A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Phase 3 Efficacy and Safety Study Of Benralizumab in Patients With Severe Nasal Polyposis
Phase: PHASE3
Conditions: Nasal Polyposis
Sponsor: AstraZeneca

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Clinical Study Protocol 
Drug Substance
Benralizumab 
Study Code
D3252C00001
Version
4.0
Date
05 Aug 2020
A Multicenter, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Phase 3 Efficacy and 
Safety Study Of Benralizumab in Patients with Severe Nasal Polyposis (OSTRO) 
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s):  
European Clinical Trials Database (EudraCT) number: 2017-003675-61
National Clinical Trial (NCT) number: 03401229

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
UPSIT removed from key secondary 
endpoints, Difficulty with Sense of 
Smell (DSS) score from NPSD and 
Lund Mackay score (LMS) added to key 
secondary endpoints.
Endpoint derivation modified to impute 
the worst possible value after the first 
occurrence of NP surgery.
COVID-19 disruptions.  Other 
modifications to key secondary 
endpoints and statistical analysis 
were made to address FDA 
comments 
 
Section 4.1 
Overall design
Updated language of inclusion in 
extended follow-up for clarity.
The grammar was corrected.
Non-substantial
Section 4.1.1 
(added 
section)
Study 
Conduct 
Mitigation in 
the event of 
evolving 
SARS-CoV-2 
(COVID-19) 
pandemic
Additional text regarding Study 
Conduct Mitigation During evolving 
SARS-CoV-2 (COVID-19) pandemic or 
other study disruption has been added to 
maintain the conduct of study-related 
activities during crisis, while securing 
data integrity and patient safety.
The impact of COVID-19 has 
highlighted the risk to continuity 
of clinical trials during times of 
study disruption. This section 
details the measures that may be 
implemented if a participant is not 
able to visit a study site to ensure 
that the clinical trial can continue 
whilst minimizing risk to the 
participant, maintaining 
compliance with GCP, and 
minimizing risks to study 
integrity.
Substantial
Section 4.2 
Scientific 
Rationale for 
Study Design
Updated language of inclusion in 
extended follow-up for clarity.
To provide clarity about 
assignment to extended follow-
up.
Non-substantial
Section 8. 
Study 
Assessments 
and 
Procedures
“Additional data to capture study 
disruptions caused by COVID-19 
pandemic will be collected in the 
eCRF.” wording has been added
To allow sponsor to collect 
additional data related to COVID-
19 pandemic in newly designed 
eCRF pandemic modules.
Non-substantial
Section 
8.1.1.1 Nasal 
Polyposis 
Symptom 
Diary
Added Total Symptom Score (TSS) as 
sum of first 8 items of NPSD.
Added analysis of  NP-associated 
symptoms as a total score from 
NPSD, excluding symptom 
impact items.
Substantial
Section 
8.1.1.1.1 
Changed timepoint of primary endpoint 
to Week 40. Week 56 is included as a 
Revised to be consistent with co-
primary endpoint NPS timepoint 
Substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
Nasal 
Blockage 
Score
key secondary endpoint.
at Week 56 and to mitigate 
potential COVID-19 disruptions 
(e.g., missed doses).
Section 
8.1.1.1.2 
Difficulty 
with Sense of 
Smell (DSS) 
score
Added section for DSS as a component 
of NPSD and a key secondary endpoint.
Added key secondary endpoint 
following FDA feedback 
Substantial
Section 
8.1.1.2
SinoNasal 
Outcome Test 
22 item
Changed timepoint of key secondary  
endpoint to Week 40. Week 56 is 
included as a key secondary endpoint.
To mitigate potential COVID-19 
disruptions.
Substantial
8.1.2 Nasal 
Polyp Score
Changed timepoint of primary endpoint 
to Week 40. Week 56 is included as 
timepoint for a key secondary endpoint.
The primary analysis timepoint 
was moved to week 40, the latest 
nasal endoscopy assessment not 
substantially impacted by 
COVID-19 disruptions
Substantial
Section 8.5.1 
Determination 
of drug 
concentration
Added information about analysis of 
baseline PK samples and on-treatment 
PK samples.
For clarification.
Non-Substantial
Section 9.1 
Statistical 
Hypotheses
Changed timepoint of primary endpoints 
to Week 40.  Week 56 outcomes are  
included as key secondary endpoints.
Reverted power and type I error rate to 
original values based on alpha of 0.01.
Removed list of tested endpoints and 
replaced with reference to section 9.4.4.
Updated model specification from 
MMRM to ANCOVA with WP/WOCF 
and MI.
Revision made following FDA 
feedback 
 
Substantial
Section 9.2 
Sample size 
determination
Updated model specification to 
ANCOVA with WP/WOCF and MI.
Changed timepoint of primary endpoint 
to Week 40.
Reverted power and type I error rate to 
The primary analysis timepoint 
was moved to week 40, the latest 
nasal endoscopy assessment not 
substantially impacted by 
COVID-19 disruptions. Other 
modifications to key secondary 
Substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
original values based on alpha of 0.01.
endpoints and statistical analysis 
were made to address FDA 
comments 
 
 
Section 9.4.1 
Efficacy 
analyses
Updated primary estimand to impute 
worst possible after NP surgery and 
WOCF after SCS for NP.
Revision made following FDA 
feedback 
 
Substantial
9.4.1.1 
Calculation or 
derivation of 
variables for 
efficacy 
analyses
Updated list of key secondary 
endpoints: DSS and LMS added, UPSIT 
removed.  Timepoint of primary 
endpoint changed to Week 40.   Week 
56 is also multiplicity protected for key 
secondary endpoints.
The primary analysis timepoint 
was moved to week 40, the latest 
nasal endoscopy assessment not 
substantially impacted by 
COVID-19 disruptions. Other 
modifications to key secondary 
endpoints and statistical analysis 
were made to address FDA 
comments
 
 
.
Substantial
Section 
9.4.1.2 
Methods for 
efficacy 
analyses
Updated model specification to 
ANCOVA with WP/WOCF and MI.
Updated primary estimand to impute 
worst possible after NP surgery and 
WOCF after SCS for NP.
Revision made following FDA 
feedback
 
.
Substantial
Section 
9.4.1.3 
Subgroup 
analysis
Expanded subgroup analysis to include 
key secondary endpoints. 
Atopic status (determined by phadiatop 
test) added as a subgroup.
A phadiatop test is considered to 
be a reliable assessment of atopic 
status at study entry.
Not substantial
Section 
9.4.3.3 
Analyses of 
biomarkers
“A limited number of exploratory 
biomarkers may be reported in the CSR. 
Details regarding analyses can be found 
in the SAP. Any remaining exploratory 
biomarkers will be reported outside of 
the CSR.” - wording has been added.
Exploratory biomarkers selected 
for their predicted ability to reveal 
PD effects of benralizumab may 
be included in the CSR. 
Remaining exploratory 
biomarkers will be reported 
outside of CSR as per previous 
version.
Not substantial

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Section # and 
Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
Section 9.4.4 
Methods for 
multiplicity 
control
List of endpoints and timepoints 
updated.
Reverted type I error rate to original 
values based on alpha of 0.01.
Revision made following FDA 
feedback 
 
Substantial
Appendix A6
Updated to correct web link.
Previously link was not correct. 
Not substantial
Appendix G
Additional text regarding Study 
Conduct Mitigation During evolving 
SARS-CoV-2 (COVID-19) pandemic or 
other study disruption has been added to 
maintain the conduct of study-related 
activities during crisis, while securing 
data integrity and patient safety.
The impact of COVID-19 has 
highlighted the risk to continuity 
of clinical trials during times of 
study disruption, This section 
details the measures that may be 
implemented if a participant is not 
able to visit a study site to ensure 
that the clinical trial can continue 
whilst minimizing risk to the 
participant, maintaining 
compliance with GCP, and 
minimizing risks to study 
integrity. 
Substantial
Appendix F
List of abbreviation has been updated.
New abbreviations have been 
added.
Non-substantial

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Section 1.2 Schema
Figure 1 – Study flow chart updated to reflect updates referring to Follow-Up visits. Update 
of the wording from First 200 pts to Approximately 200 pts and from Second 200 pts to 
Remaining pts.
Figure 2 – Study flow chart updated to reflect updates referring to Follow-Up visits. Update 
of the wording from First 200 pts to Approximately to 200 pts.
Section 3.2 Secondary objectives
Key Secondary Objective 
Nasal polyps surgery and/or SCS use was added to the multiplicity testing strategy and 
Change from baseline in University of Pennsylvania Smell Identification Test (UPSIT) was 
added as a Key Secondary objective and removed from the Other Secondary Objective 
Section.
The same update is implemented through the CSP content everywhere where this is 
mentioned. 
Other Secondary Objective
Removal of University of Pennsylvania Smell Identification Test (UPSIT) – upgraded to 
Key Secondary Objective.
Section 8.1.1 Clinical outcome assessments
Minor administrative change.
Section 8.1.1.4 Patient Global Impression of Severity and Change
PGIC – response options updated.
Section 8. 3.4 Adverse event data collection
Editorial change.
Section 8.3.5 Causality collection
Clarification added that NP surgery is not the study procedure.
Section 8.3.9 Disease-under study (DUS)
The definition of DUS and reporting criteria have been clarified.
Section 8.4.2 Pregnancy
Update of the sentence explaining when pregnancy and outcome of the pregnancy does not 
to have to be reported to AZ. 

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Section 8.4.2.1 Maternal exposure
Update of information about pregnancy reporting. It is clarified that paper-based
pregnancy outcome report is used to report the outcome of the pregnancy.
Section 8.10 Health Economics
Clarification added on reporting hospitalizations as an SAE.
Section 9.1 Statistical hypotheses
Wording changed to reflect the update of key secondary objective – “Nasal polyp surgery 
and/or SCS use” and upgrading University of Pennsylvania Smell Identification Test
(UPSIT) to the key secondary objective.
Alpha level value for testing of co-primary endpoints was updated from 0.01 to 0.05.
Section 9.2 Sample size determination
The change in significance level for hierarchical testing from two-sided alpha of 0.01 to 
two-sided alpha of 0.05 was added.  Power value of at least 99% at alpha value of 0.05 was 
added.  
Update of minimum observed mean difference that would be statistically significant at the 
two-sided alpha 0.05 level from -0.52 to -0.39 in total NPS and from ‒0.26 to –0.20 in NBS.  
Original critical values for two-sided alpha 0.01 level also included.   
Section 9.4.1.1 Calculation or derivation of variables for efficacy analyses
Wording changed to reflect the update of key secondary objective – “Nasal polyp surgery 
and/or SCS use” and upgrading University of Pennsylvania Smell Identification Test
(UPSIT) to the key secondary objective.
Section 9.4.1.1 Disease specific health-related quality of life: SNOT-22 (Key secondary 
endpoint)
The header name was updated from Health-related-quality of life: SNOT-22 to Disease 
specific health-related quality of life: SNOT-22 (Key secondary endpoint)
Indicated that the health-related-quality of life is a key secondary endpoint.
Section 9.4.1.1 Time to first NP surgery
Added additional paragraphs on Time to first NP surgery and/or SCS use for NP and 
University of Pennsylvania Smell Identification Test (UPSIT).

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procedure. Other minor changes and footnotes were made throughout Table 1 to add further 
clarity.
Table 2. Schedule of Activities-Randomization, treatment period and follow-up
Table 2 was updated to reflect the order of the procedures at the EOT visit and to highlight 
that IP administration is the last activity performed at the visit. Other minor changes were 
made throughout Table 2 to add further clarity.
Section 1.1 (Synopsis): Overall design and throughout the CSP content (Treatment 
and treatment duration; Scientific rationale for study design; Background medication 
sections) 
Requirement for patients being on a stable dose of study provided INCS for 4 weeks prior 
to randomization was changed to 4 weeks prior to V2. The change was made to align 
patients profile in regards to INCS intake.
Section 1.1 (Synopsis): Treatment and Treatment duration
Information about patients with INCS intolerance was added.
Figure 2: Background medication scheme was added
Section 4.1 (Overall design)
Requirement to maintain a 4-week gap between V1 and V2 was added.
Section 5.1 (Inclusion criteria): Inclusion #5
Requirement of 4 weeks of INCS intake prior V1 was added.
Section 5.1 (Inclusion criteria): Inclusion #6 and #9
SNOT22 score was changed from >30 to ≥ 30. 
Section 5.1 (Inclusion criteria): Inclusion #15
Male contraception requirements were updated.
Section 5.2 (Exclusion criteria): Exclusion#1
Number of months was updated from 6 months to 3 months to allow patients to be recruited 
sooner following their last nasal and/or sinus surgery.
Section 5.2 (Exclusion criteria): Exclusion#2
Allergic fungal sinusitis (AFS) was added.

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Section 5.2 (Exclusion criteria): Exclusion#5
Time period was changed from 3 months to 4 weeks prior to V1 for asthma exacerbation 
requiring systemic corticosteroids treatment or hospitalization for treatment of asthma.
Section 5.2 (Exclusion criteria): Exclusion#10
Note about hormonal therapy was added.
Section 5.2 (Exclusion criteria): Exclusion#15
Screening/run-in period timeframe was removed from this exclusion criterion.
Section 5.2 (Exclusion criteria): Exclusion#16
Removal of usage of systemic corticosteroids for condition other than short course for nasal 
polyps. 
Section 5.2 (Exclusion criteria): Exclusion#17
Change from 4 to 6 months in regards to the intake of biologic products. Additionally, 
allowance of previous receipt of mepolizumab, reslizumab and dupliumab was added. 
Change was done to allow patients with documented previous participation in other mAB 
studies to be recruited.
Section 5.2 (Exclusion criteria): Exclusion#18
Mepolizumab, reslizumab and dupliumab were removed and described under 
Exclusion#17.
Section 5.2 (Exclusion criteria): Exclusion#22
Time period for systemic corticosteroids intake was changed from 2 months to 4 weeks 
prior V1. Note about sustained release steroids or depot injections was added.
Section 5.2 (Exclusion criteria): Exclusion#25
Typo was corrected from > 3 times to ≥ 3 times.
Section 5.4.1 (Re-screening)
Re-screening section wording was updated to allow extension of the screening period and
to clarify in which cases re-screening is allowed. Additionally, it was highlighted that 
patient can be considered for re-screening once under the specific conditions. 
Table 4 (Restricted medication) was updated

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Table 5 (Prohibited medication) was updated
Section 6.5.1 (Background medication) 
Requirement for patients being on a stable dose of study provided INCS for 4 weeks before 
randomization was changed to a requirement of 4 weeks on stable dose of study provided 
INCS prior to V2.
Information about MFNS intolerance was added. Additionally, information about SCS 
intake during screening period and possible extension was added. 
Section 7.1.1 (Procedures of discontinuation of study treatment)
Change from week 60 to 56 was done in regards to the continuation of study participation 
in case patient prematurely discontinued IP treatment.
Section 8.1.1.6 (Asthma exacerbation - for asthma patient only)
Information that if patient experienced an asthma exacerbation and/or use of systemic 
corticosteroids during the screening, he/she should be screen failed was removed. 
Section 8.1.3. Sinus Computed Tomography
Recommendation that for sites participating in both CT and nasal polyp biopsy procedure, 
Sinus CT-scan should be done after biopsy at V2, and prior biopsy at EOT/IPD.
Section 8.1.4 (Nasal polyp surgery)
List of assessment which are recommended to be done at unscheduled visit prior to surgery 
was updated (ePRO questionnaires and UPSIT).
Section 8.2.1 (Clinical safety laboratory assessments)
Recommendation about fasting before blood drawn was added.
Appendix A (Regulatory, ethical and study oversight considerations)
Section A9 Study and site closure was added.
Appendix F (Anaphylaxis: signs and symptoms, management): F4.1 Immediate 
intervention
Typo was updated – from IV to IM.
Other changes:
Grammar corrections and minor wording changes were done to add more clarity.

