirograms (for patients 
participating in sputum sub-study). The IP will be administered at a scheduled visit after the 
pulmonary lung function assessments.
If the subject has taken their usual triple inhaled (ICS/LABA/LAMA) medications on the 
morning of the scheduled spirometry and FeNO visit, the Investigator/authorized delegate 
should remind the subject of the importance of withholding their usual morning maintenance 
therapy, and reschedule the visit for another day, within the allowed window. If rescheduling 
is absolutely not feasible for the subject, spirometry and FeNO may be performed with a 
notation indicating that spirometry and FeNO was performed without proper washout of the 
usual triple inhaled (ICS/LABA/LAMA) medications. Exception is randomization visit, which 
must be performed when medications restrictions are met. 

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If the subject has taken the rescue SABA and/or SAMA within 6 hours of the planned site 
visit spirometry they should ideally remain at the site until such time that the 6 hours 
withholding time has been reached if it does not exceed the 1.5-hour spirometry window or 
return on another day, within the visit window. If neither of options is feasible for the subject, 
spirometry may be performed with a notation indicating that spirometry was conducted within 
6 hours of SABA and/or SAMA use.
6.5.6
COPD Medication Restrictions at Unscheduled and Exacerbation Visits
COPD medication restrictions at an unscheduled or an exacerbation visit may not be feasible 
and may be applied at the discretion of the Investigator. Timing of the triple inhaled 
(ICS/LABA/LAMA) medications and rescue SABA and/or SAMA use relative to the 
unscheduled spirometry should be recorded.
6.5.7
COPD Medication Restrictions at Centre Visits with Scheduled ECG 
Assessment
The subjects should be instructed not to take their usual triple inhaled (ICS/LABA/LAMA) 
medications prior to the scheduled ECG assessment. The use of a SABA and/or SAMA should 
be avoided within 6 hours before the ECG assessments. See Section 8.2.6.
NOTE: Screening and Randomization ECG are not allowed without proper medication wash 
out.
6.6
Endobronchial Therapy
Subjects should not be treated with bronchial thermoplasty or receive endobronchial valves 
during the study or within 12 months prior to study enrolment.
6.7
Dose Modification
Dose modification of background COPD medications is not allowed in the study. If the 
Investigator makes the clinical decision that a subject needs dose modification, the 
Investigator must contact the AstraZeneca Study Physician to discuss justification for 
modification and document outcome of discussion in the source documentation.
6.8
Treatment After the End of the Study
Subjects who complete Week 64 should be given locally available SoC at the discretion of the 
Investigator. 

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7.
DISCONTINUATION OF TREATMENT AND SUBJECT
WITHDRAWAL 
7.1
Discontinuation of Study Treatment 
Note that discontinuation from IP does NOT mean complete withdrawal from the study.
Subject may be discontinued from IP in the following situations:

Subject decision. The subject is at any time free to discontinue IP, without 
prejudice to further treatment 

An adverse event considered to jeopardise the safety of a subject 
participating in the study

Pregnancy

Severe non-compliance with the Clinical Study Protocol 

Lost to follow up

Development of any study specific criteria for discontinuation, including:

An anaphylactic reaction to the IP requiring administration of epinephrine

A helminth parasitic infestation requiring hospitalization

Intensive care unit admission with intubation or extensive mechanical 
ventilation for a COPD related event

Any malignancy, except subjects who develop basal cell carcinoma or 
localized squamous cell carcinoma of the skin, provided that the malignancy 
has been excised and determined to have clear margins

Development of one or more of the following:

Confirmed ALT or AST increase of ≥8 x ULN

Confirmed ALT or AST increase of ≥5 x ULN for more than 2 weeks

Confirmed ALT or AST increase of ≥3 x ULN and total bilirubin of ≥2 x 
ULN

ALT or AST of ≥3 x ULN with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or 
eosinophilia (≥5% based on local laboratory results)

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
Other reasons
Before a decision to discontinue a subject from IP is instituted, the AstraZeneca Study 
Physician should be consulted regardless of the reason for discontinuation.
See the SoA 1.1 for data to be collected at the time of IP discontinuation and follow-up and 
for any further evaluations that need to be completed.
If a subject discontinues IP due to a study specific discontinuation criterion, this should 
always be recorded as ’Development of study specific withdrawal’ on the Discontinuation of 
Investigation Product form in the eCRF.
7.1.1
Procedures for Discontinuation of Study Treatment
Subjects are free to discontinue IP or withdraw from the study at any time without prejudice to 
further treatment. Discontinuing study treatment is not the same as study withdrawal. In the 
case of early study withdrawal, the EOT visit should be completed immediately. Subjects who 
do not wish to have any follow-up contacts as detailed below, will be withdrawn from the 
study. Procedures to follow for study withdrawal are detailed below in Section 7.3.  All 
withdrawn subjects must return the eDiary device at the EOT visit (and at IPD visit for 
subjects choosing option 3 below). If the subject decides to withdraw consent, then the reason 
for this must be recorded separately in the eCRF.
A subject that decides to discontinue IP should always be asked about the reason(s) and the 
presence of any adverse events. The reason for discontinuing treatment and the date of last IP 
administration should be recorded in the eCRF. Subjects permanently discontinuing IP 
administration should be given locally available SoC therapy, at the discretion of the 
Investigator. However, treatment with marketed or investigational biologics is not allowed 
until Week 64 even if the subject has discontinued IP. Interaction studies between 
tezepelumab and other biologics indicated for the treatment of COPD have not been 
conducted. For additional information regarding pharmacokinetic and pharmacodynamic 
effects of tezepelumab, please see the Investigator brochure. 
All subjects who prematurely discontinue IP should return to the site and complete the 
procedures described for the premature IP Discontinuation visit (IPD) at 4 weeks (+/-5 
days) post last IP administration. Subjects who discontinue treatment should be encouraged 
to return for all regularly scheduled visits for safety and efficacy assessments.
At the IPD visit the subject will be given three options as to how they will be followed as 
follows:

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1.
The subject should be encouraged to return for all regular clinic visits and perform 
all scheduled assessments (excluding IP administration) until the EOT visit at Week 
52 (+/-5 days). 
2.
The subject will be offered follow-up on a monthly basis via telephone calls while 
continuing eDiary completion (no further procedures will be performed) until the 
subject completes the EOT visit at Week 52 (+/-5 days). In addition to the PRO 
assessments that are performed at home, the subject may also complete the other 
clinic specified PRO assessments (as defined in the SoA 1.1) at home as well. 
3.
If the subject cannot or does not wish to comply with any of the options above, (or 
any component of them such as only telephone-based visits without completion of 
the eDiary), the Investigator will only contact the subject at 52 weeks post-
randomization. No other study assessments will be performed prior to this contact.
If the subject chooses option 2 or 3, the key information to be collected during the telephone 
calls are AEs/SAEs, changes in concomitant medication, health care utilization, and COPD 
exacerbation information.
Subjects who initially choose options 1 or 2 and subsequently cannot or do not wish to comply 
with the requirements of their option can continue with a less intensive option (i.e., subject 
initially choosing option 1 can continue with options 2 or 3, subjects initially choosing option 
2 can continue with option 3).
7.2
Lost to Follow-Up
A subject will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site.  
The following actions must be taken if a subject fails to return to the clinic for a required 
study visit:

The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule.

Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject or next of kin by either repeated 
telephone calls, certified letter to the subject´s last known mailing address or local 
equivalent methods. These contact attempts should be documented in the subject’s 
medical record.
When at least two of the following methods of contact are failed within 3 months of subjects 
last IP dose:

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o
At least 3 attempts of either phone calls, faxes or emails; 
o
Having sent 1 registered letter/certified mail;
o
One unsuccessful effort to check the status of the subject using publicly available 
sources, if allowed by local regulations
The subject should be considered lost to follow up with unknown vital status and censored at 
latest follow-up contact.
7.3
Withdrawal from the Study
A subject may withdraw from the study (e.g., withdraw consent), at any time (IP and 
assessments) at his/her own request, without prejudice to further treatment. A subject who 
considers withdrawing from the study must be informed by the Investigator about modified 
follow-up options (e.g., telephone contacts, contacts with a relative or treating physician, or 
information from medical records) as per Section 7.1.1.
A subject who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE).  The Investigator will follow-up subjects as medically indicated. A 
withdrawal visit is essential to collect as much data as possible for the subject as per EOT visit 
described in SoA, Table 2. The subject will return all study supplied equipment including 
eDiary.
If the subject withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
If a subject withdraws from the study, he/she may request destruction of any samples taken, 
and the Investigator must document this in the site study records.  
If the subject only withdraws consent for the retention of biological samples (blood, nasal, 
sputum, urine etc.) for future exploratory use (e.g., scientific health-related research), the 
subject will not be withdrawn from the study.
Withdrawal of consent from the study must be ascertained and documented by the Investigator 
and recorded in the eCRF as well as in the Informed Consent Form (ICF) or assent form.
7.3.1
Withdrawal Due to Recruitment Completion
When the required number of subjects are randomized in the study, ongoing subjects in 
screening will not be randomized and will be withdrawn from the study. The reason of the 
withdrawal should be documented in the source and eCRF. As with screen failures, no further 
study related follow-up of these patients is required.

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7.3.2
Discontinuation or Suspension of entire study and Site Closure
If AstraZeneca decides to prematurely terminate or suspend the study, the PI, and regulatory 
authorities should receive written notification of the reasons for the premature termination or 
suspension. The PI will immediately notify the decision to the subjects and if relevant give 
appropriate medical treatment; take necessary measures and document these in the source 
notes.
The sponsor designee also reserves the right to close the study site at any time for any reason 
at the sole discretion of the sponsor. Study sites will be closed upon study completion. A study 
site is considered closed when all required documents and study supplies have been collected 
and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
•
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
•
Inadequate recruitment of participants by the investigator 
•
Discontinuation of further study intervention development
8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing and order are summarized in the SoA (Table 1 and Table 
2).  The Investigator will ensure that data are recorded on the eCRFs. The Web Based Data 
Capture (WBDC) system will be used for data collection and query handling. 
Due to COVID-19 pandemic, it may not be possible to complete all study assessments 
according to SoA. Please refer to SoA (1.1) and Appendix I for further details. 
The Investigator ensures the accuracy, completeness, legibility and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement. The Investigator will sign the completed eCRFs. A copy of the completed 
electronic CRFs will be archived at the study site. Additional data to assess the impact of 
COVID-19 pandemic will be collected.  
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the subject should continue or discontinue study treatment.

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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 subjects 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
The suggested order of assessments to be completed before IP administration should be as 
follows: ePRO, Vital Signs, ECG, FeNO, Spirometry and Blood draws. 
During COVID-19 pandemic, the suggested order of screening assessments is: vital signs 
(starting with body temperature measurement), ePRO, blood draws and SARS-CoV-2 
naso/oropharyngeal swab (or rapid) testing. Screening lung function assessments and ECG 
can only be done when there are no restrictions to medications (refer to Section 6.5.5 and 
8.1.3) and Visit 1 SARS-CoV-2 naso/oropharyngeal swab test (or rapid test) result is negative. 
The amount of blood collected from each subject over the duration of the study (excluding 
optional blood samples) will be approximately 360 mL (including any extra assessments that 
may be required) and will not exceed 450 mL. Repeat or unscheduled samples may be taken 
for safety reasons or for technical issues with the samples.
8.1
Efficacy Assessments
8.1.1
COPD Exacerbation Definition
For the purpose of the protocol, a COPD exacerbation will be defined as a change in the 
subject'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), and 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 for at least 3 days

An inpatient hospitalization due to COPD (defined as an inpatient admission ≥24 
hours in the hospital, in an observation area, the emergency department or other 
equivalent healthcare facility depending on the country and healthcare system)

Results in death

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8.1.1.1
Severity of COPD Exacerbations
All protocol defined COPD exacerbations need to fulfil the symptom criteria as defined in 
Section 8.1.1.
A COPD exacerbation will be considered severe if it results in at least 1 of the following:

Hospitalization defined as inpatient admission for ≥ 24 hours to an observation area, the 
emergency department, or other equivalent healthcare facility (depending on the country 
and healthcare system) for the COPD exacerbation

Death related to COPD or COPD exacerbation
A COPD exacerbation that does not meet the requirements to be classified as severe will be 
considered moderate if it results in at least 1 of the following:

Use of systemic corticosteroids and/or antibiotics for at least 3 days 

A single depot injectable dose of corticosteroids, which will be considered equivalent to at 
least 3-day course of systemic corticosteroids
8.1.1.2
Duration of COPD Exacerbations
For moderate or severe exacerbations, the duration is defined by the prescribed treatment 
or duration of hospitalization

The start date will be defined as the start date of prescribed treatment with a systemic 
corticosteroid and/or systemic antibiotic or hospital admission, which occurs earlier.

The stop date will be defined as the last day of prescribed treatment with a systemic 
corticosteroid and/or systemic antibiotic or hospital discharge, which occurs later.

A single depot injectable dose of corticosteroids will be considered equivalent to at 
least 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 new COPD exacerbation event must be preceded by at least 7 days between the last 
COPD exacerbation (refer to Section 8.1.1.1)

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8.1.1.3
Approach for Capturing COPD Exacerbations
8.1.1.3.1
COPD Exacerbation eCRF
The investigator should record the COPD exacerbation that meets the COPD exacerbation 
definition (refer to Section 8.1.1) in the COPD exacerbation eCRF (COPDEX).  Associated 
symptoms of COPD are considered as symptoms of disease under study and should not be 
recorded as AEs unless meet conditions listed in Section 8.3.7.  The serious COPD 
exacerbation should be recorded in AE/SAE eCRF and in COPDEX. Other COPD related 
SAEs should be recorded on the AE/SAE eCRF.
8.1.1.3.2
Symptom Reporting
The subject will use the eDiary for daily symptom reporting, entering symptoms twice daily as 
detailed in Section 8.1.6.1.
If symptoms meet a specific threshold (i.e., 1 major COPD symptom and at least 1 other major 
or minor symptom for 2 consecutive days), the eDiary generates an alert to the subject and the 
investigational site. This alert should generate contact between the subject and the 
investigational site. The Investigator then makes the decision whether or not to initiate (or 
escalate, as appropriate) treatment for a COPD exacerbation. The Investigator site is 
responsible for documenting the action taken within 5 working days from the time the eDiary 
alert was triggered for every alert regardless who initiated contact (site or patient). Detailed 
instruction will be provided in separate guidance. 

Major COPD symptoms: dyspnea, sputum volume, and sputum color

Minor COPD symptoms: cough, wheeze, sore throat, cold symptoms (rhinorrhea or nasal 
congestion), and fever without other cause
If COPD exacerbation is associated with ePRO worsening alert, symptoms should not be 
reported in the COPD exacerbation eCRF. If COPD exacerbation is not associated with ePRO 
worsening alert, please refer to section 8.1.1.4 for further guidance.
8.1.1.4
Investigator Justified COPD Exacerbations
If an event is not associated with ePRO symptom worsening alert as described above (e.g., 
technical issue, subject self-reports symptom worsening/exacerbation event, the exacerbation 
is identified during a visit or phone contact, the exacerbation is evaluated and treated at non-
study centre, or an acute/severe symptom deterioration which is not captured in the ePRO 
system occurs), the Investigator should interview the subject and evaluate potential worsening 
and duration of the following symptoms:

Shortness of breath

Mucus Volume

Mucus purulence

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
Cough

Wheezing

Sore throat

Cold symptoms such as a runny nose or nasal congestion

Fever

Chest Tightness

Other findings
The Investigator should record all pertinent findings (symptom worsening) associated with the 
exacerbation event and their duration in source documents and in the COPD exacerbation 
eCRF.
If an exacerbation is not associated with worsening of COPD symptoms or it was not possible 
to capture the symptoms (e.g. patient intubated upon arrival to the emergency department), the 
Investigator must document the justification for diagnosing and treating the event as an 
exacerbation and record it in the eCRF.
8.1.1.5
COPD Exacerbation visit
COPD Exacerbation visit (EXA) may be initiated when patient experiences a COPD 
exacerbation. There is no visit window for the EXA visit. The subject should complete the 
assessments according to Table 2 if he/she experiences an exacerbation during the treatment 
and follow-up period. If the EXA visit was completed within +/- 5 days of a scheduled visit, 
the same laboratory assessments do not need to be repeated at the next scheduled visit, unless 
at the PI’s discretion. 
If a subject experience a COPD exacerbation at the time of a regular scheduled visit, the 
subject should complete the assessments from the scheduled visit. In case of additional 
assessments at EXA visit in comparison with the regular visit, subject will also need to 
complete those additional assessments from the EXA visit. 
Only for sputum sub-study subjects
Performing COPD Exacerbation visit (EXA) for sputum sub-study patients is essential to 
evaluate exploratory sputum and nasal sub-study endpoints during treatment phase. Refer to 
Section 3.
Patients participating in sputum sub-study are required to perform pre-BD and sputum post-
BD spirometry as part of sputum induction, at EXA visits during treatment. Induced sputum is 
preferred however spontaneous sputum is acceptable if patient cannot produce induced 
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regulations or guidance during the COVID-19 pandemic. Please refer to applicable sub-study 
manual for more information. 
Patient should withhold the COPD medications as instructed in Section 6.5.4. If withholding 
COPD medication is not feasible, the spirometry should be performed with a notation 
indicating under which conditions spirometry was conducted.
8.1.2
Spirometry
8.1.2.1
General Requirements
Lung function (FEV1 and FVC) will be measured by spirometry using equipment provided by 
a central vendor. The same equipment will be used for sputum induction. Spirometry will be 
performed by the Investigator or authorized delegate according to American Thoracic 
Society/European Respiratory Society (ATS/ERS) guidelines (Miller et al 2005).
The vendor providing central spirometry is responsible for assuring that the spirometer meets 
ATS/ERS recommendations and that the site personnel who will be performing the testing are 
properly certified. Spirometry calibration and data quality checks (including monitoring of 
unexpectedly high variability of results) will be detailed in a separate spirometry procedures 
manual and in the monitoring plan. Patients who exhibit unexpectedly high variability of 
FEV1 will be evaluated by the investigator for etiology of variability, necessary follow-up 
actions, and assessment of continued patient eligibility. The investigator will discuss 
unexpectedly high variability with the AZ study physician. 

Subjects should avoid engaging in strenuous exertion for at least 30 minutes prior to all 
lung function assessments at the site.

Subjects should avoid eating a large meal for at least 2 hours prior to all lung function 
assessments at the site. 

Subjects should not smoke/vape on the same day(s) prior to the lung function test is 
being performed.

Subjects should withhold their usual maintenance therapies on the day(s) when lung 
function testing is being performed as below:

SABA and SAMA should be withheld at least 6 hours prior to scheduled 
spirometry at site. 

Twice daily LABA or LAMA-containing therapies should be withheld for at least 
12 hours prior to scheduled spirometry at site.

Once daily LABA or LAMA-containing therapies should be withheld for at least 
24 hours prior to scheduled spirometry at site.

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
LTRA should be restricted for at least 24 hours prior to scheduled spirometry at 
site.

Twice daily theophylline should be withheld for at least 12 hours prior to 
scheduled spirometry at site.

Once daily theophylline for at least 24 hours prior to scheduled spirometry at site. 

Twice daily triple inhaled (ICS/LABA/LAMA) medications should be withheld at 
least 12 hours prior to scheduled spirometry at site.

Once daily triple inhaled (ICS/LABA/LAMA) medications should be withheld at 
least 24 hours prior to scheduled spirometry at site.
Note: If any of the above restriction are not met, the spirometry assessment should be 
rescheduled within the allowed visit window (See section 6.5.5).
As part of the procedure for induced sputum pre-BD and post BD spirometry will be 
performed (see Section 8.8.5 and 8.1.2.3). 
Applicable during COVID-19 pandemic
During screening, lung function assessments must be performed only when Visit 1 SARS-
CoV-2 naso/oropharyngeal swab test (or rapid test or alternative test approved locally) result 
is available and negative (refer to footnote a and footnote l under Table 1, section 1.1 and to 
section 6.5.5.).
SARS-CoV-2 testing should be performed prior to lung function assessments at subsequent 
visits, if required per local regulations and guidance. If SARS-CoV-2 testing is conducted, a 
negative result must be obtained before conducting visit assessments.
Time of day for scheduled site visit spirometry
Spirometry testing should be done according to the SoA. Spirometry testing must be initiated 
in the morning between 6:00 AM and 11:00 AM during the screening or re-screening period 
and at randomization visit. 
All post-randomization spirometry assessments should be performed within ± 1.5 hours of the 
time that the randomization spirometry was performed. For example, if the randomization 
spirometry was started at 8:00 AM, then all subsequent spirometry testing needs to be initiated 
between 6:30 AM and 9:30 AM.
Note: FeNO test should be performed prior to spirometry. Please refer to Section 8.1.3 for 
more details.
Spirometry technique

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Detailed procedure for performing spirometry will be described in a separate instruction 
manual. Details regarding assessment of the quality of spirometry and the Best Test Review 
(BTR) process will also be detailed in the manual. 
Spirometry references
The Global Lung Function Initiative (GLI) equations will be used to determine the Predicted 
Normal Values (PNV) and are pre-programmed into the spirometer (Quanjer et al 2012). 
FEV1, expressed as percent of the PNV, will be calculated as follows:
FEV1% of PNV = (FEV1 measured/FEV1PNV) x 100
Order of administration for the COPD maintenance medication and IP relative to the 
scheduled pre- and post-bronchodilator spirograms
The subject’s usual COPD morning maintenance therapy must not be given until spirograms 
are complete for the reasons discussed above. IP dosing should also be withheld until pre-
bronchodilator/post bronchodilator/sputum post-BD spirometry is completed.
Record keeping
A signed and dated copy of the pre- and post-BD and sputum post-BD spirometry printout 
must be kept at study centre for source data verification. The printout must be marked with the 
study code, enrolment code, date and time of measurement, visit number. If a printout cannot 
be printed, the mean value of the measurements will be recorded in the subject’s charts. 
8.1.2.2
Post-BD Spirometry
Post-BD spirometry will be performed at Visit 2 or at postponed Visit 1 (when Visit 1 and 
Visit 2 are combined) (to evaluate inclusion criterion 5, see Section 5.1), Visit 3, Visit 9, 
Visits 16 (EOT) and IPD. 
Endpoint maximal bronchodilation will be induced using albuterol (90μg metered dose) or 
salbutamol (100μg metered dose) with or without a spacer device up to a maximum of 4 
inhalations administrated between 15 and 45 minutes of the final pre-BD spirometry 
measurement. SABA administration should start at least 15 minutes after final pre-BD 
spirometry and should end no later than 45 minutes after final pre-BD spirometry. Post-BD 
spirometry will be performed 15-30 minutes after last SABA inhalation. SABA administration 
can start earlier (less than 15 minutes of the final pre-BD spirometry) for safety reasons.

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8.1.2.3
Sputum post-BD spirometry
Sputum post-BD spirometry should be performed per schedule in Table 2 (Visit 3, Visit 16, 
IPD and EXA) as part of induced sputum procedures if subject is participating in the sputum 
sub-study, after post-BD spirometry (where applicable, refer to Section 8.1.2.2). It is 
conducted solely to ensure patient safety in inducing sputum and results will neither be 
captured for the eCRF, nor for study endpoints. More details will be provided in applicable 
sputum sub-study manual.
8.1.3
FeNO
Airway inflammation will be evaluated using a standardized single-breath FeNO test in 
accordance with the SoA. A single exhalation technique recommended by the manufacturer 
will be followed (Alving et al 2017). Detailed procedure for performing FeNO will be 
described in a separate instruction manual.
The FeNO test will be performed prior to spirometry.  
Restrictions on the day of scheduled FeNO assessment:

The FeNO measurements should not be performed within 2 weeks of a respiratory 
infection.

Subjects should not eat or drink 1 hour prior to having the FeNO test. 

Subjects should not use their rescue SABA and/or SAMA medication within 6 hours of 
the measurement.

Inhaled BDs should be withheld for the effect duration specific to the BD as described in 
Section 6.5.5.
The assessment should be postponed till after the required time has passed since last dose of 
BD or meal/drink. However, if not possible the visit must be rescheduled within the allowed 
visit window.
The NIOX VERO® Airway Inflammation Monitor will be used to measured FeNO. 
Instructions for use of this monitor will be provided in a separate user’s manual.  
NIOX VERO® sensors will be replaced as recommended by the manufacturer. The vendor 
supplying the equipment will be responsible for ensuring that the equipment and procedures 
for the measurement of FeNO are validated prior to the start of the study. 
All post-randomization FeNO assessments should be performed within ± 1.5 hours of the time 
that the randomization FeNO was performed.

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Two acceptable FeNO measurements will be performed to establish repeatability; up to 8 
measurements can be performed. After FeNO repeatability is met, it will not be possible to 
perform any further FeNO measurements at that visit.
The sponsor will be unblinded to the FeNO values prior to randomization (Visit 2 and any 
repeat testing that is performed during screening, and prior to IP administration) and blinded 
to the subsequent FeNO values post randomization. Sites will be blinded to the FeNO values 
for the whole study duration.
8.1.4
COPDCompEx
COPDCompEx is a composite endpoint for exacerbations (moderate or severe) in COPD. 
COPDCompEx combines exacerbations with events defined from patient daily diaries. The 
definitions for both types of exacerbation are as follows:

Exacerbations: episodes leading to one or more of the following: hospitalization,
emergency room visit, treatment with systemic corticosteroids, or treatment with 
antibiotics.

