A Randomised, Double-blind, Active-controlled 52-week Study With an Open-label Extension to Evaluate the Efficacy and Safety of Benralizumab Compared to Mepolizumab in the Treatment of Eosinophilic Granulomatosis With Polyangiitis (EGPA) in Patients Receiving Standard of Care Therapy (MANDARA Study)
Phase: PHASE3
Conditions: Eosinophilic Granulomatous Vasculitis
Sponsor: AstraZeneca

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Clinical Study Protocol 
Drug Substance
Benralizumab
Study Code
D3253C00001
Version
6.0
Date
06 Mar 2024
A Randomised, Double-blind, Active-controlled 52-week Study 
with an Open-label Extension to Evaluate the Efficacy and Safety 
of Benralizumab Compared to Mepolizumab in the Treatment of 
Eosinophilic Granulomatosis with Polyangiitis (EGPA) in Patients 
Receiving Standard of Care Therapy (MANDARA Study)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s):
EudraCT number: 2019-001832-77
NCT number: NCT04157348
EU CT number: 2023-510248-19-00
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered, and the results will be 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
Redacted
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be

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SUMMARY OF CHANGES TABLE
Document
Date of Issue
Amendment 5 (CSP version 6.0)
06 March 2024
Amendment 4 (CSP version 5.0)
11 April 2023
Amendment 3 (CSP version 4.0)
24 February 2021
Amendment 2 (CSP version 3.0)
04 August 2020
Amendment 1 (CSP version 2.0)
27 March 2020
Original protocol (Initial creation 1.0)
11 June 2019
Amendment 5: 06 March 2024
This amendment is considered to be non - substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union and in the EU Clinical Trial Regulation Article 2, 2(13), as it neither significantly 
impacts the safety or physical/mental integrity of participants nor the scientific value of the 
study.
Overall Rationale for the Amendment
The CSP has been amended to comply with the European Union Clinical Trials Regulation
[EU CTR]: (EU) No 536/2014 requirements.
Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
CSP front page
EU CT Number was added on the 
CSP front page: 2023-510248-19-
00.
Conformance with EU 
CTR.: Regulation (EU) 
No 536/2014.
Non-substantial
1.1 Schedule of 
Assessments; Table 5: 
Open-label Extension 
Period (Year 4 
Onwards), if 
Applicable
Removal of ESR and CRP 
assessments requirement to perform 
on IPD/EOT visit.
Correction of error. The 
assessments were 
inadvertently added to 
the Table 5 which is not 
in line with expected 
study design. ESR and 
CRP assessments are not 
required after completion 
of first year OLE.
Non-substantial
6.2.3: Optional At-
home or Remote-
location Investigational 
Product Administration
Removal of obsolete statement 
about provision of urine pregnancy 
tests for patients’ remote visits.
Correction of error. In 
CSP v5, requirement for 
urine pregnancy testing 
was restricted to on-site 
visits. In section 6.2.3 
were inadvertently left 
references to urine 
Non-substantial

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
pregnancy tests being 
provided to patients for 
home testing. Obsolete 
information was 
removed to align with 
the CSP SoA.  
6.5 Concomitant 
Therapy
IV, IM, SC corticosteroid therapy 
administration applicable to DB 
only
Clarification added on 
corticosteroid therapy 
administration during 
OLE. 
Non-substantial
7.1 Discontinuation of 
Study treatment
Wording added: “If any of the 
following criteria are met, IP should 
be withheld, and a conversation 
between the investigator and 
Sponsor study physician/ designee 
is to take place to determine 
whether continuation on IP or 
discontinuation of IP will be in the 
best interest of the patient, and 
whether the issue can be mitigated 
by postponing or skipping the 
dose.”
Clarification language 
added to discontinuation 
of Study treatment 
section.
Non-substantial
9.4.5 OLE Period 
Analyses
Information on additional analysis 
and final DBL present originally in 
section 4.1 Overall Design added to 
section 9 Statistical Considerations.
Clarification added on 
additional analysis and 
planned data cut-off for 
OLE period analyses, 
aligning with section 4.1
Non-substantial
Appendix A1: 
Regulatory and Ethical 
Considerations –
Regulatory Reporting 
Requirements for SAEs
New CSP template text
was added.
Clarification added on 
the process for reporting 
of SUSARs by the 
sponsor to 
Eudravigilance Database 
in accordance with EU 
CTR 536/2014.
Non-substantial
Appendix A4: Data 
protection
Appendix A5: 
Dissemination of
Clinical Study Data
Appendix A6: Data 
Quality
Assurance
New CSP template text
was added.
Changes were made to 
comply with 
AstraZeneca new CSP
template guidelines 
amended to adhere to the 
EU CTR: Regulation 
(EU) No 536/2014
requirements.
Non-substantial

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
Throughout
Minor editorial
Changes.
Correction of typos,
omissions, and 
grammatical
errors.
Non-substantial
AE, adverse event; CRP, C-reactive protein; CSP, clinical study protocol; CTR, Clinical Trial Regulation; DB, 
double blind; DBL, database lock; EGPA, eosinophilic granulomatosis with polyangiitis; EOT, end of treatment; 
ESR, erythrocyte sedimentation rate; EU, European Union; IP, investigational product; IPD, IP discontinuation; 
IM, Intramuscular; IV, Intravenous; OLE, open-label extension; SAE, serious adverse event; SoA, Schedule of 
Assessments; SC, subcutaneous; SUSARs, suspected unexpected serious adverse reactions.

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
SUMMARY OF CHANGES TABLE ................................................................................... 2
TABLE OF CONTENTS......................................................................................................5
1
PROTOCOL SUMMARY................................................................................ 11
1.1
Schedule of Assessments .................................................................................. 11
1.2
Synopsis ........................................................................................................... 32
1.3
Schema............................................................................................................. 39
2
INTRODUCTION............................................................................................ 41
2.1
Study Rationale ................................................................................................ 41
2.2
Background ...................................................................................................... 42
2.2.1
EGPA Disease and Current Approaches to Disease Management...................... 42
2.2.2
Role of Interleukin-5 in Pathogenesis of EGPA................................................. 43
2.2.3
Mechanism of Action of Benralizumab and Evidence Supporting Potential as a 
Treatment for EGPA......................................................................................... 44
2.3
Benefit/Risk Assessment................................................................................... 45
2.3.1
Benralizumab.................................................................................................... 45
2.3.2
Mepolizumab.................................................................................................... 46
3
OBJECTIVES AND ENDPOINTS................................................................... 46
4
STUDY DESIGN ............................................................................................. 51
4.1
Overall Design.................................................................................................. 51
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 53
4.2
Scientific Rationale for Study Design ............................................................... 54
4.3
Justification for Dose........................................................................................ 55
4.4
End of Study Definition.................................................................................... 55
5
STUDY POPULATION ................................................................................... 56
5.1
Inclusion Criteria .............................................................................................. 57
5.2
Exclusion Criteria ............................................................................................. 60
5.3
Criteria to be Confirmed/Reconfirmed at Baseline (Visit 2) and Prior to Entry 
to OLE.............................................................................................................. 63
5.3.1
Inclusion Criteria to be Confirmed/Reconfirmed at Baseline (Visit 2)............... 64
5.3.2
Exclusion Criteria to be Confirmed/Reconfirmed at Baseline (Visit 2).............. 64
5.3.3
Criteria to be Confirmed Prior to Commencing OLE at Visit 17........................ 65
5.4
Lifestyle Restrictions ........................................................................................ 65
5.5
Screen Failures ................................................................................................. 65
5.5.1
Rescreening ...................................................................................................... 65
5.5.2
Withdrawal From Study Due to Recruitment Cap ............................................. 66
6
STUDY TREATMENT.................................................................................... 66

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6.1
Treatments Administered.................................................................................. 67
6.1.1
Investigational Products.................................................................................... 67
6.1.2
Medical Devices Including Combination Products with a Device Constituent... 68
6.2
Preparation/Handling/Storage/Accountability of Investigational Product .......... 68
6.2.1
Preparation and Handling of IP......................................................................... 68
6.2.2
Administration of IP at the Study Site............................................................... 69
6.2.2.1
Injection Site Guidance..................................................................................... 69
6.2.2.2
Benralizumab/Placebo to Benralizumab Administration.................................... 69
6.2.2.3
Preparation and Administration of Mepolizumab/Placebo to Mepolizumab....... 70
6.2.2.4
Administration of Mepolizumab/Placebo to Mepolizumab................................ 70
6.2.2.5
After Investigational Product Administration.................................................... 70
6.2.3
Optional At-home or Remote-location Investigational Product Administration . 71
6.2.4
Conditions Requiring Investigational Product Administration Rescheduling..... 72
6.2.5
Storage ............................................................................................................. 72
6.2.6
Accountability .................................................................................................. 72
6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 73
6.3.1
Patient Enrolment and Randomisation - Double-blind Period............................ 73
6.3.2
Methods for Ensuring Blinding – Double-blind Period...................................... 74
6.3.2.1
Maintaining the Blind to the Patient’s Blood Eosinophil Counts ....................... 74
6.3.2.2
Handling of Clinical Laboratory Results Obtained During the Double-blind 
Period but Ordered Outside of the Clinical Trial ............................................... 75
6.3.2.3
Maintaining the Blind to the Patient’s Induced Sputum Cell Count Analysis –
Double-blind Period.......................................................................................... 75
6.3.3
Methods for Unblinding – Double-blind Period ................................................ 75
6.3.4
Open-label Extension Period – Benralizumab Administration Only .................. 76
6.4
Treatment Compliance...................................................................................... 76
6.5
Concomitant Therapy........................................................................................ 77
6.5.1
Oral Corticosteroids and Tapering..................................................................... 79
6.5.2
Other Concomitant Treatment........................................................................... 81
6.6
Dose modification............................................................................................. 81
6.7
Treatment After the End of the Study................................................................ 81
7
DISCONTINUATION OF TREATMENT AND PATIENT WITHDRAWAL . 81
7.1
Discontinuation of Study Treatment.................................................................. 81
7.1.1
Procedures for Early Discontinuation of Study Treatment and at End of Study . 82
7.1.1.1
Early Discontinuation of Study Treatment ........................................................ 83
7.1.1.2
Discontinuation of Treatment on Notification of Closure of Study.................... 83
7.1.2
Procedures for Handling Incorrectly Enrolled or Randomised Patients.............. 84
7.2
Lost to Follow-up ............................................................................................. 84
7.3
Withdrawal From the Study.............................................................................. 85
7.3.1
Discontinuation or Suspension of the Whole Study Program............................. 85
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 86
8.1
Efficacy Assessments........................................................................................ 86
8.1.1
Clinical Outcome Assessments ......................................................................... 86

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8.1.1.1
Birmingham Vasculitis Activity Score.............................................................. 87
8.1.1.2
EGPA Remission and Relapse .......................................................................... 87
8.1.1.3
Vasculitis Damage Index .................................................................................. 90
8.1.1.4
Corticosteroid Medication Usage ...................................................................... 90
8.1.1.5
Asthma Control Questionnaire (6-Item Version)............................................... 90
8.1.1.6
Sino-nasal Symptom Questionnaire .................................................................. 91
8.1.1.7
Sino-Nasal Outcome Test-22 ............................................................................ 91
8.1.1.8
Short Form-36 Version 2 (Acute Recall)........................................................... 91
8.1.1.9
Patient Global Impression of Severity............................................................... 92
8.1.1.10
Patient Global Impression of Change ................................................................ 92
8.1.1.11
Work Productivity and Activity Impairment questionnaire................................ 92
8.1.1.12
Spirometry........................................................................................................ 93
8.1.2
Patient Qualitative Interview Sub-study............................................................ 95
8.2
Safety Assessments........................................................................................... 96
8.2.1
Clinical Safety Laboratory Assessments............................................................ 96
8.2.1.1
Pregnancy Test ................................................................................................. 98
8.2.1.2
Serology ........................................................................................................... 99
8.2.2
Physical Examinations...................................................................................... 99
8.2.2.1
Complete Physical Examination........................................................................ 99
8.2.2.2
Brief Physical Examination............................................................................... 99
8.2.3
Vital Signs........................................................................................................ 99
8.2.4
Electrocardiograms......................................................................................... 100
8.2.5
Other Safety Assessments............................................................................... 100
8.2.5.1
Weight and Height and Body Mass Index ....................................................... 100
8.3
Collection of Adverse Events.......................................................................... 100
8.3.1
Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information............................................................................ 101
8.3.2
Follow-up of Adverse Events and Serious Adverse Events.............................. 101
8.3.3
Adverse Event Data Collection ....................................................................... 102
8.3.4
Causality Collection........................................................................................ 102
8.3.5
Adverse Events Based on Signs and Symptoms .............................................. 103
8.3.6
Adverse Events Based on Examinations and Tests.......................................... 103
8.3.7
Disease Under Study....................................................................................... 103
8.4
Safety Reporting and Medical Management.................................................... 104
8.4.1
Reporting of Serious Adverse Events.............................................................. 104
8.4.2
Pregnancy....................................................................................................... 104
8.4.2.1
Maternal Exposure.......................................................................................... 104
8.4.3
Overdose ........................................................................................................ 105
8.4.3.1
Benralizumab Overdose.................................................................................. 105
8.4.3.2
Mepolizumab Overdose .................................................................................. 105
8.4.4
Medical Device Deficiencies........................................................................... 106
8.4.4.1
Time Period for Detecting Medical Device Deficiencies................................. 106
8.4.4.2
Follow-up of Medical Device Deficiencies ..................................................... 106
8.4.4.3
Prompt Reporting of Medical Device Deficiencies to Sponsor ........................ 107
8.4.4.4
Regulatory Reporting Requirements for Device Deficiencies.......................... 107
8.4.4.5
SADE Reporting............................................................................................. 107

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8.4.5
Medication Error, Drug Abuse, and Drug Misuse............................................ 107
8.4.5.1
Timelines........................................................................................................ 107
8.4.5.2
Medication Error............................................................................................. 108
8.4.5.3
Drug Abuse .................................................................................................... 108
8.4.5.4
Drug Misuse ................................................................................................... 108
8.4.6
Reporting of Overdose.................................................................................... 108
8.4.7
Management of IP-related Toxicities .............................................................. 109
8.5
Pharmacokinetics............................................................................................ 109
8.5.1
Determination of Drug Concentration ............................................................. 110
8.5.2
Storage and Destruction of Pharmacokinetic Samples..................................... 110
8.6
Pharmacodynamics......................................................................................... 110
8.7
Genetics.......................................................................................................... 110
8.7.1
Optional Exploratory Genetic Sample............................................................. 110
8.7.2
Storage and Destruction of Genetic Samples................................................... 111
8.8
Biomarkers ..................................................................................................... 111
8.8.1
Blood Eosinophils........................................................................................... 111
8.8.2
Mandatory Biomarker Samples....................................................................... 111
8.8.3
Nasal Secretions (Mandatory at Selected Sites)............................................... 112
8.8.4
Mechanistic Sub-study Sampling (Induced Sputum, Tissue Biopsy, and Whole 
Blood Cells).................................................................................................... 112
8.8.5
Storage, Reuse, and Destruction of Biomarker Samples .................................. 113
8.8.6
Reporting of Biomarker Research ................................................................... 113
8.9
Immunogenicity.............................................................................................. 113
8.9.1
Anti-drug Antibodies ...................................................................................... 113
8.9.2
Benralizumab Neutralising Antibodies............................................................ 113
8.10
Medical Resource Utilisation and Health Economics ...................................... 114
8.11
Other Assessments and Procedures ................................................................. 114
8.11.1
Patient Testing Due to Public Health Crisis..................................................... 114
9
STATISTICAL CONSIDERATIONS............................................................. 114
9.1
Statistical Hypotheses..................................................................................... 114
9.1.1
Primary Endpoint Hypothesis ......................................................................... 114
9.2
Sample Size Determination............................................................................. 115
9.3
Populations for Analyses ................................................................................ 115
9.4
Statistical Analyses......................................................................................... 116
9.4.1
Efficacy Analyses........................................................................................... 116
9.4.1.1
Calculation or Derivation of Variables for Efficacy Analyses ......................... 116
9.4.1.2
Methods for Efficacy Analyses ....................................................................... 119
9.4.2
Safety Analyses .............................................................................................. 121
9.4.3
Other Analyses ............................................................................................... 122
9.4.4
Interim Analyses............................................................................................. 122
9.4.5
OLE Period Analyses...................................................................................... 122
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...................................................................................... 123

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11
REFERENCES............................................................................................... 188
LIST OF TABLES
Table 1
Schedule of Assessments – Double-blind Treatment Period..................... 12
Table 2
Schedule of Assessments – Open-label Extension Period (First Year)...... 18
Table 3
Schedule of Assessments – Open-label Extension Period (Year 2), if 
Applicable ............................................................................................... 21
Table 4
Schedule of Assessments – Open-label Extension Period (Year 3), if 
Applicable ............................................................................................... 24
Table 5
Schedule of Assessments – Open-label Extension Period (Year 4 
Onwards), if Applicable........................................................................... 27
Table 6
Schedule of Assessments for ePRO Endpoints (Double-blind Period and 
Open-label Extension Period –First Year)................................................ 30
Table 7
Study Objectives – Double-blind Period .................................................. 33
Table 8
Study Objectives for Open-label Extension Period................................... 36
Table 9
Study Objectives – Double-blind Period .................................................. 47
Table 10
Study Objectives for Open-label Extension Period................................... 50
Table 11
Study Treatments..................................................................................... 67
Table 12
Restricted Medications............................................................................. 78
Table 13
Prohibited Medications With Defined Washout Periods before Screening 
(Visit 1) ................................................................................................... 79
Table 14
Threshold Values for the SF-36v2 Scale and Summary Measures ............ 92
Table 15
Laboratory Safety Variables..................................................................... 97
Table 16
Description of Populations for Analyses ................................................ 115
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 40
Figure 2
Study Design ........................................................................................... 53
Figure 3
Suggested Schema of Rotation of Injection Sites for Benralizumab/ 
Placebo to Benralizumab ......................................................................... 70
Figure 4
Reversibility Testing Algorithm............................................................... 95

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LIST OF APPENDICES
Appendix A
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS............................................................................. 123
Appendix B
ADVERSE EVENT DEFINITIONS AND ADDITIONAL SAFETY 
INFORMATION ................................................................................... 132
Appendix C
HANDLING OF HUMAN BIOLOGICAL SAMPLES.......................... 138
Appendix D
OPTIONAL GENOMICS INITIATIVE SAMPLE ................................ 140
Appendix E
ANAPHYLAXIS: DEFINITION, SIGNS, SYMPTOMS AND 
MANAGEMENT .................................................................................. 144
Appendix F
MEDICAL DEVICE AEs, ADEs, SAEs, SADEs, USADEs, AND 
MEDICAL DEVICE DEFICIENCIES: DEFINITIONS AND 
PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING ............................................................................... 147
Appendix G
CHANGES RELATED TO MITIGATION OF STUDY DISRUPTIONS 
DUE TO CASES OF CIVIL CRISIS, NATURAL DISASTER, OR 
PUBLIC HEALTH CRISIS................................................................... 153
Appendix H
RECOMMENDED PREDNISOLONE/PREDNISONE TAPERING 
SCHEDULE FROM WEEK 4 (VISIT 4)............................................... 156
Appendix I
ADRENAL CRISIS GUIDELINES....................................................... 157
Appendix J
ABBREVIATIONS............................................................................... 159
Appendix K
COUNTRY-SPECIFIC REQUIREMENTS........................................... 162
Appendix L
PROTOCOL VERSION HISTORY....................................................... 165

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1
PROTOCOL SUMMARY
1.1
Schedule of Assessments
This study comprises 2 distinct periods: a 52-week double-blind (DB) treatment period, during 
which patients will be randomised to receive either benralizumab or mepolizumab, and an 
OLE, during which all patients will receive benralizumab alone. The primary database lock 
will occur after all randomised patients have been followed up for the 52-week DB treatment 
period.
The SoA for the DB treatment period and for the first year of the OLE period of the study are 
provided in Table 1 and Table 2, respectively. The SoA for ePRO endpoints for the DB 
treatment period and the first year of the OLE period are provided in Table 6.
Patients may have the opportunity to participate in the OLE period of this study for at least 
one year following completion of the DB period on treatment (Section 4.1). The SoA for the 
period after the end of Year 1 of the OLE reflects the variable duration of each patient's 
participation and is described in Table 3, Table 4, and Table 5.