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TABLE OF CONTENTS
TITLE PAGE.......................................................................................................................1
VERSION HISTORY..........................................................................................................2
TABLE OF CONTENTS................................................................................................... 15
LIST OF TABLES............................................................................................................. 18
LIST OF FIGURES ........................................................................................................... 19
LIST OF APPENDICES.................................................................................................... 19
1.
PROTOCOL SUMMARY ................................................................................. 20
1.1
Synopsis ............................................................................................................ 26
1.2
Schema .............................................................................................................. 32
2.
INTRODUCTION ............................................................................................. 34
2.1
Study rationale................................................................................................... 34
2.2
Background........................................................................................................ 34
2.3
Benefit/risk assessment ...................................................................................... 35
3.
OBJECTIVES AND ENDPOINTS....................................................................37
3.1
Primary objectives ............................................................................................. 37
3.2
Secondary objectives.......................................................................................... 37
3.3
Safety objectives................................................................................................39
3.4
Exploratory objectives .......................................................................................39
4.
STUDY DESIGN............................................................................................... 40
4.1
Overall design....................................................................................................40
4.1.1
Study Conduct Mitigation in the event of evolving SARS-CoV-2 (COVID-
19) pandemic or other study disruption .............................................................. 41
4.2
Scientific rationale for study design ................................................................... 42
4.3
Justification for dose.......................................................................................... 43
4.4
End of study definition....................................................................................... 43
5.
STUDY POPULATION .................................................................................... 44
5.1
Inclusion criteria ................................................................................................44
5.2
Exclusion criteria ............................................................................................... 46
5.3
Lifestyle restrictions........................................................................................... 50
5.4
Screen failures ...................................................................................................50
5.4.1
Re-screening ......................................................................................................50

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6.
STUDY TREATMENTS................................................................................... 51
6.1
Treatments administered .................................................................................... 51
6.1.1
Investigational products ..................................................................................... 51
6.2
Preparation/handling/storage/accountability....................................................... 53
6.2.1
Preparation and handling....................................................................................53
6.2.2
Storage............................................................................................................... 54
6.2.3
Accountability.................................................................................................... 55
6.3
Measures to minimise bias: randomization and blinding..................................... 55
6.3.1
Methods for assigning treatment groups............................................................. 55
6.3.2
Methods for ensuring blinding ........................................................................... 55
6.3.2.1
Maintaining the blind to the patient’s blood eosinophil counts............................ 56
6.3.2.2
Handling of labs obtained during the study period but ordered outside of 
the clinical trial. ................................................................................................. 56
6.3.3
Methods for unblinding...................................................................................... 56
6.4
Treatment compliance........................................................................................ 57
6.5
Concomitant therapy.......................................................................................... 57
6.5.1
Background medication...................................................................................... 59
6.5.2
Other concomitant treatment .............................................................................. 59
6.6
Dose modification.............................................................................................. 59
6.7
Treatment after the end of the study ................................................................... 59
7.
DISCONTINUATION OF TREATMENT AND PATIENT
WITHDRAWAL ............................................................................................... 60
7.1
Discontinuation of study treatment..................................................................... 60
7.1.1
Procedures of discontinuation of study treatment................................................ 60
7.2
Lost to follow-up ............................................................................................... 61
7.3
Withdrawal from the study................................................................................. 62
7.3.1
Withdrawal due to recruitment completion in a randomization stratum............... 62
7.4
Procedures for handling incorrectly enrolled or randomized patients.................. 62
8.
STUDY ASSESSMENTS AND PROCEDURES............................................... 63
8.1
Efficacy assessments.......................................................................................... 63
8.1.1
Clinical outcome assessments ............................................................................ 63
8.1.1.1
Nasal Polyposis Symptom Diary........................................................................ 64
8.1.1.2
SinoNasal Outcome Test 22 item .......................................................................65
8.1.1.3
Short Form 36-item Health survey, version 2 ..................................................... 65
8.1.1.4
Patient Global Impression of Severity and Change .............................................66
8.1.1.5
Asthma Control Questionnaire (for asthma patients only)................................... 66
8.1.1.6
Asthma exacerbations (for asthma patients only)................................................ 66
8.1.1.7
University of Pennsylvania Smell Identification Test ......................................... 67
8.1.2
Nasal Polyp Score..............................................................................................67

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8.1.3
Sinus Computed Tomography............................................................................ 68
8.1.3.1
Lund-Mackay score............................................................................................68
8.1.3.2
Quantitative measurement of sinus disease burden on sinus computed 
tomography........................................................................................................ 69
8.1.4
Nasal polyp surgery ........................................................................................... 69
8.2
Safety assessments............................................................................................. 70
8.2.1
Clinical safety laboratory assessments................................................................ 70
8.2.1.1
Pregnancy Test...................................................................................................71
8.2.1.2
Serology ............................................................................................................ 71
8.2.1.3
Serum immunoglobulin E and allergen-specific Immunoglobulin E 
(Phadiatop) ........................................................................................................71
8.2.2
Physical examinations........................................................................................ 72
8.2.2.1
Complete physical examination.......................................................................... 72
8.2.2.2
Brief physical examination................................................................................. 72
8.2.3
Vital signs.......................................................................................................... 72
8.2.4
Electrocardiograms ............................................................................................ 72
8.2.5
Other assessments.............................................................................................. 73
8.2.5.1
Weight and height.............................................................................................. 73
8.3
Collection of adverse events............................................................................... 73
8.3.1
Method of detecting adverse events and serious adverse events.......................... 73
8.3.2
Time period and frequency for collecting adverse event and serious 
adverse event information .................................................................................. 73
8.3.3
Follow-up of adverse events and serious adverse events.....................................74
8.3.4
Adverse event data collection............................................................................. 74
8.3.5
Causality collection............................................................................................ 75
8.3.6
Adverse events based on signs and symptoms....................................................75
8.3.7
Adverse events based on examinations and tests ................................................75
8.3.8
Hy’s Law (HL) ..................................................................................................76
8.3.9
Disease-under study (DUS)................................................................................ 76
8.4
Safety reporting and medical management ......................................................... 76
8.4.1
Reporting of serious adverse events ................................................................... 76
8.4.2
Pregnancy ..........................................................................................................77
8.4.2.1
Maternal exposure.............................................................................................. 77
8.4.2.2
Paternal exposure...............................................................................................78
8.4.3
Overdose............................................................................................................ 78
8.4.4
Management of investigational product-related reaction..................................... 78
8.4.5
Medication error ................................................................................................79
8.5
Pharmacokinetics ............................................................................................... 79
8.5.1
Determination of drug concentration..................................................................80
8.5.2
Storage and destruction of pharmacokinetic samples..........................................80
8.6
Immunogenicity................................................................................................. 80
8.6.1
Anti-drug antibodies ..........................................................................................81
8.6.2
Neutralizing antibodies ...................................................................................... 81

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8.7
Pharmacodynamics ............................................................................................ 81
8.7.1
Collection of samples.........................................................................................81
8.8
Genetics............................................................................................................. 81
8.8.1
Optional exploratory genetic sample ..................................................................81
8.8.2
Storage and destruction of genetic samples ........................................................ 81
8.9
Biomarkers ........................................................................................................ 82
8.9.1
Storage, re-use and destruction of exploratory biomarker samples...................... 82
8.10
Health Economics.............................................................................................. 82
9.
STATISTICAL CONSIDERATIONS................................................................ 83
9.1
Statistical hypotheses ......................................................................................... 83
9.2
Sample size determination.................................................................................. 84
9.3
Populations for analyses.....................................................................................84
9.3.1
All patients analysis set...................................................................................... 85
9.3.2
Full analysis set (FAS)....................................................................................... 85
9.3.3
Safety analysis set..............................................................................................85
9.3.4
Pharmacokinetic analysis set.............................................................................. 85
9.4
Statistical analyses ............................................................................................. 85
9.4.1
Efficacy analyses ............................................................................................... 85
9.4.1.1
Calculation or derivation of variables for efficacy analyses ................................ 86
9.4.1.2
Methods for efficacy analyses ............................................................................ 88
9.4.1.3
Subgroup analysis.............................................................................................. 90
9.4.2
Safety analyses................................................................................................... 90
9.4.2.1
Calculation or derivation of Safety Variables .....................................................90
9.4.2.2
Analyses of safety variables ...............................................................................90
9.4.3
Other analyses.................................................................................................... 90
9.4.3.1
Analysis of immunogenicity variables................................................................ 90
9.4.3.2
Analysis of pharmacokinetic variables ............................................................... 91
9.4.3.3
Analyses of biomarkers......................................................................................91
9.4.4
Methods for multiplicity control......................................................................... 91
9.5
Interim analyses.................................................................................................92
9.6
Data monitoring committee (DMC)....................................................................92
9.7
Independent adjudication committee .................................................................. 92
10.
REFERENCES ..................................................................................................93
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS......................................................................................... 98
LIST OF TABLES
Table 1                  Schedule of Activities – Screening (run-in) ...........................................20

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Table 2                  Schedule of Activities – Randomization, treatment period and 
follow-up ..............................................................................................22
Table 3                  Study Treatments ..................................................................................51
Table 4
Restricted medications ..........................................................................57
Table 5
Prohibited medications..........................................................................58
Table 6
Threshold values for the SF-36v2 scale and summary measures ............66
Table 7
Endoscopic nasal polyp score................................................................67
Table 8
Lund-Mackay score...............................................................................68
Table 9
Osteomeatal complex score...................................................................69
Table 10
Laboratory safety variables ...................................................................70
LIST OF FIGURES
Figure 1
Study flow chart....................................................................................32
Figure 2
Background Medication scheme............................................................33
Figure 3 
Injection sites scheme............................................................................53
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations..........................98
Appendix B
Adverse event definitions and additional safety information................ 102
Appendix C
Handling of Human Biological Samples.............................................. 106
Appendix D
Genetics.............................................................................................. 109
Appendix E
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law ....................................................................... 112
Appendix F
Anaphylaxis: signs and symptoms, management ................................. 116
Appendix G
Study Conduct Mitigation in the event of evolving SARS-Cov-2 
(COVID19) pandemic or other study disruption.................................. 120
Appendix H
Abbreviations...................................................................................... 121

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1.
PROTOCOL SUMMARY
Table 1                  Schedule of Activities – Screening (run-in)
Study period
Enrollment/ Screening (run-in)
Refer to section
Visit
V1
V2a)
Week
w-5
w-1
Visit window (days)
±7
±7
General Procedures
Informed Consentb)
X
Appendix A 3
Inclusion/Exclusion criteria 
review
X
X
5.1, 5.2
Demographics
X
N/A
Medical and surgical history 
(including respiratory and 
NP) 
X
N/A
Safety Assessments
Complete physical 
examination
X
8.2.2.1
Brief physical examination
X
8.2.2.2
Vital signs
X
X
8.2.3
Weight, height
X
8.2.5.1
ECG
X
8.2.4
Adverse events
X
X
8.3
Concomitant medications
X
X
6.5
Patient-reported outcome Assessments
In-office PROs:
Provide ePRO diary 
instructions
X
8.1.1
NP Symptom Screening 
Assessment (2 Week Recall) 
X
8.1.1.1
Record visit in the eDiary. 
Confirm that all PRO
assessments have been 
completedc)
X
X
8.1.1
Review compliance of at-
home PROassessments
X
8.1.1
At-home PROs completed by patients:
NP Symptom Daily Diary 
(AM)
X
X
8.1.1.1
SNOT-22
X
8.1.1.2

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HRU Assessment
HRU 
X
8.10
Nasal polyposis Assessments
Nasal endoscopy
X
Xi)
8.1.2
Sinus CT- scand)
Xe)
8.1.3
Assess nasal 
surgery or/and SCS usef)
X
X
8.1.4; 6.5.2
Laboratory Assessments
Clinical chemistry
X
8.2.1
Hematology
X
8.2.1
Urine pregnancy test, dipstick
X
8.2.1.1
Serum pregnancy testg)
X
8.2.1.1
Serology (HepB, HepC, 
HIV1, HIV2)
X
8.2.1.2
FSHh
X
8.2.1.1
Exploratory biomarkers -
nasal polyp biopsyi)
X
8.9
Other
INCS distribution and 
accountability
X
6.5.1
a
The time elapsed between V1 and V2 should be at least 4 weeks.
b
ICF needs to be signed prior to any study activities/procedures.
c
Patients to complete available assessments in-clinic prior to other interventional study procedures (e.g. lab 
tests, endoscopy, Sinus CT-scan).
d
At selected clinical sites. 
e
Baseline Sinus CT- scan will be performed either at V2 or V3. CT-scan should be performed after biopsy.
f
If the patient has surgery or uses SCS (e.g. oral, parenteral) during screening, the patient should be screen 
failed. Exception listed in section 5.4.1.
g
This analysis will be only applicable for WOCBP patients.
h
FSH test done only for female patients to confirm postmenopausal status in women <50 years who have 
been amenorrheic for ≥12 months.
i
At selected clinical sites, nasal polyp tissue will be obtained by biopsy. The screening biopsy should be 
done carefully without impact of NP score and prior to taking video for NP score assessment (and prior to 
CT-scan if applicable). 
CT- Computed tomography; ECG- Electrocardiogram; FSH- Follicle stimulating hormone; HRU - Healthcare 
resource utilization; INCS- Intranasal corticosteroids; NP- Nasal polyposis; (e)PRO- (electronic) Patient-reported 
outcome; SCS- Systemic corticosteroids; SNOT-22- SinoNasal Outcome Test, 22 item

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Table 2                  Schedule of Activities – Randomization, treatment period and follow-up
Study period 
Treatment
EOT
/IPD
FU
Approx. 200 
ptsb)
FU/ 
FUD
Approx. 
200 ptsb)
FU
Remaini
ng ptsc)
UNSd)
Refer to 
section
Visit
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12a
V13
V14
V12b
Week
w0
w4
w8
w16
w24
w32
w40
w48
w56
w60
w68
w80
w60
Visit window (days)a)
±0
±3
±3
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
General Procedures
Inclusion/Exclusion criteria review
X
5.1; 5.2
Safety Assessments
Complete physical examination
X
8.2.2.1
Brief physical examination
X
X
X
X
X
X
X
X
8.2.2.2
Vital signs
X
X
X
X
X
X
X
X
X
8.2.3
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.5
Patient-Reported Outcome Assessments
In-office PROs:
Record visit in the eDiary. Confirm that all 
PRO assessments have been completede)
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1
Review compliance of at-home PRO 
assessments
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1
UPSIT smell testf)
X
X
X
X
X
X
X
X
8.1.1.7
At-home PROs completed by patients:
NP Symptom Daily Diary (AM)
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1.1
SNOT-22
X
X
X
X
X
X
X
X
X
X
8.1.1.2

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Study period 
Treatment
EOT
/IPD
FU
Approx. 200 
ptsb)
FU/ 
FUD
Approx. 
200 ptsb)
FU
Remaini
ng ptsc)
UNSd)
Refer to 
section
Visit
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12a
V13
V14
V12b
Week
w0
w4
w8
w16
w24
w32
w40
w48
w56
w60
w68
w80
w60
Visit window (days)a)
±0
±3
±3
±7
±7
±7
±7
±7
±7
±7
±7
±7
±7
SF-36v2 (standard recall)
X
X
X
X
X
X
X
8.1.1.3
PGI-S
X
X
X
X
X
X
X
X
X
8.1.1.4
PGI-C
X
X
X
X
X
X
X
X
8.1.1.4
ACQ-6 (asthma patients only)
X
X
X
X
X
X
X
X
8.1.1.5
HRU Assessment
HRU
X
X
X
X
X
X
X
X
X
X
X
X
X
8.10
Assess asthma exacerbations (asthma Pts 
only)
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1.6
Nasal polyposis Assessments
Nasal endoscopy
X
X
X
X
Xk)
X
X
8.1.2
Sinus CT- scang)
Xh)
8.1.3
Assess nasal surgery or/and SCS use
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.4; 
6.5.2
Laboratory Assessments
Clinical chemistry
X
X
X
8.2.1
Haematology
X
X
X
X
X
X
X
X
8.2.1
Urine pregnancy test, dipsticki)
X
X
X
X
X
X
X
X
X
8.2.1.1
Phadiatop
X
8.2.1.3

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h
Assessed at EOT. For IPD patients only do assessment if the time period between randomization and IPD visit is ≥24 weeks. To avoid blood 
contamination, nasal secretion collected at EOT needs to be done after nasal endoscopy and before nasal biopsy.
i
At dosing visits, must be collected pre-dose.
j
Neutralizing antibody (nAb) testing will be performed for all samples that are ADA positive. Samples that are ADA negative will not be tested for nAb.
k
At selected clinical sites, nasal polyp tissue will be obtained by biopsy. For EOT visit, biopsy should be done after NP score assessment, nasal secretion 
sampling and sinus CT-scan (if applicable).
l
Samples can be collected at any time from Week 0 (V3) after genetic consent form is obtained.                                                                                                    
m
All V3 procedures and assessments must be performed prior to randomization/IP dosing.
n        IP administration should be the last activity of the visit. All visit procedures should be done prior to dosing.
ACQ-6- Asthma Control Questionnaire-6; ADA- Anti-drug antibodies; ClinRO- Clinician-reported outcome; CT- Computed tomography; EOT- End of 
treatment; FU- Follow-up; FUD- Follow-up discontinuation; HRU- Healthcare resource utilization; IgE- Immunoglobulin E; INCS- Intranasal corticosteroids; 
IPD- Investigational product discontinuation; nAb- Neutralizing antibody; NP- Nasal polyposis; PGI-C- Patient Global Impression of Change; PGI-S- Patient 
Global Impression of Severity; PK- Pharmacokinetics; PRO- Patient -reported outcome; 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

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Objectives and Endpoints
Primary objectives
Estimand Description / Endpoints
!
To evaluate the effect of benralizumab 
on nasal polyp burden and patient-
reported nasal blockage (NB) 
!
Populationa : Full analysis set:
!
Co-primary endpoints:
Change from baseline in endoscopic 
total nasal polyp score (NPS) Change 
from baseline in mean nasal blockage 
score (NBS) 
!
Intercurrent event strategy: 
Treatment discontinuation  - treatment 
policy
NP Surgery – composite (worst 
possible)
SCS for NP – composite (WOCF)
!
Summary Measure: differences in 
least squares mean change from 
baseline in NPS and NBS between 
benralizumab and placebo. Week 40 is 
the primary timepoint.b
Secondary objectives:
Endpoint/variable:
To evaluate the effect of benralizumab on:
!
Disease specific health-related quality 
of life (HRQoL)
!
Change from baseline in SinoNasal 
Outcome Test (SNOT-22) scorebc
!
Nasal polyp surgery and/or SCS use
!
Time to first NP surgery and/or SCS 
use for NPc
!
Time to first NP surgeryc
!
Sense of smell
!
Change from baseline in mean 
difficulty with sense of smell (DSS) 
scorebc
!
Change from baseline in University of 
Pennsylvania Smell Identification Test 
(UPSIT) score

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Secondary objectives:
Endpoint/variable:
!
Sinus opacification by CT scan 
(subset of patients)
!
Change from baseline in Lund 
Mackay scorec and sinus severity 
score by Quantitative CT analysis
!
Proportion of NP surgery
!
Proportion of patients with  surgery 
for NP
!
Systemic corticosteroids (SCS) use for 
relief of nasal symptoms
!
Proportion of patients with SCS use 
for NP
!
Time to first SCS course for NP, 
number of courses of SCS for NP, 
total SCS dose used and total duration 
of SCS use for NP
!
Symptoms associated with nasal 
polyps
!
Change from baseline in nasal 
symptom score(s) as captured in the 
daily diary
!
Patient-reported general health status
!
Change from baseline in Short Form 
36-item Health survey, Version 2 (SF-
36v2) Physical Component Score 
(PCS), Mental Component Score 
(MCS) and domains
a   Treatment condition for primary estimand: Treatment with benralizumab versus placebo, regardless of 
compliance, where rescue with NP surgery and/or SCS for NP represents failure.
b   Week 56 will also be a multiplicity protected timepoint for co-primary and key secondary repeated measures 
endpoints.
c Key secondary efficacy endpoints.  A similar estimand as outlined for the co-primary endpoints will be used 
for analyses of repeated measures secondary endpoints.
Safety objective:
Endpoint/variable:
!
To assess the safety of benralizumab
!
Adverse events (AEs) and serious 
adverse events (SAEs)
!
Laboratory variables
!
Physical Examination
!
To assess the pharmacokinetics and 
immunogenicity of benralizumab
!
Serum PK
!
Benralizumab anti-drug antibodies 
(ADA)

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!
To evaluate the effect of benralizumab 
on unplanned health care resource 
utilization
!
Hospitalizations, emergency room and 
urgent care visits 
Overall design
This is a randomized, double-blind, placebo-controlled, parallel-group, international, 
multicenter, Phase 3 study to evaluate the efficacy and safety of repeat dosing of benralizumab 
30 mg administered subcutaneously (SC) versus placebo in patients with severe NP.

