A Multicentre, Randomised, Double-Blind, Parallel-Group, Placebo-Controlled Phase 3 Efficacy and Safety Study of Tezepelumab in Participants With Severe Chronic Rhinosinusitis With Nasal Polyposis (WAYPOINT)
Phase: PHASE3
Conditions: Chronic Rhinosinusitis With Nasal Polyps
Sponsor: AstraZeneca

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Clinical Study Protocol 
Study Intervention
Tezepelumab
Study Code
D5242C00001
Version
6.0
Date
17 Jan 2024
EudraCT/EU CT 
N
b
2020-003062-39
A Multicentre, Randomised, Double-Blind, Parallel-Group, 
Placebo-Controlled Phase 3 Efficacy and Safety Study of 
Tezepelumab in Participants with Severe Chronic Rhinosinusitis 
with Nasal Polyposis (WAYPOINT)
Sponsor Name: AstraZeneca AB, 151 85 Södertalje, Sweden
AstraZeneca K.K, 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan
Regulatory Agency Identifier Number(s)
IND number: 146838
EudraCT number: 2020-003062-39
ClinicalTrials.gov Number: NCT04851964
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
Redacted for Public Disclosure

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Protocol Number: Version 6.0 17-Jan-2024
Study Intervention: Tezepelumab
Study Phase: 3
Short Title: Efficacy and safety of tezepelumab in participants with Severe Chronic 
Rhinosinusitis with Nasal Polyposis
Acronym: WAYPOINT
Co-International Coordinating Investigator(s)
Scottish Centre for Respiratory Research 
Ninewells Hospital
University of Dundee
Scotland, UK
Eastern Virginia Medical School
Norfolk, Virginia, USA
PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment v6.0
17-Jan-2024
Amendment v5.0
17-Oct-2022
Amendment v4.0
28-Jan-2022
Amendment v3.0
26-May-2021
Amendment v2.0
06-Apr-2021
Original Protocol v1.0
14-Sep-2020
Amendment v6.0 17-Jan-2024
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
and in the EU Clinical Trial Regulation Article 2, 2 (13).
Overall Rationale for the Modification: 

Two key secondary objectives ‘resolution/near complete resolution of nasal polyps’, and 
‘resolution/near complete resolution of nasal polyps and NPSD TSS responses’ were 
moved to exploratory objectives.

Estimand for US FDA and multiplicity testing procedure for secondary endpoints were 
modified to align with FDA guidance.

Mandatory modifications resulting from the release of the AstraZeneca CSP template 
v9.0 were implemented.

Editorial changes were made to enhance clarity and consistency of the CSP.
The Summary of Changes tables for previous amendments to this protocol are presented in 
Appendix J.

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Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Title page
Updated version number, 
version date and removed 
Study Clinical Lead 
information
Administrative changes
Non-substantial
Section 1.1 Synopsis: 
Section 3 Objectives 
and Endpoints
Section 9.1 Statistical 
hypotheses
Section 9.4.2.2
Secondary 
Endpoint(s)
Section 9.4.4 Other 
Analyses
Key secondary objective 
‘resolution/near complete 
resolution of nasal polyps 
(defined as maximum NPS of 1 
in each nostril)’ moved to 
exploratory objectives. 
Statistical analyses revised 
accordingly
The definition of 
resolution/near complete 
resolution of polyps is not 
well-defined and not agreed 
with health authorities
Substantial
Section 1.1 Synopsis 
Section 3 Objectives 
and Endpoints 
Section 9.1 Statistical 
hypotheses
Section 9.4.2.2
Secondary 
endpoint(s)
Section 9.4.4 Other 
Analyses
Key secondary objective 
‘resolution/near complete 
resolution of nasal polyps 
(defined as maximum NPS of 1 
in each nostril) and NPSD TSS 
response’ moved to exploratory 
objective. Statistical analyses 
revised accordingly
The definition of 
resolution/near complete 
resolution of polyps is not 
well-defined and not agreed 
with health authorities
Substantial
Section 8.3.8
Reporting of Serious 
Adverse Events
Additional wording added from 
AstraZeneca CSP template v9.0 
regarding the procedure for 
SAE reporting when EDC is 
not available
Alignment with AstraZeneca 
CSP template v9.0. Mandatory 
updates according to CSP 
Release Notification
Non-substantial
Section 8.4.1
Reporting of 
Overdose
Section 8.4.2
Medication Error, 
Drug Abuse and 
Drug Misuse
Appendix B 4
Medication Error, 
Drug Abuse, and 
Drug Misuse
Added detailed Drug Abuse 
and Drug Misuse definition and 
examples
To align with AstraZeneca 
CSP template v9.0
Non-substantial

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Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 9.1 Statistical 
Hypotheses: Testing 
strategy for 
confirmatory 
endpoints.
Text added for US FDA 
Primary Estimand ‘For the US 
FDA, the described testing 
procedure will be applied to the 
US FDA primary estimand 
described in Section 9.4.1.2’
To align with FDA guidance 
and expectations
Non-substantial
Section 9.1 Statistical 
Hypotheses: Figure 4
Updated Holm procedure in 
MTP to truncated Holm. Text 
and Figure 4 updated 
accordingly
To align with FDA guidance 
and expectations
Non-substantial
Section 9.4.1 General 
Considerations
Addition of Biologic use for 
NP, steroids or biologic use for 
co-morbid conditions, and 
COVID-19 related events to 
handling of intercurrent events 
bulleted list
To provide additional details 
on intercurrent events and 
strategies for handling them
Non-substantial
Section 9.4.1 General 
Considerations
Addition of Section 9.4.1.2: US 
FDA Primary Estimand and 
corresponding text
To align with FDA guidance 
and expectations
Non-substantial
Section 9.4.2.1
Primary Endpoint(s)
Updates to supplementary and 
sensitivity analyses
To align with Health 
Authorities guidelines and 
expectations
Non-substantial
Section 9.4.2.1
Primary Endpoint
Term “seasonal” removed from 
the subgroup “seasonal allergic 
rhinitis”
To clarify that the subgroup 
will not be restricted to 
seasonal allergic rhinitis
Non-substantial
Section 9.4.2.2
Secondary Endpoint
Update to text for the analysis 
of change from baseline in 
FEV1 at Week 52 to include 
the use of a treatment policy for 
all intercurrent events described 
in Section 9.4.1.1
To clarify the analysis for 
FEV1
Non-substantial
Section 9.4.4 Other 
Analyses
Update to add selected 
exploratory endpoint analysis
To clarify that some of the 
exploratory analysis will be 
described in the exploratory 
SAP
Non-substantial
Appendix A 4 Data 
Protection
Sub-section and corresponding 
text on ’Personal Data 
Breaches’ added
Alignment with AstraZeneca 
CSP template v9.0, mandatory 
update according to CSP 
release notification
Non-substantial.
Appendix A 6
Dissemination of 
Clinical Study Data
Corrected URL for the website 
containing the description of 
AstraZeneca clinical studies.
To update the URL as the 
previous URL was incorrect.
Non-substantial

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Section Number and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Appendix A 7 Data 
Quality Assurance
Updated information about 
retention timelines of records 
and documents to 25 years after 
study archiving or as required 
by local regulations
Update required to comply 
with global company 
requirement
Non-substantial
Spelling, grammar, and formatting corrections have been made throughout the document.

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.................................... 3
TABLE OF CONTENTS...................................................................................................... 7
1
PROTOCOL SUMMARY................................................................................ 12
1.1
Synopsis ........................................................................................................... 12
1.2
Schema............................................................................................................. 17
1.3
Schedule of Activities....................................................................................... 18
2
INTRODUCTION............................................................................................ 28
2.1
Study Rationale ................................................................................................ 28
2.2
Background ...................................................................................................... 30
2.3
Benefit/Risk Assessment................................................................................... 30
2.3.1
Risk Assessment............................................................................................... 31
2.3.2
Benefit Assessment........................................................................................... 33
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 33
3
OBJECTIVES AND ENDPOINTS................................................................... 34
4
STUDY DESIGN ............................................................................................. 37
4.1
Overall Design.................................................................................................. 37
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 39
4.2
Scientific Rationale for Study Design ............................................................... 40
4.3
Justification for Dose........................................................................................ 41
4.4
End of Study Definition.................................................................................... 42
5
STUDY POPULATION ................................................................................... 42
5.1
Inclusion Criteria .............................................................................................. 42
5.2
Exclusion Criteria ............................................................................................. 45
5.3
Lifestyle Considerations ................................................................................... 48
5.3.1
Meals and Dietary Restrictions ......................................................................... 48
5.3.2
Alcohol, Tobacco and Other ............................................................................. 48
5.3.3
Activity............................................................................................................. 49
5.4
Screen Failures ................................................................................................. 49
5.4.1
Re-screening..................................................................................................... 49
6
STUDY INTERVENTION............................................................................... 50
6.1
Study Intervention(s) Administered .................................................................. 50
6.1.1
Investigational Products.................................................................................... 50
6.1.2
Medical Devices Including Combination Products with a Device Constituent... 51
6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 52
6.2.1
Preparation and handling .................................................................................. 52

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6.2.2
Dose Preparation............................................................................................... 52
6.2.3
Dose Administration......................................................................................... 53
6.2.4
Reporting Product Complaints .......................................................................... 56
6.2.5
Reporting Product Defects ................................................................................ 56
6.2.6
Single Use APFS Device Malfunction .............................................................. 57
6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 57
6.4
Concomitant Therapy........................................................................................ 60
6.4.1
Background Medication.................................................................................... 62
6.4.2
COVID-19 Vaccination .................................................................................... 62
6.5
Study Intervention Compliance......................................................................... 64
6.5.1
Rescue Medication............................................................................................ 64
6.5.2
Other Concomitant Treatment........................................................................... 65
6.6
Dose Modification ............................................................................................ 65
6.7
Intervention After the End of the Study............................................................. 65
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.......................................................... 65
7.1
Discontinuation of Study Intervention............................................................... 65
7.1.1
Procedures for Discontinuation of Study Treatment .......................................... 66
7.1.2
Withdrawal Due to Recruitment Completion in a Randomised Stratum............. 68
7.1.3
Withdrawal due to Recruitment Completion ..................................................... 69
7.1.4
Discontinuation or Suspension of Entire Study and Site Closure ....................... 69
7.2
Lost to Follow-up ............................................................................................. 69
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 70
8.1
Efficacy Assessments........................................................................................ 71
8.1.1
Nasal Polyp Score (NPS).................................................................................. 71
8.1.2
Clinical Outcome Assessments ......................................................................... 72
8.1.2.1
Nasal Polyposis Symptom Diary (NPSD) and Nasal Polyposis Symptom 
Screening Assessment (NPSSA) ....................................................................... 73
8.1.2.2
Sino-Nasal Outcome Test 22 item..................................................................... 73
8.1.2.3
European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) ......................... 74
8.1.2.4
Short-Form 36-item Health Survey, Version 2 .................................................. 74
8.1.2.5
Asthma Control Questionnaire (for Asthma/AERD/NSAID-ERD Participants 
Only) ................................................................................................................ 75
8.1.2.6
University of Pennsylvania Smell Identification Test ........................................ 75
8.1.2.7
Patient Global Impression of Severity and Change............................................ 75
8.1.2.8
Work Productivity and Activity Impairment (WPAI) Questionnaire.................. 76
8.1.3
Sinus Computed Tomography........................................................................... 76
8.1.3.1
Lund-Mackay Score.......................................................................................... 77
8.1.3.2
Quantitative Measurement of Sinus Disease Burden on Sinus Computed 
Tomography ..................................................................................................... 77
8.1.3.3
Zinreich (Modified Lund-Mackay) Score.......................................................... 78
8.1.4
Post-randomisation Nasal Polyp Surgery and/or SCS Use................................. 78
8.1.5
Spirometry (Asthma/AERD/NSAID-ERD Participants Only) ........................... 79
8.1.5.1
General Requirements....................................................................................... 79

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8.1.6
FeNO (Asthma/AERD/NSAID-ERD Participants Only) ................................... 81
8.1.7
Nasal Peak Inspiratory Flow ............................................................................. 81
8.2
Safety Assessments........................................................................................... 82
8.2.1
Physical Examinations...................................................................................... 82
8.2.2
Vital Signs........................................................................................................ 82
8.2.3
Electrocardiograms........................................................................................... 83
8.2.4
Clinical Safety Laboratory Assessments............................................................ 83
8.2.4.1
COVID-19 Entry Screening Questionnaire ....................................................... 85
8.2.4.2
SARS-CoV-2 Testing ....................................................................................... 86
8.2.4.3
Pregnancy Test ................................................................................................. 86
8.2.4.4
Serology ........................................................................................................... 87
8.2.5
Other Safety Assessments................................................................................. 87
8.2.5.1
Weight and Height............................................................................................ 87
8.2.5.2
Asthma Exacerbations (for Asthma/AERD/NSAID-ERD Participants Only) .... 87
8.2.5.3
Nasal Polyp Exacerbations................................................................................ 88
8.3
Adverse Events and Serious Adverse Events..................................................... 88
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 88
8.3.2
Follow-up of AEs and SAEs ............................................................................. 89
8.3.3
Causality Collection.......................................................................................... 90
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 90
8.3.5
Adverse Events Based on Examinations and Tests............................................ 90
8.3.6
Adverse Events of Special Interest.................................................................... 91
8.3.7
Hy’s Law.......................................................................................................... 91
8.3.8
Reporting of Serious Adverse Events................................................................ 92
8.3.9
Independent Adjudication Committee............................................................... 92
8.3.10
Disease Progression.......................................................................................... 93
8.3.11
Disease Under Study......................................................................................... 93
8.3.12
Pregnancy......................................................................................................... 93
8.3.12.1
Maternal Exposure............................................................................................ 93
8.3.12.2
Paternal Exposure............................................................................................. 94
8.3.13
Management of IP-Related Reactions ............................................................... 94
8.3.14
Medical Device Deficiencies............................................................................. 95
8.3.14.1
Time Period for Detecting Medical Device Deficiencies................................... 95
8.3.14.2
Follow-up of Medical Device Deficiencies ....................................................... 96
8.3.14.3
Prompt Reporting of Medical Device Deficiencies to Sponsor .......................... 96
8.3.14.4
Regulatory Reporting Requirements for Device Deficiencies............................ 96
8.4
Overdose .......................................................................................................... 96
8.4.1
Reporting of Overdose...................................................................................... 97
8.4.2
Medication Error, Drug Abuse, and Drug Misuse.............................................. 97
8.4.2.1
Timelines.......................................................................................................... 97
8.4.2.2
Medication Error............................................................................................... 98
8.4.2.3
Drug Abuse ...................................................................................................... 98
8.4.2.4
Drug Misuse ..................................................................................................... 98
8.5
Human Biological Samples............................................................................... 98
8.5.1
Pharmacokinetics.............................................................................................. 99
8.5.1.1
Determination of Drug Concentration ............................................................... 99

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8.5.2
Immunogenicity Assessments ........................................................................... 99
8.5.2.1
Anti-drug Antibodies ...................................................................................... 100
8.5.2.2
Neutralising Antibodies .................................................................................. 100
8.5.3
Pharmacodynamics......................................................................................... 100
8.6
Human Biological Sample Biomarkers ........................................................... 100
8.6.1
Collection of Mandatory Samples for Biomarker Analysis.............................. 100
8.6.2
Storage, Re-use and Destruction of Exploratory Biomarker Samples............... 102
8.7
Optional Genomics Initiative Sample.............................................................. 102
8.7.1
Storage and Destruction of Genetic Samples................................................... 102
8.8
Health Resource Utilisation ............................................................................ 103
9
STATISTICAL CONSIDERATIONS............................................................. 104
9.1
Statistical Hypotheses..................................................................................... 104
9.2
Sample Size Determination............................................................................. 108
9.3
Populations for Analyses ................................................................................ 109
9.4
Statistical Analyses......................................................................................... 109
9.4.1
General Considerations................................................................................... 109
9.4.1.1
Primary Estimand ........................................................................................... 111
9.4.1.2
US FDA Primary Estimand............................................................................. 112
9.4.1.3
Supplementary Estimand ................................................................................ 112
9.4.2
Efficacy .......................................................................................................... 112
9.4.2.1
Primary Endpoint(s)........................................................................................ 112
9.4.2.2
Secondary Endpoint(s).................................................................................... 113
9.4.3
Safety ............................................................................................................. 114
9.4.4
Other Analyses ............................................................................................... 114
9.5
Interim Analyses............................................................................................. 115
9.6
Data Monitoring Committee ........................................................................... 115
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...................................................................................... 115
11
REFERENCES............................................................................................... 185
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 17
Figure 2
Suggested Scheme of Rotation of Injection Sites...................................... 55
Figure 3
COVID-19 Vaccination Administration in Relation to IP Dosing............. 64
Figure 4
Testing Procedure.................................................................................. 107

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LIST OF TABLES
Table 1
Schedule of Activities - Screening, Randomisation, Treatment Period,
and Follow-Up......................................................................................... 18
Table 2
Risk Assessment...................................................................................... 31
Table 3
Objectives and Endpoints......................................................................... 34
Table 4
Investigational Products........................................................................... 50
Table 5
Restricted Medications............................................................................. 60
Table 6
Prohibited Medications............................................................................ 61
Table 7
Endoscopic NPS Within each Nostril....................................................... 71
Table 8
Threshold Values for the SF-36v2 Scale and Summary Measures ............ 75
Table 9
Lund-Mackay Score................................................................................. 77
Table 10
Ostiomeatal Complex Score..................................................................... 77
Table 11
Modified Lund-Mackay (Zinreich) Score................................................. 78
Table 12
Laboratory Safety Variables..................................................................... 84
Table 13
SARS-CoV-2 Laboratory Safety Variables .............................................. 86
Table 14
Populations for Analysis ........................................................................ 109
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 116
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 125
Appendix C
Handling of Human Biological Samples ................................................ 131
Appendix D
Optional Genomics Initiative Sample..................................................... 133
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 137
Appendix F
Anaphylaxis: signs and symptoms, management.................................... 143
Appendix G
Abbreviations ........................................................................................ 146
Appendix H
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 151
Appendix I
Medical Device AEs, ADEs, SAEs, SADEs, USADEs and Medical 
Device/Device Constituent Deficiencies: Definitions and Procedures for 
Recording, Evaluating and Follow-up.................................................... 153
Appendix J
Summary of Changes............................................................................. 158

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Multicentre, Randomised, Double-Blind, Parallel-Group, Placebo-
Controlled Phase 3 Efficacy and Safety Study of Tezepelumab in Participants with Severe 
Chronic Rhinosinusitis with Nasal Polyposis (WAYPOINT)
Short Title: Efficacy and safety of tezepelumab in participants with Severe Chronic 
Rhinosinusitis with Nasal Polyposis
Registry
ID
IND Number
146838
EudraCT Number
2020-003062-39
ClinicalTrials.gov 
Number
NCT04851964
Rationale:
The aim of the present study is to investigate the efficacy and safety of tezepelumab in 
participants with severe chronic rhinosinusitis with nasal polyps (CRSwNP), with or without 
co-morbid asthma/aspirin-exacerbated respiratory disease (AERD)/nonsteroidal 
anti-inflammatory drug exacerbated respiratory disease (NSAID-ERD), whose severity is 
consistent with a need for surgery (total nasal polyps score (NPS) ≥5 (at least 2 for each 
nostril) despite documented treatment with systemic corticosteroid (SCS) or prior surgery for 
NP. The effect of tezepelumab 210 mg every 4 weeks (Q4W) on nasal polyps will be assessed 
on top of standard of care therapy with intranasal corticosteroids (INCS) over a 52-week 
treatment period and up to 24-week post-treatment follow-up period.
Objectives and Endpoints:
Primary Objectives:
Endpoint/variables:
To evaluate the effect of tezepelumab on:

Nasal polyp score (NPS)

Co-Primary: Change from baseline in total NPS 
evaluated by nasal endoscopy at Week 52.

Participant reported Nasal Congestion (NC)

Co-Primary: Change from baseline in bi-weekly 
mean Nasal Congestion Score (NCS) evaluated 
as part of the Nasal Polyposis Symptom Diary 
(NPSD) at Week 52.

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Key Secondary Objectives:
Endpoint/variables:
To evaluate the effect of tezepelumab on:

Loss of smell

Change from baseline in bi-weekly mean loss of 
smell evaluated as part of the NPSD at Week 52.

Nasal polyp-quality of life compared with 
placebo

Change from baseline in SNOT-22 scores at 
Week 52.

NP surgery and/or receiving SCS for NP

Time to surgery decision and/or SCS for NP up 
to Week 52.

Time to NP surgery decision up to Week 52.

Time to SCS for NP up to Week 52.

Sinus opacification

Change from baseline in Lund-Mackay score 
(LMK) evaluated by CT at Week 52.

NPSD total symptom score (TSS)

Change from baseline in bi-weekly mean NPSD 
TSS at Week 52.

Lung function in participants with co-morbid 
asthma and aspirin exacerbated respiratory 
disease (AERD)/nonsteroidal anti-
inflammatory drug exacerbated respiratory 
disease (NSAID-ERD)

Change from baseline in pre-BD FEV1 at 
Week 52.
Other Secondary Objectives:
Endpoint/variables:
To evaluate the effect of tezepelumab on:

NPS

Change from baseline over time in total NPS 
evaluated by nasal endoscopy through Week 52.

Proportion of participants with (i) ≥1 -point 
reduction and (ii) ≥2 points reduction in NPS at 
Week 52.

Participant reported NC

Change from baseline over time in bi-weekly 
mean NCS evaluated as part of the NPSD 
through Week 52.

Loss of smell

Change from baseline in loss of smell evaluated 
by UPSIT test at Week 52.

Sinus opacification

Change from baseline in modified LMK score 
evaluated by CT at Week 52.

Sinus severity score by quantitative CT 
assessment at Week 52.

Systemic corticosteroid use

Exposure of SCS over 52 Weeks.  

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
NPSD

Change from baseline by domain of NPSD 
through Week 52.

Nasal peak inspiratory flow (NPIF)

Change from baseline in NPIF through Week 52. 

Asthma control in participants with co-morbid 
asthma and AERD/NSAID-ERD

Change from baseline in ACQ-6 at Week 52.

To evaluate the PK and immunogenicity of 
tezepelumab

PK: Serum Concentration.

Immunogenicity: Anti-drug antibody (ADA).
Safety Objectives:
Endpoint/variables:
To evaluate the safety and tolerability of 
tezepelumab 

Adverse events (AEs)/serious adverse events 
(SAEs).

Clinical chemistry/haematology/urinalysis.

Vital signs.

Electrocardiograms (ECG).
For Tertiary/Exploratory objectives and estimands descriptions/endpoints, see Section 3 of the protocol. 
Overall Design
This is a Phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group, 
study designed to evaluate the efficacy and safety of tezepelumab 210 mg Q4W administered 
subcutaneously (SC) using the accessorised pre-filled syringe (APFS) versus placebo in 
participants with CRSwNP. Approximately, 400 participants will be randomised globally 1:1 
to receive tezepelumab 210 mg or matching placebo.
Participants will be stratified by region, prior nasal polyp surgery and co-morbid 
asthma/AERD/NSAID-ERD. Randomisation will be monitored to ensure that 50%-70% of the 
study population will have co-morbid asthma/AERD/NSAID-ERD, and at least 50% will have 
had prior surgery for CRSwNP. When the target percentage of participants in a stratum in a 
region is reached, consideration will be given to closing the Integrated Web Response System 
(IWRS) randomisation for that subgroup, which may be done either overall or within a 
specific region. Once a subgroup is closed, participants in the screening/run-in period in the 
closed subgroup will not be allowed to be randomised and will be screen failed. 
After enrolment, eligible participants will receive a standardised dose of Intranasal 
Mometasone Furoate Nasal Spray (MFNS) or equivalent INCS and will enter a 5-week 
screening/run-in period. Equivalent dose should refer to the highest approved country INCS 
dose for CRSwNP. Participants who meet eligibility criteria will be randomised at Week 0
(Day 0) to receive either placebo or tezepelumab 210 mg SC starting at randomisation 
(Week 0) and then every 4 weeks thereafter. An end of treatment (EOT) visit will be 
conducted at Week 52. 

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There will be two different follow-up periods after the 52-week treatment period. 
Approximately, the first 200 participants randomised will have a 24-week follow-up (FU) 
period without any IMP. The remaining participants will have a 12-week FU period without 
any IMP. 
Disclosure Statement: This is a placebo-controlled, parallel-group treatment study with 
2 arms that is participant and investigator blinded.
Number of Participants:
Approximately 890 participants are estimated to be screened/enrolled to achieve 
approximately 400 randomly assigned participants to study intervention. 
Note: "Enrolled" means that a participant's, or their legally acceptable representative has 
agreed to participate in the clinical study following completion of the informed consent 
process. Potential participants who are screened for the purpose of determining eligibility for 
the study but are not randomly assigned in the study are considered “screen failures” unless 
otherwise specified by the protocol. 
Intervention Groups and Duration:
Tezepelumab 210 mg will be administered SC at randomisation (Week 0) and then every 
4 weeks (Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48) with an EOT at Week 52. 
Matching placebo will be administered SC at the same time points. In total participants may 
receive up to 13 doses of the investigational product. Approximately the first 200 randomised 
participants will be followed up for a period of 24 weeks post EOT and the remaining 
randomised participants will be followed up for a period of 12 weeks after EOT visit.
All participants will have their current INCS therapy standardised to Mometasone furoate 
(MFNS) with a total daily dose of 400 µg or equivalent dose of INCS at Visit 1 and 
throughout the screening and study period. Equivalent dose should refer to the highest 
approved country INCS dose for CRSwNP.
Independent Adjudication Committee: 
An independent adjudication committee will be established to provide an external independent 
assessment of blinded data to confirm the diagnosis and causality of major adverse cardiac 
events (MACE; to be 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; please refer to Section 8.3.9. 
Statistical Methods
The co-primary analysis will compare the effect of tezepelumab versus placebo in the change 
from baseline in NPS at Week 52 and the change from baseline in the bi-weekly mean NCS at 

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Week 52.
Assuming a population standard deviation (SD) of 2.25 in total NPS change from baseline and 
1.22 in NCS change from baseline, the sample size of 200 participants per arm will provide at 
least 95% total power to detect a statistically significant difference at a 2-sided 1% level on 
both co-primary endpoints if the true effect of tezepelumab is -1.8 in total NPS change from 
baseline and -0.87 in NCS change from baseline. Two hundred participants per arm also 
provides at least 95% power to detect a statistically significant difference at a 2-sided 1% level 
in key secondary endpoints of change from baseline in loss of smell, LMK, SNOT-22, and 
time to SCS and/or surgery decision. In addition, this sample size provides at least 80% power 
to detect a difference (at a nominal 5% significance level) in the endpoint of time to surgery 
decision, assuming a true hazard ratio (HR) of 0.33 and a placebo rate at Week 52 of 11%. 
Efficacy analyses will be based on the full analysis set (FAS) according to the randomised 
treatments. Both co-primary efficacy endpoints will be analysed using an analysis of 
covariance (ANCOVA) model. Difference in LS means and the corresponding 95% 
confidence intervals (CIs) will be provided along with the p-values. The participants who have 
SCS for NP and/or a decision to undergo surgery would be considered a poor outcome. Data 
collected for participants who did not have rescue therapy are used regardless of whether 
treatment discontinuation occurs.
Both primary endpoints will be tested at 2-sided 5% level. If both are significant at 5%, then 
testing will proceed to the key secondary endpoints. The type I error across primary and key 
secondary endpoints will be controlled at 5%. The co-primary and key secondary endpoints 
will also be tested at the 1% level.

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1.2
Schema
Figure 1
Study Design

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1.3
Schedule of Activities
Table 1
Schedule of Activities - Screening, Randomisation, Treatment Period, and Follow-Up
Assessment / 
Activity
Screen
ing
Run-
in
Rando
misa
tion
Treatment Period
EOT/
IPD
FU alld
Additional 
FU 1st 200 
participantsc
UNSe Details in 
CSP 
section or 
Appendix
Visit
V1
V2
V3
V4 
b
V5
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
V18 
b
V19
V20 
b
V21
Week
-5
-2
0
2
4
8
12
16
20
24
28
32
36
40
44
48
52
58
64
70
76
Visit window 
(days)a
N/A
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
±7
±7
N/A
N/A
General Procedures
Informed 
consent
X
Section 
5.1, 
Appendix 
A 3
Inclusion and 
exclusion 
criteria
X
X
X
Section 
5.1, 5.2
Demography
X
Section 
5.1
Medical/ 
surgical history, 
including 
respiratory and 
nasal polyp 
history
X
Section 
5.1

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Table 1
Schedule of Activities - Screening, Randomisation, Treatment Period, and Follow-Up
Assessment / 
Activity
Screen
ing
Run-
in
Rando
misa
tion
Treatment Period
EOT/
IPD
FU alld
Additional 
FU 1st 200 
participantsc
UNSe Details in 
CSP 
section or 
Appendix
Visit
V1
V2
V3
V4 
b
V5
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
V18 
b
V19
V20 
b
V21
Week
-5
-2
0
2
4
8
12
16
20
24
28
32
36
40
44
48
52
58
64
70
76
Visit window 
(days)a
N/A
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
±7
±7
N/A
N/A
Healthcare 
Resource 
Utilisation 
(HRU) 
Assessments
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.8
COVID-19/SARS-CoV-2 Assessmentsf
COVID-19 
Entry Screening 
Questionnaire
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.2.4.1
SARS-CoV-2 
nasopharyngeal 
swab test (or 
COVID-19 
rapid test)
X
Section 
8.2.4.2
SARS-CoV-2 
serology test
X
Section 
8.2.4.2
Safety Assessments
Past and current 
medical 
conditions
X
Section 
5.1

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Table 1
Schedule of Activities - Screening, Randomisation, Treatment Period, and Follow-Up
Assessment / 
Activity
Screen
ing
Run-
in
Rando
misa
tion
Treatment Period
EOT/
IPD
FU alld
Additional 
FU 1st 200 
participantsc
UNSe Details in 
CSP 
section or 
Appendix
Visit
V1
V2
V3
V4 
b
V5
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
V18 
b
V19
V20 
b
V21
Week
-5
-2
0
2
4
8
12
16
20
24
28
32
36
40
44
48
52
58
64
70
76
Visit window 
(days)a
N/A
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
±7
±7
N/A
N/A
Complete 
physical 
examination
X
X
Section 
8.2.1
Brief physical 
exam
X
X
X
X
X
X
X
Section 
8.2.1
Weight
X
X
X
X
X
X
X
X
X
Section 
8.2.5.1
Height
X
Section 
8.2.5.1
ECG
X
X
X
X
X
Section 
8.2.3
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.2.2
Adverse Events 
(AE)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.3
Concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
6.4
Efficacy and Participant Reported Outcome Assessments
Distribute 
ePRO device
X
Section 
8.1.2

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Table 1
Schedule of Activities - Screening, Randomisation, Treatment Period, and Follow-Up
Assessment / 
Activity
Screen
ing
Run-
in
Rando
misa
tion
Treatment Period
EOT/
IPD
FU alld
Additional 
FU 1st 200 
participantsc
UNSe Details in 
CSP 
section or 
Appendix
Visit
V1
V2
V3
V4 
b
V5
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
V18 
b
V19
V20 
b
V21
Week
-5
-2
0
2
4
8
12
16
20
24
28
32
36
40
44
48
52
58
64
70
76
Visit window 
(days)a
N/A
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
±7
±7
N/A
N/A
ePRO device 
training
X
X
Section 
8.1.2
NPSSA
X
Section 
8.1.2.1
NPSD
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.1.2.1
SNOT-22
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.1.2.2
SF-36v2 
(standard 
recall)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.1.2.4
EQ-5D-5L
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.1.2.3
PGI-S
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.1.2.7
PGI-C
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.1.2.7
WPAI
X
X
X
Section 
8.1.2.8
UPSIT Smell 
Testg
X
X
X
X
X
X
X
X
Section 
8.1.2.6

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Table 1
Schedule of Activities - Screening, Randomisation, Treatment Period, and Follow-Up
Assessment / 
Activity
Screen
ing
Run-
in
Rando
misa
tion
Treatment Period
EOT/
IPD
FU alld
Additional 
FU 1st 200 
participantsc
UNSe Details in 
CSP 
section or 
Appendix
Visit
V1
V2
V3
V4 
b
V5
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
V18 
b
V19
V20 
b
V21
Week
-5
-2
0
2
4
8
12
16
20
24
28
32
36
40
44
48
52
58
64
70
76
Visit window 
(days)a
N/A
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
±7
±7
N/A
N/A
Nasal peak 
inspiratory flow 
(NPIF)
X
X
X
X
X
X
X
X
Section 
8.1.7
Asthma/AERD/NSAID-ERD Participants Only
Spirometry 
(FEV1, FEF 
25-75% and 
FVC)
X
X
X
X
X
Section 
8.1.5
FeNOh
X
X
X
X
X
Section 
8.1.6
ACQ-6
X
X
X
X
X
Section 
8.1.2.5
Nasal Polyposis Assessment
Nasal 
endoscopy/
NPS
X
X
X
X
X
X
X
X
Section 
8.1.1
CT Scani,t
X
X
Section 
8.1.3
Assess decision 
for nasal 
surgery and/or 
SCS use
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xu
X
X
X
X
X
Section 
8.1.4