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Table 1
Schedule of Assessments – Double-blind Treatment Period
Study procedures
Run in
Double-blind treatment period
Details in 
CSP 
sections or 
Appendix
Visit
V1 
Screening
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16 V17 1 Unsch 
visit 2 IPD 4
Study week (calculated from 
V2)
-4 to -1 wks 
(min)
0
1
4
8
12
16
20
24
25
28
32
36
40
44
48
52
Visit windows
± 3 days
± 7 days
± 3 days
± 7 days
General procedures
Informed consent (main study)
X
5.1
Optional genetic research 
informed consent
X
8.7
Demography/history
X
5.1 and 5.2
Cardiovascular history and risk 
factors
X
5.1 and 5.2
History of EGPA and treatment
X
5.1 and 5.2
Height
X
8.2.5.1
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
X
8.2.5.1
Inclusion/exclusion
X
X
5.1 and 5.2
Randomisation criteria
X
5.3
Eligibility check to enter OLE 
X
5.3.3
Efficacy assessments
DAILY corticosteroid
medication usage 5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1.4
Record OCS dose and check 
compliance 6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1.4
BVAS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
X
8.1.1.1

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Table 1
Schedule of Assessments – Double-blind Treatment Period
Study procedures
Run in
Double-blind treatment period
Details in 
CSP 
sections or 
Appendix
Visit
V1 
Screening
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16 V17 1 Unsch 
visit 2 IPD 4
Study week (calculated from 
V2)
-4 to -1 wks 
(min)
0
1
4
8
12
16
20
24
25
28
32
36
40
44
48
52
Visit windows
± 3 days
± 7 days
± 3 days
± 7 days
VDI
X
X
X
X
8.1.1.3
Assess EGPA relapse 7/remission
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
X
8.1.1.2
ePRO device dispensing/training
X
8.1.1
ePRO assessments 9
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
X
8.1.1.4 to 
8.1.1.11
Review ePRO completion and 
confirm compliance
X
X 8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1
Health resource use
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.10
Reversibility testing (post-BD 
FEV1)
X
8.1.1.12
Spirometry (pre-BD FEV1)
X
X
X
X
X
X
X 2
X 8.1.1.12
Safety assessments
Concomitant/ post IP medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.5
Complete physical exam
X
X
X
8.2.2.1
Brief physical exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
8.2.2.2
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
X
8.2.3
ECG (triplicate recordings)
X
X
X
8.2.4
AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3

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CONFIDENTIAL AND PROPRIETARY             Page 14 of 193
Table 1
Schedule of Assessments – Double-blind Treatment Period
Study procedures
Run in
Double-blind treatment period
Details in 
CSP 
sections or 
Appendix
Visit
V1 
Screening
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16 V17 1 Unsch 
visit 2 IPD 4
Study week (calculated from 
V2)
-4 to -1 wks 
(min)
0
1
4
8
12
16
20
24
25
28
32
36
40
44
48
52
Visit windows
± 3 days
± 7 days
± 3 days
± 7 days
Laboratory assessments (always taken pre-dose at dosing visits)
Haematology, WBC 
w/differential 10
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
X
8.2.1
Serum chemistry 11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
X
8.2.1
Lipoproteins (fasting) 12
X
X
8.2.1
Hepatitis, HIV 
X
X
8.2.1.2
Urinalysis central laboratory
X
8.2.1
Troponin 13
X
X
8.2.1
Urinalysis (dipstick) 14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
X
8.2.1
Serum pregnancy test 15
X
8.2.1.1
Urine pregnancy test (dipstick) 15
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2.1.1
ESR (local)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
X
8.2.1
CRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
X
FSH 16
X
8.2.1.1
MPO/PR3 
(ANCA status)
X
X
X
X
8.2.1
Serum for biomarkers
X
X
X
X
X
X 2
8.8
Total IgE, FEIA
X
8.2.1
Nasal secretions 17
X
X
X
X
X
X 2
8.8

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CONFIDENTIAL AND PROPRIETARY             Page 15 of 193
Table 1
Schedule of Assessments – Double-blind Treatment Period
Study procedures
Run in
Double-blind treatment period
Details in 
CSP 
sections or 
Appendix
Visit
V1 
Screening
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16 V17 1 Unsch 
visit 2 IPD 4
Study week (calculated from 
V2)
-4 to -1 wks 
(min)
0
1
4
8
12
16
20
24
25
28
32
36
40
44
48
52
Visit windows
± 3 days
± 7 days
± 3 days
± 7 days
PK 18
X
X
X
X
X
X
X
X
X
X
8.5
ADA/nAb 19
X
X
X
X
X
X
X
8.9
Whole blood for RNA
X
X
8.8
Optional genetic sample 20
X
8.7.1
Mechanistic sub-study procedures (if applicable)
Mechanistic sub-study informed 
consent
X
Tissue sample 21
X
X
X 2
8.8
Induced sputum 22
X 
X
X 
X
X 2
8.8
Whole blood for cell 
phenotyping 23
X
X
X
X
8.8
Patient qualitative interviews sub-study procedures (if applicable)
Explain patient qualitative 
interview sub-study 
X
Appendix A
Patient qualitative interview sub-
study ICF
X
Patient qualitative interview 24
X
X
X
8.1.2
Other/administrative
IRT/RTSM transaction
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.3.1

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CONFIDENTIAL AND PROPRIETARY             Page 16 of 193
Table 1
Schedule of Assessments – Double-blind Treatment Period
Study procedures
Run in
Double-blind treatment period
Details in 
CSP 
sections or 
Appendix
Visit
V1 
Screening
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
V12
V13
V14
V15
V16 V17 1 Unsch 
visit 2 IPD 4
Study week (calculated from 
V2)
-4 to -1 wks 
(min)
0
1
4
8
12
16
20
24
25
28
32
36
40
44
48
52
Visit windows
± 3 days
± 7 days
± 3 days
± 7 days
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Appendix A
Investigational product administration
Administer blinded IP at the site
X
X
X
X
X
X
X
X
X
X
X
X
X
6
Administer open-label 
benralizumab at the site (first 
dose of OLE)
X
Telephone contact for patients who discontinue early from IP and unwilling/unable to continue with clinic visits
Telephone contact
7.1.1.1
1
Visit 17 is the last double-blind visit and the first OLE visit. All assessments at Visit 17 to be performed BEFORE administration of open-label benralizumab. 
2
Unscheduled visits may be initiated as needed, and any additional assessments may be performed at these visits, at the discretion of the Investigator.
3
If unscheduled visit is to assess the patient for potential EGPA relapse, include these additional assessments. Other assessments may be performed as clinically indicated.
4
In case of early discontinuation from IP, procedures of the IPD visit to be performed 4 weeks (± 7 days) after last dose of IP (replaces regular scheduled visit assessments).
5
The patient reports OCS medication usage each evening using the provided ePRO device (Visit 1-17).
6
Investigator/delegate to record the OCS dose in the eCRF at each study visit and check compliance against patient reported use between study visits.
7
In the event of an EGPA relapse, blood and urine to be collected. In addition, for patients participating in the mechanistic sub-study, a sputum and relevant biopsy sample (if 
possible) should be collected. 
8
Visit 2 must be confirmed on the handheld device by a trained site personnel prior to baseline ePRO questionnaires completion by the patient. Sites should ensure patients 
complete all baseline ePRO assessments. For subsequent visits, the site should confirm the visit either on the web portal Study Works or on the device.
9
See Table 6 for all ePRO assessment details. 
10
From baseline (Visit 2) until the second visit of the OLE (Week 56 [Visit 18]), eosinophil, basophil, and monocyte counts will be redacted from all central laboratory reports 
in order to maintain the blind.
Telephone contact every 4 weeks from the date of last clinic visit, and to continue 
until the end of the double-blind treatment period

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CONFIDENTIAL AND PROPRIETARY             Page 17 of 193
11
eGFR will be calculated according to the CKD-EPI formula at each visit where serum chemistry is collected. 
12
Patient must be in fasting state. If patient has not fasted, he/she may return to collect this sample as soon as possible. The period of fasting may be adjusted at the discretion 
of the Investigator for patients with relevant metabolic conditions (eg, diabetes mellitus).
13
Investigators can perform additional troponin assessments using a central test as clinically indicated during other visits.
14
Haematuria to be checked by dipstick test provided centrally.
15
Only for WOCBP.
16
FSH test done only for female patients to confirm postmenopausal status in women < 50 years who have been amenorrhoeic for ≥12 months.
17
Only sites with the required equipment will collect nasal secretion samples.
18
On dosing visits, PK will be collected pre-dose.
19
ADA/nAb analysis will only be done on samples from patients who received benralizumab. Neutralising antibody testing will be performed for all samples that are ADA 
positive. Samples that are ADA negative will not be tested for nAb.
20
Optional genetic sample: Sample collection is recommended at baseline (Visit 2) but may be drawn at any time after the patient is randomised.
21
In patients with chronic rhinosinusitis with or without nasal polyps, a tissue biopsy sample should be taken from the nose (Week 0 and Week 52). Biopsies from other sites 
may be taken as per clinical judgment (unscheduled visit), these biopsies must remain blinded (refer to footnote 8).
22
Spirometry is required as part of the sputum induction procedure as described in the separate laboratory manual.
23
Sampling of whole blood for cell phenotyping at Visits 2 and 16 are applicable for all North American mechanistic sub-study sites and at Visits 1 and 15 only for the 
McMaster site.
24
Each participating patient will be interviewed twice. The first interview will take place at least 7 and up to 21 days after Visit 2. The second will take place at least 7 and up 
to 21 days after Visit 16.
ADA, Anti-drug antibodies; AE(s), adverse event(s); ANCA, anti-neutrophil cytoplasmic antibodies; BD, bronchodilator; BVAS, Birmingham Vasculitis Activity Score; 
CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CRP, C-reactive protein; CSP, clinical study protocol; ECG, electrocardiogram; eCRF, electronic case report 
form; eGFR, estimated glomerular filtration rate; EGPA, eosinophilic granulomatosis with polyangiitis; ePRO, electronic patient reported outcome; ESR, erythrocyte 
sedimentation rate; FEIA, fluorenzyme immunoassay; FEV1, forced expiratory volume in 1 second; FSH, follicle stimulating hormone; HIV, human immunodeficiency virus; 
IgE, Immunoglobulin E; IP, investigational product; IPD, IP discontinuation; IRT, Interactive Response Technology; min, minimum; MPO, myeloperoxidase; nAb, neutralising 
antibodies; OC,S oral corticosteroid; OLE, open-label extension; PK, pharmacokinetics; PR3, proteinase-3; RNA, ribonucleic acid; RTSM, Randomisation and Trial Supply 
System Management; SAE(s), serious adverse event(s); Unsch, unscheduled; V, Visit (number); VDI, Vasculitis Damage Index; WBC, white blood cells; Wks, weeks.

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Benralizumab - D3253C00001
CONFIDENTIAL AND PROPRIETARY             Page 18 of 193
Table 2
Schedule of Assessments – Open-label Extension Period (First Year)
Study procedure
Open-label extension period – first year
Details in CSP 
sections or 
Appendix
Visit
V18
V19
V20
V21
V22
V23
V24
V25
V26
V27
V28
V29
V30 Unsch 
visit 2
IPD / 
EOT 4
Study week (calculated from Visit 2)
Visit windows: ± 7 days
56
60
64
68
72
76
80
84
88
92
96
100
104
Visit can be done remotely 1
X
X
X
X
General procedures
Weight
X
X
X
X
X
X
X
X
X
X 2
X
8.2.5.1
Efficacy assessments
WEEKLY corticosteroid medication usage 5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1.4
Record OCS dose and check compliance 5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1.4
BVAS
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
X
8.1.1.1
VDI
X
X
X
8.1.1.3
Assessment of EGPA relapse 7/remission
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
X
8.1.1.2
ePRO assessments 8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1.4 to 8.1.1.11
Review ePRO completion and confirm compliance
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1
Health resource use
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.10
Spirometry (pre-BD FEV1)
X
X
X 2
8.1.1.12
Safety assessments
Concomitant/post IP meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.5
Complete physical exam
X
X
8.2.2.1
Brief physical exam
X 2
8.2.2.2
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
X
8.2.3
ECG (triplicate recordings)
X
X
8.2.4
AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3

Clinical Study Protocol - 6.0
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Benralizumab - D3253C00001
CONFIDENTIAL AND PROPRIETARY             Page 19 of 193
Table 2
Schedule of Assessments – Open-label Extension Period (First Year)
Study procedure
Open-label extension period – first year
Details in CSP 
sections or 
Appendix
Visit
V18
V19
V20
V21
V22
V23
V24
V25
V26
V27
V28
V29
V30 Unsch 
visit 2
IPD / 
EOT 4
Study week (calculated from Visit 2)
Visit windows: ± 7 days
56
60
64
68
72
76
80
84
88
92
96
100
104
Visit can be done remotely 1
X
X
X
X
Laboratory assessments (always taken pre-dose at dosing visits)
Haematology, WBC w/differential
X
X
X
X
X
X 2
X
8.2.1
Serum chemistry 9
X
X
X
X
X
X
X 2
X
8.2.1
Urinalysis (dipstick) 10
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
X
8.2.1
Urine pregnancy test (dipstick) 11
X
X
X
X
X
X
X
X
X
X
8.2.1.1
ESR (local)
X
X
X 2
X
8.2.1
CRP
X
X
X
X
X
X
X
X 2
X
8.2.1
Serum for biomarkers 
X
X
8.8
PK 12
X
X
X
8.5
ADA/nAb 13
X
X
X
8.9
Other/ Administrative
IRT/RTSM transaction
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.3.1
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Appendix A
Benralizumab administration
Benralizumab administration
X
X
X
X
X
X
X
X
X
X
X
X
X
6
1
These visits can optionally be conducted remotely by telephone contact for patients who are self-administering IP. Vital signs and urinalysis (dipstick) will not be assessed 
when a visit is conducted remotely.
2
Unscheduled visits may be initiated as needed, and any additional assessments may be performed at these visits, at the discretion of the Investigator.
3
If unscheduled visit is to assess the patient for potential EGPA relapse, include these additional assessments. Other assessments may be performed as clinically indicated.
4
The IPD/EOT visit replaces the nearest regular visit: IPD visit procedures should be performed as soon as possible after decision to discontinue IP has been made, and at the 
latest 4 weeks ± 7 days after the last dose of IP. End of Treatment visit will only be scheduled following notification of closure of the study (Section 7.1.1.2), 4 weeks ± 7 days 
after the last dose of IP.
5
The patient reports OCS medication usage on a weekly basis using the provided ePRO device (Visit 18 through 30). 

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CONFIDENTIAL AND PROPRIETARY             Page 20 of 193
6
Investigator/delegate to record the OCS dose in the eCRF at each study visit and check compliance against patient reported use between study visits. 
7
In the event of an EGPA relapse, blood and urine to be collected. 
8
See Table 6 for all ePRO assessment details.
9
eGFR will be calculated according to the CKD-EPI formula. 
10
Haematuria to be checked by dipstick test provided centrally. 
11
Only for women of child-bearing potential.
12
On dosing visits, PK will be collected pre-dose.
13
Neutralising antibody testing will be performed for all samples that are ADA positive. Samples that are ADA negative will not be tested for nAb.
ADA, anti-drug antibodies; AE(s), adverse event(s); BD, bronchodilator; BVAS, Birmingham Vasculitis Activity Score; CKD-EPI, Chronic Kidney Disease Epidemiology 
Collaboration; CRP, C-reactive protein; CSP, clinical study protocol; ECG, electrocardiogram; eCRF, electronic case report form; eGFR, estimated glomerular filtration rate; 
EGPA, eosinophilic granulomatosis with polyangiitis; EOT, end of treatment; ePRO, electronic patient reported outcome; ESR, erythrocyte sedimentation rate; FEV1, forced 
expiratory volume in 1 second; HIV, human immunodeficiency virus; IP, investigational product; IPD, IP discontinuation; IRT, Interactive Response Technology; 
meds, medications; nAb, neutralising antibodies; OCS, oral corticosteroid; OLE, open-label extension; PK, pharmacokinetics; RTSM, Randomisation and Trial Supply System 
Management; SAE(s), serious adverse event(s); Unsch, unscheduled; V, Visit (number); VDI, Vasculitis Damage Index; WBC, white blood cells.