Diary events: defined by threshold and slope criteria using the following diary 
variables: individual domains of the breathlessness, cough, sputum scale, sleep, chest 
tightness and rescue medication use.
The analysis of this endpoint will primarily be time to first COPDCompEx event, but the 
events may also be analysed with models addressing event rates or time to recurrent event. 
More details on the derivation and analysis of this variable will be given in the Statistical 
Analysis Plan (SAP).
8.1.5
Clinically Important Deterioration (CID)
CID is a composite endpoint measuring worsening of the key clinical features of COPD, 
namely lung function, patient-reported outcomes and exacerbations. CID is defined as 1) a 
decrease of ≥100 mL from baseline in trough FEV1, 2) a deterioration in health-related quality 
of life defined as ≥4-unit increase from baseline in SGRQ total score, 3) the occurrence of an 
on-treatment moderate-to-severe COPD exacerbation (defined as an acute worsening of 
COPD symptoms requiring the use of additional treatment including oral corticosteroids, 
antibiotics, emergency department treatment, or hospitalization).
8.1.6
Patient Reported Outcomes
Patient reported outcomes (PRO) data will be captured electronically using a handheld device 
at home and at the site. Site personnel will be trained on the use of this device and detailed 
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will be trained on at home use of the eDiary at Visit 2 or Visit 1 (if Visit 1 and Visit 2 are 
combined). The site staff will set assessment reminder alarms on the device. Training will 
emphasize the importance of completing the PRO assessments as scheduled to capture the 
subject's experience and meet the objectives of the study. 
Subjects will complete assessments twice daily and at other timepoints specified in the SoA. 
The Investigator/authorized delegate will check subject’s adherence to the PRO assessment 
schedule as is necessary to maintain necessary to minimize missing data and at each study 
visit. Frequent compliance checks on the ePRO Study Works portal will be completed by the 
Investigator between visits to ensure sufficient data is available to meet inclusion criteria 16
and 17 at randomization (Visit 3).
8.1.6.1
Major/Minor Symptom Worsening Assessment and Alert System
Symptoms will be assessed each morning for the purposes of a symptom worsening alert. The 
purpose of this alert is to notify both the subject and the site of a potential symptom worsening 
event that warrants contact between the subject and Investigator/authorized delegate for 
further evaluation.
Each morning the subject will complete 3 questions pertaining to the major symptoms of a 
worsening event (dyspnea, sputum volume, and sputum color). Subject reported worsening of 
1 or more of these symptoms will trigger assessment of the minor symptoms of a worsening 
event (sore throat, cold, fever without other cause, cough, and wheeze). All questions will 
have a 24-hour recall period. Questions pertaining to the severity of symptoms vs. their usual 
state will have 3 response options (e.g., How breathless have you been in the last 24 hours? 
Less breathlessness than usual, Usual level of breathlessness, more breathless than usual) 
whereas questions related to the presence or absence of a symptom will have a dichotomous 
response (e.g., Have you had a sore throat in the last 24 hours? No, Yes, I had a sore throat).
An alert will be triggered if two or more major symptoms (dyspnea, sputum volume, and 
sputum color) worsen for two consecutive days or if one major symptom and one minor 
symptom (e.g., sore throat, cold, fever without other cause, cough, and wheeze) worsen for at 
least two consecutive days. When either of these criteria is met the subject will be alerted via 
the ePRO device to contact the site as soon as possible for further evaluation. Likewise, the 
site will be alerted to contact the subject within approximately 24-72 hours if he or she has not 
yet contacted the site for further evaluation.
8.1.6.2
Rescue Medication
Rescue medication usage including reliever inhaler and nebulizer use will be captured twice 
daily. Inhaler usage will be reported as the number of puffs, (i.e., the sum of different 
relievers, if applicable) in a given period whereas nebulizer use will be reported as the number 

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of times. Rescue medication usage at night will be assessed in the morning and rescue 
medication used during the day will be assessed in the evening.
8.1.6.3
Nocturnal Awakenings
Subjects will be asked to report the occurrence of nocturnal awakenings due to COPD 
symptoms each morning using the ePRO device. A single question with yes/no response 
options will be used.
8.1.6.4
Maintenance Medication
Maintenance medication adherence will be assessed each evening. The subject will be asked if 
they took their regularly scheduled inhaler and instructed not to consider instances of rescue 
inhaler usage when answering this question.
8.1.6.5
St. George’s Respiratory Questionnaire (SGRQ)
The SGRQ is a 50-item PRO instrument developed to measure the health status of patients 
with airway obstruction diseases (Jones et al 1991). The questionnaire is divided into 2 parts: 
part 1 consists of 8 items pertaining to the severity of respiratory symptoms in the preceding 4 
weeks; part 2 consists of 42 items related to the daily activity and psychosocial impacts of the 
individual’s respiratory condition. The SGRQ yields a total score and 3 domain scores 
(symptoms, activity, and impacts). The total score indicates the impact of disease on overall 
health status. This total score is expressed as a percentage of overall impairment, in which 100 
represents the worst possible health status and 0 indicates the best possible health status. 
Likewise, the domain scores range from 0 to 100, with higher scores indicative of greater 
impairment. Based on empirical data and interviews with patients, a decrease of 4 units is 
associated with a minimum clinically important difference (MCID). Specific details on the 
scoring algorithms are provided by the developer in a user manual (Jones et al 2009). SGRQ 
will be completed using eDiary in accordance with the SoA. If the subject is not able to visit 
the site, SGRQ may be completed by the subject at home/alternative location . Refer to 
Appendix I for details.
8.1.6.6
COPD Assessment Test (CAT)
The CAT is an 8-item PRO developed to measure the impact of COPD on health status (Jones 
et al 2009).  The instrument uses semantic differential six-point response scales which are 
defined by contrasting adjectives to capture the impact of COPD. Content includes items 
related to cough, phlegm, chest tightness, breathlessness going up hills/stairs, activity 
limitation at home, confidence leaving home, sleep and energy. A CAT total score is the sum 
of item responses. Scores range from 0-40 with higher scores indicative of greater COPD 
impact on health status. The CAT will be measured at Visits 1, 3, 6, 9, 12, IPD and 16/EOT. If 

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the subject is not able to visit the site, CAT may be completed by the subject at 
home/alternative location. Refer to Appendix I for details.
8.1.6.7
Exacerbations of Chronic Pulmonary Disease Tool– Patient-reported Outcome 
(EXACT-PRO) and Evaluating Respiratory Symptoms in COPD (E-RS™: 
COPD) 
The EXACT-PRO is a 14-item PRO instrument developed to assess the frequency, severity, 
and duration of COPD exacerbations (Jones et al 2011, Leidy et al 2011). The instrument was 
developed for daily, at home, administration using a handheld electronic device. Respondents 
are instructed to complete the diary each evening just prior to bedtime and to answer the 
questions while considering their experiences “today”. The daily EXACT-PRO total score has 
a range of 0-100 with higher scores indicative of greater severity. Total score changes are used 
to identify the onset and recovery from an EXACT-PRO defined exacerbation event. In 
identifying event onset and recovery, the EXACT-PRO can provide information on event 
frequency and duration as well as event severity. 
The E-RS™: COPD is an 11-item PRO developed to evaluate the severity of respiratory 
symptoms of COPD (Sexton et al 2010, Sexton et al 2011). The E-RS™: COPD is a subset of 
items from the EXACT-PRO. The E-RS™: COPD was designed to be captured as part of the 
daily EXACT-PRO assessment. Summation of E-RS™: COPD item responses produces a 
total score ranging from 0 to 40, with higher scores indicating greater severity. In addition to 
the total score, symptom domain scores can be calculated for breathlessness (5 items; score 
range: 0–17), cough and sputum (3 items; score range: 0–11) and chest symptoms (3 items; 
score range: 0–12) by summing the responses of items within a respective domain. As with 
the total score, higher domain scores indicate greater severity.
8.2
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Clinical Safety Laboratory Assessments
See Table 7 for the list of clinical safety laboratory tests to be performed, and the SoA for the 
timing and frequency. All protocol-required laboratory assessments as defined in the SoA, 
must be conducted in accordance with the laboratory manual. 
During the COVID-19 pandemic, it may not be possible to collect clinical safety laboratory 
tests at the site due to local restrictions. If the subject has re-consented to home/alternative 
location IP administration visits, it is possible that the HCP can collect clinical safety 
laboratory tests in the subject’s home/alternative location. Please refer to Appendix I.

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The Investigator should assess the available results regarding clinically relevant abnormalities. 
The laboratory results should be signed and dated and retained at centre as source data for 
laboratory variables.  
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7.
The  safety samples (clinical chemistry, hematology and urinalysis) will be performed at a 
central laboratory. If central laboratory kits are not available, the safety samples can be 
collected and analysed at the local laboratory at the discretion of the PI. However, all 
laboratory assessments for Visit 1, Visit 3 and EoT or IPD Visit (as per SoA) must be 
analysed at the central laboratory.
Maintaining the blind to the patient’s blood immunoglobulin, eosinophil, basophil and 
monocyte counts
The sponsor and site will be blinded to the immunoglobulin, eosinophil, basophil and 
monocyte counts from the central laboratory reports except screening visits (Visit 1 and 2), 
any repeat testing that is performed during the screening, and prior to 1st IP administration. 
If the investigator orders any local safety laboratory assessments, the requested tests should be 
restricted to the question at hand. For example, if hemoglobin is desired, the investigator 
should avoid ordering a complete blood cell count with a differential count.
In cases where the investigator requires an immunoglobulin, eosinophil, basophil, or 
monocyte count for managing safety issues, he/she may order these tests as per regular site 
practice. AstraZeneca should be notified of all such cases.
Site staff who are directly involved in the patient’s management should remain blinded to any 
blood immunoglobulin, eosinophil, basophil and monocyte counts results included as part of 
an outside laboratory report or electronic medical record. To help ensure this, each 
investigational site will designate an individual (e.g. administrator or another ancillary person) 
not directly involved in patient management, to receive and blind any immunoglobulin, 
eosinophil, basophil and monocyte counts results prior to the report being handed over to the 
site staff involved in the patient’s management and prior to filing the laboratory report as a 
source document. Similarly, immunoglobulin, eosinophil, basophil and monocyte counts 
results must be redacted from all communications with the sponsor.

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Table 7 - Laboratory Safety Variables
Hematology/Hemostasis (Whole Blood)
Clinical Chemistry (serum or plasma)
B-Hemoglobin (Hb)
S-Alkaline phosphatase (ALP)
B-Leukocyte count
S-Alanine transaminase (ALT)
B-Leukocyte differential count (absolute count)
S-Aspartate transaminase (AST)
B-Platelet count
S-Bilirubin, total
B-Hematocrit
S-Blood urea nitrogen
B-Mean Corpuscular Volume 
S-Calcium, total
B-Red blood cell (RBC) count
S-Chloride
S-Creatinine
Urinalysis (Dipstick)*
S-Creatinine kinase (CK)
U-Hb/Erythrocytes/Blood 
S-CRP
U-Protein/Albumin 
S-Gamma-glutamyl transpeptidase (GGT)
U-Glucose 
S-Glucose
S-Phosphorus
U-Microscopy and culture as required**
S-Potassium
S-Sodium
S-Total cholesterol
S-Uric acid
*Urinalysis (Dipstick) central laboratory report will contain results from variables as listed in the laboratory 
manual, however only for variables U-Hb/Erythrocytes/Blood, U-Protein/Albumin and U-Glucose requires 
confirmation in laboratory eCRF module if the result is clinically significant. If there are any clinically 
significant results from other variables, it will be the investigator decision to document them in the eCRF as an 
AE. 
**Urine samples will be analyzed locally and sent to the central laboratory only for microscopy and culture 
analysis when a positive dipstick result for any parameter is observed.
NB. In case a subject shows an AST or ALT ≥3xULN together with total bilirubin ≥2xULN 
please refer to Appendix E for further instructions.
8.2.1.1
Pregnancy Test 
The following tests are applicable to female subjects only and will be conducted in accordance 
with the schedule provided in Section 1.1.

Serum ß-human chorionic gonadotropin (ß-HCG) – the test done at enrolment 
(Visit 1) only, for WOCBP (analyzed at central laboratory).

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
FSH – the test done at enrolment (Visit 1) only, for female subjects to confirm 
postmenopausal status in women <50 years who have been amenorrhoeic for >12 
months. Until FSH is documented to be within menopausal range, treat the 
subject as WoCBP.                                                                                                                           

Urine HCG – the test will be performed at the study site for WOCBP at each 
treatment visit before IP administration using a dipstick. Positive urine test result 
must be confirmed with serum β-HCG.
8.2.2
Smoking Status
Smoking status will be assessed at every visit starting from enrolment (Visit 1) until the end of 
the last Follow Up Visit (Week 64) by collecting the subject’s response to a single yes/no 
question from study personnel: ‘What is your smoking status as of today, do you currently 
smoke? Smoking status changes during Visit 3 to the end of the last Follow Up Visit (Week 
64) will be captured on the eCRF but the subject will be permitted to continue in the study.
8.2.3
Weight and Height 
Weight and height will be measured in accordance with the SoA. The subject’s weight will be 
recorded in kilograms, and height will be recorded in centimetres. Weight and height 
measurements will be performed in light clothing and with shoes off.
8.2.4
Physical Examinations
A complete physical examination will be performed and include an assessment of the 
following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, musculoskeletal (including spine 
and extremities) and neurological systems. Brief physical examination will also be performed 
and include an assessment of the general appearance, abdomen, cardiovascular and respiratory 
system. For the brief physical examination, only, information on whether the assessment was 
performed or not will be recorded.
Physical examination (complete and brief) will be performed at timelines as specified in the 
SoA. Investigators should pay special attention to clinical signs related to previous serious 
illnesses, as new or worsening abnormalities may qualify as adverse events, see Section 8.3.7
for details.
8.2.5
Vital Signs
Vital signs (body temperature, pulse, blood pressure and respiration rate) will be obtained in 
accordance with the schedule provided in Table 1 and Table 2. 

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Body temperature will be measured before IP administration in accordance with local 
standards. 
Body temperature should be done as the first study assessment (at Visit 1 when ICF is 
obtained).

Subject with fever (≥ 38°C; ≥ 100.4°F) suspected due to COVID-19 infection during 
screening or at randomization should be screen failed (Exclusion criterion 38).

IP should not be administered if the subject is febrile (≥ 38°C; ≥ 100.4°F) or is 
suspected of having COVID-19. Refer to section 6.1.2.
The pulse rate and blood pressure should be measured after the subject has been resting for 
at least 5 minutes. The measurement will be taken in a sitting position. 
The respiration rate will be obtained after the subject has been resting for at least 5 minutes, 
by counting the number of breaths (how many times the chest rises) for one minute.
8.2.6
ECG
ECG will be performed in accordance with the schedule provided in Table 1 and Table 2. The 
equipment will be provided by a central vendor.
A 12-lead digital electrocardiogram (dECG) will be taken in the supine position, after the 
subject has been resting for at least 5 minutes. The assessment should be performed before 
interventions with the subject (e.g., spirometry and administration of the COPD related 
medications and IP).
The Investigator or authorized delegate will be responsible for the overall interpretation and 
determination of clinical significance of any potential ECG findings. In case of discrepancy 
between the Investigator's interpretation and that provided by the ECG machine (if 
applicable), the Investigator's interpretation will take precedence and should be noted on the 
printout and recorded in the eCRF. A copy of the ECG will be produced, and quality checked 
and kept in case of further need for re-evaluation.
It is highly recommended that the same machine is used for assessment throughout the 
subject’s participation in the study.
ECG evaluation will be recorded in the eCRF.
8.2.7
Supplemental Oxygen (O2)
Oxygen use will be assessed according to the schedule in Table 1 and Table 2. Use of LTOT 
should be recorded as a concomitant medication in the eCRF.

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8.2.8
Oxygen Saturation (SpO2)
Pulse oximetry will be used to measure the subject’s oxygen saturation according to the 
schedule in Table 1 and Table 2.
8.2.9
Chest X-ray 
A chest X-ray done during the screening period before first IP administration is required to 
ensure there are no abnormal radiological findings as per exclusion criterion 14 and exclusion 
criterion 40. 
Under special circumstances, recently done historical chest X-ray (anterior-posterior)/CT/MRI 
for other reasons (not study related) might be acceptable. The outcome of the X-ray/CT/MRI 
must be documented in the patients’ medical records. Study Physician approval of historical 
X-ray must be obtained prior to randomization.
8.2.10
Vaccination Restrictions
Pneumococcal and Annual Influenza Vaccination
Subjects should have a pneumococcal vaccination if they have not had one before, unless 
contraindicated. In the event that they have previously received a vaccination, the Investigator 
must ensure that the subject does not require a booster (generally after 5-6 years according to 
current guidelines, e.g., CDC 2010). If a booster is required, it should be given at Visit 1, or at 
any time prior to randomization. Subjects should receive an annual influenza vaccination in 
the autumn or winter period unless the subject has received it prior to study start (refer to 
current CDC guidelines e.g., CDC 2021-2022). If the subject has previously received the 
influenza vaccination within the last 12 months prior to study start, the vaccination should be 
given at the next autumn or winter period. If a subject has an egg intolerance, the vaccination 
may be omitted. If the PI decides to not vaccinate with either vaccine, the rationale should be 
clearly specified. 
See exclusion criteria 25 for subjects participating in the sub-study.
COVID-19 Vaccination
COVID-19 vaccines are either nucleic acid vaccines (which can include DNA plasmid and 
mRNA), recombinant vector vaccines (non-replicating viral vectors) or inactivated virus 
vaccines. DNA plasmid and mRNA vaccines are considered an inactivated vaccine. 
Recombinant vector candidates potentially may be in a new category. Based on available 
publications on mRNA and virus vector anti-SARS CoV-2 vaccines, the immune response 
developed rapidly after vaccine administration. For vaccines that are currently approved under 
emergency use authorization (EUA), please refer to relevant health authority websites for 

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further guidance. Any live attenuated vaccine is prohibited during study conduct (see Table 
6).  
Given the limited long term safety data of COVID-19 vaccines and the potential to confound 
the interpretation of safety results in the study, the following COVID-19 vaccination 
guidance provided in Table 8 should be followed depending on the study phase.
Table 8 - COVID-19 Vaccination Guidance
Study Period
Vaccine usage 
Patient in
screening/run-in period
If Covid-19 vaccination is in the best interest of the 
patient and the patient is vaccinated or scheduled to 
be vaccinated before the screening or run-in visit, the 
randomization visit should be scheduled to ensure 
that the first IP dose is administered at least 28 days 
after any vaccination dose. As these intervals might 
change, please discuss with study physician for the 
most current recommended time interval prior to any 
vaccine dose. 
See exclusion criteria 41.
Patient in treatment period
If Covid-19 vaccination is in the best interest of the 
patient and the patient is vaccinated during the study, 
IP dosing can continue but IP should not be 
administered within 14 days before or 28 days after a 
dose of vaccine. As these intervals might change, 
please discuss with study physician for the most 
current recommended time interval prior to any 
vaccine dose. 
If patient receives COVID vaccine less than 14 days 
from the last IP dose, the next IP administration 
should be rescheduled or skipped to ensure the next 
IP dose is at least 28 days after the vaccine 
administration.  
COVID-19 vaccination schedule should follow 
country specific health authority guidelines. 
Vaccination against COVID should be planned in 
advance to ensure the IP dosing/COVID-19 
vaccination intervals are maintained 
Study visits should still be conducted within the 
protocol specified time window even if a subject 
receives a COVID vaccine dose. However, even if IP 
is not administered at a study visit because of 

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Table 8 - COVID-19 Vaccination Guidance
Study Period
Vaccine usage 
COVID-19 vaccination restrictions, other site visit 
assessments should be still be performed according to 
the SoA.  
At every study visit during the treatment period, the 
investigator must ask if the patient has received or is 
planning to receive a COVID-19 vaccination. This is 
to ensure that the required time interval for IP dosing 
(mentioned above) is maintained. 
If it is anticipated that a patient will miss two 
consecutive IP administrations, the AstraZeneca 
study physician should be contacted to discuss further 
patient participation in the study. 
The reason for skipping IP administration should be 
recorded with “COVID-19” prefix in medical records 
and COVID-19 related eCRF modules. 
Patient in 
follow-up period
If COVID vaccination is in the best interest of the 
patient, COVID-19 vaccination could be 
administered. Patient should follow schedule of 
assessments; no special adjustments are needed. It is 
advised that subject wait for 14 days after the last IP 
dose.  
The suggested IP dosing/COVID-19 intervals is summarized in Figure 3.
Figure 3 - COVID-19 Vaccination between IP Dosing
Reporting of COVID-19 Vaccination
COVID-19 vaccine details including vaccine’s name/manufacturer, route of 
administration, and vaccination date should be entered into the eCRF CM module.

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If a patient experiences an AE/SAE associated with COVID-19 vaccination, the investigator 
should record this in source document and determine whether the IP should be continued, 
skipped, or permanently discontinued in accordance with Section 7.1 of the CSP.  
8.2.11
Other Safety Assessments
8.2.11.1
Serology
Hepatitis B surface antigen, hepatitis C antibody, HIV-1 and HIV-2 antibodies will be 
assessed at enrolment (Visit 1) only. All testing for these will be performed at a central 
laboratory.
Instructions for sample collection, processing, storage, and shipment will be provided in a 
separate laboratory manual provided to the sites.
8.2.11.2
SARS-CoV-2 testing
The following test is applicable only for new subjects enrolled into the study:

SARS-CoV-2 naso/oropharyngeal swab test, rapid test or alternative test (approved by 
local health authorities) – done at enrolment (Visit 1) only.
The following test is applicable for new subjects enrolled into the study and for remaining 
ongoing active subjects: 

SARS-CoV-2 serology test – for newly enrolled subjects done at first IP 
administration visit. For remaining ongoing active subjects, the test should be done as 
soon as possible, but preferably at next on-site visit.
SARS-CoV-2 nasopharyngeal swab test and SARS-CoV-2 serology will be analysed at central 
laboratory. Instructions for sample collection, processing, storage, and shipment will be 
included in a separate laboratory manual provided to the sites. SARS-CoV-2 serology data 
will be used to assess individual cases but will not be used for subgroup analyses (e.g. 
serology positive/negative).
In case of long turnaround time of the nasopharyngeal swab test results from central 
laboratory, the site has the following alternatives:

Perform naso/oropharyngeal swab test through local lab 

Perform a rapid antigen test or alternative tests at the site, provided it is approved by 
local health authorities 

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SARS-CoV-2 testing should be performed prior to lung function assessments and sputum sub-
study assessments at subsequent visits, if required per local regulations and guidance.
8.3
Collection of Adverse Events
The Investigator 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.
The definitions of device constituent-related safety events can be found in Appendix J. Device 
constituent deficiencies are covered in section 8.3.10.
AE will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or the 
subject's legally authorized representative). The Investigator and any designees are responsible 
for detecting, documenting, and recording events that meet the definition of an AE or SAE. 
For information on how to follow-up AEs see Section 8.3.3. 
8.3.1
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrences.  
8.3.2
Time Period and Frequency for Collecting AE and SAE Information 
Adverse Events and Serious Adverse Events will be collected from the time of informed 
consent and throughout the duration of the study. This includes subjects who discontinue 
treatment and is followed up according to the options described in Section 7.1.1.
SAEs will be recorded from the time of signing of ICF throughout the duration of the study.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix B. The Investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE in former study subjects. However, 
if the Investigator learns of any SAE, including a death and at any time after a subject’s last 
visit and he/she considers the event to be reasonably related to the Study treatment or study 
participation, the Investigator must notify the sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B. 

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8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each subject 
at subsequent visits/contacts. All SAE/non-serious AEs/AEs of special interest, AEs leading to 
premature discontinuation will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up. 
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the Investigator for as long as medically indicated, 
but without further recording in the CRF. AstraZeneca retains the right to request additional 
information for any subject with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary.
8.3.4
Adverse Event Data Collection
The following variables will be collected for each AE;

AE (verbatim)

The date when the AE started and stopped

Whether the AE is serious or not

Investigator causality rating against the IP(s) (yes or no)

Action taken with regard to IP(s)

Select the appropriate as required: AE caused subject’s withdrawal from 
study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date Investigator became aware of serious AE

Reason of AE being considered serious 

Date of hospitalisation

Date of discharge

Probable cause of death

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
Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication(s)
8.3.5
Causality Collection
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?’
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
8.3.6
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the subject 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 CRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.7
Adverse Events Based on Examinations and Tests
The results from the Clinical Study Protocol mandated laboratory tests, vital signs and ECGs 
will be summarised in the CSR. Deterioration as compared to baseline in protocol-mandated 
laboratory values/vital signs/ECG should therefore only be reported as AEs if they fulfil any 
of the SAE criteria or are the reason for discontinuation of treatment with the investigational 
product.
If deterioration in a laboratory value/vital sign/ECG is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated laboratory 
result/vital sign/ECG will be considered as additional information. Wherever possible the 
reporting Investigator uses the clinical, rather than the laboratory term (e.g., anaemia versus 

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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. 
When collecting AEs, the recording of diagnoses is preferred, when possible, to recording a 
list of signs and symptoms. COPD symptoms or signs, such as wheeze, cough, chest tightness, 
dyspnea, breathlessness and phlegm, will be recorded as AEs only when:

The sign or symptom is serious according to definitions, see Appendix B. 

The patient discontinues IP due to the sign or symptom.

The sign or symptom is new to the patient or not consistent with the patient’s pre-
existing COPD history (defined as within 1 year of Visit 1) as judged by the 
Investigator.
Worsening of COPD should be recorded as an AE or SAE only if it fulfils any of the above 
criteria. 
8.3.7.1
Adverse Events of Pneumonia Requiring a Confirmed Diagnosis
Events of suspected pneumonia should be confirmed by the presence of a new infiltrate on x-
ray within approximately 48 hours, as well as at least 2 of the following signs and symptoms: 
increased cough, increased sputum purulence or production, consistent auscultatory findings, 
dyspnea or tachypnea, fever, leukocytosis, or hypoxemia. 
Events of confirmed diagnoses of pneumonia must be recorded as the AE “Pneumonia 
(confirmed)”. The severe infection pages in eCRFs must be completed for infections which 
are defined as SAE, or requiring treatment with systemic antiviral medications, intravenous 
antibiotics, or medications for helminth parasitic infection or requiring a permanent 
discontinuation of study drug (refer to section  8.3.8).
8.3.8
Adverse Events of Special Interest
An adverse event of special interest (AESI) is an event of scientific and medical interest 
towards improving the understanding of the IP. An AESI may be serious or non-serious. For 
this study, AESIs include:

Serious hypersensitivity reactions

Malignancy

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
Helminth infections

Serious infectionsa

Guillain Barre Syndrome

Serious cardiac events
a eCRF 'Severe infection' pages to be completed for infections which are defined as SAE, or requiring treatment 
with systemic antiviral medications, intravenous antibiotics, or medications for helminth parasitic infection or 
requiring a permanent discontinuation of study drug.
8.3.9
Hy’s Law
Cases where a subject shows elevation in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN may need to 
be reported as SAEs.  Please refer to Appendix E for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
8.3.10
Medical Device Deficiencies 
Device constituents of combination products are being provided for use in this study. In order 
to fulfil regulatory reporting obligations worldwide, the investigator is responsible for the 
detection and documentation of events meeting the definitions of medical device deficiency 
that occur during the study with the device constituent of the tezepelumab combination 
product.
The definition of a Medical Device deficiency or deficiency in the device constituent of a 
combination product 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.
NOTE: Additional guidance, including expanded definitions, can be found in Appendix J of 
the protocol. 
The AstraZeneca Clinical Study Medical Device/Device Constituent Report Form and/or 
Product Complaint Intake Form will be used to collect the deficiency.
8.3.10.1
Time Period for Detecting Medical Device Deficiencies

Medical device incidents or malfunctions of the medical device will be detected, 
documented, and reported during all periods of the study in which the medical device is 
used.

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
If the investigator learns of any medical device deficiency at any time after a participant 
has been discharged from the study, and such incident is considered reasonably related to 
a medical device provided for the study, the investigator will promptly notify the sponsor.
The method of documenting Medical Device Deficiency is provided in Appendix J.
8.3.10.2
Follow-up of Medical Device Deficiencies

Follow-up applies to all participants, including those who discontinue study intervention.

The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.

New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator.
8.3.10.3
Prompt Reporting of Medical Device Deficiencies to Sponsor

Only deficiencies associated with the device constituent part of the tezepelumab 
combination product should be reported to the sponsor.

Medical device deficiencies will be reported to the sponsor within 24 hours after the 
investigator determines that the event meets the protocol definition of a medical device 
deficiency.

The AstraZeneca Clinical Study Medical Device/Device Constituent Report Form and/or 
Product Complaint Intake Form will be sent to AstraZeneca by email.

Where an SAE has occurred in addition to the malfunction, the SAE will be recorded in 
the eCRF as detailed in Section 8.4.1.

The sponsor will be the contact for the receipt of medical device deficiency reports.
8.3.10.4
Regulatory Reporting Requirements for Device Deficiencies

The investigator will promptly report all medical device deficiencies occurring with any 
medical device provided for use in the study in order for the sponsor to fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about certain 
safety information relating to medical devices being used in clinical studies.

The investigator, or responsible person according to local requirements (e.g., the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of medical device deficiencies to the IRB/IEC.

For further guidance on the definition of an SAE, see Appendix J of the CSP.

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8.4
Safety Reporting and Medical Management
8.4.1
Reporting of Serious Adverse Events
All SAEs must be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel must 
inform the appropriate AstraZeneca representatives within one day i.e., 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 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events 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 i.e., 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 WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative(s).
If the WBDC system is not available, then the Investigator or other study site staff must report 
a SAE to the appropriate AstraZeneca representative(s) by telephone.
The AstraZeneca representative(s) will advise the Investigator/study site staff how to proceed.  
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure for the AstraZeneca IP. 
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except if the 
pregnancy is discovered before the study subject has received any study drug. If a pregnancy 
is reported, the Investigator should inform the sponsor within 24 hours of learning of the 
pregnancy. Any cases of pregnancy during the study period or follow up will be recorded in 
the specific eCRF module.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.

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8.4.2.1
Maternal Exposure
If a subject becomes pregnant during the course of the study, IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the IP 
under study 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) should be followed up and documented even 
if the subject was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
must inform the appropriate AstraZeneca representatives within 1day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy.
8.4.2.2
Paternal Exposure 
Pregnancy of the subject’s partners will not be considered an AE.  However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital anomaly) should be followed up and documented in the Pregnancy Report 
Form for conceptions occurring from the date of the first administration of IP until 16 weeks 
(5 half-lives) after the last administration of IP. Consent from the partner must be obtained 
before the Pregnancy Report Form is completed.
8.4.3
Overdose
A dose in excess of tezepelumab 700 mg SC administered within a 2-week period is 
considered an overdose.
There is currently no specific treatment in the event of overdose of IP and possible symptoms 
of an overdose are not established.