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Table 1
Schedule of Activities - Screening, Randomisation, Treatment Period, and Follow-Up
Assessment / 
Activity
Screen
ing
Run-
in
Rando
misa
tion
Treatment Period
EOT/
IPD
FU alld
Additional 
FU 1st 200 
participantsc
UNSe Details in 
CSP 
section or 
Appendix
Visit
V1
V2
V3
V4 
b
V5
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
V18 
b
V19
V20 
b
V21
Week
-5
-2
0
2
4
8
12
16
20
24
28
32
36
40
44
48
52
58
64
70
76
Visit window 
(days)a
N/A
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
±7
±7
N/A
N/A
Laboratory Assessments
Clinical 
Chemistry
X
X
X
X
X
X
X
X
X
Section 
8.2.4
Haematologyj
X
X
X
X
X
X
X
X
X
Section 
8.2.4
Urinalysis
X
X
X
X
X
X
X
X
Section 
8.2.4
Urine dipstick 
pregnancy test 
(WOCBP only)
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.2.4.3
Serum 
pregnancy test 
(WOCBP only)
X
X
X
X
Section 
8.2.4.3
FSHk
X
Section 
8.2.4.3
Serology 
(HepB, HepC, 
HIV1, HIV2)
X
Section 
8.2.4.4
Exploratory Assessments
Tezepelumab 
PKl
X
X
X
X
X
X
X
Section 
8.5.1

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Table 1
Schedule of Activities - Screening, Randomisation, Treatment Period, and Follow-Up
Assessment / 
Activity
Screen
ing
Run-
in
Rando
misa
tion
Treatment Period
EOT/
IPD
FU alld
Additional 
FU 1st 200 
participantsc
UNSe Details in 
CSP 
section or 
Appendix
Visit
V1
V2
V3
V4 
b
V5
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
V18 
b
V19
V20 
b
V21
Week
-5
-2
0
2
4
8
12
16
20
24
28
32
36
40
44
48
52
58
64
70
76
Visit window 
(days)a
N/A
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
±7
±7
N/A
N/A
Tezepelumab 
ADA/nAbm
X
X
X
X
X
X
X
Section 
8.5.2
Total IgE
X
X
X
X
Section 
8.6.1
IgE FEIA
X
Section 
8.6.1
Blood for 
serum and 
plasma 
biomarkers
X
X
X
X
X
X
Section 
8.6.1
Blood for RNA 
transcriptomic 
profiling
X
X
X
X
X
X
Section 
8.6.1
Nasal epithelial 
lining fluid for 
PK and 
Exploratory 
biomarkers
Xo
X
X
X
Xn
X
Section 
8.6.1
Staph A Nasal 
Culture
X
X
X
Section 
8.6.1

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Table 1
Schedule of Activities - Screening, Randomisation, Treatment Period, and Follow-Up
Assessment / 
Activity
Screen
ing
Run-
in
Rando
misa
tion
Treatment Period
EOT/
IPD
FU alld
Additional 
FU 1st 200 
participantsc
UNSe Details in 
CSP 
section or 
Appendix
Visit
V1
V2
V3
V4 
b
V5
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
V18 
b
V19
V20 
b
V21
Week
-5
-2
0
2
4
8
12
16
20
24
28
32
36
40
44
48
52
58
64
70
76
Visit window 
(days)a
N/A
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
±7
±7
N/A
N/A
Staph A 
enterotoxin 
Specific IgE 
status (only 
participants in 
the sub-study)o
X
X
Section 
8.6.1
Nasal biopsy -
tissue for 
histology and 
RNA 
transcriptomics 
(only 
participants in 
the sub-study)o
Xp
X
Section 
8.6.1
Genomics 
Initiative 
optional, 
exploratory 
genetic sampleq
X
Section 
8.7;
Appendix
D
Randomisation, Investigational Product Administration and INCS Management
Randomisation
X
Section 
4.1

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Table 1
Schedule of Activities - Screening, Randomisation, Treatment Period, and Follow-Up
Assessment / 
Activity
Screen
ing
Run-
in
Rando
misa
tion
Treatment Period
EOT/
IPD
FU alld
Additional 
FU 1st 200 
participantsc
UNSe Details in 
CSP 
section or 
Appendix
Visit
V1
V2
V3
V4 
b
V5
V6
V7
V8
V9
V10 V11 V12 V13 V14 V15 V16
V17
V18 
b
V19
V20 
b
V21
Week
-5
-2
0
2
4
8
12
16
20
24
28
32
36
40
44
48
52
58
64
70
76
Visit window 
(days)a
N/A
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±5
±7
±7
±7
±7
N/A
N/A
IP 
Administrationr
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
6.1
Home IP 
Administration 
by HCP 
(optional)s
X
X
X
X
X
X
X
Section 
6.2.3
INCS 
Distributionv
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
6.4.1
a
All visits to be scheduled from the date of randomisation, not from the date of previous visit.
b
Visits 4, 18 and 20 is a phone/remote visit (').
c
Approximately, the first 200 participants randomised will have a 24-week follow-up period post EOT: V18 (Week 58), V19 (Week 64), V20 (Week 70) and V21 (Week 76). 
If for any reason a participant in the first set of randomised participants as described, is not willing to participant for a full 24-week FU period and would like to terminate 
participation in the study, the follow-up discontinuation (FUD) visit should be performed at V19 (Week 64).
d
The remaining, approximately 200 participants randomised will have a 12 -week Follow-up period post EOT: V18 (Week 58) and V19 (Week 64).   
e
Unscheduled visits may be initiated as needed, and additional assessments may be performed at these visits as indicated.
f
COVID-19 entry screening questionnaire must be completed for each participant prior to complete study visit activities. Sites should also follow local SARS-CoV-2 testing 
guidelines outside of CSP study assessments, if applicable.
g
UPSIT smell test will be performed in all countries participating in the study except in countries in which an UPSIT version is unavailable in the applicable native language.
h
The subjects, sites and sponsor will be unblinded to the FENO values prior to randomisation and blinded to the FeNO values post randomisation.
i
Referral for CT scan should be provided at V2 (Week -2) and must be performed after nasal biopsy procedure (if applicable) at V2 only if the participant has met all 
eligibility criteria at V2. CT should be performed between V2 and V3 after the participant meets the inclusion/exclusion criteria and receive a confirmation from central 
readers that the inclusion criteria of NPS score is met.
j
The sponsor and site will be blinded to the immunoglobulin, eosinophil, basophil and monocyte counts from the central laboratory reports except screening visits (V1 and 
V2), any repeat testing that is performed during the screening period prior to Investigational Product (IP) administration at V3.
k
FSH test done only for female participants to confirm postmenopausal status in women < 50 years who have been amenorrhoeic for > 12 month.
l
At dosing visits, PK samples must be collected pre-dose.

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m
Neutralising antibody (nAb) testing will be performed for all samples that are ADA positive. Samples that are ADA negative will not be tested for nAb.
n
For IPD, participants should only have nasal epithelial lining fluid collected if the time between randomisation and IPD Visit is ?24 weeks. 
o
The nasal biopsy sub-study will be performed at selected sites (Approximately total of 60 participants).  Collection of nasal lining fluid at V2 is applicable to participants of 
the nasal biopsy sub-study only and should be performed before nasal biopsy to avoid potential blood contamination. If nasal biopsy cannot be collected at V2, then the 
participant should be withdrawn from nasal biopsy sub-study and can continue on the main study. In this event, NLF collection at Visit 2 and Staph A enterotoxin-specific 
IgE sample collection at Visit 3 should not be performed as well. Please note that CT scans are done after nasal biopsy at baseline, while at EOT/IPD, the CT scan will be 
done before nasal biopsy. Moreover, Collection of NLF at V3, V7, V10, V17/EOT/IPD, and V19 is required for all study participants,.
p
The PI has the ability to postpone endoscopy within 3 days of V2 if nasal biopsy results in bleeding, making NPS assessment difficult.
q
Samples can be collected at any time from V3 (Week 0) after genetic consent form is obtained.
r
IP administration should be the last activity of the visit. All visit procedures should be done prior to dosing. 
s
Optional home dosing by HCP: The participant must complete at least 3 IP administration visits on-site dosing before IP administration at home by HCP is possible. 
t
The procedures for the EOT/IPD visit should be followed and a CT scan should be done prior to the first post-randomisation NP surgery. If SCS is used for treatment of NP, 
a CT scan should be performed before starting the first course of SCS, if possible, and at the EOT visit. Note, the CT scan should only be performed prior to the first 
initiation of NP surgery or first course of SCS for NP. If IP discontinuation occurs for other reasons, a CT scan should be performed at the IPD visit and at Week 52, if the 
participant opts for follow-up option 1 or 2 per section 7.1.1 of the CSP. For IPD (for any reason), only do CT if at least 12 weeks since the V2 CT scan.
u
For participants who undergo or are planned for surgery for NP during the treatment period, the Investigator may decide to continue IP up to the time of surgery or the 
EOT/IPD visit; whichever date comes first. A nasal endoscopy assessment of NPS and PROs should be available for analysis prior to the NP surgery. If no such assessment 
is available, a visit should be scheduled to obtain those assessments. At the time of surgery, participants will be permanently discontinued from IP and assessed as soon as 
possible per the EOT/IPD visit described in the SoA. If SCS is used for treatment of NP, PROs, and a nasal endoscopy assessment of NPS should be performed before 
starting treatment with SCS. If no such assessment is available, a visit should be scheduled to obtain those assessments.
v
Refer to the study Pharmacy Manual for detailed instructions regarding dispensation and accountability procedures.
Order of Assessments
•
At Visit 1, the suggested order of assessments should be followed as: ePRO, Vital Signs, ECG, Blood Draws, and the SARS-CoV-2 nasopharyngeal swab test or COVID-19 
rapid test. At Visit 2, the suggested order of assessments should be: ePRO, Vital Signs, Nasal epithelial lining fluid collection, Nasal biopsy (if applicable), Nasal endoscopy, 
and CT scan (referral at Visit 2).
•
At Visit 3, the suggested order of assessments should be followed: ePRO, UPSIT, Vital Signs, FeNO (asthma/AERD/NSAID-ERD participants), Spirometry 
(asthma/AERD/NSAID-ERD participants), NPIF, Blood Draws including SARS-CoV-2 serology test, Staph A nasal culture, Nasal epithelial lining fluid collection, IP 
administration. 
•
Based on investigator’s judgement and site resources, EOT assessments (V17) will be performed over more than one day, within a 5-day window. At EOT/IPD visit, the 
suggested order of assessments should be followed: CT scan, ePRO, UPSIT, Vital Signs, ECG, FeNO (asthma/AERD/NSAID-ERD participants), Spirometry 
(asthma/AERD/NSAID-ERD participants), NPIF, Blood Draws, Staph A nasal culture, Nasal epithelial lining fluid collection, Nasal endoscopy, Nasal biopsy (if applicable). 
Note: At EOT/IPD, for participants in the nasal biopsy sub-study, the CT scan should be completed before the nasal biopsy procedure.
ACQ-6 - Asthma Control Questionnaire-6; ADA - Anti-drug antibodies; ClinRO - Clinician-reported outcome; COVID-19 – Coronavirus Disease 2019; CT- Computed 
tomography; EOT - End of treatment; FU - Follow-up; FUD - Follow-up discontinuation; HCP – Health Care Professional; HRU - Healthcare resource utilisation; IgE -
Immunoglobulin E; INCS - Intranasal corticosteroids; IPD - Investigational product discontinuation; nAb - Neutralising antibody; NP - Nasal polyposis; PK - Pharmacokinetics; 
PRO - Participant reported outcome; SARS-CoV-2 - Severe Acute Respiratory Syndrome Coronavirus 2; SCS - Systemic corticosteroids; SF-36v2- Short-Form 36-item Health 
Survey, Version 2; SNOT-22 - SinoNasal Outcome Test, 22 item; UNS - Unscheduled; UPSIT - University of Pennsylvania Smell Identification Test; WOCBP – Women of Child 
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2
INTRODUCTION
Chronic rhinosinusitis with nasal polyps (CRSwNP) is strongly linked with asthma by 
epidemiological, pathophysiological, and clinical evidence, supporting an “united airway” 
concept to chronic inflammatory diseases of the upper and lower airways. Both diseases are 
co-morbid conditions (Håkansson K et al 2015). Compared to non-asthmatic patients, 
asthmatic patients have a higher prevalence of chronic rhinosinusitis (CRS) and CRSwNP and 
greater severity of rhinosinusitis (Jarvis D et al 2012, Seybt MW et al 2007, Pearlman AN et al 
2009, Tint D et al 2016, Settipane GA and Chafee FH 1977). Furthermore, asthmatic subjects 
with CRSwNP may have more poorly controlled asthma, increased airway obstruction, and 
greater lower airway inflammation than those without CRSwNP (Bilodeau L et al 2010). Co-
existing asthma in CRSwNP patients is associated with lower quality of life (Alobid I et al 
2005, Ehnhage A et al 2009). Mechanistically, both nasal polyps (NP) and severe eosinophilic 
asthma are considered Type-2 (T2) driven diseases and the inflammatory profile is similar 
between the upper airway in NP and the lower airway in asthma (Fokkens et al 2020, Chaaban 
MR et al 2013). Like asthma, the role of eosinophils is considered important to the pathology 
of NP in a high proportion of patients.
Nasal polyposis represents an area of significant unmet medical need, especially for a subset 
of patients with NP who have exhausted current treatment options, which include medical 
interventions (intranasal corticosteroids (INCS), systemic corticosteroids (SCS), and 
antibiotics) and surgical interventions. Patients and healthcare professionals both point to a 
greater need for new therapies that reduce the need for repeated courses of SCS or surgery for 
all patients with NP. Surgery to remove polyps remains a consideration in patients whose 
symptoms are not controlled with corticosteroids, but rates of recurrence are high 
(approximately 40%, 12 months after surgery) and repeated surgical interventions are often 
needed. Although INCS are continued after surgery, a proportion of patients will nevertheless 
experience post-surgical recurrence despite treatment with currently available therapies, and 
these participants carry an even higher risk of recurrence if they undergo further surgery
(Fokkens et al 2020, Orlandi RR et al 2013, Agarwal et al 2019, van der Veen et al 2017).
2.1
Study Rationale
Chronic rhinosinusitis with nasal polyps is a chronic heterogenous inflammatory condition of 
the nasal and paranasal mucosa (Fokkens et al 2020). The underlying pathogenesis of the 
disease is currently undefined but in recent years type 2 (T2) driven inflammation has been 
shown to be a dominant process in CRSwNP and therapeutics targeting T2 inflammation have 
demonstrated efficacy in CRSwNP (Gevaert et al 2011, Bachert et al 2016, Bachert et al 2017, 
Bachert et al 2019, Gevaert et al 2020). Thymic stromal lymphopoietin (TSLP) is an epithelial 
cytokine released in response to airborne environmental triggers. TSLP can drive T2 cytokine 
release from Th2 and ILC2 cells as well as have effects on other immune cells present in NP 
tissue. TSLP levels are elevated in nasal polyp tissue from patients with CRSwNP compared 

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with healthy sinus tissue or that from patients with CRS without NP (Kimura S et al 2011, 
Nagarkar DR et al 2013). TSLP may therefore play a role in the initiation and persistence of 
CRSwNP and blockade is predicted to be beneficial to patients.
Tezepelumab is a fully human immunoglobulin G (IgG) 2λ monoclonal antibody (mAb) 
directed against thymic stromal lymphopoietin (TSLP). It binds to human TSLP and prevents 
its interaction with heterodimeric TSLP receptor and is currently being evaluated for bronchial 
asthma, COPD, atopic dermatitis and severe CRSwNP.
Currently available biological treatment for NP is limited to an approximately 40% to 60% 
success rate (Gevaert et al 2011, Bachert et al 2016, Bachert et al 2017, Bachert et al 2019, 
Gevaert et al 2020). There are two possible explanations for the lack of complete response 
with biologics. First is that when polyps become large enough to be symptomatic, reduction of 
inflammatory cells and/or inflammation may limit and reduce new growth but may not be able 
to substantially reduce polyp size in the face of persistent tissue fibrosis (Stevens et al 2016). 
TSLP contribution to extracellular matrix (ECM) deposition may be indirect, as an initiator of 
the inflammatory processes driving fibrosis, or direct, since TSLP has been shown to have 
effects on or to be produced by lung fibroblasts (reviewed in Gauvreau et al 2020). 
Furthermore, in CRSwNP TSLP has been shown to indirectly stimulate fibroblasts via CST-1 
(Kato et al 2019) inducing periostin; a matricellular signalling protein demonstrated to 
regulate ECM structure and organisation through its ability to bind ECM and promote 
collagen fibrillogenesis and crosslinking. This suggests that in addition to its anti-
inflammatory MoA treatment with tezepelumab may potentially have an anti-fibrotic effect 
which could result in improvement of CRSwNP. The kinetics of ECM turnover is known to be 
slow therefore the 52-week treatment period proposed is required if sufficient time is to be 
given for changes in ECM to occur. Continued improvement in NPS score beyond Week 24
may be expected based on this potential anti-fibrotic MOA for tezepelumab. 
Second, there is a subset of CRSwNP patients who do not have T2 mediated disease. Analysis 
of subgroups in the tezepelumab Phase 2b study and Phase 3 studies (PATHWAY and 
NAVIGATOR) in asthma patients showed that tezepelumab benefited participants with low 
and high baseline eosinophil counts and a low and high baseline T2 profile. These analyses 
suggest that tezepelumab, unlike other currently available biologics on the market used to treat 
severe asthma, is effective in patients with T2 high and T2 low airway inflammation and 
might be effective in T2 low as well as T2 high CRSwNP. It is assumed that tezepelumab 
reduces the AAER in asthma by acting as an airway anti-inflammatory. However, information 
directly supporting this assumption in CRSwNP is currently not available, and this study will 
investigate the role of tezepelumab as an anti-inflammatory in CRSwNP.
Asthma and CRSwNP share a similar pathophysiology and are common comorbidities. A 
post-hoc analysis of patients with co-morbid nasal polyps in the PATHWAY population 

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revealed that 15.2% of the subjects had co-morbid CRSwNP. Asthma patients with NP treated 
with tezepelumab demonstrated improvement in AERR, FEV1 and ACQ-6 and T2 
inflammatory biomarkers relative to placebo to an equivalent extent as non-NP asthma 
patients. These finding support the rationale of a broad effect of tezepelumab in asthma and 
potential efficacy in CRSwNP. (Emson C et al 2020; Emson C et al 2020 ; Emson C et al
2021).
2.2
Background
Nasal polyposis is recognised to be a consequence of chronic inflammatory disease of the 
nasal mucosa. The presence of polyps can cause long-term symptoms such as prominent nasal 
obstruction, post-nasal drip and nasal discharge, loss of smell, and facial pain. These 
symptoms can greatly impact a patient’s quality of life. Patients with CRSwNP have been 
observed to have worse symptoms (as evidenced by higher Sino-Nasal Outcome Test 
[SNOT]-22 scores), more severe disease by imaging (as demonstrated by Lund-Mackay and 
modified LMK score computed tomography [CT] scores), and require more frequent revision 
surgery than patients with CRSsNP (Hull and Chandra 2017; Fokkens et al 2020).
The aetiology of NP is still considered unclear, but allergy, asthma, infection and aspirin 
sensitivity (AERD) have all been associated with this complex refractory disease in adults 
(Hull and Chandra 2017).  Both NP and asthma are T2-driven disease processes that are 
characterised by an eosinophilic infiltrate in affected tissue, either the polyps or the airways. 
The inflammatory profile observed in asthma shares many features and similarities with the 
inflammation seen in patients with NP where eosinophils are the primary effector cell in the 
pathophysiology of both upper airway sinusitis and lower airway asthma (Håkansson K et al 
2015; Ediger et al 2005). 
A detailed description of the chemistry, pharmacology, efficacy, and safety of tezepelumab is 
provided in the Investigator’s Brochure.
2.3
Benefit/Risk Assessment
Nasal polyposis represents an area of significant unmet medical need, especially for a subset 
of patients with NP who have exhausted current treatment options, which include medical
interventions (INCS, SCS and antibiotics) and surgical interventions.
More detailed information about the known and expected benefits and risks and safety profile 
of tezepelumab may be found in the Investigator’s Brochure.

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2.3.1
Risk Assessment
Table 2
Risk Assessment
Important potential risks
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 the 
last 12 weeks or 5 half-lives 
(whichever is longer) 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 optimisation phase; or 
have had tuberculosis requiring 
treatment within the 12 months prior to 
Visit 1.
Serious infections are an AESI and 
participants who develop serious 
infection will be followed up closely 
throughout study.
Malignancies
Given the potential theoretical risk, 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 increase in 
malignancies in the data to-date in either 
nonclinical 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 events, 
including malignancies that are 
considered AESI.

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Table 2
Risk Assessment
Serious cardiac events
A numerical imbalance in cardiac disorder 
SAEs was observed in the DESTINATION 
Long-Term Extension study (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 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. 
To mitigate the potential risk of serious 
hypersensitivity reactions during and 
after administration of tezepelumab, 
specific requirements 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.

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Table 2
Risk Assessment
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
Computed tomography 
(CT):
The use of CT involves ionising radiation 
that increases the risk of radiogenic 
tumours in participants
A dose constraint for the CT scan, 
based on the as low as reasonably 
achievable principle, is applied for this 
study.
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 5).
2.3.2
Benefit Assessment
Treatment with tezepelumab may significantly improve nasal congestion and reduce the size 
of nasal polyps, thus reducing the need for the use of systemic corticosteroids or the 
performance of additional surgical procedures.
2.3.3
Overall Benefit: Risk Conclusion
Use of tezepelumab has been demonstrated to show an important benefit in asthma in a phase 
2b and phase 3 study. Because of the similar pathogenesis of CRSwNP and asthma, it is 
expected that tezepelumab will improve outcomes in CRSwNP. Tezepelumab has been well 
tolerated with an acceptable safety profile and no confirmed safety signals in subjects with 

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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 programme. A numerical imbalance in serious cardiac events in the tezepelumab arm 
was observed in a single study in severe asthma, but none of the events were considered to be 
causally related to tezepelumab. Although TSLP suppression could theoretically have 
unanticipated immune-related side effects impairing host defense against certain infections 
and malignancies, there is no clear nonclinical or clinical evidence supporting such a role, and 
no safety signals related to either severe infections, parasitic infections or malignancy have 
been detected in the completed studies to date.
The benefit/risk assessment for tezepelumab in CRSwNP is considered favourable. 
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.
3
OBJECTIVES AND ENDPOINTS
Table 3
Objectives and Endpoints
Primary Objectives:
Endpoint/variables:
To evaluate the effect of tezepelumab on:

Nasal polyp score (NPS)

Co-Primary: Change from baseline in total 
NPS evaluated by nasal endoscopy at 
Week 52.

Participant reported Nasal Congestion (NC)

Co-Primary: Change from baseline in bi-
weekly mean Nasal Congestion Score (NCS) 
evaluated as part of the Nasal Polyposis 
Symptom Diary (NPSD) at Week 52.
Key Secondary Objectives:
Endpoint/variables:
To evaluate the effect of tezepelumab on:

Loss of smell

Change from baseline in bi-weekly mean loss 
of smell evaluated as part of the NPSD at 
Week 52. 

Nasal polyp-quality of life compared with placebo

Change from baseline in SNOT-22 scores at 
Week 52.

NP surgery and/or receiving SCS for NP

Time to surgery decision and/or SCS for NP 
up to Week 52.  

Time to NP surgery decision up to Week 52.

Time to SCS for NP up to Week 52.

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
Sinus opacification

Change from baseline in Lund-Mackay score 
(LMK) evaluated by CT at Week 52.

NPSD total symptom score (TSS)

Change from baseline in bi-weekly mean 
NPSD TSS at Week 52.

Lung function in participants with co-morbid 
asthma and aspirin exacerbated respiratory disease 
(AERD)/nonsteroidal anti-inflammatory drug 
exacerbated respiratory disease (NSAID-ERD)

Change from baseline in pre-BD FEV1 at 
Week 52.
Other Secondary Objectives:
Endpoint/variables:
To evaluate the effect of tezepelumab on:

NPS

Change from baseline over time in NPS 
evaluated by nasal endoscopy through 
Week 52.

Proportion of participants with (i) ≥1-point 
reduction and (ii) ≥2 points reduction in NPS 
at Week 52.

Participant reported NC

Change from baseline over time in bi-weekly 
mean NCS evaluated by NPSD through 
Week 52.

Loss of smell

Change from baseline in loss of smell 
evaluated by UPSIT test at Week 52.

Sinus opacification

Change from baseline in modified LMK 
score evaluated by CT at Week 52.

Sinus severity score by Quantitative CT 
assessment at Week 52.

Systemic corticosteroid use

Exposure of SCS over 52 Weeks.  

NPSD

Change from baseline by domain of NPSD 
through Week 52.

Nasal peak inspiratory flow (NPIF)

Change from baseline in NPIF through 
Week 52. 

Asthma control in participants with co-morbid 
asthma and AERD/NSAID-ERD

Change from baseline in ACQ-6 at Week 52.

To evaluate the PK and immunogenicity of 
tezepelumab

PK: Serum Concentration.

Immunogenicity: Anti-drug antibody (ADA).
Safety Objectives:
Endpoint/variables:
To evaluate the safety and tolerability of tezepelumab 

Adverse events (AEs)/serious adverse events 
(SAEs)

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
Clinical chemistry/hematology/urinalysis

Vital signs

Electrocardiograms (ECG)
Exploratory
To explore the off-treatment effect and the recurrence 
rate of nasal polyps after discontinuation of treatment 
with tezepelumab

Change from baseline in NPS

Change from baseline in bi-weekly mean 
NCS

Participants requiring surgery and SCS for 
NP
To explore the effect of tezepelumab on exploratory 
biomarkers of inflammation and nasal polyposis disease 
and investigate biomarkers for predicting response to 
tezepelumab
Exploratory biomarker parameters:

Serum and plasma for protein biomarkers

Whole blood for transcriptomic profiling

Nasal epithelial lining fluid for protein 
biomarkers 

Nasal polyp biopsies for inflammatory cells 
by histology and immunohistochemistry, and 
transcriptomic profiling.
To explore tezepelumab PK in nasal epithelial lining 
fluid

Exploratory PK concentrations in nasal 
epithelial lining fluid.
Optional exploratory genomics sample

A blood sample for DNA isolation will be 
collected from participants who have 
consented to participate in the genetic 
analysis component of the study.
To evaluate the effect of tezepelumab on unplanned 
health care resource utilisation 

Hospitalisations, emergency room, unplanned 
out participant visits, and urgent care visits.
To evaluate the participant reported quality of life 
outcomes

SF-36 v2 Health Survey 

EQ-5D-5L 

WPAI
Patient perception of overall symptom severity and 
change

Patient Global Impression of Severity 
(PGI-S)

Patient Global Impression of Change (PGI-C)
To evaluate airway inflammation in participants with 
co-morbid asthma/AERD/NSAID-ERD

Change from baseline in fractional exhaled 
nitric oxide (FeNO).
Resolution/near complete resolution of nasal polyps 
(defined as maximum NPS of 1 in each nostril)

Proportion of participants who achieve a 
maximum NPS of 1 in each nostril at 
Week 52.

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Resolution/near complete resolution of nasal polyps 
(defined as maximum NPS of 1 in each nostril) and 
NPSD TSS response. 

Proportion of participants who achieve a 
maximum NPS of 1 in each nostril and NPSD 
TSS response at Week 52.
4
STUDY DESIGN
4.1
Overall Design
For an overview of the study design see Section 1.2, Figure 1. For details on treatment given 
during the study, see Section 6.1.1.
For details on what is included in the efficacy and safety endpoints, see Section 3. 
This is a Phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group, 
study to evaluate the efficacy and safety of repeat dosing of tezepelumab 210 mg SC versus 
placebo in participants with severe CRSwNP. 
Approximately 400 participants will be randomised globally 1:1 to receive tezepelumab 
210 mg or matching placebo. 
Participants will be stratified by region, prior nasal polyp surgery and co-morbid asthma/
aspirin-exacerbated respiratory disease (AERD)/nonsteroidal anti-inflammatory drug 
exacerbated respiratory disease (NSAID-ERD). Randomisation will be monitored to ensure 
that 50%-70% of the study population will have co-morbid asthma/AERD/NSAID-ERD, and 
at least 50% will have had prior surgery for CRSwNP. When the target percentage of 
participants in a stratum in a region is reached, consideration will be given to closing the 
IWRS randomisation for that subgroup, which may be done either overall or within a specific 
region. Once a subgroup is closed, participants in the screening/run-in period in the closed 
subgroup will not be allowed to be randomised and will be screen failed. 
After enrolment, eligible participants will enter a screening/run-in period and will have their 
current INCS therapy standardised to Mometasone furoate (MFNS) or equivalent INCS at 
Visit 1 and throughout the screening and study period. Two doses of MFNS (50µg/actuation) 
in each nostril twice daily (total 400µg daily) or equivalent INCS will be administered unless 
there is a medical rationale to use the lower dose (QD) regimen. Equivalent dose should refer 
to the highest approved country INCS dose for CRSwNP. 
In countries that receive standardised MFNS centrally, each participant will receive enough 
background medication to cover the need until the next on-site visit. For equivalent INCS, this 
may be provided per local guidelines or pharmacy card provided by sponsor. Intranasal 
corticosteroids dispensation will be performed according to the SoA (Table 1).
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should be checked by investigators during the study period. If a participant cannot tolerate 
MFNS or equivalent INCS during screening period, the participant should be screen failed. 
The Principal Investigator should ask participants about SCS (oral and/or, parenteral) use for 
NP at each visit and record in the eCRF. Participants who require SCS and/or hospitalisation 
for an asthma exacerbation (see Section 8.2.5.2) or nasal polyp exacerbation during the 
screening period, should be screen failed and may rescreen once their symptoms improve (see 
Section 5.4.1).
Participants who experience an asthma exacerbation or worsening of nasal polyposis 
symptoms during the screening/run-in period (before Visit 2), may extend their screening 
period to accommodate the time needed for a short course (5-7 days) of systemic 
corticosteroids (SCS) treatment and return to Visit 2 no sooner than 4 weeks after the last dose 
of oral corticosteroids. If asthma exacerbation or worsening of nasal polyposis symptoms that 
require SCS or hospitalisation occurred between Visit 2 and Visit 3 (randomisation), 
participants should be screened failed and may be rescreened once their conditions are 
stabilised.
Participants will be provided with an electronic patient reported outcome (ePRO) device to 
record symptoms throughout the study (see Section 8.1.2).  Participants who continue to meet 
eligibility criteria will be randomised 1:1 at Visit 3 (Day 0) to receive either placebo or 
tezepelumab 210 mg SC at randomisation (Week 0) and every 4 weeks thereafter (Weeks 4, 8, 
12, 16, 20, 24, 28, 32, 36, 40, 44, 48).  A total of 13 doses will be administered.  An EOT Visit 
will be conducted at Week 52. 
The first approximate 200 randomised participants will have a 24-week follow-up (FU) period 
without IP administration to assess durability of benefit.  These participants will have the final 
safety assessment at Week 76.  The remaining participants will be followed for 12 weeks after 
the end of treatment visit, with the final safety assessments at Week 64.
If for any reason a participant in the first set of randomised participants, as described above, is 
not willing to participate for a full 24-week FU period and would like to terminate 
participation in the study, the follow-up discontinuation (FUD) visit should be performed.  
The FUD visit should occur at V19 (Week 64).
At Week 0, the Health Care Professional (HCP) will administer the study drug. Optional home 
IP administration by HCP can take place only at Week 16, Week 20, Week 28, Week 32, 
Week 40, Week 44, and Week 48. The rest of the IP administration visits must occur at the 
study centre.
Participants will be evaluated for efficacy, safety, pharmacokinetics (PK), ADA, and sample 
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throughout the study.  If at any point a participant meets IP discontinuation (IPD) criteria, an 
early IPD Visit will be performed (see Section 7.1).
At selected clinical sites, the participants may consent optionally to the nasal biopsy sub-study 
for up to approximately 60 participants. The target number will also be monitored closely 
throughout the study. A baseline nasal biopsy will be obtained prior to randomisation, at V2.  
The nasal biopsy at V2 must be performed prior to nasal endoscopy.  Another biopsy of nasal 
polyp tissue will be obtained at EOT visit at V17 (Week 52) (see Section 8.6).  The EOT nasal 
biopsy must be obtained after nasal endoscopy has been performed. Additionally, as part of 
the sub-study, nasal lining fluid will be collected at Visit 2 and a blood sample to assess Staph 
A enterotoxin-specific IgE status will be collected at Visit 3 and EOT/IPD.
CT scans will be performed for all participants. A baseline CT scan will be done between V2 
and V3 (after ensuring the participant has met inclusion/exclusion criteria, including NPS 
score by central reader) and a post-baseline CT scan at EOT/IPD (V17/Week 52). CT scan is 
required before first NP surgery and/or initiation of first course of SCS treatment for NP (see 
Section 8.1.3). 
An independent adjudication committee will be constituted to provide an external independent 
assessment of blinded data during the study to confirm the diagnosis of major adverse cardiac 
events (MACE) (to be defined in the charter) and investigator-reported malignancies that 
occur from randomisation until the end of the follow-up period; please refer to Section 8.3.9.
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis
The guidance given should be implemented only during cases of civil crisis, natural disaster, 
or public health crisis (eg, during quarantines and resulting site closures, regional travel 
restrictions, and considerations if site personnel or study participants become infected with 
SARS-CoV-2 or similar pandemic infection) which would prevent the conduct of study related 
activities at study sites, thereby compromising the study site staff or the participant’s ability to 
conduct the study. The investigator or designee should contact the study Sponsor to discuss 
whether the mitigation plans below should be implemented. 
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with Good Clinical Practice (GCP), and minimise risks to study integrity. 
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options:

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
Obtaining consent/reconsent for the mitigation procedures (note, in the case of verbal 
consent/reconsent, the Informed Consent Form (ICF) should be signed at the participant’s
next contact with the study site).