Clinical Study Protocol - 6.0
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Benralizumab - D3253C00001
CONFIDENTIAL AND PROPRIETARY             Page 21 of 193
Table 3
Schedule of Assessments – Open-label Extension Period (Year 2), if Applicable
Study procedure
Open-label extension period – Year 2 (if applicable)
Details in 
CSP 
sections or 
Appendix
Visit
V31
V32 V33
V34
V35 V36
V37 V38
V39
V40 V41
V42
V43
Unsch visit 2
IPD/ EOT 4
Study week (calculated from V2)
Visit windows: ± 7 days
108
112
116
120
124
128
132
136
140
144
148
152
156
Visit can be done remotely 1
X
X
X
X
X
X
X
X
X
X
X
General procedures
Weight
X 2
X
8.2.5.1
Efficacy assessments
Record OCS dose and check compliance 5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1.4
BVAS
X 2
X
8.1.1.1
VDI
X
X
X
8.1.1.3
Clinical assessment of EGPA 
relapse/remission 6
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
X
8.1.1.2
Health resource use
X
8.10
Spirometry (pre-BD FEV1)
X 2
8.1.1.12
Safety assessments
Concomitant/ post IP meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.5
Complete physical exam
X
8.2.2.1
Brief physical exam
X 2
8.2.2.2
Vital signs
X
X
X 2
X
8.2.3
ECG (triplicate recordings)
X
X
8.2.4
AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3
Laboratory assessments (always taken pre-dose at dosing visits)
Haematology, WBC w/differential 7
X
X
X 2
X
8.2.1
Serum chemistry 7,8
X
X
X 2
X
8.2.1
Urinalysis (dipstick) 9
X
X
X
X
8.2.1

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CONFIDENTIAL AND PROPRIETARY             Page 22 of 193
Table 3
Schedule of Assessments – Open-label Extension Period (Year 2), if Applicable
Study procedure
Open-label extension period – Year 2 (if applicable)
Details in 
CSP 
sections or 
Appendix
Visit
V31
V32 V33
V34
V35 V36
V37 V38
V39
V40 V41
V42
V43
Unsch visit 2
IPD/ EOT 4
Study week (calculated from V2)
Visit windows: ± 7 days
108
112
116
120
124
128
132
136
140
144
148
152
156
Visit can be done remotely 1
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test (dipstick) 10
X
X
X
8.2.1.1
ESR (local)
X 2
8.2.1
CRP
X 2
8.2.1
PK 11
X
X
X
8.5
ADA/nAb 12
X
X
X
8.9
Other/ Administrative
IRT/RTSM transaction
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.3.1
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Appendix A
Benralizumab administration
Benralizumab administration
X
X
X
X
X
X
X
X
X
X
X
X
X
6
1
These visits can optionally be conducted remotely by telephone contact for patients who are self-administering IP. 
2
Unscheduled visits may be initiated as needed, and any additional assessments may be performed at these visits, at the discretion of the Investigator.
3
If unscheduled visit is to assess the patient for potential EGPA relapse, include these additional assessments. Other assessments may be performed as clinically indicated.
4
The IPD/EOT visit replaces the nearest regular visit: IPD visit procedures should be performed as soon as possible after decision to discontinue IP has been made, and at the 
latest 4 weeks ± 7 days after the last dose of IP. EOT visit will only be scheduled following notification of closure of the study (Section 7.1.1.2), 4 weeks ± 7 days after the 
last dose of IP.
5
Investigator/delegate to record the OCS dose in the eCRF at each study visit.
6
Clinical assessment of relapse/remission based on Investigators’ overall clinical assessment. In case of clinically suspected relapse, an unscheduled visit should be performed.
7
Haematology and chemistry samples may be collected more frequently if clinically indicated at Investigators’ discretion.
8
eGFR will be calculated according to the CKD-EPI formula. 
9
Haematuria to be checked by dipstick test provided centrally.
10
Only for women of child-bearing potential.
11
On dosing visits, PK will be collected pre-dose.
12
Neutralising antibody testing will be performed for all samples that are ADA positive. Samples that are ADA negative will not be tested for nAb.

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Benralizumab - D3253C00001
CONFIDENTIAL AND PROPRIETARY             Page 23 of 193
ADA, anti-drug antibodies; AE(s), adverse event(s); BD, bronchodilator; BVAS, Birmingham Vasculitis Activity Score; CKD-EPI, Chronic Kidney Disease Epidemiology 
Collaboration; CRP, C-reactive protein; CSP, clinical study protocol; ECG, electrocardiogram; eCRF, electronic case report form; eGFR, estimated glomerular filtration rate; 
EGPA, eosinophilic granulomatosis with polyangiitis; EOT, end of treatment; ESR, erythrocyte sedimentation rate; FEV1, forced expiratory volume in 1 second; IP, 
investigational product; IPD, IP discontinuation; IRT, Interactive Response Technology; meds, medications; nAb, neutralising antibodies; OCS, oral corticosteroid; 
PK, pharmacokinetics; RTSM, Randomisation and Trial Supply System Management; SAE(s), serious adverse event(s); Unsch, unscheduled; V, Visit (number); VDI, Vasculitis 
Damage Index; WBC, white blood cells.

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Table 4
Schedule of Assessments – Open-label Extension Period (Year 3), if Applicable
Study procedure
Open-label extension period – Year 3 (if applicable)
Details in 
CSP 
sections or 
Appendix
Visit
V44
V45
V46
V47
V48
V49
V50
V51
V52
V53
V54
V55
V56
Unsch 
visit 2
IPD/ 
EOT 4
Study week (calculated from Visit 2)
Visit windows: ± 7 days
160 
164
168
172
176
180
184
188
192
196
200
204
208
Visit can be done remotely 1
X
X
X
X
X
X
X
X
X
X
X
General procedures
Weight
X 2
X
8.2.5.1
Efficacy assessments
Record OCS dose and check compliance 5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1.4
BVAS
X 2
X
8.1.1.1
VDI
X
X
X
8.1.1.3
Clinical assessment of EGPA 
relapse/remission 6
X
X
X
X
X
X
X
X
X
X
X
X
X
X 2
X
8.1.1.2
Health resource use
X
8.10
Spirometry (pre-BD FEV1)
X 2
8.1.1.12
Safety assessments
Concomitant/ post IP meds
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.5
Complete physical exam
X
8.2.2.1
Brief physical exam
X 2
8.2.2.2
Vital signs
X
X
X 2
X
8.2.3
ECG (triplicate recordings)
X
X
8.2.4
AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3
Laboratory assessments (always taken pre-dose at dosing visits)
Haematology, WBC w/differential 7
X
X
X 2
X
8.2.1
Serum chemistry 7,8
X
X
X 2
X
8.2.1
Urinalysis (dipstick) 9
X
X
X
X
8.2.1

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Table 4
Schedule of Assessments – Open-label Extension Period (Year 3), if Applicable
Study procedure
Open-label extension period – Year 3 (if applicable)
Details in 
CSP 
sections or 
Appendix
Visit
V44
V45
V46
V47
V48
V49
V50
V51
V52
V53
V54
V55
V56
Unsch 
visit 2
IPD/ 
EOT 4
Study week (calculated from Visit 2)
Visit windows: ± 7 days
160 
164
168
172
176
180
184
188
192
196
200
204
208
Visit can be done remotely 1
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test (dipstick) 10
X
X
X
8.2.1.1
ESR (local)
X 2
8.2.1
CRP
X 2
8.2.1
PK 11
X
X
X
8.5
ADA/nAb 12
X
X
X
8.9
Other/administrative
IRT/RTSM transaction
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.3.1
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Appendix
A
Benralizumab administration
Benralizumab administration
X
X
X
X
X
X
X
X
X
X
X
X
X
6
1
These visits can optionally be conducted remotely by telephone contact for patients who are self-administering IP. 
2
Unscheduled visits may be initiated as needed, and any additional assessments may be performed at these visits, at the discretion of the Investigator.
3
If unscheduled visit is to assess the patient for potential EGPA relapse, include these additional assessments. Other assessments may be performed as clinically indicated.
4
The IPD/EOT visit replaces the nearest regular visit: IPD visit procedures should be performed as soon as possible after decision to discontinue IP has been made, and at the 
latest 4 weeks ± 7 days after the last dose of IP. EOT visit will only be scheduled following notification of closure of the study (Section 7.1.1.2), 4 weeks ± 7 days after the last 
dose of IP.
5
Investigator/delegate to record the OCS dose in the eCRF at each study visit.
6
Clinical assessment of relapse/remission based on Investigators’ overall clinical assessment. In case of clinically suspected relapse, an unscheduled visit should be performed.
7
Haematology and chemistry samples may be collected more frequently if clinically indicated at Investigator’s discretion.
8
eGFR will be calculated according to the CKD-EPI formula.
9
Haematuria to be checked by dip-stick test provided centrally.
10
Only for women of child-bearing potential.
11
On dosing visits, PK will be collected pre-dose.
12
Neutralising antibody testing will be performed for all samples that are ADA positive. Samples that are ADA negative will not be tested for nAb.

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ADA, anti-drug antibodies; AE(s), adverse event(s); BD, bronchodilator; BVAS, Birmingham Vasculitis Activity Score; CKD-EPI, Chronic Kidney Disease Epidemiology 
Collaboration; CRP, C-reactive protein; CSP, clinical study protocol; ECG, electrocardiogram; eCRF, electronic case report form; eGFR, estimated glomerular filtration rate; 
EGPA, eosinophilic granulomatosis with polyangiitis; EOT, end of treatment; ESR, erythrocyte sedimentation rate; FEV1, forced expiratory volume in 1 second; IP, 
investigational product; IPD, IP discontinuation; IRT, Interactive Response Technology; meds, medications; nAb, neutralising antibodies; OCS, oral corticosteroid; OLE, open-
label extension; PK, pharmacokinetics; RTSM, Randomisation and Trial Supply System Management; SAE(s), serious adverse event(s); Unsch, unscheduled; V, Visit (number); 
VDI, Vasculitis Damage Index; WBC, white blood cells.

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Table 5
Schedule of Assessments – Open-label Extension Period (Year 4 Onwards), if Applicable
Study procedure
Open-label extension period – Year 4 onwards (if applicable)
Details in 
CSP 
sections or 
Appendix
Visits
V57/
70/
83
V58/
71/
84
V59/
72/
85
V60/
73/
86
V61/
74/
87
V62/
75/
88
V63/
76/
89
V64/
77/
90
V65/
78/
91
V66/
79/
92
V67/
80/
93
V68/
81/
94
V69/
82/
95
Unsch 
visit 2
IPD/ 
EOT 4
Study weeks (calculated from Visit 2)
Visit windows: ± 7 days
212/
264/
316 
216/
268/
320
220/
272/
324
224/
276/
328
228/
280/
332
232/
284/
336
236/
288/
340
240/
292/
344
244/
296/
348
248/
300/
352
252/
304/
356
256/
308/
360
260/
312/
364
Visit can be done remotely 1
X
X
X
X
X
X
X
X
X
X
X
X
General procedures
Weight
X 2
X
8.2.5.1
Efficacy assessments
Record OCS dose and check compliance 5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1.4
BVAS
X 2
X
8.1.1.1
VDI
X
X
X
8.1.1.3
Clinical assessment of EGPA 
relapse/remission 6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.1.2
Health resource use
X
8.10
Safety assessments
Concomitant/ post IP meds (only in case of 
SAE and relevant for SAE) 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.5
Complete physical exam
X
8.2.2.1
Brief physical exam
X
8.2.2.2
Vital signs
X
X
X
8.2.3
ECG (triplicate recordings)
X
8.2.4
SAEs 8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3
Laboratory assessments
Haematology, WBC w/differential 9
X
X
X
8.2.1
Serum chemistry 9,10
X
X
X
8.2.1

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Table 5
Schedule of Assessments – Open-label Extension Period (Year 4 Onwards), if Applicable
Study procedure
Open-label extension period – Year 4 onwards (if applicable)
Details in 
CSP 
sections or 
Appendix
Visits
V57/
70/
83
V58/
71/
84
V59/
72/
85
V60/
73/
86
V61/
74/
87
V62/
75/
88
V63/
76/
89
V64/
77/
90
V65/
78/
91
V66/
79/
92
V67/
80/
93
V68/
81/
94
V69/
82/
95
Unsch 
visit 2
IPD/ 
EOT 4
Study weeks (calculated from Visit 2)
Visit windows: ± 7 days
212/
264/
316 
216/
268/
320
220/
272/
324
224/
276/
328
228/
280/
332
232/
284/
336
236/
288/
340
240/
292/
344
244/
296/
348
248/
300/
352
252/
304/
356
256/
308/
360
260/
312/
364
Visit can be done remotely 1
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis (dipstick) 11
X
X
8.2.1
Urine pregnancy test (dipstick) 12
X
X
8.2.1.1
ESR (local)
X 2
8.2.1
CRP
X 2
8.2.1
PK
X
8.5
ADA/nAb 13
X
8.9
Other/administrative
IRT/RTSM transaction
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.3.1
Complete eCRF
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Appendix
A
Benralizumab administration
Benralizumab administration
X
X
X
X
X
X
X
X
X
X
X
X
X
6
1
These visits can optionally be conducted remotely by telephone contact for patients who are self-administering IP. 
2
Unscheduled visits may be initiated as needed, and any additional assessments may be performed at these visits, at the discretion of the Investigator.
3
If unscheduled visit is to assess the patient for potential EGPA relapse, include these additional assessments. Other assessments may be performed as clinically indicated.
4
The IPD/EOT visit replaces the nearest regular visit: IPD visit procedures should be performed as soon as possible after decision to discontinue IP has been made, and at the 
latest 4 weeks ± 7 days after the last dose of IP. EOT visit will only be scheduled following notification of closure of the study (Section 7.1.1.2), 4 weeks ± 7 days after the 
last dose of IP.
5
Investigator/delegate to record the OCS dose in the eCRF at each study visit.
6
Clinical assessment of relapse/remission based on Investigators’ overall clinical assessment. In case of clinically suspected relapse, an unscheduled visit should be performed.
7
Concomitant medications taken for and relevant for SAE or significant medical/adverse event should be recorded in the eCRF.
8
Only SAEs or significant medical/adverse events that lead to an intervention should be captured and recorded in the eCRF.
9
Haematology and chemistry samples may be collected more frequently if clinically indicated at Investigator’s discretion.

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10
eGFR will be calculated according to the CKD-EPI formula.
11
Haematuria to be checked by dip-stick test provided centrally.
12
Only for women of child-bearing potential.
13
Neutralising antibody testing will be performed for all samples that are ADA positive. Samples that are ADA negative will not be tested for nAb.
ADA, anti-drug antibodies; BVAS, Birmingham Vasculitis Activity Score; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CRP, C-reactive protein; 
CSP, clinical study protocol; ECG, electrocardiogram; eCRF, electronic case report form; eGFR, estimated glomerular filtration rate; EGPA, eosinophilic granulomatosis with 
polyangiitis; EOT, end of treatment; ESR, erythrocyte sedimentation rate; IP, investigational product; IPD, IP discontinuation; IRT, Interactive Response Technology; meds, 
medications; nAb, neutralising antibodies; OCS, oral corticosteroid; PK, pharmacokinetics; RTSM, Randomisation and Trial Supply System Management; SAE(s), serious adverse 
event(s); Unsch, unscheduled; V, Visit (number); VDI, Vasculitis Damage Index; WBC, white blood cells.

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Table 6
Schedule of Assessments for ePRO Endpoints (Double-blind Period and Open-label Extension Period –
First Year)
PRO assessment
Double-blind treatment period (V1-V17)
After Visit 2, all assessments may be completed at home. 
If any assessment has not been completed prior to the site 
visit, it will be completed at the site prior to other study 
procedures.
OLE period – first year (V18-V30)
All assessments will be completed at Visit 18. After Visit 18, all 
assessments may be completed at home. 
If any assessment has not been completed prior to the site visit, 
it will be completed at the site prior to other study procedures.
Corticosteroid 
medication usage
V1-V17: daily at home in the evening
Unscheduled visit a: at site
IPD visit: at site
After V18: every 7 days (± 2 days) until V30
IPD visit: at site
EOT visit: at site
ACQ-6
V1: at site
V2: at site
After V2: every 7 days (± 2 days) until V17
Unscheduled visit a: at site
IPD visit: at site
After V18: every 28 days (± 2 days) until V30
IPD visit: at site
EOT visit: at site
Sino-nasal 
questionnaire
V1: at site
V2: at site
After V2: every 7 days (± 2 days) until V17
Unscheduled visit a: at site
IPD visit: at site
After V18: every 28 days (± 2 days) until V30
IPD visit: at site
EOT visit: at site
SNOT-22
V1: at site
V2: at site
After V2: every 28 days (± 2 days) until V7
After V7: every 84 days (± 2 days) until V17
IPD visit: at site
After V18: every 84 days (± 2 days) until V30
IPD visit: at site
EOT visit: at site
SF-36v2
V1: at site
V2: at site
V3: 7 days (± 2 days) after V2
After V3: every 28 days (± 2 days) after V2 until V7
After V7: every 84 days (± 2 days) until V17
IPD visit: at site
After V18: every 84 days (± 2 days) until V30
IPD visit: at site
EOT visit: at site

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Table 6
Schedule of Assessments for ePRO Endpoints (Double-blind Period and Open-label Extension Period –
First Year)
PRO assessment
Double-blind treatment period (V1-V17)
After Visit 2, all assessments may be completed at home. 
If any assessment has not been completed prior to the site 
visit, it will be completed at the site prior to other study 
procedures.
OLE period – first year (V18-V30)
All assessments will be completed at Visit 18. After Visit 18, all 
assessments may be completed at home. 
If any assessment has not been completed prior to the site visit, 
it will be completed at the site prior to other study procedures.
PGIC
After V2: every 7 days (± 2 days) for 28 days
Not applicable
PGIS
V1: at site
V2: at site
After V2: every 7 days (± 2 days) until V17
IPD visit: at site
Not applicable
WPAI-GH
V1: at site
V2: at site
After V2: every 28 days (± 2 days) until V7
After V7: every 84 days (± 2 days) until V17
IPD visit: at site
After V18: every 84 days (± 2 days) until V30
IPD visit: at site
EOT visit: at site
a
Only if the unscheduled visit is to assess the patient for potential EGPA relapse.
ACQ-6, Asthma Control Questionnaire (6-item version); EOT, end of treatment; ePRO electronic patient reported outcome; IPD, investigational product 
discontinuation; OLE, open-label extension; PGIC, Patient Global Impression of Change; PGIS, Patient Global Impression of Severity; PRO, patient reported 
outcome; SF-36v2, Short Form 36-Item Health Survey (version 2, acute recall); SNOT-22, Sino-nasal Outcome Test-22; V, visit (number); WPAI, Work 
Productivity and Activity Impairment Questionnaire (General Health version 2.0).