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An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE module in the CRF and on the Overdose CRF module.
An overdose without associated symptoms is only reported on the Overdose CRF module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or 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.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 
8.3.2.  For other overdoses, reporting must occur within 30 days.
8.4.4
Medication Error, Drug Abuse and Drug Misuse
8.4.4.1
Timelines
If an event of medication error, drug abuse or drug misuse occurs in the course of 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 
he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow-up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is an 
SAE associated with the medication error (see Section 8.4.1) and within 30 days for all other 
medication errors.
8.4.4.2
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 definition of a Medication Error can be found in Appendix B 8.
8.4.4.3
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 8

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8.4.4.4
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 8
8.4.5
Management of IP-related Toxicities 
Appropriate drugs, such as epinephrine, antihistamines, and corticosteroids, as well as medical 
equipment to treat acute anaphylactic reactions, must be immediately available when IP is 
being administered. Study site personnel must be trained to recognize and treat anaphylaxis 
(Lieberman et al 2010). Details on anaphylaxis management are provided in Appendix G.
Anaphylaxis will be defined as a serious reaction that is rapid in onset and may cause death 
(Sampson et al 2006). Anaphylaxis typically manifest as 1 of 3 clinical scenarios:
1. The acute onset of a reaction (minutes to hours) with involvement of the skin, 
mucosal tissue or both and at least one of the following: a) respiratory compromise; 
or b) reduced blood pressure or symptoms of end-organ dysfunction. 
2. Two or more of the following that occur rapidly after exposure: involvement of the 
skin/mucosal tissue, respiratory compromise, reduced blood pressure or associated 
symptoms and/or persistent gastrointestinal symptoms.
3. Reduced blood pressure after exposure.
Subjects will have had a pre-assessment (i.e., vital signs and lung function) prior to IP 
administration. At Visits 3 and 4, subjects should be observed for a minimum of 2 hours after 
IP administration for the appearance of any acute drug reactions. For the remaining visits 
involving IP administration, subjects will be observed for a minimum of 1 hour after IP 
administration for any such reaction.
If an anaphylactic reaction occurs, a blood sample will be drawn from the subject as soon as 
possible after the event, at 60 minutes ± 30 minutes after the event, and at discharge for 
analysis of serum tryptase. The sample will be tested at the local lab or central lab where 
applicable.
8.4.6
Independent Data Monitoring Committee
The Independent Data Monitoring Committee (IDMC) is an independent expert advisory 
group commissioned and charged with the responsibility of assessing all SAEs (including 
deaths and all hospitalizations), non-serious AEs and cardiovascular events. The IDMC will 

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evaluate cumulative safety and other clinical trial data at regular intervals and making 
appropriate recommendations based on the available data. The IDMC will function 
independently of all other individuals associated with the conduct of the studies, including the 
study sponsor, AstraZeneca. The committee will operate in accordance with an IDMC 
Charter. 
The IDMC will have access to the individual treatment codes and will be able to merge these 
with the collected study data while the study is ongoing. The personnel involved in the clinical 
study at AstraZeneca will remain blinded to these analyses and will have no knowledge of the 
results presented to the IDMC.
8.4.7
Independent Adjudication Committee
An IAC will assess blinded data to confirm the diagnosis and causality of MACE (defined in 
the IAC charter), serious cardiac events, and deaths, as well as diagnosis of malignancies that 
occur from randomisation until the end of the follow-up period.
The IAC will also assess whether cases of ER or urgent care visits and hospitalizations, that 
occur from randomisation until the end of the follow-up period, are due to a worsening of 
COPD. 
Details on the adjudication process, including scope of adjudication and the committee 
membership, will be included in the Adjudication Committee Charter/Manual of Operations.
8.5
Pharmacokinetics
8.5.1
Collection of Samples to Measure Drug Concentration
Serum samples for determination of tezepelumab will be collected according to the SoA 
(Table 2).
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
Samples for determination of tezepelumab concentration in serum will be analyzed by a 
designated third party on behalf of AstraZeneca using a validated bioanalytical method. 
Details of the analytical method used will be described in a bioanalytical report.
Samples from patients who receive placebo will not be measured initially but will be retained 
for subsequent analysis if deemed appropriate
Full details of the analytical method used will be described in a separate Bioanalytical 
Validation Report.

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8.5.2
Collection of Samples to Measure for the Presence of ADAs
The presence of ADA will be assessed in serum samples according to the SoA (Table 2). 
Samples will be measured for the presence of ADAs for tezepelumab using validated assays. 
Tiered analysis will be performed to include screening, confirmatory, and titer assay 
components, and positive-negative cut points statistically determined from drug-naïve samples 
will be employed. Samples confirmed positive for ADA will be archived for possible testing 
for neutralizing antibodies (nAb).
8.5.3
Storage and Destruction of Pharmacokinetic/Immunogenicity Samples
The PK and immunogenicity samples will be retained for future use at AstraZeneca or 
designee for a maximum of 15 years following Last Subject’s Last Visit.
Pharmacokinetic and immunogenicity samples may be disposed of or destroyed or 
anonymized by pooling. Additional analyses may be conducted on the anonymized, pooled 
pharmacokinetic or immunogenicity samples to further evaluate and validate the analytical 
method. Any results from such analyses may be reported separately from the CSR.
8.6
Pharmacodynamics
Pharmacodynamic parameters will be evaluated using biomarkers (see Section 8.8).
8.7
Genetics
8.7.1
Optional Exploratory Genetic Sample
Whole blood will be collected from adult subjects that have been randomized into the study 
for extraction of DNA and genetic analyses including but not limited to genetic 
polymorphisms, epigenetic modifications and the microbiome associated with COPD, TSLP 
or response to tezepelumab.
Approximately 6 mL blood sample for DNA isolation will be collected from subjects who
have consented to participate in the genetic analysis component of the study as per Table 2 in 
the SoA.
The collection of blood for a DNA sample for genetic research is optional. Should a subject 
not wish to provide a sample for this research, he/she will still be allowed to participate in the 
main study.
The blood sample for genetic research should be obtained from the subjects at Visit 3, as 
outlined in the SoA. 

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Samples will be collected, labelled, stored and shipped as detailed in the Laboratory Manual. 
The results of any analyses of these samples will not be reported in the CSR itself but as an 
addendum, or separately in a scientific report or publication.
Please refer to Appendix D for further details.
8.7.2
Storage and Destruction of Genetic Samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality. Samples may be stored for a maximum of 15 
years or as per local regulations from the date of the Last Subject’s Last Visit, after which 
they will be destroyed. DNA is a finite resource that may be used up during analyses. The 
results of any further analyses will be reported either in the CSR itself or as an addendum, or 
separately in a scientific report or publication.
No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA.
8.8
Biomarkers
Serum and plasma samples will be collected according to the schedule in Table 2 in the SoA 
to evaluate the pharmacology of tezepelumab and to evaluate changes in biomarkers related to 
COPD, inflammation and the TSLP pathway. Baseline and early post-dose levels of serum 
and plasma biomarkers may also be used to explore for potential predictive biomarkers of 
response or exposure to tezepelumab. The specific biomarkers that may be analyzed are 
cytokines, chemokines and inflammatory mediators associated with COPD and the TSLP 
pathway. The results of exploratory biomarker analyses will not be reported in the CSR but in 
an addendum, or separately in a scientific report or publication.
Instructions for sample collection, processing, storage, and shipment can be found in a 
separate laboratory manual provided to the sites.
8.8.1
Storage, Re-use and Destruction of Biomarker Samples
All biomarker samples described in Section 8.8 (for example blood, sputum, nasal, and urine 
samples) will be stored for a maximum of 15 years from the date of the Last Subject’s Last 
Visit, after which they will be destroyed. The results of this biomarker research will not be 
reported in the CSR but in an addendum, or separately in a scientific report or publication. 
The results of this biomarker research may be pooled with biomarker data from other studies 
with the study drug to generate hypotheses to be tested in future research. Any residual 
biological samples may be retained for up to 15 years and used for the purpose of 
investigating COPD, the pharmacology of tezepelumab, predictors of response, or assay 
development. If a subject does not allow samples to be used for future biomarker research 

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(e.g., scientific health-related research), they may continue with their samples being used for 
the main study. The results of any future analyses will not be reported in the CSR itself but as 
an addendum, or separately in a scientific report or publication
8.8.2
Total Serum Immunoglobulin
The levels of total serum IgE, IgA, IgG and IgM will be tested by a central laboratory in 
accordance with the SoA. The results of the total serum immunoglobulin data will not be 
reported in the CSR but in an addendum, or separately in a scientific report or publication. 
Instructions for sample collection, processing, storage and shipment will be provided in a 
separate laboratory manual. The sponsor and site will be blinded to the values except 
screening visits (Visit 1 and 2), any repeat testing that is performed during the screen visits, 
and prior to IP administration.
8.8.3
Transcriptomics
Whole blood samples will be collected in PAXgene® tubes for ribonucleic acid (RNA) sample 
preparation in accordance with Table 2 in the SoA. RNA may be used in the analyses of host 
gene expression and microbiome research using quantitative methods that may include but not 
be limited to RNA microarrays, RNA-Seq and quantitative reverse-transcriptase polymerase 
chain reaction technologies and stored for future analyses. The results of this transcriptomic 
research will not be reported in the CSR but in an addendum, or separately in a scientific 
report or publication. Instruction for sample collection, processing, storage and shipment will 
be provided in a separate laboratory manual.
8.8.4
Nasal Epithelial Cell and Sputum Cell Transcriptomics
Nasal epithelial cell transcriptomic samples and/or sputum cell transcriptomic samples will be 
obtained, in accordance with the schedule provided in Table 2 in the SoA, in a subset of 
subjects only participating in the sub-study. If sputum and nasal collections occur at the same 
visit, nasal sampling should occur before sputum collection. If the subject is not able to 
produce sputum (spontaneous or induced) at Visit 3, then the subject should be withdrawn 
from the sub-study only and nasal samples should be discarded. Please note that the subject 
can continue in the main study. 
Nasal epithelial and/or sputum cell RNA may be used in the analyses of host gene expression 
research using quantitative methods that may include but not be limited to RNA microarrays, 
RNA-Seq and quantitative reverse-transcriptase polymerase chain reaction technologies and 
stored for future analyses. 
The results of this transcriptomic research will not be reported in the CSR but in an 
addendum, or separately in a scientific report or publication. Detailed procedures for 

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obtaining, processing, storing, transporting and analysing the samples will be described in 
applicable manual.
8.8.5
Sputum Induction
The aim of sputum induction is to obtain satisfactory samples of sputum originating from the 
lower airways. Sputum induction will be performed in accordance with the schedule provided 
in Table 2 in a subset of subjects only participating in the sub-study. If sputum and nasal 
collections occur at the same visit, nasal sampling should occur before collection of 
spontaneous or induced sputum. Attempts will be made to perform sputum induction as close 
to the baseline assessment time at each of the scheduled visits. If the subject is not able to 
produce sputum (spontaneous or induced) at Visit 3, then the subject should be withdrawn 
from the sub-study and nasal samples should be discarded. Please note that the subject can 
continue in the main study. For other sub-study visits, sputum sub-study samples will be 
collected if sub-study laboratory kits and supplies are available within visit window. In the 
event of missing supplies, sites should make reasonable effort to collect and process samples 
where feasible, and with the approval of Study Physician. During the COVID-19 pandemic, 
sputum samples will only be collected if allowed per local Health and Safety regulations or 
guidance and if sub-study laboratory test kits are available.
Sputum induction is conducted by inhalation of nebulised sterile saline solution followed by 
coughing and expectoration of airway secretions. Since saline inhalations may cause 
bronchoconstriction lung function will be monitored during the process. Detailed procedure 
for performing induced sputum will be described in applicable instruction manual.
If spontaneous sputum is produced immediately prior to beginning the induced sputum 
procedure, it may be used as a secondary option for outcome measures if an adequate volume 
of induced sputum is not acquired or induced sputum is not permitted per local regulations or 
guidance during COVID-19 pandemic.
Sputum biomarkers may be measured to evaluate the pharmacology of tezepelumab, 
microbiome and to evaluate changes in biomarkers related to COPD, inflammation and the 
TSLP pathway. Baseline levels of sputum biomarkers will also be used to explore for potential 
predictive biomarkers of response or exposure to tezepelumab. The specific biomarkers that 
may be analyzed may include but are not limited to cytokines, chemokines and inflammatory 
mediators associated with COPD and the TSLP pathway. Drug concentrations may also be 
measured in the sputum samples, if feasible.  If appropriate, urea concentrations may be 
measured to correct for the dilution factor of the sputum samples. The results of these 
exploratory analyses will not be reported in the CSR but in an addendum, or separately in a 
scientific report or publication.

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The sputum will be induced and processed locally at the clinical sites according to the 
methods and processes detailed in the applicable sputum induction and processing manual. 
Depending on individual site capability, sputum processing will follow one of two sputum 
processing protocols (full processing or partial processing). Sputum sample processing will 
result in the production of cytospin slides (for full sputum processing only), microbiome 
sample, cell pellets for RNA transcriptome, and aliquots of sputum supernatant. The clinical 
sites performing full sputum processing procedures will also generate and record total cell 
count and cell viability data on their sputum processing worksheets. The microbiome sample, 
cytospin slides, cell pellet for RNA transcriptome and the sputum supernatants will be 
analyzed by a different central laboratory. 
Additional local or national regulations or guidance must be followed for sputum processing 
during COVID-19 pandemic.
The sputum microbiome, cytospin slides, cell pellets and the sputum supernatants will be 
retained at AstraZeneca or designee for a maximum of 15 years following the Last Patient’s 
Last Visit. The results of this biomarker research will not be reported in the CSR but in an 
addendum, or separately in a scientific report or publication.
8.8.6
Nasal Lining Fluid
The nasal lining fluid procedure is a quick and simple technique for sampling nasal secretions. 
Nasal lining fluid samples will be obtained in accordance with the schedule provided in Table 
2 in a subset of subjects only participating in the sub-study, and if nasal lining fluid sampling 
supplies are available. If sputum and nasal collections occur at the same visit, nasal sampling 
should occur before spontaneous/sputum induction. Nasal lining fluid biomarkers will be 
measured to evaluate the pharmacology of tezepelumab and to evaluate changes in biomarkers 
related to COPD, inflammation and the TSLP pathway. Baseline and early post-dose levels of 
nasal lining fluid biomarkers may also be used to explore for potential predictive biomarkers 
of response or exposure to tezepelumab. The specific biomarkers that may be analyzed 
include but are not limited to cytokines, chemokines and inflammatory mediators associated 
with COPD and the TSLP pathway. Drug concentrations may also be measured in the nasal 
lining fluid samples, if feasible. If appropriate, urea concentrations may be measured to 
correct for the dilution factor of the nasal lining fluid samples. The results of these exploratory 
analyses will not be reported in the CSR but in an addendum, or separately in a scientific 
report or publication. Detailed procedures for obtaining, processing, storing, transporting and 
analysing the samples will be described in applicable manual.  During the COVID-19 
pandemic, nasal samples will only be collected if allowed per local Health and Safety 
regulations or guidance if sub-study laboratory test kits are available.
The nasal lining fluid samples will be retained at AstraZeneca or designee for a maximum of 

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15 years following the Last Patient’s Last Visit. The results of this biomarker research will not 
be reported in the CSR but in an addendum, or separately in a scientific report or publication.
8.8.7
Urine Biomarkers
Urine will be collected in accordance to the schedule provided in Table 2. Urine analysis may 
include but is not limited to biomarkers of inflammation associated with COPD and TSLP 
pathway. The results of these exploratory analyses will not be reported in the CSR but in an 
addendum, or separately in a scientific report or publication. The urine samples will be 
retained by AstraZeneca or a designee for a maximum of 15 years following Last Patient Last 
Visit. 
8.9
Healthcare Resource Utilization and Health Economics
Healthcare resource utilization and health economics data, associated with medical 
encounters, will be collected in the CRF by the Investigator and study-site personnel for all 
subjects throughout the study. At randomization, Healthcare Resource Utilization (HRU) 
information will be collected with a ‘one year’ recall period. All the subsequent visits will 
collect HRU information with a recall period of ‘since the last scheduled visit’. The data may 
be used as input to health economic analysis for example cost utility analysis or cost 
effectiveness analysis. Protocol-mandated procedures, tests, and encounters are excluded. Any 
results from such analyses may be reported separately from the CSR.
9.
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypothesis
The null hypothesis is that the exacerbation rate on tezepelumab is greater than or equal to the 
exacerbation rate on placebo. The alternative hypothesis is that the exacerbation rate on 
tezepelumab is less than the exacerbation rate on placebo, i.e., 
H0: Rate ratio (tezepelumab vs Placebo) ≥ 1
Ha: Rate ratio (tezepelumab vs Placebo) <1.
9.2
Sample Size Determination 
Original Sample Size
For the primary endpoint of reduction in COPD exacerbation rate, 141 subjects per treatment 
arm (282 total) will be randomized to achieve 80% power of detecting a 30% reduction in 
tezepelumab versus placebo over a fixed time period of 52 weeks. This calculation has 
assumed a one-sided 5% alpha level test, an annual placebo rate of 1.6 events/subject/52 

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weeks, a negative binomial shape parameter of 0.6, and 10% uniform drop out. 
In the absence of the interim analysis for futility, this design would provide 81.2% power, and 
only 136 subjects per treatment arm would be required for 80% power.  
This power statement accounts for the power loss associated with the futility interim analysis 
that was originally planned to occur when 182 subjects had been randomized.  In simulated 
results, 1.2% of simulated trials were stopped early for futility but would have been successful 
at the final analysis of the primary endpoint had they been allowed to continue.  Therefore, the 
overall power for this trial accounting for the interim analysis is 80%.  Note that as a result of 
the pause in recruitment due to COVID-19, the futility analysis is now planned to occur when 
approximately 30% of follow-up data are available but the expected power loss will be 
comparable under these conditions.
The primary endpoint will also be tested using a one-sided 2.5% alpha level test, but the 
sample size has not been determined based on providing power for this test.
Updated Sample Size
The sample size has been reassessed due to the potential for reduced exacerbation rates due to 
limited person-to-person contact and exposure to respiratory infections during the COVID-19 
pandemic. Assuming the same treatment effect (0.7) and dispersion parameter (0.6) as 
originally assumed, a sample size of 169 subjects per treatment arm (338 overall) will 
maintain the study power if the placebo exacerbation rate is as low as 1.2 
exacerbations/subject-year.
9.2.1
Estimands
The Primary estimand is described as follows:

Population - subjects with moderate to very severe COPD who are randomised and 
receive at least one dose of IP

Variable - annual rate of moderate or severe COPD exacerbations up to Week 52

Population-level summary measure – exacerbation rate ratio of tezepelumab versus 
placebo

Handling of intercurrent events:
o
Treatment discontinuation: All available data are used regardless of whether 
treatment discontinuation occurs.

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o
Use of an alternative biologic: All available data are used regardless of whether 
subject switches to an alternative biologic therapy.
The Supplemental estimand is described as follows: 

Population - subjects with moderate to very severe COPD who are randomised and 
receive at least one dose of IP

Variable - annual rate of moderate or severe COPD exacerbations up to Week 52

Population-level summary measure – exacerbation rate ratio of tezepelumab versus 
placebo

Handling of intercurrent events:
o
Treatment discontinuation: All available data are used up until randomised 
treatment is discontinued.
o
Use of an alternative biologic: All available data are used up until subject 
switches to an alternative biologic therapy.
A different approach may be considered depending on the number and pattern of drop-outs.  
Further detail will be provided in the SAP.
Secondary estimands and estimands to explore the impact of the COVID-19 pandemic may be 
detailed in the SAP.
9.3
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Analysis Set Description
All subjects 
analysis set
This analysis set comprises all enrolled subjects who signed the 
informed consent form, including screening failures, and will be 
used for the reporting of disposition.
Randomized 
subjects analysis 
set
This analysis set comprises all subjects randomized to study 
treatment, irrespective of whether IP was subsequently taken, and 
will also be used for the reporting of disposition.
Full analysis set 
(FAS)
This analysis set comprises all subjects randomized to study 
treatment who received at least one dose of IP, irrespective of their 
protocol adherence and continued participation in the study.

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Efficacy analyses will be performed using all subjects in the FAS. 
Subjects will be analyzed according to their randomized treatment 
(including in the case of any discrepancies between randomized 
and actual treatment at one or more visits).
PK analysis set
All subjects who received at least one dose of tezepelumab and 
have at least one detectable serum concentration post first dose that 
is not affected by factors such as protocol deviations (e.g., 
disallowed medication or incorrect study medication received).
Safety analysis 
set
This analysis set comprises all subjects who received at least one 
dose of IP.
Safety analyses will be performed using all subjects in the safety 
analysis set. Subjects will be analyzed according to their actual 
treatment in the case of any discrepancies between randomized and 
actual treatment. Specifically, a subject randomized to placebo 
who has on one or more occasion actually received active 
(tezepelumab) treatment will be assigned to the tezepelumab 
group. A subject who has on no occasion actually received any 
active (tezepelumab) treatment will be assigned to the placebo 
group.
9.4
Outcome Measures for Analyses
9.4.1
Definition of Baseline and Subject Baseline Analyses
In general, the last measurement on or prior to the date of randomization will serve as the 
baseline measurement. If there is no value on or prior to the date of randomization, then the 
baseline value will not be imputed and will be set to missing. The baseline for outcome 
variables based on efficacy biomarkers is defined as the value recorded at randomization; if a 
measurement is not scheduled to be measured at randomization visit or if the randomization 
visit measurement is missing, the last non-missing value before randomization will be used as 
baseline instead.
For spirometry, laboratory data and physical examination, baseline will be defined as the latest 
non-missing assessment prior to first dose.
Absolute change from baseline is computed as 
(post-randomization value –baseline value).

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Percent change from baseline is computed as 
100 x ((post-randomization value – baseline value) / baseline value) %.
If either the post-randomization value or the baseline value is missing, then the absolute or 
percent change from baseline value will also be set to missing.
9.4.2
Calculation or Derivation of Efficacy Variables
9.4.2.1
Exacerbation Rate
The annual COPD exacerbation rate will be used as the primary efficacy variable.
A COPD exacerbation is defined in Section 8.1.1.
In order to calculate the number of exacerbations experienced by a subject during the 
treatment period, the following rule will be applied:
The start of an exacerbation is defined as the start date of systemic corticosteroids or 
antibiotic treatment or hospital admission, whichever occurs earlier, and the end date is 
defined as the last day of systemic corticosteroids or antibiotic treatment or hospital 
discharge, whichever occurs later. 
Additional systemic corticosteroid treatments, emergency room visits requiring use of 
systemic corticosteroids, or inpatient hospitalization due to COPD occurring during an 
exacerbation should not be regarded as a new exacerbation. In order to be counted as a new 
exacerbation it must be preceded by at least 7 days in which neither criterion is fulfilled.
The follow-up time for exacerbations for a subject is approximately 52 weeks; defined as the 
time from randomization to the date of Visit 16, regardless of whether subjects remain on 
randomized treatment. For a subject lost to follow-up or prematurely withdrawing from the 
study prior to Visit 16, this will be defined as the time from randomization to the time point 
after which an exacerbation could not be assessed. 
The number of days that the subject experiences an exacerbation during the follow-up time, 
including the subsequent 7 days (when a further exacerbation would not be considered a 
separate event (and if within the follow-up time) will be subtracted from the follow-up time to 
give the time at risk of exacerbation.
In the statistical analysis, the number of COPD exacerbations experienced by a subject during 
their follow-up time will be used as response variable, and the logarithm of the subject’s 
corresponding time at risk will be used as an offset in the analysis to adjust for subjects having 
different observation times during which the events occur.

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For the production of summary statistics, the annual exacerbation rate per subject is 
calculated, and standardized per 52-week period according to the formula described below.
Annual exacerbation rate=Number of exacerbations*365.25 / (Time at Risk of Exacerbation).
For subjects who prematurely discontinue treatment, efforts will be made to continue 
collecting the exacerbation data until the scheduled Visit 16/EOT at Week 52 after 
randomization. In the statistical analysis of exacerbation rate for the primary estimand, the 
data collected up to Visit 16/EOT will be included for the patients who prematurely 
discontinue treatment according to the intent-to-treat principle. For the patients who died 
during the treatment period the exacerbation data collected up to the date of death will be 
included in the statistical analysis.
If the cause of any death is related to COPD or a COPD exacerbation, the event will also be 
included in the rate calculation as a severe exacerbation.
To examine the sensitivity of results of the primary analysis to the underlying assumptions, 
sensitivity analyses may be performed using different assumptions for missing data following 
study withdrawal.  Further details will be given in the SAP.
The annual rate of moderate or severe COPD exacerbations, excluding those moderate 
exacerbations treated only with antibiotics, will be used as a supportive endpoint for the 
primary endpoint.  This supportive endpoint includes all severe COPD exacerbations and 
moderate COPD exacerbations treated by OCS with or without antibiotics.  
9.4.2.2
Proportion of Subjects with ≥ 1 COPD Exacerbation
The proportion of subjects with ≥ 1 COPD exacerbation will be a secondary efficacy variable.  
9.4.2.3
Time to First Exacerbation
Time from randomization to the first COPD exacerbation will be a secondary efficacy 
variable, and is calculated as follows:
Start Date of first COPD exacerbation – Date of randomization + 1.
The time to first COPD exacerbation for subjects who do not experience a COPD 
exacerbation will be censored at the time point after which an exacerbation could not be 
assessed.  For subjects lost to follow-up or prematurely withdrawing from the study, the time 
to first COPD exacerbation will be censored at the end of the maximum follow-up time, as 
described in Section 9.4.2.1.