Additional re-screening for screen failure and to confirm eligibility to participate in the
clinical study can be performed in previously screened participants. The screening period 
may also be extended. Both re-screening and screening extension options should be 
discussed with the designated AstraZeneca study physician. Before randomisation, the 
Principal Investigator must ensure that all eligibility criteria are fulfilled. The investigator 
should confirm with the designated AstraZeneca study physician which option can be 
used.

Home or Remote visit: Performed by a qualified Health Care Professional (HCP).

Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices. 

At home Investigational Product (IP) administration: Performed by a qualified HCP. 
Additional information related to the visit can be obtained via telemedicine. 
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix H.
4.2
Scientific Rationale for Study Design
This is a global study designed to investigate the safety and efficacy of fixed dose 
tezepelumab (210 mg) administered SC starting at randomisation and then every 4 weeks 
(Q4W) for a total of 13 doses, on top of standardised INCS, in participants with severe 
bilateral NP who remain symptomatic despite standard of care therapy. To avoid bias the study 
will be randomised and double blinded. The population is composed of participants with 
ongoing chronic symptoms for at least 8 weeks prior to enrolment with moderate to severe 
participant reported nasal congestion, and a physician endoscopic diagnosis of bilateral NP 
(NPS of at least 5 out of a maximum of 8), despite documented treatment with SCS within the 
past 2 years and/or history of any NP surgical intervention. The disease severity at enrolment 
and history of failure with standard pharmacological treatment constitute an accepted 
indication for surgery or for a targeted biologic therapy such as tezepelumab, for participants 
who are not willing to or are contraindicated to have surgery. 
CRSwNP is a heterogeneous disease (Hull and Chandra 2017). The eosinophilic (Type 2 high) 
endotype is most common in the United States, Europe, and Japan whilst non-eosinophilic 
endotype is more frequent in other Asian countries (Lou H et al 2018, Hull and Chandra 2017, 
Fokkens et al 2020, Shin SH et al 2014, Chitsuthipakorn W et al 2018). To ensure that 
endotypes are represented appropriately in all countries in this study capping will be used in 
China to ensure that approximately 80% of participants have an eosinophilic endotype 

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(defined by JESREC score of ≥11) (Tokunaga T et al 2015) to match the distribution 
predicted in the rest of the world.
The sample size (approximately 400 participants) is considered appropriate to demonstrate 
treatment effects with tezepelumab. The 52-week treatment duration is considered appropriate 
to capture maintenance effects in this chronic disease, assessment of endpoints of time to first 
SCS use and/or surgery (and the individual components), and proportion of participants with 
resolution/near complete resolution of nasal polyps as well as providing 1-year treatment 
safety data in the intended population. Approximately the first 200 randomised participants 
will have a 24-week follow-up period to evaluate durability of response and to provide off-
treatment safety data. 
Nasal polyp tissue will be obtained by biopsy in a subset of participants and in a limited 
number of sites globally. Histopathology of tissue inflammatory cells is commonly used 
globally as the most definitive method for defining participant endotype.  The aim of the nasal 
biopsy is to characterise the inflammatory patterns of participants entering the sub-study as 
well as to explore the effect of tezepelumab treatment on nasal polyp inflammatory cells.
4.3
Justification for Dose
A 210 mg Q4W dosing regimen was selected for this Phase 3 study based on the similarity of 
the pathophysiology of CRSwNP and asthma and the efficacy, safety and exposure-response 
analysis from the Phase 2b Study CD-RI-MEDI9929-1146 (D5180C00001) in asthma. 
Efficacy data from Study CD-RI-MEDI9929-1146 demonstrated that the 210 mg tezepelumab 
Q4W dose led to improved clinical efficacy compared to 70 mg Q4W, whereas the 280 mg 
Q2W dose did not further increase efficacy compared to 210 mg Q4W, and the safety profiles 
were similar across the 3 doses. Exposure-response modelling further confirmed the 210 mg 
Q4W dose is at the plateau of the exposure-response curves for the effect of tezepelumab on 
asthma exacerbation rate and FeNO. Given these results, the dose of 210 mg SC Q4W was 
confirmed in the tezepelumab Phase 3 programme for patients with severe asthma.
Given the similarity of the underlying inflammatory pathophysiology of asthma and nasal 
polyps and significant overlap in patient populations (Fokkens et al 2020), it is expected that 
the same dose of 210 mg Q4W SC would effectively target the inflammatory pathways 
relevant to both diseases and show efficacy in CRSwNP.  This is supported by the post-hoc 
analysis of data from study CD-RI-MEDI9929-1146 in asthma patients with co-morbid nasal 
polyps (N= 18 in the placebo group and N= 23 in the 210 mg Q4W tezepelumab group). In 
these patients, treatment with tezepelumab resulted in marked reductions in blood eosinophil, 
IL-5, and IL-13 levels, all of which play a role in the pathogenesis of CRSwNP. Furthermore,
there was similar efficacy with respect to asthma outcomes in patients with and without a 
history of nasal polyps, and to date there has been no change in the benefit/risk profile based 
on the completed studies. Based on the above rationale, the same tezepelumab dose as used in 

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the asthma Phase 3 studies, 210 mg Q4W SC is selected for this Phase 3 study in patients with 
CRSwNP.
4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last scheduled procedure shown in the Schedule of Activities (Table 1).
The end of the study is defined as the date of the last scheduled procedure shown in the 
Schedule of Activities for the last participant in the study globally.
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 participant should meet all the inclusion and none of the exclusion criteria for this study 
in order to be assigned/randomised to a study intervention.  Under no circumstances can there 
be exceptions to this rule.  Participants who do not meet the entry requirements are screen 
failures (see Section 5.4).
In this protocol, “enrolled’ participants are defined as those who sign informed consent. 
“Randomised” participants are defined as those who undergo randomisation and receive a 
randomisation number.
For procedures regarding withdrawal of incorrectly enrolled or randomised participants see 
Section 6.3.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1
Participant must be 18 years of age or older, at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2
Participants with physician-diagnosed CRSwNP for at least 12 months prior to Visit 1
that have:

Severity consistent with need for surgery as defined by total NPS ≥ 5 (at least 2 for 
each nostril) at screening, as determined by the central reader

Nasal Congestion Score (NCS) ≥ 2 at Visit 1

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
Ongoing documented NP symptoms for > 8 weeks prior to screening such as 
rhinorrhoea and/or reduction or loss of smell
3
SNOT-22 total score ≥ 30 at screening (Visit 1).
4
Any standard of care for treatment of CRSwNP provided the participant is stable on that 
treatment for at least 30 days prior to Visit 1.
5
Documented treatment of nasal polyp exacerbation with SCS for at least 3 consecutive 
days or one IM depo-injectable dose (or contraindications/intolerance to) within the past 
12 months prior to Visit 1 but not within the last 3 months prior to Visit 1 and/or any 
history of NP surgery (or contraindications/intolerance to).
Weight
6
Body weight of ≥40 kg at Visit 1.
Sex
7
Male or female.
8
Female participants: Women not of childbearing potential are defined as women who are 
either permanently sterilised (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 randomisation 
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 levels in the postmenopausal range.
(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.
9
Female participants of childbearing potential must use one highly effective form of birth 
control. A highly effective method of contraception is defined as one that can achieve a 
failure rate of less than 1% per year when used consistently and correctly. Females of 
childbearing potential who are sexually active with a non-sterilised male partner must 
agree to use one highly effective method of birth control as defined below, from screening 
throughout the study and until at least 16 weeks after the final dose of IP. Contraceptive 
use by women should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. Cessation of contraception after 
this point should be discussed with a responsible physician. Periodic abstinence (calendar, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhoea method are not acceptable methods of contraception. 
Female condom and male condom should not be used together. All women of 
childbearing potential must have a negative serum pregnancy test results at Visit 1 and a 
negative urine pregnancy test at randomisation. 

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
Highly effective birth control methods include: true sexual abstinence, a 
vasectomised sexual partner, Implanon™, bilateral tubal occlusion, intrauterine 
device/levonorgestrel intrauterine system (IUD/IUS), Depo-Provera™ injections, oral 
contraceptive, and Evra Patch ™, Xulane™, or NuvaRing™. Women of childbearing 
potential must agree to use one highly effective method of birth control, as defined 
above, from screening throughout the study and until at least 16 weeks after the final 
dose of IP.
Informed Consent
10 Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol.
11 Provision of signed and dated, written informed consent form (ICF) prior to any 
mandatory study specific procedures, sampling, and analyses and according to 
international guidelines and/or applicable EU guidelines.
12 Provision of signed and dated written optional Genetic Research Information informed 
consent prior to collection of samples for optional genetic research that supports Genomic 
Initiative (if applicable).
13 Provision of signed and dated written addendum to optional informed consent form for 
nasal biopsy sub-study prior to collection of nasal biopsy samples (if applicable).  
Participant must meet the following criteria at the randomisation visit (Visit 3):
14 Confirmed central reading total NPS ≥ 5 (at least 2 for each nostril) at Visit 2.
15 Inclusion Criterion 15 replaced with Criterion 15a in a prior version of the Clinical Study 
Protocol
15a) At randomisation visit (Visit 3), a bi-weekly mean NCS≥ 2 (baseline bi-weekly score 
collected from study Day -13 to study Day 0).
16 SNOT-22 score ≥ 30 at randomisation (Visit 3).
17 At least 8 days of evaluable daily diary data in the 14-day period prior to randomisation 
(baseline bi-weekly mean score collected from study Day – 13 to study Day 0).
18 Minimum compliance with the daily eDiary during the screening and run-in periods 
(having a minimum of 70% fully compliant days from Visit 1 to the day of randomisation 
at Visit 3).
19 Minimum compliance with background INCS as captured in the eDiary during the 
screening and run-in periods (having a minimum of 70% fully compliant days from 
Visit 1 to the day of randomisation at Visit 3).

Days of missing eDiary data treated as non-compliant for this criterion.

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5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Any clinically important comorbidities other than asthma (eg, active lung infection, 
bronchiectasis, pulmonary fibrosis, cystic fibrosis, primary ciliary dyskinesia, allergic 
bronchopulmonary mycosis, hypereosinophilic syndromes, etc) that could confound 
interpretation of clinical efficacy results.
2
Exclusion criterion number 2 was removed and merged with Exclusion number 5.
3
Any disorder, including but not limited to cardiovascular, gastrointestinal, hepatic, renal, 
neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, 
psychiatric, or major physical impairment that is not stable in the opinion of the 
Investigator or AstraZeneca and could:
(a) Affect the safety of the participant throughout the study;
(b) Influence the findings of the studies or their interpretations;
(c) Impede the participant’s ability to complete the entire duration of study.
4
Sinus surgery within 6 months of screening visit OR any sinus surgery in the past which 
changed the lateral wall of the nose making NPS evaluation impossible.
5
Participants with conditions or concomitant disease that makes them non-evaluable for 
the primary efficacy endpoint such as: 

antrochoanal polyps; 

nasal septal deviation that occludes at least one nostril;

acute sinusitis, nasal infection, asthma exacerbation or upper respiratory infection at 
screening or in the 2 weeks before screening; or Churg-Strauss syndrome (also 
known as known as Eosinophilic granulomatosis with polyangiitis (EGPA)), Young’s 
syndrome or Kartagener’s syndrome.
6
A history of known immunodeficiency disorder, including a positive human 
immunodeficiency virus (HIV) test at Visit 1, or the participant taking antiretroviral 
medications as determined by medical history and/or participants verbal report.
7
Positive hepatitis B surface antigen, or hepatitis C virus antibody serology at screening, or 
a positive medical history for hepatitis B or C. Participants with a history of hepatitis B 
vaccination without a history of hepatitis B and participants with hepatitis C who have 
been cured are allowed to participate.   
8
Known history of chronic drug or alcohol abuse within 12 months prior to Visit 1, based 
on Investigator’s assessment.
9
Primary Ciliary Dyskinesia (PCD).
10 Uncontrolled epistaxis within 2 months of Visit 1.

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11 Known or suspected history of immunosuppression, immune dysfunction or immune 
dysregulation which may include but is not limited to conditions such as: Guillain-Barré 
syndrome, invasive opportunistic infections (eg, histoplasmosis, listeriosis, 
coccidioidomycosis, pneumocystosis, aspergillosis), or unusually frequent, recurrent, or 
prolonged infections, per Investigator judgement. 
12 History of cancer:
(a) Participants who have had basal cell carcinoma or localised squamous cell carcinoma 
of the skin or in situ carcinoma of the cervix are eligible to participate in the study 
provided that the participant is in remission and curative therapy was completed at 
least 12 months prior to Visit 1.
(b) Participants who have had other malignancies are eligible provided that curative 
therapy was completed at least 5 years prior to Visit 1.
13 A helminth parasitic infection diagnosed within 24 weeks prior to the date of informed 
consent that has not been treated with or has failed to respond to standard of care therapy.
14 Tuberculosis requiring treatment within the 12 months prior to Visit 1.
15 Major surgery within 8 weeks prior to Visit 1 or planned nasal polyp surgery during the 
conduct of the study.
16 Infection requiring systemic antibiotics within 14 days prior to Visit 1.
17 Positive SARS-CoV-2 nasopharyngeal swab test (or COVID-19 rapid test) or COVID-19 
entry screening questionnaire during the screening visit.

Evaluation will be based on local standard of care as determined by current local 
guidelines.
Prior/Concomitant Therapy
18 Receipt of any marketed or investigational biologic (monoclonal or polyclonal antibody) 
within 4 months or 5 half-lives prior to the date informed consent is obtained, whichever 
is longer, and during the study period.  This also applies to participants who previously 
participated in clinical studies and were treated with monoclonal antibodies (eg, 
mepolizumab, reslizumab, dupilumab, benralizumab, omalizumab). Note that this 
restriction does not apply to participants, who are confirmed to have only received 
treatment with placebo.
19 Initiation of new allergen immunotherapy is not allowed unless participant is already on 
stable therapy started 30 days prior to Visit 1 with no change during the treatment period.  
20 Regular use of decongestants (topical or systemic) at enrolment is not allowed unless used 
for endoscopic procedure.
21 Use of immunosuppressive medication (including but not limited to methotrexate, 
troleandomycin, cyclosporine, azathioprine, mycophenolate, tacrolimus, gold, 
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experimental anti-inflammatory therapy) within 3 months prior to Visit 1 and during the 
study period.

Systemic corticosteroid use is defined as treatment with a burst of systemic 
corticosteroids for at least 3 consecutive days or a single IM depo-injectable dose of 
corticosteroids (considered equivalent to a 3-day burst of systemic corticosteroids)
22 Use of corticosteroid-eluting intranasal stents within 6 months prior to Visit 1 and during 
the study period.  
23 Receipt of immunoglobulin or blood products within 30 days prior to Visit 1.
24 Receipt of any non-biologic investigational drug within 30 days or 5 half-lives whichever 
is longer prior to the date of informed consent.
25 Known history of allergy or reaction to any component of the IP formulation.
26 History of anaphylaxis or documented immune complex disease (Type III 
hypersensitivity reactions) following any biologic therapy. 
27 Recent Aspirin desensitisation within 6 months of enrolment.
28 Receipt of live attenuated vaccines 30 days prior to the date of randomisation.  

Receipt of inactive/killed vaccinations (eg, inactive influenza) is allowed provided 
they are not administered within 5 days before/after any tezepelumab administration.
Diagnostic Assessments
29 Any clinically significant abnormal findings in physical examination, vital signs, 
haematology, clinical chemistry, or urinalysis during screening/run-in period, which in 
the opinion of the Investigator, may put the participant at risk because of his/her 
participation in the study, or may influence the results of the study, or the participant’s
ability to complete entire duration of the study.
30 Any clinically significant cardiac disease or any electrocardiogram (ECG) abnormality 
obtained during the screening/run-in period, which in the opinion of the investigator, may 
put the participant at risk or interfere with study assessments.
31 Evidence of active liver disease, including jaundice or aspartate transaminase (AST), 
alanine transaminase (ALT), or alkaline phosphatase (ALP) > 2 times the upper limit of 
normal (ULN) at Visit 1.  
Other Exclusions
32 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
33 Judgement by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements.
34 Previous randomisation in the present study.
35 For women only - currently pregnant (confirmed with positive pregnancy test), 
breastfeeding or lactating women.

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
A serum pregnancy test will be done for women of childbearing potential at 
screening Visit 1 and a urine pregnancy test must be performed for women of 
childbearing potential at each treatment visit prior to IP administration.  A positive 
urine test result must be confirmed with a serum pregnancy test.  If serum test is 
positive, the participant should be excluded.
36 Chronic alcohol or drug abuse within 12 months prior to Visit 1 and throughout the 
conduct of the study. 

For participants with co-morbid asthma: Current smokers or participants with 
smoking history ≥ 10 pack-years at Visit 1 will not be allowed to randomise in the 
study. Former smokers with a smoking history of < 10 pack-years must have stopped 
for at least 6 months to be eligible. Smoking is not allowed throughout the course of 
the study; this includes e-cigarettes.
37 Receipt of COVID-19 vaccine (regardless of vaccine delivery platform) 28 days prior to 
date of IP administration at V3 (randomisation visit).
5.3
Lifestyle Considerations
Participants must abstain from donating blood and plasma from the time of informed consent 
for 16 weeks after last dose of tezepelumab.
Fertile and sexually active female participants or their partners should use highly effective 
contraceptive methods throughout the study and 16 weeks after last dose of the IP. 
5.3.1
Meals and Dietary Restrictions
Participants with co-morbid asthma should avoid eating a large meal for at least 2 hours prior 
to all lung function assessments at the centre.
Participants 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.
For participants with co-morbid asthma: current smokers or participants with smoking history 
≥10 pack-years at Visit 1 are not allowed.  Former smokers with a smoking history of < 10 
pack-years must have stopped for at least 6 months to be eligible. Smoking is not allowed 
throughout the course of the study.
The use of e-cigarettes is also not allowed during the course of the study.

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5.3.3
Activity
Participants will abstain from strenuous exercise for at least 30 minutes before each blood 
collection for clinical laboratory tests. 
Participants should avoid engaging in strenuous exertion for at least 30 minutes prior to all 
lung function assessments at the centre.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned to study intervention. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities (RA). Minimal information includes 
demography, screen failure details, eligibility criteria, and any serious adverse event (SAE).
These participants should have a reason for study withdrawal recorded in the electronic case 
report form (eCRF) as ‘Screen Fail’ (ie, Participant does not meet the required 
inclusion/exclusion criteria). This reason for study withdrawal is only valid for screen failures, 
and not randomised participants.
5.4.1
Re-screening
Re-screening is allowed only once under the following circumstances:
Participants with respiratory infections requiring antibiotics or antiviral medication within 14 
days prior to Visit 1 or during the screening/run-in period may be rescreened (exclusion 
criterion 16) 14 days after recovery, ie, completion of the therapy.
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), 
participants may potentially be rescreened. These cases should be discussed with the 
AstraZeneca study physician and documented in the Investigator Study File (ISF). 
Participants who are positive for the SARS-CoV-2 nasopharyngeal swab test (or COVID-19 
rapid test) or COVID-19 entry screening questionnaire and temperature screen during the 
screening visit and are screened failed may be re-evaluated after approximately 4 weeks for 
potential re-screening upon discussion with AstraZeneca global physician.
Participants who experience an asthma exacerbation or exacerbation of nasal polyposis during 
the screening/run-in period (before Visit 2), may extend their screening period to 
accommodate the time needed for a short course (5-7 days) of systemic corticosteroids (SCS) 
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corticosteroids.  If asthma or nasal polyp exacerbation requires SCS or hospitalisation 
occurred between Visit 2 and Visit 3 (randomisation), participants should be screened failed 
and may be rescreened once their conditions are stabilised. 
Rescreened participants should be assigned the same participant number as for the initial 
screening. It means that participant should keep the same E-code as was originally assigned. 
Rescreened participants should re-sign informed consent. All procedures from the 
screening/run-in period should be repeated except the sinus CT, if this was already performed 
in the first screening/run-in period, unless express permission for a repeat screening CT has 
been given by the study physician. Re-screening should be documented so that its effect on 
study results, if any, can be assessed.
IMPORTANT! Participants may not be rescreened or have an extended screening period for 
failure to meet minimum symptom severity, NPS, or SinoNasal Outcome Test (SNOT-22) 
requirements.
Re-screening of a participant for any other 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).
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.  Such treatment in this study refers to tezepelumab 210 mg or matching 
placebo.
6.1
Study Intervention(s) Administered
6.1.1
Investigational Products
All IPs will be manufactured in accordance with Good Manufacturing Practices (GMP).
Table 4
Investigational Products
ARM Name
Treatment 1
Treatment 2
Intervention Name
Tezepelumab
Placebo
Type 
Biologic, combination product
Placebo, combination product
Dose Formulation
110 mg/mL in 10 mM acetate, 3.0% 
(w/v) L-proline, 0.01 % (w/v) 
polysorbate 80, pH 5.2
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

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Table 4
Investigational Products
Unit Dose 
Strength(s)
210 mg 
N/A 
Dosage Level(s)
210 mg Q4W
Placebo Q4W
Route of 
Administration
Subcutaneous injection
Subcutaneous injection 
Use
Experimental
Placebo
IMP and NIMP
IMP 
IMP 
Sourcing
Provided centrally by the Sponsor
Provided centrally by the Sponsor
Packaging and 
Labelling
Study treatment will be provided in an 
APFS with 1.91 mL fill volume. 
Each syringe will be labelled in 
accordance with GMP Annex 13 and per 
country regulatory requirement. The 
labels will be translated into the local 
language where applicable.
Study treatment will be provided in an 
APFS with 1.91 mL fill volume. 
Each syringe will be labelled in accordance 
with GMP Annex 13 and per country 
regulatory requirement. The labels will be 
translated into the local language where 
applicable.
Current/Former 
Name(s) or 
Alias(es)
Formerly MEDI9929 and AMG 157
N/A
APFS, Accessorised pre-filled syringe; Q4W, every 4 weeks; GMP, Good Manufacturing Practice; IMP,
Investigational Medicinal Product; NIMP, Non-Investigational Medicinal Product; w/v, weight per volume.
The accessorised 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; 2.25 mL long pre-filled 
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 Including Combination Products with a Device 
Constituent 
The sponsor’s manufactured medical device/combination product, which includes a device 
constituent, is:

Accessorised pre-filled syringe (Status, Investigational) 
Instructions for medical device use are provided in IP Handling Instructions and Pharmacy 
Manual
All medical device deficiencies and device constituent deficiencies (including malfunction, 

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use error and inadequate labelling), hereafter referred to as medical device deficiencies, shall 
be documented and reported by the Investigator throughout the study (see Section 8.3.14.4
and appropriately managed by the manufacturer.
6.2
Preparation/Handling/Storage/Accountability of Interventions
6.2.1
Preparation and handling 
IP will be supplied to the site in a kit containing APFS tezepelumab or matching placebo. The 
kit has a unique number that is printed on all labels within the kit (ie, the outer carton label 
and the label of the 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).
In the following cases the centre staff should not use the affected IP and should immediately 
contact an AstraZeneca representative for further guidance:

Temperature excursion upon receipt or during storage at the study centre

Storage conditions were not met (eg, 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).
6.2.2
Dose Preparation 
Prior to each IP administration at clinic site and at home setting:

Investigator/authorised delegate will assess injection site as per standards of medical care.

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
For WOCBP, urine pregnancy test will be done; IP will be administered only when the 
result of the test is negative (see Section 8.2.4.3).
The APFS should be visually inspected prior to dose preparation. The IP will be provided to 
the study sites as a clear to slightly opalescent, colourless to light yellow liquid, practically 
free from particles 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 the IP must be performed by a qualified person (eg, pharmacist, 
Investigator, or nurse) at the site.
The IP does not contain preservatives and any unused portion must be discarded. 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 participant’s dose, an IP kit will be selected for administration according to the 
kit identification number assigned by IWRS.
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 in the original carton 
protected from light during the warming process.
2
To prepare the 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 to slightly 
opalescent, colourless to light yellow liquid, practically free from particles. Do not inject 
the IP if the liquid is cloudy, discoloured, 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 APFS must be discarded 
immediately after dose preparation as per the site’s Standard Operating Procedures (SOP), the 
kit boxes must be retained for IP accountability.
6.2.3
Dose Administration
The administration of all study drugs (including IPs) should be recorded in the appropriate 

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sections of the Case Report Form (CRF). The IP will be administered at the study centre. 
Optional at home IP administration by HCP can take place only at Week 16, Week 20, 
Week 28, Week 32, Week 40, Week 44, and Week 48. The rest of the IP administration visits 
must occur at the study centre. 
The IP will be administered by the Investigator/authorised delegate as specified in Table 1. If 
participant does not want to consent for optional home IP administration, participant can 
continue to receive the IP at the study centre.
Each participant will receive tezepelumab 210 mg (one 1.91 mL injection) or matching 
placebo administered SC Q4W for 13 doses in the abdomen, thigh, or upper arm by APFS. 
At Week 0, the Health Care Professional (HCP) will administer the study drug. 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. Starting from Week 16,
tezepelumab can be administered by the HCP at home if the participant agrees to this option 
on the ICF. The HCP administering the dose will also fill out the source documentation to 
capture that the dose was successfully administered. Both the completed source 
documentation and the used device are to be returned to the site once the visit is completed for 
IP accountability.
It is suggested that the site of injection of the IP be rotated such that the participant receives IP 
at a different anatomical site each time. Suggested injection site rotation sequence is presented 
below (see Figure 2). In the case when rotation of the injection site is not favourable for the 
participant and/or Investigator, the reason should be recorded in the source documents. The 
injection site must be recorded in the source documents and the eCRF at each treatment visit.
When the injection is performed by the health care professional (HCP), the injection can be 
made in the abdomen, thigh or upper arm. It is recommended that the same person should 
administer the IP throughout the study.

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Figure 2
Suggested Scheme of Rotation of Injection Sites
Further details on IP administration are provided in the IP handling instructions. 
Investigational product administration must be carried out in line with the instructions 
provided. 
At Visits 3 and 5 (Weeks 0 and 4), participants should be observed by the HCP for a minimum 
of 2 hours after IP administration for the appearance of any acute drug reactions. For the 
remaining visits involving IP administration, participants will be observed by the HCP (or 
adult if injection was done at home) for a minimum of 1 hour after IP administration for the 
appearance of any such reaction. 
If any of the following occur, the Investigator should reschedule the visit and the IP should not 
be administered until the rescheduled visit:

The participant received allergen immunotherapy injection on the same day as scheduled 
IP administration.

The participant has an intercurrent illness that, in the opinion of the Investigator, may 
compromise the safety of the participant in the study (eg, viral illnesses).

The participant is febrile (≥ 38°C; ≥ 100.4°F) within 72 hours prior to IP administration.

The participant is confirmed to have an active COVID-19 infection based on positive 
SARS-CoV-2 test results.

The participant is suspected to have an active COVID-19 infection based on assessment 
of COVID-19 symptoms.

The participant is planning to receive COVID-19 vaccination during the screening or 
treatment period. Please refer to section 6.4.2.
The visit should be rescheduled within the allowed visit window and IP should be 

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administered at that visit. If this is not possible the IP administration should be skipped. 
If the participant 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 deferred) and participant should be re-assessed for symptoms of COVID-19 
prior to rescheduled visit. 
The AstraZeneca study physician should be contacted to discuss further participation in the 
following situations:

The participant has been diagnosed with an active COVID-19 infection.

The participant skips 2 consecutive IP administrations.
If the participant reports an injection site reaction, the Investigator or qualified designee will 
complete the AE eCRF page and an additional eCRF questions about the injection site 
reaction.
6.2.4
Reporting Product Complaints
Any defects with the IP must be reported immediately to the AstraZeneca representative (s), as 
per the Pharmacy Manual. The Site Monitor must also be notified. All defects will be 
communicated to the Sponsor and investigated further with AstraZeneca 
During the investigation of the product complaint, all IP must be stored at labelled conditions 
2°C to 8°C (36°F to 46°F), separated from other IP kits, unless otherwise instructed.
6.2.5
Reporting Product Defects
Product defects may be related to component, product, or packaging and labelling issues prior 
to or during use. Product defects should be reported to the AstraZeneca representative(s) as 
per the Pharmacy Manual. The Study Monitor must also be notified. The list below includes 
the 3 categories of product complaints that should be reported as defects. Descriptions of 
product complaints in these 3 categories include, but are not limited to:

Component Issue: Defect in container or dosing mechanism of the IP. The component 
defect may be damaged, missing, or broken. For the APFS, component examples include 
syringes and the accessory housing the syringe.

Product Issue: Defect in the product itself. The product appearance has visual 
imperfections such as foreign particles, crystallisation, discolouration, turbidity, 
insufficient volume, or anything that does not apply to the product description in the IP 
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
Packaging/Labelling Issue: Defect in the packaging or labelling of the product. The 
packaging (eg, carton, thermo-fitted tray, or tamper-evident seal) or labelling defects may 
be damaged or unreadable, or the label may be missing.
6.2.6
Single Use APFS Device Malfunction
An APFS malfunction is when the APFS appeared normal during verification of shipment and 
then does not work during administration, eg, the safety feature activated prematurely, part of 
the device (finger flange, plunger rod, etc.) came off or broke, needle shield could not be 
removed only partial dose administered, needle guard safety feature did not activate, needle 
bent or broke upon use.
Device malfunctions should be reported using the appropriate form as per the Pharmacy 
Manual and the Study Monitor should be notified. Please see 8.3.14.
If a device malfunction is identified at the study centre:

Before IP administration has started, another IP kit (replacement) should be dispensed to 
perform IP administration.

After IP administration has started and participant has been administered unknown dose 
of IP, another IP kit must not be dispensed, and participant must not be administered with 
another IP kit. The AstraZeneca study physician and Study Monitor should be notified.
If it is determined that a replacement should be issued based on the same guidance for device 
malfunction at study centre described above, the HCP will return to the study site to obtain the 
replacement device. 
For definitions for recording, evaluating and follow-up of medical device AEs, SAEs, and 
deficiencies, please see Appendix I.
6.3
Measures to Minimise Bias: Randomisation and Blinding
The Investigator(s) will:
1
Obtain signed informed consent from the potential participant before any study specific 
procedures are performed. 
2
Assign the potential participant a unique enrolment number (which begins with an ‘E’) 
via IWRS. 
3
Determine participant eligibility. 
4
Assign the eligible participant a unique randomisation code via IWRS. 
5
Participants will be allocated to receive tezepelumab or placebo in a 1:1 ratio and 
according to the stratification factors listed in Section 4.1. Randomisation numbers will 

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be grouped in blocks. If a participant withdraws from the study, then his/her 
enrolment/randomisation code cannot be reused. Withdrawn participants 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 randomised participants
Participants who fail to meet the eligibility criteria should not, under any circumstances, be 
randomised or receive study medication. There can be no exceptions to this rule. Participants 
who are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomised or initiated on treatment and must be withdrawn from the study.
Where a participant does not meet all the eligibility criteria but is randomised 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 participant 
from treatment. Study treatment must be discontinued in all cases where continued treatment 
is deemed to pose a safety risk to the participant and AstraZeneca study physician must ensure 
the decision is appropriately documented. Participants 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
Randomisation codes will be assigned 
 in each stratum as participants 
become eligible for randomisation.
The randomisation code will be assigned from a randomisation list prepared by a 
computerised system provided by Calyx on behalf of AZ (AZRand). All participants will be 
stratified at randomisation by region, prior nasal polyp surgery and co-morbid 
asthma/AERD/NSAID-ERD).
Consideration will be given to closing the Interactive Web Response System (IWRS) 
randomisation for a subgroup to ensure that 50%-70% of the study population will have co-
morbid asthma/AERD/NSAID-ERD, and at least 50% will have had prior surgery for 
CRSwNP, which may be done either overall or within a specific region. Once a subgroup is 
closed, participants in the screening/run-in period in the closed subgroup will not be allowed 
to be randomised and will be screen failed.
PPD

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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 participant nor any of the 
investigators or sponsor staff who are involved in the treatment or clinical evaluation and 
monitoring of the participants will be aware of the treatment received. Since tezepelumab and 
placebo are not visually distinct, IP will be handled by a qualified person (eg, pharmacist or 
study nurse) at the site. 
An AstraZeneca site monitor will perform IP accountability. In the event that the treatment 
allocation for a participant becomes known to the Investigator or other study staff involved in 
the management of study participants or needs to be known to treat an individual participant 
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 randomisation list:

Those carrying out the packaging and labelling of IP

Those generating the randomisation list

Personnel at the IWRS company

Supply Chain Management department

Patient Safety department at AstraZeneca

Bioanalytical lab analyst performing the PK sample analysis
The information in the randomisation 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 randomisation scheme during the 
conduct of the study until after the primary database lock.
Methods for unblinding
Individual treatment codes, indicating the treatment assignment for each randomised 
participant, 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 participant requires knowledge of the treatment assignment. The 
Investigator should document and report the action to AstraZeneca, without revealing the 

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treatment given to the participant to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an 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 participant have been 
made and documented and until primary database lock occurs.
6.4
Concomitant Therapy
Any medication or vaccine included over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the participant is receiving at the time of enrolment or receives 
during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
List of the restricted and prohibited medications can be found in Table 5 and Table 6, provided 
below:
Table 5
Restricted Medications
Medication/class of drug:
Recommendation (including limits for duration permitted and 
special situations in which it is allowed):
Inactive/killed vaccinations (eg, 
inactive influenza)
Not allowed within the 5 days before or within 5 days after any IP 
dosing study visit.
COVID-19 vaccinations (eg, whole 
virus, protein subunit, nucleic acid, 
viral vector) 
If COVID-19 vaccination is in the best interest of the participant and 
the participant is vaccinated during the study, IP dosing can continue 
but the recommendation is that IP dosing should not occur within 14 
days before and 28 days after a dose of vaccine. As these intervals 
might change, please discuss with the study physician for the most 
current recommended time interval, prior to any vaccine dose. Refer
to section 6.4.2 for more details.
Any Immunosuppressive – topical
Topical administration of Immunosuppressive medication may be 
allowed at the discretion of the Investigator.  
Allergen Immunotherapy
Allowed if on stable therapy started 30 days prior to V1; no change 
during the treatment period.
Should not be administered on the same day as study intervention 
administration. 
Decongestants (topical or systemic)  
Only allowed for endoscopic procedure.