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1.2
Synopsis
International Coordinating Investigator
National Jewish Health
1400 Jackson St
Denver, CO 80206
Protocol Title
A Randomised, Double-blind, Active-controlled 52-Week Study with an Open-label 
Extension to Evaluate the Efficacy and Safety of Benralizumab Compared to Mepolizumab in 
the Treatment of Eosinophilic Granulomatosis with Polyangiitis (EGPA) in Patients Receiving 
Standard of Care Therapy (MANDARA Study)
Rationale
Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss syndrome) is 
a rare disease characterised by potentially life-threatening systemic eosinophilic small-vessel 
vasculitis in association with asthma, sinusitis, and pulmonary infiltrates. Eosinophilic 
granulomatosis with polyangiitis and hypereosinophilic syndrome (HES) have distinct, but 
partly overlapping clinical and histologic features, including target organs. Because 
eosinophilia is central to the pathophysiology of EGPA, it is hypothesised that direct or 
indirect depletion of eosinophils could also treat EGPA.
Benralizumab (FASENRA™ 1) is a humanised, afucosylated monoclonal antibody (mAb) 
(immunoglobulin G subclass 1 [IgG1], immunoglobulin G1 kappa isotype [IgG1κ]) that binds 
to the human interleukin-5 receptor alpha subunit (IL-5Rα) with high affinity and specificity. 
The IL-5 receptor is specifically expressed on the surface of eosinophils and basophils. The 
absence of fucose in the fragment crystallizable (Fc) domain of benralizumab results in high 
affinity for FcγRIII receptors on immune effector cells such as natural killer cells leading to 
depletion by apoptosis of eosinophils and basophils through enhanced antibody-dependent 
cell-mediated cytotoxicity. The direct eosinophil-depleting ability of benralizumab has been 
shown to be effective in eosinophilic asthma and in steroid-dependent asthma. Benralizumab 
has also shown potential for benefit in HES, a group of diseases with persistent blood 
eosinophilia and evidence of eosinophil-mediated end-organ damage.
This Phase III study in patients with relapsing or refractory EGPA on corticosteroid therapy 
with or without stable immunosuppressive therapy includes a 52-week double-blind (DB) 
period in which the efficacy and safety of benralizumab will be compared with an active 
comparator, mepolizumab, which has regulatory approval in several markets for use in 
1 FASENRA (benralizumab) is a trademark of the AstraZeneca group of companies.
PPD

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patients with EGPA. The study also includes an open-label extension (OLE) period intended 
to allow each patient at least one additional year of treatment with open-label benralizumab, 
which will provide an opportunity to assess long-term safety and tolerability of benralizumab 
in this patient population.
Overall Design
The objectives and endpoints for the DB treatment period and the OLE period of the study are 
presented in Table 7 and Table 8, respectively. 
Table 7
Study Objectives – Double-blind Period
The following objectives/endpoints are for the double-blind period (double-blind) of the study.
Primary objective: 
Endpoint/variable:
To assess the durability of response to treatment with 
benralizumab compared with mepolizumab in patients 
with relapsing or refractory EGPA who are receiving 
standard of care therapy, assessed by the proportion of 
patients in remission at both Weeks 36 and 48
Primary endpoint: Proportion of patients with 
relapsing or refractory EGPA, achieving remission, 
defined as BVAS = 0 and OCS dose ≤4 mg/day (main 
remission definition) at both Weeks 36 and 48
Supportive endpoint: Proportion of patients who have 
achieved remission defined by BVAS = 0 and OCS 
dose ≤7.5 mg/day (supportive remission definition) at 
both Weeks 36 and 48
Secondary objectives:
Endpoint/variable:
To assess the efficacy of benralizumab compared with 
mepolizumab on duration of clinical remission, 
defined as accrued duration in weeks where a patient 
achieves remission
Total accrued duration of remission for the following 
categories: 0 wk, > 0 to < 12 wk, 12 to < 24 wk, 
24 to < 36 wk, ≥36 wk. Analysis will be repeated 
based on main and supportive remission definitions 
To assess the efficacy of benralizumab compared with 
mepolizumab on time to first relapse 
Time from randomisation to first EGPA relapse, where 
relapse is defined as any of the following:
•
Active vasculitis (BVAS > 0); OR
•
Active asthma symptoms and/or signs with a 
corresponding worsening in ACQ-6 score; OR
•
Active nasal and/or sinus disease, with a 
corresponding worsening in at least one of the 
sino-nasal symptom questions; 
warranting any of the following: 
!
An increased dose of OCS therapy to 
> 4 mg/day prednisolone total daily dose; 
OR
!
An increased dose or addition of 
immunosuppressive therapy; OR
!
Hospitalisation related to EGPA worsening

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Table 7
Study Objectives – Double-blind Period
To assess the effect of benralizumab on corticosteroid 
dose required during Weeks 48 through 52 compared 
to mepolizumab 
Based on the average daily prednisolone/prednisone 
dose during Weeks 48 through 52:
•
Proportion of patients in each category: 0 mg; > 0 
to ≤4 mg; > 4 to ≤ 7.5 mg, and > 7.5 mg.
•
Proportion of patients in each category of percent 
reduction from baseline: no reduction or 
withdrawal from treatment; < 25% reduction; 25 
to < 50% reduction; 50 to < 75% reduction; 75 to 
< 100% reduction; 100% reduction.
•
Proportion of patients with ≥ 50% reduction from 
baseline.
•
Proportion of patients with 100% reduction from 
baseline.
•
Proportion of patients with ≤4 mg in average 
daily dose.
To assess the clinical benefit of benralizumab 
compared to mepolizumab
Proportion of patients who have achieved any clinical 
benefit when meeting any of the criteria below.
Proportion of patients who have achieved complete 
response when meeting all of the criteria below.
•
Remission (defined as BVAS = 0 and 
prednisolone/prednisone dose ≤ 4 mg/day) at any 
time during the double-blind treatment period
•
≥ 50% reduction in average daily 
prednisolone/prednisone dose during Weeks 48 
through 52
•
EGPA relapse free during the double-blind 
treatment period.
Analysis will be repeated for the supportive remission 
definition.
To assess the annualised relapse rate in patients 
receiving benralizumab compared to mepolizumab 
Annualised relapse rate
To assess the proportion of patients who achieve 
remission within the first 24 weeks and remain in
remission for the remainder of the double-blind period 
in patients receiving benralizumab compared to 
mepolizumab
Proportion of patients who have achieved remission 
within the first 24 weeks and remained in remission 
for remainder of the double-blind treatment period. 
Analysis will be repeated based on main and 
supportive remission definitions.
To assess additional measures of the efficacy and 
health status/health-related quality of life in patients 
receiving benralizumab compared to mepolizumab
BVAS, VDI, pulmonary function testing, asthma 
symptoms (ACQ-6), sino-nasal symptoms (including 
SNOT-22 questionnaire), health-related quality of life 
(SF-36v2), PGIS, WPAI, and blood eosinophil counts 
will be assessed as change from baseline over the 
52-week double-blind treatment period.
PGIC will be assessed as response proportions at each 
weekly assessment between Visits 2 and 4. 

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Table 7
Study Objectives – Double-blind Period
Safety objectives:
Endpoint/variable:
To assess the safety and tolerability of benralizumab 
compared to mepolizumab
Safety and tolerability will be evaluated based on AEs, 
vital signs, physical exam, clinical laboratory, and 
ECG. 
Assessments related to AEs include:
•
Occurrence/frequency
•
Relationship to IP as assessed by the Investigator
•
Intensity 
•
Seriousness
•
Death
•
AEs leading to discontinuation of IP
•
Other significant AEs
To assess the pharmacokinetics and immunogenicity 
of benralizumab
Serum benralizumab concentrations
Anti-benralizumab antibodies and neutralising 
antibodies
Exploratory objectives:
Endpoint/variable:
To assess the cumulative OCS use in response to 
treatment with benralizumab compared to 
mepolizumab
Cumulative OCS use, as measured by AUC for daily 
prednisolone/prednisone dose, over the 52-week 
double-blind treatment period
To evaluate the effect of benralizumab compared to 
mepolizumab on health care resource utilisation due to 
EGPA
Number of EGPA-related hospitalisations; length of 
hospital stay; ICU days; number of EGPA-related ER 
visits; number of EGPA-related outpatient visits (by 
type); number of EGPA-related procedures/tests (by 
specific procedure/test) 
To evaluate the effect of benralizumab compared to 
mepolizumab on biomarkers of inflammation 
Biomarkers of inflammation, eg, CRP and ESR
To evaluate the effect of benralizumab compared to 
mepolizumab on biomarkers related to the MoA, 
eosinophilic inflammation, and EGPA disease 
pathogenesis, as well as baseline predictors of 
response to benralizumab or mepolizumab
Exploratory biomarkers in:
•
Serum
•
Whole blood
•
Nasal secretions
•
Tissue biopsies and sputum (mechanistic sub-
study only) 
To characterise the patient-reported experience and 
treatment benefits of benralizumab compared with 
mepolizumab through patient interviews
Patient interviews to characterise patient-reported 
experience and treatment benefits (sub-study)
ACQ-6, Asthma Control Questionnaire (6-item version); AE(s), adverse event(s); AUC, area under the curve; 
BVAS, Birmingham Vasculitis Activity Score; CRP, C-reactive protein; ECG, electrocardiogram; 
EGPA, eosinophilic granulomatosis with polyangiitis; ER, emergency room; ESR, erythrocyte sedimentation 
rate; ICU, intensive care unit; IP, investigational product; MoA, mechanism of action; OCS, oral corticosteroid; 
OLE, open-label extension; PGIC, Patient Global Impression of Change; PGIS, Patient Global Impression of 
Severity; PK, pharmacokinetics; SAE(s), serious adverse event(s); SF-36v2, Short Form 36-Item Health Survey 
(version 2, acute recall); SNOT-22, Sino-nasal Outcome Test-22; VDI, Vasculitis Damage Index; WPAI, Work 
Productivity and Activity Impairment Questionnaire; wk, weeks

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Table 8
Study Objectives for Open-label Extension Period
The following objectives/endpoints are for the open-label extension portion of the study:
Objectives:
Endpoint/variable:
To evaluate the effect of benralizumab on remission, 
relapse, and OCS use a
Remission, relapse (as defined in Table 7 c), OCS use
To assess patient reported outcomes in patients 
receiving benralizumab b
Asthma symptoms (ACQ-6), sino-nasal symptoms 
(including SNOT-22 questionnaire), health-related 
quality of life (SF-36v2), and WPAI
To assess the safety and tolerability of benralizumab a
Safety and tolerability will be evaluated based on AEs, 
vital signs, physical exam, clinical laboratory, and 
ECG.
Assessments related to AEs cover: 
•
Occurrence/frequency
•
Relationship to IP as assessed by the Investigator
•
Intensity 
•
Seriousness
•
Death
•
AEs leading to discontinuation of IP
•
Other significant AEs
To assess the pharmacokinetics and immunogenicity 
of benralizumab d
Serum benralizumab concentrations
Anti-benralizumab antibodies and neutralising 
antibodies
To evaluate the effect of benralizumab on health care 
resource utilisation due to EGPA b
Number of EGPA-related hospitalisations; length of 
hospital stay; ICU days; number of EGPA-related ER 
visits; number of EGPA-related outpatient visits (by 
type); number of EGPA-related procedures/tests (by 
specific procedure/test)
To assess biomarkers of inflammation b
Biomarkers of inflammation, eg, CRP and ESR 
To assess biomarkers related to the MoA of 
benralizumab, eosinophilic inflammation, and EGPA 
disease pathogenesis b
Exploratory biomarkers in serum
a
Applicable to full duration of OLE.
b
Applicable to first year of OLE only.
c
Applicable to first year of OLE only. From the second year, the definitions of remission and relapse will be 
based on the Investigator’s overall clinical assessment.
d
Applicable to OLE Year 1-3.
ACQ-6, Asthma Control Questionnaire (6-item version); AE(s) adverse event(s); CRP, C-reactive protein; 
ECG, electrocardiogram; EGPA eosinophilic granulomatosis with polyangiitis; ER, emergency room; 
ESR, erythrocyte sedimentation rate; ICU, intensive care unit; IP, investigational product; MoA, mechanism of 
action; OCS, oral corticosteroids; OLE, Open-label extension PK, pharmacokinetics; RNA, ribonucleic acid; 
SF-36v2, Short Form 36-Item Health Survey (version 2, acute recall); SNOT-22, Sino-nasal Outcome Test-22; 
WPAI, Work Productivity and Activity Impairment Questionnaire.

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Overall Design
This is a randomised, DB, active-controlled, parallel group, multicentre 52-week Phase III 
study to compare the efficacy and safety of benralizumab 30 mg versus mepolizumab 300 mg 
administered by subcutaneous (SC) injection every 4 weeks (Q4W) in patients with relapsing 
or refractory EGPA on corticosteroid therapy with or without stable immunosuppressive 
therapy.
The target population is adult female or male patients aged 18 years and above who have 
documented EGPA diagnosis plus documentation of at least 2 additional features of EGPA 
and a history of relapsing or refractory disease. After initial enrolment and confirmation of 
entry criteria (Visit 1), potentially eligible patients will enter a screening period of up to 
4 weeks (minimum of one week) and will be required to be on a stable dose of oral 
corticosteroids (OCS) ≥7.5 mg/day prednisolone/prednisone (but not > 50 mg/day), for at 
least 4 weeks prior to baseline (Visit 2) (see Appendix K for Belgium). Patients on 
immunosupressive therapy must be on a stable dose for at least 4 weeks prior to baseline 
(Visit 2) and should remain on the same dose until the end of the DB period (if the patient 
does not enter the OLE) or until completion of the first 6 months of the OLE period (if the 
patient continues into the OLE). Dose reductions for safety reasons will be permitted. Note 
that the dose of immunosuppressive therapy must not exceed the maximal doses used in 
clinical practice.
Study Period
Estimated date of first patient enrolled: third quarter 2019
Estimated date of last patient completed: third quarter 2024. 
Number of Patients
Approximately 140 eligible patients will be randomised in a 1:1 ratio to either the 
benralizumab 30 mg or mepolizumab 300 mg treatment groups, respectively.
Treatments and Treatment Duration
Patients who meet the eligibility criteria at Visit 1 and criteria needing to be 
confirmed/reconfirmed at baseline (Visit 2) will be randomised to a 52-week treatment period 
with investigational product (IP) Q4W. Patients will receive either one SC injection of 
benralizumab 30 mg plus 3 SC injections of placebo to mepolizumab, or 3 injections of 
mepolizumab 100 mg SC plus one SC injection of placebo to benralizumab at each dosing 
visit. In the DB treatment period, patients will receive IP Q4W, starting from Week 0 and 
ending at Week 48; the DB treatment period will end at Week 52. All patients who complete 
the 52-week DB treatment period on IP may be eligible to continue into an OLE period. The 
OLE period is intended to allow every patient at least one year of treatment with open-label 
benralizumab 30 mg administered SC every fourth week.

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Statistical Methods
The primary database lock will occur after all randomised patients have been followed up for 
the 52-week DB treatment period. The study will remain blinded until the primary database 
lock. The primary analysis will include all data captured during the DB treatment period 
(intention-to-treat approach). Safety data from the open-label period available at the time of 
the primary database lock will also be reported. Additional analyses may be performed after 
the primary database lock to analyse the data that were not available in the primary analysis. 
The final database lock will occur after the last patient has completed at least one year in the 
OLE and when the end of the study has been declared.
The primary efficacy endpoint is the proportion of patients who achieve EGPA main 
remission at both Week 36 and Week 48 of the DB period. The primary analysis is to 
demonstrate non-inferiority (NI) of benralizumab versus mepolizumab in terms of durability 
of response to treatment based on the primary endpoint of remission using a logistic 
regression model adjusted for treatment arm, baseline dose of prednisone, baseline BVAS, and 
region. From this model, the absolute difference in remission rates (benralizumab -
mepolizumab) will be estimated, with the associated two-sided 95% confidence interval. If the 
primary analysis demonstrates NI (further detail below), a formal test of superiority between 
benralizumab and mepolizumab will be assessed. In addition, to assess external validity of the 
study, an indirect comparison of benralizumab to historic placebo will be evaluated using 
remission rate.
For NI of benralizumab compared to mepolizumab to be demonstrated for the primary 
endpoint, the lower 95% confidence limit for the absolute difference between benralizumab 
and mepolizumab needs to be above the NI margin of -25%.
The study sample size is based on the assumption that mepolizumab and benralizumab each 
have a remission rate of 32%; 140 patients will provide ~90% power to demonstrate NI with a 
NI margin of -25% at the 2.5% one-sided significance level. 
Secondary efficacy endpoints of the DB period include comparison of benralizumab to 
mepolizumab in terms of the following: duration of clinical remission accrued in weeks where 
a patient achieves remission (assessed for main and supportive remission definitions, 
separately); time from randomisation to first relapse; average daily dose of OCS required 
during Weeks 48 through 52; percent reduction from baseline in average daily 
prednisolone/prednisone dose during Weeks 48 through 52; proportion of patients who have 
achieved any clinical benefit and complete response during the double-blind treatment period; 
annualised relapse rate; proportion of patients achieving remission within the first 24 weeks 
and remaining in remission for the remainder of the DB period (main and supportive 
remission, separately); and durability of response assessed by the proportion of patients in 
supportive remission at both Week 36 and Week 48. 

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Logistic regression will be used to analyse the average daily prednisolone/prednisone dose 
≤4 mg/day during Weeks 48 through 52, ≥ 50% (and 100% seperately) reduction from 
baseline in average daily prednisolone/prednisone dose during Weeks 48 through 52, any 
clinical benefit, complete response, and remission within the 24 weeks and remaining in 
remission for the remainder of the DB period. A negative binomial model will be used to 
analyse annualised relapse rate. The Cox-proportional hazards model will be used to analyse 
time to relapse. A proportional odds model will be used to analyse accrued duration of 
remission, the average of daily prednisolone/prednisone dose during Weeks 48 through 52 
(with categories 0 mg; > 0 to ≤4 mg; > 4 to ≤7.5 mg, and > 7.5 mg), and percentage 
reduction from baseline in average prednisolone/prednisone dose during Weeks 48 through 52 
(with categories no reduction or premature discontinuation from treatment before Week 48, < 
25% reduction, 25 to < 50% reduction, 50 to < 75% reduction, 75 to < 100% reduction, and 
100% reduction).
Further secondary endpoints include additional measures of efficacy and health status/health-
related quality of life (HRQoL) assessed as change from baseline over the 52-week DB period 
as follows: Birmingham Vasculitis Activity Score (BVAS), Vasculitis Damage Index (VDI), 
pulmonary function testing, asthma symptoms (Asthma Control Questionnaire, 6-item 
version) [ACQ-6]), sino-nasal symptoms (including Sino-nasal Outcome Test-22 [SNOT-22]), 
HRQoL (Short Form 36-Item Health Survey, version 2 [SF-36v2]), and blood eosinophil 
counts. The change from baseline in these continuous secondary endpoints will be analysed 
using a mixed effect model for repeated measures (MMRM) analysis. Descriptive statistics 
will be provided for Patient Global Impression of Severity (PGIS) and Work Productivity and 
Activity Impairment questionnaire (WPAI) to assess change from baseline over the 52-week 
DB period. In addition, Patient Global Impression of Change (PGIC) responses will also be 
assessed between Visits 2 and 4.
In addition, safety and tolerability of the benralizumab and mepolizumab treatments will be 
assessed for the DB period, and relevant endpoints will be summarised descriptively and 
reported in the primary analysis based on the safety analysis set. The pharmacokinetics (PK) 
and immunogenicity of the benralizumab treatment during the DB period will be reported 
based on the safety analysis set.
A further assessment of safety, tolerability, efficacy, PK, and immunogenicity will be reported 
after the final database lock including summaries of data from the OLE period only based on 
descriptive summaries.
1.3
Schema
The general study design is summarised in Figure 1. 

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Figure 1
Study Design
BVAS, Birmingham vasculitis activity score; OCS oral corticosteroids; OLE, open-label extension; Q4W, every 
4 weeks; SC, subcutaneous; V, Visit (number).