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9.4.2.4
Annual Rate of Severe COPD Exacerbations
The annual rate of severe COPD exacerbations will be a secondary efficacy variable.  If the 
cause of any death is related to COPD or a COPD exacerbation, the event will also be 
included.
In the statistical analysis, the number of severe COPD exacerbations will be used as response 
variable, and the logarithm of the subject’s corresponding follow-up time will be used as an 
offset in the analysis to adjust for subjects having different observation times during which the 
events occur.
Follow-up time is derived as described in Section 9.4.2.1.
Time to first severe COPD exacerbation and proportion of subjects with at least one severe 
COPD exacerbation will be used as supportive variables to this secondary efficacy variable. 
9.4.2.5
Forced Expiratory Volume in 1 Second
The change in FEV1 from baseline to each of the post-randomization visits up to and including 
the Week 52 visit (Visit 16) will be assessed with change from baseline at week 52 used as the 
secondary efficacy variable. The last pre-bronchodilator measurement recorded prior to the 
first dose of IP  will be used as baseline FEV1. 
9.4.3
Calculation or Derivation of Safety Variables
9.4.3.1
Safety Variables
The following safety data will be collected: vital signs, physical examination, 12-lead ECG, 
hematology, clinical chemistry, urinalysis, and reported AEs.
Change from baseline (last measurement prior to first IP administration) to each post-
treatment time point where scheduled assessments were made will be calculated for relevant 
measurements.  AEs will be summarized by means of descriptive statistics and qualitative 
summaries. 
9.4.3.2
Adverse Events
Adverse events experienced by the subjects will be collected throughout the entire study and 
will be coded by the AstraZeneca designee using the latest version of the Medical Dictionary 
for Regulatory Activities (MedDRA).
Adverse event data will be categorized according to their onset date into the following study 
periods:

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
AEs occurring during screening (onset date ≥ Visit 1 and before the first dose 
of study treatment)

AEs occurring during treatment (onset date ≥ the first day of study treatment 
and ≤ the last day of study treatment + 4 weeks)

AEs occurring during follow-up

(onset date > the last day of study treatment + 4 weeks and ≤ the last day 
of study treatment + 16 weeks)
The timing of AEs will be assigned to the period in which they first occurred. If an AE has a 
missing onset date, then unless the stop date of the AE indicates otherwise, this will be 
considered an on-treatment event. Similarly, if an AE has a partial onset date, then unless the 
partial onset date or the stop date indicates otherwise, this will be considered an on-treatment 
AE.
9.4.3.3
Other Significant Adverse Events
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs or discontinuations due to AEs.
Based on the expert’s judgment, significant AEs of particular clinical importance may, after 
consultation with the Global Patient Safety Physician, be considered other significant AEs 
(OAEs) and reported as such in the CSR.
Examples of these are marked hematological and other laboratory abnormalities, and certain 
events that led to intervention (other than those already classified as serious), dose reduction, 
or significant additional treatment.
9.4.3.4
Laboratory Variables
Blood and urine samples for determination of clinical chemistry, hematology and urinalysis 
parameters will be taken at the times detailed in the CSP and will be assessed in a central 
laboratory. The parameters outlined in Table 7 in Section 8.2.1, will be collected. Laboratory 
data will be reported in SI units.
Changes in haematology and clinical chemistry variables between baseline and each 
subsequent on treatment assessment will be calculated as described in Section 8.2.1. There 
will be no imputation for missing values.
Absolute values will be compared to the relevant reference range and classified as low (below 
range), normal (within range or on limits) or high (above range). The AstraZeneca extended 

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reference ranges will be used for laboratory variables (where they exist). All values (absolute 
and change) falling outside the reference ranges will be flagged.
Urinalysis data will be categorized as negative (0), positive (+), or strongly positive (++, +++,
or >+++) at each time-point.
For the purposes of hematology, clinical chemistry and urinalysis shift tables, baseline will be 
defined as the latest non-missing assessment prior to first dose, and on-treatment will be 
defined as the latest non-missing assessment whilst the subject is ongoing on treatment.
For the liver function tests: AST, ALT, ALP, GGT and total bilirubin, the multiple of the 
AstraZeneca ULN (not extended) range will be calculated for each data point.
Multiple = Value / ULN
i.e., if the ALT value was 72 IU/L (ULN 36) then the multiple would be 2.
Subjects who meet any of the following criteria at any point during the study will be flagged:

AST ≥ 3x ULN

ALT ≥ 3x ULN

TBL ≥ 2xULN
9.4.3.5
ECGs
12 lead digital ECG measurements will be recorded in accordance with the protocol, with the 
baseline visit being defined as any time between Visit 1 and Visit 2 inclusive.
The outcome of the overall evaluation is to be recorded as normal/abnormal in the eCRF, with 
any abnormalities being recorded as not clinically significant or clinically significant.
9.4.3.6
Physical Examination
Complete and brief physical examinations will be performed at time points specified in Table 
2.
What is included in the assessment will be dependent on whether the examination is complete 
or brief, as described in Section 8.2.4. For the brief physical examination, only information on 
whether the assessment was performed or not will be recorded.
Each component of the complete physical examination at baseline visit will be recorded as 
normal or abnormal. Each component of the physical examinations at follow-up will be 
recorded as normal, same as baseline, or new/aggravated.

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Any new finding(s), or aggravated existing finding(s), judged as clinically significant by the 
Investigator, will be reported as an AE.
9.4.3.7
Vital signs
Vital signs (pulse, systolic blood pressure, diastolic blood pressure, respiration rate and body 
temperature) will be obtained in accordance with the schedule provided in Table 1 and Table 
2.
Changes in vital sign variables between baseline and each subsequent scheduled assessment 
will be calculated as described in Section 9.4.1. There will be no imputation for missing 
values.
Absolute values will be compared to the relevant reference range and classified as low (below 
range), normal (within range or on limits) or high (above range). All values (absolute and 
change) falling outside the reference ranges will be flagged.
Body mass index (BMI) will be calculated from the height (in meters) and weight (in 
kilograms) as BMI = kg/m2.
9.4.4
Calculation or Derivation of PRO variables
9.4.4.1
SGRQ
Potential health status treatment benefits of tezepelumab will be evaluated by comparing the 
change from the baseline at Week 52 in SGRQ total scores.  For the responder analysis of 
SGRQ a responder will be defined as an individual with a ≥ 4-point decrease (improvement) 
in SGRQ total score at Week 52.
9.4.5
Calculation or Derivation of Pharmacokinetic Variables
Serum samples will be collected at specified time points according to the schedule of 
assessment for determination of tezepelumab concentrations. Serum trough tezepelumab 
concentrations in the tezepelumab group will be summarized by time point. 
9.4.6
Calculation or Derivation of Immunogenicity Variables
Serum samples will be collected at specified time points according to the schedule of 
assessment to detect the presence of ADAs against tezepelumab. The number and percentage 
of patients who develop detectable ADAs, as well as ADA titers for the samples confirmed 
positive for the presences of ADAs will be summarized by time point for both tezepelumab 
and placebo treatment groups. The prevalence and incidence of ADA over the course of the 
study will be calculated and tabulated for both treatment groups. 

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9.5
Statistical Analyses
There will be two DBLs in this study. The primary DBL will be conducted after the last 
subject completes Week 52, and the final DBL will be conducted once the last subject has 
completed the last safety follow-up visit (Week 64).  Main analyses of the primary, key 
secondary efficacy objectives and some supportive summaries will be performed based on 
both the primary and final DBL data. The results produced at the time of primary DBL will be 
used to facilitate further design development for Phase 3 only. Although no changes are 
anticipated in conclusions given the primary DBL occurs after all subjects complete the 
planned treatment period, any discrepancies in the conclusions between the two DBLs will be 
discussed in the CSR. The CSR will be produced following the final DBL.
All personnel involved with the analysis and conduct of the study will remain blinded until 
primary database lock and important protocol deviations identified.  
After primary database lock, treatment allocation for subjects during this study will become 
known to the Sponsor staff and/or designated CRO. The blind will be maintained for the 
Investigator, investigational site staff, and for the subject.
Analyses will be performed by AstraZeneca or its representatives. A comprehensive statistical 
analysis plan will be developed and finalized before primary database lock and will describe 
the subject populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data.
Additional analyses assessing the impact of COVID-19 may be included in the SAP.
9.5.1
Multiple Testing Procedure
In this Phase 2a study, in order to describe the nature of the benefits with tezepelumab and to 
define study success, the primary endpoint will be tested using a one-sided 5% significance 
level.  In addition, and although not powered, the primary endpoint will also be tested using a 
one-sided 2.5% alpha in order to strongly control type I error.  No additional adjustment for 
multiplicity will be implemented.  
9.5.2
Efficacy Analyses
9.5.2.1
Primary Analysis Methods
The primary efficacy variable is the annual COPD exacerbation rate and the primary analysis 
is to compare the annual COPD exacerbation rate of tezepelumab with placebo. Patients will 
be analyzed using the full analysis set according to randomized treatment.

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The null hypothesis is that the exacerbation rate on tezepelumab is greater than or equal to the 
exacerbation rate on placebo. The alternative hypothesis is that the exacerbation rate on 
tezepelumab is less than the exacerbation rate on placebo, i.e.,
H0: Rate ratio (tezepelumab vs Placebo) ≥ 1
Ha: Rate ratio (tezepelumab vs Placebo) < 1
Annual exacerbation rate in the tezepelumab group will be compared to annual exacerbation 
rate in the placebo group using a negative binomial model for the primary analysis. The 
response variable in the model will be the number of COPD exacerbations experienced by a 
patient during the follow-up for exacerbations. The model will include covariates of treatment 
group and the stratification factors (region, and the number of exacerbations in the year prior 
to study entry). The logarithm of the patient’s corresponding time at risk of exacerbation will 
be used as an offset variable in the model to adjust for patients having different observation 
times during which the events occur.
The COPD exacerbation rate and the corresponding 90% confidence interval (CI) within each 
treatment group will be presented. The estimated treatment difference from placebo (i.e., the 
absolute difference between tezepelumab and placebo, and the rate ratio of tezepelumab 
versus placebo), corresponding 90% CI, and 1-sided p-value for the rate ratio will be 
presented. The 95% CI, and 2-sided p-value for the rate ratio will also be presented. Marginal 
standardization methods will be used on the model estimates for all negative binomial 
analyses, unless otherwise specified. 
9.5.2.2
Secondary Analysis Methods
Secondary efficacy endpoints in this study are:

Time to first COPD exacerbation

Proportion of subjects with at least 1 COPD exacerbation

Rate of severe exacerbations

Time to first severe exacerbation

Proportion of subjects with at least one severe COPD exacerbation 

Change from baseline in pre-BD FEV1 at week 52

Proportion of subjects achieving an MCID of 4 units or more in SGRQ total score over 
52 weeks

Change from baseline in SGRQ at Week 52

Change from baseline in CAT at Week 52
Time to first COPD exacerbation over the 52-week treatment period will be analyzed to 
explore the extent to which treatment with tezepelumab delays the time to first exacerbation 
compared to placebo. A Cox proportional hazard model will be fitted to the data with 

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covariates of treatment, region and number of exacerbations prior to study entry in the year 
before the study 
Proportion of subjects with at least one COPD exacerbation in tezepelumab group will be 
compared to with the proportion in the placebo group using a logistic regression model with 
region and number of exacerbations in the year prior to the study entry as covariates.  
Annual rate of severe COPD exacerbations will be analyzed using a Negative Binomial Model 
as outlined for the primary efficacy variable.
Time to first severe COPD exacerbation will be analyzed using a similar model for time to 
first COPD exacerbation.  
Change from baseline in pre-dose/pre-BD FEV1 at Week 52 will be compared between 
tezepelumab and placebo using a repeated measures analysis on subjects with a baseline pre-
dose/pre-BD FEV1 and at least one post-randomization pre-dose/pre-BD FEV1 in the FAS. 
The dependent variable will be the change from baseline in pre-bronchodilator FEV1 at post-
baseline protocol-specified visits (up to the EOT visit). Treatment group will be fitted as the 
explanatory variable, and region, visit, baseline pre-bronchodilator FEV1 and the interaction 
between visit and treatment will be fitted as covariates. Visit will be fitted as a categorical 
variable, and the variance-covariance matrix will be assumed to be unstructured. If the 
procedure does not converge then a compound symmetric variance covariance matrix will be 
used instead. The model is:
Change in FEV1=Treatment group+ baseline FEV1+ region + prior exacerbation strata + 
visit + treatment*visit
Changes from baseline in SGRQ total score and CAT total score at Week 52 will be analyzed 
using a similar model for change from baseline in pre-dose/pre-BD FEV1; the appropriate 
baseline value will be used in each model.  
Proportion of subjects achieving an MCID of 4 units or more in SGRQ total score over 52 
weeks in tezepelumab group will be compared with the proportion in the placebo group using 
a similar logistic regression model as that used for the proportion of subjects with at least one 
COPD exacerbation.  The baseline SGRQ score will be included as a covariate in this model.
9.5.3
Subgroup Analyses
Details of all subgroup analyses and statistical modelling including possible testing of 
interaction between treatment group and covariates will be described in the SAP. 

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9.5.4
Safety Analyses
AEs will be summarized by means of counts and exposure adjusted rate summaries by study 
period (treatment period and follow-up period). AEs will be listed for each subject and 
summarized by System Organ Class (SOC) and Preferred Term (PT) assigned to the event by 
MedDRA. Laboratory safety variables will be summarized using standard summary statistics 
and plots as appropriate. Other safety variables will be summarized as appropriate. Further 
details will be provided in the SAP.
Laboratory data for hematology and clinical chemistry will be summarized. The frequency of 
changes with respect to normal ranges between baseline and each post-treatment time point 
will be tabulated. Frequencies of clinically noteworthy values (defined in the SAP) occurring 
during the clinical study will also be given. Shifts from normal to abnormal between baseline 
and each post-baseline time point will be evaluated for urinalysis. Changes in vital signs and 
ECGs will be examined at each visit and at endpoint. Frequencies of clinically noteworthy 
values (defined in the SAP) occurring during the clinical study will be presented. Shifts from 
normal to abnormal between baseline and follow-up will be evaluated for the physical 
examination.
9.5.5
Pharmacokinetic and Immunogenicity Analyses
Tezepelumab serum concentrations will be summarized using descriptive statistics by visit. 
Observed serum concentrations of tezepelumab for each individual will be listed by visit. The 
PK data collected in this study may be combined with data from other studies for population 
PK analysis. The results of such an analysis, if performed, will be reported separately.
The prevalence and incidence of anti-drug antibodies (ADA) will be reported by treatment 
group. ADA data will be summarized using descriptive statistics at each visit by treatment 
group. Samples confirmed positive for ADA will be archived for possible testing for 
neutralizing antibodies (nAb). The potential effects of ADA status and ADA titer on 
pharmacokinetics of tezepelumab will be evaluated. The potential association of 
immunogenicity with efficacy and safety may be evaluated if appropriate.
9.5.6
Biomarker Analyses
Biomarkers will be summarized using descriptive statistics. Details of the analyses will be 
described in the exploratory analyses plan, which will be finalized before the database lock. 
The results will be reported outside the CSR.
9.6
Interim Analyses 
A data cut off for an interim analysis to potentially stop the study due to futility of efficacy 

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was originally planned to occur when 182 subjects had been randomized. As a result of the 
pause in recruitment due to COVID-19, the futility analysis is now planned to occur when 
approximately 30% of information has been achieved.  An Independent Data Monitoring 
Committee (IDMC) will be used.  Futility will be declared if the lower bound of an 80% 
Confidence Interval for the exacerbation rate ratio of tezepelumab vs. placebo is greater than 
0.80. The futility boundary and method of assessing futility were chosen based on the 
operating characteristics of ~33% chance of stopping the study under the null hypothesis and 
~4% chance of stopping the study assuming an exacerbation rate ratio of 0.70.  Full details 
about the futility analysis decision rules and procedures will be specified in an IDMC charter, 
which will also specify the roles and responsibility of the IDMC members.  Conducting the 
futility analysis results in power loss, but no alpha adjustment is required as there is no 
decision rule in place for stopping the study early to claim efficacy and no recovery of alpha 
from the futility analysis.  
A data cut off for an interim analysis to inform sponsor Phase 3 planning will be conducted 
approximately 1 month after Last Subject Randomized. The study will continue, even if 
sufficient efficacy is observed to inform an early go for planning purposes. The Independent 
Data Monitoring Committee (IDMC) will be used and a blinding plan will be written to ensure 
that the study team, investigational site staff and patients remain blinded to subject level 
treatment revealing data if an early planning decision is made. As the study will continue 
regardless, no adjustment to the type I error is required. 
9.6.1
Independent Data Monitoring Committee (IDMC)
An IDMC will be utilized for this study. Details regarding IDMC are provided in Section 
8.4.6.

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10.
REFERENCES
Aithal et al 2011
Clinical Pharmacology and Therapeutics 89(6):806-815.
Alving et al 2017
Alving K, Anolik R, Crater G, LaForce C F, Rickard K. Validation of a New Portable Exhaled 
Nitric Oxide Analyzer, NIOX VERO®: Randomized Studies in Asthma. Pulm Ther. 2017 
Jun;3(1):207-218. 
Anzalone et al 2018
Anzalone G, Albano GD, Montalbano AM, Riccobono L, Bonanno A, Gagliardo R, Bucchieri 
F, Marchese R, Moscato M, Profita M. IL-17A-associated IKK-α signalling induced TSLP 
production in epithelial cells of COPD patients. Exp Mol Med. 2018 Oct 5;50(10):131.
Calvern et al 2012
Calvén J, Yudina Y, Hallgren O, Westergren-Thorsson G, Davies DE, Brandelius A, Uller L. 
Viral stimuli trigger exaggerated thymic stromal lymphopoietin expression by chronic 
obstructive pulmonary disease epithelium: role of endosomal TLR3 and cytosolic RIG-I-like 
helicases. J Innate Immun. 2012;4(1):86-99.
Camelo et al 2017
Camelo A, Rosignoli G, Ohne Y, Stewart RA, Overed-Sayer C, Sleeman MA, et al. IL-33, IL-
25, and TSLP induce a distinct phenotypic and activation profile in human type 2 innate 
lymphoid cells. Blood Adv. 2017 Mar 30;1(10):577-589.
CDC 2010
CDC guidelines 2010, Updated Recommendations for Prevention of Invasive Pneumococcal 
Disease Among Adults Using the 23-Valent Pneumococcal Polysaccharide Vaccine 
(PPSV23). Centers for Disease Control and Prevention (CDC). Morbidity and Mortality 
Weekly Report .2010 / 59(34);1102-1106. Available from: URL: 
https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/pneumo.html
CDC 2021-2022
CDC guidelines 2021-2022, Summary: Prevention and Control of Seasonal Influenza with 
Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 
United States, 2021-2022. Centers for Disease Control and Prevention (CDC). Available 
from: URL: https://www.cdc.gov/flu/professionals/acip/summary/summary-
recommendations.htm
Corren et al 2017
Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, et al. Tezepelumab in adults 
with uncontrolled asthma. N Engl J Med. 2017; 377:936-46.
Donaldson et al 2002
Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between 
exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. 
Thorax. 2002; 57(10):847-52.

Clinical Study Protocol - 7.0
AstraZeneca
Tezepelumab - D5241C00001
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Page 136 of 217
FDA Guidance for Industry (issued July 2009)
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’.
GINA 2018
Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention 
2018. Available from: www.ginasthma.org. 
GOLD 2019
2019 Global Strategy for Prevention, Diagnosis and Management of COPD, Global Initiative
for Chronic Obstructive Lung Disease (GOLD) 2019. Available from: 
http://www.goldcopd.org.
Johansson et al 2004
Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, Motala C, Ortega 
Martell JA, Platts-Mills TA, Ring J, Thien F, Van Cauwenberge P, Williams HC. A revised 
nomenclature for allergy for global use: report of the nomenclature review committee of world 
allergy organization. J Allergy Clin Immunol. 2004; 113:832–6.
Jones et al 2011 
Jones PW, Chen WH, Wilcox TK, Sethi S, Leidy NK. Characterizing and quantifying the 
symptomatic features of COPD exacerbations. Chest 2011;139(6):1388–1394.
Jones et al 1991 
Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory Questionnaire. Respir 
Med. 1991;85 Suppl B:25-31.
Jones et al 2009 
Jones PW, Harding G, Berry P, Wiklund I, Chen W-H, Leidy NK. Development and first 
validation of the COPD Assessment Test. Eur Respir J 2009, 34: 648–654.
Kato et al 2007
Kato A, Favoreto S Jr, Avila PC, Schleimer RP. TLR3- and Th2 cytokine-dependent 
production of thymic stromal lymphopoietin in human airway epithelial cells. J Immunol. 
2007 Jul 15;179(2):1080-7.
Kemp et al 2008
Kemp SF, Lockey RF, Simons FE; World Allergy Organization Ad hoc Committee on 
Epinephrine in Anaphylaxis. Epinephrine: the drug of choice for anaphylaxis. A statement of 
the World Allergy Organization. Allergy. 2008; 63(8):1061-70.
Lee and Ziegler 2007
Lee HC, Ziegler SF. Inducible expression of the proallergic cytokine thymic stromal 
lymphopoietin in airway epithelial cells is controlled by NFkappaB. Proc Natl Acad Sci U S 
A. 2007 Jan 16;104(3):914-9.
Leidy et al 2011 
Leidy NK, Wilcox TK, Jones PW, 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):323–329.

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Lieberman et al 2010 
Lieberman P, Nicklas RA, Oppenheimer J, Kemp SF, Lang DM, Bernstein DI, Bernstein JA, 
Burks AW, Feldweg AM, Fink JN, Greenberger PA, Golden DB, James JM, Kemp SF, 
Ledford DK, Lieberman P, Sheffer AL, Bernstein DI, Blessing-Moore J, Cox L, Khan DA, 
Lang D, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph C, Schuller DE, Spector SL,  
Tilles S, Wallace D . The diagnosis and management of anaphylaxis practice parameter: 2010 
update. J Allergy Clin Immunol. 2010 Sep;126(3):477-80. e1-42.
Miller et al 2005
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, 
van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas 
D, Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force. Standardisation of 
spirometry. Eur Respir J. 2005 Aug;26(2):319-38.
Pavord et al 2017
Pavord ID, Chanez P, Criner GJ, Kerstjens HAM, Korn S, Lugogo N, et al. Mepolizumab for 
eosinophilic chronic obstructive pulmonary disease. N Engl J Med. 2017; 377:1613-29.
Perez et al 2014
Perez GF, Pancham K, Huseni S, Preciado D, Freishtat RJ, Colberg-Poley AM, Hoffman EP, 
Rose MC, Nino G. Rhinovirus infection in young children is associated with elevated airway 
TSLP levels. Eur Respir J. 2014 Oct;44(4):1075-8.
Quanjer et al 2012
Quanjer PH, Stanojevic S, Cole TJ, Baur X, L Hall GL, Culver B, et al. Multi ethnic reference
values for spirometry for the 3-95 year age range: the global lung function 2012 equations.
2012 Dec;40(6):1324-43.
Rodriquez-Roisin R 2000
Rodriquez-Roisin R. Toward a consensus definition for COPD exacerbations. Chest. 2000; 
117:398S-401S.
Sampson et al 2006 
Sampson H, Muñoz-Furlong A, Campbell R, Adkinson F, Bock A, Branum A, Brown S, 
Camargo C, Cydulka R, Galli S, Gidudu J, Gruchalla R, Harlor A, Hepner D, Lewis L, 
Lieberman P, Metcalfe D, O’Connor R, Muraro A, Rudman A, Schmitt C, Scherrer D, Simons 
E, Thomas S, Wood J, Decker W. Second symposium on the definition and management of 
anaphylaxis: Summary report—Second National Institute of Allergy and Infectious 
Disease/Food Allergy and Anaphylaxis Network symposium. The Journal of Allergy and 
Clinical Immunology 117.2 (2006): 391-397.
Sexton et al 2010 
Sexton C, Notte S, Murray L, Leidy NK. PRO evidence dossier to support the use of the E-
RS™: COPD to evaluate respiratory symptoms in patients with COPD. United BioSource 
Corporation; Bethesda, MD: May 2010. 
Sexton et al 2011 
Sexton C, Leidy NK, Notte SM, et al. Quantifying the severity of respiratory symptoms of 
COPD: reliability and validity of a patient diary. Poster presented at the American Thoracic 
Society International Meeting; May 2011: Denver, CO.

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Singh et al 2014
Singh D, Kolsum U, Brightling CE, Locantore N, Agusti A, Tal-Singer R. Eosinophilic 
inflammation in COPD: prevalence and clinical characteristics. Eur Resp J. 2014; 44:1697-
1700.
Tanaka et al 2009
Tanaka J, Watanabe N, Kido M, Saga K, Akamatsu T, Nishio A, et al. Human TSLP and 
TLR3 ligands promote differentiation of Th17 cells with a central memory phenotype under 
Th2-polarizing conditions. Clin Exp Allergy. 2009; 39(1):89-100.
Watson and Gauvreau 2014
Watson BM, Gauvreau GM. Thymic stromal erythropoietin: a central regulator of allergic 
asthma. Expert Opin Ther Targets. 2014; 18:771-785.
Wedzicha et al 2013 
Wedzicha JA, Decramer M, Ficker JH, Niewoehner DE, Sandström T, Taylor AF, et al. 
Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator 
QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomized, double-
blind, parallel-group study. The Lancet. 2013;1(3):199-209.
Ying et al 2008
Ying S, O’Connor B, Ratoff J, Meng Q, Fang C, Cousins D, Zhang G, Gu S, Gao Z, Shamji 
B, Edwards MJ, Lee TH, Corrigan CJ. Expression and cellular provenance of thymic stromal 
lymphopoietin and chemokines in patients with severe asthma and chronic obstructive 
pulmonary disease. J Immunol. 2008; 181:2790-8.
Ziegler et al 2013
Ziegler SF, Roan F, Bell BD, Stoklasek TA, Kitajima M, Han H. The biology of thymic 
stromal lymphopoietin (TSLP). Adv Pharmacol. 2013; 66:129-55. 

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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Appendix A
Regulatory, Ethical and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC and applicable Regulatory Authority 
approval before implementation of changes made to the study design, except for changes 
necessary to eliminate an immediate hazard to study subjects.  
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 the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 

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relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

For all studies except those utilizing medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.
- European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the [Investigator’s Brochure or state other 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.

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A 2
Financial Disclosure
Investigators and Sub-Investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process
The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her legally authorized representative and answer all questions regarding the study.  
Subjects must be informed that their participation is voluntary. Subjects or their legally 
authorized representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or site.  
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was obtained.  
The authorized person obtaining the informed consent must also sign the ICF.
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
A copy of the ICF(s) must be provided to the subject or the subject’s legally authorized 
representative.  
If subject declines to participate in any voluntary exploratory genetic research component of 
the study, there will be no penalty or loss of benefit to the subject and he/she will not be 
excluded from other aspects of the study.
If a subject’s partner becomes pregnant during the study from the date of the first 
administration of IP until 16 weeks (5 half-lives) after the last administration of IP, the partner 
is asked to sign the Adult Study Informed Consent Form for Pregnant Partners of Study 
Subjects and provide information about the pregnancy accordingly.
Subjects who are re-screened are required to sign a new ICF. 
During the COVID-19 pandemic, re-consenting of subjects must follow local and regional 
guidelines with regard to informed consent. It is critical that where written re-consent cannot 
be obtained, and local and regional guidance allows, the subject's verbal consent via phone or 
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COVID-19 pandemic. Confirmation of subject’s re-consent needs to be documented in the 
source documents.
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The Investigator or authorized designee will 
explain to each subject the objectives of the exploratory research. Subjects will be told that 
they are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period. The subject will give a separate agreement to allow any 
remaining specimens to be used for exploratory research. Subjects who decline to participate 
in this optional research will indicate this in the ICF. If a subject withdraws consent to the use 
of donated biological samples, the samples will be disposed of/destroyed, and the action 
documented.  If samples already have been analyzed at the time of the request, AstraZeneca 
will not be obliged to destroy the results of this research.
A 4
Data Protection
Each subject will be assigned a unique identifier by the sponsor.  Any subject records or data 
sets transferred to the sponsor will contain only the identifier; subject names or any 
information which would make the subject identifiable will not be transferred.  
The subject must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the subject.  
The subject must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees Structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the Clinical Study Protocol and 
letters to Investigators.
A 6
Dissemination of Clinical Study Data
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS within 
a year from global End of Trial Date in all participating countries, due to scientific reasons, as 
otherwise statistical analysis is not relevant.
A description of this clinical trial 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 trial and/or summary 

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of main study results may also be available on other websites according to the regulations of 
the countries in which the main study is conducted.
A 7
Data Quality Assurance
All subject data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (e.g., laboratory data).  The Investigator 
is responsible for verifying that data entries are accurate and correct by electronically signing 
the CRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects 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.  Monitoring details 
describing strategy (e.g., risk-based initiatives in operations and quality such as Risk 
Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote, or on-site monitoring) are provided in the Monitoring Plan.
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 25 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor.  No records may be transferred to 
another location or party without written notification to the sponsor. 
A 8
Source Documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected.  Source documents are filed at the Investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained.  The Investigator may need to 

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request previous medical records or transfer records, depending on the study.  Also, current 
medical records must be available.
Definitions of what constitutes source data can be found in the monitoring plan.
A 9
Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. The study may be stopped if, in the 
judgment of AstraZeneca, trial subjects are placed at undue risk because of clinically 
significant findings that:
•
meet individual stopping criteria or are otherwise considered significant 
•
are assessed as causally related to study drug 
•
are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests.
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or Investigator may include but are 
not limited to:
•
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines
•
Inadequate recruitment of participants by the Investigator
•
Discontinuation of further study intervention development
A 10
Publication Policy

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The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission.  This allows the sponsor to protect proprietary information and to provide 
comments.  
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data.  In this case, a 
coordinating Investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.