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Table 5
Restricted Medications
Medication/class of drug:
Recommendation (including limits for duration permitted and 
special situations in which it is allowed):
Systemic Corticosteroids as 
maintenance treatment
Not allowed 3 months prior to V1. During study conduct, SCS are 
allowed as a rescue to relieve NP worsening of symptoms, to treat 
asthma exacerbations or to treat other indications at PI’s discretion. 
However, it is recommended that participants abstain from using SCS 
for the first 3 months after randomisation, unless in case of an 
emergency or if it is deemed necessary by the PI.
Table 6
Prohibited Medications
Prohibited medication/class of drug:
Corticosteroid-eluting intranasal stents
Not allowed 6 months prior to V1 or during the study.
Intranasal Medication including intranasal 
corticosteroids drops
Only study provided MFNS or equivalent INCS is 
allowed.
Any immunosuppressive treatment including but 
not limited to: methotrexate, cyclosporine, 
mycophenolate, tacrolimus, gold, penicillamine, 
sulfasalazine, hydroxychloroquine, azathioprine, 
cyclophosphamide
Not allowed within 3 months prior to V1; during the 
study period and 3 months or 5 half-lives (whichever is 
longer) after last dose of the IP. 
Aspirin desensitisation
Use of aspirin as a desensitisation regimen for the 
management of aspirin exacerbated respiratory disease 
(AERD) is not allowed; all other uses of aspirin are 
allowed for any other medical conditions.
Any marketed or investigational biologic 
(monoclonal or polyclonal antibody) 
Not allowed within 4 months or 5 half-lives (whichever 
is longer) prior to V1; during screening/run-in and 
throughout the IP treatment, and 4 months or 5 half-lives 
(whichever is longer) after the last dose of IP.  
Other investigational product 
Not allowed within 30 days or 5 half-lives (whichever is 
longer) prior V1, during screening/run-in and throughout 
the IP treatment and preferably 4 weeks after the last 
dose of IP.
Live attenuated vaccines
Not allowed within 30 days prior to randomisation; 
during the study period, and 16 weeks or 5 half-lives 
(whichever is longer) after the last dose of the IP.
Blood products or immunoglobulin therapy
Not allowed 30 days prior to Visit 1, during 
screening/run-in and throughout the IP treatment and 
preferably 4 weeks after the last dose of IP.
Herbal remedies for the treatment of CRSwNP 
Not allowed 30 days prior to Visit 1, during 
screening/run-in and throughout the IP treatment and 
preferably 4 weeks after the last dose of IP.
The Medical Monitor should be contacted if there are any questions regarding concomitant or 

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prior therapy.
Participants must abstain from taking prescription or non-prescription drugs for nasal polyps 
(including vitamins and dietary or herbal supplements) within 7 days (or 14 days if the drug is 
a potential enzyme inducer) or 5 half-lives (whichever is longer) before the start of study 
intervention until completion of the follow-up visit, unless, in the opinion of the investigator 
and sponsor, the medication will not interfere with the study.
6.4.1
Background Medication
The aim of this study is to evaluate the treatment effect of tezepelumab on polyp reduction. 
Therefore, the background INCS medications should be maintained at a stable dose from 
Visit 1 and throughout the screening and study period and no other medications intended to 
prevent polyp recurrence should be used. All participants will use INCS for a minimum of 4 
weeks prior to V3 and continued throughout the study period. 
Standardised MFNS (50 µg/actuation) nasal spray is contained in a bottle that contains 120 
actuations for US and 140 actuations for all other countries. Two doses of MFNS 
(50µg/actuation) in each nostril twice daily (total 400µg daily) or equivalent INCS will be 
administered unless there is a medical rationale to use the lower dose (QD) regimen.
Equivalent dose should refer to the highest approved country INCS dose for CRSwNP. The 
generic name of the INCS and the total daily dose should be recorded in the eCRF. 
6.4.2
COVID-19 Vaccination
As there is an expected broad vaccination against COVID-19 virus in most countries, the CSP 
allows participants to be vaccinated following certain precautions.
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 both the prime vaccine and the booster dose. No live attenuated 
COVID-19 vaccines are currently available. For vaccines that are currently approved under 
emergency use authorisation (EUA), please refer to the relevant health authority websites for 
further guidance. As per this CSP, any live attenuated vaccine is prohibited during study 
conduct. 
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 
should be followed depending on the study phase of the participant. As the below intervals 

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might change, please consult with the study physician for the most current recommended time 
interval prior to any vaccine dose.
Study Period
Recommendations
Participant in 
screening/run-in period
•
If COVID-19 vaccination is in the best interest of the participant and they 
are vaccinated or scheduled to be vaccinated before the screening or run-in 
visit, the randomisation visit should be scheduled to ensure that the first IP 
dose is administered at least 28 days after any vaccination dose.
Participant in treatment 
period
•
If COVID-19 vaccination is in the best interest of the participant and they 
are vaccinated during the study, IP dosing can continue but IP is not 
recommended to be administered within 14 days before or 28 days 
after a dose of vaccine.
•
If the participant receives a COVID-19 vaccination less than 14 days from 
the last IP dose, the next IP administration is recommended to be 
rescheduled or skipped to ensure the next IP dose is at least 28 days after 
the vaccine administration. 
•
The participant’s COVID-19 vaccination schedule should follow country-
specific health authority guidelines. Vaccination against COVID-19 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 participant receives a COVID-19 vaccine dose. 
However, even if IP is not administered at a study visit because of COVID-
19 vaccination restrictions, other site visit assessments should still be 
performed according to the CSP schedule. 
•
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 IP dosing 
(mentioned above) is maintained.
•
If it is anticipated that a participant will miss 2 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, protocol deviation and COVID-19 
related eCRF modules.
Patient in Follow-up 
period
•
If COVID-19 vaccination is in the best interest of the participant, COVID-
19 vaccination could be administered. The participant should follow the 
schedule of assessments listed in CSP in the Schedule of Assessments 
(SoA, Section 1.3); no special adjustments are needed. 
•
It is advised that the participant wait for 14 days after the last IP dose. 

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Figure 3
COVID-19 Vaccination Administration in Relation to IP Dosing
Reporting of COVID vaccination: 

COVID-19 vaccine details including vaccine’s name/manufacturer, route of 
administration, and vaccination date should be entered without delay into the eCRF CM 
module. This includes any history of COVID-19 vaccination.

If a participant 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 the CSP. 
6.5
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date, and time if applicable, of dose 
administered in the clinic will be recorded in the source documents and recorded in the eCRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention.
The study treatment provided for this study will be used only as directed in this Clinical Study 
Protocol (CSP). The investigational product will be administered at the study site or home (if 
applicable) on treatment visits and within visit windows as specified in the SoA.
In cases where a treatment visit needs to be rescheduled, the IP must be administered within 
the visit window or as soon as possible. The PI should make every effort to assure that no IP 
administrations are missed during the course of the study. 
Any change from the dosing schedule, dose interruptions, dose discontinuations should be 
recorded in the eCRF.
Principal Investigators should also assure that participants are compliant and on a stable dose 
of the background medication (INCS) during study period. 
6.5.1
Rescue Medication
Rescue medications may be given at the discretion of the Investigator per local guidelines.
IP
Vaccine
At least 28 days
IP

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6.5.2
Other Concomitant Treatment
Medications other than the ones described above, which are considered necessary for the 
participant’s safety and well-being, may be given at the discretion of the Investigator and 
recorded in the appropriate sections of the eCRF.
6.6
Dose Modification
Dose modification of background medications is not allowed in the study. If the Investigator 
makes the clinical decision that a participant 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.
6.7
Intervention After the End of the Study
At the end of the study, the participant should be given standard of care therapy, at the 
discretion of the Investigator, per local practice.
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue from study intervention. If 
study intervention is permanently discontinued, the participant will remain in the study to be 
evaluated for safety as per follow-up. See the SoA (Table 1) for data to be collected at the time 
of discontinuation or study intervention and follow-up and for any further evaluations that 
need to be completed. 
Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study.
See the SoA (Table 1) for data to be collected at the time of intervention discontinuation and 
follow-up and for any further evaluation that need to be completed. Participant may be 
discontinued from IP in the following situations:

Participant decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment.

An AE that in the opinion of the Investigator, contraindicates further dosing.

Severe non-compliance with the CSP.

Risk to participant as judged by the Investigator or AstraZeneca.

Pregnancy and breastfeeding.

IP unblinding (PI).

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
Lost to follow-up.

If participant had undergone NP surgery during the treatment period.

Development of any study specific criteria for discontinuation:

Anaphylactic reaction to IP requiring administration of epinephrine;

Development of helminth parasitic infestations requiring hospitalisation;

A respiratory-related event requiring intubation; 

Any malignancy, except participants who develop basal cell carcinoma or localised 
squamous cell carcinoma of the skin, provided that the malignancy has been excised 
and determined to have clean 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%) 
Before a decision to discontinue a participant from IP is instituted, the AstraZeneca Study 
Physician should be consulted regardless of the reason for discontinuation. See the SoA 
(Table 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 participant 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
Participants 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. Procedures to follow for study withdrawal are detailed below. If the participant 
decides to withdraw consent, then the reason for this must be recorded separately in the eCRF. 
A participant 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. Participants permanently discontinuing IP 
administration should be given locally available standard of care therapy, at the discretion of 
the Investigator. However, treatment with marketed or investigational biologics is not allowed 
until Week 76 (for the first 200 participants approximately) or Week 64 (last 200 participants 
randomised) even if the participant has discontinued IP. Interaction studies between 
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conducted. For additional information regarding pharmacokinetic and pharmacodynamic 
effects of tezepelumab reference should be made to the Investigator Brochure. 
All participants 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, except in case of IP discontinuation due to NP 
surgery. 
In case of IP discontinuation due to NP surgery, the IPD procedures (including CT scan if at 
least 12 weeks passed since the baseline CT scan) must be performed prior to the surgery. 
Sites are encouraged to schedule the IPD visit (in case of NP surgery) prior to, and as close as 
possible to the planned surgery date.
Participants who discontinue treatment should be encouraged to return for all regularly 
scheduled visits for safety and efficacy assessments. In case of IP discontinuation due to NP 
surgery, no further nasal endoscopies or CT scans are required after the IPD visit.
At the IPD visit the participant will be given 3 options as to how they will be followed as 
follows:
1
The participant should be encouraged to return for all regular clinic visits and perform all 
scheduled assessments (excluding IP administration and, in the case of IP discontinuation 
due to NP surgery, nasal endoscopy and CT) until the EOT visit at Week 52 (+/-5 days).
2
The participant will be offered follow-up on a monthly basis via telephone calls while 
continuing ePRO data collection on the handheld device at home until the participant 
completes the EOT visit at Week 52 (+/-5 days).  The UPSIT assessments will not be 
completed as per SoA at home after IPD visit until the participant returns to site at the 
EOT visit.
3
If the participant 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 contact the participant at 52 weeks post-randomisation. No 
other study assessments will be performed prior to this contact.
The EOT visit will be completed immediately in the case of subsequent early withdrawal from 
option 1 or 2. Participants who do not wish to have any follow-up contacts will be 
discontinued from the study. All discontinued participants must return the eDiary at the EOT 
visit.
If the participant chooses option 1, all assessments will be completed as per the SoA as 
indicated in Table 1. If the participant chooses option 2 or 3, the key information to be 
collected during the telephone calls are AEs/SAEs, changes in concomitant medication, health 

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care utilisation, and asthma exacerbation information (asthma/AERD/NSAID-ERD
participants). Participants 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 (ie, participant initially choosing option 1 can continue with options 2 or 3, participants 
initially choosing option 2 can continue with option 3). Participant Withdrawal from the Study
A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural, compliance, 
or administrative reasons. This is expected to be uncommon.
A participant who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (eg, telephone contact, a contact with a relative or treating 
physician, or information from medical records).
A participant who withdraws consent will always be asked about the reason(s) and the 
presence of any AEs. The Investigator will follow-up participants as medically indicated. A 
withdrawal visit is essential to collect as much data as possible for the participant as per EOT 
visit described in SoA, Table 1.
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
If a participant withdraws from the study, he/she may request destruction of any samples 
taken, and the Investigator must document this in the site study records.  
If the participant only withdraws consent for the retention of blood samples for future 
exploratory use (eg, study of markers of CRSwNP, identifying potential new drug targets for 
CRSwNP, assay development purposes, or for other scientific health-related research), the 
participant 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.
AstraZeneca reserves the right to discontinue a participant’s participation in the study for any 
safety reasons.
7.1.2
Withdrawal Due to Recruitment Completion in a Randomised Stratum 
When randomisation in a specific stratum is completed, participants in the screening period 
who are assigned to the completed stratum will not be randomised and will be screen failed 
from the study. The reason of the screen failure should be documented in the source and eCRF 
as a development of study specific criterion for discontinuation. Same as with screen failures, 
no further study related follow-up of these participants is required.

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7.1.3
Withdrawal due to Recruitment Completion
When the required number of participants are randomised in the study, ongoing participants in 
screening will not be randomised 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 participants is required.
7.1.4
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 participants and if relevant give 
appropriate medical treatment; take necessary measures and document these in the source 
notes.
The sponsor or 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
7.2
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The participant is considered lost to follow-up when any of the following attempts to contact 
fails: 3 attempts of either phone calls, faxes, or emails; having sent 1 registered/certified mail; 
and 1 unsuccessful effort to check the vital status of the participant using publicly available 
sources, if allowed, by local regulations.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

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
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.

Efforts to reach the participant should continue until the end of the study. Should the 
participant be unreachable at the end of the study the participant should be considered lost 
to follow-up with unknown vital status at end of study and censored at latest follow-up 
contact.

Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomised, including 
those who did not get investigational product. Public sources may be searched for vital 
status information. If vital status is determined as deceased, this will be documented, and 
the participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarised in the SoA (Table 1). Protocol waivers 
or exemptions are not allowed.

The Investigator will ensure that data are recorded on the eCRF.  Medidata Rave Web 
Based Data Capture system will be used for data collection and query handling.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.

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
The amount of blood collected from each participant over the duration of the study will be 
approximately 450 mL. Repeat or unscheduled samples may be taken for safety reasons 
or for technical issues with the samples.

Instructions for the collection and handling of HBS will be provided in the study specific 
laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on handling of HBS see 
Section 8.5.

The Investigator ensures the accuracy, and completeness, of the eCRFs including: the 
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 eCRF. A copy of the completed eCRF will be archived at the study site.
8.1
Efficacy Assessments
8.1.1
Nasal Polyp Score (NPS)
The NPS is the sum of the right and left nostril scores (maximum 8), as evaluated by nasal 
endoscopy. Total NPS is graded based on polyp size described in Table 7. Nasal endoscopy 
may be preceded by local administration of anaesthetic drugs in combination with a 
decongestant, as per local medical practice.
Standard video sequences will be conducted by trained personnel and sent to a central reader. 
Centralised imaging data assessments and scoring by independent physician reviewer(s) who 
are blinded for the imaging data will be performed for all endoscopies. To confirm eligibility 
at V3, the V2 central reading results will be made available to the site. 
The sites will verify image quality and remove participant-identifying information from the 
imaging data header prior to sending the imaging data to the central reader.
Further details on nasal endoscopy will be available in a separate Imaging Site Guide provided 
to the sites. The Imaging Core Lab will outline the equipment requirements and follow an 
Independent Review Charter (IRC). The IRC will define the logic and basis for the 
independent analysis methodology including the assessments to be recorded and 
corresponding assessment criteria to be used by the individual(s) conducting the analysis.
Table 7
Endoscopic NPS Within each Nostril
Polyp score
Polyp size
0
No polyps
1
Small polyps in the middle meatus not reaching below the inferior border of the 
middle turbinate
2
Polyps reaching below the lower border of the middle turbinate

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Table 7
Endoscopic NPS Within each Nostril
Polyp score
Polyp size
3
Polyps reaching the lower border of the inferior turbinate or a middle meatal polyp 
with a score of 2 with any additional polyp medial to the middle turbinate
4
Large polyps causing complete or near complete obstruction of the inferior nasal 
cavity ie, touching the floor of the nose 
8.1.2
Clinical Outcome Assessments 
Participants will complete all patient reported outcomes assessments (PRO) using a handheld 
ePRO device. The ePRO device will be the only accepted source of patient reported data.
The Investigator or designee will ensure that participants are properly trained on the use of 
this device and the importance of completing assessments as scheduled. The ePRO device will 
be used to capture symptoms (Nasal Polyposis Symptom Screening Assessment) and health-
related quality of life [(HRQoL) SNOT-22] screening data at Visit 1. If the participant does 
not meet the screening requirements, the device will be deactivated and retained at the site. If 
eligible to continue, the participant will receive additional training on the device regarding at
home use.
The ePRO device will be programmed at Visit 1 with reminder alarms for the daily diary. 
Study site staff will be able to adjust alarms for specific participant needs as required. The 
participant will be required to complete a training module before taking the device home. If a 
participant fails to meet eligibility criteria after V1 (for example regarding total NPS), the 
participant will be scheduled to return to the site, return the ePRO device and will be screen 
failed at that time.
The Investigator or designee will be responsible for monitoring participant adherence with the 
daily diary and follow-up as necessary to minimise missing data. Participant compliance 
should be checked weekly (at minimum) to ensure that the participant is completing the 
assessments as scheduled. 
Monitoring of participant adherence to the diary is critical during the baseline period (Study 
Day -13 to Day 0) to ensure that the participant meets applicable criteria for randomisation. 
Continued weekly monitoring of adherence throughout the study and follow-up with 
participants via phone and at the visits is required to ensure sufficient data are available for 
supporting the co-primary endpoint of this study.  
All PRO assessments should be completed prior to any other interventional study procedure 
(eg, laboratory tests, nasal endoscopy) except for informed consent at Visit 1 and the CT scan. 
The at home PRO assessments scheduled for V3 will be completed at the site once the site 
staff enable the visit on the device. If a scheduled at home assessment has not been completed 

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at the time of the visit it will be completed at the site prior to other study procedures.
8.1.2.1
Nasal Polyposis Symptom Diary (NPSD) and Nasal Polyposis Symptom 
Screening Assessment (NPSSA)
The participant will complete an 11-item NP symptom diary (NPSD) each morning 
throughout the screening, treatment, and follow-up periods. The participant is asked to 
consider their experience with NP/nasal polyps over the past 24 hours when responding to 
each question. Participants are asked to report their experience with NP symptoms (nasal 
blockage, nasal congestion, runny nose, post-nasal drip (mucous drainage down the throat), 
headache, facial pain, facial pressure, and difficulty with sense of smell) and symptom 
impacts (difficulty with sleeping due to nasal symptoms and difficulty with daily activities due 
to nasal symptoms). Participants report the severity of each symptom and symptom impact at 
its worst using a 4-point verbal rating scale (0-None to 3-Severe). A total symptom score 
(TSS) is calculated by taking the sum of the 8 equally weighted symptom items. A single item 
to capture INCS compliance (yes or no) will be administered after the symptom and symptom 
impact items.
A 2-week recall version of the diary, the Nasal Polyposis Symptom Screening Assessment 
(NPSSA), will be used to evaluate minimum symptom criteria at Visit 1. This screening 
assessment has one additional item about consistency of symptoms over the past 12 weeks and 
omits the INCS compliance item.
The NPSD and NPSSA will be completed on the ePRO device per the SoA.
8.1.2.1.1
Nasal Congestion Score 
Nasal congestion score (NCS) is captured by an item in the NPSD asking participants to rate 
the severity of their worst nasal congestion over the past 24 hours using the following 
response options: 0 – None; 1 – Mild; 2 – Moderate; 3 – Severe. Baseline will be the mean of 
daily responses from Day -13 to Day 0. Bi-weekly (14-day) mean NCS will be calculated if at 
least 8 days in each 14-day period has evaluable data; otherwise the bi-weekly mean is set to 
missing.
8.1.2.1.2
Loss of Smell 
Loss of smell is captured by an item in the NPSD asking participants to rate the severity of 
their worst difficulty with sense of smell over the past 24 hours using the following response 
options: 0 – None; 1 – Mild; 2 – Moderate; 3 – Severe. Baseline will be the mean of daily 
responses from Day -13 to Day 0. Bi-weekly (14-day) mean loss of smell will be calculated if 
at least 8 days in each 14-day period has evaluable data; otherwise the bi-weekly mean is set 
to missing.
8.1.2.2
Sino-Nasal Outcome Test 22 item
The SNOT-22 is a condition-specific HRQoL assessment which captures participant reported 

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physical problems, functional limitations, and emotional consequences of SinoNasal 
conditions (Piccirillo et al 2002; Hopkins et al 2009). Patient reported symptom severity and 
symptom impact over the past 2 weeks are captured via a 6-point scale (0- No Problem to 5-
Problem as bad as it can be). The total score is the sum of item scores and has a range from 0 
to 110 (higher scores indicate poorer outcomes). A Minimal Clinical Importance Difference 
(MCID) of 8.90 has been established for individual score change (Hopkins et al 2009).
The SNOT-22 will be completed on the ePRO per the SoA.
8.1.2.3
European Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L)
The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 response options (no
problems, slight problems, moderate problems, severe problems, and extreme problems) that 
reflect increasing levels of difficulty.
The participant will be asked to indicate his/her current health state by selecting the most 
appropriate level in each of the 5 dimensions. The questionnaire also includes a VAS, where 
the participant will be asked to rate current health status on a scale of 0 to 100, with 0 being 
the worst imaginable health state.
The EQ-5D-5L will be completed using the eDiary in accordance with the SoA.
8.1.2.4
Short-Form 36-item Health Survey, Version 2
The Short-Form 36-item Health survey, Version 2 (standard recall) (SF-36v2) is a 36-item, 
self-report survey of functional health and well-being, with a 4-week recall period 
(QualityMetric 2011). Responses to 35 of the 36 items are used to compute an 8-domain 
profile of functional health and well-being scores. The remaining item, referred to as the 
‘Health Transition’ item, asks participants to rate how their current state of health compared to 
their state of health 1 year ago, and is not used to calculate domain scores. The 8-domain 
profile consists of the following subscales: Physical Functioning (PF), Role Limitations due to 
Physical Health (RP), Bodily Pain (BP), General Health Perceptions (GH), Vitality (VT), 
Social Functioning (SF), Role Limitations due to Emotional Problems (RE), and Mental 
Health (MH). Psychometrically-based physical and mental health component summary scores 
(PCS and MCS, respectively) are computed from subscale scores to give a broader metric of 
physical and mental HRQoL.
Two types of thresholds have been developed for interpretation of SF-36v2 scores. The first 
type is suitable for comparing group mean scores and is generally referred to as the MCID. 
The second type is suitable for interpreting change at the individual level and is referred to as 
the responder threshold or responder definition (QualityMetric 2011). Threshold values are 
presented in Table 8

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Table 8
Threshold Values for the SF-36v2 Scale and Summary Measures
SF-36v2 score
Threshold
PCS
MCS
PF
RP
BP
GH
VT
SF
RE
MH
Group difference
2
3
3
3
3
2
2
3
4
3
Individual change
3.4
4.6
4.3
3.4
6.2
7.2
6.2
6.9
4.5
6.2
BP Bodily Pain; GH General Health Perceptions; MCS mental health component summary; MH Mental Health; 
PCS physical component summary; PF Physical Functioning; RE Emotional Problems; RP Role Limitations due 
to Physical Health; SF Social Functioning; VT Vitality
The SF-36v2 will be completed on the ePRO per the SoA.
8.1.2.5
Asthma Control Questionnaire (for Asthma/AERD/NSAID-ERD Participants 
Only)
The Asthma Control Questionnaire (ACQ-6) is an assessment of asthma symptoms (night-
time waking, symptoms on waking, activity limitation, shortness of breath, wheezing, and 
short-acting beta-agonist use).
Participants are asked to recall their level of asthma control during the previous week by 
responding to one bronchodilator use question and 5 symptom questions.
Questions are weighted equally and scored from 0 (totally controlled) to 6 (severely 
uncontrolled). The mean ACQ-6 score is the mean of the responses. Mean scores of ≤0.75 
indicate well-controlled asthma, scores between 0.75 and < 1.5 indicate partly controlled 
asthma, and a score ≥1.5 indicates not well-controlled asthma (Juniper et al 2006). Individual 
changes of at least 0.5 are considered to be clinically meaningful.
The questionnaire will be completed on ePRO as per SoA. 
8.1.2.6
University of Pennsylvania Smell Identification Test
The University of Pennsylvania Smell Identification Test (UPSIT) is a quantitative test of 
olfactory function which uses microencapsulated odorants that are released by scratching 
standardised odour-impregnated test booklets (Doty et al 1984). Four booklets each with 10 
odorants each are used for the test. Participants are asked to identify the odour using multiple 
choice format which lists different possibilities. The test is forced-choice, ie, the participant is 
required to mark one of the 4 alternatives even if no smell is perceived. Scores are based on 
number of correctly identified odours (score range 0 to 40).
Please note that the UPSIT smell test will be performed in all countries participating in the 
study except countries in which an UPSIT version in the native language is unavailable. 
8.1.2.7
Patient Global Impression of Severity and Change
The Patient Global Impression of Severity (PGI-S) is a single item designed to capture the 

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participant’s perception of overall NP symptom severity at the time of completion using a 6-
point categorical response scale (0 - No Symptoms to 5 - Very Severe). 
The Patient Global Impression of Change (PGI-C) instrument captures the participant’s 
overall evaluation of response to treatment since first dose of IP. The participant is asked to 
report the degree to which their health status has changed using a 7-point scale (1 - Much 
Better to 7 - Much Worse). 
Participants will complete the PGI-S and PGI-C at the site using the ePRO prior to other study 
procedures.
8.1.2.8
Work Productivity and Activity Impairment (WPAI) Questionnaire
The Work Productivity and Activity Impairment questionnaire (WPAI, General Health 
version 2.0) is a self-administered tool comprised of 6 questions which address absenteeism, 
presenteeism (reduced effectiveness while working), overall work productivity loss 
(absenteeism plus presenteeism), and activity impairment. This validated tool captures data 
from the past 7 days. WPAI outcomes are scored as impairment percentages, with a higher 
percentage indicating greater impairment and less productivity (Reilly et al 1993).
The WPAI will be completed using the eDiary in accordance with the SoA.
8.1.3
Sinus Computed Tomography 
Computed tomography (CT) will be performed in all participants. Referral for baseline CT 
scan should be provided at V2 (Week -2) and must be performed after nasal biopsy procedure 
(if applicable) at V2 only if the participant has met all eligibility criteria at V2 including NPS 
score confirmation by central readers. At V17 (EOT/IPD), the CT scan should be performed 
before the nasal biopsy procedure is completed for participants in the nasal biopsy sub-study.
For participants who undergo or are planned for surgery for NP during the treatment period, a 
CT scan should be performed prior to the first NP surgery per the IPD visit. For participants 
who require SCS for the treatment of NP, a CT scan should be performed prior to the first 
course of SCS, if possible, and at Week 52. For participants who receive multiple NP surgeries 
and/or SCS treatments for NP, the CT scan should be performed prior to the first occurrence of 
either NP Surgery or SCS treatment for NP. For participants who discontinue IP for other 
reasons, a CT scan should be performed at the IPD visit as well as at Week 52, if participant 
opts for follow-up option 1 or 2 per Section 7.1.1 of the CSP. CT should only be performed at 
IPD visit (regardless of the reason for IPD) if at least 12 weeks have passed since the baseline 
CT scan.
Sinus CT images will be used to derive Lund-Mackay scores (LMSs) and Zinreich (modified 
Lund-Mackay) scores based on the visual assessment by independent central readers (see 
Section 8.1.3.1), and for quantitative estimation of a sinus severity score (see Section 8.1.3.2) 

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which is representative of sinus disease burden. 
The sites will remove participant-identifying information from the image data (DICOM) 
header prior to sending the imaging data to the central lab. 
Further details on sinus CT will be available in a separate Imaging Site Guide provided to the 
sites. The Imaging Core Lab will outline the equipment requirements and follow an IRC. The 
IRC will define the logic and basis for the independent analysis methodology including the 
assessments to be recorded and corresponding assessment criteria to be used by the 
individual(s) conducting the analysis. 
Sites are encouraged to consult the Study Physician and their CRA in case of any unclarity 
regarding timing of sinus CT during the study.
8.1.3.1
Lund-Mackay Score
The Lund-Mackay score scoring system is used to provide a semi-quantitative assessment of 
nasal sinuses on sinus CT scans (Lund and Mackay 1993). Based on the sinus CT images, the 
5 sinuses (maxillary, anterior ethmoid, posterior ethmoid, sphenoid and frontal) on each side 
are scored by central radiologist as described in Table 9: 
Table 9
Lund-Mackay Score
Score
CT scan assessment
0
No abnormality
1
Partial opacification
2
Total opacification
The ostiomeatal complex (Table 10) is scored for right and left sides:
Table 10
Ostiomeatal Complex Score
Score
CT scan assessment
0
Not occluded
2
Occluded
The maximum total score is 24.
8.1.3.2
Quantitative Measurement of Sinus Disease Burden on Sinus Computed 
Tomography
Quantitative assessment of sinus CT image data will be used to derive an objective measure of 
sinus disease burden called sinus severity score (Pallanch et al 2013).
This is defined as:

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Sinus severity score = sinus mucosal volume/
(sinus mucosal volume + sinus air volume) *100%.
The following parameters used to calculate the sinus severity score:

sinus air volume (mL);

sinus mucosal volume (mL).
Image analysis will be performed centrally.
8.1.3.3
Zinreich (Modified Lund-Mackay) Score
In addition to the Lund-Mackay scoring described above, the same CT images will also be 
scored using the modified Lund-Mackay (Zinreich) scoring system (Okushi et al 2013, 
Likness et al 2014).
All 5 sinuses (maxillary, anterior ethmoid, posterior ethmoid, sphenoid and frontal) on each 
side will be scored based on the percentage of opacification from mucosal thickening 
according to Table 11.
Table 11
Modified Lund-Mackay (Zinreich) Score
Score
Percent opacification
0
0%
1
1%-25%
2
26%-50%
3
51%-75%
4
76%-99%
5
100%
The maximum total Zinreich score is 50 (54 when including the ostiomeatal complex score 
described above).
Scoring will be performed centrally by the imaging core lab.
8.1.4
Post-randomisation Nasal Polyp Surgery and/or SCS Use
Participants who have a scheduled NP surgery at the time of the study enrolment and 
randomisation should not be randomised (refer to exclusion criterion 15). After randomisation, 
surgery should not be planned for the first 3 months unless emergent or deemed necessary by 
the PI. These cases should be discussed with the AstraZeneca study physician.
Post-randomisation nasal polyposis surgery will, by definition, define a study endpoint. Both 
the date the decision is made that surgery is warranted (as agreed jointly by both the 

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participant and the investigator), as well as the date of actual surgery (if available), will be 
recorded in the eCRF. NP surgery is defined as any procedure involving instruments resulting 
in an incision and removal of tissue (eg, polypectomy, endoscopic sinus surgery). Post-
randomisation surgery procedures performed for NP during the study, including reason for 
surgery and information whether the surgery was performed as an outpatient or inpatient (ie, 
including an overnight stay in the hospital) procedure, should be recorded in the Nasal Polyp 
Surgery eCRF. A nasal endoscopy assessment of NPS (to provide evidence of NP recurrence), 
a CT scan and PROs should be performed prior to the first (post-randomisation) actual NP 
surgery. If no such assessment is available, a visit should be scheduled to obtain those 
assessments. At the time of surgery, participants will be permanently discontinued from IP and 
assessed as soon as possible per the EOT visit described in the SoA. If surgery is planned 
during the follow-up period, participants will be assessed by the Investigator and may decide 
to continue follow-up to the time of surgery or final visit of the study, whichever date comes 
first.
Rescue treatment of NP or other reasons is defined as requiring treatment with systemic 
corticosteroids (SCS) for at least 3 consecutive days (a single depo-injectable dose of 
corticosteroids will be considered equivalent to a 3-day course of systemic corticosteroids). A 
course of SCS is considered continuous if treatment episodes are separated by less than 
7 days. Participants receiving SCS during the study should continue on IP unless the 
Investigator decides to withdraw the participant from IP due to safety reasons. 

If SCS is used for treatment of NP for ≥3 consecutive days, a CT scan and a nasal 
endoscopy assessment of NPS should be performed prior to first course of treatment with 
SCS (unless the subject has already had a CT scan prior to a NP surgery post 
randomisation).  If no such assessment is available, an unscheduled visit should be 
scheduled to obtain those assessments. 

If SCS use for treatment of any other reason than NP is close to V10 (Week 24) or V17 
(Week 52), the visit should be rescheduled at least 2 weeks after the last dose of SCS.