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2
INTRODUCTION
2.1
Study Rationale
The aim of this randomised, double blind, active-controlled, parallel group, multicentre 
52-week Phase III study is to compare the efficacy and safety of benralizumab 30 mg versus 
mepolizumab 300 mg administered by SC injection Q4W in patients with relapsing or 
refractory EGPA on corticosteroid therapy with or without stable immunosuppressive therapy. 
Because eosinophilia is central to the pathophysiology of EGPA, it is hypothesised that direct 
or indirect depletion of eosinophils could treat EGPA. A reduction in eosinophils could be 
achieved through blockade of IL-5 or the IL-5 receptor (specifically expressed on the surface 
of eosinophils and basophils) because IL-5 is the major hematopoietin regulating the life cycle 
of eosinophils (Clutterbuck et al 1989, Lopez et al 1988, Rothenberg and Hogan 2006).
Benralizumab (FASENRATM 2) is a humanised, afucosylated mAb (IgG1, IgG1κ) that binds to 
the human IL-5Rα subunit with high affinity and specificity. The direct eosinophil-depleting 
ability of benralizumab is effective in eosinophilic asthma (Bleecker et al 2016, Fitzgerald et 
al 2016) and in steroid-dependent asthma (Nair et al 2017). Preliminary evidence of the 
efficacy of benralizumab in HES is also available from a Phase IIa investigator-initiated study 
(Kuang et al 2019). An IL-5 cytokine inhibitor, mepolizumab was recently approved for 
treatment of EGPA in several countries including the US, Canada, Japan, Australia, and Israel, 
based on a single Phase III study conducted in the EU and RoW countries (MIRRA study; 
Wechsler et al 2017). Although, mepolizumab increased the accrued time that patients were in 
remission compared with placebo in this registrational study (results summarised in 
Section 2.2.1), 47% of patients treated with mepolizumab did not meet the primary endpoint 
definition of remission in the study. This suggests that although an IL-5 cytokine-depleting 
approach is of benefit in patients with EGPA, an unmet need remains.
Potential advantages of benralizumab compared with mepolizumab for treatment of EGPA 
patients may be the direct near complete depletion or apoptosis of eosinophils. By inducing 
direct, near complete depletion of eosinophil levels in blood and tissue, it is believed that 
benralizumab will deliver at least similar efficacy to mepolizumab as measured through 
EGPA remission with a comparable safety profile. In accordance with increasing scientific 
discussion regarding comparative effectiveness studies and US FDA regulatory guidance that 
patients with EGPA should be given access to approved therapies, this study is designed to 
compare the efficacy and safety of benralizaumab with mepolizumab in the treatment of 
relapsing or refractory EGPA.
                                               
2 FASENRA (benralizumab) is a trademark of the AstraZeneca group of companies.

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2.2
Background
2.2.1
EGPA Disease and Current Approaches to Disease Management
Eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome) is a rare 
disease characterised by potentially life-threatening systemic eosinophilic small vessel 
vasculitis in association with asthma, sinusitis, and pulmonary infiltrates. Multiple organs can 
be affected including the heart, lungs, skin, gastrointestinal tract, kidneys, and nervous system 
(Keogh et al 2006, Holle and Gross 2009, Vaglio et al 2012). The mean age of diagnosis of 
EGPA is 48 years, with a gender ratio of approximately 1:1 (Pagnoux et al 2007); the 
incidence has been estimated as 1-4 per million per year (Lane et al 2005). Eosinophilic 
granulomatosis with polyangiitis pathophysiology remains only partly understood, but it is 
associated with a positive status for ANCAs usually directed against MPO or PR3 on enzyme-
linked immunosorbent assay in approximately 40% of patients (Holle and Gross 2009, Sinico 
et al 2005). Two different phenotypes of EGPA are described: ANCA positive and ANCA 
negative. Data show differences in clinical disease presentation based on ANCA status and 
indicate that ANCA-positive patients should be treated more aggressively (Sokolowska et al 
2014).
Before the use of corticosteroids for EGPA, more than 50% of patients died within 3 months 
of diagnosis; with the advance in treatment strategies, patient survival has been reported as 
> 90% at one year and 60% to 97% at 5 years (Baldini et al 2010).
The current approach to the management of EGPA is based on reduction of active 
inflammation, suppression of the immune response, and treatment of disease-specific and/or 
treatment-related complications. Systemic corticosteroid therapy is the cornerstone therapy for 
the treatment of EGPA patients. However, use of corticosteroids, particularly longer term, is 
associated with significant adverse effects, including weight gain, osteoporosis, 
hyperglycaemia, depression, and increased risk of infection, which can limit the treatment 
benefits (Poetker and Reh 2010). Furthermore, although remission can be achieved in a 
proportion of patients with corticosteroid therapy alone, addition of more potent 
immunosuppressive therapies (eg, azathioprine, methotrexate, or mycophenolate mofetil) to 
maintain remission is commonly required (Baldini et al 2010, Vaglio et al 2012, Dunogué et al 
2011, Holle and Gross 2009, Mukhtyar et al 2009a). In general, although the use of these 
treatments is effective for establishing remission, patients remain vulnerable to either the 
complications of long-term use of these therapies or the risk of relapse, particularly if the dose 
of corticosteroid or immunosuppressant is reduced or stopped. A relapse rate of 30% to 40% 
is reported, which increases with time (Busse et al 2019). Furthermore, recurrent relapse is 
considered to place the patient at risk of permanent tissue and/or organ damage secondary to 
the vasculitic process. Therefore, the key goal in the treatment of EGPA is to induce and 
maintain remission whilst reducing the burden of corticosteroid usage and other 
immunosuppressive therapies.

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Mepolizumab (NUCALA® 3) is a fully humanised mAb (Ig G1, IgG1κ mAb) that binds 
specifically to human IL-5 and thus blocks binding of human IL-5 to the alpha chain of the 
IL-5 receptor complex expressed on the eosinophil cell surface (Pavord et al 2012, Stein et al 
2006, Rothenberg et al 2008, Nair et al 2009). In the Phase III MIRRA study, 136 patients 
with relapsing or refractory EGPA were assigned to mepolizumab or placebo administered SC 
Q4W plus standard care for 52 weeks (Wechsler et al 2017). A significantly higher percentage 
of patients treated with mepolizumab were in remission at both Week 36 and Week 48 
compared to placebo (32% vs 3%). Remission was defined as BVAS of 0 and the receipt of 
prednisolone or prednisone at a dose of 4.0 mg or less per day. A total of 44% of the patients 
in the mepolizumab group, as compared with 7% of those in the placebo group, had an 
average daily dose of prednisolone or prednisone of 4.0 mg or less per day during Weeks 48 
through 52. Even so, only approximately half the patients treated with mepolizumab had 
protocol-defined remission (Wechsler et al 2017). Based on these data, mepolizumab has 
recently been approved in several countries as treatment for EGPA (Section 2.1).
Clinical benefit was defined post hoc in the MIRRA study as follows: remission at any time 
(2 definitions used), 50% or greater OCS dose reduction during Weeks 48 through 52, or no 
EGPA relapse. The 2 remission definitions were BVAS of 0 plus prednisolone or prednisone 
at a dose of 4.0 mg or less per day (main remission) or 7.5 mg/d or less (supportive 
remission). With mepolizumab versus placebo, 78% versus 32% of patients experienced 
clinical benefit 1, and 87% versus 53% of patients experienced clinical benefit 2 (both 
p < 0.001) (Steinfeld et al 2019).
2.2.2
Role of Interleukin-5 in Pathogenesis of EGPA
Interlukin-5 is the major hematopoietin regulating the life cycle of eosinophils (Clutterbuck et 
al 1989, Lopez et al 1988, Rothenberg and Hogan 2006). In EGPA, the mechanism of tissue 
injury is poorly understood, but the degree of blood and tissue eosinophilia appears to be 
associated with disease pathogenesis (Schnabel et al 1999). In a series of in vitro studies, it 
has been shown that circulating levels of IL-5 are increased in patients with active EGPA, that 
PBMCs are the likely source of elevated circulating IL-5 in the disease, and that T-cell 
activation is required for increased IL-5 release by PBMCs (Shonermarck et al 2000, Kiene et 
al 2001, Hellmich et al 2005, Hellmich et al 2003). Of particular interest with regard to the 
pathogenesis of EGPA and associated vasculitis is the ability of IL-5 to promote the adhesion 
of eosinophils to vascular endothelium and CC chemokine receptor 3-dependent migration of 
eosinophils from the vasculature (Shahabuddin et al 2000). Thus, the elevated production of 
IL-5 by PMBCs in EGPA may be relevant pathogenetically for the development of vasculitis 
by promoting transvascular migration and functional activation of eosinophils.
                                               
3 NUCALA is a registered trademark of the GlaxoSmithKline group of companies.

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2.2.3
Mechanism of Action of Benralizumab and Evidence Supporting 
Potential as a Treatment for EGPA
Benralizumab (FASENRA) is a humanised, afucosylated mAb (IgG1, IgG1κ). Benralizumab 
binds to the human IL-5Rα with high affinity and specificity. The IL-5 receptor is specifically 
expressed on the surface of eosinophils and basophils. The absence of fucose in the Fc domain 
of benralizumab results in high affinity for FcγRIII receptors on immune effector cells such as 
natural killer cells leading to depletion by apoptosis of eosinophils and basophils through 
enhanced antibody-dependent cell-mediated cytotoxicity (Humbles et al 2011, Kolbeck et al 
2010.
The direct eosinophil-depleting ability of benralizumab is effective in eosinophilic asthma 
(Bleecker et al 2016, Fitzgerald et al 2016) and in steroid-dependent asthma (Nair et al 2017). 
Benralizumab has also shown benefit in HES (Kuang et al 2019). Eosinophilic asthma is 
recognised as an important subphenotype of asthma, and asthma is a common feature across 
patients with EGPA and the main feature of the prodromal phase of EGPA (Baldini et al 
2010). Hypereosinophilic syndrome is a group of diseases with persistent blood eosinophilia 
and evidence of eosinophil-mediated end-organ damage. Although any organ system can be 
involved, HES commonly involves the skin, heart, lungs, gastrointestinal tract or central 
nervous system, and shares clinical and histologic features with EGPA (Baldini et al 2010). 
Eosinophilic granulomatosis with polyangiitis and HES have distinct but partly overlapping 
clinical and histologic features, including target organs (Wu et al 2018). Studies in asthma and 
HES therefore provide relevant evidence for the potential benefit of benralizumab’s 
eosinophil-depleting MoA in treating EGPA.
The safety and efficacy of benralizumab in patients with HES was evaluated in a single centre, 
Phase IIa, DB, placebo-controlled, investigator-initiated study (Kuang et al 2019). The 
primary objective of the study was to determine the efficacy of benralizumab in reducing 
eosinophilia at Week 12. Patients received SC benralizumab 30 mg or placebo monthly for a 
12-week DB period (Week 1 to 12), after which all patients received active benralizumab for a 
12-week open-label treatment period (Weeks 13 to 24) and a 24-week OLE period 
(Weeks 25 to 48). Tapering of background therapy was allowed in the OLE period of the 
study. The study population was 20 platelet-derived growth factor receptor alpha-negative 
HES patients with eosinophil counts of greater than or equal to 1000 cells/μL. The mean
baseline absolute eosinophil count was 2331 cells/μL in the benralizumab group and 
2535 cells/μL in the placebo group. One patient had a diagnosis of EGPA. Benralizumab 
depleted eosinophils at Week 12 compared with placebo: 9 of 10 patients treated with 
benralizumab had a 50% reduction in absolute eosinophil counts (the primary endpoint of the 
study) with the majority reaching almost complete depletion of eosinophil counts compared 
with 3 of 10 patients treated with placebo that met the primary endpoint. Benralizumab also 
resulted in near-complete depletion of eosinophils in the bone marrow and tissues in most 
patients at Week 12. The effect was sustained in most patients for 48 weeks. Eosinophil 

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reduction was associated with clinical improvement and the ability to taper background 
therapy, including OCS.
The results of this Phase IIa study of benralizumab in HES patients provide further evidence 
of benralizumab’s significant eosinophil-depleting capabilities and suggest that benralizumab 
may also be effective for the treatment of EGPA. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of benralizumab is 
provided in the Investigator’s Brochure.
2.3
Benefit/Risk Assessment
2.3.1
Benralizumab
Previous studies (Bleecker et al 2016, Fitzgerald et al 2016) have shown that the overall safety 
profile of benralizumab in severe asthma patients is similar to placebo for exposures up to 
approximately one year. The most commonly reported AEs included nasopharyngitis, asthma, 
and upper respiratory tract infections. Most AEs were mild to moderate in nature. Fewer 
patients in the benralizumab group reported SAEs compared with placebo. Longer-term safety 
studies have been conducted in asthma patients who completed one of the predecessor studies 
for up to an additional one year (adults) and 2 years (adolescents). In general, the safety 
results (Busse et al 2019) were commensurate with the predecessor studies.
Safety and tolerability data from the Phase IIa study of benralizumab in patients with HES 
(Kuang et al 2019) showed that benralizumab was well tolerated, with similar rates of AEs 
observed between active and placebo groups. In total, 238 AEs were reported during the DB 
treatment period. Total AEs, Grade 3 AEs, and the numbers of patients reporting an AE were 
similar between the benralizumab and placebo arms. No new safety signals for benralizumab 
were identified in this study in patients with HES, and the safety profile of benralizumab was 
similar to that in the asthma pivotal studies.
Development of ADA to benralizumab has been documented. Potential risks of developing 
ADA include decreased drug efficacy and hypersensitivity reactions (eg, anaphylaxis or 
immune complex disease). To date, no confirmed cases of immune complex disease have been 
observed and no appearance of a relationship between ADA and treatment-emergent AEs has 
been established.
Eosinophils are a prominent feature of the inflammatory response to helminthic parasitic 
infections, and the presence of infiltrating eosinophils has been circumstantially associated 
with a positive prognosis in certain solid tumours. Helminthic parasitic infections and 
malignancy will continue to be monitored as part of routine pharmacovigilance practices.

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Based on benralizumab’s MoA and evidence of benefit in other eosinophil driven diseases 
(asthma and HES), there is a potential for benralizumab to provide benefits in patients with 
EGPA. In addition, given the extensive safety data already available, the benefit risk profile in 
patients with EGPA is expected to be favourable, commensurate with that observed in the 
benralizumab asthma pivotal trials. Risk minimisation measures include exclusion of patients 
with diagnosed granulomatosis with polyangiitis, microscopic polyangiitis, or organ- or life-
threatening EGPA, untreated parasitic infection, a history of anaphylaxis to any biologic 
therapy, active or recent malignancy, and exclusion of pregnant women. Risk minimisation 
measures will be maintained during the conduct of this study, in conjunction with the 
performance of the AstraZeneca’s routine pharmacovigilance activities.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of benralizumab can be found in the Investigator’s Brochure.
2.3.2
Mepolizumab
The benefit/risk profile of mepolizumab is supported by the previously demonstrated increase 
in remission in patients with EGPA (Wechsler et al 2017) and known safety profile. No 
additional AEs were identified in the mepolizumab study in patients with EGPA compared to 
those reported in the mepolizumab severe asthma trials (refer to the mepolizumab core 
Reference Safety Information). Mepolizumab is currently approved for EGPA in several 
countries including the US, Canada, Japan, Australia, and Israel. In addition, mepolizumab is 
approved for severe asthma in US, the EU, and other countries.
Risk minimisation measures in this study, in respect of treatment with mepolizumab, are as 
listed above for benralizumab, in conjunction with the performance of routine 
pharmacovigilance activities.
3
OBJECTIVES AND ENDPOINTS
The objectives and endpoints for the DB treatment period and the OLE period of the study are 
presented in Table 9 and Table 10, respectively. 

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Table 9
Study Objectives – Double-blind Period
The following objectives/endpoints are for the double-blind period of the study 
Primary objective: 
Endpoint/variable:
To assess the durability of response to treatment with 
benralizumab compared with mepolizumab in patients 
with relapsing or refractory EGPA who are receiving 
standard of care therapy, assessed by the proportion of 
patients in remission at both Weeks 36 and 48
Primary endpoint: Proportion of patients with 
relapsing or refractory EGPA, achieving remission, 
defined as BVAS = 0 and OCS dose ≤4 mg/day (main 
remission definition) at both Weeks 36 and 48.
Supportive endpoint: Proportion of patients who have 
achieved remission defined by BVAS = 0 and OCS 
dose ≤ 7.5 mg/day (supportive remission definition) at 
both Weeks 36 and 48.
Secondary objectives:
Endpoint/variable:
To assess the efficacy of benralizumab compared with
mepolizumab on duration of clinical remission, 
defined as accrued duration in weeks where a patient 
achieves remission
Total accrued duration of remission for the following 
categories: 0 wk, > 0 to < 12 wk, 12 to < 24 wk, 24 to 
< 36 wk, ≥36 wk. Analysis will be repeated based on 
main and supportive remission definitions. 
To assess the efficacy of benralizumab compared with 
mepolizumab on time to first relapse 
Time from randomisation to first EGPA relapse, where 
relapse is defined as any of the following:
•
Active vasculitis (BVAS > 0); OR
•
Active asthma symptoms and/or signs with a 
corresponding worsening in ACQ-6 score; OR
•
Active nasal and/or sinus disease, with a 
corresponding worsening in at least one of the 
sino-nasal symptom questions;
warranting any of the following: 
!
An increased dose of OCS therapy to 
> 4 mg/day prednisolone total daily dose; 
OR
!
An increased dose or addition of 
immunosuppressive therapy; OR
!
Hospitalisation related to EGPA worsening.

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Table 9
Study Objectives – Double-blind Period
To assess the effect of benralizumab on corticosteroid 
dose required during Weeks 48 through 52 compared 
to mepolizumab 
Based on the average daily prednisolone/prednisone 
dose during Weeks 48 through 52:
•
Proportion of patients in each category: 0 mg; > 0 
to ≤4 mg; > 4 to ≤ 7.5 mg, and > 7.5 mg.
•
Proportion of patients in each category of percent 
reduction from baseline: no reduction or 
withdrawal from treatment; < 25% reduction; 25 
to < 50% reduction; 50 to < 75% reduction; 75 to 
< 100% reduction; 100% reduction.
•
Proportion of patients with ≥ 50% reduction from 
baseline.
•
Proportion of patients with 100% reduction from 
baseline.
•
Proportion of patients with ≤4 mg in average 
daily dose.
To assess the clinical benefit of benralizumab 
compared to mepolizumab
Proportion of patients who have achieved any clinical 
benefit when meeting any of the criteria below.
Proportion of patients who have achieved complete 
response when meeting all of the criteria below.
•
Remission (defined as BVAS = 0 and 
prednisolone/prednisone dose ≤ 4 mg/day) at any 
time during the double-blind treatment period
•
≥ 50% reduction in average daily 
prednisolone/prednisone dose during Weeks 48 
through 52
•
EGPA relapse free during the double-blind 
treatment period.
•
Analysis will be repeated for the supportive 
remission definition.
To assess the annualised relapse rate in patients 
receiving benralizumab compared to mepolizumab 
Annualised relapse rate
To assess the proportion of patients who achieve 
remission within the first 24 weeks and remain in 
remission for the remainder of the double-blind 
treatment period in patients receiving benralizumab 
compared to mepolizumab 
Proportion of patients who have achieved remission 
within the first 24 weeks and remained in remission 
for remainder of the double-blind treatment period. 
Analysis will be repeated based on main and 
supportive remission definitions.
To assess additional measures of the efficacy and 
health status/health-related quality of life in patients 
receiving benralizumab compared to mepolizumab
BVAS, VDI, pulmonary function testing, asthma 
symptoms (ACQ-6), sino-nasal symptoms (including 
SNOT 22 questionnaire), health-related quality of life 
(SF 36v2), PGIS, WPAI and blood eosinophil counts 
will be assessed as change from baseline over the 
52-week double-blind treatment period.
PGIC will be assessed as response proportions at each 
weekly assessment between Visits 2 and 4. 