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Approximately 400 patients will be randomized globally to receive benralizumab 30 mg sc or 
matching placebo. 
Patients will be stratified by region (United States [US] vs non-US) and by baseline comorbid 
asthma status (yes vs no). It is intended that approximately half of the randomized patients 
recruited into this study will have comorbid asthma.
After enrolment, eligible patients will receive a centrally sourced standardized dose of INCS 
and will enter a 5-week screening/run in period. Patients who meet eligibility criteria will be 
randomized 1:1 at Week 0 (Day 0) to receive either placebo or benralizumab 30 mg SC every 
4 weeks for the first 3 doses (Weeks 0, 4 and 8) and every 8 weeks thereafter (Weeks 16, 24, 
32, 40 and 48). A total of 8 doses will be administered to patients who complete the treatment 
period per protocol. An end of treatment (EOT) visit will be conducted at Week 56. 
The first approximately 200 patients who complete the 56-week treatment will have a 24-
week follow-up (FU) period without dosing to assess durability of benefit. These patients will 
have the FU for the final safety assessment at week 80. The remaining patients will have a last 
FU visit 12 weeks after last dose for final safety assessments at week 60. 
Study Period
Estimated date of first patient enrolled: Q1 2018
Estimated date of last patient completed: Q3 2020
Number of Patients 
This study will be conducted in approximately 8 countries at approximately 100 sites. The 
target is to randomize 400 patients.
Treatments and treatment duration
Benralizumab 30 mg will be administered SC every 4 weeks for the first 3 doses (Weeks 0, 4, 
and 8) and every 8 weeks thereafter (Weeks 16, 24, 32, 40, and 48) with an EOT at Week 56. 
Matching placebo will be administered SC at the same time points. In total patients will 
receive 8 doses of investigational product (IP). 
All patients will have their current INCS therapy standardized to Mometasone Furoate Nasal 
Spray (MFNS) at V1 and for a minimum of 4 weeks prior to V2 and continued throughout the 
screening and study period. If a subject cannot tolerate MFNS during screening, the subject 
would be screen failed.
Statistical methods

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1.2
Schema
The study design schema is summarized in Figure 1.
The background medication scheme is summarized in Figure 2.
Figure 1
Study flow chart

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Figure 2
Background Medication scheme   

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3.
OBJECTIVES AND ENDPOINTS
3.1
Primary objectives
Primary objectives
Estimand Description / Endpoints
!
To evaluate the effect of benralizumab 
on nasal polyp burden and patient-
reported nasal blockage (NB) 
!
Populationa: Full analysis set:
!
Co-primary endpoints:
Change from baseline in endoscopic total 
nasal polyp score (NPS)
!
Change from baseline mean nasal 
blockage score (NBS) 
!
Intercurrent event strategy: 
Treatment discontinuation – treatment 
policy
NP surgery – composite (Worst Possible)
SCS for NP – composite (WOCF)
!
Summary Measure: differences in least 
squares mean change from baseline in 
NPS and NBS between benralizumab and 
placebo. Week 40 is the primary 
timepointb
3.2
Secondary objectives
Secondary objectives:
Endpoint/variable:
To evaluate the effect of benralizumab on:
!
Disease specific health-related quality 
of life (HRQoL)
!
Change from baseline in SinoNasal 
Outcome Test (SNOT-22) scorebc
!
Nasal polyp surgery and/or SCS use
!
Time to first NP surgery and/or SCS 
use for NP c
!
Time to first NP surgeryc

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Secondary objectives:
Endpoint/variable:
!
Sense of smell
!
Change from baseline in mean 
difficulty with sense of smell (DSS) 
scorebc
!
Change from baseline in University of 
Pennsylvania Smell Identification Test 
(UPSIT) score
!
Sinus opacification by CT scan 
(subset of patients)
!
Change from baseline in Lund 
Mackay scorec and sinus severity 
score by Quantitative CT analysis
!
Proportion of NP surgery
!
Proportion of patients with  surgery 
for NP
!
Systemic corticosteroids (SCS) use for 
relief of nasal symptoms
!
Proportion of patients with SCS use 
for NP
!
Time to first SCS course for NP, 
number of courses of SCS for NP, 
total SCS dose used and total duration 
of SCS use for NP
!
Symptoms associated with nasal 
polyps
!
Change from baseline in nasal 
symptom score(s) as captured in the 
daily diary
!
Patient-reported general health status
!
Change from baseline in Short Form 
36-item Health survey, Version 2 (SF-
36v2) Physical Component Score 
(PCS), Mental Component Score 
(MCS) and domains
a   Treatment condition for primary estimand: Treatment with benralizumab versus placebo, regardless of 
compliance, where rescue with NP surgery and/or SCS for NP represents failure
b   Week 56 will also be a multiplicity protected timepoint for co-primary and key secondary repeated measures 
endpoints.
c Key secondary efficacy endpoints.  A similar estimand as outlined for the co-primary endpoints will be used 
for analyses of repeated measures secondary endpoints.

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3.3
Safety objectives
Safety objective:
Endpoint/variable:
!
To assess the safety of benralizumab
!
Adverse events (AEs) and serious 
adverse events (SAEs)
!
Laboratory variables
!
Physical Examination
!
To assess the pharmacokinetics and 
immunogenicity of benralizumab
!
Serum pharmacokinetics (PK)
!
Benralizumab anti-drug antibodies 
(ADA)
3.4
Exploratory objectives
 
 
 
 

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!
To evaluate the effect of benralizumab 
on unplanned health care resource 
utilization
!
Hospitalizations, emergency room and 
urgent care visits 
4.
STUDY DESIGN
4.1
Overall design
This is a randomized, double-blind, placebo-controlled, parallel-group, Phase 3 study to 
evaluate the efficacy and safety of repeat dosing of benralizumab 30 mg administered SC 
versus placebo in patients with severe NP. 
Approximately 400 patients will be randomized, globally, to receive benralizumab 30mg SC 
or matching placebo. 
Patients will be stratified by region (US vs non-US) and by baseline comorbid asthma status 
(yes vs no). At least 50% of the randomized patients will have comorbid asthma. 

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After enrolment, eligible patients will enter a screening/run in period on a stable dose of study 
provided MFNS. It is required to maintain a 4-week gap between V1 and V2 during the 
screening/run-in period. Patients will be provided with an electronic patient-reported outcome 
(ePRO) device to record symptoms throughout the study (see Section 8.1.1 Clinical outcome 
assessments). Patients who continue to meet eligibility criteria will be randomized 1:1 at Visit 
3 (Day 0) to receive either placebo or benralizumab 30 mg SC every 4 weeks for the first 3 
doses (Weeks 0, 4 and 8) and every 8 weeks thereafter (Weeks 16, 24, 32, 40 and 48). A total 
of 8 doses will be administered. An EOT visit will be conducted at Week 56. 
Patients will return to the study site at dosing visits and at EOT during the treatment period for 
evaluation of efficacy, safety, pharmacokinetics (PK), ADA, sample collection of blood and 
nasal secretion for exploratory biomarkers. Throughout the entire study period, participants 
will continue to receive daily MFNS. If at any point a patient meets IP discontinuation (IPD) 
criteria, an early IPD visits will be performed (see Section 7.1 Discontinuation of study 
treatment).
At selected clinical sites, nasal polyp tissue will be obtained by biopsy according to the 
schedule of activities (SoA). A baseline biopsy will be obtained prior to randomization, at 
visit 2 (V2). Another biopsy of nasal polyp tissue will be obtained at Week 56 (EOT) (see 
Section 8.9 Biomarkers). 
At selected clinical sites, CT scans will be performed. A baseline CT scan will be done at V2 
or V3 and the next one at the EOT/IPD visit (Week 56) (see Section 8.1.3 Sinus Computed 
Tomography ). 
The first approximately 200 patients who complete the 56-week treatment will have a 24-
week follow-up (FU) period without dosing to assess durability of benefit. These patients will 
have the FU for the final safety assessments at week 80. The remaining patients will have a 
last FU visit 12 weeks after last dose for final safety assessments at week 60.
If for any reason a patient in the first set of randomized patients 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 as soon as it is convenient to the patient and site, but not prior to Week 60 (visit 
12).
For an overview of the study design, see Figure 1, Section 1.2 Schema. For details on 
treatments given during the study, see Section 6.1 Treatments administered. 
For details on efficacy and safety endpoints, see Section 3 Objectives and Endpoints.
4.1.1
Study Conduct Mitigation in the event of evolving SARS-CoV-2 (COVID-19)
pandemic or other study disruption
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during COVID-19 global pandemic (e.g. during quarantines resulting in 
site closures, regional travel restrictions, and considerations regarding the safety of site 

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A patient is considered to have completed the study when he/she has completed his/her last 
scheduled visit. 
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 patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomized to a study intervention. Under no circumstances can 
there be exceptions to this rule. Patients who do not meet the entry requirements are screen 
failures (see Section 5.4 Screen failures).
In this protocol, “enrolled” patients are defined as those who sign informed consent. 
“Randomized” patients are defined as those who undergo randomization and receive a 
randomization number.
For procedures regarding withdrawal of incorrectly enrolled or randomized patients see 
Section 7.4 Procedures for handling incorrectly enrolled or randomized patients. 
5.1
Inclusion criteria
Patients are eligible to be included in the study only if all of the following inclusion criteria 
and none of the exclusion criteria are met:
Informed consent
1.
Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions, listed in the informed consent form (ICF) and in this 
protocol.
2.
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.
3.
Provision of signed and dated written genetic informed consent in patients that 
agree to participate in the genetic sampling, prior to collection of sample for genetic 
analysis.
The ICF process is described in Appendix A 3.
Age

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4.
Female or male patients aged 18 to 75 years inclusive, at the time of signing the 
ICF.
Type of patient and disease characteristics
5.
Patients with bilateral sinonasal polyposis that, despite treatment with a stable dose 
of INCS for at least 4 weeks prior to V1, in addition to a history of treatment with 
SCS (oral, parenteral) or prior surgery for NP, have severity consistent with a need 
for surgery as described by:
!
A minimum total NPS of 5 out of a maximum score of 8 (with a unilateral 
score of at least 2 for each nostril) at V1, and continuously maintained at V2 
to meet the randomization criterion, as determined by the study Imaging 
Core Lab;
!
Ongoing symptoms for at least 12 weeks prior to V1; 
!
Patient-reported moderate to severe nasal blockage (score 2 or 3) over the 2-
weeks prior to V1 (2-week recall assessment of symptoms, scores 0-none to 
3-severe).
6.
SNOT-22 total score ≥ 30 at enrolment (V1).
Patient must meet the following criteria at the randomization visit (V3):
7.
At least 8 days of evaluable daily diary data in the 14-day period prior to 
randomization (baseline bi-weekly mean score collected from study Day -13 to 
study Day 0).
8.
At randomization, a bi-weekly mean NBS ≥ 1.5.
9.
SNOT-22 total score ≥ 30 at randomization (V3).
10.
At least 70% compliance with INCS during the run-in period based on daily diary.
Weight
11.
Patients with a minimum weight of 40kg. 
Reproduction
12.
Negative serum pregnancy test result at V1 and a negative urine pregnancy test at 
randomization for female patients of childbearing potential.
13.
Women of childbearing potential (WOCBP) must use an effective form of birth 
control (confirmed by the Investigator) eg, total sexual abstinence, a vasectomized 
sexual partner, Implanon. Female sterilization by tubal occlusion, any effective IUD 

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intrauterine device/IUS levonorgestrel Intrauterine system, Depo-ProveraTM
injections, oral contraceptive, Evra PatchTM, or NuvaringTM. Women of 
childbearing potential must agree to use highly effective method of birth control, as 
defined above, from enrolment, throughout the study duration and for 16 weeks 
after the last dose of IP. 
14.
Women not of childbearing potential are defined as women who are either 
permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy), or who are postmenopausal. Women will be considerd 
postmenopausal if they have been amenorrheic for 12 months prior to the planned 
date of the randomization without alternative medical cause. The following age-
specific requirements apply:
!
Women <50 years old are considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous 
hormonal treatment and if follicle stimulating hormone (FSH) levels are in 
the postmenopausal range;
!
Women ≥ 50 years old are considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatment.
15.
Male subjects who are sexually active must be surgically sterile at least one year 
prior to Visit 1 or must use an adequate method of contraception (condom or 
condom with spermicide depending on local regulations) from the first dose of IP 
until 16 weeks after their last dose. Men with a partner or partners who is (are) not 
of childbearing potential are exempt of these requirements
5.2
Exclusion criteria 
Patients should not enter the study if any of the following exclusion criteria are fulfilled. 
Medical conditions
1.
Patients who have undergone any nasal and/or sinus surgery within 3 months prior 
to V1. 
2.
Patients with conditions or concomitant disease that makes them non evaluable for 
the co-primary efficacy endpoint such as:
!
Unilateral antrochoanal polyps;
!
Nasal septal deviation that occludes at least one nostril;
!
Acute sinusitis, nasal infection, or upper respiratory infection at screening or 
in the 2 weeks before screening;

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!
Current rhinitis medicamentosa;
!
Allergic fungal rhinosinusitis(AFRS) or Allergic fungal sinusitis (AFS);
!
Nasal cavity tumors.
3.
Clinically important comorbidities that could confound interpretation of clinical 
efficacy results including, but not limited to: active upper or lower respiratory tract 
infection, cystic fibrosis, primary ciliary dyskinesia, eosinophilic diseases other than 
asthma (eg, allergic bronchopulmonary aspergillosis/mycosis, eosinophilic 
granulomatosis with polyangitis [Churg-Strauss syndrome], hypereosinophilic 
syndromes), granulomatosis with polyangitis (Wegener's granulomatosis), Young’s 
syndrome, etc.
4.
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:
!
Affect the safety of the patient throughout the study;
!
Influence the findings of the studies or their interpretations;
!
Impede the patient’s ability to complete the entire duration of study.
5.
Patients experiencing an asthma exacerbation requiring systemic (oral and/or 
parenteral) corticosteroids treatment or hospitalization (>24hrs) for treatment of 
asthma within 4 weeks prior to V1. 
6.
History of anaphylaxis to any biologic therapy or vaccine.
7.
Known history of allergy or reaction to any component of the IP formulation.
8.
History of Guillain-Barré syndrome.
9.
A helminth parasitic infection diagnosed within 24 weeks prior to V1 and has not 
been treated with, or has failed to respond to standard of care therapy.
10.
Current malignancy, or history of malignancy, except for:
!
Patients who have had basal cell carcinoma, localized squamous cell 
carcinoma of the skin, or in situ carcinoma of the cervix are eligible 
provided that patient is in remission and curative therapy was completed at 
least 12 months prior to V1.