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Appendix B
Adverse Event Definitions and Additional Safety Information
B 1
Definition of Adverse Events
An adverse event is the development of any untoward medical occurrence in a subject or clinical 
study subject 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 
(e.g., an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product.  
The term AE is used to include both serious and non-serious AEs and can include a deterioration 
of a pre-existing medical occurrence. An AE may occur at any time, including screening or 
washout periods, even if no Study treatment has been administered.
B 2
Definitions of Serious Adverse Event
A serious adverse event is an AE occurring during any study phase (i.e., screening, treatment, 
follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-subject 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 subject or may require medical 
treatment to prevent one of the outcomes listed above
B 3
Life Threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred, or it is suspected that use or continued use of the product would result in the subject’s 
death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it might 
have caused death (e.g., hepatitis that resolved without hepatic failure).
B 4
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons for 
it may be (e.g., bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 

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existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
B 5
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 jeopardize the subject 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.
Examples of such events are:

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
B 6
Intensity Rating Scale:
1.
Mild (awareness of sign or symptom, but easily tolerated)
2.
Moderate (discomfort sufficient to cause interference with normal activities)
3.
Severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Appendix B 2.  An AE of severe intensity need 
not necessarily be considered serious.  For example, nausea that persists for several hours may be 
considered severe nausea, but not a SAE unless it meets the criteria shown in Appendix B 2. On 
the other hand, a stroke that results in only a limited degree of disability may be considered a 
mild stroke but would be a SAE when it satisfies the criteria shown in Appendix B 2.
B 7
A Guide to Interpreting the Causality Question

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When making an assessment of causality consider the following factors when deciding if there is 
a ‘reasonable possibility’ that an AE may have been caused by the drug.
Time Course. Exposure to suspect drug. Has the subject actually received the suspect drug?  Did 
the AE occur in a reasonable temporal relationship to the administration of the suspect drug?
Consistency with known drug profile. Was the AE consistent with the previous knowledge of 
the suspect drug (pharmacology and toxicology) or drugs of the same pharmacological class? Or 
could the AE be anticipated from its pharmacological properties?
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose of
the suspect drug?
No alternative cause. The AE cannot be reasonably explained by another aetiology such as the 
underlying disease, other drugs, other host or environmental factors.
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-challenge.
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
Is this a recognized feature of overdose of the drug?
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are facts 
(evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough information 
to make an informed judgment. With limited or insufficient information in the case, it is likely 
that 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 8
Medication Error, Drug Abuse and Drug Misuse
Medication error

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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.  
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error:  

occurred

was identified and intercepted before the participant received the drug

did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error e.g., medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated e.g., tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed e.g., kept in the fridge when it should be at room 
temperature 

Wrong participant received the medication (excluding IWRS errors)

Wrong drug administered to participant (excluding IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IWRS - 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) e.g., forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

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
Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product 

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 involves 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

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

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
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
Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody of Biological Samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator keeps full traceability of collected biological samples from the 
subjects while in storage at the centre until shipment or disposal (where appropriate).
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 documentation of receipt of arrival.
AstraZeneca 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 AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for Donated Biological 
Samples 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analyzed, AstraZeneca 
is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an integral part of the study, then the subject is 
withdrawn from further study participation.
The Investigator:

Ensures subjects’ withdrawal of informed consent to the use of donated 
samples is notified immediately to AstraZeneca

Ensures that biological samples from that subject, if stored at the study site, 
are immediately identified, disposed of /destroyed, and the action 
documented

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
Ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed 
of/destroyed, the action documented, and the signed document returned to 
the study site

Ensures that the subject and AstraZeneca are informed about the sample 
disposal
AstraZeneca ensures the organizations holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed and the action documented and 
returned to the study site.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories (https://www.iata.org/whatwedo/cargo/dgr/Documents/infectious-substance-
classification-DGR56-en.pdf.). For transport purposes the classification of infectious substances 
according to risk groups was removed from the Dangerous Goods Regulations in the 46th edition 
(2005). Infectious substances are now classified either as Category A, Category B or Exempt. 
There is no direct relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to it 
occurs, is capable of causing permanent disability, life-threatening or fatal disease in otherwise 
healthy humans or animals. Category A pathogens are e.g., Ebola, Lassa fever virus:

are to be packed and shipped in accordance with IATA Instruction 602
Category B Infectious Substances are infectious substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are e.g., Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number and 
proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA 
regulations

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
Clinical trial samples will routinely be packed and transported at ambient

Temperature in IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/infectious-
substance-classification-DGR56-en.pdf.)

Biological samples transported in dry ice require additional dangerous 
goods specification for the dry-ice content

IATA compliant courier and packaging materials should be used for 
packing and transportation and packing should be done by an IATA 
certified person, as applicable

Samples routinely transported by road or rail are subject to local 
regulations which require that they are also packed and transported in a 
safe and appropriate way to contain any risk of infection or contamination 
by using approved couriers and packaging/containment materials at all 
times. The IATA 650 biological sample containment standards are 
encouraged wherever possible when road or rail transport is used.

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Appendix D
Genetics
D 1
Use/analysis of DNA
Genetic variation may impact a subject’s response to therapy, susceptibility to, and severity and 
progression of disease.  Variable response to therapy may be due to genetic determinants that 
impact drug absorption, distribution, metabolism, and excretion; mechanism of action of the 
drug; disease etiology; and/or molecular subtype of the disease being treated.  Therefore, where 
local regulations and IRB/IEC allow, blood samples will be collected for DNA analysis from 
consenting subjects.
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.  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.  
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the subject´s DNA, i.e., the entire 
genome. 
The results of genetic analyses may be reported in the clinical study report (CSR) or 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
Study selection record
All subjects will be asked to participate in this genetic research.  Participation is voluntary and if 
subject declines to participate there will be no penalty or loss of benefit. The subject will not be 
excluded from any aspect of the main or the sub study.
Inclusion criteria
For inclusion in this genetic research, subjects must fulfil all the inclusion criteria described in 
the main body of the Clinical Study Protocol and provide informed consent for the genetic 
sampling and analyses.

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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:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection
Withdrawal of consent for genetic research  
Subjects may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary withdrawal will not 
prejudice further treatment. Procedures for withdrawal are outlined in Section 7.3 of the main 
Clinical Study Protocol.
Collection of samples for genetic research
Blood samples for genetic research will be obtained from subjects at randomization visit. 
Although DNA is stable, early sample collection is preferred to avoid introducing bias through 
excluding subjects who may withdraw due to an adverse event (AE), such subjects would be 
important to include in any genetic analysis. If for any reason the sample is not drawn at 
randomization visit, it may be taken at any visit until the last study visit. Only one sample should 
be collected per subject for genetics during the study. Samples will be collected, labelled, stored, 
and shipped as detailed in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are important to 
maintain subject 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 blood either before or at the time of DNA 
extraction 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 organization.  
No personal details identifying the individual will be available to any person (AstraZeneca 
employee or designated organizations working with the DNA).
The link between the subject enrolment/randomization code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organizations. The link will be used to identify the relevant DNA samples for 

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analysis, facilitate correlation of genotypic 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 genetics 
research component, are outlined in Appendix D.
Informed consent
The genetic component of this study is optional, and the subject may participate in other 
components of the main or the sub study without participating in the genetic component. To 
participate in the genetic component of the study the subject must sign and date both the consent 
form for the main and the sub study and the genetic component of the study. Copies of both 
signed and dated consent forms must be given to the subject and the original filed at the study 
centre. The Principal Investigator(s) is responsible for ensuring that consent is given freely and 
that the subject understands that they may freely withdraw from the genetic aspect of the study at 
any time.
Subject data protection
AstraZeneca will not provide individual genotype results to subjects, 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 subject. Regulatory authorities may require access to the relevant files, though 
the subject’s medical information and the genetic files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyze the samples.
AstraZeneca and its designated organizations 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 organizations 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 subject 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.
Statistical methods and determination of sample size

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The number of subjects that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A Statistical 
Analysis Plan may be prepared where appropriate.

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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 (PHL) cases and Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. Specific guidance on 
managing liver abnormalities can be found in Section 7.1 of the Clinical Study Protocol.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a subject meets potential 
PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; this 
includes samples taken at scheduled study visits and other visits including central and all local 
laboratory evaluations even if collected outside of the study visits; for example, PHL criteria 
could be met by an elevated ALT from a central laboratory and/or elevated TBL from a local 
laboratory.
The Investigator will also review Adverse Event data (for example, for AEs that may indicate
elevations in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry other 
than drug induced liver injury (DILI) caused by the Investigational Medicinal Product (IMP).
The Investigator is responsible for recording data pertaining to PHL/HL cases and for reporting 
AEs and SAEs according to the outcome of the review and assessment in line with standard 
safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP).
Hy’s Law (HL)

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AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug.  
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e., 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 PHL it is important to perform a comprehensive review of laboratory 
data for any subject who meets any of the following identification criteria in isolation or in 
combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
When a subject meet any of the PHL identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (and also to the AstraZeneca 
representative).  
The Investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the Investigator will:

Notify the AstraZeneca representative

Request a repeat of the test (new blood draw) by the central laboratory without delay

Complete the appropriate unscheduled laboratory CRF module(s) with the original 
local laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the subject meets PHL criteria (see Appendix E 2 Definitions 
within this Appendix for definition) by reviewing laboratory reports from all previous 
visits (including both central and local laboratory results)
E 4
Follow-Up
E 4.1
Potential Hy’s Law Criteria Not Met

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If the subject does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the subject has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
E 4.2
Potential Hy’s Law Criteria Met
If the subject does meet PHL criteria the Investigator will:

Determine whether PHL criteria were met at any study visit prior to starting Study treatment 
(See Section 8.3.10 Safety Reporting)

Notify the AstraZeneca representative who will then inform the central Study Team 

Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting

For subjects that met PHL criterial prior to starting IMP, the Investigator is not required 
to submit a PHL SAE unless there is a significant change in the subject’s condition
The AstraZeneca Study Physician contacts the Investigator, to provide guidance, discuss and 
agree an approach for the study subjects’ follow-up (including any further laboratory testing) and 
the continuous review of data. Subsequent to this contact the Investigator will:

Monitor the subject 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 
lab kit should be used.

Complete the three Liver CRF Modules as information becomes available 
E 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the AstraZeneca 
Study Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the IMP, 
to ensure timely analysis and reporting to health authorities within 15 calendar days from date 
PHL criteria was met. The AstraZeneca Global Clinical Lead or equivalent and Global Safety 

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Physician will also be involved in this review together with other subject matter experts as 
appropriate.  
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF.

If the alternative explanation is an AE/SAE:  update the previously submitted Potential 
Hy’s Law SAE and AE CRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.  

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply.

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If there is an unavoidable delay, of over 15 calendar days in obtaining the information necessary 
to assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE 
reporting. 

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.

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E 6
Laboratory Tests
The list below represents the standard, comprehensive list of follow-up tests which are 
recommended but not mandatory when using a central laboratory. 
If required, additional assistance on which tests could be used to evaluate other potential causes of 
liver dysfunction consult with the Hepatic Safety Knowledge Group. Any test results need to be 
recorded in the eCRF.
Hy’s Law lab kit for central laboratories
Additional standard chemistry and 
coagulation tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA
IgG anti-HCV
HCV RNA* 
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)
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
Transferrin saturation
* HCV RNA is only tested when IgG anti-HCV is positive or inconclusive
References
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing clinical 
evaluation’

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Appendix F
Maintenance Therapy Equivalence Table
Inhaled Corticosteroids dose conversion tables should be used to assess Inclusion 7.
ICS component
Conversion Factor
(i.e. multiply dose by X)
Minimum acceptable 
daily dose (mcg)
Fluticasone propionate
1
>250
Fluticasone propionate HFA
1.14
>220 (per actuation)
Fluticasone furoate 
2.5
≥100 (metered)
≥92 (delivered)
Budesonide (metered/delivered dose)
0.63/0.78
>400 (metered)
>320 (delivered)
Budesonide (nebulized)
0.5
>0.5 mg (2 ml ampules)
Beclomethasone
0.5
>500
Beclomethasone (Trimbow)
1.25
400 (metered)
348 (delivered dose)
Beclomethasone extra-fine particles 
and HFA (Fostair, QVAR)
1.04 (metered dose)
1.25 (dose per actuation)
>250 (metered dose)
>200 (per actuation)
Ciclesonide 
1.56
>160
Mometasone furoate
1.14
>220 (metered)
>200 (per actuation)
Flunisolide
0.25
>1000
Triamcinolone 
0.25
>1000
Sources: GOLD 2018; GINA 2018 
Example conversion
Converting budesonide (delivered dose) to fluticasone propionate (in mcg): 
ICS component
Conversion Factor
(i.e. multiply dose by X)
Minimum acceptable 
daily dose (mcg)
Budesonide (metered/delivered dose)
0.63/0.78
>400 (metered)
>320 (delivered)
For a budesonide dose of 160 mcg, use a conversion factor of 0.78
160 mcg of budesonide x 0.78 = 124.8 mcg fluticasone propionate equivalent
The minimum acceptable daily dose (mcg) for Budesonide (delivered dose) must be higher than 
320mg daily for subject to be eligible for the study (320mcg daily dose is not acceptable).

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Appendix G
Anaphylaxis: Signs and Symptoms, Management
G 1
Introduction
As with any antibody, allergic reactions to dose administration are possible. The World Health 
Organization (WHO) has categorized anaphylaxis into 2 subgroups, which are clinically 
indistinguishable: immunologic [IgE-mediated and non-IgE-mediated (e.g., IgG and immune
complex mediated) and nonimmunologic (Johansson et al 2004). The clinical criteria for 
defining anaphylaxis for this study are listed in Appendix G 2. A guide to the signs and 
symptoms and management of acute anaphylaxis is provided in Appendix G 3. Appropriate 
drugs, such as epinephrine, antihistamines, corticosteroids, etc., and medical equipment to treat 
anaphylactic reactions must be immediately available at study sites, and study personnel should 
be trained to recognize and treat anaphylaxis according to local guidelines. 
If an anaphylactic reaction occurs, a blood sample will be drawn from the subject as soon as 
possible after the event, at 60 minutes ± 30 minutes after the event, and at discharge for analysis 
of serum tryptase.
G 2
Clinical Criteria for Defining Anaphylaxis and Immune 
Complex Disease
Anaphylaxis
In adults, anaphylaxis is highly likely when any one of the following 3 criteria is fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula).
AND AT LEAST ONE OF THE FOLLOWING
(a)
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
hypoxemia).
(b)
Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 
(e.g., hypotonia [collapse], syncope, incontinence).
2.
Two or more of the following that occur rapidly after exposure to a likely allergen for 
that subject (minutes to several hours):
(a)
Involvement of the skin-mucosal tissue (e.g., generalized hives, itch-flush, swollen 
lips-tongue-uvula).
(b)
Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, 
hypoxemia).

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(c)
Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence).
(d)
Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting).
3.
Reduced BP after exposure to known allergen for that subject (minutes to several 
hours): Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from 
that subject’s baseline.
Immune Complex Disease
Immune complex disease or Hypersensitivity Type III is evoked by the deposition of antigen-
antibody or antigen-antibody-complement complexes on cell surfaces, with subsequent 
involvement of breakdown products of complement, platelets, and polymorphonuclear 
leukocytes, and development of vasculitis; serum sickness and nephritis are common.
G 3
Signs and Symptoms and Management of Acute Anaphylaxis
Anaphylaxis is an acute and potentially lethal multi-system allergic reaction in which some or all 
of the following signs and symptoms occur: 

Diffuse erythema

Pruritus

Urticaria and/or angioedema

Bronchospasm

Laryngeal edema

Hypotension

Cardiac arrhythmias

Feeling of impending doom

Unconsciousness

Shock
Other earlier or concomitant signs and symptoms can include:

Itchy nose, eyes, pharynx, genitalia, palms, and soles

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
Rhinorrhea

Change in voice

Metallic taste

Nausea, vomiting, diarrhea, abdominal cramps and bloating

Lightheadedness

Headache

Uterine cramps

Generalized warmth
G 4
Management of Acute Anaphylaxis
Immediate intervention
1.
Assessment of airway, breathing, circulation, and adequacy of mentation.
2.
Administer epinephrine intramuscularly every 5-15 minutes, in appropriate doses, as 
necessary, depending on the presenting signs and symptoms of anaphylaxis, to control 
signs and symptoms and prevent progression to more severe symptoms such as 
respiratory distress, hypotension, shock and unconsciousness.
Possibly appropriate, subsequent measures depending on response to epinephrine
(a)
Place subject in recumbent position and elevate lower extremities.
(b)
Establish and maintain airway.
(c)
Administer oxygen.
(d)
Establish venous access.
(e)
Normal saline IV for fluid replacement.
Specific measures to consider after epinephrine injections, where appropriate
(f)
Consider epinephrine infusion.
(g)
Consider H1 and H2 antihistamines.
(h)
Consider nebulized β2 agonist [e.g., albuterol (salbutamol)] for bronchospasm 
resistant to epinephrine.

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(i)
Consider systemic corticosteroids.
(j)
Consider vasopressor (e.g., dopamine).
(k)
Consider glucagon for subject taking β-blocker.
(l)
Consider atropine for symptomatic bradycardia.
(m)
Consider transportation to an emergency department or an intensive care facility.
(n)
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and prolonged 
resuscitation efforts are encouraged, if necessary.
Adapted from: Kemp et al 2008
Kemp SF, Lockey RF, Simons FE; World Allergy Organization Ad hoc Committee on 
Epinephrine in Anaphylaxis. Epinephrine: the drug of choice for anaphylaxis. A statement of the 
World Allergy Organization. Allergy. 2008; 63(8):1061-70.

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Appendix H
Abbreviations 
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or special 
term
Explanation
21 CFR 
21 Code of Federal Regulations 
ABPA
Allergic bronchopulmonary aspergillosis 
ACOS
Asthma-COPD Overlap Syndrome
AD
Atopic Dermatitis
ADA
Anti-Drug Antibodies
ADE
Adverse Device Effect
AE
Adverse Event
AECOPD
Acute Exacerbations of COPD
AESI
Adverse Event of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
APFS
Accessorized pre-filled syringes
ATS
American Thoracic Society
AST
Aspartate Aminotransferase
AUC
Area under the curve
AZ
AstraZeneca
BAL
Bronchoalveolar Lavage
BD
Bronchodilator
β-HCG
Beta-Human Chorionic Gonadotropin
BiPAP
Bilevel Positive Airway Pressure
BMI
Body Mass Index
BP
Blood Pressure
BTR
Best Test Review
BUN
Blood Urea Nitrogen
CAT
COPD Assessment Test
CDC
Centers for Disease Control and Prevention

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Abbreviation or special 
term
Explanation
CSP
Clinical Study Protocol
CID
Clinically Important Deterioration
CIOMS
Council for International Organizations of Medical Sciences
CK
Creatine kinase
CONSORT
Consolidated Standards of Reporting Trials
COPD
Chronic Obstructive Pulmonary Disease
COVID-19
Coronavirus Disease 2019
CPAP
Continuous Positive Airway Pressure
CRF
Case Report Form (electronic/paper)
CRO
Contract Research Organization
CSR
Clinical Study Report
CT Scan
Computed Tomography Scan
CTIS
Clinical Trial Information System
CTT
Clinical Trial Transparency
DAE
Discontinuation of Investigational Product due to Adverse Event
dECG
Digital electrocardiogram
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid 
eCRF
Electronic case report form
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
EGPA
Eosinophilic granulomatosis with polyangiitis
EOT
End of Treatment 
ePRO
Electronic Patient Reported Outcome 
ER
Emergency Room
E-RS™: COPD
Exacerbations of Chronic Pulmonary Disease Tool – Respiratory 
Symptoms
ERS
European Respiratory Society

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Abbreviation or special 
term
Explanation
EU
European Union
EUA
Emergency Use Authorization
EXA
COPD exacerbation visit
EXACT-PRO
Exacerbations of Chronic Pulmonary Disease Tool – Patient-reported 
Outcome
FAS
Full Analysis Set
FeNO
Fractional Exhaled Nitric Oxide
FEV1
Forced Expiratory Volume in 1 second
FSH
Follicle-Stimulating Hormone
FU
Follow-Up
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transpeptidase
GINA
Global Initiative for Asthma
GLI
Global Lung Function Initiative
GMP
Good Manufacturing Practice
GOLD
Global Initiative for Chronic Obstructive Lung Disease
Hb
Hemoglobin
HCG
Human chorionic gonadotropin
HCP
Healthcare practitioner
HFA
Hydrofluoroalkane
Hg
Mercury
HIPAA
Health Insurance Portability and Accountability Act
HIV-1/2
Human immunodeficiency virus-1/2
HL
Hy’s Law
HRU
Healthcare resource utilization
IATA
International Air Transport Association
ICH
International Conference on Harmonization

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Abbreviation or special 
term
Explanation
ICI
International Co-ordinating Investigator (If a study is conducted in 
several countries the International Co-ordinating Investigator is the 
Investigator coordinating the Investigators and/or activities 
internationally). 
ICF 
Informed Consent Form 
ICS
Inhaled Corticosteroids
IDMC
Independent data monitoring committee
IEC
Independent ethics committees
IFU
Instructions for Use
Ig
Immunoglobulin 
IHC
Immunohistochemistry
IL-5
Interleukin-5
IL-13
Interleukin-13
IL-25
Interleukin-25
IL-33
Interleukin-33
ILC2
Type 2 Innate Lymphoid Cells
IMP
Investigational Medicinal Product
IND
Investigation New Drug (application)
IP
Investigational Product 
IPD
Investigational Product Discontinuation
IRB
Institutional Review Board
ISF
Investigator Site File
IUD
Intrauterine device
IUS
Intrauterine system
ITT
Intent-to-Treat
IV
Intravenous
IWRS
Interactive Web Response System
LABA
Long-Acting β2-Agonist
LAMA
Long-Acting Muscarinic Antagonists

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Abbreviation or special 
term
Explanation
LRTI
Low Respiratory Tract Infection
LTRA
Leukotriene Receptor Antagonists
LSLV
Last Subject Last Visit
LTOT
Long term oxygen therapy
mAb
Monoclonal Antibody
MACE
Major Adverse Cardiac Events
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MCID
Minimum Clinically Important Difference
mmHg
Millimeter of mercury
MMRM
Mixed effect Model Repeated Measures
MRI
Magnetic Resonance Imaging
mRNA
Messenger Ribonucleic Acid
nAb
Neutralizing Antibodies
NIMP
Non- Investigational Medicinal Product
NIPPV
Noninvasive positive-pressure ventilation
O2
Oxygen
OAE
Other Significant Adverse Event
OCS
Oral Corticosteroids
PD
Pharmacodynamic
PGx
Genetic research
PHL
Potential Hy’s Law
PI
Principal Investigator
PK
Pharmacokinetic(s)
PNV
Predicted Normal Value
PRN
Pro Re Nata (as needed)
PRO
Patient Reported Outcome
PT
Preferred Term

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Abbreviation or special 
term
Explanation
Q4W
Every 4 Weeks
R
Randomization
RBC
Red blood cell
RNA
Ribonucleic Acid
SABA
Short-Acting β2-Agonist
SADE
Serious Adverse Device Effect
SAE
Serious Adverse Event 
SAMA
Short acting muscarinic antagonists
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SC
Subcutaneous
SGRQ
St. George’s Respiratory Questionnaire
SNP
Single-nucleotide polymorphism
SoA
Schedule of Activities 
SoC
Standard of Care
SOC
System Organ Class
SOP
Standard Operating Procedure
SpO2
Oxygen saturation via pulse oximetry
SDV
Source Data Verification
TB
Tuberculosis
TBL
Total Bilirubin
Th2
T-helper cell type 2
TLR
Toll-like Receptor
TPV
Third-Party Vendor
TSLP
Thymic Stromal Lymphopoietin
TSLPR
Thymic Stromal Lymphopoietin Receptor
ULN
Upper Limit of Normal
UNS
Unscheduled

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Abbreviation or special 
term
Explanation
USADE
Unanticipated Serious Adverse Device Effect
V
Visit
W
Week
WBC
White blood cell
WBDC
Web Based Data Capture
WOCBP
Women of Childbearing Potential

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Appendix I
Coronavirus (COVID-19) Pandemic Guidance 
During the COVID-19 pandemic, all actively enrolled subjects in the screening period will be 
screen failed and randomization visits will be temporarily placed on hold until the pandemic 
normalizes, and AZ approves the continuation of the study. Sputum and nasal samples will not 
be collected from subjects in treatment until the pandemic normalizes and AZ approves the 
continuation of sampling. Sputum and nasal sampling will be performed, if allowed per local 
regulations and guidance.
Please Note: Changes below should only be implemented during the COVID-19 pandemic and 
if allowed by local and regional guidelines. 
I 1
Pre-visit assessment during COVID-19 pandemic
A COVID-19 screening questionnaire must be completed via telephone within 72 hours prior to 
every study visit, regardless of the visit being on-site, at subject’s home, or at an alternative 
location. During the call, subject should be instructed to contact site prior to visit, if subject 
experiences any COVID-19 symptoms or was exposed to someone diagnosed with COVID-19. 
For remote visits (phone call and/or virtual visits), the COVID-19 screening questionnaire should 
be conducted as a part of study visit assessments. Patient COVID-19 screening should include:

Symptom history

Exposure to someone diagnosed with COVID-19 in the past 14 days

Recent travel including to countries with CDC Level 2 or higher travel warning or 
equivalent or known COVID-19 hot spots

Unexplained fever, cough, shortness of breath, chills, muscle pain, headache, sore throat 
and/or new loss of taste or smell within the past 14 days
This questionnaire is to be conducted at minimum and local regulation and guidance should be 
followed.
Example of questionnaire:
1. Have you experienced unexplained fever, cough, shortness of breath, chills, muscle pain, 
headache, sore throat, and/or new loss of taste or smell within the past 14 days?
2. Have you been in contact with anyone who is sick or with symptoms (refer to question 1) 
in the last 14 days? 
3. Have you been exposed to someone diagnosed with COVID-19 in the last 14 days?
4. Have you been practicing social distancing over the last 14 days? 
(refer to region/city/country regulations)
5. Have you traveled in the last 14 days, if so where? 