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Table 9
Study Objectives – Double-blind Period
Safety objectives:
Endpoint/variable:
To assess the safety and tolerability of benralizumab 
compared to mepolizumab 
Safety and tolerability will be evaluated based on AEs, 
vital signs, physical exam, clinical laboratory, and 
ECG. 
Assessments related to AEs include:
•
Occurrence/frequency
•
Relationship to IP as assessed by the Investigator
•
Intensity 
•
Seriousness
•
Death
•
AEs leading to discontinuation of IP
•
Other significant AEs
To assess the pharmacokinetics and immunogenicity 
of benralizumab 
Serum benralizumab concentrations
Anti-benralizumab antibodies and neutralising 
antibodies
Exploratory objectives:
Endpoint/variable:
To assess the cumulative OCS use in response to 
treatment with benralizumab compared to 
mepolizumab
Cumulative OCS use, as measured by AUC for daily 
prednisolone/prednisone dose, over the 52-week 
double-blind treatment period
To evaluate the effect of benralizumab compared to 
mepolizumab on health care resource utilisation due to 
EGPA
Number of EGPA-related hospitalisations; length of 
hospital stay; ICU days; number of EGPA-related ER 
visits; number of EGPA-related outpatient visits (by
type); number of EGPA-related procedures/tests (by 
specific procedure/test) 
To evaluate the effect of benralizumab compared to 
mepolizumab on biomarkers of inflammation 
Biomarkers of inflammation, eg, CRP and ESR
To evaluate the effect of benralizumab compared to 
mepolizumab on biomarkers related to the MoA, 
eosinophilic inflammation and EGPA disease 
pathogenesis, as well as baseline predictors of 
response to benralizumab or mepolizumab.
Exploratory biomarkers in:
•
serum
•
whole blood
•
nasal secretions
•
tissue biopsies and sputum (mechanistic sub-
study only) 
To characterise the patient-reported experience and 
treatment benefits of benralizumab compared with 
mepolizumab through patient interviews
Patient interviews to characterise patient-reported 
experience and treatment benefits (sub-study)
ACQ-6, Asthma Control Questionnaire (6-item version); AE(s), adverse event(s); AUC, area under the curve; 
BVAS, Birmingham Vasculitis Activity Score; CRP, C-reactive protein; ECG, electrocardiogram; 
EGPA, eosinophilic granulomatosis with polyangiitis; ER, emergency room; ESR, erythrocyte sedimentation 
rate; ICU, intensive care unit; IP, investigational product; MoA, mechanism of action; OCS, oral corticosteroid; 
PGIC, Patient Global Impression of Change; PGIS, Patient Global Impression of Severity; 
PK, pharmacokinetics; SAE(s), serious adverse event(s); SF-36v2, Short Form 36-Item Health Survey (version 2, 
acute recall); SNOT-22, Sino-nasal Outcome Test-22; VDI, Vasculitis Damage Index; WPAI, Work Productivity 
and Activity Impairment Questionnaire; wk, week(s).

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Table 10
Study Objectives for Open-label Extension Period
The following objectives/endpoints are for the open-label extension portion of the study:
Objectives
Endpoint/variable:
To evaluate the effect of benralizumab on remission, 
relapse, and OCS use a
Remission, relapse (as defined in Table 9 c), OCS use
To assess patient reported outcomes in patients 
receiving benralizumab b
Asthma symptoms (ACQ-6), sino-nasal symptoms 
(including SNOT-22 questionnaire), health-related 
quality of life (SF-36v2) and WPAI
To assess the safety and tolerability of benralizumab a
Safety and tolerability will be evaluated in terms of 
AEs, vital signs, physical exam, clinical laboratory, 
and ECG 
Assessments related to AEs cover: 
•
Occurrence/frequency
•
Relationship to IP as assessed by the Investigator
•
Intensity 
•
Seriousness
•
Death
•
AEs leading to discontinuation of IP
•
Other significant AEs
To assess the pharmacokinetics and immunogenicity 
of benralizumab d
Serum benralizumab concentrations
Anti-benralizumab antibodies and neutralising 
antibodies
To evaluate the effect of benralizumab on health care 
resource utilisation due to EGPA b
Number of EGPA-related hospitalisations; length of 
hospital stay; ICU days; number of EGPA-related ER 
visits; number of EGPA-related outpatient visits (by 
type); number of EGPA-related procedures/tests (by 
specific procedure/test)
To assess biomarkers of inflammation b
Biomarkers of inflammation, eg, CRP and ESR 
To assess biomarkers related to the MoA of 
benralizumab, eosinophilic inflammation and EGPA 
disease pathogenesis b
Exploratory biomarkers in serum
a
Applicable to full duration of OLE 
b
Applicable to first year of OLE only 
c
Applicable to first year of OLE only. From the second year, the definitions of remission and relapse will be 
based on the Investigator’s overall clinical assessment.
d
Applicable to OLE Year 1-3.
ACQ-6, Asthma Control Questionnaire (6-item version); AE(s), adverse event(s); CRP, C-reactive protein; 
ECG, electrocardiogram; EGPA, eosinophilic granulomatosis with polyangiitis; ER, emergency room; 
ESR, erythrocyte sedimentation rate; ICU, intensive care unit; IP, investigational product; MoA, mechanism of 
action; OCS, oral corticosteroids; OLE, open-label extension; PK, pharmacokinetics; RNA, ribonucleic acid; 
SF-36v2, Short Form 36-Item Health Survey (version 2, acute recall); SNOT-22, Sino-nasal Outcome Test-22; 
WPAI, Work Productivity and Activity Impairment Questionnaire.

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4
STUDY DESIGN
4.1
Overall Design
This is a randomised, double blind, active-controlled, parallel group, multicentre 52-week 
Phase III study to compare the efficacy and safety of benralizumab 30 mg versus 
mepolizumab 300 mg administered by SC injection Q4W in patients with relapsing or 
refractory EGPA on corticosteroid therapy with or without stable immunosuppressive therapy.
The target population is adult female or male patients aged 18 years and above who have 
documented EGPA diagnosis plus documentation of at least 2 additional features of EGPA 
and a history of relapsing or refractory disease. In addition, potentially eligible patients will 
enter a screening period of up to 4 weeks (minimum of one week) and will be required to be 
on a stable dose of OCS ≥7.5 mg/day prednisolone/prednisone (but not > 50 mg/day), for at 
least 4 weeks prior to baseline (Visit 2) (see Appendix K for Belgium). If dose adjustment is 
necessary during the screening period, or the Investigator determines that the patient has not 
maintained a stable dose, the patient will be screen failed. Patients on immunosuppressive 
therapy must be on a stable dose for at least 4 weeks prior to baseline (Visit 2) and should 
remain on the same dose until the end of the DB period (if the patient does not enter the OLE) 
or until completion of the first 6 months of the OLE period (if the patient continues into the 
OLE). Dose reductions for safety reasons will be permitted. For full details on the study 
population and inclusion and exclusion criteria, refer to Section 5.
Approximately 140 eligible patients will be randomised 1:1 at baseline (Visit 2), to receive 
benralizumab or mepolizumab Q4W for a 52-week DB treatment period. Randomisation will 
be stratified by region (North America, Western Europe, Japan). A minimum of 
approximately 25% patients will be included in a mechanistic sub-study to explore the PD 
response and MoA of benralizumab compared to mepolizumab (Section 8.8.4). The number of 
patients with ANCA-positive status or an eosinophil count < 150 cells/μL (< 0.15 × 109/L) 
will be restricted to approximately 10% and 40%, respectively, of the total number of 
randomised patients. Approximately 45 patients will participate in a non-interventional 
interview to collect data on HRQoL and the patients’ experience during the DB portion of the 
study (Section 8.1.2).
Between baseline (Visit 2) and Week 4, patients will be required to maintain a stable oral 
prednisolone/prednisone dose of ≥7.5 mg/day (but not > 50 mg/day). If necessary, upward 
adjustments are permitted for clinical management of the patient. From Week 4 onward, if the 
patient’s BVAS = 0 their oral prednisolone/prednisone dose should be tapered downwards 
according to standard-of-care practice. A recommended tapering schedule is provided in 
Appendix H and enables a reduction in OCS dose every 2 weeks, with the intention of 
achieving a prednisone/prednisolone dose of 4 mg/day or less. For details on 
prednisolone/prednisone tapering, see Section 6.5.1.

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The final dose of the DB treatment period will be given at Week 48 and the DB treatment 
period will complete at Week 52.
All patients who complete the 52-week DB treatment period on IP may be eligible to continue 
into an OLE period. The OLE period is intended to allow each patient at least one year of 
treatment with open-label benralizumab 30 mg administered SC every fourth week (earlier 
enrolled patients may therefore be in the OLE for longer than one year). AstraZeneca may 
choose to extend the study depending on the overall development program and reserves the 
right of terminating the OLE early.
The primary database lock will occur after all randomised patients have been followed up for 
the 52-week DB treatment period. The study will remain blinded until the primary database 
lock. The primary analysis will include data from the DB period of the study (intention-to-
treat approach). Safety data from the open-label period available at the time of the primary 
database lock will also be reported. Additional analyses may be performed after the primary 
database lock to analyse the data that were not available in the primary analysis. The final 
database lock will occur after the last patient has completed at least one year in the OLE and 
when the end of the study has been declared. Data from the OLE period of the study will be 
presented in an addendum to the primary analysis CSR, and/or a separate OLE period CSR.
In this study, 2 definitions of EGPA remission will be investigated as: (i) main remission 
definition: BVAS = 0 plus OCS dose of prednisolone/prednisone ≤4 mg/day, and 
(ii) supportive remission definition: BVAS = 0 plus OCS dose of 
prednisolone/prednisone ≤7.5 mg/day. 
The primary efficacy endpoint is the proportion of patients who achieve EGPA main 
remission at both Week 36 and Week 48 of the DB period. The primary analysis is to 
demonstrate NI of benralizumab versus mepolizumab in terms of durability of response to 
treatment based on the primary endpoint of remission using a logistic regression model 
adjusted for treatment arm, baseline dose of prednisone, baseline BVAS, and region. If the 
primary analysis demonstrates NI, a formal test of superiority between benralizumab and 
mepolizumab will be assessed. In addition, to assess external validity of the study an indirect 
comparison of benralizumab to historic placebo will be evaluated using remission rate.
For full details of all objectives and endpoints for the DB period and the OLE period, refer to 
Section 3.
This study will be conducted at approximately 80 sites in 9 countries.
The general study design is summarised in Figure 2.

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Figure 2
Study Design 
BVAS, Birmingham vasculitis activity score; OCS, oral corticosteroids; OLE, open-label extension; Q4W, every 
4 weeks; SC, subcutaneous; V, Visit (number).
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (eg, 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study patients become infected with SARS-CoV-2 or similar pandemic 
infection) which would prevent the conduct of study-related activities at study sites, thereby 
compromising the study site staff or the patient’s ability to conduct the study. The investigator 
or designee should contact the study Sponsor to discuss whether the mitigation plans below 
should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study patients, maintain 
compliance with GCP, and minimize risks to study integrity.
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options: 

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∀
Obtaining consent/reconsent for the mitigation procedures (note, in the case of verbal 
consent/ reconsent the ICF should be signed at the patient’s next contact with the study 
site).
∀
Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened patients. The 
investigator should confirm this with the designated study physician. 
∀
Home or Remote visit: Performed by a site qualified HCP or HCP provided by a TPV.
∀
Telemedicine visit: Remote contact with the patients using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.
∀
At-home IP administration (would only be applicable during the OLE): Performed by a 
site qualified HCP, HCP provided by a TPV, or by the patients or the patient’s caregiver, 
if possible. Additional information related to the visit can be obtained via telemedicine. 
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to Appendix G.
4.2
Scientific Rationale for Study Design
As detailed in Section 2, the central role of eosinophilia in the pathophysiology of EGPA 
suggests that a direct eosinophil-depleting approach, as provided by benralizumab, may prove 
beneficial in the treatment of EGPA. In addition to benralizumab’s proven efficacy in 
eosinophilic asthma (Bleecker et al 2016, Fitzgerald et al 2016) and in steroid-dependent 
asthma (Nair et al 2017), the efficacy results of benralizumab in HES patients (Kuang et al 
2019) provide further evidence of benralizumab’s significant eosinophil-depleting capabilities 
and suggest that benralizumab will also be effective for the treatment of EGPA.
Key features of this study include: a 52-week DB active-controlled period; an adult study 
population with documented relapsing or refractory EGPA on corticosteroid therapy with or 
without stable immunosuppressive therapy; use of mepolizumab 300 mg SC Q4W as 
comparator to benralizumab 30 mg SC Q4W; and the definition of the proportion of patients 
who achieve remission at both Weeks 36 and 48 as the primary efficacy endpoint. These 
features are consistent with the mepolizumab Phase III EGPA study conducted in the EU and 
in RoW countries (Wechsler et al 2017); the labelled dosing regimen for mepolizumab in 
markets where it has been approved for treatment of patients with EGPA; general regulatory 
guidance for design of efficacy studies; and the outcomes of pre-Phase III regulatory 
interactions between AstraZeneca and the US FDA.
The DB portion of this study is designed to compare the efficacy and safety of benralizumab 
to mepolizumab while the OLE will primarily provide an opportunity to assess long-term 
safety and tolerability of benralizumab in this patient population.

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Fifty-two weeks of DB treatment is sufficient duration to observe EGPA remission and 
relapse based on the Phase III study of mepolizumab in a very similar population of patients 
with relapsing or refractory EGPA (Wechsler et al 2017).
The study sample size in this study is based on the assumption that mepolizumab and 
benralizumab each have a remission rate of 32% (as previously shown for mepolizumab 
[Wechsler et al 2017]); therefore, 140 patients will provide ~90% power to demonstrate NI 
with a NI margin of -25% at the 2.5% one-sided significance level. For the study to be 
positive, the lower 95% confidence limit for the difference between benralizumab and 
mepolizumab needs to be above the NI margin of -25%.
4.3
Justification for Dose
The dose of mepolizumab chosen, 300 mg SC Q4W is consistent with the labelled dosing 
regimen in markets where mepolizumab has been approved for EGPA and is the dose of 
mepolizumab studied in the Phase III study conducted in EU and RoW countries in patients 
with EGPA (Wechsler et al 2017).
Given it is not feasible to conduct formal dose ranging in EGPA (as it is a rare condition) and 
that depletion of eosinophils in the circulation as well as in the tissues of patients is considered 
critical for control of EGPA, the proposed dosing regimen for benralizumab in this study is 
30 mg SC Q4W. Key clinical information supporting this proposed dosing regimen is 
summarised below.
The approved dosing regimen of benralizumab in severe asthma is 30 mg administered Q4W 
for the first 3 doses, and then Q8W thereafter by SC injection. In the severe asthma studies, 
(SIROCCO [Bleecker et al 2016] and CALIMA [Fitzgerald et al 2016]), near complete 
depletion of blood eosinophils was observed in patients receiving benralizumab 30 mg at both 
the approved Q8W regimen and the Q4W regimen, with both regimens demonstrating 
acceptable safety profiles. However, patients with EGPA generally have a greater blood and 
tissue eosinophil burden than patients with severe asthma and are more akin to those observed 
in HES (Wu et al 2018). In an investigator-initiated Phase IIa study of patients with HES, 
benralizumab 30 mg Q4W was the regimen studied (Kuang et al 2019). The Q4W dose was 
effective in reducing blood and tissue eosinophilia in patients with several clinical subtypes of 
HES, with an acceptable safety profile. Thus, this more frequent regimen (30 mg Q4W) was 
selected as an appropriate Phase III dose to ensure blood eosinophil depletions in EGPA 
patients with higher eosinophil burden.
4.4
End of Study Definition
For the purpose of Clinical Trial Transparency, the definition of the end of the study differs 
under FDA and EU regulatory requirements:

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EU requirements define study completion as the last visit of the last subject for any protocol 
related activity.
FDA requirements define two completion dates:
∀
Primary Completion Date – the date that the final patient is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure 
with different completion dates, this term refers to the date on which data collection is 
completed for all of the primary outcomes.
∀
Study Completion Date – the date the final patient is examined or receives an intervention 
for purposes of final collection of data for the primary and secondary outcome measures 
and AEs (for example, last patient’s last visit), whether the clinical study concludes 
according to the pre-specified protocol or is terminated.
A patient is considered to have completed the study when he/she has completed his/her last 
scheduled visit/telephone contact.
As patients may be offered the opportunity to participate in an OLE of at least one year after 
completing the DB period of the study on IP, the end of study is initially planned to be when 
the last randomised patient completes one year in the OLE (approximately third quarter of 
2024).
However, as AstraZeneca may choose to extend the OLE period and reserves the right to 
terminate the OLE early (Section 4.1), this decision will determine when the end of the study 
is declared. Notification of closure of the study will be communicated to sites at least 
3 months in advance of the end of study, unless faster termination is warranted (eg, emergence 
of a safety concern).
After the end of the study, patients should be given standard of care therapy, at the discretion 
of the Investigator, per local practice.
See Appendix A 5 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.
To compare the efficacy and safety of benralizumab with mepolizumab, this study's 
population is intended to be consistent with the population studied in the mepolizumab 
MIRRA Phase III study conducted in EU and RoW countries in patients with EGPA 
(Wechsler et al 2017). Each patient should meet all the inclusion criteria and none of the 