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!
Patients who have had other malignancies are eligible provided that the 
patient is in remission and curative therapy was completed at least 5 years 
prior to V1.
NOTE: Hormonal therapy is allowed. As long as the cancer is in remission 
for 5 years, the patient is eligible.
11.
Any clinical 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 patient at risk, because of his/her 
participation in the study, or may influence the results of the study, or the patients’ 
ability to complete entire duration of the study.
12.
Any clinically significant cardiac disease or any electrocardiogram (ECG) 
abnormality obtained during the screening/run-in period, which may put the patient 
at risk or interfere with study assessments.
13.
Positive hepatitis B surface antigen, or hepatitis C virus antibody serology 
(confirmed by additional testing, e.g. hepatitis C RNA test, if indicated), or a 
positive medical history for hepatitis B or C (Note: Patients with history of hepatitis 
B vaccination without history of hepatitis B are allowed to enrol). 
14.
History of known immunodeficiency disorder, including a positive human 
immunodeficiency virus (HIV) test.
15.
Infection requiring systemic antibiotics (Ab) within 14 days prior to V1.
Prior/concomitant therapy
16.
Use of immunosuppressive medication (including but not limited to: methotrexate, 
troleandomycin, cyclosporine, azathioprine, or any experimental anti-inflammatory 
therapy) within 3 months prior to V1 and during the study period.
17.
Receipt of any marketed or investigational biologic products (monoclonal or 
polyclonal antibody) within 6 months or 5 half-lives, whichever is longer, prior to 
V1 and during the study period. This also applies to patients who previously 
participated in clinical studies and were treated with monoclonal antibodies (e.g. 
mepolizumab, reslizumab, dupilumab, omalizumab). Note that this restriction do 
not apply to patients, who are confirmed to have only received treatment with 
placebo.
18.
Previous receipt of benralizumab. 
19.
Receipt of immunoglobulin or blood products within 30 days prior to V1.
20.
Receipt of live attenuated vaccines 30 days prior to the date of randomization.

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21.
Receipt of any investigational drug within 30 days or 5 half-lives whichever is 
longer prior to randomization. 
22.
Receipt of systemic corticosteroid 4 weeks prior to V1, or a scheduled systemic 
corticosteroid treatment during the study period.
NOTE: Sustained release steroids (e.g. Kenalog [Triamcinolone acetonide]) or 
depot injections require minimum 6 weeks washout prior to V1.  
23.
Receipt of leukotriene antagonist/modifiers for patients who were not on a 
continuous stable dose for ≥30 days prior to V1.
Prior/concurrent clinical study experience
24.
Concurrent enrolment in another clinical drug interventional trial.
Diagnostic assessments
25.
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥3 
times the upper limit of normal (ULN) confirmed during screening period.
Other exclusions
26.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site or immediate family members of 
such individuals).
27.
Judgment by the Investigator that the patient should not participate in the study if 
the patient is unlikely to comply with study procedures, restrictions and 
requirements.
28.
Previous randomization in the present study. 
29.
Planned major surgical procedures or scheduled NP surgery at the time of the study 
enrolment and randomization.
30.
Initiated or is being maintained on an aspirin desensitization regimen for the 
management of AERD at the time of study enrolment or during the run-in period.
31.
History of alcohol or drug abuse within 12 months prior to V1, based on 
Investigator’s assessment. 
32.
For women only – currently pregnant (or intend to become pregnant), breastfeeding 
or lactating.

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5.3
Lifestyle restrictions
1.
Fertile and sexually active patients or their partners should use effective 
contraceptive methods throughout the study and 16 weeks after last dose of the IP. 
Male patients should refrain from fathering children or donating sperm from the 
time of informed consent, to 16 weeks after last dose of the IP (see Inclusion 
criterion 15).
2.
Patients must abstain from donating blood and plasma from the time of informed 
consent, to 16 weeks after last dose of the IP.
5.4
Screen failures
Screen failures are defined as patients who signed the ICF to participate in the clinical study 
but are not subsequently randomized and must not be assigned to the study treatment. These 
patients must be withdrawn from the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure patients to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries form 
regulatory authorities (RAs). Minimal information includes demography, screen failure 
details, eligibility criteria, and any SAE.
These patients should have the reason for study withdrawal recorded in the electronic case 
report form (eCRF) as “Incorrect Enrolment” (ie. Patient does not meet the required
inclusion/exclusion criteria). This reason for study withdrawal is only valid for screen failures 
(not randomized patients).
5.4.1
Re-screening
Re-screening is allowed only once for a patient.
Rescreening and/or up to 14 days extension of the screening period, is allowed for transient 
reasons (including but not limited to equipment/procedure failure, e.g. problems with the 
ePRO device impacting availability of data or documenting compliance with INCS, or 
unforeseen personal events that result in a missed visit).  
For patients who require SCS and/or antibiotics for an asthma exacerbation or worsening of 
nasal polyp symptoms during the screening period (prior to V2), the screening period may be 
extended for up to 6 weeks, provided the treatment duration with SCS and/or Ab is ≤ 14 days. 
The next regular study visit (Visit 2) will be delayed and may proceed no sooner than 4 weeks 
after the last dose of SCS and/or Ab. 
If the duration of treatment with SCS and/or Ab is >14 days, or asthma exacerbation/ 
worsening of nasal polyp symptoms occurred after V2, patients should be screen failed, but 
can be considered for re-screening.
Patients who fail to meet the required total NP score at V1 or V2, may be considered for re-
screening once an appropriate time interval, as deemed by the investigator, has elapsed. 

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Patients may not be re-screened or have an extended screening period for failure to meet 
minimum symptom severity or SinoNasal Outcome Test (SNOT-22) requirements.
Re-screened patients should be assigned the same patient number as for the initial screening. It 
means that patient should keep the same E-code as was originally assigned. 
Re-screened patients should re-sign informed consent. All procedures from the screening/run-
in period should be repeated. Re-screening should be documented so that its effect on study 
results, if any, can be assessed.
6.
STUDY TREATMENTS
Study treatment is defined as any IP(s) (including marketed product comparator and placebo) 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. Study treatment in this study refers to benralizumab 30 mg or matching placebo, 1 
mL.
6.1
Treatments administered
6.1.1
Investigational products
All IPs will be manufactured in accordance with Good Manufacturing Practice (GMP).
Table 3                  Study Treatments
Treatment 1
Treatment 2
Study treatment name:
Benralizumab
Placebo
Dosage formulation:
30 mg/mL solution for injection 
in accessorized pre-filled 
syringe, 1 mL fill volume
Matching placebo solution for 
injection in accessorized pre-
filled syringe, 1 mL fill volume
Clear to opalescent, colourless 
to yellow solution.
Clear to opalescent, colourless 
to yellow solution.
Route of administration 
subcutaneously
subcutaneously
Dosing instructions:
Benralizumab active solution 
will be administered 
subcutaneously to patients by 
health care professionals in this 
clinical study using an 
accessorized prefilled syringe 
(APFS).
Placebo solution will be 
administered subcutaneously to 
patients by health care 
professionals in this clinical 
study using an accessorized 
prefilled syringe (APFS). 

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Treatment 1
Treatment 2
Each prefilled syringe is 
designated for single use only 
and is not to be administered to 
more than one patient.
Each prefilled syringe is 
designated for single use only 
and is not to be administered to 
more than one patient.
Packaging and labelling
Study treatment will be 
provided in accessorized pre-
filled syringe. 
Each syringe will be labelled in 
accordance with Good 
Manufacturing Practice (GMP) 
Annex 13 and per country 
regulatory requirement. 
Label text will be translated into 
local language as required.
The label will include the 
following information:
• study code
• Investigational product/study 
treatment dosage form, route of 
administration, and
quantity of dosage units
• kit ID
• P Lot ID
• Expiry date
• Investigator Name (to be 
written on the label)
• E-code (to be written on the 
label)
• Sponsor name and contact 
details
• Directions for use
• Storage condition
• Standard statements required 
by regulatory authorities
Study treatment will be 
provided in accessorized pre-
filled syringe. 
Each syringe will be labelled in 
accordance with Good 
Manufacturing Practice (GMP) 
Annex 13 and per country 
regulatory requirement. 
Label text will be translated into 
local language as required.
The label will include the 
following information:
• study code
• Investigational product/study 
treatment dosage form, route of 
administration, and quantity of 
dosage units
• kit ID
• P Lot ID
• Expiry date
• Investigator Name (to be 
written on the label)
• E-code (to be written on the 
label)
• Sponsor name and contact 
details
• Directions for use
• Storage condition
• Standard statements required 
by regulatory authorities
Provider
AstraZeneca
AstraZeneca

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6.2
Preparation/handling/storage/accountability
6.2.1
Preparation and handling
The investigational product will be administered at the study site on treatment visits and 
within visit windows as specified in the SoA.
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit and storage for all study treatment received and any discrepancies 
are reported and resolved before use of the study treatment.
Only patients enrolled in the study may receive study treatment and only authorised site staff 
may supply or administer study treatment. 
Before investigational product administration
Prior to each IP administration:
!
Investigator/authorized delegate will assess injection site as per standards of 
medical care;
!
For WOCBP, urine pregnancy test will be done; IP will be administered only when 
the result of the test is negative.

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Further details on IP administration are described in the IP Handling Instruction provided to 
study sites. Investigational product administration must be carried out in line with the 
Instruction.
After investigational product administration
After IP administration, the patient should be observed for a minimum of 1 hour in case of any 
acute drug reactions.
Conditions requiring investigational product administration rescheduling
If any of the following occur, the Investigator should reschedule the visit and the IP should not 
be administered until the rescheduled visit:
!
The patient has an intercurrent illness, that in the opinion of the Investigator may 
compromise the safety of the patient in the study (e.g. viral illnesses);
!
The patient, in the opinion of the Investigator, is experiencing an acute or emerging 
asthma exacerbation;
!
The patient is febrile (≥38°C; ≥100.4°F) within 72 hours prior to the IP 
administration.
6.2.2
Storage
All study treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labelled storage conditions with access 
limited to the Investigator and authorised site staff.
The temperature should be monitored on a daily basis and documented in the temperature 
monitoring log.
The investigational product must be kept in the original outer container and under conditions 
specified on the label (between 2 to 8°C (36 to 46°F), protected from the light).
In the following cases, the site staff should not use affected IP and should immediately contact 
an AstraZeneca representative for further guidance:
!
Temperature excursion upon receipt or during storage at the study;
!
Damaged kit upon receipt;
!
Damaged syringe/cartridge.
Damaged IP should be documented via Interactive Web Response System/ Interactive Voice 
Response System (IWRS/IVRS; refer to IWRS/IVRS manual for further details).

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6.2.3
Accountability
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records).
An AstraZeneca site monitor will account for all study treatments received at the site, for 
unused study treatments, and for appropriate destruction or return of unused study treatments. 
Certificates of delivery, destruction, and/or return should be signed.
In the case of a malfunctioning accessorized prefilled syringe (APFS), the site should contact 
the study monitor to initiate a product complaint process according to applicable guidelines.
Further guidance and information for the final disposition of unused study treatment are 
described in the Pharmacy Manual provided to the sites. 
6.3
Measures to minimise bias: randomization and blinding
6.3.1
Methods for assigning treatment groups
Patients will be stratified by region (US vs non-US) and by baseline comorbid asthma status 
(yes vs no). It is expected that at most 50% of the randomized patients will not have comorbid 
asthma. The corresponding strata will be closed for randomization (see Section 7.3.1
Withdrawal due to recruitment completion in a randomization stratum). 
All patients will be centrally assigned to randomized study treatment using an IWRS/IVRS. 
Before the study is initiated, the telephone number and call-in directions for the IVRS and/or 
the log-in information and directions for the IWRS will be provided to each site. 
Randomization codes will be assigned strictly sequentially in each stratum as patients become 
eligible for randomization. 
Patients who fail to meet the inclusion/exclusion criteria should not, under any circumstances, 
be enrolled or receive study treatment. There can be no exceptions to this rule.
If a randomized patient withdraws from the study, then his/her enrolment/randomization code 
cannot be reused. Withdrawn patients will not be replaced.
6.3.2
Methods for ensuring blinding
This is a double-blind study. AstraZeneca staff involved in the study, the patients, and the 
Investigators involved in the treatment of patients or in their clinical evaluation will not be 
aware of treatment allocation. 
Placebo solution will be visually matched with benralizumab solution. Both benralizumab and 
placebo will be provided in an APFS.

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6.3.2.1
Maintaining the blind to the patient’s blood eosinophil counts
While not entirely specific, patients on active benralizumab treatment are expected to have 
lower blood eosinophil counts than patients on placebo. In order to mitigate potential 
unblinding on this basis, per protocol haematology will be run by the central laboratory. After 
Visit 3, eosinophil, basophil and monocyte counts will be redacted from any central laboratory 
reports sent to investigative sites to prevent the Principal Investigator (PI)/designee from 
possibly deducting the ‘eosinophil + basophil + monocyte’ contribution to the complete blood 
count (CBC). 
If the Investigator orders any local safety laboratory assessments, the requested tests should be 
restricted to the question at hand. For example, if haemoglobin (Hb) is desired the Investigator 
should avoid ordering a complete blood cell count with differential.
6.3.2.2
Handling of labs obtained during the study period but ordered outside of the 
clinical trial. 
Site staff who are directly involved in the patient’s management should remain blinded to any 
eosinophil, basophil and monocyte results included as part of outside lab reports. To help 
ensure this, each investigational site will designate an individual (e.g. administrator or another 
ancillary person) not directly involved in patient management, to receive and blind any 
eosinophil, basophil and monocyte results prior to the report being handed over to the site 
staff involved in the patient’s management and prior to filing as a source document. Similarly, 
eosinophil and basophil results must be redacted from all communications with AstraZeneca.
In cases where the Investigator requires an eosinophil, basophil, or monocyte count for 
managing safety issues he/she may order these tests. AstraZeneca should be notified of all 
such cases, but should not be informed about lab results. 
6.3.3
Methods for unblinding
Individual treatment codes, indicating the treatment randomization for each randomized 
patient, will be available to the Investigator(s) or Pharmacists at the study site from the 
IWRS/IVRS. Further detail on how to unblind a patient’s treatment allocation will be 
described in the IWRS/IVRS user manual provided to each study site.
The randomization code should not be broken except in medical emergencies when the 
appropriate management of the patient requires knowledge of the treatment randomization. 
The Investigator documents and reports the action to AstraZeneca, without revealing the 
treatment given to the patient 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 (RAs). Randomization codes will not be broken for the planned 
analyses of data until all decisions on the evaluability of the data from each individual patient 
have been made and documented.

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6.4
Treatment compliance
The administration of all study treatments (including IPs) should be recorded in the 
appropriate section of the eCRF.
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 on treatment 
visits and within visit windows as specified in the SoA. 
In cases where a treatment visit needs to be re-scheduled, 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. 
If 2 doses of the IP are missed during course of the study the patient should be discontinued 
from the study treatment. 
Any change from the dosing schedule, dose interruptions, dose discontinuations should be 
recorded in the eCRF.
Principal Investigators should also assure that patients are compliant and on a stable dose of 
the background medication (INCS) during study period. 
6.5
Concomitant therapy
The Investigator must be informed as soon as possible about any medication taken from the 
time of screening until the end of the study (final study visit). Any concomitant medication(s), 
including herbal preparations, taken during the study will be recorded in the eCRF, 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 medication can be found in the Table 4 and Table 5, 
provided below:
Table 4
Restricted medications
Medication/class of drug:
Usage (including limits for duration permitted 
and special situations in which it’s allowed ):
Inactive/killed vaccinations (e.g. inactive 
influenza)
Not allowed within the 7 days before or within 7 
days after any IP dosing study visit
Any Immunosuppressives – topical
Topical administration of Immunosuppressive 
medication may be allowed at the discretion of the 
Investigator 

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Medication/class of drug:
Usage (including limits for duration permitted 
and special situations in which it’s allowed ):
Allergen Immunotherapy
Allowed if on stable therapy started 30 days prior 
to V1; no change during the treatment period
Systemic corticosteroids (SCS) 
A short course of SCS (3-14 days), allowed at PI’s 
discretion to relieve symptoms of nasal polyposis 
worsening or asthma exacerbations
Decongestants (topical or systemic)  
Only allowed for endoscopic procedure
Table 5
Prohibited medications
Prohibited medication/class of drug:
Intranasal Medication including intranasal 
corticosteroids drops
Only study provided MFNS is allowed.
Any immunosuppressive treatment including but 
not limited to: methotrexate, cyclosporine, 
mycophenolate, tacrolimus, gold, penicillamine, 
sulfasalazine, hydroxylchloroquine, 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 desensitization
Use of aspirin as a desensitization regimen for the 
management of aspirin exacerbated respiratory 
disease (AERD) is not allowed; all other uses of 
aspirin is allowed for any other medical 
conditions.
Any marketed or investigational biologic 
(monoclonal or polyclonal antibody)
Not allowed within 6 months or 5 half-lives 
(whichever is longer) prior to V1; during the 
study period 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 to randomization; and 
during the study period.
Live attenuated Vaccines
Not allowed within 30 days prior to 
randomization; 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 within 30 days prior to V1 and 
during the study period.

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6.5.1
Background medication
If a patient is using an alternative INCS product other than MFNS prior to visit 1, the 
Investigator will switch the INCS to MFNS at visit 1. All patients will receive study provided 
standardized MFNS for a minimum of 4 weeks prior to V2, continued throughout the 
screening and study period.  
  