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(recent travel including to countries/regions with CDC Level 2 or higher travel warning 
or equivalent or known Covid-19 hot spots)
6. Have you been in isolation or quarantine for any reason in the past 14 days?
7. Have you been diagnosed with Covid-19 at any time, if so where and when? 
Sites may use their own version of questionnaire per local guidance. Responses are not 
considered as part of clinical trial data and are not recorded in RAVE. The site will determine the 
appropriate course of action based on the responses to questionnaire. Subject reporting 
symptoms should be referred for further evaluation as per investigator judgment. Visit should be 
cancelled or re-scheduled, if needed as judged by Investigator. 
I 2
Home Visits to Replace On-Site Visits (where applicable)
Due to local travel restrictions and/or site restrictions, patients may not wish to or may not be 
able to go to the study site for study visits and related procedures. If an on-site visit is not 
possible, it is recommended to have a home administration of IP by a qualified HCP, provided 
this is acceptable within local regulation/guidance. This is to ensure safety of the study subjects 
and minimum disruption to IP administration that may occur during the COVID-19 pandemic. 
NOTE: Before initiating consent for home IP administration visit, the subject must have 
received at least the first 2 IP administrations at the site. 
Where possible study assessments should be conducted according to the SoA. Central lung 
function assessment at home is not implemented in COURSE study.
Site must contact the subject by telephone to assess possible COVID-19 symptoms before 
initiating home visit. Refer to I 1.
At minimum, during home visit the qualified HCP is expected to:

Collect vital signs (visit should start with temperature measurement)

Collect adverse events reported since last contact with the subject

Collect information about new or changes in concomitant medications since last contact 
with the subject 

Completion of SGRQ and CAT (if applicable)

ePRO compliance check (if applicable)

Collect information about any worsening of underlying COPD symptoms/COPD 
exacerbations since last contact with the subject

Collect smoking status

Collect information on healthcare resources utilization

Perform physical examination (if applicable)

Measure oxygen saturation (SpO2) (if applicable)

Collect use of Supplemental O2 status (if applicable)

Urine Pregnancy (dipstick) prior to IP administration (if applicable)

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
If possible, collect blood and urine samples according to the SoA 

Administer IP. Please refer to the IP home administration instructions for use during 
COVID-19 pandemic for more information

Observe the subject for one hour after IP administration for the signs or symptoms of any 
acute drug reactions 

Document the visit. The form of contact should be documented in the medical records
Laboratory assessments during home visit
If safety blood samples are being collected, they may be obtained within 1-hour post IP 
administration, to allow additional time for processing of the safety samples at site according to 
the laboratory manual.
If PK and/or ADA samples are being collected, they have to be obtained prior to IP 
administration. If it is not possible, these samples are not required to be collected during the 
home visit. 
I 3
Visit at an Alternative Location (where applicable) 
Study visits including administration of IP and study assessments according to the SoA can take 
place at an alternative location away from infection risk zones, or closer to subjects’ homes, 
provided this is acceptable within local regulation and guidance. 
Site must contact the subject by telephone to assess for possible COVID-19 symptoms before 
initiating visit at an alternative location. Refer to I 1.
Central lung function assessments at alternative location is not implemented in COURSE study.
I 4
Phone call and/or virtual visits to replace on-site visits (where 
applicable)
During the COVID-19 pandemic, on-site visits that are not replaced by home/alternative location 
visits may be replaced by a phone call and/or a virtual visit. 
Having a phone call and/or a virtual visit with the subject will allow collection of information
regarding:

Assessment of COVID-19 symptoms (refer to I 1)

Collect adverse events reported since last contact with the subject

Collect information about new or changes in concomitant medications since last contact 
with the subject 

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
Completion of SGRQ and CAT (if applicable)

ePRO compliance check

Collect information about any worsening of underlying COPD symptoms/COPD 
exacerbations since last contact with the subject

Collect smoking status

Collect information on healthcare resources utilization

Measure oxygen saturation (SpO2) (if applicable)

Collect use of Supplemental O2 status (if applicable)

Document the visit. The form of contact should be documented in the medical records
I 5
Re-consenting of subjects during the COVID-19 pandemic 
COVID-19 addendum to ICF (SoA, Table 2) must be obtained prior to starting any procedures 
according to Appendix A 3. The standard informed consent process in the trial should be 
followed. However, if the subject may not be able to visit the site due to COVID-19 illness or 
travel restrictions, local regulation and guidance should be followed if the subject is re-
consenting to the approved updated ICF. This will minimize the risk to the subject of COVID-19 
exposure at clinic visits.
I 6
Benefit-risk assessment of re-starting recruitment during 
COVID-19 Pandemic
Since the first subject was enrolled in this study, coronavirus disease 2019 (COVID-19) has 
emerged as a worldwide pandemic disease with significant public health implications. 
AstraZeneca’s decision was to place enrolment temporarily on hold until the pandemic 
normalizes as not all screening assessments required for the evaluation of subject eligibility 
could be done. Subjects already randomized were allowed to continue with study but alternative 
options were given to minimize the risk of subject exposure to COVID-19.
However, AstraZeneca is not aware of any current evidence suggesting that tezepelumab either 
increases the susceptibility to COVID-19 infection or worsens the outcomes of COVID-19 
infection. Moreover, available information strongly supports potential benefit of tezepelumab 
treatment in various diseases including asthma and COPD with low safety concerns. The benefit-
risk assessment favours re-starting enrolment in the COURSE study.
AstraZeneca accepts that a careful benefit-risk analysis should be performed in each region 
before resuming recruitment in a clinical trial that impacts on clinical resources needed for the 
COVID-19 pandemic. AstraZeneca will resume recruitment in this study in regions only when 
local and national guidance and clinical sites have indicated that it is acceptable to conduct 
clinical studies and the safety of site staff and subjects can be ensured. The Sponsor will conduct 

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risk-based enrolment assessments on a country and site level on a regular basis during the 
pandemic phase, and decisions will be documented. 
Risks mitigations
It is recognised that depending on the location and facilities of a clinical site, study visit 
attendance may place subjects at risk of exposure to COVID-19. COPD may be a risk-factor for 
severe COVID-19 illness and subjects with active COVID-19 infection. Furthermore, it is 
recognised that more general population-level measures to reduce infection rates (e.g. travel 
restrictions) may inhibit the ability of subjects to attend study visits. Necessary healthcare 
responses at sites to the pandemic (e.g. additional infection control measures) may also inhibit 
the ability of a clinical site to effectively and properly conduct the study. Study visit attendance 
for dosing and for clinical assessments are critical for the scientific value of the study.
To ensure the safety of the subject and site staff, at every visit will follow these guidelines:

All subjects will have a COVID-19 screening assessment performed by telephone within 
72 hours prior to study visit. The site will determine the appropriate course of action 
based on the responses to the questions. 

Naso/oropharyngeal swab testing (or rapid test) for severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) is required at screening Visit 1 for new patients entering in 
the study to minimize the risk of enrolling a subject with active COVID-19 infection into 
the study. 

Testing for SARS-CoV-2 at subsequent visits with spirometry and sputum induction may 
and should be performed, if required, by local and national guidelines. If SARS-CoV-2 
testing is conducted, a negative result should be obtained before conducting visit 
assessments if required by local regulations and guidelines

If, a subject is not able to attend their scheduled study visit at the site, alternative visit 
options are available. 

All site staff should wear personal protective equipment in accordance with local or 
national guidelines.
Moreover, Investigators should not enrol subjects unless they have reasonable confidence that 
throughout the duration of the study:

Subjects will be able to attend study visits, including remote visits, whilst avoiding contact 
with concentrations of COVID-19 patients (e.g. hospital entrances used by such patients); 
and

The site will be able to conduct the study effectively and safely, considering relevant 
national and local factors; and

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Subjects agree to alternate site visits or home visits as an alternative to on-site visits (if allowed 
by local and regional guideline), if pandemic restrictions are in place.
Conclusion
Given the limited additional risks to the study population related to COVID-19, from study 
participation, beyond those they would experience in everyday life, the mitigations described 
above are considered sufficient to ensure a favourable benefit-risk balance.
Appendix J
Medical Device AEs, ADEs, SAEs, SADEs, USADEs and 
Medical Device Deficiencies: Definitions and Procedures for 
Recording, Evaluating and Follow-up

This appendix supports the activities described in section 8.3.10

The definitions and procedures detailed in this appendix are in accordance with 
International Organization for Standardization 14155 and European Medical Device 
Regulation (MDR) 2017/745 for clinical device research (if applicable). 

Both the investigator and the sponsor will comply with all local reporting 
requirements for medical devices.

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
The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study. See section 6.1.2 for the list of 
sponsor medical devices.
J 1
Definition of Medical Device AE and ADE
Medical Device AE and ADE Definition

An AE is any untoward medical occurrence in a clinical study participant, users, or other 
persons, temporally associated with the use of study intervention, whether or not 
considered related to the medical device. A Medical Device AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease (new or exacerbated) temporally associated with the use of a medical device. 
This definition includes events related to the medical device or comparator and events 
related to the procedures involved.

An adverse device effect (ADE) is defined as an AE related to the use of a medical device. 
This definition includes any AE resulting from insufficient or inadequate instructions for 
use, deployment, implantation, installation, or operation, or any malfunction of the 
investigational medical device as well as any event resulting from use error or from 
intentional misuse of the medical device.
J 2
Definition of Medical Device SAE, SADE and USADE
A Medical Device SAE is any Medical Device adverse event that:
a.
Led to death
b.
Led to serious deterioration in the health of the participant, that either resulted in:

A life-threatening illness or injury. The term “life-threatening” in the definition of 
“serious” refers to an event in which the participant was at risk of death at the time of the 
event. It does not refer to an event, which hypothetically might have caused death if it 
were more severe.

A permanent impairment of a body structure or a body function.

Inpatient or prolonged hospitalization. Planned hospitalization for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in health, 
is not considered an SAE.

Medical or surgical intervention to prevent life-threatening illness or injury or permanent 
impairment to a body structure or a body function.

Chronic disease (MDR 2017/745).
c.
Led to fetal distress, fetal death, or a congenital anomaly or birth defect

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SADE definition

A serious adverse device effect (SADE) is defined as an adverse medical device effect that 
has resulted in any of the consequences characteristic of an SAE (e.g. needle stick requiring 
surgical intervention or battery leakage chemical burn causing scaring).

Any medical device deficiency that might have led to an SAE if appropriate action had not 
been taken, intervention had not occurred, or circumstances had been less fortunate.
Unanticipated SADE (USADE) definition

An unanticipated serious adverse device effect (USADE) (also identified as UADE in 
United States Regulations 21 CFR 813.3), is defined as a serious adverse medical device 
effect that by its nature, incidence, severity, or outcome has not been identified in the current 
version of the risk analysis report (see Section 2.3).
J 3
Definition of Medical Device Deficiency
Medical Device Deficiency Definition
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 inadequacy in the information supplied by the manufacturer 
including labelling.
J 4
Recording and Follow-up of AE and/or SAE and Medical 
Device Deficiencies
AE, SAE, and Medical Device Deficiency Recording

When an AE/SAE/medical device deficiency occurs, it is the responsibility of the 
investigator to review all documentation (e.g., hospital progress notes, laboratory reports, 
and diagnostics reports) related to the event.

The investigator will then record all relevant AE/SAE/medical device deficiency 
information in the participant’s medical records, in accordance with the investigator’s 
normal clinical practice and on the appropriate form.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Sponsor in lieu of completion of the AE/SAE/medical device deficiency form.

There may be instances when copies of medical records for certain cases are requested by 
Sponsor. In this case, all participant identifiers, with the exception of the participant number, 
will be redacted on the copies of the medical records before submission to Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.

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
For medical device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency.

A remedial action is any action other than routine maintenance or servicing of a medical 
device where such action is necessary to prevent recurrence of a medical device 
deficiency. This includes any amendment to the medical device design to prevent 
recurrence.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE/SAE/medical device 
deficiency reported during the study and assign it to one of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with an SAE. “Severe” is a category used for rating the intensity of
an event; both AEs and SAEs can be assessed as severe.

An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention and each 
occurrence of each AE/SAE/medical device deficiency.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship, cannot be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention administration 
will be considered and investigated.

The investigator will also consult the IB in his/her assessment.

For each AE/SAE/medical device deficiency, the investigator must document in the medical 
notes that he/she has reviewed the AE/SAE/medical device deficiency and has provided an 
assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to Sponsor. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Sponsor.

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
The investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.

Causality of ‘related’ is made if following a review of the relevant data, there is evidence for 
a ‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.

The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With no available facts or arguments to suggest 
a causal relationship, the event(s) will be assessed as ‘not related’.
Follow-up of AE/SAE/Medical Device Deficiency

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE/SAE/medical device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide Sponsor with a copy of any post-mortem findings 
including histopathology.

New or updated information will be recorded in the originally completed form.

The investigator will submit any updated SAE data to Sponsor within 24 hours of receipt of 
the information.

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Appendix K
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents.
Version 6.0, 21 Mar 2022
Changes to the protocol are summarized below.
Section 1.2 Synopsis, Updated the estimated date of last subject completed to Q1 2024.
Section 2.3 Benefit/Risk Assessment, Added “Use of tezepelumab has been demonstrated to 
show an important benefit in asthma in a phase 2b and phase 3 study.”
Section 2.3 Benefit/Risk Assessment, Added “Tezepelumab has been well tolerated with an 
acceptable safety profile and no safety signals in subjects with severe, uncontrolled asthma 
identified in the completed studies to date.”
Section 2.3 Benefit/Risk Assessment, Added “No serious allergic reactions or anaphylactic 
reactions considered related to tezepelumab were reported in the Phase 3 program. 
Although TSLP suppression could theoretically have unanticipated immune-related side 
effects impairing host defense against certain infections, there is no clear preclinical or 
clinical evidence supporting such a role, and no safety signals related to either severe 
infections or parasitic infections have been detected in the completed studies to date. Risk 
minimisation measures for important potential risks will be in place during the conduct of 
this study, in conjunction with the performance of the AstraZeneca’s routine
pharmacovigilance activities.”
Section 4.1 Overall Design, Added “Extension of the screening/run-in for any other reason 
will be allowed only upon approval of the AstraZeneca Study Physician (refer to section 
5.4)”
Section 4.1 Overall Design, Added “Subjects who have a blood eosinophil count <300 at 
enrolment Visit 1 can be re-tested at an unscheduled visit, upon approval of the
AstraZeneca Study Physician. It is recommended that any re-test for blood eosinophils is 
performed not earlier than 4 weeks from the previous testing. In case of recent treatment 
with systemic corticosteroids, an interval of ≥6 weeks from the last dose is recommended.”
Section 4.3 Justification for Dose, “Based on the efficacy and safety data, as well as 
exposure-response analysis, of the Phase 2b asthma study CD-RI-MEDI9929-1146, 210 mg 
Q4W SC was selected as the optimal dose of tezepelumab for adult and adolescent patients 
with severe asthma and is  tested in the Phase 3 studies in severe asthma” updated to “Based 
on the efficacy and safety data, as well as exposure-response analysis, of the Phase 2b 

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asthma study CD-RI-MEDI9929-1146, 210 mg Q4W SC was selected as the optimal dose 
of tezepelumab for adult and adolescent patients with severe asthma and is  confirmed in the 
Phase 3 studies in severe asthma”
Section 5.1 Inclusion Criteria and Section 8.2.1.1 Pregnancy Test, Added “Until FSH is 
documented to be within menopausal range, treat the subject as WoCBP”.
Section 5.1 Inclusion Criteria, Inclusion 7 – Added “See appendix F for ICS dose 
conversion table.”
Section 5.2 Exclusion Criteria, Exclusion 22 - “Receipt of any marketed (eg, omalizumab) 
or any investigational monoclonal or polyclonal antibody therapy (eg, gamma globulin) 
taken for any reason within 6 months or 5 half-lives prior to Visit 1, whichever is longer.” 
updated to “Receipt of any marketed (eg, omalizumab) or any investigational monoclonal or 
polyclonal antibody therapy (eg, gamma globulin) taken for any reason within 4 months or 
5 half-lives prior to Visit 1, whichever is longer.”
Section 6.1.2 Medical Devices, Added Section 6.1.2 – Medical Devices: regarding sponsor 
manufactured medical device use in this study and all medical device deficiencies should be 
documented and reported by investigator throughout the study.
Section 6.5 Concomitant Therapy, Table 5 – “Prohibited if taken for any reason within 6 
months or 5 half-lives (whichever is longer) prior to Visit 1 and during the study (even if 
the subject has discontinued IP).” updated to “Prohibited if taken for any reason within 4 
months or 5 half-lives (whichever is longer) prior to Visit 1 and during the study (even if 
the subject has discontinued IP).”
Section 8 Study Assessments and Procedures, Updated “The amount of blood collected 
from each subject over the duration of the study (excluding optional blood samples) will be 
approximately 285 mL (including any extra assessments that may be required) and will not 
exceed 450 mL” to “The amount of blood collected from each subject over the duration of 
the study (excluding optional blood samples) will be approximately 360 mL (including any 
extra assessments that may be required) and will not exceed 450 mL”
Section 8.2.10 Vaccination Restrictions, Updated CDC guidelines reference from “2018-
2019” to “2021-2022”
Section 8.3 Collection of Adverse Events, Added “The definitions of medical device-related 
safety events, can be found in Appendix J. Medical Device deficiencies are covered in 
section 8.3.10”

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Section 8.3.7 Adverse Events Based on Examinations and Tests, Updated “COPD 
exacerbation should be recorded as an AE or SAE only if it fulfils any of the above criteria” 
with “Worsening of COPD should be recorded as an AE or SAE only if it fulfils any of the 
above criteria.”
Section 8.3.10 Medical Device Deficiencies, Added Section 8.3.10 - definitions of medical 
device deficiency and requirements to fulfil regulatory reporting obligations worldwide and 
investigator’s responsibility for detection and documentation of events meeting the 
definition of device deficiency occurring during the study.
Section 8.4.4 Medication Error, Removed “Medication errors with AZ IP are collected in all 
studies where medication error is possible.  Refer to the PSSR or other appropriate project 
document for specific considerations for collection of medication errors. For guidance, refer 
to AZ SOP ‘Reporting of Individual Safety Events in Clinical Studies’”
Section 8.5.1 Collection of Samples to Measure Drug Concentration, Added “Samples from 
patients who receive placebo will not be measured initially but will be retained for 
subsequent analysis if deemed appropriate”
Section 9.5 Statistical Analyses, Replaced “All analyses of the primary and secondary 
objectives will be performed based on the primary DBL data” with “Main analyses of the 
primary, key secondary efficacy objectives and some supportive summaries will be 
performed based on both the primary and final DBL data. The results produced at the time 
of primary DBL will be used to facilitate further design development for Phase 3 only. 
Although no changes are anticipated in conclusions given the primary DBL occurs after all 
subjects complete the planned treatment period, any discrepancies in the conclusions 
between the two DBLs will be discussed in the CSR. The CSR will be produced following 
the final DBL.”
Section 10 References, Updated CDC 2010 guidelines link to
“https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/pneumo.html”
Section 10 References, Removed reference for 2018-2019 CDC guidelines and added 
reference for 2021-2022 CDC guidelines.
Appendix A 1 Regulatory and Ethical Considerations, Added “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.”

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Appendix A 1 Regulatory and Ethical Considerations, Added “European Medical Device 
Regulation 2017/745 for clinical device research (if applicable), and all other applicable 
local regulations”
Appendix A 7 Data Quality Assurance, Updated study documents retention period from “15 
years” to “25 years”
Appendix C 3 International Airline Transportation Association (IATA) 6.2 Guidance 
Document, Updated IATA classification link to 
https://www.iata.org/whatwedo/cargo/dgr/Documents/infectious-substance-classification-
DGR56-en.pdf.
Appendix H Abbreviations, Added “ADE: Adverse Device Effect”, “SADE: Serious 
Adverse Device Effect” and “USADE: Unanticipated Serious Adverse Device Effect”.
Appendix J Medical Device AEs, ADEs, SAEs, SADEs, US ADEs and Medical Device 
Deficiencies: Definitions and Procedures for Recording, Evaluating and Follow-up, Added 
Appendix J – Medical Device AEs, ADEs, SAEs, ADEs, US ADEs and Medical Device 
Deficiencies: Definitions and Procedures for Recording, Evaluating and Follow-up
Appendix K Protocol Amendment History, Added Appendix K – Moved protocol 
amendment history to Appendix K.
Version 5.0, 15 Mar 2021
Changes to the protocol are summarized below.
Section 1.1 SoA, Table 1: removed ‘if applicable’ from ‘Chest x-ray (if applicable)’ to 
clarify chest x-ray is a mandatory assessment.
Section 1.1 SoA, Table 1, Footnote f, Footnote l, Section 4.1 Overall Design, Section 5.4
Screen Failures and Re-Screening, Section 6.5.5 COPD Medication Restrictions on the 
Days of Scheduled Spirometry and FeNO Visits, Section 8 Study Assessments and 
Procedures, Section 8.1.2.1 General Requirements, 8.2.11.2 SARS-CoV-2 testing, 
Appendix I 6 Benefit-risk assessment of starting recruitment during COVID-19 Pandemic: 
added ‘naso/oropharyngeal’ and ‘or rapid test’ to permit flexibility with the method of 
SARS-CoV-2 testing to be performed. 
Section 1.1 SoA, Table 1, Footnote l and Section 8.2.11.2 SARS-CoV-2 Testing: clarified 
local versus central testing. Due to long turnaround times for central laboratory SARS-CoV-
2 testing results and the requirement in some countries to have SARS-CoV-2 testing results 
available within 24-72 hours before visit assessments, considerations have been made to 
allow the option of SARS-CoV-2 testing to be performed locally.  

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Section 1.1 SoA, Table 1, Footnote a, Section 4.1 Overall Design, Screening Period 
(Enrolment and Run-in), Section 6.5.5 COPD Medication Restrictions on the Days of 
Scheduled Spirometry and FeNO Visits, Section 8 Study Assessments and Procedures: 
revised to clarify assessments that must be done at Visit 1 and which assessments can be 
postponed based on the type of SARS-CoV-2 testing performed. 
Section 1.1 SoA, Table 1, Footnote g, Section 5.2 Exclusion Criteria (Exclusion 40), 
Section 8.2.9 Chest X-ray: added ‘Under special circumstances, a recently done historical 
chest X-ray (anterior-posterior and lateral)/CT/MRI for other reasons (not study related) 
might be acceptable. The outcome of the X-ray/CT/MRI must be documented in the 
patients’ medical records. Study Physician approval of historical chest X-ray must be 
obtained prior to randomization.’ This is to minimize the need for a subject who recently 
had a chest X-ray done for non-study related reasons having to repeat a chest X-ray 
assessment during screening in the study (to limit radiation exposure).
Section 1.1 SoA, Table 1, Footnote k, Section 4.1 Overall Design, Appendix I 1 Pre-visit 
assessment during COVID-19 pandemic, I 6 Benefit-risk assessment of re-starting 
recruitment during COVID-19 Pandemic: extended the timeframe for completion of the 
COVID-19 screening assessment from 'within 24 hours' to ‘within 72 hours’ prior to every 
study visit (except remote visits). The extension to 72 hours is to accommodate weekend 
schedules where site contact with subjects on the weekend may not be possible. 
Section 1.1 SoA, Table 2, NOTE: revised the suggested order of assessments to be 
completed prior to IP administration to, ‘ePRO, Vital signs, ECG, FeNO, spirometry and 
blood draws.’ Added clarification, ‘Applicable during COVID-19 pandemic: Vital signs, 
ePRO, ECG, FeNO, spirometry and blood draws’ to be consistent with Table 1, Footnote f 
order of assessments. Vital signs should be performed first to ensure that the patient does 
not have a fever before performing other assessments.
Section 1.1 SoA, Table 2, Sputum cell pellet: revised wording to ‘cell counts and/or RNA 
transcriptomic profiling’ to allow flexibility due to partial sputum processing
Section 1.1 SoA, Table 2, Footnote f, Section 8.1.2.2 Post-PD Spirometry: removed ‘X’ for 
post-BD spirometry assessment at EXA visit as sputum post-BD spirometry assessment 
required as part of sputum induction procedure is already captured in the SOA under 
sputum sub-study section. Also for footnote f, ‘post-BD’ removed and added clarification to 
pre-BD spirometry that it will be performed at EXA visit as part of induced sputum 
procedures ‘during treatment phase’. 
Section 1.1 SoA, Table 2, Footnote k, Section 8.8.5 Sputum Induction, Section 8.8.6 Nasal 
Lining Fluid: rephrased statement regarding sputum and nasal sample collection during the 
COVID-19 pandemic to the following, ‘During the COVID-19 pandemic, sputum and nasal 

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samples will only be collected if allowed per local Health and Safety regulations or 
guidance and if sub-study laboratory test kits are available,’ since AstraZeneca approves the 
continuation of sampling as the study has resumed recruitment.
Section 1.2 Synopsis, Section 4.1 Overall Design: removed ‘During the COVID-19 
pandemic, sputum and nasal samples will not be collected from subjects in treatment phase 
to minimize risk to subject and site staff from virus. Please refer to Appendix I,’ from 
Section 1.2, and removed ‘During COVID-19 pandemic, sputum samples will not be 
collected from subjects in treatment phase until the pandemic normalizes and AZ approves 
the continuation of sampling. Please refer to Appendix I,’ from Section 4.1, since 
AstraZeneca approves the continuation of sampling as the study has resumed recruitment.
Section 1.1 SoA, Table 2, Footnote q: added ‘(in treatment or in follow-up)’ to clarify that 
the SARS-CoV-2 serology test is also applicable to subjects in follow-up.
Section 1.2 Synopsis, Section 3 Objectives and Endpoints, Section 4.1 Overall Design: 
updated study randomization from approximately ‘282’ to ‘338’ subjects due to sample size 
reassessment as a suggestion of the IDMC following interim analysis to account for a 
possible decrease in COPD exacerbations related to the COVID pandemic and social 
distancing.
Section 1.2 Synopsis, Section 3 Objectives and Endpoints: updated the estimated date of 
last subject completed to Q2 2023 based on revised estimated date of Q1 2022 for last 
subject enrolled.
Section 1.2 Synopsis and Section 3 Objectives and Endpoints, Table Table 4, Exploratory 
Objectives: added clarification ‘during treatment phase’ to the objective ‘to evaluate the 
effect of tezepelumab on sputum biomarkers, sputum cell counts and sputum microbiome, 
in subjects participating in sub-study, at baseline, end of treatment, and at the start of all 
exacerbations.’ 
Section 1.3 Schema, Figure 1: revised sample size to ‘169’ per treatment arm per sample 
size revision in Section 9.2.
Appendix I 1 Pre-visit assessment during COVID-19 pandemic: added clarification, 
‘During the call, subject should be instructed to contact site prior to on-site study visit, if 
subject experiences any COVID-19 symptoms or was exposed to someone diagnosed with 
COVID-19’.  
Section 4.1 Overall Design, Screening Period (Enrolment and Run-in): 

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added clarification to the 35-day run-in can be extended by: ‘waiting time required to obtain 
Visit 1 SARS-CoV-2 naso/oropharyngeal swab test (or rapid test) result’ and ‘28 days for 
patients receiving COVID-19 vaccine during screening’. 
Added clarification to the 35-day run-in can be extended by: ‘28 days for waiting time 
required to receive central lab kits’ if central laboratory kits are unavailable. 
Section 4.1 Overall Design, Randomization, Treatment and Follow-up: added clarification 
on requirements of signing COVID-19 addendum to informed consent prior to starting 
alterative options of on-site IP administration; option of phone call visit is included in the 
main informed consent 
Section 5.2 Exclusion Criteria:
updated Exclusion 5: removed ‘or screening period’ to be consistent with Section 5.4.  Also 
added clarification, ‘Note: Refer to Exclusion criteria 19 for restriction with maintenance 
systemic steroid treatment.’ 
updated Exclusion 19: added ‘systemic’ to ‘Use of systemic immunosuppressive 
medication’ to further clarify.
updated Exclusion 24: ‘Chronic use of macrolide or other antibiotics for prophylactic use of 
COPD exacerbation if duration of treatment is < 9 months prior to enrolment (Visit 1) or re-
screening visit. If the patient was previously on prophylactic treatment but is no longer 
taking it, the patient cannot be randomized until 6 weeks after the last dose. Chronic 
macrolide or other antibiotic therapy is allowed provided the patient has been on a stable 
dose/regimen for ≥ 9 months prior to enrolment (Visit 1) or re-screening visit and have had 
at least 2 historical COPD exacerbations while on prophylactic treatment.’ This reference 
was updated from randomization to enrolment visit to correct inconsistency between 
Inclusion 6 and Exclusion 24.
updated Exclusion 39: added ‘naso/oropharyngeal’ and ‘or positive rapid antigen test’ to 
SARS-CoV-2 testing methods, to be consistent with other protocol updates concerning 
allowable methods of testing.
added Exclusion 41 ‘Receipt of any COVID-19 vaccine 28 days prior to date of 
randomization.
Section 6.1.2 Preparation/Handling/Storage/Accountability: 
added ‘The subject received COVID-19 vaccination or is planning to receive COVID-19 
vaccination where the required time interval between IP dosing and COVID-19 vaccination 

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as specified in section 8.2.10, Table Table 8 cannot be followed,’ to be consistent with 
COVID-19 vaccination restrictions added to other sections.
added visual characteristics of the IP to specify more details related to appearance and 
clarity of the IP.
Section 6.3 Measures to Minimize Bias: Updated vendor name for randomization code 
provider, from 
 to 
 due to company name change.
Section 6.5 Concomitant Therapy:
Added ‘follow-up period’ to paragraph describing subject’s usual pre-study triple inhaled 
therapy, to align with Section 6.5.1.
Added for eCRF entry, ‘COVID-19 vaccine given at any time’, to align with Table Table 6
revisions.
Table Table 6 – Allowed, Restricted, and Prohibited Medications: 
systemic corticosteroids (tablets or injections), revised details to ‘Allowed to treat a COPD 
exacerbation or an AE where there is no alternative treatment available, for no more than 14 
days’ to further clarify the restrictions on use of systemic corticosteroids.
added ‘COVID-19 vaccinations’ restrictions 
replaced ‘any’ with ‘systemic’ in Systemic immunomodulators and immunosuppressive 
medication and removed ‘maintenance systemic steroid treatment’ from ‘any 
immunomodulators and immunosuppressive medication (including but not limited to 
methotrexate, cyclosporine, any experimental anti-inflammatory therapy)’. Also in details, 
added ‘refer to Systemic corticosteroids (tablets or injections) for further restrictions’. This 
is to further clarify the restrictions on use of systemic corticosteroids.
Section 7.3 Withdrawal from the Study, Section 8.8.1 Storage, Re-use and Destruction of 
Biomarker Samples: For the statement that indicates, if the subject only withdraws consent 
for retention of biological samples for future exploratory use, it has been revised to include 
a broadened definition of future use. 
Section 8.1.1.5 COPD Exacerbation Visit: added section ‘Only for sputum sub-study 
subjects: Performing COPD Exacerbation visit (EXA) for sputum sub-study patients is 
essential to evaluate exploratory sputum and nasal sub-study endpoints during treatment 
phase. Refer to Section 3. Patients participating in sputum sub-study are required to perform 
pre-BD and sputum post-BD spirometry as part of sputum induction, at EXA visits during 
treatment. Induced sputum is preferred however spontaneous sputum is acceptable if patient 
PPD
PPD

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cannot provide induced sputum sample or if the collection of induced sputum is not
permitted per local Healthy and Safety regulations or guidance during the COVID-19 
pandemic. Please refer to applicable sub-study manual for more information.’ for 
clarification.
Section 8.1.2.2 Post-BD Spirometry: updated to allow SABA administration to start earlier 
(less than 15 minutes of the final pre-BD spirometry) if needed for safety reasons.
Section 8.1.2.3 Sputum Post-BD Spirometry, Section 8.8.4 Nasal Epithelial Cell and 
Sputum Cell Transcriptomics, Section 8.8.5 Sputum Induction, Section 8.8.6 Nasal Lining 
Fluid:: added ‘applicable’ to manual to allow for full or partial processing manual. 
Section 8.2.1 Clinical Safety Laboratory Assessments: added language to allow for local 
laboratory testing of safety samples (clinical chemistry, hematology and urinalysis) at the 
discretion of the PI if central laboratory kits are unavailable. Also indicated that all 
laboratory assessments for Visit 1, Visit 3, and EoT or IPD Visit (as per SoA) must be 
analysed at the central laboratory. Also, added sub-section ‘Maintaining the blind to the 
patient’s blood immunoglobulin, eosinophil, basophil and monocyte counts’ with 
procedures to mitigate unblinding.
Section 8.2.5 Vital Signs, 9.4.3.7 Vital signs: removed ‘pre-dose’ from vital signs 
description as vital signs assessments are also required at follow-up visits.
Section 8.2.10 Vaccination Restrictions: updated section name from ‘Pneumococcal and 
Annual Influenza Vaccination’ to ‘Vaccination Restrictions’ and added sub-section 
‘COVID Vaccination’ to include COVID-19 vaccination restrictions.
Section 8.4.2.1 Maternal Exposure, 8.4.2.2 Paternal Exposure, B 2 Definitions of Serious 
Adverse Event: revised wording related to congenital anomalies (‘congenital anomaly’ 
instead of ‘congenital abnormality’) to be consistent with wording provided in new clinical 
study protocol template.
Section 8.8.5 Sputum Induction
added new guidance for partial sputum processing, ‘Depending on individual site capability, 
sputum processing will follow one of two sputum processing protocols (full processing or 
partial processing). Sputum sample processing will result in the production of cytospin 
slides (for full sputum processing only), microbiome sample, cell pellets for RNA 
transcriptome, and aliquots of sputum supernatant. The clinical sites performing full sputum 
processing procedures will also generate and record total cell count and cell viability data 
on their sputum processing worksheets.’