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exclusion criteria for this study in order to be assigned/randomised to a study intervention. 
Under no circumstances can there be exceptions to this rule. Patients who do not meet the 
entry requirements are screen failures, refer to Section 5.4. 
In this protocol, enrolled patients are defined as those who sign informed consent. 
Randomised patients are defined as those who undergo randomisation and receive a 
randomisation number.
For procedures for withdrawal of incorrectly enrolled patients see Section 7.1.2.
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 apply. 
In addition, as some eligibility criteria cannot be confirmed at Visit 1, these must be verified 
at the end of the screening period (ie, at baseline [Visit 2]) prior to randomisation 
(Section 5.3).
Informed consent/age/gender
1
Provision of signed and dated, written ICF prior to any mandatory study specific 
procedures, sampling, and analyses. 
The ICF process is described in Appendix A 3.
2
Patient; males and females must be 18 years of age and older at the time of signing the 
ICF.
Type of patients and disease 
3
Patients who have documented EGPA diagnosis: patients who have been diagnosed 
with EGPA for at least 6 months before screening visit (Visit 1) date based on the history 
or presence of: asthma plus documented eosinophilia (> 1.0 × 109/litre and/or > 10% of 
leukocytes) plus documentation of at least 2 of the following additional features of 
EGPA:
(a) A biopsy showing histopathological evidence of eosinophilic vasculitis, OR 
perivascular eosinophilic infiltration, OR eosinophil-rich granulomatous 
inflammation
(b) Neuropathy, mono or poly (motor deficit or nerve conduction abnormality) 
(c) Pulmonary infiltrates, non-fixed 
(d) Sino-nasal abnormality 
(e) Cardiomyopathy (established by echocardiography or magnetic resonance imaging) 

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(f) Glomerulonephritis (haematuria, red cell casts, proteinuria) 
(g) Alveolar haemorrhage (by bronchoalveolar lavage) 
(h) Palpable purpura 
(i)
Positive test for ANCA immunofluorescence and/or positive test for MPO and/or 
PR3 antibodies
4
History of relapsing OR refractory disease defined as: 
Relapsing disease: Patients must have a history of at least one confirmed EGPA relapse 
(ie, requiring increase in investigator-initiated OCS dose, initiation/increased dose of 
immunosuppressive therapy or hospitalisation) within the past 2 years which occurred at 
least 12 weeks prior to screening (Visit 1) while receiving a dose of prednisolone (or 
equivalent) of ≥7.5 milligram per day (mg/day). 
Japan-only definition of relapsing disease: patients must have a past history of at least 
one confirmed EGPA relapse (ie, requiring increase in investigator-initiated OCS dose, 
initiation of IV prednisolone [or equivalent], initiation /increased dose of 
immunosuppressive therapy, initiation/increased dose of IV Ig or hospitalisation) within 
the past 2 years which occurred at least 12 weeks prior to screening (Visit 1) while 
receiving a dose of prednisolone (or equivalent) of ≥7.5 mg/day.
Refractory disease:
Either: Failure to attain remission within the 6 months prior to Visit 1 (BVAS 
[scale 0-63] = 0 and OCS dose ≤7.5 mg/day prednisolone or equivalent) following 
induction treatment with a standard regimen, administered for at least 3 months.
Note:
(a) Patients who have received CYC induction regimen may be included a minimum of 
2 weeks after the last dose of daily oral CYC, or 3 weeks after the last dose of pulsed 
IV CYC prior to baseline (Visit 2), if their total WBC is ≥4 × 109/L (tested at local 
laboratory if necessary) prior to randomisation. 
(b) Patients who have received an azathioprine, methotrexate, or mycophenolate mofetil 
induction regimen may be included if on a stable dose for at least 4 weeks prior to 
baseline (Visit 2). 
(c) Patients who have received an induction regimen comprising corticosteroids alone 
may be included only if they have failed to attain remission after 3 months of 
treatment and the corticosteroids dose is ≥15 mg/day prednisolone for the 4 weeks 
prior to baseline (Visit 2).
OR: Within 6 months prior to screening (Visit 1), recurrence of symptoms of EGPA (not 
necessarily meeting the protocol definition of relapse) while tapering OCS, occurring at 
any dose level ≥7.5 mg/day prednisolone or equivalent.

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5
Therapy with corticosteroids: The prescribed dose of oral prednisolone or prednisone 
must be stable (ie, no adjustment of the dose) and must be ≥7.5 mg/day but 
not > 50 mg/day) for at least 4 weeks prior to baseline (Visit 2). Stable doses of OCS 
other than prednisolone or prednisone may be acceptable, but must be discussed with the 
AstraZeneca study physician (see Appendix K for Belgium). 
6
Immunosuppressive therapy: If receiving immunosuppressive therapy (excluding CYC), 
the dosage must be stable for the 4 weeks prior to baseline (Visit 2). Note: The dose of 
immunosuppressive therapy must not exceed the maximal doses used in clinical practice.
7
ECG evaluation at screening (Visit 1): QTcF < 450 msec or QTcF < 480 msec for patients 
with bundle branch block 
#
The QTc is the QT interval corrected for heart rate according to Fridericia’s formula 
#
For purposes of data analysis, QTcF will be used as primary though data using both 
correction formulas will be collected and analysed.
#
The QTc should be based on averaged QTc values of triplicate ECGs obtained over a 
brief recording period.
#
QTcF will be used for patient eligibility.
Reproduction
8
Negative serum pregnancy test for WOCBP at screening (Visit 1)
9
WOCBP must agree to use a highly effective method of birth control (confirmed by the 
Investigator) from randomisation throughout the study duration and for at least 12 weeks 
after last dose of IP. Highly effective forms of birth control (those that can achieve a 
failure rate of less than 1% per year when used consistently and correctly) include: 
#
Combined (oestrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation- oral, intravaginal, or transdermal
#
Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, or implantable)
#
Intrauterine device
#
Intrauterine hormone-releasing system
#
Bilateral tubal occlusion
#
Sexual abstinence, ie, refraining from heterosexual intercourse (The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the patient.)
#
Vasectomised sexual partner (provided that partner is the sole sexual partner of the 
WOCBP study patient and that the vasectomised partner has received medical 
assessment of the surgical success) 

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∀
Women not of childbearing potential are defined as women who are either permanently 
sterilised (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are 
postmenopausal. Women will be considered postmenopausal if they have been 
amenorrhoeic for ≥12 months prior to the planned date of randomisation without an 
alternative medical cause. The following age-specific requirements apply:
#
Women < 50 years old will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatment and FSH levels in the postmenopausal range. Until FSH is documented to 
be within menopausal range, treat the patient as WOCBP.
#
Women ≥50 years old will be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous hormonal 
treatment.
Other
French patients: in France, a patient will be eligible for inclusion in this study only if 
either affiliated to or a beneficiary of a social security category.
5.2
Exclusion Criteria 
Patients should be excluded from the study if any of the following criteria apply:
Medical conditions
1
Diagnosed with granulomatosis with polyangiitis (previously known as Wegener’s 
granulomatosis) or microscopic polyangiitis.
2
Organ-threatening EGPA: organ-threatening EGPA as per the European League against 
Rheumatism criteria (Yates et al 2016), ie, organ failure due to active vasculitis, 
creatinine > 5.8 mg/dL (> 513 μmol/L) within 3 months prior to screening (Visit 1) and 
through randomisation (Visit 2).
3
Life-threatening EGPA: imminently life-threatening EGPA disease defined as any of 
the following within 3 months prior to screening (Visit 1) and through randomisation 
(Visit 2). 
#
Intensive care required 
#
Severe alveolar haemorrhage or haemoptysis requiring transfusion or ventilation or 
haemoglobin < 8 g/dL (< 80 g/L) or drop in haemoglobin > 2 g/dL (> 20 g/L) over a 
48-hour period due to alveolar haemorrhage
#
Rapidly progressive glomerulonephritis with creatinine > 2.5 mg/dL (> 221 μmol/L) 
or rise in creatinine > 2 mg/dL (> 177 μmol/L) over a 48-hour period
#
Severe gastrointestinal involvement, for example, gangrene, bleeding requiring 
surgery

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#
Severe central nervous system involvement
#
Severe cardiac involvement, for example, life-threatening arrhythmia, cardiac failure: 
ejection fraction < 20%, NYHA Class III/IV (NYHA 2012), acute myocardial 
infarction.
4
Malignancy: current malignancy, or history of malignancy, except:
#
Patients who have had basal cell carcinoma, localised squamous cell carcinoma of the 
skin or in situ carcinoma of the cervix are eligible provided that the patient is in 
remission and curative therapy was completed at least 12 months prior to screening 
(Visit 1).
#
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 the date 
informed consent was obtained
5
Liver disease: unstable liver disease (as defined by the presence of ascites, 
encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices or 
persistent jaundice), cirrhosis, and known biliary abnormalities (with the exception of 
Gilbert’s syndrome or asymptomatic gallstones)
6
Cardiovascular: patients who have severe or clinically significant cardiovascular disease 
uncontrolled with standard treatment including but not limited to:
#
Known ejection fraction < 30%, OR
#
Severe heart failure that meet NYHA Class IV (NYHA 2012), OR
#
Hospitalised in the 12 months prior to screening (Visit 1) for severe heart failure 
meeting NYHA Class III (NYHA 2012), OR
#
Angina diagnosed within 3 months prior to screening (Visit 1) and through 
randomisation (Visit 2).
7
Infectious disease: chronic or ongoing active infectious disease requiring systemic 
treatment.
8
Parasitic infection: a helminth parasitic infection diagnosed within 6 months prior to 
screening (Visit 1) and through randomisation (Visit 2) that has not been treated with or 
has failed to respond to standard of care therapy.
9
Hepatitis status: chronic stable hepatitis B and C (including positive testing for HBsAg 
or hepatitis C antibody), or other stable chronic liver disease are acceptable if patient 
otherwise meets eligibility criteria. Stable chronic liver disease should generally be 
defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, 
oesophageal or gastric varices, or persistent jaundice, or cirrhosis.
10 Immunodeficiency: A history of known immunodeficiency disorder including a positive 
HIV test.
11 History of known allergy, intolerance, or anaphylaxis to any biologic therapy or vaccine. 

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12 Known history of allergy or reaction to any component of the IP formulation.
13 Other concurrent medical conditions: patients who have known, preexisting, clinically 
significant endocrine, autoimmune, metabolic, neurologic, renal, gastrointestinal, hepatic, 
haematological, respiratory or any other system abnormalities that are not associated with 
EGPA and are uncontrolled with standard treatment. Any clinically significant abnormal 
findings in physical examination, vital signs, haematology, clinical chemistry, or 
urinalysis during screening/run-in period, which in the opinion of the Investigator, may 
put the 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.
Prior/concomitant therapy
14 Prohibited medications: patients receiving any of the following:
#
OCS: patient requires an OCS dose of > 50 mg/day prednisolone/prednisone in the 
4-week period prior to baseline (Visit 2)
#
IV, IM, or SC corticosteroids in the 4-week period prior to baseline (Visit 2)
#
Omalizumab within 130 days prior to screening (Visit 1)
#
CYC: oral CYC within 2 weeks prior to Baseline (Visit 2) and IV CYC within 
3 weeks prior to baseline (Visit 2).
#
Rituximab within 6 months prior to screening (Visit 1); in addition, the patient must 
have shown recovery of peripheral B-cell count to within the normal range. 
#
IV or SC immunoglobulin within 30 days prior to screening (Visit 1)
#
Interferon-∃within 6 months prior to screening (Visit 1)
#
Anti-tumour necrosis factor therapy within 12 weeks prior to screening (Visit 1)
#
Anti-CD52 (alemtuzumab) within 6 months prior to screening (Visit 1)
#
Any prior or current treatment with mepolizumab, reslizumab, dupilumab, or 
benralizumab either as a marketed or investigational biologic.
#
Receipt of any other marketed or investigational biologic products within 4 months 
or 5 half-lives prior to screening, whichever is longer.
Other exclusions
15 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
16 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.
17 Previous randomisation in the present study.

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18 Patient is currently participating in any other interventional clinical study (text addition 
for France (Appendix K): , with the exception of “registry”/ “cohort” trials which may 
include periodic biological sampling and/or patient questionnaires but in which no other 
un-licenced investigational product is administered).
19 For women only: Currently pregnant, breastfeeding, or lactating. Patients should not be 
enrolled if they plan to become pregnant during the time of study participation. A serum 
pregnancy test will be done for WOCBP at screening (Visit 1) and a urine pregnancy test 
must be performed for WOCBP at each treatment visit prior to IP administration.
20 Other laboratory parameter exclusions at screening (Visit 1) and on repeat testing (if 
applicable) prior to Visit 2:
#
Creatinine > 2.5 mg/dL (221 %mol/L)
#
WBC < 4 × 109/L
#
Platelet count < 120000/mm3
#
Haemoglobin < 8 g/dL (< 80 g/L)
21 Alcohol/substance abuse: a history (or suspected history) or alcohol misuse or substance 
abuse within 2 years prior to screening (Visit 1).
22 Other investigational non-biologic product: receipt of any investigational non-biologic 
product within 30 days or 5 half-lives prior to screening (Visit 1), whichever is longer.
23 Adherence: patients who have known evidence of lack of adherence to prescribed 
medications and/or ability to follow physician's recommendations. 
24 ALT or AST level ≥3 times the ULN confirmed during screening period, confirmed by 
repeated testing (if applicable) during screening period. Transient increase of AST/ALT 
level that resolves by the time of randomisation is acceptable if, in the Investigator’s 
opinion, the patient does not have an active liver disease and meets other eligibility 
criteria.
25 Any clinically significant abnormal findings in physical examination, vital signs, 
haematology, clinical chemistry, or urinalysis during screening/run-in period, which in 
the opinion of the Investigator, may put the 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. Any other medical illness that precludes study involvement
26 Receipt of blood products within 30 days prior to screening (Visit 1).
27 Receipt of live attenuated vaccines 30 days prior to screening (Visit 1).
5.3
Criteria to be Confirmed/Reconfirmed at Baseline (Visit 2) and 
Prior to Entry to OLE 
At the end of the screening period, study patients must fulfil the following additional criteria 
in order to be randomised to study treatment at baseline (Visit 2):

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5.3.1
Inclusion Criteria to be Confirmed/Reconfirmed at Baseline (Visit 2)
The following criteria must be verified prior to randomisation. 
∀
Corticosteroid and immunosuppressive therapy: oral prednisolone/prednisone 
(≥7.5 mg/day) and immunosuppressive therapy (if being taken) have been stable for a 
period of at least 4 weeks prior to baseline (Visit 2) (see Appendix K for Belgium). 
∀
Laboratory abnormality: no evidence of clinically significant abnormality in the 
haematological, biochemical or urinalysis screen at screening (Visit 1), as judged by the 
Investigator. 
Exception: Only for patients who have received a CYC induction regimen may be 
randomised a minimum of 2 weeks after the last dose of daily oral CYC, or 3 weeks after the 
last dose of pulsed IV CYC, if their total WBC is ≥4 × 109/L (tested at the local laboratory, if 
necessary; results must be available prior to baseline (Visit 2) and recorded only in the source 
documentation).
∀
Liver Function Tests: obtained at screening (Visit 1) or on repeat testing prior to Visit 2 
if applicable:
#
ALT < 3 × ULN
#
AST < 3 × ULN
#
Alkaline phosphatase ≤2.0 × ULN
#
Bilirubin ≤1.5 × ULN (isolated bilirubin > 1.5 × ULN is acceptable if bilirubin is 
fractionated and direct bilirubin < 35%).
∀
ECG over-read: no evidence of significant abnormality in the triplicate 12-lead ECG 
over-read from the screening visit (Visit 1).
∀
Refractory disease: 
#
Patients who have received an azathioprine, methotrexate, or mycophenolate mofetil 
induction regimen may be included if on a stable dose for at least 4 weeks prior to 
baseline (Visit 2).
#
Patients who have received an induction regimen comprising corticosteroids alone 
may be included only if they have failed to attain remission after 3 months of 
treatment AND the corticosteroid dose is ≥15 mg/day prednisolone for the 4 weeks 
prior to baseline (Visit 2).
5.3.2
Exclusion Criteria to be Confirmed/Reconfirmed at Baseline (Visit 2)
∀
Prohibited medications: patients receiving any of the medications listed in exclusion 
criterion 14 between screening (Visit 1) and baseline (Visit 2).
∀
Other laboratory parameter exclusions as defined in exclusion criterion 20 on repeat 
testing (if applicable) prior to Visit 2.

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5.3.3
Criteria to be Confirmed Prior to Commencing OLE at Visit 17
Patients that complete the DB period of the study on treatment may be eligible to continue 
into the OLE. If a patient had been randomised in error but the Investigator considers 
participation in the OLE to be safe and in the best interests of the patient, the Investigator 
should discuss the potential entry of the patient into the OLE with the AstraZeneca study 
physician. In order to confirm suitability to continue into the OLE at Visit 17, hepatitis status 
and immunodeficiency must be reconfirmed at Visit 16 (exclusion criteria 9 and 10, 
Section 5.2), and ECG (inclusion criterion 7, Section 5.1) at Visit 16.
5.4
Lifestyle Restrictions
Restrictions on strenuous exertion and dietary considerations are required prior to spirometry 
measurements, as described in Section 8.1.1.12.
Women of child-bearing potential must use a highly effective contraceptive method from 
randomisation throughout the study and for at least 12 weeks after last administration of the 
IP, as stated in inclusion criterion 9, Section 5.1.
Patients must abstain from donating blood, plasma, or platelets from the time of informed 
consent for 12 weeks after last dose of IP.
5.5
Screen Failures
Screen failures are defined as patients who signed the ICF to participate in the clinical study 
but are not subsequently, randomly assigned to Study treatment/entered in 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 from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any SAE.
These patients should have the reason for study withdrawal recorded as screen failure (ie, 
patient does not meet the required inclusion/exclusion criteria) in the eCRF. This reason for 
study withdrawal is only valid for screen failures and not randomised patients. 
5.5.1
Rescreening
Rescreening is allowed only once for a patient and is based on the criteria below:
If the reason for screen failure was transient (including but not limited to study-supplied 
equipment failure, unforeseen personal events that mandate missed screening visits, etc), 
patients may potentially be rescreened. These cases must be discussed with the AstraZeneca 
study physician prior to rescreening and documented in the Investigator study file.