Mometasone furoate (50 micrograms/actuation) nasal spray is contained in a bottle that 
contains 120 actuations for US and 140 actuations for all other countries. Two doses 
(50mcg/actuation) in each nostril twice daily (total daily dose of 400 mcg) will be 
administered, unless there is a medical rationale to use the lower dose (QD) regimen. 
Each patient will receive enough background medication to cover the need until the next on 
site visit. Intranasal corticosteroids dispensation will be performed according to the SoA table 
(Table 1). 
Intranasal corticosteroid compliance will be recorded by the patient in the ePRO diary and 
should be checked by Investigators during the study period. If a subject cannot tolerate MFNS 
during screening period, the subject should be screen failed.
The Principal Investigator should ask patients about SCS (oral, parenteral) use for NP at each 
visit and record in the eCRF. If medically justified, a short course of SCS (3-14 days) is 
allowed for NP worsening during the study, at PI’s discretion, according to local standard of 
care. If SCS is used for ≤ 14 days between V1 and V2, the screening may be extended for 
maximum 6 more weeks. Otherwise, patient should be screen failed, but can be considered for 
rescreening once (please refer to section 5.4.1 Re-screening). 
6.5.2
Other concomitant treatment
Medications other than the ones described above, which are considered necessary for the 
patient’s safety and wellbeing, may be given at the discretion of the Investigator and recorded 
in the appropriate sections of the eCRF.
6.6
Dose modification
N/A
6.7
Treatment after the end of the study
After the end of the study, the patient should be given standard of care therapy, at the 
discretion of the Investigator, per local practice.

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7.
DISCONTINUATION OF TREATMENT AND PATIENT
WITHDRAWAL
7.1
Discontinuation of study treatment
Patients may be discontinued from IP in the following situations. Note that discontinuation 
from study treatment is NOT the same thing as a complete withdrawal from the study:
1.             Patient decision. The patient is at any time free to discontinue treatment, without 
prejudice to further treatment.
2. 
     AE that, in the opinion of the Investigator, contraindicates further dosing.
3.
Severe non-compliance with the CSP.
4.
Risk to patient as judged by the Investigator or AstraZeneca.
5.
Pregnancy.
6.
IP unblinding (PI).
7.
Development of any study specific criteria for discontinuation:
!
Anaphylactic reaction to the IP requiring administration of epinephrine;
!
Development of helminth parasitic infestations requiring hospitalization;
!
If 2 doses of the IP are missed during course of the study;
!
A respiratory-related event requiring mechanical ventilation.
7.1.1
Procedures of discontinuation of study treatment
At any time, patients are free to discontinue IP without prejudice to further treatment. A 
patient that decides to discontinue IP should always be asked about the reason(s) and the 
presence of any AEs.
All patients who prematurely discontinue IP should return to the study site and complete the 
procedures described for premature IPD visit within 8 weeks after the last dose of IP. At that 
visit, although no longer on IP, patients should be encouraged to remain in the study to 
complete all subsequent study visits, procedures, and assessments. Data collection should 
continue according to the study protocol. Note that in this case, the IPD visit replaces the 
nearest regular visit while the following visits continue as possible. 
If the patient does not agree to complete all subsequent visits and procedures, the patient 
should be encouraged to stay in the study, keep the daily diary (ePRO device), and continue 
selected visits until Week 56. 

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If the patient does not agree to continue in-person study visits, telephone visits should be 
performed to ensure the collection of endpoints and safety information. Patients will be 
encourage to keep the ePRO device and do assessments, participate in the telephone visits, 
and return ePRO handheld device at the end of the study. If a patient is not willing to complete 
ePRO procedures, device should be returned at the IPD visit and the telephone FU should be 
continued. A patient that agrees to modify FU is not considered to have withdrawn consent or 
to have withdrawn from the study.
If a patient is not willing to participate further in the study after the IPD visit, the ePRO will 
be returned at the IPD visit. The patient should be asked to return for a FU visit 12 weeks after 
the last dose of IP for final study-related assessments.
The reason for premature discontinuation of IP should be recorded in the eCRF.
See the SoA for data to be collected at the time of treatment discontinuation and follow-up 
and for any further evaluations that need to be completed.
7.2
Lost to follow-up
A patient will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The patient 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; or 1 
unsuccessful effort to check the vital status of the patient using publicly available sources, if 
allowed, by local regulations.
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit:
!
The site must attempt to contact the patient and reschedule the missed visit as soon 
as possible and counsel the patient on the importance of maintaining the assigned 
visit schedule;
!
Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient or next of kin by e.g. repeat telephone 
calls, certified letter to the patient´s last known mailing address or local equivalent 
methods. These contact attempts should be documented in the patient’s medical 
record; 
!
Efforts to reach the patient should continue until the end of the study. Should the 
patient be unreachable at the end of the study the patient should be considered to be 
lost to follow-up with unknown vital status at end of study and censored at latest 
follow-up contact.

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7.3
Withdrawal from the study
A patient may withdraw from the study (e.g. withdraw consent), at any time (IP and 
assessments) at his/her own request, without prejudice to further treatment.
If the patient withdraws consent for disclosure of future information, AstraZeneca may retain 
and continue to use any data collected before such a withdrawal of consent.
If a patient withdraws from the study, he/she may request destruction of any samples taken, 
and the Investigator must document this in the site study records. 
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AEs. The Investigator will follow up patients as medically indicated. The patient will 
return ePRO devices to the site staff.
See SoA (Table 2) for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed. All Study treatment should be 
returned by the patient.
7.3.1
Withdrawal due to recruitment completion in a randomization stratum
When a specific stratum is full, patients in the completed stratum will not be randomized and 
will be withdrawn from the study. The reason of the withdrawal should be documented in the
source and eCRF as a development of study specific criterion for discontinuation. Same as 
with screen failures, no further study related follow-up of these patients is required.
The no-comorbid asthma stratum will be closed when the total number of patients in the 
stratum reaches approximately 200.
7.4
Procedures for handling incorrectly enrolled or randomized 
patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive study treatment. There can be no exceptions to this rule. Patients who 
are enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomized or initiated on treatment, and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca Study
Physician immediately, and an agreement should be made between the AstraZeneca Study
Physician and the Investigator regarding whether to continue or discontinue the patient from
treatment. The AstraZeneca Study Team must ensure all decisions are appropriately
documented.

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8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA. 
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.
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.
Immediate safety concerns should be discussed with AstraZeneca immediately upon 
occurrence or awareness to determine if the patient should continue or discontinue study 
treatment.
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 patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
Additional data to assess the impact of study disruption caused e.g. by COVID-19 pandemic 
will be collected in additional eCRF modules. For more information please refer to the recent 
version of eCRF instruction.
8.1
Efficacy assessments 
8.1.1
Clinical outcome assessments
Patients will complete all patient-reported outcomes (PRO) assessments using a handheld 
ePRO device. The ePRO device will be the only accepted source of patient reported data.
The Investigator will ensure that patients 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 patient does not meet the screening 
requirements, the device will be deactivated and retained at the site. If eligible to continue, the 
patient 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 patient needs as required. The patient 
will be required to complete a training module before taking the device home. If a patient fails 
to meet eligibility criteria after V1 (for example regarding total NPS), the patient will be 
scheduled to return to the site, return the ePRO device and will be screen failed at that time. 

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The Investigator or designee will be responsible for monitoring patient adherence with the 
daily diary and follow-up as necessary to minimize missing data. Patient compliance should 
be checked weekly (at minimum) to ensure that the patient is completing the assessments as 
scheduled. Monitoring of patient adherence to the diary is critical during the baseline period 
(Study day -13 to Day 0) to ensure that the patient meets applicable criteria for randomization. 
Continued weekly monitoring of adherence throughout the study and follow-up with patients 
via phone and at the visits is required to ensure sufficient data is available for supporting the 
co-primary endpoint of this study.
All PRO assessments should be completed prior to any other interventional study procedure 
(e.g. laboratory tests, endoscopy, CT-scan) with the exception of informed consent at Visit 1. 
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 
at the time of the visit it will be completed at the site prior to other study procedures.
8.1.1.1
Nasal Polyposis Symptom Diary
The patient will complete an 11-item NP symptom diary (NPSD) each morning throughout the 
screening, treatment and follow-up periods. The patient is asked to consider their experience 
with NP / nasal polyps over the past 24 hours when responding to each question. Patients are 
asked to report their experience with NP symptoms (nasal blockage, nasal congestion, runny 
nose, postnasal drip (mucus 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). Patients 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 (Nasal Polyposis Symptom Screening Assessment) 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; otherwise concepts measured are the same as the daily diary.
The NPSD will be completed on the ePRO device per the SoA.
8.1.1.1.1
Nasal Blockage Score
One of the co-primary endpoints of the study is the change from baseline in the bi-weekly 
mean of NBS at Week 40 (change from baseline at Week 56 is a key secondary endpoint). 
NBS is captured by an item in the NPSD asking patients to rate the severity of their worst 
nasal blockage 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 NBS 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.

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8.1.1.1.2 Difficulty with Sense of Smell (DSS) score
One of the key secondary endpoints of the study is the change from baseline in the bi-weekly 
mean of DSS at Week 40 (change from baseline at Week 56 is also a key secondary endpoint). 
DSS is captured by an item in the NPSD asking patients 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 DSS 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.
8.1.1.2
SinoNasal Outcome Test 22 item 
One of the key secondary endpoints of the study is the change from baseline in SNOT-22 total 
score at Week 40 (change from baseline at Week 56 is also a key secondary endpoint). The 
SNOT-22 is a condition-specific HRQoL assessment which captures patient-reported 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 device per the SoA.
8.1.1.3
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 patients 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). 

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8.1.1.7
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 
standardized odor-impregnated test booklets (Doty et al, 1984). Four booklets each with 10 
odorants each are used for the test. Patients are asked to identify the odor using multiple 
choice format which lists different possibilities. The test is forced-choice; i.e., the patient is 
required to mark one of the four alternatives even if no smell is perceived. Scores are based on 
number of correctly identified odors (score range 0 to 40).
Please note that the UPSIT smell test will be performed in all countries participating in the 
study except Denmark. No Danish version of the test is available. 
8.1.2
Nasal Polyp Score 
One of the co-primary endpoints of the study is the change from baseline in bilateral 
endoscopic total NPS at week 40 (change at week 56 is a key secondary endpoint). The score 
(maximum 8) is the sum of the right and left nostril scores, 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 sent to centralized reader. Centralized imaging data 
assessments and scoring by an independent physician reviewer for the imaging data will be 
performed for all endoscopies. To confirm eligibility at V3, the V1 and V2 central reading 
results will be made available to the site. 
The sites will remove patient-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 also 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 nasal polyp score
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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Polyp score
Polyp size
3
Large polyps reaching the lower border of the inferior turbinate or large 
polyps of score 2 with additional large polyps medial to the middle turbinate
4
Large polyps causing complete or near-complete obstruction of the inferior 
nasal cavity i.e. touching the floor of the nose
8.1.3
Sinus Computed Tomography 
Computed tomography will be performed in up to 200 patients at selected sites. Baseline CT 
will be performed at V2 or V3 and a final CT will be performed at EOT (or IPD if 24 weeks 
passed since baseline CT).
Baseline CT should be performed after the nasal polyp biopsy (biopsy and CT can be 
performed on separate days) and before nasal polyp biopsy at EOT/IPD.
Sinus CT images will be used to derive LMSs based on the visual assessment by independent 
central readers (see Section 8.1.3.1 Lund-Mackay score), and for quantitative estimation of a 
sinus severity score (see Section 8.1.3.2 Quantitative measurement of sinus disease burden on 
sinus computed tomography ), which is representative of sinus disease burden. 
The sites will remove patient-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 also 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.
8.1.3.1
Lund-Mackay score 
The Lund-Mackay score scoring system (see Table 8 below) is used to provide a semi-
quantitative assessment of nasal sinuses on sinus CT scans (Lund et al 1993). Based on the 
sinus CT images, the five sinuses (maxillary, anterior ethmoid, posterior ethmoid, sphenoid 
and frontal) on each side are scored by central radiologist as follows: 
Table 8
Lund-Mackay score
Score
CT scan assessment
0
No abnormality
1
Partial opacification
2
Total opacification

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The osteomeatal complex is scored for right and left sides:
Table 9
Osteomeatal complex score
Score
CT scan assessment
0
Not occluded
2
Occluded
The change in score between baseline and EOT will be analyzed (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:
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 and baseline and EOT will be compared.
8.1.4
Nasal polyp surgery
Nasal polyposis surgery is defined as any procedure involving instruments resulting in 
incision and removal of tissue (e.g. polypectomy, endoscopic sinus surgery). 
Surgery procedures performed for NP during the study, including reason for surgery and 
information whether the surgery was performed as an outpatient or inpatient (i.e. including an 
overnight stay in the hospital) procedure, should be recorded in the Nasal Polyp Surgery 
eCRF.
Administration of IP post NP surgery is discretionary and subject to assessment by the 
Investigator. If the patient is scheduled for NP surgery, an unscheduled visit, should ideally be 
performed prior to the surgery to assess safety and efficacy (including total NPS, SNOT-22, 
SF-36v2, PGI-S, PGI-C, ACQ-6 [for asthma patients only] and UPSIT). 

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Note: protocol mandated nasal polyp biopsy sampling (see Section 8.9 Biomarkers) will not 
be regarded as NP surgery.
8.2
Safety assessments 
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Clinical safety laboratory assessments
See Table 10 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. 
For information on methods of collection, assessment, labelling, storage, and shipment of 
samples, please refer to the separate Laboratory Manual.
The Investigator should make an assessment of 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.
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.7 Adverse events based on examinations and tests.
Table 10
Laboratory safety variables
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
B-Haemoglobin (Hb)
S/P-Alkaline phosphatase (ALP)
B-Leukocyte count
S/P-Aspartate aminotransferase (AST)
B-Mean corpuscular volume (MCV)
S/P-Alanine aminotransferase (ALT)
B-Red blood cell (RBC)
S/P-Bilirubin, total
B-Platelet count
S/P-Blood urea nitrogen (BUN)
B-White blood cell (WBC) count with differentiala
S/P-Calcium, total
S/P-Creatinine
S/P-Gamma-GT (gamma-glutamyl 
transpeptidaze)
S/P-Glucose 
S/P-Potassium
S/P-Sodium
a
Eosinophils, basophils and monocytes counts will be redacted from central laboratory reports
The clinical chemistry and haematology analysis 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.
Note: In case a patient shows an AST or ALT ≥3xULN together with total bilirubin (TBL) 
≥2xULN please refer to Appendix E ‘Actions required in cases of increases in liver 
biochemistry and evaluation of Hy’s Law (HL)’, for further instructions.
8.2.1.1
Pregnancy Test
The following tests are applicable to female patients only and will be conducted in accordance 
with the schedules provided in the SoA.
!
Serum beta-HCG: To be performed for all females at screening Visit 1except for 
those who are NOT of child bearing potential as defined in inclusion criterion 14. 
This test is to be sent to and analyzed at the central laboratory;
!
FSH: To be performed at screening Visit 1 only, for female patients to confirm 
postmenopausal status in women <50 years who have been amenorrheic for >12 
months; 
!
Urine HCG: To be performed at the study site for all females at each treatment visit 
before IP administration using a dipstick except for those females who are NOT of 
child bearing potential as defined in inclusion criterion 14. A positive urine test 
result must be confirmed with serum beta-HCG.
8.2.1.2
Serology
Hepatitis B surface antigen, hepatitis C antibody: To be performed only at screening; test to be 
performed at central laboratory.
In case of positive result of hepatitis B surface antigen or hepatitis C virus antibody, additional 
testing (e.g. hepatitis C RNA PCR test) may be performed to confirm eligibility.
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.
8.2.1.3
Serum immunoglobulin E and allergen-specific Immunoglobulin E (Phadiatop)
The levels of total immunoglobulin E (IgE) and a qualitative assessment for the presence of 
allergen-specific IgE (ImmunoCAP Phadiatop) will be evaluated by a central laboratory. 
These tests will be performed at Visit 3 according to the SoA.
Instructions for sample collection, processing, storage, and shipment can be found in the 
separate Laboratory Manual provided to the sites.

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8.2.2
Physical examinations
Physical examinations will be performed at timepoints as specified in the SoA. The 
Investigators should pay special attention to clinical signs related to previous serious illnesses 
as new or worsening abnormalities may qualify as AEs, see Section 8.3.7 Adverse events 
based on examinations and tests, for details. 
8.2.2.1
Complete physical examination
A complete physical examination will be performed and include an assessment of the 
following: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, musculo-skeletal (including 
spine and extremities) and neurological systems.
8.2.2.2
Brief physical examination
The brief physical examination will include an assessment of the general appearance, 
abdomen, cardiovascular and respiratory system. For the brief physical examination only 
information on whether the assessment was performed or not is to be recorded.
8.2.3
Vital signs
Pre-dose vital signs are to be obtained in accordance with 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;
!
Blood pressure and pulse measurements will be assessed while sitting, and will be 
assessed utilizing 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 patient in a quiet setting without distractions (eg, television, cell 
phones);
!
Respiration rate will be obtained after patient has been resting for at least 5 minutes, 
by counting number of breaths (how many times the chest rises) for 1 minute.
8.2.4
Electrocardiograms
Electrocardiograms are to be performed at Visit 1 to assess eligibility for this study, and then 
as clinically indicated during the treatment period.