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added clarification, ‘For other sub-study visits, sputum sub-study samples will be collected 
if sub-study laboratory kits and supplies are available within visit window. In the event of 
missing supplies, sites should make reasonable effort to collect and process samples where 
feasible, and with the approval of Study Physician.’ 
Section 8.8.6: added clarification for nasal lining fluid samples that will be obtained in 
accordance with the schedule provided in Table 2 in a subset of subjects only participating 
in the sub-study, ‘if nasal lining fluid sampling supplies are available.’
Section 9.2 Sample Size Determination: revised into two sections, ‘Original Sample Size’ 
and ‘Updated Sample Size’ and added ‘The sample size has been reassessed due to the 
potential for reduced exacerbation rates due to limited person-to-person contact and 
exposure to respiratory infections during the COVID-19 pandemic.  Assuming the same 
treatment effect (0.7) and dispersion parameter (0.6) as originally assumed, a sample size of 
169 subjects per treatment arm (338 overall) will maintain the study power if the placebo 
exacerbation rate is as low as 1.2 exacerbations/subject-year.’
Section 9.2.1 Estimands: presentation of the primary and supplemental estimands has been 
updated to more clearly specify the 4 attributes of an estimand.  The handling of IP 
discontinuation as an intercurrent event in the supplemental estimand has been amended 
(previously addressed by an on-treatment estimand detailed in the SAP only). 
Section 9.4.2.5 Forced Expiratory Volume in 1 Second: removed, ‘If the Visit 3 pre-
bronchodilator measurement is missing, the last non-missing pre-bronchodilator value 
before Visit 3 will be used as baseline instead.’ to be consistent with Section 9.4.1.  
Appendix A 7 Data Quality Assurance: Added clarification describing details of monitoring 
strategy, including remote monitoring.
Appendix F Maintenance Therapy Equivalence Table: added to support Inclusion 7 
criterion assessment. 
Appendix H Abbreviations: added ‘EUA: Emergency Use Authorization’ as newly 
referenced in Section 8.2.10.
Throughout CSP:
removed references associating baseline assessments with Visit 3. The association has been 
redefined as follows, “randomization” or “randomization visit” for efficacy related 
assessments, and “first IP administration” for safety related assessments, to remove 
ambiguity. 

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various typographical and grammatical corrections have been made.
Version 4.0, 11 August 2020
Changes to the protocol are summarized below.
Section 1.1 SoA, Table 1:
Added pre-visit assessment: telephone assessment of possible COVID-19 symptoms, to 
visits 1 and 2. Also, added footnote k ‘During the COVID-19 pandemic, subjects must be 
contacted by telephone for COVID-19 screening assessments within 24 hours prior to every 
study visit (except remote visits). Refer to Appendix I for details.’ This is to minimize the 
risk of subject performing study visits with active COVID-19 infection.
Added study procedure: COVID-19 addendum to ICF (if applicable). Also, added footnote 
m ‘During re-consenting of subjects during the COVID-19 pandemic, local and regional 
guidelines must be followed. Refer to Appendix I for further details’. This is to minimize 
the risk of enrolling subject who do not agree to any alternatives when on-site visit is not 
possible due to COVID-19 pandemic’.
Added laboratory assessment: SARS-CoV-2 nasopharyngeal swab test to Visit 1. Also, 
added footnote l ‘Central laboratory SARS-CoV-2 nasopharyngeal swab test result must be 
available and negative prior to performing screening lung function assessments and ECG 
(refer to 1.1 footnote a)’. This is to minimize the risk of subject completing lung function 
assessments with active COVID-19 infection.
Footnote a: updated to ‘The screening lung function assessments and ECG must be 
postponed until the Visit 1 SARS-CoV-2 nasopharyngeal swab test result is available and 
negative. At the postponed Visit 1, the spirometry equipment will allow pre-BD, post-BD 
spirometry, FeNO and ECG (combined Visit 1 and Visit 2) to be performed. Visit 2 should 
be scheduled, if the post-BD spirometry and FeNO were not done at the postponed Visit 1. 
Preferably, Visit 2 should be scheduled no later than 1 week after Visit 1 but the enrolment 
can be extended to accommodate additional waiting time required to obtain Visit 1 SARS-
CoV-2 nasopharyngeal swab test result. Lung assessments can only be done if there are no 
restrictions to medications (refer to Section 6.5.5 and 8.1.3).’ This is to minimize the risk of 
subject completing lung function assessments with active COVID-19 infection.
Footnote c: removed ‘Sponsor and’ from ‘the Sponsor and sites will be blinded to the FeNO 
values for the whole study duration’ and added ‘The sponsor will be blinded to the FeNO 
values except at screening visit, at any repeat testing that is performed during the screening 

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period and prior to Investigational Product (IP) administration at Visit 3.’ Sponsor only 
needs to be blinded to the FeNO values after randomization. 
Footnote f: added ‘IMPORTANT: Applicable during COVID-19 pandemic: the suggested 
order of assessments: vital signs, ePRO, blood draws and SARS-CoV-2 nasopharyngeal 
swab testing. The lung function assessments and ECG must be postponed and scheduled 
after Visit 1 SARS-CoV-2 nasopharyngeal swab test result is available and negative.’  This 
is to minimize the risk of subject completing lung function assessments with active COVID-
19 infection.
Footnote g: updated to specify that for all subjects enrolled during COVID-19 pandemic, a 
chest X-ray must be done at Visit 1, or at any time that allows the chest X-ray assessment 
prior to randomization. This is to minimize the risk of enrolling subjects with COVID-19 
pneumonia or other lung pathology.
Section 1.1 SoA, Table 2:
Added pre-visit assessment applicable during COVID-19 pandemic: telephone assessment 
of possible COVID-19 symptoms, to every visit. Also, added footnote p ‘During the 
COVID-19 pandemic, subjects must be contacted by telephone for COVID-19 screening 
assessments within 24 hours prior to every study visit (except remote visits). Refer to 
Appendix I for details.’ This is to minimize the risk of subject performing study visits with 
active COVID-19 infection.
Added assessment applicable during COVID-19 pandemic: SARS-CoV-2 serology test to 
Visit 3 and footnote q to clarify that ‘SARS-CoV-2 serology test at Visit 3 is applicable for 
newly enrolled subjects. For remaining ongoing active subjects, the test should be done as 
soon as possible but preferably at the next site visit’. This is to determine whether subjects 
have been previously infected with SARS-CoV-2 for safety reasons (e.g. assessment of 
adverse events during study participation). 
Footnote c: removed ‘Sponsor and’ from ‘the Sponsor and sites will be blinded to the FeNO 
values for the whole study duration’ and added ‘The sponsor will be blinded to the FeNO 
values except at screening visit, at any repeat testing that is performed during the screening 
period and prior to Investigational Product (IP) administration at Visit 3.’ Sponsor only 
needs to be blinded to the FeNO values after randomization. 
Footnote k: updated to clarify that during the COVID-19 pandemic, sputum and nasal 
sampling will not be collected from subjects in treatment phase until the pandemic 
normalizes and AZ approves the continuation of sampling. 

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Added footnote r: ‘Randomization transaction in IWRS should be completed after 
confirmation of subject eligibility’. This is to further clarify the order of assessments and 
prevent randomization in error.
Section 1.2 Synopsis: updated the estimated date of last subject completed to Q4 2022 as 
delays have occurred due to putting recruitment on hold during COVID-19 pandemic.
Section 4.1 Overall design: 
Added ‘Pre-visit assessment during COVID-19 pandemic: Subjects must be contacted by 
telephone for assessment of possible COVID-19 symptoms within 24 hours prior to every 
study visit (except remote visits). Please refer to Appendix I for details’. This is to minimize 
the risk of subject completing study procedures with active COVID-19 infection.
Screening Period (Enrolment and Run-in): removed ‘Run-in Visit 2 should be initiated no 
later than 1 week after Enrolment at Visit 1’ and added ‘The screening lung function 
assessments and ECG must be postponed until the Visit 1 SARS-CoV-2 nasopharyngeal 
swab test result is available and negative. At the postponed Visit 1, the spirometry 
equipment will allow pre-BD, post-BD spirometry, FeNO and ECG (combined Visit 1 and 
Visit 2) to be performed. Visit 2 should be scheduled, if the post-BD spirometry and FeNO 
were not done at the postponed Visit 1. Preferably, Visit 2 should be scheduled no later than 
1 week after Visit 1 but the enrolment can be extended to accommodate additional waiting 
time required to obtain Visit 1 SARS-CoV-2 nasopharyngeal swab test result.’
Section 4.1 Overall design and Section 5.1 Inclusion 6: Added a note from section 5.4 on 
how historical COPD exacerbations should be reported in case of re-screening, for further 
clarifications. 
Section 5.1 Inclusion 12: removed with version 4.0 of Clinical Study Protocol and replaced 
with Exclusion criterion 40.
Section 5.2 Exclusion Criteria: added Exclusion criterion 38 applicable during COVID-19 
pandemic to exclude subjects with suspected COVID-19 infection based on signs and 
symptoms assessed by Investigator. This is to minimize the risk of enrolling subject with 
active COVID-19 infection.
Section 5.2 Exclusion Criteria: added Exclusion criterion 39 during COVID-19 pandemic to 
exclude subjects with positive SARS-CoV-2 nasopharyngeal swab test for active infection 
at Visit 1. This is to minimize the risk of enrolling subject with active COVID-19 infection.
Section 5.2 Exclusion Criteria: added Exclusion criterion 40 during COVID-19 pandemic to 
exclude subjects with chest X-ray performed during the screening period which shows 

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abnormalities or evidence of COVID-19 pneumonia that precludes the patient’s ability to 
complete the study. 
Section 5.4 Screen Failures and Re-screening: Added situations, applicable during COVID-
19 pandemic, when subject must be screen failed: 
‘Judgement by the Investigator that the subject should not participate in the study based on 
assessment of COVID-19 signs and symptoms for active infection. Subject can be re-
screened within 2 to 4 weeks upon approval of the AZ Study Physician (exclusion criterion 
38)’. 
‘Subject who had positive SARS-CoV-2 nasopharyngeal test at Visit 1 for active infection 
during screening should be screen failed. They may be re-screened once recovered from the 
infection, upon approval of the AZ Study Physician (exclusion criterion 39)’. 
Section 5.4 Screen Failures and Re-screening: Removed ‘and only once’ under re-screening 
requirements as subject screen failed due to COVID-19 can be re-screened additionally. Re-
screening of a subject for any reason will be allowed only upon approval of the AZ Study 
Physician.
Section 6.1.2 Preparation/handling/storage/accountability, Dose Administration – added 
situations, applicable during COVID-19 pandemic, when IP should not be administered: if 
the subject has suspected or confirmed active COVID-19 infection. Also added that AZ 
Study Physician should be contacted to discuss further subject participation if the subject 
has been diagnosed with an active COVID-19 infection. This is to minimize the risk of 
subjects completing study assessments with COVID-19 infection.
Section 6.4 Compliance to IP: added ‘with the reason for drug interruption’ to ‘The date and 
time of all IP administrations, as well as any missed doses with the reason for drug 
interruption, should be recorded in the appropriate section of the eCRF’ to further clarify 
eCRF reporting requirements.
Section 6.5.5 COPD Medication Restrictions on the Days of Scheduled Spirometry and 
FeNO Visits: updated instructions for Screening Visit 1 and Visit 2 to ‘the screening lung 
function assessments must be postponed until the Visit 1 SARS-CoV-2 nasopharyngeal 
swab test result is available and negative (refer to SoA Table 1)’ At the postponed Visit 1, 
the spirometry equipment will allow pre- and post-BD spirometry and FeNO (combined 
Visit 1 and Visit 2) to be performed. Visit 2 should be scheduled, if the post-BD spirometry 
was not done at the postponed Visit 1. Preferably, Visit 2 should be scheduled no later than 
1 week after Visit 1 but the enrolment can be extended to accommodate additional waiting 
time required to obtain Visit 1 SARS-CoV-2 nasopharyngeal swab test result. The subject 
must meet the COPD medications restrictions in order to perform the lung assessments.’ 

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This is to minimize the risk of a subject completing lung assessments with active COVID-
19 infection. 
Section 6.5.7 COPD Medication Restrictions at Centre Visits with Scheduled ECG 
Assessment: removed ‘Medications do not have to be withheld for the ECG performed at 
any time between Visit 1 and Visit 2 inclusive’ as medication wash out during enrolment is 
a requirement.   
Section 8 Study Assessments and Procedures: added ‘During COVID-19 pandemic, the 
suggested order of screening assessments is: Vital signs (starting with body temperature 
measurement), ePRO, blood draws and SARS-CoV-2 nasopharyngeal swab testing. The 
screening lung function and ECG assessments must be postponed and scheduled after Visit 
1 SARS-CoV-2 nasopharyngeal swab test result is available and negative’. This is to 
minimize the risk of subjects completing study assessments with COVID-19 infection.
Section 8.1.2.1  Spirometry, General Requirements: added sub-section ‘Applicable during 
COVID-19 pandemic: The screening lung function assessments must be performed only 
when Visit 1 SARS-CoV-2 nasopharyngeal swab test result is available and negative (refer 
to footnote a and footnote l under Table 1, section 1.1 and to section 6.5.5). SARS-CoV-2 
testing should be performed prior to lung function assessments at subsequent visits, if 
required per local regulations and guidance. If SARS-CoV-2 testing is conducted, a 
negative result must be obtained before conducting visit assessments’ This is to minimize 
the risk of a subject completing lung function assessments with active COVID-19 infection.
Section 8.1.2.2 Post-BD Spirometry: added ‘postponed’ to ‘Visit 1’ for clarification. 
Section 8.1.3 FeNO: removed visit 1 from list of visits prior to randomization, for which the 
FeNO values will be unblinded for the sponsor. 
Section 8.1.4 COPDCompEx: added ‘systemic’ replacing ‘oral’ to corticosteroids to further 
clarify medication type. Also, removed ‘wheeze’ as a diary variable as it is not used in the 
analysis of COPDCompEx.
Section 8.1.6.5 St. George’s Respiratory Questionnaire (SGRQ) and Section 8.1.6.6 COPD 
Assessment Test (CAT): Removed ‘during the COVID-19 pandemic due to local 
restrictions’ and added reference to Appendix I. 
Section 8.2.5 Vital Signs: added instructions that ‘body temperature should be done as the 
first study assessment (at Visit 1 when ICF is obtained)’ and ‘Subject with fever (≥ 38°C; ≥ 
100.4°F) suspected due to COVID-19 infection during screening or at randomization (Visit 
3) should be screen failed (Exclusion criterion 38). IP should not be administered if the 

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subject is febrile (≥ 38°C; ≥ 100.4°F) or is suspected of having COVID-19.  Refer to section 
6.1.2’. 
Section 8.2.9 Chest-X-ray, CT scan or MRI: section title update to ‘Section 8.2.9 Chest-X-
ray. The section was updated to ‘a chest X-ray done during the screening period before 
randomization visit (Visit 3) is required to ensure there are no abnormal radiological 
findings as per exclusion criterion 14 and exclusion criterion 40.’ This is to minimize the 
risk of enrolling subjects with COVID-19 pneumonia.
Section 8.2.11.2 SARS-CoV-2 testing: added a new section to describe tests that are 
applicable during the COVID-19 pandemic, for subjects enrolling into the study after 
recruitment is resumed and for subjects ongoing in the study.
Section 8.8.5 Sputum Induction: 
updated to clarify spontaneous sputum may also be used as a secondary option for outcome 
measures if induced sputum is not permitted per local regulations or guidance during 
COVID-19 pandemic.
added ‘additional local or national regulations or guidance must be followed for sputum 
processing during COVID-19 pandemic’.
Section 9.3 Populations for Analyses: revised PK analysis set description from ‘all subjects 
who received at least one dose of tezepelumab and have PK blood samples…’ to ‘all 
subjects who received at least one dose of tezepelumab and have at least one detectable 
serum concentration post first dose…’ to be consistent with other studies in tezepelumab 
clinical program.
Appendix H Abbreviations: added SARS-CoV-2 (Severe Acute Respiratory Syndrome 
Coronavirus 20 and CDC (Centers for Disease Control and Prevention)
Appendix I Coronavirus (COVID-19) Pandemic Guidance: 
Clarified that sputum and nasal samples will not be collected from subjects in treatment 
until the pandemic normalizes and AZ approves the continuation of sampling. Sputum and 
nasal sampling will be performed, if allowed per local regulations and guidance.
Added a new section I 1 to describe the pre-visit assessment applicable during COVID-19 
pandemic. 
Updated sections I 2, I 3 and I 4 to include telephone assessment of possible COVID-19 
symptoms.

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Added a new section I 6 to describe the benefit/risk assessment of re-starting recruitment 
during COVID-19 pandemic.
Various typographical and grammatical corrections have been made.
Version 3.0, 26 May 2020
Changes to the protocol are summarized below.
Section 1.1 SoA, Table 1:
Footnote b: clarified that screening phase can be extended up to 14 days to meet FeNO 
restrictions (refer to section 5.4).
Footnote c: clarified that the sponsor and site will be blinded to the FeNO values for the 
whole study duration to minimize the possibility that changes in FeNO levels might unblind 
the subject, ie indicate to the site/sponsor that the subject was on tezepelumab rather than 
placebo. 
Footnote j: added that inactive/killed vaccinations e.g. influenzae should be withheld 3 
weeks prior to EOT visit for patients in the sub study (if no safety concerns) as it might 
influence exploratory sputum analysis.
Section 1.1 SoA, Table 2:
Added ‘Healthcare resource utilization’ to Follow up visits 17 and 18 to correct a 
typographical error in the SoA. 
Footnote b: clarified that exacerbation (EXA) visit is an optional visit and may be initiated 
when patient experiences COPD exacerbation.’
Footnote c: clarified that the sponsor and site will be blinded to the FeNO values for the 
whole study duration to minimize the possibility that changes in FeNO levels might unblind 
the subject, ie indicate to the site/sponsor that the subject was on tezepelumab rather than 
placebo.
Footnote e: clarified that during COVID-19 pandemic, spirometry may not be completed as 
per local regulations and guidance.
Footnote k: clarified that during COVID-19 pandemic, sputum and nasal samples will not 
be collected from subjects that have consented to the sub study until the pandemic stabilizes 
and AZ approves the continuation of sampling. This is to limit the possibility of COVID-19 
spread to subjects and site staff.

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Footnote l: clarified that during COVID-19 pandemic: IP administration can be performed 
at the subject’s home or alternative location along with study assessments. This step is taken 
to limit subject exposure to COVID-19. Also, the laboratory assessments can be completed 
post IP administration, to allow additional time for processing of the safety samples at site 
according to the laboratory manual. 
Added Footnote m: to clarify that during re-consenting of trial subjects during the COVID-
19 pandemic, local/regional guidelines must be followed with regard to verbal informed 
consent. Pleases refer to Appendix I. Also, added ‘COVID-19 addendum to ICF (if 
applicable)’ as assessment to Table 2.
Added Footnote n: to clarify that during the COVID-19 pandemic for at home IP 
administration visits, where possible study assessments should be conducted according to 
the SoA. However, the qualified HCP is expected to collect a minimum information as 
detailed in Appendix I. This is to minimize the risk of subject exposure to COVID-19.
Added Footnote o: These assessments can be replaced by a phone visit during COVID-19 
pandemic. Please refer to Appendix I. This is to limit the possibility of COVID-19 spread to 
subjects and site staff.
Section 1.2 Synopsis and Section 3 Objectives and Endpoints: Evaluating the effect of 
tezepelumab on the frequency, duration and severity of EXACT-PRO defined events has 
been added as an exploratory objective (with the rate of EXACT-PRO defined 
exacerbations and the EXACT-PRO defined exacerbation rate ratio (tezepelumab vs 
placebo) as the outcome variable and measure respectively). Previously these data were 
being recorded but not analysed.
Section 1.2 Synopsis and Section 4.1 Overall design, Section 6.3 Measures to minimize 
Bias: Corrected typo in the target of subjects based on eosinophils count to: approximately 
20% of the subjects with ≥300 eosinophils/μL, 40% of the subjects between ≥150 to <300 
eosinophils/μL and a maximum of approximately 40% of the subjects with <150 
eosinophils/μL at enrolment.’ 
Section 1.2 Synopsis, Overall design and Section 4.1 Overall design: clarified that ‘During 
the COVID-19 pandemic, sputum and nasal samples will not be collected from subjects in 
treatment phase, until the pandemic normalizes, and AZ approves the continuation of 
sampling. Please refer to Appendix I.’ This is to limit the possibility of COVID-19 spread to 
subjects and site staff.
Section 4.1 Overall design: 

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Screening Period (Enrolment and Run-in): added ECG as assessment that cannot be 
performed during screening without meeting wash-out requirement due to ECG device 
settings to ‘If the subject does not meet the COPD medications restrictions at Visit 1, the 
lung function assessments (Spirometry, FeNO) and ECG should be postponed and 
performed no later than one week after Visit 1.’.
Randomization, Treatment and Follow-up: clarified that ‘If allowed by local/regional 
guidance during the COVID-19 pandemic, a phone call visit can replace an on-site visit and 
on-site IP administration can be replaced with home/alternative location IP administration. 
Patient must sign the COVID-19 addendum to informed consent form prior to starting these 
alternative options. If obtaining signed addendum is not feasible, patient can follow 
alternative options after verbal consenting. Please refer to Appendix I for details.’ These 
steps are being taken to limit subject exposure to COVID-19 with clinic visits.
Randomization, Treatment and Follow-up: clarified that COPD exacerbation visit (EXA) is 
optional visit.
Section 4.1 Overall Design, Section 9.2 Sample Determination, 9.6 Interim Analysis: The 
futility analysis was originally planned to occur when 182 patients had been 
randomized. As a result of the pause in recruitment due to COVID-19, the futility analysis 
is now planned to occur when approximately 30% of information has been achieved.  This 
time point has been chosen on the recommendation of the Independent Data Monitoring 
Committee (IDMC) chair.
Section 5.1 Inclusion 6: updated to clarify that in case of re-screening, historical COPD 
exacerbation from period within 2 to 52 weeks prior to re-screening Visit 1 should be 
included.
Section 5.1 Inclusion 8 and 18: updated to clarify that CAT score only based on ePRO 
questionnaire should be used for assessing patient eligibility.
Section 5.1 Inclusion 19: updated to clarify that only screening Visit 1 pre-BD result can be 
used for assessing FEV1 screening variability due to spirometer device settings ‘Stable 
FEV1 during the screening period, defined as a change in pre-BD FEV1 ≤400 mL and/or 
≤25% compared to baseline pre-BD (Visit 1) assessment’ (i.e. Inclusion 19 requirements 
have not changed).
Section 5.4 Screen Failures and Re-screening:
Updated to clarify in which situations, the screening may be extended without prior 
approval form AstraZeneca Study Physician and added that ‘Extension of the screening 

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period for any other reason will be allowed only upon approval of the AstraZeneca Study 
Physician.’
Added clarification that ‘Subjects with respiratory infection (excluding pneumonia) NOT 
requiring antibiotics or antiviral medication during the screening period: May remain in 
screening and the screening period may be extended up to 14 days to allow subject to meet 
FeNO restrictions.’
Added guidance on how to proceed with re-screening of subjects that were screened failed 
due to the COVID-19 pandemic and were re-screened once since re-screening is only 
allowed once. 
Section 6.1.2 Preparation/handling/storage/accountability, Dose Administration – added 
“Please Note: During the COVID-19 pandemic, if allowed by local/regional guidelines, IP 
preparation and administration may be performed at the subject’s home/alternative location 
by a qualified HCP. Please refer to Appendix I for further details” at the end of the section 
to accommodate for home/alternative location visits. This option is being included to limit 
subject exposure to COVID-19 with clinic visits.
Section 6.5 Concomitant Therapy Table Table 6: 
SABA and SAMA combination products are added as ‘Allowed for rescue medication and 
treatment of acute COPD exacerbation and prohibited if administered as maintenance 
medication or in a scheduled dose’ as patients might be on SABA and SAMA combination 
product. 
For omalizumab, denosumab or any other monoclonal or polyclonal antibody therapy, 
added clarification that medications are prohibited during the study even if the subject has 
discontinued IP.
For clarification, added Immunomodulators as prohibited medication to ‘Any 
Immunomodulators and immunosuppressive medication (…)’. Also, updated restrictions 
conditions: medications 4 weeks after the last dose.
For inactive/killed vaccinations, added restriction ‘3 weeks prior to EOT visit for sub-study 
subjects only’ as it might influence exploratory sputum analysis.
Section 6.5.5 COPD Medication Restrictions on the Days of Scheduled Spirometry and 
FeNO Visits: 
For clarification, added note that screening (Visit 1 and Visit 2) and randomization (Visit 3) 
spirometry and FeNO are not allowed without proper medication wash out.  