If SCS will be used for any other reason than NP, the investigator is recommended to 
consult with the AstraZeneca study physician.
8.1.5
Spirometry (Asthma/AERD/NSAID-ERD Participants Only)
8.1.5.1
General Requirements 
Lung function (FEV1, FEF 25-75% and FVC) will be measured by spirometry at the study 
site using equipment provided by a central vendor. The MasterScope is a system which will be 
used on-site to perform and record results for procedures including, but not limited to, 
spirometry, NPIF and FeNO.
Spirometry will be performed by the Investigator or authorised delegate according to 

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American Thoracic Society/European Respiratory Society (ATS/ERS) guidelines or local 
guidelines (Graham et al 2019)
The MasterScope kit will include a spirometer handle which will be used to record spirometry 
values at the site. The vendor providing central spirometry is responsible for assuring that the 
spirometer meets ATS/ERS recommendations and that the study centre personnel who will be 
performing the testing are properly certified. Spirometry calibration will be detailed in a 
separate spirometry procedures manual.
Important!

Participants should avoid engaging in strenuous exertion for at least 30 minutes prior to 
all lung function assessments at the centre.

Participants should avoid eating a large meal for at least 2 hours prior to all lung function 
assessments at the centre. 

Participants should withhold their usual maintenance therapies on the day(s) when lung 
function testing is being performed as below:

SABAs 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

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
Note: If any of the above restrictions are not met, the spirometry assessment should be 
rescheduled within the allowed visit window
Time of day for scheduled centre 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 randomisation visit (Visit 3).
All spirometry assessments should be performed within ± 1.5 hours of the time it was 
performed during Visit 3. For example, if the Visit 3 spirometry was started at 8:00 AM, then 
all subsequent spirometry testing needs to be initiated between 6:30 AM and 9:30 AM.
Spirometry techniques 
Detailed procedures for performing spirometry will be described in a separate instruction 

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manual. Details regarding assessment of the quality of spirometry and the best test report 
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
Record Keeping 
A signed and dated copy of the pre-BD printout must be kept at study centre for source data 
verification. The printout must be marked with the study code, enrolment code, date and time 
of measurement, and visit number. If a printout cannot be printed, the mean value of the 
measurements will be recorded in the participant’s charts. 
8.1.6
FeNO (Asthma/AERD/NSAID-ERD Participants Only)
Airway inflammation will be evaluated using a standardised single-breath FeNO test in 
accordance with the SoA. A single exhalation technique recommended by the manufacturer 
will be followed (Alving et al 2017).
Participants will be asked whether they have had a respiratory infection in the 2 weeks prior to 
the measurement. The FeNO measurements will not be performed within 2 weeks of a 
respiratory infection. The FeNO test will be performed prior to spirometry. Participants should 
not eat or drink 1 hour prior to having the FeNO test. Participants should not use their rescue 
SABA medication (eg, albuterol/salbutamol) within 6 hours of the measurement. Inhaled BDs 
(including ICS/LABA) should be withheld for the effect duration specific to the BD as 
described in the spirometry section. If not, the assessment should be postponed till after the 
required time has passed since the meal or drink or 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.
8.1.7
Nasal Peak Inspiratory Flow
Nasal peak inspiratory flow (NPIF) evaluation represents a physiological measure of the air 
flow through both nasal cavities during forced inspiration expressed in liters per minute. Nasal 

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inspiration correlates most with the participative feeling of obstruction and is the best 
validated technique for monitoring nasal flow in clinical trials.
A minimum of 3, up to a maximum of 8NPIF efforts will be performed by the participant; all 
values will be recorded by the participant on the MasterScope and the highest value will be 
used for evaluation.
The NPIF will be performed at enrolment/screening V1 (Week -5), V3 (Week 0), 
V7 (Week 12), V10 (Week 24), V13 (Week 36), V17 (Week 52), V19 (Week 64), 
V21 (Week 76).
The nasal flow is expressed in liters per minute, and consecutive measurements are performed.
Taking the best of 3 outcomes with less than 10% variation is considered to be the best means 
of expression of the result (Scadding et al 2011).
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Table 1).
8.2.1
Physical Examinations
Investigator’s should pay special attention to clinical signs related to previous serious illnesses 
as new or worsening abnormalities may qualify as AEs, see section 8.3.5 for details.

A complete physical examination will be performed and include assessments of the 
following; general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, muscular-skeletal (including 
spine and extremities) and neurological systems. 

A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). For the brief physical assessment 
only, information on whether the assessment was performed or not is to be recorded. 
Physical examination will be performed at timepoints as specified in the SoA.
8.2.2
Vital Signs
Vital signs will be performed at timelines as specified in the SoA.
Vital signs are to be taken prior to IP administration, and if possible, before blood draw.
Body temperature, pulse rate, respiratory rate, and blood pressure (BP) will be assessed:

Body temperature will be measured in Celsius before IP administration in accordance 
with local standards;

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
Blood pressure and pulse measurements will be assessed in sitting position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available;

Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones);

Pulse rate will be obtained before blood pressure if the manual technique is used. 

Respiration rate will be obtained after participant has been resting for at least 5 minutes, 
by counting number of breaths (how many times the chest rises) for 1 minute.
8.2.3
Electrocardiograms
An electrocardiogram (ECG) will be performed at timepoints as specified in the SoA.
ECG will be taken in supine position, after the participant has been resting for at least 5 
minutes. The assessment should be performed before interventions with the participant (eg, 
nasal endoscopy, blood draw).  
The Investigator or authorised 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 
participant’s participation in the study. ECG evaluation will be recorded in the eCRF. ECG 
evaluation will be recorded in the eCRF.
8.2.4
Clinical Safety Laboratory Assessments
See Table 12 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 table, 
must be conducted in accordance with the Laboratory Manual and the SoA.  Fasting before 
blood draw is recommended but not mandatory.
Blood and urine samples for determination of clinical chemistry, haematology and urinalysis 
will be taken at the visits indicated in the SoA. The date and results will be recorded on the 
appropriate eCRF. 
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.5. 
The clinical chemistry, haematology and urinalysis will be performed at a central laboratory. 

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Additional (repeated or unscheduled) safety samples may be collected if clinically indicated at 
the discretion of the Investigator, for safety reasons or for technical issues with the samples.
The Investigator should assess the available results with regard to clinically relevant 
abnormalities. The laboratory results should be signed and dated and retained at site as source 
data for laboratory variables. 
The following laboratory variables will be measured.
Table 12
Laboratory Safety Variables
Haematology/Hemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin (Hb)
S-Alkaline phosphatase (ALP)
B-Leucocyte count
S-Alanine transaminase (ALT)
B-Leucocyte differential count (absolute count)
S-Aspartate transaminase (AST)
B-Platelet count
S-Bilirubin, total
B-Haematocrit
S-Blood urea nitrogen
B-Mean Corpuscular Volume 
S-Calcium, total
B-Red blood cell (RBC) counta
S-Chloride
S-Creatinine
Urinalysis (dipstick)
S-Creatinine kinase (CK)
U- Blood 
S-CRP
U-Protein 
S-Gamma-glutamyl transpeptidase (GGT)
U-Glucose 
S-Glucose
U-Microscopy and culture as requiredb
S-Lipid Profilec
S-Phosphorus
S-Potassium
S-Sodium
S-Total Cholesterol
S-Uric acid
a
The sponsor personnel involved in the analysis and conduct of the study and site will be blinded to the 
immunoglobulin, eosinophil, basophil and monocyte (both absolute and percentage) values from the central 
laboratory reports except screening visits (V1 and V2) and any repeat testing that is performed during the 
screening period and prior to Investigational Product (IP) administration at V3.
b
Urine sample will be analysed by urine dipstick at site and sent to the central laboratory only for analysis 
when a positive dipstick result for any parameter is observed. 
c
Lipid profile consists of the following tests: Direct high-density lipoprotein cholesterol (HDL-C) 4th
Generation, Triglycerides, Cholesterol, Low-density lipoprotein (LDL) cholesterol Friedewald 4th
(calculation), Very-low-density lipoprotein (VLDL) cholesterol Friedewal (calculation). 

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NB. In case a participant shows an AST or ALT ≥3xULN together with total bilirubin 
≥2xULN please refer to Appendix E. Actions required in cases of increases in liver 
biochemistry and evaluation of Hy’s Law’, for further instructions.
8.2.4.1
COVID-19 Entry Screening Questionnaire
A COVID-19 screening questionnaire must be completed via telephone approximately within 
72 hours prior to every study visit, regardless of the visit being on-site, at participant’s home, 
or at an alternative location. Participant 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 travelled in the last 14 days, if so, where? (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. Participants who 
report symptoms should be referred for further evaluation as per investigator judgement. Visit 
should be cancelled or rescheduled, if needed as judged by Investigator.

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8.2.4.2
SARS-CoV-2 Testing
Laboratory safety variables for SARS-CoV-2 testing are described in Table 13. 
At screening visit (V1), sites should perform testing for SARS-CoV-2 in line with local 
guidelines. Either a nasopharyngeal swab (PCR) test or a rapid antigen test are acceptable. 
PCR tests should be analysed at the central laboratory. Rapid antigen tests should be analysed 
locally and the results entered on the eCRF.
SARS-CoV-2 nasopharyngeal swab test and SARS-CoV-2 serology (collected at Visit 3) 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 AEs but will not be used for subgroup analyses 
(eg, serology positive/negative).
In case of re-screening due to previous screen failure because of a positive SARS-CoV-2 
nasopharyngeal swab (PCR) test, a rapid antigen test should be performed locally at site 
instead of performing a repeat central laboratory nasopharyngeal swab (PCR) test (as long as 
this is acceptable with respect to local guidelines).
Table 13
SARS-CoV-2 Laboratory Safety Variables
Laboratory Test
Visit
SARS-CoV-2 nasopharyngeal swab test (or COVID-
19 rapid test)
Visit 1
SARS-CoV-2 serology test
Visit 3
Sites should also follow local SARS-CoV-2 testing guidelines outside of CSP study 
assessments, if applicable.
8.2.4.3
Pregnancy Test
The following tests are applicable to female participants only and will be conducted in 
accordance with the schedules provided in the SoA.

Serum ß-human chorionic gonadotropin (ß-HCG) – To be performed for all females at 
Visit 1 except for those who are NOT of childbearing potential as defined in inclusion 
criterion 8. This test is to be sent to and analysed at the central laboratory;

FSH: To be performed at Visit 1 only, for female participants to confirm postmenopausal 
status in women < 50 years who have been amenorrheic for > 12 months;

Urine HCG: To be performed at the study site or at home for all females at each treatment 
visit before IP administration using a dipstick except for those females who are NOT of 
childbearing potential as defined in inclusion criterion 8. A positive urine test result must 
be confirmed with serum ß-HCG.

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8.2.4.4
Serology
Hepatitis B surface antigen, hepatitis C antibody: To be performed only at screening; test to be 
performed at central laboratory.
HIV-1 and HIV-2 antibodies: To be performed only at screening; test to be performed at 
central laboratory.
Instructions for sample collection, processing, storage, and shipment can be found in a 
separate Laboratory Manual provided to the sites.
8.2.5
Other Safety Assessments
8.2.5.1
Weight and Height
Weight and height will be measured in accordance with schedules provided in the SoA.
The participant’s weight will be recorded in kilograms; height will be recorded in centimetres. 
Weight and height measurements will be performed in light clothing and with shoes off.
8.2.5.2
Asthma Exacerbations (for Asthma/AERD/NSAID-ERD Participants Only)
During the study, an asthma exacerbation will be defined as a worsening of asthma that leads 
to any of the following:

A temporary bolus/burst of systemic corticosteroids (or a temporary increase in stable 
OCS background dose) for at least 3 consecutive days to treat symptoms of asthma 
worsening; a single depo-injectable dose of corticosteroids will be considered equivalent 
to a 3-day burst of systemic corticosteroids.

An emergency room or urgent care visit (defined as evaluation and treatment for 
< 24 hours in an emergency department or urgent care centre) due to asthma that required 
systemic corticosteroids (as per the above).

An inpatient hospitalisation (defined as admission to an inpatient facility and/or 
evaluation and treatment in a healthcare facility for ≥ 24 hours) due to asthma.
In addition, participants are required to report any of the following in the eDiary:

An increase in rescue medication use of 4 or more puffs on at least 2 consecutive days 
compared with the average use during baseline or use of 12 puffs/day on any one day, 
and/or;

An additional nebulised β2 agonist use on at least 2 consecutive days compared with the 
average use during baseline, and/or;

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
An increase of 2 or more nights with awakenings due to asthma requiring rescue 
medication over a 7-day period compared with the average during baseline, and/or ≥ 6 out 
of previous 7 nights with awakenings due to asthma requiring rescue medication (this 
criterion should be met on 2 consecutive days).
If an exacerbation event is not associated with deterioration in at least 1 of the pre-specified 
objective measurements, the Investigator will have to justify the decision for defining the 
event as an exacerbation and record it in the eCRF. Events that are not supported by any 
objective assessment will be deemed not to be a protocol defined exacerbation.
The start of an exacerbation is defined as the start date of systemic corticosteroids or of a 
temporary increase in a stable OCS background dose, date of ER or urgent care visits 
requiring systemic corticosteroids, or date of hospital admission due to asthma, whichever 
occurs earlier.
The end date of an exacerbation is defined as the last date of systemic corticosteroids or of a 
temporary increase in a stable OCS background dose, date of ER or urgent care visit, or date 
of hospital discharge, whichever occurs later.
If less than 7 days have elapsed since the end date of an asthma exacerbation and the start date 
of a new asthma exacerbation, the second event will be considered a relapse of the prior 
asthma exacerbation.
See section 8.3.5 for additional information on recording asthma exacerbations as an AE/SAE 
during the study.
8.2.5.3
Nasal Polyp Exacerbations 
During the study, nasal polyp exacerbation will be defined as a worsening of nasal polyp 
symptoms that leads to use of systemic corticosteroids or systemic antibiotics for at least 3 
consecutive days or requires hospitalisation.
The start of nasal polyp exacerbation is defined as the start date of systemic 
corticosteroids/systemic antibiotics or hospitalisation whichever is earlier and the end date of 
nasal polyp exacerbation is defined as the last date of systemic corticosteroids/systemic 
antibiotics or hospitalisation whichever is later.
8.3
Adverse Events and Serious Adverse Events
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events and Serious Adverse Events will be collected from time of signature of 
informed consent form throughout the treatment period and including the follow-up period.
All SAEs will be recorded and reported to AstraZeneca or designee within 24 hours, as 

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indicated in Appendix B. The Investigator will submit any updated SAE data to AstraZeneca 
within 24 hours of it being available.
If the investigator becomes aware of a serious adverse event with a suspected causal 
relationship to the investigational medicinal product that occurs after the end of the clinical 
study in a participant treated by him or her, the investigator shall, without undue delay, report 
the serious adverse event to 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.
8.3.2
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs and SAEs will be followed until resolution, 
stabilisation, the event is otherwise explained, or the participant is lost to follow-up. 
Any AEs that are unresolved at the participant’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 eCRF.  AstraZeneca retains the right to request 
additional information for any participant with ongoing AE(s)/SAE(s) at the end of the study, 
if judged necessary.
Adverse events variables
The following variables will be collected for each AE:

AE (verbatim)

The date and time when the AE started and stopped

Maximum Intensity of the AE

Whether the AE is serious or not

Investigator causality rating against the Investigational Product(s) (yes or no)

Action taken with regard to Investigational Product(s)

AE caused participant’s withdrawal from study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date investigator became aware of SAE

AE is serious due to (specify the SAE criteria per definition in Appendix B)

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
Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication
8.3.3
Causality Collection
The investigator should assess causal relationship between Investigational Product and each 
AE, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable 
possibility that the event may have been caused by the investigational product?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B of the CSP.
8.3.4
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’ or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.5
Adverse Events Based on Examinations and Tests
The results from the CSP mandated laboratory tests, vital signs and ECG 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 IP.
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 will be considered as additional information. Wherever possible the reporting 
Investigator uses the clinical, rather than the laboratory term (eg, anaemia versus low 
haemoglobin value). In the absence of clinical signs or symptoms, clinically relevant 

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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. Asthma symptoms or signs, such as wheeze, cough, chest 
tightness, dyspnoea, breathlessness and phlegm, will be recorded as AEs only when:

The sign or symptom is serious according to definitions, see Appendix B

The participant discontinues IP due to the sign or symptom

The sign or symptom is new to the participant or not consistent with the participant’s pre-
existing asthma history (defined as within 1 year of V1) as judged by the Investigator.
Asthma exacerbation should be recorded as an AE or SAE only if it fulfils any of the above 
criteria 
8.3.6
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 reaction  

Serious infections1

Helminth infections 

Guillain Barre Syndrome

Malignancy  

Serious cardiac events
8.3.7
Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 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.
                                               
1 eCRF ‘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.

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8.3.8
Reporting of Serious Adverse Events
All SAEs must be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs during the study, investigators or other site personnel will inform the 
appropriate AstraZeneca representatives within one day ie, immediately but no later than 24 
hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Participant Safety data entry site within 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated e-mail alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the investigator or other study site staff reports the 
SAE via a secure method to the appropriate AstraZeneca representative.
When the EDC is temporarily not accessible, the AstraZeneca Study Representative should 
confirm that the investigator/site staff enters the SAE in the AstraZeneca EDC when access 
resumes.
The AstraZeneca representative will advise the investigator/study site staff how to proceed. 
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study 
Protocol.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug. 
8.3.9
Independent Adjudication Committee
An IAC will be established in the study to provide an external independent assessment of 
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 diagnosis of 
malignancies that occur from randomisation until the end of the follow-up period. Details on 

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the adjudication process, including score of adjudication and the committee membership, will 
be included in the Adjudication Committee Charter/Manual of Operations. 
8.3.10
Disease Progression 
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the IMP is being studied. It may be an increase in the severity of the 
DUS and/or increases in the symptoms of the disease. The development of worsening signs 
and/or symptoms of CRSwNP should be considered as disease progression and not an unless 
they meet protocol defined criteria for NP exacerbation (Section 8.2.5.3). Events, which are 
unequivocally due to disease progression, should not be reported as AEs during the study.
8.3.11
Disease Under Study 
Symptoms of DUS are those which might be expected to occur as a direct result of CRSwNP. 
Events which are unequivocally due to DUS should not be reported as AEs during the study 
unless they meet protocol defined thresholds for NP exacerbation (Section 8.2.5.3), SAE 
criteria or lead to discontinuation of the IMP.
8.3.12
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except if the 
pregnancy is discovered before the study participant has received any study intervention.
If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy.  Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal
death, stillbirth, congenital abnormalities, ectopic pregnancy) are considered SAEs.
8.3.12.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, investigational product 
should be discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs. Elective abortions without 
complications should not be handled as AEs. The outcome of all pregnancies (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should be followed up and documented even if the participant was discontinued from the 
study.  
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.

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The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Participant Safety data entry site within 1 
or 5 calendar days for SAEs (see Section 8.3.10) and within 30 days for all other 
pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module is used to report the outcome of the pregnancy.
8.3.12.2
Paternal Exposure
Pregnancy of the participant’s partners is not considered to be an adverse event. However, the 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality), occurring from the date of the first dose until 
16 weeks (5 half-lives) after the last administration of IP should, if possible, be followed up 
and documented in the Pregnancy Report Form. Consent from the partner must be obtained 
before the Pregnancy Report Form is completed.
8.3.13
Management of IP-Related Reactions
Appropriate drugs, such as epinephrine, H1 and H2 antihistamines, and corticosteroids, as 
well as medical equipment to treat acute anaphylactic reactions, must be immediately 
available when IP is being administered at the study site.  Study site personnel must be trained 
to recognise and treat anaphylaxis (Lieberman et al 2010). Details on anaphylaxis 
management are provided in Appendix F.
Anaphylaxis will be defined as a serious reaction that is rapid in onset and may cause death 
(Sampson et al 2006). Anaphylaxis to an IP that the participant has not been previously
exposed to (such as tezepelumab) is deemed highly likely when Sampson criterion 1 is 
fulfilled. Sampson criteria 2 and 3 are also listed for completeness:
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.
Participants will have had a pre-assessment (ie, vital signs and lung function) prior to IP 
administration. At Visits 3 and 5, participants should be observed for a minimum of 2 hours 
after IP administration for the appearance of any acute drug reactions. For the remaining visits 

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involving IP administration, participants 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 participant 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.
8.3.14
Medical Device Deficiencies
Medical devices and device constituents of combination product 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 study drug 
combination product.
Device deficiencies from this study will be collected and monitored to ensure the safety of 
participants and to improve the safety and performance of the device. 
Device deficiencies will not be presented in the CSR, but where required by local regulations, 
device deficiencies will be summarised in the relevant periodic report. 
The definition of a medical device deficiency in the device constituent of a combination 
product is an inadequacy of the 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 I 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.  
8.3.14.1
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.

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 I and the 
Pharmacy Manual.

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8.3.14.2
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.
8.3.14.3
Prompt Reporting of Medical Device Deficiencies to Sponsor

Only deficiencies associated with the study drug combination product should be reported 
to the AstraZeneca representative. 

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 e-mail, as per the 
pharmacy manual.

Where an SAE has occurred in addition to the malfunction, the SAE will be recorded in 
the eCRF as detailed in Section 8.3.8.
The sponsor will be the contact for the receipt of medical device deficiency reports.
8.3.14.4
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 (eg, 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 definitions, see Appendix I of the CSP.
8.4
Overdose
For this study, any dose of study intervention greater than 280 mg administered within a 2-
week period will be considered an overdose. 
There is currently no specific antidote in the event of overdose of IP.  No specific antidote to 
tezepelumab is available, so adverse reactions should be treated symptomatically as per local 
standards.

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
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study intervention occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Participant Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 
8.3.1. For other overdoses, reporting must occur within 30 days.
8.4.1
Reporting of Overdose 
Refer to Section 8.4 for definition and treatment of overdose.
An overdose with associated AEs is recorded as the AE diagnoses/symptoms on the relevant 
AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an IMP or AstraZeneca non-investigational medicinal product (NIMP) 
occurs in the course of the study, the investigator or other site personnel inform appropriate 
AstraZeneca representatives immediately, but no later than 24 hours of when he or she 
becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 
or 5 calendar days for overdoses associated with an SAE (see Section 8.4) and within 
30 days for all other overdoses.
8.4.2
Medication Error, Drug Abuse, and Drug Misuse 
8.4.2.1
Timelines 
If an event of medication error, drug abuse, or drug misuse occurs during the study, then the 
investigator or other site personnel informs the appropriate AstraZeneca representatives within 
one calendar day, ie, immediately but no later than 24 hours of when they become aware of 
it. 
The designated AstraZeneca representative works with the investigator to ensure that all 

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relevant information is completed within one (initial fatal/life-threatening or follow-up 
fatal/life-threatening) or 5 calendar days (other serious initial and follow-up) if there is an 
SAE associated with the event of medication error, drug abuse, or misuse (see Section 8.3.8) 
and within 30 days for all other events.
8.4.2.2
Medication Error 
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant.
The full definition and examples of medication error can be found in Appendix B 4.
8.4.2.3
Drug Abuse 
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect.
The full definition and examples of Drug Abuse can be found in Appendix B 4.
8.4.2.4
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 study interventions, outside the intended use as 
specified in the protocol and includes deliberate administration of the product by the wrong 
route.
The full definition and examples of Drug Misuse can be found in Appendix B 4.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Samples see Appendix C.
Samples will be stored for a maximum of 15 years from the date of the last subject’s last visit 
(LSLV) in line with consent and local requirements, after which they will be 
destroyed/repatriated.

Pharmacokinetic (PK) samples will be disposed of after the Bioanalytical Report 
finalisation or 6 months after issuance of the draft Bioanalytical Report (whichever is 
earlier), unless consented for future analyses. 

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
PK samples may be disposed of or anonymised by pooling. Additional analyses may be 
conducted on the anonymised, pooled pharmacokinetic samples to further evaluate and 
validate the analytical method. Any results from such analyses may be reported separately 
from the Clinical Study Report (CSR).

Remaining anti-drug antibody (ADA) sample aliquots will be retained at AstraZeneca or 
its designee for a maximum of 15 years following issue of the LSLV. Additional analyses 
may be conducted on the anonymised, pooled ADA samples to further evaluate and 
validate the analytical method. Any results from such analyses may be reported separately 
from the CSR. 
8.5.1
Pharmacokinetics
Serum samples will be collected for measurement of serum concentrations of tezepelumab as 
specified in the SoA. Serum will be collected pre-dose.
For the PK analysis, it is important that the date and time of each SC injection is recorded for 
each participant.
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
The actual date and time (24-hour clock time) of each sample will be recorded by sites.
8.5.1.1
Determination of Drug Concentration
Samples for determination of tezepelumab concentration in serum will be assayed by 
bioanalytical test sites operated by or on behalf of AstraZeneca, using a validated bioanalytical 
method.  Full details of the analytical method used will be described in a separate 
bioanalytical report 
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report.
A summary of PK concentration results will be reported in the CSR.
8.5.2
Immunogenicity Assessments
Blood samples for determination of ADA and neutralising antibodies in serum will be assayed 
by bioanalytical test sites operated by or on behalf of AstraZeneca, using an appropriately 
validated bioanalytical method. Full details of the methods used will be described in a separate 
report. A summary of the immunogenicity analysis results will be presented in the CSR.

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Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual. 
The immunogenicity samples will be retained at AstraZeneca or designee for a maximum of 
15 years following the date of last subject last visit (LSLV) to properly address potential 
questions from RAs.
8.5.2.1
Anti-drug Antibodies
Serum samples for analysis of ADA will be collected at selected visits as per SoA.
The presence or absence of ADA will be determined in the serum samples using validated 
bioanalytical methods. Tiered analysis will be performed to include screening, confirmatory, 
and titre assay components, and positive-negative cut points statistically determined from 
drug-naïve samples will be employed. 
8.5.2.2
Neutralising Antibodies
Samples confirmed positive for ADA will be further evaluated for the presence or absence of 
neutralising antibodies (nAb) using a validated bioanalytical method. Samples that are ADA 
negative will not be tested for nAb. 
8.5.3
Pharmacodynamics
Pharmacodynamic parameters will be evaluated using biomarkers (see Section 8.6).
8.6
Human Biological Sample Biomarkers
8.6.1
Collection of Mandatory Samples for Biomarker Analysis
By consenting to participate in the study the participant consents to participate in the 
mandatory research components of the study. 

Samples for biomarker research are required and will be collected from all participants in 
this study as specified in the SoA. 

This analysis is required so biological samples can be tested for exploratory analyses to 
evaluate the effect of tezepelumab on biomarkers of inflammation, recurrence, NP 
disease, pharmacology of tezepelumab and for potential predictors of clinical responses.

Whole blood, serum and plasma samples, as well as nasal epithelial lining fluid will be 
collected at the pre-specified scheduled visits prior to IP administration (pre-dose) 
according to the SoA.  Whole blood will be collected for transcriptomic (RNA) profiling. 
Serum, plasma, and nasal epithelial lining fluid samples will be collected for exploratory 
biomarker analysis. Results from these exploratory assessments will be blinded to sponsor 
and sites after the randomisation visit (Visit 3).

The levels of total immunoglobulin E (IgE) and an assessment for the presence of 
allergen-specific IgE (IgE FEIA) will be collected at the pre-specified scheduled visits 

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prior to IP administration (pre-dose) according to the SoA and evaluated by a central 
laboratory. Results from total serum IgE results will be blinded to sponsor and sites after 
the randomisation visit (V3).  

Nasal epithelial lining fluid samples will be obtained at the scheduled visits according to 
the SoA. Nasal epithelial lining fluid biomarkers will be measured to evaluate the 
pharmacology of tezepelumab and to evaluate changes in biomarkers related to CRSwNP, 
inflammation and the TSLP pathway. Baseline and early post-dose levels of nasal 
epithelial 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 
analysed include but are not limited to cytokines, chemokines and inflammatory 
mediators associated with CRSwNP and the TSLP pathway. Drug concentrations may 
also be measured in the nasal epithelial lining fluid samples, if feasible. If appropriate, 
urea concentrations may be measured to correct for the dilution factor of the nasal lining 
fluid samples. Results from these exploratory assessments will be blinded to sponsor and 
sites after randomisation visit (Visit 3).

In addition, a nasal biopsy sub-study will be conducted at selected sites, for up to 
approximately 60 participants in total. Nasal biopsies will be collected at V2 (Week -2) 
and EOT (Week 52) to evaluate the effect of tezepelumab on inflammatory cell infiltrate 
and gene expression by transcriptomic profiling. At V2, nasal biopsy should be performed 
after nasal epithelial lining fluid collection and before NPS assessment or CT scan. If 
nasal biopsy sample cannot be collected at Visit 2, then participant should be withdrawn 
from nasal biopsy sub-study and can continue on the main study. In this event, NLF 
collection at Visit 2 and Staph A enterotoxin specific IgE status sample collection at 
Visit 3 should be not performed. At EOT, nasal biopsy should be performed after NPS 
assessment, nasal epithelial lining fluid collection, and CT scan. Collection of nasal 
biopsy sample may be postponed for up to 7 days after EOT visit, only if appropriate kit 
supplies are not available at the time of EOT visit. Refer to Order of Assessments under 
Table 1 for more details. Results from these exploratory assessments will be blinded to 
sponsor and sites after randomisation visit (Visit 3).

Staph A enterotoxin IgE will only be performed in the nasal biopsy sub-study 
participants. Staph A bacterial culture from nasal swabs will be collected for all 
participants and evaluated by a central laboratory. These tests will be performed at the 
scheduled visits according to the SoA. Results from these exploratory assessments will be 
blinded to sponsor and sites after randomisation visit (Visit 3).
Instructions for sample collection, processing, storage, and shipment can be found in the 
separate Laboratory Manual provided to the sites.
The results of the exploratory biomarker analyses may be reported separately from the CSR in 
a scientific report or publication.

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For storage, re-use and destruction of biomarker samples see Section 8.6.2.
8.6.2
Storage, Re-use and Destruction of Exploratory Biomarker Samples
AstraZeneca or a designee will retain biomarker samples (including nasal biopsy tissue) for 
investigation of research NP disease, the pharmacology of tezepelumab and potential 
predictors of response no longer than 15 years after LSLV or other period as per local 
requirements.
The results of this biomarker research may be pooled with biomarker data from other studies 
with the study treatment to generate hypotheses to be tested in future research. Any residual 
samples may be used for future biomarker research (eg, scientific health-related research). If a 
participant does not allow samples to be used for future biomarker research, they may 
continue with their samples being used for the main study.
8.7
Optional Genomics Initiative Sample
Collection of optional samples for genomics initiative research is also part of this study as 
specified in the SoA and consent will be provided via separate ICF. 
The blood sample for DNA isolation will be collected from participants who have consented 
to participate in the genomics initiative. Participation is optional.
Participants who do not wish to participate in the genetic research may still participate in the 
study. Exploratory genetic samples will be collected in participating countries, except China.
See Appendix D for information regarding the Genomics Initiative genetic sample. Details on 
processes for collection and shipment and destruction of these samples can be found either in 
the appendices or in the Laboratory Manual. 
The results of the analyses may be reported separately from the CSR in a scientific report or 
publication.
8.7.1
Storage and Destruction of Genetic Samples 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples may be stored no longer than 15 
years following LSLV or other period as per local requirements, after which they will be 
destroyed. DNA is a finite resource that may be used up during analyses. 
No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA.
For storage and destruction of genetic samples see Appendix D. 

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8.8
Health Resource Utilisation 
Health resource utilisation (HRU) and health economics data, associated with medical 
encounters, will be collected in the eCRF by the investigator and study site personnel for all 
participants throughout the study. Protocol-mandated procedures, tests, and encounters are 
excluded. At enrolment (V1), HRU information will be collected with a ‘one year’ recall 
period. At subsequent visits, HRU information will be collected with a recall period of ‘since 
the last scheduled visit’. Overall, NP-specific and asthma specific HRU data will be collected.
The data collected may be used to conduct explanatory economic analyses and will include: 

Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient), including type of surgery performed

Duration of hospitalisation (total days or length of stay, including duration by wards 
[eg, intensive care unit])

Visits

Type of NP surgery

Asthma-related and other reason procedures

Number and type of diagnostic and therapeutic tests and procedures

Outpatient participant medical encounters and interventions (including physician or 
emergency room visits, tests and procedures, and medications).
Use of systemic corticosteroids (oral, parenteral) for at least 3 days, an emergency 
room/urgent care visit with use of SCS or hospitalisation due to asthma should be recorded in 
the corresponding eCRFs. 
Any hospitalisations for more than 24 hours should be reported as an SAE. Refer to 
Appendix B 2 for reporting hospitalisation.