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A 12-lead ECG will be taken in supine position, after the patient has been resting for at least 5 
minutes. The assessment should be performed before interventions with the patient (eg, 
endoscopy, blood draw).
An independent reader will provide overall interpretation as normal or abnormal and assess 
the clinical significance of any potential ECG findings. A reassessment ECG may support 
evaluation of clinical significance, when uncertain.
A patient with a clinical significant abnormal finding on the ECG, assessed by PI, should be 
screen failed.
8.2.5
Other assessments
8.2.5.1
Weight and height
Weight and height will be measured in accordance with schedules provided in the SoA.
The patient'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.
8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
Adverse event will be reported by the patient (or, when appropriate, by a caregiver, surrogate, 
or the patient's legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs 
see Section 8.3.3 Follow-up of adverse events and serious adverse events. 
8.3.1
Method of detecting adverse events and serious adverse events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences. 
8.3.2
Time period and frequency for collecting adverse event and serious 
adverse event information 
Adverse events (serious and non-serious) will be collected from time of signature of ICF
throughout the treatment period and including the FU period. 
All SAEs will be recorded and reported to AstraZeneca or designee within 24 hours, as 
indicated in Appendix B. The Investigator will submit any updated SAE data to AstraZeneca 
within 24 hours of it being available.

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Investigators are not obligated to actively seek AE or SAE in former study patients. However, 
if the Investigator learns of any SAE, including a death, at any time after a patient’s last visit 
and he/she considers the event to be reasonably related to the study treatment or study 
participation, the Investigator may notify AstraZeneca.
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.
8.3.3
Follow-up of adverse events and serious adverse events
After the initial AE/SAE report, the Investigator is required to proactively follow each patient 
at subsequent visits/contacts. All AEs and SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the patient is lost to follow-up. 
Any AEs that are unresolved at the patient’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 patient with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary.
8.3.4
Adverse event data collection
The following variables will be collected for each AE:
!
AE (verbatim);
!
The date when the AE started and stopped;
!
Maximum intensity of the AE;
!
Whether the AE is serious or not;
!
Investigator causality rating against the IP(s) (yes or no);
!
Action taken with regard to IP(s);
!
AE caused patient’s withdrawal from study (yes or no);
!
Outcome.
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for serious AE;
!
Date Investigator became aware of serious AE;
!
AE is serious due to (specify the SAE criteria per definition in Appendix B);

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!
Date of hospitalization;
!
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.
8.3.5
Causality collection
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?’
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure* the causal relationship 
is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the CSP.
*Note: NP surgery is not a planned study procedure. 
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient 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.
8.3.7
Adverse events based on examinations and tests
The results from the CSP mandated laboratory tests and vital signs will be summarized in the 
Clinical Study Report (CSR). Deterioration as compared to baseline in protocol-mandated 
laboratory values, vital signs should therefore only be reported as AEs if they fulfil any of the 
SAE criteria or are the reason for discontinuation of treatment with the IP.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting Investigator 

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uses the clinical, rather than the laboratory term (e.g. anaemia versus low Hb value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Any new or aggravated, clinically relevant, abnormal medical finding at a physical 
examination as compared with the baseline assessment will be reported as an AE unless 
unequivocally related to the disease-under study (DUS) (see Section 8.3.9 Disease-under 
study (DUS)).
8.3.8
Hy’s Law (HL)
Cases where patient shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥ 3xULN together with TBL ≥ 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 HL.
8.3.9
Disease-under study (DUS)
Symptoms of DUS are those which might be expected to occur as a direct result of NP or the 
nasal endoscopy procedure. 
Events which are unequivocally due to disease under study should not be reported as an AE 
during the study unless there is a deterioration or worsening of the expected symptoms that led 
to discontinuation of the investigational product OR the events meet SAE criteria. 
Hospital admissions and/or surgical operations due to NP planned during the study are not 
considered SAEs.  If the condition unexpectedly deteriorated after NP surgery, the reported 
SAE term should be the reason for hospitalization/prolongation of hospitalization.  NP surgery 
should not be reported as the SAE term. 
NP surgery is a clinical endpoint and assessment of subject discontinuation from IP should not 
be based on the NP surgery. Refer to section 7.1 Discontinuation of study treatment for 
additional information. 
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day (i.e., 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 the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life threatening AEs where important or relevant information is missing, active FU 
is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any FU information on a previously reported SAE within one calendar day 
(i.e., immediately but no later than 24 hours) of when he or she becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to the designated AstraZeneca 
representative.
If the EDC system is not available, then the Investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed. 
For further guidance on the definition of a SAE, see Appendix B of the CSP.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca. Except for:
!
If the pregnancy is discovered before the study and before the subject has received 
any study treatment.
If a pregnancy is reported, the Investigator should inform AstraZeneca within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (e.g. spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal exposure
If a patient becomes pregnant during the course of the study, IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP 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 patient 
was discontinued from the study.

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If any pregnancy occurs during the study, then the Investigator or other site personnel informs 
the appropriate AstraZeneca representatives within 1day (i.e., immediately but no later than 
24 hours) of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 to 5 
calendar days for SAEs and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the CRF is used to report the pregnancy and the paper-based
pregnancy outcome report is used to report the outcome of the pregnancy.
8.4.2.2
Paternal exposure. 
Male patients should refrain from fathering a child or donating sperm during the study and for 
16 weeks (5 half-lives) following the last dose of IP.
Pregnancy of the patient’s partners will not be considered an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital abnormality) should be followed up and documented for conceptions occurring 
from the date of the first administration of IP until 16 weeks (5 half-lives) after the last 
administration of IP. The Investigators must obtain the consent of the patient’s partner prior to 
obtaining information on the pregnancy.
8.4.3
Overdose
!
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 treatment occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours, of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply (see Section 8.3.2
Time period and frequency for collecting adverse event and serious adverse event 
information). For other overdoses, reporting must occur within 30 days.
8.4.4
Management of investigational product-related reaction
Appropriate drugs (e.g. epinephrine, H1 and H2 antihistamines, and corticosteroids), and 
medical equipment to treat acute anaphylactic reactions must be immediately available at the 

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clinical research site where IP is administered. Study personnel must be trained to recognize 
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 (minutes to hours) and 
that may result in death (Sampson et al 2006). Anaphylaxis to an IP that the patient has not 
been previously exposed to (such as benralizumab) 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 1 of the following: a) respiratory 
compromise or b) reduced BP or symptoms of end-organ dysfunction.
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient including: involvement of the skin/mucosal tissue, respiratory 
compromise, reduced BP or associated symptoms and/or persistent gastrointestinal 
symptoms.
3.
Reduced BP after exposure.
Patients will have had a pre-assessment (i.e. vital signs) prior to IP administration and should 
be observed after IP administration for a minimum of 1 hour for the appearance of any acute 
drug reactions.
Serum tryptase or other blood or urine testing relevant to the diagnosis of anaphylaxis may be 
obtained at a local lab at the discretion of the Investigator.
8.4.5
Medication error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day (i.e., immediately 
but no later than 24 hours) of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life Threatening or follow-up 
Fatal/Life Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.2 Time period and frequency for 
collecting adverse event and serious adverse event information) and within 30 days for all 
other medication errors.
The definition of a Medication Error can be found in Appendix B.
8.5
Pharmacokinetics
For the PK analysis, it is important that the date and time of each SC injection is recorded for 
each patient.

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Serum samples will be collected for measurement of serum concentrations of benralizumab as 
specified in the SoA. Serum will be collected pre-dose.
Samples may be collected at additional time points during the study if warranted and agreed 
upon between the Investigator and AstraZeneca. Instructions for the collection and handling 
(processing, storage and shipment) of biological samples can be found in the separate 
Laboratory Manual provided by AstraZeneca to the sites. The actual date and time (24-hour 
clock time) of each sample will be recorded.
Samples collected for analyses of benralizumab concentration in serum may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study.
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
A summary of PK concentrations results will be reported in the CSR.
8.5.1
Determination of drug concentration
Samples for determination of benralizumab concentration in serum will be analysed by 
analytical test sites on behalf of AstraZeneca, using an appropriate bioanalytical method. 
The following samples will be analysed:
!
Baseline (Visit 3) PK samples from all patients who are subsequently randomised to 
either treatment group
!
On-treatment PK samples from patients assigned to the benralizumab treatment group
Full details of the analytical method used will be described in a separate bioanalytical report.
8.5.2
Storage and destruction of pharmacokinetic samples
The PK samples will be retained at AstraZeneca or designee for a maximum of 3 years 
following publication of CSR to properly address potential questions from RAs. 
Pharmacokinetic samples may be disposed of or destroyed and anonymised by pooling. 
Additional analyses may be conducted on the anonymised, pooled PK samples to further 
evaluate and validate the analytical method. Any results from such analyses may be reported 
separately from the CSR.
8.6
Immunogenicity
Instructions for immunogenicity (ADA and neutralizing antibody [nAb]) sample collection, 
processing, storage, and shipment can be found in the separate Laboratory Manual provided to 
the sites.

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The immunogenicity samples will be retained at AstraZeneca or designee for a maximum of 3 
years following publication of the CSR to properly address potential questions from RAs.
A summary of the analysis will be presented in the CSR. Details of the analytical method used 
will be described in a bioanalytical report.
8.6.1
Anti-drug antibodies
Serum samples for analysis of ADA will be collected pre-dose at selected visits according to 
SoA.
The presence or absence of ADA will be determined in the serum samples using validated 
bioanalytical methods. 
8.6.2
Neutralizing antibodies
In vitro nAb activity testing will occur for all samples that are ADA positive. Samples that are 
ADA negative will not be tested for nAb.
The presence or absence of neutralizing ADA will be determined using a validated 
bioanalytical method.
8.7
Pharmacodynamics Collection of samples
Pharmacodynamics’ samples will be taken during the study prior to IP according to the SoA.
Samples for the analysis of the peripheral blood eosinophils will be performed in the central 
laboratory as part of the routine haematology assessment (CBC).
8.8
Genetics
8.8.1
Optional exploratory genetic sample
The blood sample for DNA isolation will be collected from patients who have consented to 
participate in the genetic analysis component of the study. Participation is optional. Patients 
who do not wish to participate in the genetic research may still participate in the study.
Samples can be collected at any time after the genetic consent form is signed. 
See Appendix D for Information regarding genetic research. Details on processes for 
collection and shipment and destruction of these samples can be found in Appendix D or in 
the separate Laboratory Manual provided to the sites.
The results of the analyses will be reported separately from the CSR in a scientific report or 
publication.
8.8.2
Storage and destruction of genetic samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. Samples may be stored for a maximum of 15 

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the study, as shown in the SoA. The data may be used as input to cost analyses for example 
cost utility analysis or cost effectiveness analysis. Protocol-mandated procedures, tests, and 
encounters are excluded.
The following healthcare resource use variables will be collected at Visit 1 with a 1-year recall 
period and then at each visit after randomization. They measure the amount of 
unplanned/unscheduled healthcare resource use since the patient previous visit due to (a) nasal 
polyps, (b) asthma exacerbation (c) other reasons: 
!
General and intensive care hospitalizations and lengths of stay;
!
Emergency room visits; 
!
Urgent care visits.
All hospitalizations, ER, and urgent care visits will be collected, even when an ER visit results 
in a hospital admission. All hospital admissions (including dates) will also be collected, even 
when readmission occurs within a short period of time.
Unplanned hospitalization for symptoms/diagnosis other than NP must be reported as an SAE. 
Hospitalization due to NP surgery should only be reported as SAE, if the condition 
unexpectedly deteriorated after surgery. 
For hospitalizations resulting from all other events should be reported as SAEs. 
Refer to Appendix B4 for reporting hospitalization.
9.
STATISTICAL CONSIDERATIONS 
9.1
Statistical hypotheses
The co-primary efficacy endpoints are the change from baseline in total NPS at Week 40 and 
the change from baseline in bi-weekly mean NBS at Week 40. The primary analysis is to 
compare the changes from baseline in total NPS and in NBS of benralizumab with placebo  
(change from baseline for both endpoints at week 56 are included as key secondary 
endpoints).
The null hypothesis is that the change from baseline in total NPS and/or the change from 
baseline in NBS are similar between benralizumab and placebo. The alternative hypothesis is 
that both of the change from baseline in total NPS and the change from baseline in NBS are 
different between benralizumab and placebo.
The type I error will be controlled across co-primary and key secondary endpoints at 0.05 
two-sided) statistical significance level. Both of the co-primary endpoints will be tested at
0.01 (two-sided) and the key secondary endpoints will be tested hierarchically at 0.05 (two-

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9.3.1
All patients analysis set
This analysis set will comprise all patients screened for the study and will be used for 
reporting of disposition and screening failures.
9.3.2
Full analysis set (FAS)
All patients randomized and receiving any IP will be included in the FAS, irrespective of their 
protocol adherence and continued participation in the study. Patients will be analyzed 
according to their randomized treatment. Patients who withdraw consent, and assent when 
applicable, to participate in the study will be included up to the date of their study termination.
9.3.3
Safety analysis set
All patients who received at least 1 dose of IP will be included in the safety analysis set. 
Patients will be classified according to the treatment they actually received. A patient who has 
on one or several occasions received active treatment will be classified as active. 
9.3.4
Pharmacokinetic analysis set
All patients who received benralizumab and from whom PK blood samples are assumed not to 
be affected by factors such as protocol violations and who had at least one quantifiable serum 
PK observation post first dose will be included in the PK analysis dataset. 
9.4
Statistical analyses
All personnel involved with the analysis of the study will remain blinded until database lock. 
The efficacy analyses will be based on FAS population. Analyses will be performed by
AstraZeneca or its representatives. A comprehensive statistical analysis plan (SAP) will be 
prepared prior to first patient randomized and any subsequent amendments will be 
documented, with final amendments completed prior to database lock. This section is a 
summary of the planned statistical analyses. Details will be included in the SAP. Any
deviations from this plan will be reported in the CSR.
9.4.1
Efficacy analyses
All analyses described below apply to the full analysis of all patients, through to IPD/EOT 
(Week 56) unless otherwise stated. Efficacy endpoints will also be summarized separately for 
the patients who entered the long-term FU, and summaries for this cohort of patients will be 
repeated over the entire FU period to characterize the durability of the treatment effect.
The primary estimand will be used for the primary analysis and quantifies the difference in 
outcomes for subjects randomized to the benralizumab and placebo arms at the planned 
timepoints of the study, regardless of the treatments that subjects actually received.  It 
includes all the data collected during the study including data collected after discontinuation 
of study treatment except data collected after NP surgery and/or SCS use for NP.  A 
composite strategy will be used for patients who undergo NP surgery and/or receive SCS for 
NP. Data collected post-SCS for NP will be set to missing, and the patient’s worst observed 

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post-baseline value on or before the time of SCS use for NP will be imputed from that point 
through Week 56.  Data collected post-surgery will be set to missing, and the worst possible 
value will be imputed from that point through Week 56.  For patients who discontinue the 
study without NP surgery or SCS use for NP, missing data will be imputed using multiple 
imputation (MI) using all patients who did not have NP surgery or receive SCS for NP under a 
missing at random assumption.  Further details of the primary analysis as well as sensitivity 
analyses will be included in the SAP.  
9.4.1.1
Calculation or derivation of variables for efficacy analyses
The changes from baseline in total NPS and NBS at Week 40 are co-primary endpoints. The 
change from baseline in SNOT-22 total score at Week 40, time to the earlier of first NP 
surgery and/or SCS use for NP by Week 56, time to first NP surgery by Week 56, change 
from baseline in DSS score at Week 40, change from baseline in total NPS at Week 56, 
change from baseline in NBS at Week 56, change from baseline in SNOT-22 total score at 
Week 56, change from baseline in DSS score at Week 56, and change from baseline in LMS 
at EOT/IPD are the 9 key secondary endpoints.
Total nasal polyps score (Co-primary endpoint and key secondary endpoint)
The change from baseline in total NPS at Week 40 is one of the co-primary endpoints and at
Week 56 is one of the key secondary endpoints. The total NPS is the sum of the bilateral NPS, 
which will be evaluated centrally. The total scores and the corresponding changes from 
baseline at each visit will be calculated. In addition, the proportion of NPS responders, which 
is defined as patients with at least 1 point improvement (reduction) in total NPS will be a 
supportive variable to the primary objective. 
Nasal blockage score (Co-primary endpoint and key secondary endpoint)
The change from baseline in NBS at Week 40 is the other co-primary endpoint and at Week 
56 is one of the key secondary endpoints. The NBS will be summarized bi-weekly (14-day 
periods). The bi-weekly mean and the changes from the baseline will be calculated. 
Disease specific health-related quality of life: SNOT-22 (Key secondary endpoint)
Disease specific health-related quality of life will be evaluated by SNOT-22. The changes 
from baseline in SNOT-22 total score at Weeks 40 and 56 are key secondary endpoints. The 
observed values and the changes from baseline in SNOT-22 total score at each timepoint will 
be calculated. 
                                                                                                                                                            
Time to first NP surgery and/or SCS use for NP (Key secondary endpoint)
The time to the first NP surgery and/or SCS use for NP by Week 56 is another key secondary 
endpoint.  The time will be calculated based on the earliest occurrence of NP surgery and/or 
SCS use for NP and will be calculated as follows:

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Earlier of (Start date of first NP surgery, Start date of first SCS use for NP) - date of 
randomization +1
For patients who do not experience any surgery or SCS use for NP, the time to will be 
censored at the date of their last visit for the 56-week treatment period, or at the time point 
after which a surgery or SCS use could not be assessed (for lost to follow-up patients).
Time to first NP surgery (Key secondary endpoint)
The time to the first NP surgery by Week 56 is another key secondary endpoint and will be 
evaluated for all patients. The time to first NP surgery is calculated as follows:
Start date of first NP surgery - date of randomization +1
For patients who do not experience any surgery, the time to first NP surgery will be censored 
at the date of their last visit for the 56-week treatment period, or at the time point after which a 
surgery could not be assessed (for lost to follow-up patients).
Difficulty with Sense of Smell (DSS) score (Key secondary endpoint)
The changes from baseline in DSS score at Weeks 40 and 56 are key secondary endpoints. 
The DSS score will be summarized bi-weekly (14-day periods). The bi-weekly mean and the 
changes from the baseline will be calculated. 
Lund Mackay (key secondary endpoint) and sinus severity score
Only the data from blinded central reader will be used for analysis. Both LMS (key secondary 
endpoint) and sinus severity score as described in Section 8.1.3.2 will be evaluated centrally. 
The observed values and the change from baseline at EOT/IPD will be calculated. 
University of Pennsylvania Smell Identification Test (UPSIT)
Sense of smell will be evaluated by UPSIT.  The observed values and changes from baseline 
at each timepoint will be calculated.  The proportion of patients with different thresholds of 
smell impairment or normal smell abilities will be calculated overall as well as by sex. The 
thresholds will be pre-specified in the SAP. 
SCS use for NP and proportion of NP surgery 
The proportion of patients who had NP surgery, the proportion of patients who use SCS for 
NP, and the proportion of patients who had surgery or use SCS for NP will be calculated by 
Week 56 for all patients. 
In addition, the number of courses of SCS for NP, total SCS dose used and total duration of 
SCS use for NP, will also be summarized by Week 56.