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For clarification added FeNO in various places in the section to include with scheduled 
Spirometry assessments. 
Section 6.5.7 COPD Medication Restrictions at Centre Visits with Scheduled ECG 
Assessment: For clarification added note that screening and randomization ECG are not 
allowed without proper medication wash out due to ECG device settings. 
Section 8 Study Assessment and Procedures: Added ‘Due to COVID-19 pandemic, it may 
not be possible to complete all study assessments, such as spirometry, according to SoA. 
Please refer to SoA and Appendix I for further details.’ This is added to limit the risk of 
COVID-19 exposure to subject and site staff.
Section 8 Study Assessments and Procedures: Added ‘Additional data to assess the impact 
of COVID-19 pandemic will be collected.’ 
Section 8.1.1.2 Duration of COPD Exacerbations: 
For clarification, updated COPD exacerbation start date: ‘The start date will be defined as 
the start date of prescribed treatment with a systemic corticosteroid and/or systemic 
antibiotic or hospital admission, which occurs earlier.’ by including hospital admission.
For clarification, updated COPD exacerbation stop date: ‘The stop date will be defined as 
the last day of prescribed treatment with a systemic corticosteroid and/or systemic antibiotic 
or hospital discharge, which occurs later.’
Section 8.1.1.3.2 Symptom Reporting: added clarification that ‘If COPD exacerbation is 
associated with ePRO worsening alert, symptoms should not be reported in the COPD 
exacerbation eCRF. If COPD exacerbation is not associated with ePRO worsening alert, 
please refer to section 8.1.1.4 for further guidance’
Section 8.1.2.1 Spirometry, General Requirements: Added that ‘During the COVID-19 
pandemic, spirometry assessments should be performed only as allowed per local 
regulations and guidance.’ This is to provide guidance on how to proceed with respect to 
Schedule of Activities during the COVID-19 pandemic.
Section 8.1.6 Patient Reported Outcomes: Added clarification that subject can be trained at 
home use of eDiary also at Visit 1, if Visit 1 and Visit 2 are combined.
Section 8.1.6.5 St. George’s Respiratory Questionnaire (SGRQ): added clarification ‘If the 
subject is not able to visit the site during the COVID-19 pandemic due to local restrictions, 
SGRQ may be completed by the subject at home/alternative location.’

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Section 8.1.6.6 COPD Assessment Test (CAT): added clarification ‘If the subject is not able 
to visit the site during the COVID-19 pandemic due to local restrictions, CAT may be 
completed by the subject at home/alternative location.’
Section 8.2.2 Clinical Safety Laboratory Assessments: added clarification ‘During the 
COVID-19 pandemic, it may not be possible to collect clinical safety laboratory tests at the 
site due to local restriction. If the subject has re-consented to home/alternative location IP 
administration visits, it is possible that the HCP can collect clinical safety laboratory tests in 
the subject’s home/alternative location.’ This change is to minimize the subject's risk of 
COVID-19 exposure with clinic visits.
Section 8.3.2 Time Period and Frequency for Collecting AE and SAE Information:  
Clarified that Adverse Events and Serious Adverse Events have to be collected from the 
time of informed consent and throughout the duration of the study. The AE/SAE collection 
requirements have not changed.
Section 8.7.1 Optional Exploratory Genetic Sample, Section 8.8.1 Storage, Re-use and 
Destruction of Biomarker Samples: For clarification added that the results of any analyses 
will not be reported in the CSR itself but as an addendum, or separately in a scientific report 
or publication for clarification.
Section 8.8.4 Nasal Epithelial Cell and Sputum Cell Transcriptomics: added clarification
‘During the COVID-19 pandemic, nasal and sputum samples will not be collected from 
treatment subjects to minimize the risk of subject and site staff exposure to the virus.
Section 8.8.5 Sputum Induction: Added that during the COVID-19 pandemic, sputum 
samples will not be collected from subjects in treatment phase to reduce the risk of subject 
and site staff exposure to the virus.
Section 8.8.6 Nasal Lining Fluid: Added that during the COVID-19 pandemic, nasal 
samples will not be collected from subjects in treatment phase to reduce the risk of subject 
and site staff exposure to the virus.
Section 9 Statistical considerations: For clarification of the analysis plan added that 
additional estimands (Section 9.2.1) and additional analyses (Section 9.5) to assess the 
impact of COVID-19 will be detailed in the SAP.
Appendix A 3 Informed Consent Process: Added ‘During the COVID-19 pandemic, re-
consenting of subjects must follow local/regional guidelines with regard to informed 
consent. It is critical that where written re-consent cannot be obtained, and local and 
regional guidance allows, the subject's verbal consent via phone or teleconference is 
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pandemic. Confirmation of subject’s re-consent needs to be documented in the source 
documents.’ This step is taken to minimize the risk of subject exposure to COVID-19 with 
site visits.
Appendix H Table of Abbreviations: For clarification added COVID-19 and TPV.
Appendix I Coronavirus (COVID-19) Pandemic Guidance: Added Appendix I to describe 
in more detail the changes made during the COVID-19 pandemic.
Various typographical and grammatical corrections have been made.  
Version 2.0, 16 December 2019
Changes to the protocol are summarized below.
Section 1.1, SoA – Table 1- Schedule of Assessments: corrected visit windows days.
Section 1.1, SoA – Table 1- Schedule of Assessment, footnotes:
‘a’: Updated to clarify that Visit 1 and Visit 2 can occur on the same day when all 
restrictions to medications for Visit 1 assessments are met, not only spirometry. Added 
wording clarifying that if the medication restrictions are not meet at Visit 1 then the lung 
function assessments (Spirometry and FeNO) should be postponed and done within a week 
after Visit 1. At the postponed visit, spirometry equipment will allow to combined Visit 1 
and Visit 2 pre-BD and post BD Spirometry. The remaining Table 1 (Visit 1 and Visit 2) 
assessments should be done at Visit 1, if combined Visit 1 and Visit 2 spirometry is planned 
at the postponed visit.
‘b’: Updated to align with changes made in Section 5.4 as patients with respiratory infection 
may remain in screening and the run-in period may be extended up to 14 days to allow the 
completion of therapy if deemed suitable by the Investigator. 
‘c’: Added ‘Visit 1’ to clarify that sponsor is also unblinded to FeNO values from enrolment 
(Visit 1) when Visit 1 and Visit 2 are combined; added ‘The site will be blinded to the 
FeNO values for the whole study duration,’ to clarify that sites do not have access to FeNO 
central results for the whole study duration.
‘g’: Added Magnetic Resonance Imaging (MRI) to ‘If a historical (not older than 6 months) 
chest x-ray (posterior/ anterior and lateral) is not available, historical (not older than 6 
months) Computed Tomography (CT) scan/ MRI is acceptable,’ as an acceptable historical 
MRI could replace chest x-ray during screening. 

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'f': The order of assessments during the screening period was changed from 'The suggested 
order of assessments in the clinic should occur as follows: Patient Reported Outcomes 
(PRO), Vitals, ECG, blood draw, FeNO and spirometry to 'The suggested order of 
assessments in the clinic: Vital Signs, ECG, FeNO, spirometry and blood draw,' as the 
blood sampling is not required if the patient does not meet spirometry eligibility criteria. 
‘h’: Added ‘immunoglobulin’ as sponsor and site are blinded to immunoglobulin results 
from the central laboratory results except at screening visits, for any repeat testing that is 
performed during the screening and at Visit 3 prior to IP administration.
‘j’: Updated to clarify that ‘Pneumococcal vaccination can be done at Visit 1 or at any time 
prior to randomization’ and ‘Annual influenza vaccination can be done at any other time 
throughout the study (except for within ±7 days of IP administration) at the discretion of 
Investigator’ and added reference to Section 8.2.10.
Section 1.1, SoA – Table 2 - Schedule of Assessments:
Removed Healthcare resource utilization assessment from COPD Exacerbation (EXA) visit 
as data is not to be captured in the case report form.
Under section ‘Subset of Subjects Participating in Sputum and Nasal Lining Fluid/Epithelial 
Cells Sub Studies Only’ added assessment ‘Sputum post-BD spirometry’ that is part of the 
sputum sub-study and is conducted to ensure patient safety during the induction as 
described in Section 8.1.2.3 and in the sputum manual.
'NOTE' was updated from 'The suggested order of assessments to be completed before IP 
administration should be as follows: ePRO, Vital Signs, ECG, Blood draws, FeNO, and 
Spirometry' to 'The suggested order of assessments to be completed prior IP administration: 
ePRO, Vital Signs, ECG, FeNO, Spirometry and Blood draws' to be consistent with Table 1 
footnote 'f'. 
Section 1.1, SoA – Table 2- Schedule of Assessments, footnotes:
‘b’: Added missing reference to Section 8.1.1.5.
‘c’: Updated to clarify that sponsor is also unblinded to FeNO values from enrolment (Visit 
1) when Visit 1 and Visit 2 are combined. Also, added ‘The site will be blinded to the 
FeNO values for the whole study duration’ to clarify that the sites should not have access to 
FeNO central results. 
‘f’: Footnote f is removed from IPD visit as pre- and post-BD spirometry is required for all 
subjects at IPD visit, and not only for subjects in the sub study. 

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‘g’: Amended to clarify that ‘sponsor and site will be blinded to the immunoglobulin, 
eosinophil, basophil and monocyte counts from the central laboratory reports except 
screening visits (Visit 1 and 2), any repeat testing that is performed during the screen visits, 
and at Visit 3 prior to IP administration.’
‘h’ was removed as footnotes ‘g’ and ‘h’ were merged.
‘k’: Amended to clarify that if subject is not able to produce sputum (spontaneous or 
induced) at Visit 3, then subject should be withdrawn from the sub-study and nasal samples 
should be discarded. 
Section 1.2 Synopsis: Added International coordinating investigator details.
Section 1.2 Synopsis and Section 3. Objectives and Endpoints, Safety Objectives:
Removed ’Physical examinations’ from Safety Endpoints/Variables as specific details from 
the assessment will not be captured in the case report form.
Added ‘participating in sub-study’ in ‘To evaluate the effect of tezepelumab on sputum 
biomarkers, sputum cell counts and sputum microbiome in subjects participating in sub-
study at baseline, end of treatment, and at the start of all exacerbations’ to specify the 
subgroup.
Section 1.2 Synopsis, Section 4.1 Overall design, Section 6.3 Measures to minimize Bias: 
Updated the target of subjects based on eosinophils count to include approximately 20% of 
the subjects with >300 eosinophils/μL as ‘Approximately 20% of the subjects will be 
targeted to have >300 eosinophils/μL, 40% of the subjects between ≥150 to 300 
eosinophils/μL and a maximum of approximately 40% of the subjects with <150 
eosinophils/μL at enrolment’ to improve distribution of subjects across the range of baseline 
eosinophils levels. 
Section 2.1 Synopsis and Section 8.1.6.5: Updated from ‘proportion of subjects with at least 
4 units changed in SGRQ’ to ‘proportion of subjects with at least 4 units decrease in SGRQ’ 
to clarify the clinically significant change.
Section 4.1 Overall design: 
Changed section heading from ‘Screening Period’ to ‘Screening Period (Enrolment and 
Run-in)’ and added description of enrolment and run-in visits based on Table 1.

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Removed ‘In case of an exacerbation within 2 weeks of randomization; run-in period can be 
extended to allow for recovery,’ as instructions on how to manage a COPD exacerbation are 
provided in Section 5.4 Screen Failure and Re-screening.
Added ‘If the subject does not meet the COPD medications restrictions at Visit 1, the lung 
function assessments (Spirometry, FeNO) should be postponed and performed no later than 
one week after Visit 1. At the postponed visit, spirometry equipment will allow to combined 
Visit 1 and Visit 2 pre-BD and post BD Spirometry. The remaining Table 1 (Visit 1 and 
Visit 2) assessments should be done at Visit 1, if combined Visit 1 and Visit 2 spirometry is 
planned at the postponed visit.’ clarification from Table 1 footnote ‘a’.
Added ‘COPD disease state’ in ’Acceptable Documentation for COPD disease state and 
Historical COPD Exacerbations and Background Therapy’ to clarify that the section defines 
the acceptable documentation for COPD disease.
Changed section heading from ‘Treatment’ to ‘Randomization, Treatment and Follow-up’ 
to align with section content. 
Removed ‘If the EXA visit was completed within +/-5 days of as scheduled visit, the same 
assessment does not need to be repeated at the next scheduled visit, unless at the PI’s 
discretion’ and added instead reference to Section 8.1.1.5 COPD Exacerbation Visit.
Section 5.1 Inclusion criteria:
#5: Added ‘(Visit 1 if Visit 1 and 2 are combined)’ as the inclusion is applicable at Visit 1 if 
Visit 1 and Visit 2 are combined. 
#6: Added reference ‘See Section 4.1 for required source documentation for this inclusion.’
#7: Removed the reference, ‘Equivalent ICS doses as detailed in Appendix F’ as Appendix 
F was removed as data included in the Appendix were from GINA Asthma guidance 2018 
and were not in congruence with ICS doses for COPD. 
#7: Added ‘If an Investigator decides to switch a subject who is on an ICS in a separate 
single device to a fixed-dose combination device therapy, this should be done at Visit 1 and 
the ICS component must remain at the same dose and schedule as used in the 3 months 
prior to Visit 1 (provided dose and regimen are locally approved for COPD)’ from Table 5 
for Background (maintenance) COPD medications details pertain to Inclusion #7.
#12: Added Magnetic Resonance Imaging (MRI) and correct double negative wording as it 
should read that ‘Chest x-ray, computed tomography (CT) scan or Magnetic Resonance 

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Imaging (MRI) of the chest/lungs must not show suspected lung pathology that precludes 
the patient’s ability to complete the study.’
#19: Added ‘pre-BD’ to clarify that stable pre-BD FEV1 is expected during the run-in 
period; updated the run-in period baseline pre-BD definition from ‘Visit 1’ to ‘Visit 1 if 
visits are combined or Visit 2’ as Visit 1 or Visit 2 pre-BD FEV1 result can be used as 
baseline.
Section 5.2 Exclusion criteria: 
#1: Added ‘as judged by Investigator’ to clarify that patients with clinically important 
pulmonary disease other than COPD in Investigator’s judgement should not be enrolled if it 
may put the patient at risk or negatively affect the outcome of the study.
#6: Changed from ‘History of clinically significant infection (excluding pneumonia), acute 
upper or lower respiratory infection, requiring antibiotics or antiviral medication within 14 
days prior to enrolment (Visit 1) or during the screening period based on the last day of 
antibiotic/antiviral treatment or hospitalization date, whatever occurred later or during the 
enrolment and screening’ to ‘History of clinically significant infection (excluding 
pneumonia), acute upper or lower respiratory infection, requiring antibiotics or antiviral 
medication within 14 days prior to enrolment (Visit 1) or 14 days prior to randomization 
(Visit 3), based on the last day of antibiotic/antiviral treatment or hospitalization date, 
whatever occurred later,’ as patients with respiratory infection can continue with screening 
as per updated Section 5.4.
#16: Added reference to Section 6.5.1.
#20: Added ‘immunoglobulin’ to ‘Receipt of immunoglobulin or blood products within 30 
days prior to enrolment (Visit 1)’ as we assess the effect of tezepelumab on total serum 
immunoglobulins in exploratory analysis.
#24: Updated to ‘Patients who received ≥6 months of antibiotics treatment (including 
macrolides or other antibiotic) in the previous year must have a hearing assessment 
performed as per local standard of care within 3 months prior to randomization’ to further 
clarify when the hearing assessment is applicable.
#32: Added ‘with or without ongoing treatment’ to further clarify that patients with 
evidence of active liver disease even on ongoing treatment should be excluded.
Section 5.3.2 Alcohol, Tobacco and Other and Section 8.2.2 Smoking Status: Removed 
‘Any changes in smoking status between Visit 1 (enrolment) and Visit 3 (randomization) 
will result in screen failure’ as change of smoking status is acceptable throughout the study.

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Section 5.3.2 Alcohol, Tobacco and Other and Section 8.1.2.1 General requirements: Added 
‘Subjects should not smoke on day(s) prior to lung function assessments at the site’ to 
clarify that current smokers should withhold smoking until the lung assessments are 
completed.
Section 5.4 Screen Failures and Re-screening: Updated ‘Subjects with respiratory infection 
(excluding pneumonia) requiring antibiotics or antiviral medication within 14 days prior to 
Visit 1 or during the run-in period: May remain in screening and the run-in period may be 
extended up to 14 days to allow for the completion of therapy if deemed suitable by the 
Investigator’ to allow patients with respiratory infection to continue with enrolment and be 
randomized if they managed to complete the treatment within allowed run-in window. 
Section 6.1.2 Preparation/Handling/Storage/Accountability, Dose administration: Added 
clarification that ‘IP should be equilibrated to room temperature for at least 60 minutes prior 
to administration’ and that ‘The second injection should be administered immediately after 
the first injection.’
Section 6.3 Measures to Minimise Bias, Randomization and Blinding: Added ‘or re-
screening Visit 1’ to reflect that number of historical exacerbations should be revised in 
case of re-screening.
Section 6.5 Table 5 Allowed, Restricted and Prohibited Medications: 
‘Background (maintenance) COPD medications’ details: updated from ‘The dose of 
background (maintenance) COPD medications (ICS/LABA/LAMA) should be stable 3 
months prior to V1 and throughout the study’ to ‘The dose of ICS should be stable 3 months 
prior to V1 and throughout the study’ as only ICS stable dose is required 3 months prior to 
V1 and throughout the study.
‘Mucolytics’ details: removed ‘Allowed if not containing ephedrine’ as ‘Medications 
containing ephedrine’ were added to Table 5 as prohibited medications.
‘Antitussive prn’ details: removed ‘Allowed if not containing ephedrine and/or opiates 
and/or other bronchodilator’ from as Medications containing ephedrine’ were added to 
Table 5 as prohibited medications.
Updated from ‘Antihistamines prn not containing ephedrine or bronchodilators’ to 
‘Antihistamines prn’ and removed from details ‘Allowed if not containing ephedrine or 
bronchodilators’ as ‘Medications containing ephedrine’ were added to Table 5 as prohibited 
medications.

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Added ‘Dermal topical steroids, intra-articular, nasal steroids, topical ophthalmic and otic 
corticosteroids’ to clarify other allowed medications.
Added ‘Immunoglobulin and blood products’ as prohibited medications within 30 days 
prior to enrolment (Visit 1) as per Exclusion 20 and throughout the treatment period.
added ‘Medications containing ephedrine’ as prohibited medications from Visit 3 
throughout the treatment period.
for ‘Allergen immunotherapy,’ added ‘run-in’ to ‘Allowed, if on stable therapy for at least 2 
months prior to date of Visit 1 with no anticipated change during the run-in and the 
treatment period’ to clarify that no change is anticipated also during the run-in.
‘Inactive/killed vaccinations’ details: changed from ‘within 5 days before and after any IP 
dosing visit’ to ‘within 7 days before or after any IP dosing visit’ to correct inconsistency 
between Table 5 and Table 1 footnote ‘j’.
‘Long term oxygen therapy (LTOT)’ status changed from ‘Prohibited’ to ‘Restricted’ and 
details were added, ‘During the treatment phase, any increase in maintenance oxygen 
therapy up to 4 L/min is allowed, based on investigator’s judgement’ in order to clarify that 
the increase in maintenance oxygen therapy may be allowed under specific circumstances.
Added ‘Investigational non-biologic products’ as prohibited medications within 30 days or 
5 half-lives, whichever is longer prior to Visit 1 and during the study as already prohibited 
per Exclusion Criterion 22.
Section 6.5.5, COPD Medication Restrictions on the Days of Scheduled Spirometry Visits: 
Updated the screening section to clarify that for subject who does not meet the COPD 
medications restrictions at Visit 1, the spirometry should be postponed no later than 1 week 
after Visit 1 to allow the patient to follow the COPD medications restrictions. At postponed 
visit, the spirometry equipment will allow to combined Visit 1 and Visit 2 pre-BD and post 
BD Spirometry. The remaining Table 1 (Visit 1 and Visit 2) assessments should be done at 
Visit 1, if combined Visit 1 and Visit 2 spirometry is planned at the postponed visit.’
Removed ‘preferably’ from ‘(preferably should be at least 12 hours prior to the assessment 
for twice daily medication and for 24 hours prior to the assessment for once daily 
medications)’ as there is a requirement to withhold triple inhaled medications at least 12 
hours for twice daily medications and for 24 hours for once daily medications.
To sub-section ‘Treatment Visits 3-15’ and to Section 8.1.2.1, added ‘or sputum post-BD 
spirograms (for patients participating in sputum sub-study’ to clarify that for subject 

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participating in the sputum sub-study, the usual COPD medications may be administered 
following completion of sputum post-BD assessment.
Added ‘The spirometry without proper medication washout is not allowed during the 
screening period (between Visit 1 and Visit 2 inclusive) and at Randomization Visit 3’ to 
clarify the medication conditions for the screening and randomizations visits. 
Section 7.1 Discontinuation of Study Treatment: added ‘eosinophilia (≥5% based on local 
laboratory results)’ as sponsor and site staff are blinded to central lab results after IP 
administration at Visit 3. 
Section 7.3.2, Discontinuation or suspension of entire study and site closure – Updated the 
title of this section and added additional comments about site closure. The rationale for this 
change is to specify the conditions for closure of sites during and after study completion.
Section 8.1.1.2 ‘Duration of COPD exacerbations’: Added reference to Section 8.1.1.1.
Section 8.1.1.3.1 ‘COPD Exacerbation eCRF’:
Removed ‘The investigator should record all pertinent findings and symptoms associated 
with the exacerbation event and their duration in source documents and in the COPD 
exacerbation’ as symptoms reporting are properly described in Section 8.1.1.3.2 Symptom 
Reporting. 
Added: ‘The investigator should record the COPD exacerbation that meets the COPD 
exacerbation definition (refer to Section 8.1.1) in the COPD exacerbation eCRF 
(COPDEX)’ to clarify when COPD exacerbation should be reported in COPDEX.
Updated the rule for reporting the serious COPD exacerbation, ‘The serious COPD 
exacerbation should be recorded in AE/SAE eCRF and in COPDEX. Other COPD related 
SAEs should be recorded on the AE/SAE eCRF’ to clarify the rules. 
Section 8.1.1.3.2 ‘Symptom reporting’: Added timeframe of 5 working days for investigator 
to document the action taken after an e-diary alert has been triggered.
Added ‘Section 8.1.1.5- COPD Exacerbation visit’: To describe the COPD exacerbation 
(EXA) visit from SoA Table 2.
Section 8.1.2.1 General requirements: 
Added restrictions for subjects not to smoke/vape on the same day(s) prior to the lung 
function test is being performed; 

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Added reference to Section 8.1.2.3.  
Section 8.1.2.2 Post-BD Spirometry: The revised text reads, ‘Endpoint maximal 
bronchodilation will be induced using albuterol (90μg metered dose) or salbutamol (100μg 
metered dose) with or without a spacer device up to a maximum of 4 inhalations 
administrated between 15 and 45 minutes of the final pre-BD spirometry measurement. 
SABA administration should start at least 15 minutes after final pre-BD spirometry and 
should end no later than 45 minutes after final pre-BD spirometry. Post-BD spirometry will 
be performed 15-30 minutes after last SABA inhalation’ to clarify SABA administration 
details for Post-BD spirometry.’
Added Section ‘8.1.2.3 Sputum post-BD Spirometry’: Sputum post-BD spirometry should 
be performed per schedule in Table 2 (Visit 3, Visit 16, IPD and EXA) as part of induced 
sputum procedures if subject is participating in the sputum sub study, after post-BD 
spirometry (refer to Section 8.1.2.2). It is conducted solely to ensure patient safety in 
inducing sputum and results will neither be captured for the eCRF, nor for study endpoints. 
More details will be provided in the sputum sub-study manual to clarify assessment 
applicability and purpose.  
Section 8.1.3 FeNO: Removed ‘including ICS/LABA’ and added reference to Section 
6.5.5. The inhaled BDs should be withheld for the effect duration specific to the BD as 
described in the Section 6.5.5. Updated to clarify that sponsor is unblinded to FeNO values 
prior to randomization and blinded for values post-randomization. Sites will be blinded to 
FeNO values for the whole study duration.
Section 8.2.1 Clinical Safety Laboratory Assessments, Table 7 Laboratory Safety Variables: 
Added a footnote with clarification on the urinalysis dipstick and added instruction on how 
site should manage reporting of clinically significant results as, ‘Urinalysis (Dipstick) 
central laboratory report will contain results from variables as listed in the laboratory 
manual, however only for variables U-Hb/Erythrocytes/Blood, U-Protein/Albumin and U-
Glucose is required confirmation in the laboratory eCRF module if the result is clinically 
significant. If there are any clinically significant results from other variables, it will be the 
investigator decision to document them in the eCRF as an AE.’
Section 8.2.7 Supplemental Oxygen (O2): Added eCRF reporting instruction, ‘Use of 
oxygen should be recorded as a concomitant medication in the eCRF.’ 
Section 8.2.9: Updated section, ‘Chest X-ray, CT Scan or MRI’ to include MRI as an 
acceptable historical scan.
Section 8.3.2 Time Period and Frequency for Collecting AE and SAE Information: Updated 
to clarify that Adverse Events (AEs) are to be collected only for randomized patients and 

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Serious Adverse Events (SAEs) should be recorded and reported from the time of signing of 
ICF throughout the duration of the study for all patients.
Section 8.8.4 Nasal Epithelial Cell and Sputum Cell Transcriptomics and Section 8.8.5
Sputum Induction: Added ‘In a subset of subjects only participating in the sub-study. If 
sputum and nasal collections occur at the same visit, nasal sampling should occur before 
spontaneous/sputum induction’ to clarify that the assessment is only applicable for patients 
participating in the sub-study and the nasal sampling should be done prior to sputum 
sampling. Also added ‘If subject is not able to produce sputum (spontaneous or induced) at 
Visit 3 then subject should be withdrawn from the sub-study and nasal samples should be 
discarded.’ Nasal samples will not be analyzed if the subject cannot produce sputum sample 
at Visit 3.
Section 8.8.6 Nasal Lining Fluid: Added ‘In a subset of subjects only participating in the 
sub-study. If sputum and nasal collections occur at the same visit, nasal sampling should 
occur before spontaneous/sputum induction’ to clarify that assessment is only applicable for 
patients participating in sub-study and the nasal sampling should be done prior to sputum 
sampling.
Section 9.2 Sample Size Determination: Added ‘In the absence of the interim analysis for 
futility, this design would provide 81.2% power, and only 136 subjects per treatment arm 
would be required for 80% power. This power statement accounts for the power loss 
associated with the futility interim analysis that will occur when 182 subjects have been 
randomized.  In simulated results, 1.2% of simulated trials were stopped early for futility 
but would have been successful at the final analysis of the primary endpoint had they been 
allowed to continue.  Therefore, the overall power for this trial accounting for the interim 
analysis is 80%.’ This section was added to explain how the sample size was adjusted to 
account for the futility analysis, so that the sample size calculations could be fully 
reconstructed.
Section 9.4.2.1 Exacerbation rate: Added ‘The number of days that the subject experiences 
an exacerbation during the follow-up time, including the subsequent 7 days (when a further 
exacerbation would not be considered a separate event (and if within the follow-up time) 
will be subtracted from the follow-up time to give the time at risk of exacerbation’ and 
updated the formula to calculate the annual exacerbation rate to be, ‘Annual exacerbation 
rate=Number of exacerbations*365.25 / (Time at Risk of Exacerbation).’ Using time at risk 
rather than total follow-up time (i.e. taking into account the duration of exacerbation & 
recovery) when estimating annual exacerbation rates, can avoid an under-estimation of the 
treatment effect.

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Section 9.5.2.1 Primary Analysis Methods and Section 9.4.2.1 Exacerbation rate: Amended 
from ‘corresponding follow up time’ to ‘corresponding time at risk of exacerbation’.
Appendix A1, Regulatory and Ethical Considerations: Added Regulatory Reporting 
Requirements for SAEs in accordance with the European Directive 2001/20/EC.
Appendix F Maintenance Therapy Equivalence Table: Appendix F removed as data 
included in the appendix were from GINA Asthma guidance 2018 and were not in 
congruence with ICS doses for COPD.  
Version 1.0, 03 May 2019
Initial Version, 1.0

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Document Name: d5241c00001-csp-v7
Document Title:
D5241C00001 Clinical Study Protocol version 7
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