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9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The co-primary endpoints are the change from baseline in total NPS at Week 52 and the 
change from baseline in bi-weekly (a 14-day period) mean NCS at Week 52. 
The following 2-sided hypotheses will be evaluated in this trial:
Endpoint
Null Hypotheses
Alternative Hypotheses
Direction of 
superiority of 
tezepelumab is 
indicated by
Co-primary endpoints
NPS at 
Week 52
H01a: Difference in mean change 
from baseline in NPS at 52 weeks 
(tezepelumab minus placebo) = 0
H11a: Difference in mean change 
from baseline in NPS at 52 weeks 
(tezepelumab minus placebo) ≠ 0
A difference in 
means less than 0.
NCS at 
Week 52
H01b: Difference in mean change 
from baseline in NCS at 
52 weeks (tezepelumab minus 
placebo) = 0
H11b: Difference in mean change 
from baseline in NCS at 52 weeks 
(tezepelumab minus placebo) ≠ 0
A difference in 
means less than 0.
Key secondary endpoints
Loss of
smell at 
Week 52
H02a: Difference in mean change 
from baseline in loss of smell at 
52 weeks (tezepelumab minus 
placebo) = 0
H12a: Difference in mean change 
from baseline in loss of smell at 
52 weeks (tezepelumab minus 
placebo) ≠ 0
A difference in 
means less than 0.
SNOT-22 at 
Week 52
H02b: Difference in mean change 
from baseline in SNOT-22 at 
52 weeks (tezepelumab minus 
placebo) = 0
H12b: Difference in mean change 
from baseline in SNOT-22 at 
52 weeks (tezepelumab minus 
placebo) ≠ 0
A difference in 
means less than 0.
LMK at 
Week 52
H02c: Difference in mean change 
from baseline in LMK at 
52 weeks (tezepelumab minus 
placebo) = 0
H12c: Difference in mean change 
from baseline in LMK score at 
52 weeks (tezepelumab minus 
placebo) ≠ 0
A difference in 
means less than 0.
Time to SCS 
and/or 
surgery 
decision up 
to Week 52
H02d: HR of time to first SCS 
and/or surgery decision 
(tezepelumab/placebo) = 1
H12d: HR of time to first SCS 
and/or surgery decision 
(tezepelumab/placebo) ≠ 1
A HR less than 1.
Time to 
surgery 
decision up 
to Week 52
H03: HR of time to first surgery 
decision (tezepelumab/
placebo) = 1
H13: HR of time to first surgery 
decision (tezepelumab/placebo) ≠ 1
A HR less than 1.

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Endpoint
Null Hypotheses
Alternative Hypotheses
Direction of 
superiority of 
tezepelumab is 
indicated by
Time to SCS 
up to 
Week 52
H04: HR of time to first SCS 
(tezepelumab/placebo) = 1
H14: HR of time to first SCS 
(tezepelumab/placebo) ≠ 1
A HR less than 1.
NPSD TSS
H05: Difference in mean change 
from baseline in NPSD TSS at 
52 weeks (tezepelumab minus 
placebo) = 0
H15: Difference in mean change 
from baseline in NPSD TSS at 
52 weeks (tezepelumab minus 
placebo) ≠ 0
A difference in 
means less than 0.
FEV1 at 
Week 52
Subset of 
participants 
with co-
morbid 
asthma 
/AERD/ 
NSAID-
ERD 
H06: Difference in mean change 
from baseline in pre-BD FEV1 at 
52 weeks (tezepelumab minus 
placebo) = 0
H16: Difference in mean change 
from baseline in pre-BD FEV1 at 
52 weeks (tezepelumab minus 
placebo) ≠ 0
A difference in 
means greater than 
0.
BD bronchodilator; FEV1 forced exhalation volume in 1 second; LMK Lund-MacKay score; NPS nasal polyp 
score; NCS nasal congestion score; SCS systemic corticosteroids; SNOT-22 SinoNasal outcome test.
Testing strategy for confirmatory endpoints
The overall type I error rate will be strongly controlled at the 0.05 level across primary and 
key secondary endpoints. The NPS and NCS are co-primary endpoints and, as such, both 
primary endpoints will be tested at the 5% level to determine the success of the study. If both 
are significant at 5%, then testing will proceed to the key secondary endpoints. 
The following hierarchical testing strategy will be applied:
Level 1
The null hypotheses H01a and H01b (for endpoints NPS and NCS at Week 52) will be tested 
at a 2-sided 5% significance level
Level 2
If both H01a and H01b are rejected at the 2-sided 5% significance level, then the null 
hypotheses H02a, H02b, H02c, and H02d will be tested using the truncated Holm procedure 
(truncation parameter gamma = 0.8) at an overall 2-sided 5% significance level for endpoints:

Change from baseline in loss of smell at Week 52

Change from baseline in SNOT-22 at Week 52

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
Change from baseline in LMK at Week 52

Time to SCS and/or surgery decision for NP up to Week 52
Under this approach, the 4 p-values are first ordered from smallest to the largest. If the 
smallest p-values (2-sided) within level 2 is < 0.0125, the treatment effect for the endpoint 
associated with this p-value is considered significant. The test then evaluates the next smallest 
p-value at (0.05 + 0.8/3)*5% significance level (2-sided) and if significant, the third smallest 
at (0.05 + 0.8/2)*5% significance level (2-sided), and if significant, the fourth at 
(0.05 + 0.8)*5% significance level (2-sided). If none of the level 2 hypotheses are rejected, the 
procedure will stop. 
Level 3 - 6
If one, two, three, or four of H02a, H02b, H02c, and H02d are rejected the null hypotheses 
H03, H04, H05, and H06 will be tested in a sequential order at 0.25%, 0.5%, 0.75%, or 5% 
significance level (2-sided), respectively. 
The testing procedure is summarised graphically in Figure 4. For the US FDA, the described 
testing procedure will be applied to the US FDA primary estimand described in 
Section 9.4.1.2.

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Figure 4
Testing Procedure
FEV1, forced expiratory volume in 1 second; LMK, Lund-Mackay score; NCS, nasal congestion score; NPSD, 
nasal polyp symptom diary; NPS, nasal polyp score; Q4W, every four weeks; SCS, systemic corticosteroids;
SNOT-22, Sino-Nasal Outcome Test, 22 item; TSS, total nasal symptom score.

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9.2
Sample Size Determination
Approximately 400 participants will be randomised to tezepelumab 210 mg Q4W or matching 
placebo in a 1:1 ratio.
The study is sized to provide compelling statistical evidence for the co-primary endpoints 
(NPS and NCS) and key secondary endpoints of change from baseline in loss of smell, LMK, 
and SNOT-22 (considering a significance level of 0.01 in the sample size calculations), as well 
as sufficient power to assess the composite endpoint of time to SCS and/or surgery (2-sided 
level of 1%). In addition, this sample size allows assessment of the effect of tezepelumab vs 
placebo on NPS and NCS in key subgroups and provides a reasonably-sized safety database.
Assuming a population standard deviation (SD) of 2.25 in total NPS change from baseline and 
1.22 in NCS change from baseline, this sample size of 200 participants per arm will provide at 
least 95% total power to observe a statistically significant difference at a 2-sided 1% level on 
both co-primary endpoints if the true effect of tezepelumab is -1.8 in total NPS change from 
baseline and -0.87 in NCS change from baseline. The assumption of true effects is based on 
reported estimates in the dupilumab Phase III nasal polyp studies. It is expected that treatment 
with tezepelumab will demonstrate similar or better treatment effects over a 52-week period. 
The assumed SD was estimated based on the CIs of the corresponding endpoints in the 
dupilumab Phase III nasal polyp studies (Bachert et al 2019).
Two hundred participants per arm also provides at least 95% power to detect a statistically 
significant difference at a 2-sided 1% level in secondary endpoints of change from baseline in 
loss of smell LMK, and SNOT-22 (assuming mean [SD] of -1 [1.3], -5 [5.45], and -17.4 
[26.8], respectively). The size of the study also provides at least 95% power to detect a 
statistically significant difference at the 2-sided 1% level in the key secondary endpoint time 
to SCS and/or decision of surgery for NP, assuming a true reduction in risk of 67% (hazard 
ratio [HR] of 0.33) with a placebo rate at Week 52 of 35% (placebo data estimated from 
dupilumab SINUS-52). In addition, this provides at least 80% power to detect a difference (at 
a nominal 5% significance level) in the key secondary endpoint of time to decision of surgery, 
assuming a true HR of 0.33 and a placebo rate at Week 52 of 11% (placebo data estimated 
from pooled dupilumab studies SINUS-24 and SINUS-52). Assuming 50-70% of participants 
will have co-morbid asthma, the sample size will also provide > 80% power for the co-
primary endpoints at a 2-sided 5% significance level in the co-morbid asthma subgroups.

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9.3
Populations for Analyses
The following populations are defined:
Table 14
Populations for Analysis
Population/Analysis set
Description
Enrolled
All participants who sign the informed consent form (ICF).
Randomly Assigned to Study 
Intervention
All participants randomised to study treatment (irrespective of whether 
treatment is subsequently taken).
Full Analysis Set
All participants randomised to study treatment who received at least one 
dose of IMP, irrespective of their protocol adherence and continued 
participation in the study.
Safety Set
All participants who received at least one dose of IMP.
Pharmacokinetic analysis set 
(PK)
All participants in the FAS who received active (tezepelumab) treatment 
and had at least one detectable tezepelumab serum concentration from a 
sample collected post-treatment that is assumed not to be affected by factors 
such as protocol deviations (PDs).
Efficacy analyses will be based on the FAS (defined above) according to their randomised 
treatment. 
Safety analyses and anti-drug antibodies (ADA) analyses will be based on the safety analysis 
set, with participants assigned according to their actual treatment. Further details of how 
actual treatment will be determined for analysis in the event of treatment dispensing errors,
etc. will be specified in the SAP. Any important deviations from the randomised treatment 
assignment, and any participants that have received investigational product without being 
randomised, will be listed and considered when interpreting the safety data. 
All PK summaries will be based on the PK analysis set.
9.4
Statistical Analyses
Analyses will be performed by AstraZeneca or its representatives. A comprehensive statistical 
analysis plan will be developed and finalised before primary database lock and will describe 
the participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical 
analyses. Any deviations from this plan will be reported in the clinical study report. Additional 
analyses assessing the impact of COVID-19 will be included in the SAP, as needed.
9.4.1
General Considerations
There will be 2 database locks (DBLs) in this study. The primary DBL will be conducted after 
the last participant completes Week 52, and the final DBL will be conducted once the last 
participant has completed the last safety follow-up visit (Week 76 for the first 200 participants 

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completing the treatment period and Week 64 for the remaining participants). All analyses of 
the primary and key secondary endpoints will be performed based on the primary DBL data.
All personnel involved with the analysis and conduct of the study will remain blinded until 
primary database lock and important protocol deviations during the double-blind treatment 
period identified.
After primary DBL, treatment allocation for participants 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 participant. Frequency and percentages of participant 
disposition and reasons for discontinuation of IP will be presented. In addition, frequency and 
percentages of withdrawal from the study together with reasons will be presented.
Demographics and participant characteristics will be summarised by treatment group using 
frequency and percentages (for categorical variables) and n, mean, standard deviation, 
minimum, median and maximum (for continuous variables) using the full analysis set.
Relevant medical history/current medical conditions will be summarised by treatment group, 
system organ class and preferred term of the MedDRA dictionary using frequency and 
percentage of participants for each treatment group.
Prior and concomitant medications, categorised according to the WHO Drug Reference List 
dictionary which employs the Anatomical Therapeutic Chemical (ATC) classification system, 
will be summarised by treatment group as frequency and percentage of participant reporting 
usage. 
Important protocol deviations during the double-blind treatment period will be defined prior to 
unblinding and will be summarised by treatment group. The definitions of each category of 
important protocol deviation will be specified in the study Non-Compliance Handling Plan, 
and will include (but may not be limited to): participants who were randomised to study 
treatment without fulfilling key entry criteria; participants who received prohibited or 
restricted concomitant medications, participants who received the incorrect study treatment or 
study dose at any time during the 52-week double-blind treatment period.

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9.4.1.1
Primary Estimand
The primary estimand is described as follows:

Treatment: Randomised treatment of tezepelumab 210 mg Q4W or placebo 

Population of interest: Adult participants with severe CRSwNP (total NPS ≥5) and an 
inadequate response to standard of care therapy, based on their randomised treatment and 
receiving at least one dose of IP

Endpoints of interest: Change from baseline in co-primary endpoints: NPS and bi-
weekly mean NCS at Week 52.

Population level summary for the endpoint: Difference in means between tezepelumab 
and placebo treatment groups

Handling of intercurrent events (ICEs):

Nasal polyp surgery: The participants who had nasal polyp surgery during the study 
conduct would be considered poor outcome. The composite variable strategy will be 
applied where the worst possible score (ie, 8 for NPS and 3 for NCS) will be used for 
the post-surgery scores.

SCS for NP: The participants who received SCS (at least 3 consecutive days of OCS 
or equivalent 1 intramuscular injection) for NP would be considered poor outcome 
but less severe than surgery. The composite variable strategy will be applied where 
the worst observation prior to the SCS will be carried forward (WOCF) for the post-
SCS scores.

Treatment discontinuation: The treatment policy strategy will be applied. Data 
collected for participants who do not have rescue therapy are used regardless of 
whether treatment discontinuation occurs.

Adherence to background MFNS or an equivalent INCS and IP: The treatment 
policy strategy will be applied. Data collected for participants who do not have 
rescue NP surgery or SCS are used regardless of the adherence of background MFNS 
or an equivalent INCS and IP.

Biologic use for NP: The participants who received another biologic for NP would 
be considered poor outcome but less severe than surgery. The composite variable 
strategy will be applied where the worst observation prior to the biologic for NP will 
be carried forward (WOCF) for the post-biologic scores.

Steroids or biologic use for co-morbid conditions: The treatment policy strategy 
will be applied for the participants who received steroids or another biologic for co-
morbid conditions.

COVID-19 related: intercurrent events caused by COVID-19 including protocol 
deviations caused by COVID-19, COVID vaccination, and COVID-19 infection. The 
treatment policy strategy will be applied.

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9.4.1.2
US FDA Primary Estimand
Following the US FDA Chronic Rhinosinusitis with Nasal Polyps: Developing Drugs for 
Treatment Guidance for Industry (FDA 2023), different strategies will be used for the ICEs of 
SCS rescue for NP and biologic use for NP.

SCS for NP: The treatment policy strategy will be applied and data after SCS rescue will
be included in the analysis.

Biologic use for NP: The composite variable strategy will be applied where the worst 
possible score (ie, 8 for NPS and 3 for NCS) will be used for the post-biologic scores.
9.4.1.3
Supplementary Estimand
Composite variable strategy will be used for SCS for NP, biologic use for NP, and treatment 
discontinuation: the worst possible score will be used after the ICEs.
9.4.2
Efficacy 
9.4.2.1
Primary Endpoint(s)
For the primary estimand, data collected after surgery will be replaced with the worst possible 
score. Data collected after SCS will be replaced with the worst observation prior to the SCS 
(WOCF). Data collected after treatment discontinuation without surgery or SCS will be 
included in the analysis. For participants whose post-baseline data are all missing, the baseline 
value will be used in the analysis. For participants who discontinue the study without surgery 
or SCS, multiple imputation will be used to impute missing data assuming missing at random 
(MAR). 
Each of the imputed datasets will be analysed using an analysis of covariance (ANCOVA) 
model with the baseline value as a covariate, and treatment group, baseline co-morbid 
asthma/AERD/NSAID-ERD status, prior surgery status, and regions as factors. Rubin’s rule 
will be applied to combine analysis results (point estimates and standard errors) from the 
imputed datasets. Descriptive statistics including number of participants, mean, standard error, 
and least squares (LS) means will be provided for each time point. In addition, difference in 
LS means and the corresponding 95% confidence intervals (CIs) will be provided along with 
the p-values.
For the FDA and supplementary estimands, strategies for the ICEs are described in 
Sections 9.4.1.2 and 9.4.1.3 and will be applied accordingly. Additional sensitivity analyses 
will be performed to examine the MAR assumptions about missing data. Details of the 
supplementary and sensitivity analyses will be included in the SAP.

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Subgroup analyses
For the purpose of exploring consistency of treatment effect across subgroups, a similar model 
will be fitted as for the primary analysis with additional factors for the relevant subgroup 
variable and its interaction with treatment.  Key subgroups include:

Age 

Gender

Race

Prior surgery status

Allergic rhinitis 

Co-morbid asthma status 

AERD/NSAID-ERD 

Baseline eosinophil count 

Body mass index 

Region 
9.4.2.2
Secondary Endpoint(s)
The analyses of the key secondary endpoints are described as follows:
The change from baseline in LMK, SNOT-22, loss of smell, and NPSD TSS at Week 52 will 
be analysed using the method as described in the primary analyses approach for the co-
primary endpoints. 
Time to first decision of surgery or SCS for NP during the 52-week treatment period will be 
analysed using a Cox proportional hazards model, adjusting for treatment, baseline co-morbid 
asthma/AERD/NSAID-ERD status, prior surgery status, and regions. The event of interest is 
the first SCS use or decision for nasal polyp surgery, whichever is earlier if both occur. 
Hazard ratios and corresponding 95% CIs and p-values will be presented. The proportion of 
participants having a surgery decision or SCS up to Week 52 will be estimated using the 
Kaplan-Meier method. The same method will be used to analyse the time to first surgery 
decision and time to first SCS separately.  
Analysis of the change from baseline in FEV1 at Week 52 will use a treatment policy for all 
intercurrent events defined in Section 9.4.1.1. The population of interest will be the subset of 
participants with baseline co-morbid asthma/AERD/NSAID-ERD. The model includes 
baseline value of FEV1 as a covariate and treatment, prior surgery status, and regions as 
factors.
Details on statistical analyses for other secondary endpoints, including the tezepelumab serum 

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concentration and ADA for the evaluation of PK and immunogenicity, will be provided in the 
SAP.
9.4.3
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version in force at each database lock. The definition of on treatment and post-
treatment for adverse event analyses will be given in the SAP.
The number and percentage of participants with on treatment and post-treatment adverse 
events will be tabulated separately by preferred term and system organ class. An event that 
occurred one or more times during a period will contribute 1 observation to the numerator of 
the proportion. The denominator of the proportion will comprise all participants in the safety 
population. On treatment adverse events will also be summarised by intensity/severity and 
separately, by causality/relatedness (as determined by the investigator). Should a participant 
report the same preferred term/system organ class within multiple intensity/severity or 
causality/relatedness categories, the participant’s worst occurrence (most severe/most related) 
will be tabulated. Adverse events, SAEs, AEs leading to death, and AEs leading to 
discontinuation of IP will be summarised for each treatment group as applicable.
An overall summary of on treatment AEs will be presented by treatment group adjusted for 
participant exposure to treatment.
AEs of Special Interest (AESIs), as defined in Section 8.3.6 will also be summarised 
descriptively by treatment group.
Laboratory data will be summarised by presenting shift tables using normal ranges (baseline 
to most extreme post-baseline value) and by presenting summary statistics of observed and 
change from baseline values (means, medians, quartiles, ranges). The incidence of clinically 
notable laboratory abnormalities will be summarised.
Vital signs data will be summarised by presenting summary statistics of observed and change 
from baseline values. The incidence of clinically notable vital signs abnormalities will be 
summarised. Abnormal ECGs as per Investigator's overall interpretation will be summarised.
9.4.4
Other Analyses 
Biomarker and selected exploratory endpoint analysis details will be described in the 
exploratory analysis plan, which will be finalised before primary database lock. The results 
may be reported outside the CSR. Analyses for other exploratory endpoints will be detailed in 
the SAP.

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9.5
Interim Analyses 
No interim analyses are planned in this trial.
9.6
Data Monitoring Committee
A data safety monitoring board will not be utilised for this study.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki as amended at 64th WMA General Assembly, Fortaleza, 
Brazil, October 2013, and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations

The protocol, revised protocol, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated.

Any revised protocol will require IRB/IEC and applicable Regulatory Authority approval 
before implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO, but the accountability remains with AstraZeneca.

The investigator will be responsible for providing oversight of the conduct of the study at
the site and adherence to requirements of 21 CFR 312.120, 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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Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to AstraZeneca 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.

AstraZeneca has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

For all studies except those utilising 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.

Adherence to European Medical Device Regulation 2017/745 for clinical device research 
(if applicable), and all other applicable local regulations

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from AstraZeneca 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.

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
The investigator should have a process in place to ensure that:

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 (e-mail address or telephone number) provided by AstraZeneca.
A 2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary, and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorised representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study centre.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative.

If a participant’s partner becomes pregnant from the date of the first administration of IP 
until 16 weeks after the last administration of IP, the partner is asked to sign the Adult 
Study Informed Consent Form for Pregnant Partners of Study Participant and provide 
information about the pregnancy accordingly.
Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses and documents the collection and use of 

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any mandatory and/or optional human biological samples. The investigator or authorised 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and any potential future use. Participants will be told that they are free to refuse to 
participate in any optional samples or the future use and may withdraw their consent at any 
time and for any reason during the retention period. 
A 4
Data Protection

Participants will be assigned a unique identifier by AstraZeneca. Any participant records 
or datasets that are transferred to AstraZeneca will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

The participant must be informed that his/her personal study related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent.

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.

The participant must be informed that data will be collected only for the business needs. 
We will only collect and use the minimum amount of personal data to support our 
business activities and will not make personal data available to anyone (including internal 
staff) who is not authorised or does not have a business need to know the information. 

The participant must be informed that in some cases their data may be pseudonymised. 
The General data Protection Regulation (GDPR) defines pseudonymisation as the 
processing of personal data in such a way that the personal data can no longer be 
attributed to a specific individual without the use of additional information, provided that 
such additional information is kept separately and protected by technical and 
organisational measures to ensure that the personal data are not attributed to an identified 
or identifiable natural person.

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Personal Data Breaches
A ‘personal data breach’ means a breach of security leading to the accidental or unlawful 
destruction, loss, alteration, unauthorised disclosure of, or access to, personal data transmitted, 
stored or otherwise processed.

In compliance with applicable laws, the Data Controller2 for the processing activity where 
the personal data breach occurred (AstraZeneca or respectively the site), will notify the 
data protection authorities without undue delay within the legal terms provided for such 
notification and within the prescribed form and content.

Whilst AstraZeneca has processes in place to deal with personal data breaches it is 
important that investigators that work with AstraZeneca have controls in place to protect 
patient data privacy.
The Investigator should have a process in place to ensure that:

allow site staff or service providers delegated by the investigator/institution to identify the 
occurrence of a (potential) personal data breaches.

Any (potential) personal data breach is promptly reported to AstraZeneca or delegated 
party, through the contacts (e-mail address or telephone number) provided by 
AstraZeneca.
AstraZeneca and the site must demonstrate that they:

have taken all necessary steps to avoid personal data breaches and 

have undertaken measures to prevent such breaches from occurring in the first place and 
to mitigate the impact of occurred data breaches (eg, applying encryption, maintaining 
and keeping systems and IT security measures up-to-date, regular reviews and testing, 
regular training of employees, and developed security policies and standards).

where possible, have developed an internal data breach reporting and investigation 
process and internal protocols with guidance on how to respond swiftly and diligently to 
the occurrence of a personal data breach.

where it has not been possible to develop an internal data breach reporting and 
investigation process, the site follows AstraZeneca’s instructions.
                                               
2The data controller determines the purposes for which and the means by which personal 
data is processed, as defined by the European Commission

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Notification of personal Data Breach to participants:

Notification to participants is done by the site for the data breaches that occurred within 
the processing activities for which the site is the Data Controller and for data breaches 
occurred within the processing activities of AstraZeneca as the Data Controller, the 
notification is done in collaboration with the site and is performed by the site and/or 
Principal Investigator, acting on behalf of AstraZeneca, so that AstraZeneca has no access 
to the identifying personal information of the participants. The site and/or Principal 
Investigator shall conduct the notification by contacting the participants using the 
information that they gave for communication purposes in clinical research.

If a personal data breach occurs in a processor’s systems, engaged by AstraZeneca, the 
processor under contractual obligations with AstraZeneca promptly and in due course 
after discovering the breach notifies AstraZeneca and provides full cooperation with the 
investigation. In these cases, to the extent AstraZeneca is the Data Controller for the 
processing activity where the breach occurred, it will be responsible for the notification to 
data protection authorities and, if applicable, to participants. If the personal data breach 
needs to be notified to the participants, the notification to participants is done in 
collaboration with the site and is performed by the site and/or Principal Investigator, 
acting on behalf of the Sponsor, so that AstraZeneca has no access to the identifying 
personal information of the participants.

If a personal data breach involving an AstraZeneca's representative device (ie, Study 
Monitor laptop), AstraZeneca representative will provide AstraZeneca with all of the 
information needed for notification of the breach, without disclosing data that allows 
AstraZeneca directly or indirectly to identify the participants. The notification will be 
done by AstraZeneca solely with the information provided by the Study Monitor and in 
no event with access to information that could entail a risk of re-identification of the 
participants. If the data breach must be notified to the data subjects, the notification will 
be done directly by the Study Monitor in collaboration with the site and/or Principal 
Investigator, acting on behalf of the Sponsor, so that AstraZeneca has no access to the 
identifying personal information of the participants. The contract between AstraZeneca 
and the Study Monitor shall expressly specify these conditions.

The contract between the site and AstraZeneca for performing the clinical research 
includes the provisions and rules regarding who is responsible for coordinating and 
directing the actions in relation to the breaches and performing the mandatory 
notifications to authorities and participants, where applicable.
A 5
Committees Structure
The safety of all AstraZeneca clinical studies is closely monitored on an ongoing basis by 
AstraZeneca representatives in consultation with Participant Safety.  Issues identified will be 

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addressed; for instance, this could involve amendments to the Clinical Study Protocol and 
letters to investigators. 
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the main study results when they are available. The clinical study and/or 
summary of main study results may also be available on other websites according to the 
regulations of the countries in which the main study is conducted.
A 7
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy, including definition of study critical data items 
and processes (eg, risk-based initiatives in operations and quality such as Risk 
Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of non-compliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the 
Monitoring Plan. 

AstraZeneca or designee is responsible for medical oversight throughout the conduct of 
the study which includes clinical reviews of study data in accordance with the currently 
approved protocol. Monitoring details describing clinical reviews of study data from a 
medical perspective are included in more detail in the Medical Oversight Plan.

AstraZeneca or designee is responsible for the data management of this study including 
quality checking of the data.

AstraZeneca assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations).

Study monitors will perform ongoing source data verification as per the Monitoring 
Plan(s) to confirm that data entered into the eCRF by authorised site personnel are 
accurate, complete, and verifiable from source documents; that the safety and rights of 
participants are being protected; and that the study is being conducted in accordance with 

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the currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for a minimum of 25 years after study archiving or as 
required by local regulation, according to the AstraZeneca Global Retention and Disposal 
(GRAD) Schedule. No records may be destroyed during the retention period without the 
written approval of AstraZeneca. No records may be transferred to another location or 
party without written notification to AstraZeneca.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.

Definition of what constitutes source data can be found in the monitoring plan.
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first site open and will be the study start date.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development

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If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant
and should assure appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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

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Life-threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred, or it is suspected that use or continued use of the product would result in the 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important medical event or medical treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
Intensity rating scale:

mild (awareness of sign or symptom, but easily tolerated)

moderate (discomfort sufficient to cause interference with normal activities)

severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 

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

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The causality assessment is performed based on the available data including enough 
information to make an informed judgement. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 4
Medication Error, Drug Abuse, and Drug Misuse
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an 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 recognised that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, eg, wrong route or wrong site of administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a
solid tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 

Wrong participant received the medication (excluding IRT/RTSM errors)

Wrong drug administered to participant (excluding IRT/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT/RTSM - including those which lead to one of the 
above listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) eg,, forgot to take medication

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
Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the Data Entry Site (DES) using the Drug Abuse Report Form. This form should be used both 
if the drug abuse happened in a study participant or if the drug abuse 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

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
The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole

Only half the dose is taken because the study participant feels that he/she is feeling better 
when not taking the whole dose

Someone who is not enrolled in the study intentionally takes the drug

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Appendix C
Handling of Human Biological Samples
C 1
Chain of custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers.
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
or destroyed 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 participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed, and the action documented. If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:

Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate

Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented

Ensures that the participant and AstraZeneca are informed about the sample disposal

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AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented, and study site notified.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A pathogens are eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to UN 
2814. Infectious substances which cause disease only in animals must be assigned to UN 
2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not participant to these Regulations unless 
they meet the criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry ice content

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Appendix D
Optional Genomics Initiative Sample
D 1
Use/analysis of DNA
Genetic variation may impact a participant’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 aetiology; 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 participants.

AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response 
to medications. This genetic research may lead to better understanding of diseases, better 
diagnosis of diseases or other improvements in health care and to the discovery of new 
diagnostics, treatments or medications. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting participants.

This optional genetic research may consist of the analysis of the structure of the 
participant´s DNA, ie, the entire genome. 

The results of genetic analyses may be reported in a separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.

The samples will be retained while research on tezepelumab continues but no longer than 
15 years after LSLV or other period as per local requirements.
D 2
Genetic research plan and procedures
Selection of genetic research population

All participants will be asked to participate in this genetic research. Participation is 
voluntary and if a participant declines to participate there will be no penalty or loss of 
benefit. The participant will not be excluded from any aspect of the main study.
Inclusion criteria

For inclusion in this genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and provide informed consent 
for the Genomics Initiative 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-leucocyte depleted whole blood transfusion in 120 days of genetic sample 
collection
Withdrawal of consent for genetic research:  

Participants may withdraw from this genetic research at any time, independent of any 
decision concerning participation in other aspects of the main study. Voluntary 
withdrawal will not prejudice further treatment. Procedures for withdrawal are outlined in 
Section 7 of the main Clinical Study Protocol.
Collection of samples for genetic research

The blood sample for this genetic research will be obtained from the participants at the 
Randomisation Visit. Although DNA is stable, early sample collection is preferred to 
avoid introducing bias through excluding participants who may withdraw due to an AE. If 
for any reason the sample is not drawn at the Randomisation Visit, it may be taken at any 
visit until the last study visit. Only one sample should be collected per participant for 
genetics during the study.
Coding and storage of DNA samples

The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum 
of 15 years from date of last subject last visit or may differ depending on local retention, 
after which they will be destroyed. DNA is a finite resource that is used up during 
analyses. Samples will be stored and used until no further analyses are possible or the 
maximum storage time has been reached.

An additional second code will be assigned to the sample either before or at the time of 
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 organisation. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organisations working with the DNA).

The link between the participant enrolment/randomisation code and the second number 
will be maintained and stored in a secure environment, with restricted access at 
AstraZeneca or designated organisations. The link will be used to identify the relevant 
DNA samples for analysis, facilitate correlation of genotypic results with clinical data, 

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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 genetic 
research component, are outlined in Appendix A.
Informed consent

The genetic component of this study is optional, and the participant may participate in 
other components of the main study without participating in this genetic component. To 
participate in the genetic component of the study the participant must sign and date both 
the consent form for the main study and the addendum for the Genomics Initiative 
component of the study. Copies of both signed and dated consent forms must be given to 
the participant and the original filed at the study centre. The Principal Investigator(s) is 
responsible for ensuring that consent is given freely and that the participant understands 
that they may freely withdrawal from the genetic aspect of the study at any time.
Participant data protection

AstraZeneca will not provide individual genotype results to participants, any insurance 
company, any employer, their family members, general physician unless required to do so 
by law.

Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the participant. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a participant.
For example, in the case of a medical emergency, an AstraZeneca Physician or an 
investigator might know a participant’s identity and also have access to his or her genetic 
data. Regulatory authorities may require access to the relevant files, though the 
participant’s medical information and the genetic files would remain physically separate.
Data management

Any genetic data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyse the samples.

AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with 
other researchers, such as hospitals, academic organisations or health insurance 
companies. This can be done by placing the results in scientific databases, where they can 
be combined with the results of similar studies to learn even more about health and 
disease. The researchers can only use this information for health-related research 

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purposes. Researchers may see summary results, but they will not be able to see 
individual participant data or any personal identifiers. 

Some or all of the clinical datasets from the main study may be merged with the genetic 
data in a suitable secure environment separate from the clinical database.

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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. 
During the course of the study the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a participant meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review 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 Hy’s Law (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 Serious Adverse Events (SAEs) and Adverse Events (AEs) 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)
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, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 

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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
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 participant who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3xULN

AST ≥ 3xULN

TBL ≥ 2xULN
Central laboratories being used:
When a participant meets any of the PHL identification criteria, in isolation or in combination, 
the central laboratory will immediately send an alert to the investigator (also sent to 
AstraZeneca representative). 
The investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the investigator will:

Notify the AstraZeneca representative 

Request a repeat of the test (new blood draw) by the central laboratory without 
delay

Complete the appropriate unscheduled laboratory eCRF module(s) with the 
original local laboratory test result
When the identification criteria are met from central or local laboratory results the investigator 
will without delay:

Determine whether the participant meets PHL criteria (see Section E 2 for 
definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results)

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E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria not met
If the participant does not meet PHL criteria the investigator will:

Inform the AstraZeneca representative that the participant has not met PHL 
criteria

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
E 4.2
Potential Hy’s Law Criteria met
If the participant does meet PHL criteria the investigator will:

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 participants that met PHL criteria prior to starting IMP, the investigator is not 
required to submit a PHL SAE unless there is a significant change in the participant’s 
condition

The study physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) 
and the continuous review of data

Subsequent to this contact the investigator will:

Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.

Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the study physician. This includes deciding which the tests available 
in the Hy’s Law lab kit should be used. 

Complete the 3 Liver eCRF Modules as information becomes available.
A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST or total bilirubin) in isolation 
or in combination, or a clinically relevant change in associated symptoms. The determination 
of whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the study physician if there is any uncertainty.