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Nasal polyps associated symptom scores
Individual components of the NPSD as well as the TSS will be summarized bi-weekly (14-day 
period). The bi-weekly mean and the corresponding changes from baseline at each timepoint 
will be calculated.
Patient-reported general health status: SF-36
The observed values and the changes from baseline in SF-36v2 PCS, MCS, and domain scores 
at each timepoint will be calculated. 
Other patient reported outcomes-related variables
The following variables will be calculated at each visit for all patients in the FAS. 
!
Change from baseline in PGI-S; 
!
PGI-C scale will be summarized categorically (proportion).
In addition, mean ACQ-6, the changes from baseline in ACQ-6 and ACQ-6 responders, which 
is defined as change from baseline≤ ‒ 0.5, will also be calculated for the patients who have 
comorbid asthma at baseline.
Asthma exacerbations
In the patients with comorbid asthma at baseline, the number of exacerbations and the annual 
exacerbation rate will be calculated. The number of exacerbations related to ER/urgent 
care/hospitalization/SCS will be summarized.
9.4.1.2
Methods for efficacy analyses
Analyses of the co-primary endpoints
The primary estimand will be applied to the co-primary endpoints, the change from baseline in 
total NPS and the change from baseline in NBS, using a hybrid method of WP/WOCF and MI 
followed by ANCOVA with treatment arm, baseline score, region (US vs non-US), and 
baseline comorbid asthma status (yes vs no) as covariates.  The estimates of the treatment 
effects at Week 40 and Week 56 will be based on  contrasts from this ANCOVA model. The 
analyses will use the data collected up to Week 56 visit regardless of whether patients 
remained on treatment or not except data collected after NP surgery and/or SCS use for NP.  
A composite strategy will be used for NP surgery and SCS use for NP.  If a patient had any 
NP surgery before Week 56, the data will be censored after the first NP surgery and the worst 
possible value will be imputed in its place.  If a patient had any course of SCS use for NP 
before Week 56, the data will be censored after the time of having the first course of SCS use 
for NP and the patient’s previously worst observed value will be imputed in its place.

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Sensitivity analyses will be conducted based on different estimands and different missing data 
mechanism assumptions, including those expected to be more conservative such as missing 
not at random, to explore the robustness of any treatment effect, utilizing multiple imputation 
approaches. Specifically, a sensitivity analysis will be conducted in which the worst possible 
value is imputed after NP surgery and a treatment policy strategy is used for both treatment 
discontinuation and use of SCS for NP.  Full details of the sensitivity analyses will be pre-
specified in the SAP.
Analyses of secondary endpoints 
All secondary continuous efficacy endpoints will be summarized by visit and treatment group. 
In addition, the changes from baseline at scheduled visits in total NPS, NBS, SNOT-22 total 
score, DSS score, TSS, UPSIT, SF-36v2 (PCS, MCS, and domains), ACQ-6, will be analyzed 
under the primary estimand using ANCOVA, in a similar manner to that outlined for the co-
primary endpoints above.
The changes from baseline at EOT/IPD in CT-scores will be analyzed under a similar 
estimand to that used for the primary and other secondary endpoints, but with a treatment 
policy rather than composite strategy for SCS use for NP.  The analyses will use the data 
collected up to Week 56 visit regardless of whether patients remained on treatment or received 
SCS for NP except data collected after NP surgery.  A composite strategy will be used for NP 
surgery.  If a patient had any NP surgery before Week 56, the data will be censored after the 
first NP surgery and the worst possible value will be imputed in its place.  The composite 
strategy of imputing WOCF after SCS use for NP will not be used for CT-scores because 
there is only one post-baseline assessment. 
The estimates of the treatment effects at Week 40 and Week 56 for SNOT-22 total score and 
DSS score and at EOT/IPD for LMS for the analyses of key secondary endpoints will be 
based on contrasts from the respective ANCOVA models.  
Time to first NP surgery up to Week 56, time to first course of SCS use for NP up to Week 56, 
and the Time to first NP surgery and/or first course of SCS use for NP up to Week 56 will be 
analyzed using a Cox proportional hazard model with treatment, region (US vs non-US) and 
baseline comorbid asthma status (yes vs no), as covariates.
The proportions of responders at selected timepoints in total NPS, in SNOT-22 total score and 
in ACQ-6, will be analyzed using logistic regression with treatment arm, baseline scores, 
region (US vs non-US), and baseline comorbid asthma status (yes vs no) as covariates. 
The proportion of patients who had NP surgery and the proportion of patients who had courses 
of SCS for NP up to Week 56 will be analyzed using a Cochran–Mantel–Haenszel test
controlling for region (US vs non-US) and baseline comorbid asthma status (yes vs no). The 
total number of courses of SCS_NP will be analyzed using a negative binomial model 
adjusting for region (US vs non-US), baseline comorbid asthma status (yes vs no), and prior 
use of SCS for NP (yes vs no).

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9.4.3.2
Analysis of pharmacokinetic variables          
Benralizumab serum concentrations will be summarized using descriptive statistics. The 
population PK analysis and pharmacodynamic analyses will be presented separately from the 
main CSR.
9.4.3.3
Analyses of biomarkers
Biomarkers will be summarized using standard summary statistics. Limited exploratory 
biomarkers may be reported in the CSR. These analyses will be detailed in the SAP. 
The remaining exploratory biomarkers will be reported outside of the CSR. 
Details of the remaining exploratory biomarker analyses will be described in the exploratory 
analyses plan, which will be finalized before the database lock.
9.4.4
Methods for multiplicity control
To account for multiplicity to test the co-primary endpoints (change from baseline in total 
NPS at Week 40 and change from baseline in NBS at Week 40) and the 9 key secondary 
endpoints (the change from baseline in SNOT-22 total score at Week 40, time to first NP 
surgery and/or SCS use for NP by Week 56, time to first NP surgery by Week 56, the change 
from baseline in DSS score at Week 40, the change from baseline in total NPS at Week 56, 
the change from baseline in NBS at Week 56, the change from baseline in SNOT-22 total 
score at Week 56, the change from baseline in DSS score at Week 56, the change from 
baseline in LMS at EOT/IPD), the type I error will be controlled across co-primary and key 
secondary endpoints at 0.05 (two-sided) statistical significance level. Both of the co-primary 
endpoints will be tested at a 0.01 (two-sided level) and the key secondary endpoints will be 
tested hierarchically at a 0.05 (two-sided) level. The  testing strategy will be as follows:
!
Step 1: Perform the 2 tests of co-primary endpoints at a significance level of 0.01. If 
both p-values are less than 0.01, and the treatment effect favours benralizumab, then 
proceed to Step 2. Otherwise no null hypothesis is rejected.
!
Step 2: Test the 9 key secondary endpoints at a significance level of 0.05 using a 
hierarchical fixed sequence testing approach following the order below.
∀
Change from baseline in SNOT-22 total score at Week 40.
∀
Time to first NP surgery and/or SCS use for NP up to Week 56.
∀
Time to first NP surgery up to Week 56
∀
Change from baseline in DSS score at Week 40.
∀
Change from baseline in NPS at Week 56.
∀
Change from baseline in NBS at Week 56.

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∀
Change from baseline in SNOT-22 total score at Week 56.
∀
Change from baseline in DSS score at Week 56.
∀
Change from baseline in LMS at EOT/IPD.
9.5
Interim analyses 
No interim analysis is planned for this study. 
9.6
Data monitoring committee (DMC)
No data monitoring committee (DMC) is planned for this study. 
9.7
Independent adjudication committee
No independent adjudication committee is planned for this study.

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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
Appendix A
Regulatory, ethical and study oversight considerations
A 1
Regulatory and ethical considerations
This study will be conducted in accordance with the protocol and with the following:
!
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines;
!
Applicable International Conference on Harmonisation (ICH)/Good Clinical 
Practice (GCP) Guidelines;
!
Applicable laws and regulations.
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, 
and other relevant documents (e.g. advertisements) must be submitted to an Institutional 
Review Board/Independent Ethics Committee (IRB/IEC) by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients. Where applicable as per relevant laws and regulations, amendments 
will also be submitted to, reviewed and approved by regulatory authorities/national competent 
authorities. 
The Investigator will be responsible for the following:
!
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC;
!
Notifying the IRB/IEC of serious adverse events or other significant safety findings 
as required by IRB/IEC procedures;
!
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations.
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples.

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A 2
Financial disclosure
Investigators and Sub-Investigators will provide AstraZeneca with sufficient, accurate 
financial information as requested to allow AstraZeneca to submit complete and accurate 
financial certification or disclosure statements to the appropriate Regulatory Authorities 
(RAs). 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 patient and 
answer all questions regarding the study. 
Patients must be informed that their participation is voluntary. Patients 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 requirements, where 
applicable, and the IRB/IEC or study site. 
The medical record must include a statement that written informed consent was obtained 
before the patient 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.
Patients 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 patient or the patient’s legally authorised 
representative. 
If a patient declines to participate in any voluntary exploratory genetic research component of 
the study, there will be no penalty or loss of benefit to the patient and he/she will not be 
excluded from other aspects of the study.
Patients who are re-screened are required to sign a new ICF.
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional future exploratory research. The Investigator or authorised designee will 
explain to each patient the objectives of the future exploratory research. Patients will be told 
that they are free to refuse to participate and may withdraw their consent at any time and for 
any reason during the storage period. The patient will give a separate agreement to allow any 
remaining specimens to be used for future exploratory research. Patients who decline to 
participate in this optional research will indicate this in the ICF. If a patient withdraws consent 
to the use of donated biological samples, the samples will be disposed of/destroyed, and the 
action documented. If samples already have been analyzed at the time of the request,
AstraZeneca will not be obliged to destroy the results of this research.

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A 4
Data protection
Each patient will be assigned a unique identifier by AstraZeneca. Any patient records or data 
sets transferred to AstraZeneca will contain only the identifier; patient names or any 
information which would make the patient identifiable will not be transferred. 
The patient must be informed that his/her personal study-related data will be used by 
AstraZeneca in accordance with local data protection law. The level of disclosure must also be 
explained to the patient. 
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by AstraZeneca, by 
appropriate IRB/IEC members, and by inspectors from RAs.
A 5
Committees structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed; for instance, this could involve amendments to the Clinical Study Protocol and 
letters to Investigators.
A 6
Dissemination of clinical study data
A description of this clinical trial will be available on 
http://astrazenecagrouptrials.pharmacm.com and http://www.clinicaltrials.gov as will the 
summary of the main study results when they are available. The clinical trial and/or summary 
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 patient data relating to the study will be recorded on printed or electronic case report form 
(eCRF) unless transmitted to AstraZeneca 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. 
AstraZeneca or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorised site personnel are accurate, complete, and verifiable from source 

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documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of 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 patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The Investigator may need 
to request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.
A 9
Study and Site closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. The study may be stopped if, in the 
judgment of AstraZeneca, trial subjects are placed at undue risk because of clinically 
significant findings that:
!
meet individual stopping criteria or are otherwise considered significant 
!
are assessed as causally related to study drug, 
!
are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the subject at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

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!
Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines
!
Inadequate recruitment of participants by the investigator
!
Discontinuation of further study intervention development.
A 10 Publication policy
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to AstraZeneca before 
submission. This allows AstraZeneca to protect proprietary information and to provide 
comments. 
AstraZeneca will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, AstraZeneca will generally support publication of 
multicenter 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.
Appendix B
Adverse event definitions and additional safety information
B 1
Definition of adverse events
An adverse event (AE) is the development of any untoward medical occurrence in a patient or 
clinical study patient administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (e.g. an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
B 2
Definitions of serious adverse event
A serious adverse event (SAE) is an AE occurring during any study phase (i.e., run-in, 
treatment, washout, follow-up), that fulfils one or more of the following criteria:
!
Results in death;
!
Is immediately life threatening;
!
Requires in-patient hospitalization or prolongation of existing hospitalization; 

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!
Results in persistent or significant disability or incapacity;  
!
Is a congenital abnormality or birth defect;
!
Is an important medical event that may jeopardise the patient or may require 
medical treatment to prevent one of the outcomes listed above.
Adverse Events (AEs) for malignant tumours reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement on an individual 
event basis should be applied to clarify that the malignant tumour event should be assessed 
and reported as a Non-Serious AE. For example, if the tumour is included as medical history 
and progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfill the attributes for being assessed as 
Serious, although reporting of the progression of the malignant tumor as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalization, may be assessed as Non-Serious; 
examples include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via 
cone biopsy.
B 3
Life threatening
‘Life threatening’ means that the patient 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 patient’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).
B 4
Hospitalization
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 patient was enrolled in the study, provided that it did not deteriorate in an
unexpected way during the study.
B 5
Important medical event or medical treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the patient 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.

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!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment;
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine;
!
Intensive treatment in an emergency room or at home for allergic bronchospasm;
!
Blood dyscrasias (e.g. neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization;
!
Development of drug dependency or drug abuse.
B 6
Intensity rating scale:
1.
Mild (awareness of sign or symptom, but easily tolerated).
2.
Moderate (discomfort sufficient to cause interference with normal activities).
3.
Severe (incapacitating, with inability to perform normal activities).
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 7
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.
!
Time Course. Exposure to suspect drug. Has the patient 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?

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!
No alternative cause. The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience. Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? AstraZeneca would not normally 
recommend or support a re-challenge.
!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed 
the relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study treatment 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 recognize that could have led to an error.
Examples of events to be reported in clinical studies as medication errors:

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!
Drug name confusion;
!
Dispensing error e.g. medication prepared incorrectly, even if it was not actually 
given to the participant;
!
Drug not administered as indicated, for example, wrong route or wrong site of 
administration;
!
Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as 
a solid tablet;
!
Drug not stored as instructed e.g. kept in the fridge when it should be at room 
temperature; 
!
Wrong participant received the medication (excluding Interactive Web Response 
System/ Interactive Voice Response System (IWRS/IVRS) errors);
!
Wrong drug administered to participant (excluding IWRS/IVRS errors).
Examples of events that do not require reporting as medication errors in clinical studies:
!
Errors related to or resulting from IWRS/IVRS - including those which lead to one 
of the above listed events that would otherwise have been a medication error; 
!
Participant accidentally missed drug dose(s) e.g. forgot to take medication;
!
Accidental overdose (will be captured as an overdose);
!
Participant failed to return unused medication or empty packaging;
!
Errors related to background and rescue medication, or standard of care medication 
in open label studies, even if an AZ product. 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
Appendix C
Handling of Human Biological Samples
C 1
Bicustody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each site keeps full traceability of collected biological samples from the 
patients while in storage at the site until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.

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AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers.
Samples retained for further use will be stored in the AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.
If a patient does not allow samples to be used for future biomarker research they may continue 
with their samples being used for the main study.
If required, AstraZeneca will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analyzed,
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an integral part of the study, then the patient is 
withdrawn from further study participation.
The Investigator:
!
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca;
!
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented;
!
Ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed, the 
action documented and the signed document returned to the study site;
!
Ensures that the patient and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
C 3
International Airline Transportation Association 6.2 Guidance 
Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories 

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(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm).        
For transport purposes, the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations in the 46th edition (2005). Infectious 
substances are now classified either as Category A, Category B or Exempt. There is no direct 
relationship between Risk Groups and Categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life threatening or fatal disease in 
otherwise healthy humans or animals. Category A pathogens are e.g. Ebola, Lassa fever virus:
!
are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are e.g. Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus types 1 and 2. They are assigned the following UN number 
and proper shipping name:
!
UN 3373 – Biological Substance, Category B;
!
are to be packed in accordance with UN3373 and IATA 650.
Exempt - all other materials with minimal risk of containing pathogens
!
Clinical trial samples will fall into Category B or exempt under IATA regulations;
!
Clinical trial samples will routinely be packed and transported at ambient;
!
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm);
!
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content;
!
IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as 
applicable;
!
Samples routinely transported by road or rail are patient to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport 
is used.