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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 study 
physician contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days from 
date PHL criteria was met. The AstraZeneca Global Clinical Lead or equivalent and Global 
Safety Physician will also be involved in this review together with other participant 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 eCRF

If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE eCRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 

The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply

As there is no alternative explanation for the 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 

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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 and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.
E 6
Laboratory tests
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 a
IgG anti-HCV
HCV RNA a
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-
transferrin) b
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)

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Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin b
Transferrin saturation
a
HCV RNA; HCV DNA are only tested when IgG anti-HCV is positive or inconclusive
b
CD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly
E 7
References
Aithal et al, 2011
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation

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Appendix F
Anaphylaxis: signs and symptoms, management
F 1
Introduction 
As with any antibody, allergic reactions to dose administration are possible. The World Health 
Organization has categorised anaphylaxis into 2 subgroups, which are clinically 
indistinguishable: immunologic [IgE-mediated and non-IgE-mediated (eg, IgG and immune 
complex mediated) and nonimmunologic (Johansson et al 2004). The clinical criteria for 
defining anaphylaxis for this study are listed in Appendix F 2. A guide to the signs and 
symptoms and management of acute anaphylaxis is provided in Appendix F 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 recognise and treat anaphylaxis according to local guidelines. If an 
anaphylactic reaction occurs, a blood sample will be drawn from the participant as soon as 
possible after the event, at 60 minutes ± 30 minutes after the event, and at discharge for 
analysis of serum tryptase.
F 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 (eg, generalised hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST ONE OF THE FOLLOWING
(a) Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, hypoxemia).
(b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg,, 
hypotonia [collapse], syncope, incontinence).
2
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
participant (minutes to several hours): 
(a) Involvement of the skin-mucosal tissue (eg,, generalised hives, itch-flush, swollen 
lips-tongue-uvula).
(b) Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, hypoxemia).
(c) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence).
(d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting).
3
Reduced BP after exposure to known allergen for that participant (minutes to several 
hours): Adults: systolic BP of less than 90 mmhg or greater than 30% decrease from that 
participant’s baseline

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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 is common.
F 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 oedema

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

Rhinorrhoea

Change in voice

Metallic taste

Nausea, vomiting, diarrhoea, abdominal cramps and bloating

Light-headedness

Headache

Uterine cramps

Generalised warmth

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F 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 participant 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 
(a) Consider epinephrine infusion.
(b) Consider H1 and H2 antihistamines.
(c) Consider nebulised β2 agonist [eg, albuterol (salbutamol)] for bronchospasm resistant 
to epinephrine.
(d) Consider systemic corticosteroids.
(e) Consider vasopressor (eg, dopamine).
(f) Consider glucagon for participant taking β-blocker.
(g) Consider atropine for symptomatic bradycardia.
(h) Consider transportation to an emergency department or an intensive care facility.
(i)
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and prolonged 
resuscitation efforts are encouraged, if necessary.
Adapted from: 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.
Johansson et al 2004
Johansson SGO, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al. Revised 
nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the 
World Allergy Organization, October 2003. J Allergy Clin Immunol. 2004; 113(5): 832-6.

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Appendix G
Abbreviations
Abbreviation or 
special term
Explanation
ACQ-6
Asthma Control Questionnaire-6
ADA
Anti-drug antibodies
ADE
Adverse Device Effect
AE
Adverse Event
AERD
Aspirin exacerbated respiratory disease
AAER
Annualised asthma exacerbation rate
AESI
Adverse Event of Significant Interest
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANCOVA
Analysis of Covariance
APFS
Accessorised pre-filled syringe
AST
Aspartate aminotransferase
ATS
American Thoracic Society
BD
Bronchodilator
BP
Blood Pressure
BP
Bodily Pain (in SF-36v2 scale only)
BUN
Blood urea nitrogen
CDC
The Centers for Disease Control and Prevention
CI
Confidence Intervals
CIOMS
Council for International Organizations of Medical Sciences
CK
Creatine kinase
COVID-19
Coronavirus disease 2019
CRO
Contract Research Organisation
CRF
Case Report Form
CRSwNP
Chronic rhinosinusitis with nasal polyps
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CT
Computed tomography
CTIS
Clinical Trials Information System
DBL
Database Lock
DCO
Data Cut Off
DILI
Drug Induced Liver Injury
DNA
Deoxyribonucleic acid 

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Abbreviation or 
special term
Explanation
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
eCRF
electronic Case Report Form
EDC
Electronic Data Capture
EGPA
Eosinophilic Granulomatosis with Polyangiitis
EMA
European Medical Agency
EOT
End of Treatment
ePRO
Electronic Patient Reported Outcome
EQ-5D-5L
European Quality of Life-5 Dimensions-5 Levels
ER
Emergency Room
ERS
European Respiratory Society
EU
European Union 
EUA
Emergency Use Authorisation 
FAS
Full Analysis Set
FDA
U.S. Food and Drug Administration
FEF
Forced Expiratory Flow
FeNO
Fractional Exhaled Nitric Oxide
FEV1
Forced expiratory volume in 1 second
FSH
Follicle-stimulating Hormone
FSI
First Participant In
FU
Follow-up
FUD
Follow-Up Discontinuation Visit
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GLI
Global Lung Function Initiative
GMP
Good Manufacturing Practice
Hb
Haemoglobin
HBS
Human Biological Sample
HCG
Human Chorionic Gonadotropin
HCP
Health Care Professional
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio
HRQoL
Health-Related Quality of Life

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Abbreviation or 
special term
Explanation
HRU
Healthcare Resource Utilisation
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
IAC
Independent Adjudication Committee 
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IgE
Immunoglobulin E
ILC2
Group 2 Innate lymphoid cells
IMP
Investigational Medicinal Product
INCS
Intranasal corticosteroids 
IP
Investigational product
IPD
Investigation Product Discontinuation
IRC
Independent Review Charter
ISF
Investigator Study File
IUD
Intrauterine Device
IUS
Intrauterine System
IWRS
Integrated Web Response System
JESREC
Japanese Epidemiological Survey of Refractory Eosinophilic Chronic 
Rhinosinusitis Classification
LABA
Long-Acting Beta-Agonist
LAMA
Long‐Acting Muscarinic Antagonists
LMK
Lund-Mackay score
LS
Least Squares
LSLV
Last Participant Last Visit
LTRA
Leukotriene Receptor Antagonists
mAb
Monoclonal Antibody
MACE
Major Adverse Cardiac Events
MAR
Missing At Random
MCID
Minimal Clinical Importance Difference
MCV
Mean Corpuscular Volume
MedDRA
Medical Dictionary for Regulatory Activities
MFNS
Mometasone Furoate Nasal Spray
MoA
Mechanism of Action
nAb
Neutralising Antibody
NC
Nasal Congestion

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Abbreviation or 
special term
Explanation
NCS
Nasal Congestion Score
NIMP
Non-Investigational Medicinal Product
NP
Nasal polyposis
NPIF
Nasal peak inspiratory flow
NPS
Nasal polyp score
NPSD
Nasal Polyp Symptom Diary
NPSSA
Nasal Polyposis Symptom Screening Assessment
NSAID-ERD
Nonsteroidal anti-inflammatory drug exacerbated respiratory disease
OCS
Oral Corticosteroids
PCD
Primary Ciliary Dyskinesia
PCR
Polymerase Chain Reaction
PD
Protocol Deviation
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PHL
Potential Hy’s Law
PI
Principal Investigator 
PK
Pharmacokinetics
PNV
Predicted Normal Values
PRO
Patient reported outcome
PSSR
Project Specific Safety Requirements
Q4W
Every four weeks
QD
Once a day
RA
Regulatory Authority
RBC
Red Blood Cells
RNA
Ribonucleic Acid
SABA
Short-Acting Beta-Agonist
SADE
Serious Adverse Device Effect
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SARS-CoV-2
Severe Acute Respiratory Syndrome Coronavirus 2
SD
Standard Deviation
SF-36v2
Short-Form 36-Item Health Survey Version 2
SmPC
Summary of Product Characteristics
SoA
Schedule of Activities
SOP
Standard Operating Procedure

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Abbreviation or 
special term
Explanation
SC
Subcutaneously
SCS
Systemic corticosteroids
SNOT-22
Sino-Nasal Outcome Test, 22 item
SOC
Standard of Care
SUSAR
Suspected Unexpected Serious Adverse Reactions
TA
Therapeutic Area
TBL
Total Bilirubin
TSLP
Thymic stromal lymphopoietin
TSS
Total Nasal Symptom Score
ULN
Upper Limit of Normal
UPSIT
University of Pennsylvania Smell Identification Test
USADE
Unanticipated Serious Adverse Device Effect
WBC
White Blood Cell
WOCBP
Women of Child Bearing Potential
WOCF
Worst Observation Prior to the SCS Carried Forward
WPAI
Work Productivity and Activity Impairment
w/v
Weight per volume

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Appendix H
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
notification from the Sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation.
H 1
Reconsent of Study Participants During Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on-site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Appendix H 2 to H 6. Local and regional regulations and/or guidelines regarding 
reconsent of study participants should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the participant’s next contact with the study site). Visiting the study sites for the 
sole purpose of obtaining reconsent should be avoided. 
H 2
Re-screening of Participants to Reconfirm Study Eligibility
Additional re-screening for screen failure due to study disruption can be performed in 
previously screened participants. The investigator should confirm this with the designated 
study physician.
In addition, during study disruption there may be a delay between confirming eligibility of a 
participant and either enrolment into the study or commencing of dosing with IP. If this delay 
is outside the screening window specified in (Section 1.3 Schedule of Activities), the 
participant will need to be rescreened to reconfirm eligibility before commencing study 
procedures. This will provide another opportunity to rescreen a participant in addition to that 
detailed in (Section 4.1.1). The procedures detailed in (Section 5.4.1) must be undertaken to 
confirm eligibility using the same randomisation number as for the participant.
H 3
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified HCP from the study site will visit the participants home/or other remote location 
as per local Standard Operating Procedures, as applicable. Supplies will be provided for a safe 

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and efficient visit. The qualified HCP will be expected to collect information per the CSP.
H 4
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix the term telemedicine visit refers to remote contact with the participants using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the participants will allow adverse events, concomitant medication, ePRO and other 
assessments at the discretion of the PI to be collected and entered on the source documents.
H 5
At home or Remote Location IP Administration Instructions
If a site visit is not possible, at home or remote location administration of IP may be 
performed by a qualified HCP, provided this is acceptable within local regulation/guidance, or 
by the participant or his/her caregiver. The option of at home or remote location IP 
administration ensures participants safety in cases of a pandemic where participants may be at 
increased risk by traveling to the site/clinic. This will also minimise interruption of IP 
administration during other study disruptions, eg, site closures due to natural disaster. 
NOTE: Before initiating consent for home IP administration visit during study disruptions 
due to cases of civil crisis, natural disaster, or public health crisis, the participant must have 
received at least the first 3 IP administrations at the site. 
Site must contact the participant by telephone to assess possible COVID-19 symptoms before 
initiating home visit.
H 5.1
At home or Remote Location IP Administration by a Qualified HCP
A qualified HCP from the study site may administer the IP at the participant’s home or other 
remote location according to the CSP. All necessary supplies and instructions for 
administration and documentation of IP administration will be provided. Additional 
information related to the visit can be obtained via a telemedicine or home visit.
H 6
Data Capture During Telemedicine or Home/Remote Visits
Data collected during telemedicine or home/remote visits will be captured by the qualified 
HCP from the study site in the source documents, or by the participant themselves.

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Appendix I
Medical Device AEs, ADEs, SAEs, SADEs, USADEs and 
Medical Device/Device Constituent Deficiencies: Definitions 
and Procedures for Recording, Evaluating and Follow-up

This appendix supports the activities described in Section 8.3.14.

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.

The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study.

For simplicity, medical device will be used to cover device constituent parts of 
combination products and standalone medical device whether investigational or approved. 
I 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. An 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 except for events in users or other persons, which only include 
events related to medical devices.

An adverse device effect (ADE) is defined as an AE related to the use of an 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.

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I 2
Definition of Medical Device SAE, SADE and USADE
A Medical Device SAE is an any serious 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 hospitalisation. Planned hospitalisation 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 foetal distress, foetal death, or a congenital anomaly or birth defect
A Medical Device SADE is:

Any ADE that has resulted in any of the consequences characteristic of an SAE 

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)
I 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 issues with information supplied by the 
manufacturer.

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I 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 (eg, 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.

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 (awareness of sign or symptom, but easily tolerated) 

Moderate (discomfort sufficient to cause interference with normal activities)

Severe (incapacitating, with inability to perform normal activities)
Other measures to evaluate AEs and SAEs may be used (eg, National Cancer Institute 
CTCAE)

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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.

The investigator will use clinical judgement 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.

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.
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 recognised follow-up 
period, the investigator will provide Sponsor with a copy of any postmortem 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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I 5
Reporting of Medical Device SAEs and SADEs 

All medical device SAEs will be reported in accordance with Section 8.3.8.
NOTE: There are additional reporting obligations for SADEs that must 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.

Any medical device deficiency that is associated with an SAE must be reported to 
AstraZeneca within 24 hours after the investigator determines that the event meets the 
definition of a medical device deficiency.

In addition to the reporting process described in Section 8.3.8, the AstraZeneca Clinical 
Study Medical Device/Device Constituent Report Form will be used to capture details of 
the device and related deficiency.

Initial notification via telephone does not replace the need for the investigator to complete 
and sign the AstraZeneca Clinical Study Medical Device/Device Constituent Report Form 
within the designated reporting time frames.

AstraZeneca will review all medical device deficiencies and determine and document in 
writing whether they could have led to an SAE. These medical device deficiencies will be 
reported to the regulatory authorities and IRBs/IECs as required by national regulations.

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Appendix J
Summary of Changes 
Amendment v5.0 17-Oct-2022
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
and in the EU Clinical Trial Regulation Article 2, 2 (13) because it significantly impacts the 
safety or physical/mental integrity of participants and the scientific value of the study.
Overall Rational for the Modification: 
This Clinical Study Protocol has been amended to update the nasal polyp surgery endpoint, 
and to align the risk assessments with the updated Investigator Brochure edition 5.1, and to 
add assessment of pre-specified events by an Independent Event Adjudication Committee to 
the study design.
Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Protocol title 
page and 
Section 1.1
Synopsis
Added EudraCT/EU CT Number, 
clinicaltrials.gov Number and Study 
Physician details
To align with regulatory 
requirements related to 
Clinical Trial Transparency 
(CTT) language.
Non-substantial
1.1 Key 
Secondary 
Objectives
Time to surgery and/or SCS for NP 
up to Week 52 updated to Time to 
surgery decision and/or SCS for NP 
up to Week 52
Time to NP surgery up to Week 52
updated to Time to NP surgery 
decision up to Week 52
Change to use the date of 
decision for NP surgery as this 
indicates when NP surgery is 
judged necessary and is not 
impacted by logistical issues 
and the backlog of surgeries, 
due to COVID-19 pandemic, 
which can be inconsistent 
across the sites/countries.
Substantial
1.1 Overall 
Design
Added “randomised” and removed 
“that complete the 52 week 
treatment” as well as updated “the 
remaining participants” to the 
follow-up groups
To clarify that the first 200 
participants randomised 
should have a 24-week follow-
up period, and the remaining 
participants will have a 
12-week follow-up.
Non-substantial
1.1 Overall 
Design
Added independent adjudication 
committee details
To adopt a uniform approach 
to independently review the 
diagnosis and causality 
assessments by the 
investigator.
Substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.3 Schedule of 
Activities: Visit 
Window
7.1.1 Procedures 
for 
Discontinuation 
of Study
Updated the Treatment window from 
± 3 days to ± 5 days and the Follow-
Up window from ± 5 days to ± 7
days
To align with other clinical 
study protocols within the 
programme and to minimise 
the occurrence of out of 
window visits.
Non-substantial
1.3 Schedule of 
Activities: 
Removed 
asthma 
exacerbations
Removed the assessment of asthma 
exacerbations
Removed this as an 
assessment, since this 
information is being collected 
as AEs.
Non-substantial
1.3 Schedule of 
Activities: Table 
1 subpoint C
Removed “who complete the 
52 week treatment”
To clarify that the first 
approximately 200 
participants randomised 
should have a 24-week follow-
up period, even if they did not
complete the 52-week 
treatment.
Non-substantial
1.3 Schedule of 
Activities: Table 
1 subpoint D
Updated to “the remaining, 
approximately 200 participants”
To clarify that the remaining 
participants will have a 
12-week follow-up period.
Non-substantial
1.3 Schedule of 
Activities: Table 
1 subpoint T
Added “For IPD (for any reason), 
only do a CT scan if at least 
12 weeks since the V2 CT scan”
To avoid repeat radiation 
exposure. It is unlikely to 
observe a change in disease 
< 12 weeks.
Non-substantial
2.3.1 Risk 
Assessment: 
Table 2
New category of “Important 
potential risks” including serious 
infections, malignancies and serious 
cardiac events added, “Potential 
risks of clinical significance” 
updated to “Potential risks” and text 
on risk of serious infections, serious 
hypersensitivity reactions and 
COVID-19 updated.
To align with the updated 
Investigator’s Brochure 
edition 5.1. The rationale for 
each risk is included in 
Table 2.
Substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
2.3.3 Overall 
Benefit: Risk 
Conclusion
Updated table to include a new 
category of “Important potential 
risks” including serious infections, 
malignancies, and serious cardiac 
events. The “Potential risks of 
clinical significance” was updated to 
“Potential risks” and text on risk of 
serious infections and serious 
hypersensitivity reasons updated.
Updated to include the new 
important potential risks as per 
the updated Investigator’s 
Brochure edition 5.1.
Substantial
3.0 Objectives 
and Endpoints: 
Table 3
Time to surgery and/or SCS for NP 
up to Week 52 updated to Time to 
surgery decision and/or SCS for NP 
up to Week 52
Time to NP surgery up to Week 52
updated to Time to NP surgery 
decision up to Week 52
Change to use the date of 
decision for NP surgery as this 
indicates when NP surgery is 
judged necessary and is not 
impacted by logistical issues 
which can be inconsistent 
across the sites/countries.
Substantial
4.1 Overall 
Design
Removed “that complete the 
52 week treatment” as well as 
updated “the remaining participants” 
to the follow-up groups
Updated to include Independent 
Event Adjudication to the study
Updated “worsening of nasal polyp 
symptoms” to “nasal polyp 
exacerbation”
To clarify that the first 
approximately 200 
participants randomised 
should have a 24-week follow-
up period, and the remaining 
participants will have a 
12-week follow-up.
To adopt a uniform approach 
to independently review the 
diagnosis and causality 
assessments by the 
investigator.
Updated to nasal polyp 
exacerbations since it is now 
defined in the protocol.
Non-substantial
4.2 Scientific 
Rationale for 
Study Design
Removed “who complete the 
52 week treatment”.
To clarify that the first 200 
participants randomised 
should have a 24-week follow-
up period.
Non-substantial
5.1 Inclusion 
Criteria #15
Updated from “in Version 4.0” to “in 
a prior version”
Updated to clarify EC#15 in 
subsequent protocol versions.
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
5.2 Exclusion 
Criteria #17
Updated COVID-19 testing 
requirements to “Evaluation will be 
based on local standard of care as 
determined by current local 
guidelines”
Updated to reflect real world 
practice and to be less 
burdensome for sites.
Non-substantial
5.3.3 Activity
Removed “Participants may 
participant in light recreational 
activities during the study (eg, 
watching television, reading)”
Determined this language was 
misleading and not necessary.
Non-substantial
6.1.1
Investigational 
Products: 
Table 4
Added “combination product” to 
Type
To reflect the most recent 
updates made to the 
Investigator’s Brochure 
edition 5.1.
Non-substantial
6.1.2 Medical 
Devices
Updated section title to Medical 
Devices Including Combination 
Products with a Device Constituent
Updated to “combination product 
which includes a device constituent”
To be aligned with 
International
Organization for 
Standardization 14155 
(edition 3) and European 
Medical Device Regulation.
Non-substantial
6.2.2 Dose 
Preparation
Replaced ”adequately” with “in the 
original carton”
To clarify the requirements for 
dose preparation.
Non-substantial
6.4 Concomitant 
Therapy: Table 
5
Added that allergen immunotherapy 
“Should not be administered on the 
same day as study intervention 
administration”
To align with the updated 
Investigator’s Brochure 
edition 5.1.
Non-substantial
7.1.1 Procedures 
for 
Discontinuation 
of Study 
Treatment
Added “scan if at least 12 weeks 
passed since the baseline CT scan”
To avoid repeat radiation 
exposure, and unlikely to 
observe a change in disease 
< 12 weeks.
Non-substantial
7.2.1
Withdrawal Due 
to Recruitment 
Completion in a 
Randomised 
Stratum
Added “screening period who are 
assigned to the” completed stratum.
To clarify that participants in 
screening that are assigned to 
a completed stratum will be 
screen failed from the study, 
as they are still in screening.
Non-substantial
8.0 Study 
Assessments and 
Procedures
Added language that collection and 
handling of HBS will be outlined in 
the laboratory manual
To clarify that specific details 
for handling and collecting 
HBS will be in the laboratory 
manual.
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
8.1.3 Sinus 
Computed 
Tomography
Updated to only do CT scan if at 
least 12 weeks passed since the 
baseline CT
To avoid repeat radiation 
exposure, and unlikely to 
observe a change in disease 
< 12 weeks.
Non-substantial
8.1.4 Post-
randomisation 
Nasal Polyp 
Surgery and/or 
SCS Use
Added “decision” date to NPS 
surgery.
Added “as agreed jointly both by the 
participant and the investigator”
To clarify that the date for 
decision to surgery is jointly 
by the Investigator and 
participant.
Non-substantial
8.2.4 Clinical 
Safety 
Laboratory 
Assessments: 
Table 12 and 
subpoints A and 
C
Added “S-Lipid Profile”
Updated language in footnote “a”
Added footnote “c” to detail the tests 
included in the Lipid Profile.
To assess participant lipid 
profile for a better 
understanding of participant's 
risk for cardiovascular 
disorder.
Substantial
8.2.4.2 SARS-
CoV-2 Testing
Added guidance to perform SARS-
CoV-2 testing as per local guidelines
Updated to reflect real world 
practice and to be less 
burdensome for sites.
Non-substantial
8.2.4.3
Pregnancy Test
Added “or at home”
To clarify that the Urine HCG 
test should be collected on-site
or at home if the IP 
administration visit takes 
place at home.
Non-substantial
8.2.5.3 Nasal 
Polyp 
Exacerbations
Section added to provide nasal polyp 
exacerbation definition
To clarify nasal poly 
exacerbation definition.
Non-substantial
8.3.6 Adverse 
Events of 
Special Interest
Re-organised and added “serious 
cardiac events” and “including 
opportunistic infections”
Added footnote “a” for the eCRF 
Severe Infection pages to be 
completed
To align with the updated 
Investigator’s Brochure 
edition 5.1.
Substantial
8.3.9
Independent 
Adjudication 
Committee
Added Independent Adjudication 
Committee section
To adopt a uniform approach 
to independently review the 
diagnosis and causality 
assessments by the 
investigator.
Substantial
8.3.10 Disease 
Progression
Added Disease Progression section
Updated to clarify definition 
of disease under study 
progress as per updated SOP.
Non-Substantial

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Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
8.3.11 Disease 
Under Study
Added Disease Under Study section
Updated to clarify reporting of 
disease under study progress 
as per updated SOP.
Non-Substantial
8.3.14 Medical 
Device 
Deficiencies
Updated language on how to 
properly report medical device 
deficiencies, and that they will be 
not be reported in the CSR, but as 
required per local regulations.
To align with the updated  
processes as outlined in the 
SOP for medical device 
deficiencies, AEs, and SAEs.
Non-substantial
8.4.1 Reporting 
of Overdose
Appendix B
Added definition and timelines for 
reporting overdose. Also ensure 
information aligned with Appendix 
B.
To align with EU regulatory 
trials regulations.
Non-substantial
8.4.2 Medication 
Error, Drug 
Abuse, and Drug 
Misuse
8.4.2.1
Timelines
8.4.2.2
Medication 
Error
8.4.2.3 Drug 
Abuse
8.4.2.4 Drug 
Misuse
Appendix B4
Added definition and timelines for 
reporting drug misuse and abuse. 
Also ensure information aligned 
with Appendix B with updated title.
To align with EU regulatory 
trials regulations.
Non-substantial
9.1 Statistical 
Hypothesis
Added “decision” to NP Surgery 
endpoint.
To align with the key 
secondary endpoints.
Non-Substantial
9.2 Sample Size 
Determination
Added “decision” to NP Surgery 
endpoint.
To align with the key 
secondary endpoints.
Non-substantial
9.4.2.2
Secondary 
Endpoints
Added “decision” to NP Surgery 
endpoint.
To align with the key 
secondary endpoints.
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Appendix A1
Added language relating to the 
investigator requirements for 
oversight and conduct of the study
Added language for regulatory 
reporting requirements for serious 
breaches
To align with EU regulatory 
trials regulations.
Non-substantial
Appendix A4
Added additional language for data 
protection
To align with EU regulatory 
trials regulations.
Non-substantial
Appendix B2 
Added additional language relating 
to AE reporting of malignancies
Updated to clarify safety 
reporting as per updated SOPs
Non-substantial
Appendix I
Medical Device 
AEs, ADEs, 
SAEs, SADEs, 
USADEs and 
Medical 
Device/Device 
Constituent 
Deficiencies: 
Definitions and 
Procedures for 
Recording, 
Evaluating and 
Follow-up
I2 Definition of 
Medical Device 
SAE, SADE and 
USADE
I3 Definition of
Medical Device 
Deficiency
I5 Reporting of 
Medical Device 
SAEs and 
SADEs
Added “Device Constituent” to 
appendix title
Added definitions and details 
outlining the reporting for SAEs and 
SADEs as well as assessment of 
intensity
To be aligned with 
International Organization for 
Standardization 14155 and 
European Medical Device 
Regulation.
Non-substantial
I3 Definition of 
Medical Device 
Deficiency
Added “issues with” to the Medical 
Devices Deficiency Definition
To correct an error of 
omission in the previous CSP 
version.
Non-substantial

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Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Appendix G 
Abbreviations
Updated the table of abbreviations
To ensure relevant 
abbreviations have been 
included as seen throughout 
the protocol.
Appendix J 
Summary of 
Changes
Relocated the previous Summary of 
Changes to a new appendix.
To ensure the most relevant 
information is at the beginning
of the protocol.
Non-substantial
Typographical and grammatical corrections have been made to this Clinical Study Protocol.
Amendment v4.0 28-Jan-2022
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it impacts the safety or physical/mental integrity of participants and the scientific 
value of the study.
Overall Rationale for the Amendment:
This Clinical Study Protocol has been amended to update the Co-primary, key secondary and 
other secondary endpoints and also to update inclusion Criterion 15 for bi-weekly mean NCS 
instead of NCS on the day of randomisation visit. APFS device malfunction, Medical device 
deficiencies, Appendix I Medical Device AEs were added to align with International 
Organization for Standardization 14155 and European Medical Device Regulation.
Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 1.1 –
Synopsis 
(Objectives and 
Endpoints)
Co-primary endpoint updated: 
“Change from baseline in NCS 
evaluated as part of…NPSD at 
Week 52” changed to “Change 
from baseline in bi-weekly mean 
Nasal Congestion Score (NCS) 
evaluated as part of …NPSD at 
Week 52.”
To ensure correct evaluation of 
NCS between baseline and 
Week 52.
Substantial
Section 1.1 –
Synopsis 
(Objectives and 
Endpoints)
Key secondary endpoint updated: 
“Change from baseline in loss of 
smell evaluated as part of…NPSD 
at Week 52” to “Change from 
baseline in bi-weekly mean loss of 
smell evaluated as part of…NPSD 
at Week 52.”
To ensure correct evaluation of 
participant loss of smell 
between baseline and 
Week 52.
Substantial

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Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 1.1 –
Synopsis
(Objectives and 
Endpoints)
Key secondary endpoint updated: 
“Change from baseline in NPSD 
TSS at Week 52” to “Change from 
baseline in bi-weekly mean NPSD 
TSS at Week 52.”
To ensure correct evaluation of 
NPSD TSS between baseline 
and Week 52.
Substantial 
Section 1.1 –
Synopsis 
(Objectives and 
Endpoints)
Other secondary endpoint updated: 
“Change from baseline over time in 
NCS evaluated as part of NPSD 
through Week 52” to “Change from 
baseline over time in bi-weekly 
mean NCS evaluated as part of 
NPSD through Week 52.”
To ensure correct evaluation of 
NCS from baseline through 
Week 52.
Substantial
Section 1.3 –
Table 1: 
Schedule of 
Activities
Footnote h updated to state that 
“subjects, sites and Sponsor will be 
unblinded to FeNO values prior to 
randomisation and blinded to FeNO 
post randomisation”
To clarify FeNO blinding 
procedures for subjects, sites 
and sponsor.
Non-substantial
Section 2.1 –
Study Rationale
Added reference “Phase 3 
NAVIGATOR study” in asthma 
patients showed that tezepelumab 
benefited participants with low and 
high baseline eosinophil counts and 
a low and high baseline T2 profile.
To include analysis findings 
from Phase 3 study.
Non-substantial
Section 2.1 –
Study Rationale
Added Journal Article reference 
“Emson C et al. 2021”
To include findings which 
support the rationale of a broad 
effect of tezepelumab in 
asthma and potential efficacy 
in Chronic rhinosinusitis with 
nasal polyps (CRSwNP).
Non-substantial
Section 2.3.1 –
Table 2
Removed the word “important” 
from Potential Risks of 
tezepelumab
To align with Investigator’s 
Brochure Edition 5.0 (dated 
21Oct2021).
Non-substantial
Section 2.3.3 –
Overall Benefit: 
Risk Conclusion 
Added “Phase 3” study where the 
use of tezepelumab has been 
demonstrated to show an important 
benefit in asthma study.
To reference Phase 3 study 
which demonstrated important 
benefit in asthma study with 
the use of tezepelumab. 
Non-substantial 
Section 2.3.3 –
Overall Benefit: 
Risk Conclusion
Added “Phase 3” and removed 
“Phase 2” for no serious allergic 
reactions or anaphylactic reactions 
considered related to the 
tezepelumab were reported in the 
programme
To reference Phase 3 
programme where no serious 
allergic reactions or 
anaphylactic reactions were 
reported. 
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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 2.3.3 –
Overall Benefit: 
Risk Conclusion
“Tezepelumab has been well 
tolerated with no safety signals 
identified in the completed studies 
to date” updated to “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.”
To align with Investigator’s 
Brochure Edition 5.0 (dated 
21Oct2021).
Substantial
Section 3 
(Objectives and 
Endpoints)
Co-primary endpoint updated: 
“Change from baseline in NCS 
evaluated as part of…NPSD at 
Week 52” changed to “Change 
from baseline in bi-weekly mean 
Nasal Congestion Score (NCS) 
evaluated as part of …NPSD at 
Week 52.”
To ensure correct evaluation of 
NCS between baseline and 
Week 52.
Substantial
Section 3 
(Objectives and 
Endpoints)
Key secondary endpoint updated: 
“Change from baseline in loss of 
smell evaluated as part of…NPSD 
at Week 52” to “Change from 
baseline in bi-weekly mean loss of 
smell evaluated as part of…NPSD 
at Week 52.”
To ensure correct evaluation of 
participant loss of smell 
between baseline and 
Week 52.
Substantial
Section 3 
(Objectives and 
Endpoints)
Key secondary endpoint updated: 
“Change from baseline in NPSD 
TSS at Week 52” to “Change from 
baseline in bi-weekly mean NPSD 
TSS at Week 52”
To ensure correct evaluation of 
NPSD TSS between baseline 
and Week 52.
Substantial
Section 3 
(Objectives and 
Endpoints)
Other secondary endpoint updated: 
“Change from baseline over time in 
NCS evaluated as part of NPSD 
through Week 52” to “Change from 
baseline over time in bi-weekly 
mean NCS evaluated as part of 
NPSD through Week 52.”
To ensure correct evaluation of 
NCS from baseline through 
Week 52.
Substantial
Section 3 
(Objectives and 
Endpoints)
Exploratory endpoint updated: 
“Change from baseline in NCS” 
changed to “Change from baseline 
in bi-weekly mean NCS”
To ensure effective 
evaluation of off-treatment 
effect and recurrence rate of 
nasal polyps after 
discontinuation of treatment 
with tezepelumab.
Substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 4.3 –
Justification for 
Dose
“Given these results, the dose of 
210 mg SC Q4W was selected for 
evaluation in the tezepelumab 
Phase 3 programme for patients 
with severe asthma” updated to 
“Given these results, the dose of 
210 mg SC Q4W was confirmed in 
the tezepelumab  Phase 3 
programme for patients with severe 
asthma”
To clarify dose of 210 mg SC 
Q4W was confirmed from 
Phase 3 programme for 
patients with severe asthma.
Non-substantial
Section 5.1 –
Inclusion 
Criteria
Inclusion Criterion 15 “NCS≥ 2 at 
Visit 3” removed. Inclusion 15a 
added to replace previous Inclusion 
Criterion 15.
Inclusion 15a added:
“At randomisation visit (Visit 3), a 
bi-weekly mean NCS≥ 2 (baseline 
bi-weekly mean score collected 
from study Day -13 to study 
Day 0).”
A new Inclusion Criterion 15a 
added to align with 
corresponding co-primary 
endpoint.
Substantial
Section 5.1 –
Inclusion 
Criteria
Inclusion Criterion 18 updated from 
“Minimum compliance with the 
daily eDiary during the run-in 
period (having a minimum of 70% 
fully compliant days during run-in 
period from Visit 1 to the day of 
randomisation at Visit 3)” to 
“Minimum compliance with the 
daily eDiary during the screening 
and run-in periods (having a 
minimum of 70% fully compliant 
days from Visit 1 to the day of 
randomisation at Visit 3).”
To clarify that the compliance 
with daily diary is evaluated 
for the entire period from 
Visit 1 up to the day of Visit 3
that includes both the 
screening period (between 
Visit 1 and 2) and the run-in 
period (between Visit 2 and 3).  
Non-substantial
Section 5.1 –
Inclusion 
Criteria
Inclusion Criterion 19  updated 
from “Minimum compliance with 
background INCS as captured in 
the eDiary during the run-in period 
(having a minimum of 70% fully 
compliant days during run-in period 
from Visit 1 to the day of 
randomisation at Visit 3)” to 
“Minimum compliance with 
background INCS as captured in 
the eDiary during the screening and 
run-in periods (having a minimum 
To clarify that the compliance 
with background INCS is 
evaluated for the entire period 
from Visit 1 up to the day of 
Visit 3 that includes both the 
screening period (between 
Visit 1 and 2) and the run-in 
period (between Visit 2 and 3).  
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Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
of 70% fully compliant days from 
Visit 1 to the day of randomisation 
at Visit 3).”
Section 5.2 –
Exclusion 
Criteria
Exclusion Criterion 12 has been 
updated. Participants who have had 
basal cell carcinoma or localised 
squamous cell carcinoma of the 
skin or in situ carcinoma of the 
cervix are now also eligible to 
participate, provided that “the 
patient is in remission”, in addition 
to the previous statement that the 
participant completed curative 
therapy at least 12 months prior to 
Visit 1
To align this Clinical Study 
Protocol with programme-level 
safety documentation 
regarding participants with a 
history of cancer.
Substantial
Section 5.4.1 –
Re-screening
Added clarification for Re-
screening that all procedures from 
the screening/run-in period should 
be repeated “except the sinus CT, if 
this was already performed in the 
first screening/run-in period, unless 
express permission for a repeat 
screening CT has been given by the 
study physician”
To clarify sinus CT does not 
need to be repeated if already 
performed during the initial 
screening/run-in period and 
study physician should be 
consulted if a repeat is 
required.
Non-substantial
Section 6.1.2
Medical Devices
Added section 6.1.2 regarding 
sponsor manufactured medical 
device use in this study and all 
medical device deficiencies should 
be documented and reported by 
investigator throughout the study
To align with International 
Organization for 
Standardization 14155 and 
European Medical Device 
Regulation.
Substantial
Section 6.2.4
Reporting 
Product 
Complaints 
Added clarification regarding any 
defects with IP must be reported 
immediately to the AstraZeneca 
representative as per the pharmacy 
manual and defects will be 
investigated further with 
AstraZeneca.
To align with Pharmacy 
manual.
Non- substantial
Section 6.2.5 
Reporting 
Product Defects
Added clarification regarding 
product defects should be reported 
to the AstraZeneca representative 
as per the pharmacy manual
To align with Pharmacy 
manual.
Non- substantial
Section 6.2.6 
Single Use 
Added clarification that Device 
malfunctions should be reported 
using appropriate form as per the
To align with Pharmacy 
manual.
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Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
APFS device 
malfunction
pharmacy manual and removed 
Device Malfunction return form. 
“Address and attention for 
malfunctioning device is available 
in the Device Malfunction Return 
Instructions” removed
Section 6.4 –
Concomitant 
Therapy
Table 5: Systemic Corticosteroids 
as maintenance treatment:
“Not allowed 3 months prior to V1. 
During study conduct, SCS is 
allowed as a rescue to relieve 
symptoms of NP worsening or 
asthma exacerbations at PI’s 
discretion. However, participants 
are not recommended to use SCS 
for the first 3 months after 
randomisation, unless emergent or 
deemed necessary by the PI.” 
updated to
“Not allowed 3 months prior to 
V1. During study conduct, SCS are 
allowed as a rescue to relieve NP 
worsening symptoms, to treat 
asthma exacerbations or treat other 
indications at PI’s discretion. 
However, it is recommended that 
participants abstain from using SCS 
for the first 3 months after 
randomisation, unless in case of an 
emergency or if it is deem 
necessary by the PI”
To clarify SCS is allowed as a 
rescue to treat other indications 
at PI’s discretion.
Non-substantial
Section 7.1.1 –
Procedure for 
Discontinuation 
of Study 
Treatment
Added “In case of IP 
discontinuation due to NP surgery, 
no further nasal endoscopies or CT 
scans are required after the IPD 
visit” 
To clarify no further nasal 
endoscopies or CT scans are 
required if IP discontinuation 
is due to NP surgery.
Non-substantial
Section 8.2.4 
Table 12 –
Footnote a
Footnote a was changed from “The 
sponsor and site will be blinded to 
the immunoglobulin, eosinophil, 
basophil and monocyte counts from 
the central laboratory reports except 
screening visits (V1 and V2), any 
repeat testing that is performed 
during the screening period and 
To clarify that both absolute 
and percentage values are 
blinded post randomisation.
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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
prior to Investigational Product (IP) 
administration at V3” to “The 
sponsor and site will be blinded to 
the immunoglobulin, eosinophil, 
basophil and monocyte (both 
absolute and percentage values) 
from the central laboratory reports 
except screening visits (V1 and 
V2), any repeat testing that is 
performed during the screening 
period and prior to Investigational 
Product (IP) administration at V3”
Section 8.3.14 
Medical Device 
Deficiencies
Added Section 8.3.14 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 occur during the 
study.
To align with International 
Organization for 
Standardization 14155 and 
European Medical Device 
Regulation.
Substantial
Section 8.6 –
Human 
Biological 
Sample 
Biomarkers
Added “Whole blood will be 
collected for transcriptomic (RNA) 
profiling. Serum, plasma, and nasal 
epithelial lining fluid samples will 
be collected for exploratory 
biomarker analysis.”
To clarify sample analysis. 
Non-substantial 
Section 8.6 –
Human 
Biological 
Sample 
Biomarkers
Added that results from the 
following exploratory assessments 
will need to be blinded to sponsor 
and sites:
Whole blood for transcriptomic 
RNA profiling, serum, plasma, and 
nasal epithelial lining fluid
Total IgE samples
Staph A enterotoxin samples in 
Nasal biopsy sub-study 
To clarify blinding of key 
exploratory laboratory results 
to sponsor and sites after 
randomisation Visit 3.
Non-substantial
Section 9.4.1 –
General 
Considerations
Endpoints of interests: “Change 
from baseline in co-primary 
endpoints: NPS and mean daily 
NCS at Week 52” updated to 
“Change from baseline in co-
primary endpoints: NPS and bi-
weekly mean NCS at Week 52. ”
To align with corresponding 
co-primary endpoint.
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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Appendix F 
Anaphylaxis: 
signs and 
symptoms, 
management
Corrected formatting of 
“Anaphylaxis: signs and symptoms, 
management”; from sub-heading to 
lettered Appendix F. Subsequent 
appendices lettering changed by 
one letter.
To correct a previous error in 
the formatting of this protocol 
and allow for proper 
referencing of this appendix.
Non-substantial
Appendix I
Added Appendix I Medical Device 
AEs, ADEs, SAEs, SADEs, US 
ADEs and Medical Device 
Deficiencies: Definitions and 
Procedures for Recording, 
Evaluating and Follow-up
To align with International 
Organization for 
Standardization 14155 and 
European Medical Device 
Regulation.
Substantial
Typographical and grammatical corrections have been made to this Clinical Study Protocol.
Amendment v3.0 26-May-2021
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study.
Overall Rationale for the Amendment:
This Clinical Study Protocol has been amended to clarify procedures regarding CT scan use
Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Table 1 -
Schedule of 
Activities -
Screening, 
Randomisation, 
Treatment 
Period, and 
Follow-Up
From footnote "a" - removed the 
sentence "except for early 
discontinuation from IP"
Procedures for 
discontinuation are noted 
clearly in Section 7.1.1.
Non-substantial
Table 1 -
Schedule of 
Activities -
Screening, 
Randomisation, 
Treatment 
Period, and 
Follow-Up
From footnote "t" - clarified 
scenarios for CT scans during the 
study in case of the subject's first 
post-randomisation nasal polyps 
(NP) surgery and first course of 
systemic corticosteroid (SCS) 
treatment for NP.
Clarifies scenarios where CT 
scan is required due to NP 
surgery or SCS treatment 
during study conduct.
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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 4.1 -
Overall Design
Clarified that CT scan "...is required 
before first NP surgery and/or 
initiation of first course of SCS 
treatment for NP."
Clarifies scenarios where CT 
scan is required due to NP 
surgery or SCS treatment 
during study conduct.
Non-substantial
Section 7.1.1 -
Procedures for 
Discontinuation 
of Study 
Treatment
Clarified that subjects who 
prematurely discontinue from IP 
due to NP surgery must follow 
modified timing for IPD procedures. 
Instead of returning to the site to 
complete IPD visit procedures at 4 
weeks +/- 3 days after the 
participant's last IP administration, 
IPD procedures must simply be 
performed prior to, and as close as 
possible to, the planned surgery 
date. 
In cases of premature IPD 
due to post-randomisation 
NP surgery, it is possible 
that the subject may have 
scheduled surgery for a date 
outside the 4 weeks +/- 3 
days window prescribed for 
IPD visits performed due to 
other reasons. 
The language was changed 
to allow for the collection of 
the patient's CT scan results 
before surgery.
Non-substantial
Section 8.1.2.1 -
Nasal Polyposis 
Symptom Diary 
(NPSD) and 
Nasal Polyposis 
Symptom 
Screening 
Assessment 
(NPSSA)
The assessment that captures NP 
symptom data at Visit 1 is properly 
known as the "Nasal Polyposis 
Symptom Screening Assessment". 
This section's title and text were 
corrected to ensure consistency with 
the information added to Table 1 
(Schedule of Activities) in the 
previous amendment.
Ensures consistency between 
CSP body text and the 
description of assessments as 
per the Schedule of 
Activities.
Non-substantial
Section 8.1.3 -
Sinus Computed 
Tomography
Clarified use cases for CT scans 
during the study in case of post-
randomisation NP surger(ies), 
course(s) of SCS treatment for NP 
or any combination of either 
intervention. 
The site has also been encouraged to 
consult the study physician to 
ensure a clear understanding of the 
timing of CT scans during the study.
Clarifies the guidance given 
in the previous amendment 
and ensures consistency with 
the rest of the CSP and 
regulatory considerations.
CT scan is required prior to 
the subjects' first post-
randomisation NP surgery, 
or their first SCS treatment 
for NP. In case of a 
combination of NP 
surger(ies) or SCS 
treatment(s), the CT scan 
should be performed prior to 
the first occurrence of either 
NP surgery or SCS treatment 
for NP.
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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 8.1.4 -
Post-
randomisation 
Nasal Polyp 
Surgery and/or 
SCS use
Clarified use cases for CT scans 
during the study in case of post-
randomisation NP surger(ies), 
course(s) of SCS treatment for NP 
or any combination of either 
intervention. 
Clarifies the guidance given 
in the previous amendment 
and ensures consistency with 
the rest of the CSP and 
regulatory considerations.
Non-substantial
Section 8.1.5 -
Spirometry 
(asthma/AERD/
NSAID-ERD 
participants 
only)
Provided readers with a summary of 
the MasterScope; the system which 
will be used to perform procedures 
including but not limited to 
spirometry, nasal peak inspiratory 
flow (NPIF) and fractional exhaled 
nitric oxide (FeNO).
Minor content change: helps 
to introduce readers to the 
tool being used to perform 
spirometry, NPIF and FeNO.
Non-substantial
Table 12 -
Laboratory 
Safety Variables
List of safety tests updated.:
Haematology/Hemostasis (whole 
blood): Added B-Leucocyte 
differential count (absolute count); 
Added B-Haematocrit
Urinalysis (dipstick): Removed U-
Hb/Erythrocytes/Blood, changed to 
U-Blood; Removed U-
Protein/Albumin, changed to U-
Protein; 
Clinical Chemistry: Removed 
serum/plasma albumin.
Ensures consistency with 
safety tests performed at the 
programme level.
Non-substantial
Section 8.5.2 -
Immunogenicity 
Assessments
Changed period for immunogenicity 
samples retention from "3 years 
following publication of CSR" to 
"15 years following date of last 
subject last visit (LSLV)".
This change is consistent 
with internal processes 
regarding sample retention 
after a study.
Non-substantial
Various typographical and grammatical corrections have been made to this Clinical Study Protocol.
Amendment v2.0 06-Apr-2021
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study.

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Overall Rationale for the Amendment:
This Clinical Study Protocol has been amended to align the study assessments with the 
scientific and operational objectives of the study. Language was also added to clarify guidance 
for enrolling and treating patients during significant regional disruptions and/or public health 
crises such as the COVID-19 pandemic.
Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Title Page
Added International Coordinating 
Investigator details
To ensure the International 
Coordinating Investigator’s 
details are available 
Non-substantial
Section 1.1 –
Objectives and 
Endpoints and 
Section 3 –
Objectives and 
Endpoints 
(Table 3)
Removal of NPS and Participant 
reported NC at Week 24 as a key 
secondary endpoint/variable
To simplify and reduce the 
number of endpoints 
included in the multiplicity 
control procedure
Non-Substantial
Section 1.1 –
Objectives and 
Endpoints and 
Section 3 –
Objectives and 
Endpoints 
(Table 3)
Added “sinus severity score by 
quantitative CT assessment at 
Week 52” as a secondary endpoint
To be aligned with Section 
8.1.3.2 of the CSP
Non-substantial
Section 1.1 –
Objectives and 
Endpoints
Added that “The co-primary and key 
secondary endpoints will also be 
tested at the 1% level.”
To include additional 
statistical methods for the 
co-primary and key 
secondary endpoints
Non-substantial
Section 1.3 -
Schedule of 
Activities 
(Table 1)
Included SARS-CoV-2 
nasopharyngeal swab test to be tested 
locally
COVID-19 rapid test allowed per 
local regulations
Additional SARS-CoV-2 
testing added for flexibility 
at the site level
Non-substantial
Section 1.3 -
Schedule of 
Activities 
(Table 1)
Removed Visit 13 (Week 36) for 
Nasal epithelial lining fluid for PK 
and Exploratory biomarkers
Additional sample for Nasal 
epithelial lining fluid at 
Visit 13 is removed to 
reduce patient burden of 
NLF sampling where 
information afforded by this 
time point is not critical
Non-substantial
Section 1.3 -
Schedule of 
Activities 
(Table 1)
Limited sampling at Visit 2 (Week -
2) for Nasal epithelial lining fluid for 
PK and Exploratory biomarkers, only 
to sub-study participants
Limited to sub-study 
participants to reduce patient 
burden of NLF sampling 
where information afforded 
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
by this time point is not 
critical
Section 1.3 -
Schedule of 
Activities 
(Table 1)
Removed the word "including"  from 
"At Visit 1, the suggested order of 
assessments should be followed as: 
ePRO, Vital Signs, ECG, Blood 
Draws including SARS-CoV-2 
nasopharyngeal swab test (or 
COVID-19 rapid test) "
Clarification that SARS-
CoV-2 nasopharyngeal swab 
test (or COVID-19 rapid 
test) is not part of the blood 
draw.
Non-substantial
Section 1.3 -
Schedule of 
Activities 
(Table 1)
Removed ECG and Nasal Endoscopy 
from the following text under 
Table 1:
At Visit 3, the suggested order of 
assessments should be followed: 
ePRO, UPSIT, Vital Signs, FeNO 
(asthma/AERD/NSAID-ERD 
participants), Spirometry 
(asthma/AERD/NSAID-ERD 
participants), NPIF, Blood Draws 
including SARS-CoV-2 serology test, 
Staph A nasal culture, Nasal 
epithelial lining fluid collection, IP 
administration.
To clarify that ECG and 
Nasal Endoscopy are not 
performed at Visit 3.
Non-substantial
Section 1.3 -
Schedule of 
Activities 
(Table 1)
Added the following text under 
Table 1, “Based on investigator’s 
judgement and site resources, EOT 
assessments (V17) will be performed 
over more than one day, within a 5-
day window” under Table 1
Additional visit window is 
added to accommodate 
flexibility at the site level to 
complete all the assessments 
as part of EOT
Non-substantial
Section 1.3 -
Schedule of 
Activities 
(Table 1) and 
Section 8.1.2.1 -
8.1.2.1 Nasal 
Polyposis 
Symptom Diary 
(NPSD)
Added NPSSA (Nasal Polyposis 
Symptom Screening Assessment) to 
SoA for Visit 1 and description about 
assessment
The NPSSA is only used to 
evaluate minimum symptom 
criteria over the past 12 
weeks prior to Visit 1.
Non-substantial
Section 1.3 -
Schedule of 
Activities 
(Table 1)
Removed INCS Distribution and 
Accountability from V18, V20 and 
V21.
Relabelled INCS Distribution and 
Accountability to INCS Distribution 
INCS distribution and 
accountability cannot be 
performed during remote 
visits (V18 and V20) and 
V21 is the final visit of the 
study so it is not needed. 
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Added footnote v to the Schedule of 
Activities table to explain where to 
find information on accountability 
procedures
Accountability procedures 
are described in detail in the 
study Pharmacy Manual, 
which is also made available 
to sites.
Section 1.3 -
Schedule of 
Activities 
(Table 1)
In footnote h, updated the wording 
that the sponsor will be unblinded to 
the FENO values prior to 
randomisation and blinded to the
FENO values post randomisation.
To clarify that FENO is 
unblinded during screening 
visits but is blinded after 
randomisation.
Non-substantial
Section 1.3 -
Schedule of 
Activities 
(Table 1)
For footnote i, added that “CT should 
be performed between V2 and V3 
after the participant meets the 
inclusion/exclusion criteria and 
receive a confirmation from central 
readers that the inclusion criteria of 
NPS score is met.”
Clarification was added 
when CT scan should be 
performed during the 
screening period
Non-substantial
Section 1.3 -
Schedule of 
Activities 
(Table 1) and 
Section 8.6.1 -
Collection of 
mandatory 
samples for 
biomarker 
analysis
For footnote o, added that “If nasal 
biopsy cannot be collected at V2, 
then participant should be withdrawn 
from nasal biopsy sub-study, and can 
continue on the main study. In this 
event, NLF collection at Visit 2 and 
Staph A enterotoxin-specific IgE 
sample collection at Visit 3 should 
not be performed as well. Please note 
that CT scans are done after nasal 
biopsy at baseline, while at EOT/IPD, 
the CT scan will be done before nasal 
biopsy. Moreover, Collection of NLF 
at V3, V7, V10, V17/EOT/IPD, and 
V19 is required for all study 
participants.
Clarification was added 
about the collection of nasal 
biopsy assessments if Visit 2
sample is not collected.
Non-substantial
Section 1.3 -
Schedule of 
Activities 
(Table 1)
Added footnote t to specify CT scan 
assessment requirements if the 
participant has planned surgery for 
NP or uses SCS during the study
Details regarding CT scan 
have been added to clarify 
scenario if the participant 
undergoes post-
randomisation surgery or 
uses SCS
Non-substantial
Section 1.3 -
Schedule of 
Activities 
(Table 1)
Added footnote u to indicate nasal 
endoscopy requirements if the 
participant has planned surgery for 
NP or uses SCS during the study
Details regarding nasal 
endoscopy have been added 
to clarify scenario if the 
participant undergoes post-
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
randomisation surgery or 
uses SCS
Section 2.3.3 -
Overall Benefit: 
Risk Conclusion
Added “completed” to clarify no 
safety signals identified in the 
completed studies to date.
Used “the completed studies” to 
replace “the tezepelumab 
programme” 
To clarify no safety signal 
detected in the completed 
studies
Non-substantial
Section 4.1 –
Overall Design
Added that participants who require 
SCS and/or hospitalisation for an 
asthma exacerbation or worsening of 
nasal polyp symptoms during the 
screening period, should be screen 
failed and may rescreen once their 
symptoms improve.
To address discrepancy in 
the CSP and consistency 
with Section 5.4.1 to extend 
the screening period until 
worsening event is resolved.
Non-substantial
Section 4.1 -
Overall Design
Added that a second, post-baseline 
CT scan will be done at EOT/IPD 
(Week 52).
To clarify that CT scan is 
also now performed at post-
baseline at EOT/IPD
Non-substantial
Section 5.1 –
Inclusion 
Criteria
For inclusion criterion #5, added that 
documented treatment with SCS 
should be for at least 3 consecutive 
days or one IM depo-injectable dose 
within the past 12 months prior to 
Visit 1. but not within the last 3 
months prior to Visit 1
To clarify length of period 
for SCS treatment prior to 
Visit 1 and include IM depo-
injectable dose
Non-substantial
Section 5.2 –
Exclusion 
Criteria
Removed exclusion criterion #2
All information from 
exclusion #2 is consolidated 
into exclusion criterion #5 as 
a result of overlapping 
information.
Non-substantial
Section 5.2 –
Exclusion 
Criteria
For exclusion criteria #17, Clarified 
SARS-CoV-2 nasopharyngeal swab 
test description to include local swab 
testing (or COVID-19 rapid test) per 
local regulations.
Additional SARS-CoV-2 
testing added for flexibility 
at the site level
Non-substantial
Section 5.2 –
Exclusion 
Criteria
Added additional exclusion criterion 
#37 regarding COVID-19 vaccination
To specify exclusion 
criterion for enrolling new 
participants in the study that 
are vaccinated with a 
COVID-19 vaccine.
Non-substantial
Section 5.2 –
Exclusion 
Criteria
Added a bullet point that systemic 
corticosteroid use is defined as 
treatment with a burst of systemic 
To clarify exclusion criteria 
#21 with further definition 
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
corticosteroids for at least 3 days or a 
single IM depo-injectable dose of 
corticosteroids (considered 
equivalent to a 3-day burst of 
systemic corticosteroids) to exclusion 
#21
on systemic corticosteroid 
use
Section 5.2 –
Exclusion 
Criteria and 
Section 5.3.2 –
Alcohol, 
Tobacco and 
Other
Added a new exclusion criteria #36 
regarding chronic alcohol or drug 
abuse and smoking
Also, clarified that for participants 
with co-morbid asthma: current 
smokers or participants with smoking 
history ≥ 10 pack-years at Visit 1 are 
not allowed.  
To clarify lifestyle 
restrictions addressed in 
section 5.3 of the CSP that is 
now added as part of the 
exclusion criteria
Non-substantial
Section 6.2.2 -
Dose Preparation
Visual characteristics of the IP were 
provided
To specify more details 
related to appearance and 
clarity of the IP
Non-substantial
Section 6.2.2 -
Dose Preparation
Dose preparation steps were added 
To specify details in the CSP 
that references the separate 
handling instructions.
Non-substantial
Section 6.2.3 –
Dose 
Administration
Dose administration steps were added
To specify details in the CSP 
that references the separate 
handling instructions.
Non-substantial
Section 6.2.3 –
Dose 
Administration
Added an additional point , “The 
participant is planning to receive 
COVID-19 vaccination during the 
screening or treatment period. Please 
refer to section 6.4.2.”
To specific dose 
administration criteria for 
the Investigator if participant 
decides to take a COVID-19 
vaccine
Non-substantial
Section 6.3 -
Measures to 
Minimise Bias: 
Randomisation 
and Blinding
Vendor name, Parexel was changed 
to Calyx
To specify vendor name 
change supporting IWRS 
services
Non-substantial
Section 6.4 –
Restricted 
Medications 
(Table 5)
Clarified that SCS as maintenance 
treatment is not allowed 3 months 
prior to V1, and that SCS may be 
used as a rescue medication during 
study conduct.
To clarify acceptable use of 
systemic corticosteroid
during the study.
Non-substantial
Section  6.4 -
Concomitant 
Therapy 
(Table 5) and 
COVID-19 vaccination restrictions 
were added 
To specify criteria for 
COVID-19 vaccination 
during the study conduct
Non-Substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 6.4.2 –
COVID-19 
Vaccination
Section  6.4 -
Concomitant 
Therapy 
(Table 6)
Added “Herbal remedies for the 
treatment of CRSwNP not allowed 30 
days prior to Visit 1, during 
screening/run-in and throughout the 
IP treatment and preferably 4 weeks 
after the last dose of IP.”
To add additional 
restrictions to concomitant 
medications
Non-substantial
Section 7.1 –
Discontinuation 
of Study 
Intervention
Added additional bullet point “If 
participant had undergone NP 
surgery during the treatment period”
To clarify details for IP 
discontinuation if participant 
undergoes/plans for NP 
surgery during the treatment 
period
Non-substantial
Section 7.1.1 -
Procedures for 
Discontinuation 
of Study 
Treatment
Clarified that if option 2 was 
selected, the participant completing 
ePRO data collection on the handheld 
device at home and UPSIT 
assessment will not be completed 
after IPD visit until participant 
returns back for EOT.   
As participant will not be 
attending site visits, the 
ePRO data are completed on 
the handheld device and 
UPSIT can only be 
completed at the site as a 
paper questionnaire so this is 
an exception
Non-substantial
Section 8.1.1 –
Nasal Polyp 
Score (NPS) –
Table 7
Clarified for polyp score Grade 3 that 
“Polyps reaching the lower border of 
the inferior turbinate or a middle 
meatal polyp with a score of 2 with 
any additional polyp medial to the 
middle turbinate”
For Grade 4, clarified that “Large 
polyps causing complete or near
complete obstruction of the inferior 
nasal cavity ie, touching the floor of 
the nose”
Additional clarification for 
nasal polyp score 3 and 4
Non-substantial
Section 8.1.3 –
Sinus Computed 
Tomography
Added that “For participants who 
undergo or who have planned NP 
surgery during the treatment period, a 
CT scan should be performed prior to 
the NP surgery per the IPD visit. For 
participants who require SCS (at least 
3 consecutive days of OCS or 
equivalent 1 intramuscular injection) 
for the treatment of NP, a CT scan 
should be performed prior to starting 
Details regarding CT scan 
have been added to clarify 
scenario if participant 
undergoes post-
randomisation surgery, uses 
SCS or discontinues IP
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
treatment with SCS if possible, and at 
Week 52 per the SoA. 
For participants who discontinue IP 
for other reasons, a CT scan should 
be performed at the IPD visit as well 
as at Week 52, if participant opts for 
follow-up option 1 or 2 per section 
7.1.1 of the CSP.”
Section 8.1.4 -
Post-
randomisation 
Nasal Polyp 
Surgery and/or 
SCS use
Clarified procedures to be performed 
prior to SCS treatment of NP.
To support the statistical 
analysis of SCS use in the 
study.
Non-substantial
Section 8.1.4 -
Post-
randomisation 
Nasal Polyp 
Surgery and/or 
SCS use
Shortened time window for 
rescheduling visits in case of non NP-
related SCS use close to V10 
(Week 24) or V17 (Week 52), to 2 
weeks after last dose of SCS
To ensure proper timing of 
visits, whilst aligning with 
information previously 
provided to regulatory 
authorities
Non-substantial
Section 8.1.5 –
Spirometry 
(asthma/AERD/
NSAID-ERD 
participants 
only)
Added that spirometry testing must 
be initiated in the morning between 
6:00 AM and 11:00 AM during the 
randomisation visit (Visit 3).
To clarify spirometry test 
timing at Visit 3
(randomisation visit)
Non-substantial
Section 8.1.5.1 –
General 
requirements
Removed Reversibility as part of 
Lung Function testing
To clarify that reversibility 
will not be measured by 
spirometry at the study site
Non-substantial
Section 8.2.4 –
Clinical Safety 
Laboratory 
Assessments 
(Table 12)
For footnote b under Table 12, 
clarified that the safety urine sample 
will be analysed by urine dipstick at 
site.
To provide clarification that 
the safety urine sample is not 
performed as a local test but 
is completed on-site with a 
urine dipstick provided by 
Covance
Non-substantial
Section 8.2.4.1 –
COVID-19 Entry 
Screening 
Questionnaire
Clarified that the COVID-19 
screening questionnaire must be 
completed via telephone 
approximately within 72 hours prior 
to every study visit. This section 
previously specified 24 hours.
To provide additional 
flexibility for investigator 
site to conduct COVID-19 
screening questionnaire prior 
to visit
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 8.2.4.2 –
SARS-CoV-2 
Testing
Clarified SARS-CoV-2 
nasopharyngeal swab test description 
to include local swab testing (or 
COVID-19 rapid test) per local 
regulations.
Additional SARS-CoV-2 
testing added for flexibility 
at the site level
Non-substantial
Section 8.2.4.4 -
Serology
Removed the following text, “In case 
of positive result of hepatitis B 
surface antigen or hepatitis C virus 
antibody, additional
testing (eg, hepatitis C RNA PCR 
test) may be performed to confirm 
eligibility.” 
Additional confirmatory test 
in case of positive result of 
hepatitis B surface antigen 
or hepatitis C virus antibody 
is not needed
Non-substantial
Section 8.5 –
Human 
Biological 
Samples, Section 
8.6.1.2 - Storage, 
re-use and 
destruction of 
exploratory 
biomarker 
samples, Section 
8.7.1 - Storage 
and destruction 
of genetic 
samples. 
Appendix D1 -
Use/analysis of 
DNA and 
Appendix D2 -
Genetic research 
plan and 
procedures
Updated retention period of human 
biological samples, exploratory 
biomarker samples and genetic 
samples for a maximum of 15 years 
from the date of the last subject’s last 
visit (LSLV)
To align retention period 
with human biological 
samples SOP
Non-substantial
Section 8.6.1
Collection of 
mandatory 
samples for 
biomarker 
analysis
Text changed:
•
Whole blood for transcriptomic 
profiling (RNA profiling), 
serum and plasma samples, 
nasal epithelial lining fluid and 
urine for proteins and 
inflammatory markers will be 
collected at the pre-specified 
scheduled visits prior to IP 
administration (pre-dose) 
according to the SoA.
To clarify that urine will not 
be collected to analyse 
proteins and inflammatory 
markers in the study
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
•
Whole blood for transcriptomic 
profiling (RNA profiling), 
serum and plasma samples, 
nasal epithelial lining fluid will 
be collected at the pre-specified 
scheduled visits prior to IP 
administration (pre-dose) 
according to the SoA.
Section 8.6.1
Collection of 
mandatory 
samples for 
biomarker 
analysis
Text changed:
•
The levels of total 
immunoglobulin E (IgE) and a 
quantitative assessment for the 
presence of allergen-specific 
IgE (IgE FEIA) will be 
collected at the pre-specified 
scheduled visits prior to IP 
administration (pre-dose) 
according to the SoA and 
evaluated by a central 
laboratory. All total serum IgE 
results will be redacted from the 
laboratory reports after 
randomisation visit (V3).
•
The levels of total 
immunoglobulin E (IgE) and an 
assessment for the presence of 
allergen-specific IgE (IgE 
FEIA) will be collected at the 
pre-specified scheduled visits 
prior to IP administration (pre-
dose) according to the SoA and 
evaluated by a central 
laboratory. All total serum IgE 
results will be redacted from the 
laboratory reports after 
randomisation visit (V3).
To clarify that the IgE FEIA 
test is not a quantitative 
assessment.
Non-substantial
Section 9.1 –
Statistical 
Hypotheses, 
Section 9.2 –
Sample Size 
Determination, 
Section 9.4.1 –
General 
Considerations 
and Section 
9.4.2.3 –
Secondary 
Endpoint(s)
Removal of NPS and Participant 
reported NC at Week 24 as a key 
secondary endpoint/variable in the 
text and Figure 3.
To simplify and reduce the 
number of endpoints 
included in the multiplicity 
control procedure
Non-Substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Section 9.1 –
Statistical 
Hypotheses
Moved “time to surgery up to 
Week 52” to level 3 in the testing 
strategy text and Figure 3.
To reflect the higher clinical 
importance of the “time to 
surgery up to Week 52” as 
compared to the lower level 
endpoints. 
Non-Substantial
Section 9.1 –
Statistical 
Hypotheses
Added more details about Holm 
procedure for the level 2 endpoints in 
the testing strategy.
To clarify that the Holm 
procedure controls the 
familywise type I error in a 
strong sense because the full 
alpha will only be passed to 
the next level endpoint when 
all level 2 endpoints are 
significant.
Non-substantial
Section 9.4.2.1 
Primary 
Endpoints, 
Subgroup 
Analyses
Removed Baseline NCS, NPS, 
number of prior surgeries and time 
since last surgery from the list of key 
subgroups which will be analysed to 
explore consistency of treatment 
effect.
Baseline NCS, NPS, number 
of prior surgeries, and time 
since last surgery will be 
included in the summary of 
baseline characteristics
Non-substantial
Section 9.4.2.1 
Primary 
Endpoints, 
Subgroup 
Analyses
Added age, gender and race to the list 
of key subgroups which will be 
analysed to explore consistency of 
treatment effect.
To clarify that subgroup 
analyses will be performed 
for the key demographic 
characteristics.
Non-substantial
Appendix B -
Adverse Events: 
Definitions and 
Procedures for 
Recording, 
Evaluating, 
Follow-up, and 
Reporting
Added that Adverse Events (AEs) for 
malignant tumours reported during a 
study should generally be assessed as 
Serious AEs. If no other seriousness 
criteria apply, the ‘Important Medical 
Event’ criterion should be used.
Additional information was 
added to reflect latest CSP 
template language.
Non-substantial
Appendix D -
Optional 
Genomics 
Initiative Sample
Clarified that “Samples will be stored 
for a maximum of 15 years from date 
of last subject last visit or may differ 
depending on local retention, after 
which they will be destroyed.”
To align with the current 
AstraZeneca HBS retention 
policy of 15 years from 
LSLV for the genomics 
initiative sample.
Non-substantial
Appendix E -
Actions 
Required in 
Cases of 
Increases in 
Liver 
Biochemistry 
Removed “Determine whether PHL 
criteria were met at any study visit 
prior to starting study treatment”
Removed the sections – E6 and E7:
This is only applicable for 
studies with target 
population of malignant 
disease with liver 
involvement, severe 
infection or liver disease.
Non-substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
and Evaluation 
of Hy’s Law
•Actions Required When Potential 
Hy’s Law Criteria are Met Before 
and After Starting Study Treatment  
•Actions Required for Repeat 
Episodes of Potential Hy’s Law
Additional information was 
added to reflect latest CSP 
template language.
Various typographical and grammatical corrections have been made on the Clinical Study Protocol.
11
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