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Appendix D
Genetics
D 1
Use/analysis of DNA
Genetic variation may impact a patient’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 Institutional Review Board/Independent Ethics Committee allow, 
a blood sample will be collected for DNA analysis from consenting patients. 
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications. Genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications. 
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the patient´s DNA, i.e. the 
entire genome. 
The results of genetic analyses may be reported in the clinical study report or in a separate 
study summary.
AstraZeneca will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained while research on study treatment continues but no longer than 
15 years or other period as per local requirements from the date of the Last Patient Last Visit 
(LPLV), after which they will be destroyed.
D 2
Genetic research plan and procedures
Selection of genetic research population
Study selection record
All patients will be asked to participate in this genetic research. Participation is voluntary and 
if a patient declines to participate there will be no penalty or loss of benefit. The patient will 
not be excluded from any aspect of the main study.

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Inclusion criteria
!
For inclusion in this genetic research, patients must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol (CSP) and: Provide 
informed consent for the genetic sampling and analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:
!
Previous allogeneic bone marrow transplant;
!
Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection.
Withdrawal of consent for genetic research:  
Patients may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study. Voluntary withdrawal will not 
prejudice further treatment. Procedures for withdrawal are outlined in Section 7.3 Withdrawal 
from the study, of the main CSP.
Collection of samples for genetic research
The blood sample for genetic research may be obtained from the patients at any time after 
randomization. Although DNA is stable, early sample collection is preferred to avoid 
introducing bias through excluding patients who may withdraw due to an adverse event, such 
patients would be important to include in any genetic analysis. If for any reason the sample is 
not drawn at Visit 3, it may be taken at any visit until the last study visit. Only one sample 
should be collected per patient for genetics during the study. Samples will be collected, 
labelled, stored, and shipped as detailed in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. Samples will be stored for a maximum of 15
years, from the date of LPLV, after which they will be destroyed. DNA is a finite resource 
that is used up during analyses. Samples will be stored and used until no further analyses are 
possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable only by the second, unique number. This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organisation. No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organisations working with the DNA).

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The link between the patient enrolment/randomization 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, allow regulatory audit, 
and permit tracing of samples for destruction in the case of withdrawal of consent.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix B.
Informed consent
The genetic component of this study is optional and the patient may participate in other 
components of the main study without participating in the genetic component. To participate 
in the genetic component of the study the patient must sign and date both the consent form for 
the main study and the genetic component of the study. Copies of both signed and dated 
consent forms must be given to the patient and the original filed at the study site. The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
patient understands that they may freely withdrawal from the genetic aspect of the study at 
any time.
Patient data protection
AstraZeneca will not provide individual genotype results to patients, 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 patient. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an Investigator might know a patient’s 
identity and also have access to his or her genetic data. In addition, Regulatory Authorities 
may require access to the relevant files, though the patient’s medical information and the 
genetic files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to 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 

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only use this information for health related research purposes. Researchers may see summary 
results but they will not be able to see individual patient 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.
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 cases of Hy’s Law (HL). 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 patient meets 
potential Hy’s Law (PHL) criteria at any point during the study.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. 
Hy’s Law criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug induced liver injury (DILI) caused by the investigational 
medicinal product (IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting adverse events (AEs) and serious adverse events (SAEs) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 3× upper limit of 
normal (ULN) together with total bilirubin (TBL) ≥ 2×ULN at any point during the study 
following the start of study treatment irrespective of an increase in alkaline phosphatase 
(ALP). 
Hy’s Law
Aspartate aminotransferase or ALT ≥ 3 × ULN together with TBL ≥ 2 ×ULN, where no other 
reason, other than the IMP, can be found to explain the combination of increases, e.g. elevated 
ALP indicating cholestasis, viral hepatitis, another drug. 
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified time frame within which the 
elevations in transaminases and TBL must occur.

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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 patient who meets any of the following identification criteria in 
isolation or in combination:
!
ALT ≥ 3 × ULN;
!
AST ≥ 3 × ULN;
!
TBL ≥ 2 × ULN.
When a patient meets any of the identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (and also to the 
AstraZeneca representative). 
The Investigator will also remain vigilant for any local laboratory reports where the 
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;
!
Complete the appropriate unscheduled laboratory electronic case report form 
(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 patient meets PHL criteria (see Appendix E 2 for definition) 
by reviewing laboratory reports from all previous visits (including both central and 
local laboratory results).
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Notify the AstraZeneca representative;
!
Determine whether the patient meets PHL criteria (see Appendix E 2 for definition) 
by reviewing laboratory reports from all previous visits;
!
Promptly enter the laboratory data into the laboratory eCRF.
E 4
Follow-up
E 4.1 Potential Hy’s Law criteria not met

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If the patient does not meet PHL criteria the Investigator will:
!
Inform the AstraZeneca representative that the patient 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 patient does meet PHL criteria the Investigator will:
Determine whether PHL criteria were met at any study visit prior to starting Study treatment 
(see Section 8.4 Safety reporting and medical management)
!
Notify the AstraZeneca representative who will then inform the central Study Team. 
The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study patients’ follow-up and the continuous review of data. Subsequent to 
this contact the Investigator will:
!
Monitor the patient until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated; 
!
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 HL lab kit should be used; 
!
Complete the three Liver eCRF Modules as information becomes available; 
!
If at any time (in consultation with the Study Physician the PHL case meets serious 
criteria, report it as an SAE using standard reporting procedures.
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.
No later than 3 weeks 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. The AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will 
also be involved in this review together with other patient matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.

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If 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, record the AE /SAE in the eCRF 
accordingly and follow the AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:
!
Report an 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 3 weeks in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:
!
Report an SAE (report term ‘Potential Hy’s Law’) applying serious criteria and 
causality assessment as per above;
!
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 met. Update the SAE report according to the 
outcome of the review amending the reported term if an alternative explanation for 
the liver biochemistry elevations is determined.
E 6
Actions required when potential Hy’s Law criteria are met before and 
after starting study treatment
This section is applicable to patients who meet PHL criteria on study treatment having 
previously met PHL criteria at a study visit prior to starting study treatment.
At the first on-study treatment occurrence of PHL criteria being met, the Investigator will 
determine if there has been a significant change in the patients’ condition compared with the 
last visit where PHL criteria were met. 
!
If there is no significant change, no action is required;

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!
If there is a significant change, notify the AstraZeneca representative, who will 
inform the central Study Team, then follow the subsequent process described in 
Appendix B 5;
!
A ‘significant’ change in the patient’s condition refers to a clinically relevant 
change in any of the individual liver biochemistry parameters (ALT, AST or TBL) 
in isolation or in combination, or a clinically relevant change in associated 
symptoms. The determination of whether there has been a significant change will be 
at the discretion of the Investigator, this may be in consultation with the Study 
Physician if there is any uncertainty.
E 7
Actions required for repeat episodes of potential Hy’s Law
This section is applicable when a patient meets PHL criteria on study treatment, and has 
already met PHL criteria at a previous on study treatment visit.
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The Investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found to be 
the disease under study (e.g. chronic or progressing malignant disease, severe infection or 
liver disease), 
If No: Follow the process described in Appendix E 4.1.
If Yes: Determine if there has been a significant change in the patient’s condition compared 
with when PHL criteria were previously met.
If there is no significant change, no action is required.
If there is a significant change, follow the process described in Appendix E 4.
A ‘significant’ change in the patient’s condition refers to a clinically relevant change in any of 
the individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the Investigator; this 
may be in consultation with the Study Physician if there is any uncertainty.
Appendix F
Anaphylaxis: signs and symptoms, management
F 1
INTRODUCTION
As with any antibody, allergic reactions to dose administration are possible. The clinical 
criteria for defining anaphylaxis for this study are listed in Section 2 Introduction. A guide to 

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the signs and symptoms and management of acute anaphylaxis is provided in Section 3
Objectives and Endpoints. Appropriate drugs, such as epinephrine, antihistamines, 
corticosteroids, etc., and medical equipment to treat anaphylactic reactions must be 
immediately available at study sites, and study personnel should be trained to recognize and 
treat anaphylaxis according to local guidelines.
Serum tryptase or other blood or urine testing relevant to the diagnosis of anaphylaxis may be 
obtained at a local lab at the discretion of the Investigator.
F 2
CLINICAL CRITERIA FOR DEFINING ANAPHYLAXIS 
Anaphylaxis
In adults, anaphylaxis is highly likely when any 1 of the following 3 criteria is fulfilled:
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (e.g., generalized hives, pruritus or flushing, swollen lips-
tongue-uvula).
AND AT LEAST 1 OF THE FOLLOWING
(a) Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia);
(b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 
(e.g., hypotonia [collapse], syncope, incontinence).
2.
Two or more of the following that occur rapidly after exposure to a likely allergen 
for that patient (minutes to several hours):
(a)
Involvement of the skin-mucosal tissue (e.g. generalized hives, itch-flush, 
swollen lips tongue-uvula);
(b)
Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, 
reduced PEF, hypoxemia);
(c)
Reduced BP or associated symptoms (e.g. hypotonia [collapse], syncope, 
incontinence);
(d)
Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, 
vomiting).
3.
Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease 
from that patient’s baseline.

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Immune Complex Disease
Immune complex disease or Hypersensivity Type III is evoked by the deposition of 
antigenantibody or antigen-antibody-completed 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 edema;
∀
Hypotension;
∀
Cardiac arrhythmias;
∀
Feeling of impending doom;
∀
Unconsciousness;
∀
Shock.
Other earlier or concomitant signs and symptoms can include:
∀
Itchy nose, eyes, pharynx, genitalia, palms, and soles;
∀
Rhinorrhea;
∀
Change in voice;
∀
Metallic taste;
∀
Nausea, vomiting, diarrhea, abdominal cramps, and bloating;
∀
Lightheadedness;

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∀
Headache;
∀
Uterine cramps;
∀
Generalized warmth.
F 4
MANAGEMENT OF ACUTE ANAPHYLAXIS
F 4.1
Immediate intervention
1.
Assessment of airway, breathing, circulation, and adequacy of mentation.
2.
Administer epinephrine intramuscular (IM) 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.
F 4.2
Possibly appropriate, subsequent measures depending on response to 
epinephrine
(a)
Place patient 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.
F 4.3
Specific measures to consider after epinephrine injections, where 
appropriate
(a)
Consider epinephrine infusion;
(b)
Consider H1 and H2 antihistamines;
(c)
Consider nebulized β2 agonist [e.g. albuterol (salbutamol)] for bronchospasm 
resistant to epinephrine;
(d)
Consider systemic corticosteroids;
(e)
Consider vasopressor (e.g. dopamine);
(f)
Consider glucagon for patient taking β-blocker;
(g)
Consider atropine for symptomatic bradycardia;

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(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 Sampson et al 2006.
F 5
REFERENCES
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.
Appendix G
Study Conduct Mitigation in the event of evolving SARS-
Cov-2 (COVID19) pandemic or other study disruption
Note: The changes below should be implemented only during study disruptions caused by 
COVID-19 or similar pandemic (e.g. during quarantines and resulting site closures, regional 
travel restrictions and considerations if site personnel or study patients become infected with 
SARS-CoV-2), during which patients 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. Instructions on how to perform these procedures will 
be provided at the time of implementation. 
G 1
Obtaining verbal consent (where applicable)
During study interruptions, it may not be possible for the patients to complete study visits and 
assessments on site and alternative means for carrying out the visits and assessments may be 
necessary, e.g. remote visits. Patient’s consent  should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in the following sections. Local and regional regulations and/or guidelines regarding 
consent of study patients should be checked and followed. As a minimum requirement 
patients verbal consent obtained for the alternative means of carrying out visits and 
assessments in the OSTRO study should be documented in the patient source data.  
G 2
Telemedicine Visit to Replace On-site Visit (where applicable)
During the COVID-19 pandemic or other study disruption, visits to sites and collection of 
study assessments should only be performed if the Investigator considers it to be safe for the 
patient and personnel.

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On-site visits may be replaced by a telemedicine visit if allowed by local/regional guidelines. 
A telemedicine contact will allow for collection of adverse events and concomitant 
medication, verification of background medication compliance, completion of ePRO 
questionnaires and UPSIT assessments and where applicable, evaluation of pregnancy test 
results.
Missing assessments, which cannot be performed via remote visit or are omitted due to  safety 
precautions, may be performed outside of visit window. 
G 3
Study procedures may be postponed/omitted (where applicable)
Study procedures (e.g. nasal endoscopy, nasal biopsy and nasal secretion) which may 
represent a safety risk to patients or site staff if performed during the peak period of the 
COVID-19  pandemic or other study disruption may be postponed based on Sponsor´s 
recommendation, Investigator’s clinical judgement and local, international or professional 
guidance and recommendations.
G 4     Remote completion of on-site ePRO assessments (where applicable) 
During the COVID-19 pandemic or other study disruptions, ePRO questionnaires (SNOT-22, 
ACQ-6, SF-36v2, PGI-S, and PGI-C) may be completed remotely at the patient's home using 
the handheld ePRO device, without the need of in-office visit confirmation.
G 5     Patients’ Home delivery of study supplies (where applicable)
To secure continuity of background medication intake and compliance, collection of UPSIT 
and safety pregnancy assessments, home delivery of these study items may be introduced, 
where applicable and allowed per local regulations
G 6      Data Capture During Telemedicine Visit (where applicable)
Site staff and/or designated HCP should always refer to the CSP and conduct all study 
procedures that can be performed/collected remotely for that study visit. 
Data collected during a telemedicine visit should be captured by a qualified HCP from the 
study site and recorded in the source documents and in the electronic data capture (EDC) 
system.
Appendix H
Abbreviations 

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Abbreviation or 
special term
Explanation
Ab
Antibiotics
ACQ-6
Asthma Control Questionnaire-6
ADA
Anti-drug antibodies
AE
Adverse event
AER
Asthma exacerbation rate
AERD
Aspirin exacerbated respiratory disease
AFS
Allergic fungal sinusitis 
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANCOVA
Analysis of Covariance
APFS
Accessorized prefilled syringe
AST
Aspartate aminotransferase
BP
Blood pressure
CBC
Complete blood count
CRSwNP
Chronic rhinosinusitis with nasal polyps
CSP
Clinical study protocol
CSR
Clinical study report
CT
Computed tomography
DILI
Drug induced liver injury
DMC
Data monitoring committee
DSS
Difficulty with sense of smell
DUS
Disease-under study
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EOT
End of treatment
ePRO
Electronic patient-reported outcome
EU
European Union
FAS
Full analysis set
FEV1
Forced expiratory volume in 1 second
FSH
Follicle stimulating hormone

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Abbreviation or 
special term
Explanation
FU
Follow-up
FUD
Follow-up discontinuation
GCP
Good Clinical Practice
GH
General health perceptions
GMP
Good Manufacturing Practice
Hb
Haemoglobin
HIV
Human immunodeficiency virus
HL
Hy’s law
HRQoL
Health-related quality of life
HRU
Healthcare resource utilization
IATA
International Airline Transportation Association
ICF
Informed consent form
ICH
International Conference on Harmonisation
IgE
Immunoglobulin E
IL-5
Interleukin-5
IL-5Rα
IL-5 receptor alpha subunit
IM
Intramuscular
IMP
Investigational medicinal product
INCS
Intranasal corticosteroids
IP
Investigational product
IPD
IP discontinuation
IRB/IEC
Institutional Review Board/ Independent Ethics Committee
IRC
Independent review charter
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LMS
Lund-Mackay score
LPLV
Last patient last visit
mAb
Monoclonal antibody
MCID
Minimal clinical importance difference
MCS
Mental component score

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Abbreviation or 
special term
Explanation
MFNS
Mometasone furoate nasal spray
MH
Mental health
MI
Multiple Imputation
nAb
Neutralizing antibody
NB
Nasal blockage
NBS
Nasal blockage score
NP
Nasal polyposis
NPS
Nasal polyp score
NPSD
Nasal Polyposis Symptom Diary
PCS
Physical component score
PF
Physical functioning
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PHL
Potential Hy’s law
PI
Principal investigator 
PK
Pharmacokinetics
PPE
Personal protective equipment
PRO
Patient-reported outcome
RA
Regulatory authority
RBC
Red blood cell
RE
Role limitations due to emotional problems
RP
Role limitations due to physical health
SAE
Serious adverse event 
SAP
Statistical analysis plan
SC
Subcutaneously
SCS
Systemic corticosteroids
SF
Social functioning
SF-36v2
Short Form 36-item Health Survey, Version 2
SNOT-22
SinoNasal Outcome Test, 22 item
SoA
Schedule of activities
TBL
Total bilirubin

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Abbreviation or 
special term
Explanation
TSS
Total Symptom Score
ULN
Upper limit of normal
UPSIT
University of Pennsylvania Smell Identification Test
WBC
White blood cell
WOCBP
Women of childbearing potential
WOCF
Worst Observation Carried Forward
WP
Worst Possible

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Document Name: d3252c00001-csp-v4
Document Title:
D3252C00001 Clinical Study Protocol version 4
Document ID:
Doc ID-003655555
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14-Aug-2020 17:23 UTC
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Author Approval
14-Aug-2020 15:49 UTC
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Content Approval
17-Aug-2020 12:12 UTC
Mark Odorisio
Content Approval
14-Aug-2020 16:09 UTC
Peter Barker
Content Approval
14-Aug-2020 16:05 UTC
Sofia Necander
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.