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Rescreening of a patient for any other reason (eg, the OCS dose is not stable during run-in 
period) will also be allowed only upon approval of the AstraZeneca study physician and only 
once. A documented approval for rescreening should be filed in the Investigator study file.
Rescreened 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.
Rescreened patients should sign a new ICF. All procedures from the screening/run-in period 
should be repeated (with the exception of testing for HIV-1 and HIV-2, hepatitis B and C, and 
FSH).
For re-screening during a study disruptions due to cases of civil crisis, natural disaster, or 
public health crisis, see Section 4.1.1.
5.5.2
Withdrawal From Study Due to Recruitment Cap
In order to limit the total number of ‘ANCA-positive’ patients (ie, ANCA 
immunofluorescence and/or positive test for MPO and/or PR3 antibodies) in the trial, after 
approximately 10% of the total number of randomised patients are determined to be ANCA 
positive (based on PR3 or MPO positive result of assessment at screening [Visit 1]), further 
ANCA-positive patients will not be randomised into the study and will be considered screen 
failures. Disposition will be recorded as ‘Development of Study-Specific Withdrawal Criteria’ 
and the reason given as ‘withdrawn prior to randomisation due to ANCA +ve cap’.
In addition, in order to limit the total number of patients in the trial with a screening (Visit 1) 
eosinophil count of < 150 cells/μL (< 0.15 × 109/L), after approximately 40% of the total 
number of randomised patients with an eosinophil count of < 150 cells/μL (based on result of 
assessment at screening [Visit 1]) are randomised, further patients with an eosinophil count 
of < 150 cells/μL will not be randomised into the study and will be considered screen failures.
Disposition will be recorded as ‘Development of Study Specific Withdrawal Criteria’, and the 
reason given as ‘withdrawn prior to randomisation due to eosinophil cap’.
6
STUDY TREATMENT
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 patient according to the study 
protocol. Study treatment in this study refers to benralizumab, mepolizumab, placebo to 
benralizumab, and placebo to mepolizumab. Placebo to mepolizumab and placebo to 
benralizumab is used only to ensure blinding for the study treatments.
Investigational product will be administered Q4W from baseline (Visit 2) until Week 48 
(Visit 16) in a DB fashion. Those patients that complete the DB treatment period on IP, will 

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receive open-label benralizumab administered Q4W from Week 52 (Visit 17) onwards (until 
the end of the study or early discontinuation).
Investigational product administration should ideally occur at approximately the same time of 
day, throughout the study, within the same patient.
6.1
Treatments Administered
6.1.1
Investigational Products
All IPs will be manufactured in accordance with Good Manufacturing Practice. 
Study treatments are outlined in Table 11. Preparation, handling, storage, and accountability is 
covered in Section 6.2.
Table 11
Study Treatments
Treatment 1
Treatment 2
Study 
treatment 
name
Benralizumab
Placebo to 
mepolizumab a, b
(0.9% sodium 
chloride)
Mepolizumab a, b
Placebo to 
benralizumab
Dosage 
formulation
30 mg/mL 
solution for 
injection in APFS;
1 mL fill volume
Matching placebo: 
solutions for 
injection in 1 mL 
polypropylene 
syringes (3 syringes 
will be used on each 
dosing occasion). 
Injection volume per 
syringe is 1 mL.
3 × 100 mg vials of 
powder for solution 
for injection 
reconstituted into 
3 separate 1 mL 
polypropylene 
syringes for 
administration on 
each dosing 
occasion. Injection 
volume per syringe is 
1 mL.
Matching placebo 
solution for injection 
in APFS; 1 mL fill 
volume.
Route of 
administration 
SC injection
SC injection
SC injection
SC injection
Dosing 
instructions
Benralizumab 
active solution 
will be 
administered to 
patients by 
healthcare 
professionals, 
patients, or their 
caregivers SC 
using an APFS in 
this clinical study.
Placebo solution will 
be administered to 
patients by 
healthcare 
professionals SC 
using a syringe in 
this clinical study.
Mepolizumab active 
solution will be 
administered to 
patients by health 
care professionals SC 
using a syringe in 
this clinical study.
Placebo solution will 
be administered to 
patients by health 
care professionals SC 
using an APFS in this 
clinical study.

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Table 11
Study Treatments
Treatment 1
Treatment 2
Packaging and 
labelling
Refer to pharmacy 
manual
Refer to pharmacy 
manual
Refer to pharmacy 
manual
Refer to pharmacy 
manual
Provider
AstraZeneca
Study site
AstraZeneca
AstraZeneca
a
Mepolizumab is sourced locally in Japan.
b
Mepolizumab/placebo to mepolizumab in Japan will be administrated with a 2-3 mL polypropylene syringe 
and 21-27 gauge needle.
APFS, accessorised prefilled syringe; SC, subcutaneous(ly).
6.1.2
Medical Devices Including Combination Products with a Device 
Constituent
The AstraZeneca manufactured combination product with a device constituent provided for 
use in this study is:
∀
Benralizumab accessorised pre-filled syringe (status: investigational)
Other medical devices (not manufactured by or for AstraZeneca) provided for use in this study 
are:
∀
12-lead ECG/spirometer device 
Instructions for medical device use are provided in the Instructions for Use for the 
AstraZeneca manufactured combination product with a device constituent and the device 
manuals provided by the vendor for the third party device. 
All medical device deficiencies and device constituent deficiencies (including malfunction, 
use error, and inadequate labelling), hereafter referred to as medical device deficiencies, shall 
be documented and reported by the investigator throughout the clinical investigation (see 
Section 8.4.4) and appropriately managed by AstraZeneca.
6.2
Preparation/Handling/Storage/Accountability of Investigational 
Product
6.2.1
Preparation and Handling of IP
Up to and including on Visit 23, the IP will be administered at the study site on treatment 
visits and within visit windows as specified in the schedule in the SoA (Table 1, Table 2, 
Table 3, Table 4, and Table 5). After Visit 23, IP may be administered within the visit 
windows as described in Table 2, Table 3, Table 4, and Table 5 either on-site by an HCP or, 
optionally, at home or a remote location by the patient or their caregiver. Self-administration 
of the IP requires assessment and training by the Investigator (Section 6.2.3).

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Investigational product will be supplied to the site in a kit with either benralizumab or placebo 
to benralizumab or mepolizumab. Placebo to mepolizumab consists of 0.9% sodium chloride 
and is to be supplied and prepared by each study site. For further details, see the separate 
pharmacy manual.
Only patients randomised in the study may receive IP and only authorised site staff may 
supply or administer IP.
Prior to each IP administration:
∀
The Investigator/authorised delegate will assess the injection site as per the standards of 
medical care.
∀
For WOCBP, a serum pregnancy test will be performed at screening (Visit 1) and a urine 
pregnancy test before every subsequent dose of IP, except for those visits in the OLE 
which can be done remotely, where no pregnancy testing will be performed. 
Investigational product will be administered (and the patient randomised) only if the 
result of the test is negative.
6.2.2
Administration of IP at the Study Site
6.2.2.1
Injection Site Guidance
As 2 different IPs will be administered at each dosing visit during the DB period of the study, 
the anatomical injection site for each IP should be different in order to minimise risk of 
injection site reactions: For example, if benralizumab/placebo to benralizumab is administered 
in the arm, then mepolizumab/placebo to mepolizumab should be administered in the opposite 
arm, the thigh, or the abdomen. It is recommended that the site of injection is rotated such that 
the patient receives IP at a different anatomical site at each treatment visit. Investigational 
product should not be administered into areas where the skin is tender, bruised, erythematous, 
or hardened.
6.2.2.2
Benralizumab/Placebo to Benralizumab Administration
The benralizumab/placebo to benralizumab will be administered by the 
Investigator/authorised delegate using the supplied APFS into the upper arm, thigh, or the 
abdomen (Figure 3). It is recommended that the site of injection is rotated such that the patient 
receives IP at a different anatomical site at each treatment visit.

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Figure 3
Suggested Schema of Rotation of Injection Sites for Benralizumab/ 
Placebo to Benralizumab
6.2.2.3
Preparation and Administration of Mepolizumab/Placebo to Mepolizumab
The mepolizumab/placebo to mepolizumab will be reconstituted/prepared by an unblinded site 
pharmacist, or suitably qualified delegate, and administered by the Investigator/authorised 
delegate. Reconstitution of mepolizumab, and preparation of the placebo to mepolizumab is 
described in a separate pharmacy manual.
6.2.2.4
Administration of Mepolizumab/Placebo to Mepolizumab
Administer the mepolizumab/placebo to mepolizumab SC into the upper arm, thigh, or 
abdomen as three separate SC injections. It is recommended that the individual injections be 
administered at least 5 cm (approximately 2 inches) apart. 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.
6.2.2.5
After Investigational Product Administration
After IP administration at the study site, the patient should be observed in case of any acute 
drug reactions in line with clinical practice (Section 8.4.7).
See warnings and precautions information in the core Reference Safety Information for 
mepolizumab.

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6.2.3
Optional At-home or Remote-location Investigational Product 
Administration
To reduce patient burden and to allow flexibility, patients will have the option to 
self-administer IP or have IP administered by their caregiver at home or at a remote location 
using the APFS after Visit 23 (Week 76). The Investigator must evaluate the patient and/or 
their caregiver to ensure they are capable of performing the IP self-administration and provide 
them with appropriate training. All necessary supplies and instructions for administration and 
documentation of IP administration will be provided. 
After Visit 23, some visits do not include extensive on-site assessments and can optionally be 
performed as remote visits through telephone/telemedicine contact (see Table 2, Table 3, 
Table 4, and Table 5) for patients who opted for IP self-administration. IP kits for the remote 
visits may be dispensed starting from Visit 23 as described in Study Instructions for Self-
Administration of Investigational Product by the Patient and/or Caregiver. After Visit 23, 
on-site visits will occur as per SoA, and patients may be dispensed IP kits to perform 
self-administration in between. 
If the IP is administered by the patient or their caregiver, IP should be administered on a day 
of scheduled visit after all visit assessments are completed.
The Investigator or designee will conduct a telemedicine contact prior to IP 
self-administration to confirm that the patient does not have any contraindications for IP 
dosing. WOCBP will be asked about any concerns for pregnancy.
It is strongly recommended that the patient is contacted by the Investigator or qualified 
designee after the dose is administered, to evaluate for any potential acute reactions, in line 
with clinical practice. Any AEs reported by the patient should be recorded in source 
documents and entered in the eCRF.
Refer to the Study Instructions for Self-Administration of Investigational Product by the 
Patient and/or Caregiver for step-by-step guidance including Investigator assessment/training 
of patient and/or caregiver and drug accountability. 
The option of self-administration of IP will only be available in countries where allowed 
according to local regulations.
The site can at any time invite the patient for an on-site visit instead of an at-home visit or for 
an on-site unscheduled or flare visit, as necessary, and perform additional unscheduled 
assessments in case of medical need.

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6.2.4
Conditions Requiring Investigational Product Administration 
Rescheduling
If any of the following occur, the Investigator should not administer IP, and either reschedule 
the visit within the allowed visit window (Table 1, Table 2, Table 3, Table 4, and Table 5) OR
the dose of IP should be delayed or skipped, as considered appropriate by the investigator:
∀
The patient has an intercurrent illness that in the opinion of the Investigator may 
compromise the safety of the patient in the study (eg, viral illnesses).
∀
The patient, in the opinion of the Investigator, is experiencing an acute or emerging 
asthma exacerbation/EGPA relapse.
See Section 6.4 for further instructions on delayed or missed doses. It is recommended that the 
Sponsor study physician, or designee, be contacted in case of any questions.
6.2.5
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. Further details are provided in the separate 
pharmacy manual.
6.2.6
Accountability
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
An unblinded AstraZeneca site monitor will account for all study treatments received at the 
site, for unused study treatments, and for appropriate destruction of unused study treatments.
Any unused kits will be destroyed locally (for further details, refer to the pharmacy manual). 
Documentation of IP delivery and destruction should be maintained according to applicable 
AstraZeneca and institution procedures.
Further guidance and information for the final disposition of unused study treatment are 
described in the pharmacy manual provided to the sites. In the case of a malfunctioning 
benralizumab/placebo to benralizumab APFS/device, the site should contact the unblinded 
study monitor to initiate a product complaint process according to applicable guidelines.

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6.3
Measures to Minimise Bias: Randomisation and Blinding
6.3.1
Patient Enrolment and Randomisation - Double-blind Period
All patients will be centrally assigned to randomised study treatment using an IRT/RTSM. 
Before the study is initiated, the log-in information and directions for the IRT/RTSM will be 
provided to each site.
The Investigator(s) will:
At screening (Visit 1)
1
Obtain signed informed consent from the potential patient before any study-specific 
procedures are performed.
2
Assign the potential patient a unique enrolment number (which begins with an ‘E’) via 
the IRT/RTSM.
3
Confirm whether patient consented at screening (Visit 1) to participate in the mechanistic 
sub-study (applicable only for sites participating in mechanistic sub-study).
At baseline (Visit 2)
1
Determine patient eligibility for randomisation at baseline (Visit 2)
2
Confirm stable dose of OCS for at least 4 weeks before baseline (Visit 2) 
3
Confirm ANCA status ('positive' or 'negative') (Section 5.5.2)
4
Confirm eosinophil count < 150 or ≥150 cells/μL (Section 5.5.2)
5
Confirm whether patient consented to participate in the patient interview sub-study 
(applicable only for countries participating in patient interview sub-study)
6
Randomise the eligible patient at baseline (Visit 2) via the IRT/RTSM. The IRT/RTSM 
will assign the patient with a unique randomisation code.
7
Confirm Visit 2 on the handheld device prior to ePRO questionnaire completion by the 
patient. Ensure patients complete all baseline ePRO assessments.
Patients will be allocated to treatment arms in a 1:1 ratio. The randomisation will be stratified 
by region:
#
Patients recruited in North America 
#
Patients recruited in Japan
#
Patients recruited in Western Europe 
Randomisation codes will be assigned 
 in each stratum as patients become 
eligible for randomisation. The randomisation code will be assigned from a randomisation list 
PPD

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prepared by a computerised system provided by PAREXEL Informatics on behalf of 
AstraZeneca (AZRand). 
If a patient withdraws from the study, then his/her enrolment/randomisation code cannot be 
reused. Withdrawn patients will not be replaced.
6.3.2
Methods for Ensuring Blinding – Double-blind Period
The first 52 weeks of this study is a DB design: AstraZeneca staff involved in the study, the 
patients, and the Investigators involved in the treatment of patients or in their clinical 
evaluation and monitoring of the patients will not be aware of the treatment allocation.
Placebo to benralizumab solution will be visually matched with benralizumab solution. 
Placebo to mepolizumab solution will be visually matched with mepolizumab solution.
All packaging and labelling of the IP will be done in such way as to ensure blinding for all 
AstraZeneca and investigational site staff.
Placebo to mepolizumab (0.9% sodium chloride) will prepared and dispensed by the study site 
using labels provided by the unblinded site pharmacist, for labelling instructions see the 
pharmacy manual.
Due to the need to reconstitute the mepolizumab shortly before administration, and for the 
study sites to supply, and prepare the placebo to mepolizumab, each site will need an 
appropriately qualified unblinded pharmacist/suitably qualified delegate to prepare IP during 
the DB period of the study. The unblinded pharmacist/delegate must not communicate with 
AstraZeneca, the Investigator, or any other site staff about the patient treatment allocation. An 
AstraZeneca unblinded site monitor will perform IP accountability. In the event that the 
treatment allocation for a patient becomes known to the Investigator or other study staff 
involved in the management of study patients or needs to be known to treat an individual 
patient for an AE, AstraZeneca staff must be notified promptly by the Investigator before 
unblinding (if possible).
The information in the randomisation list will be kept from other personnel involved in the 
conduct of the study in a secure location until the end of the study. No other member of the 
extended study team at AstraZeneca, or any Contract Research Organisation handling data, 
will have access to the randomisation scheme during the conduct of the study.
6.3.2.1
Maintaining the Blind to the Patient’s Blood Eosinophil Counts
While not entirely specific, patients on both benralizumab and mepolizumab treatment are 
expected to have lower blood eosinophil counts, but the degree of depletion may be different. 
In order to mitigate potential unblinding on this basis, per protocol haematology will be run by 
the central laboratory. From baseline (Visit 2) until the second visit of the OLE, Week 56 

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(Visit 18), eosinophil, basophil and monocyte counts will be redacted from any central 
laboratory reports sent to investigative sites to prevent the Principal Investigator/designee 
from possibly deducing the 'eosinophil + basophil + monocyte' contribution to the complete 
blood count. If the Investigator orders any local safety laboratory assessments, the requested 
tests should be restricted to the question at hand. For example, if haemoglobin is desired the 
Investigator should avoid ordering a complete blood cell count with differential count.
6.3.2.2
Handling of Clinical Laboratory Results Obtained During the Double-blind 
Period but Ordered Outside of the Clinical Trial
During the DB period of the study until Week 56 (Visit 18), 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 (eg, 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.
6.3.2.3
Maintaining the Blind to the Patient’s Induced Sputum Cell Count Analysis –
Double-blind Period
For patients who consent to participate in the optional mechanistic sub-study, the induced 
sputum analysis will be run by the central laboratory. 
Except for the Visit 2 sputum cell count, results will not be reported back to the site until after 
the primary database lock.
6.3.3
Methods for Unblinding – Double-blind Period
The IRT/RTSM will provide the IP kit identification number(s) to be allocated to the patient at 
each dispensing visit to the unblinded site pharmacists/delegate. Blinded and unblinded access 
and notifications will be controlled using the IRT/RTSM. Investigators will remain blinded to 
each patient’s assigned study treatment until the primary database lock. To maintain this blind, 
an otherwise uninvolved third party (site personnel, eg, pharmacist or qualified delegate) will 
be unblinded and responsible for the reconstitution and dispensation of all study treatment and 
will endeavour to ensure that there are no differences in time taken to dispense following 
randomisation.
The unblinded pharmacist/delegate’s study-related activities will be monitored by unblinded 
site monitors, all of whom will have no further role in the management of study patients, or 
data collection, and will not have access to the study database.

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Detail on how to unblind a patient’s treatment allocation will be described in the IRT/RTSM 
user manual provided to each study site. The treatment code should not be broken except in 
medical emergencies when the appropriate management of the patient requires knowledge of 
the treatment randomisation. The Investigator should document and report 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. Randomisation 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.
6.3.4
Open-label Extension Period – Benralizumab Administration Only
Patients will keep the same E-Code in the OLE as assigned in the DB period of the study. 
Open-label IP administration will begin at Week 52 (Visit 17). The IRT/RTSM will continue 
to allocate IP kit number for each dosing visit of the OLE. 
6.4
Treatment Compliance
The administration of all study treatments (both in the DB and OLE period of the study) 
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 CSP.
Investigational product will be administered at the study site on treatment visits, at
approximately the same time of day as administered at baseline (Visit 2), and within visit 
windows as specified in the SoA (Table 1, Table 2, Table 3, Table 4, and Table 5). Any 
change from the dosing schedule (dose interruptions or dose discontinuations) should be 
recorded in the eCRF. It should be noted that dose reductions are prohibited. It is 
recommended that the Sponsor study physician, or designee, be contacted in case of any 
questions.
Investigational product dosing should only occur within the allowed visit windows specified 
in the SoA (Table 1, Table 2, Table 3, Table 4, and Table 5). Conditions requiring re-
scheduling of IP administration are described in Section 6.2.4. Subsequent doses should be 
scheduled according to the original schedule (counted from baseline (Visit 2).
When IP dosing needs to be postponed, it is recommended that all scheduled treatment visit 
procedures (except for IP administration) are still performed within the visit window.
Re-scheduled IP dose can then be administered at an unscheduled visit. Vital sign 
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be performed at this visit. It may also include remaining visit procedures (not performed at the 
scheduled visit) and additional assessments as deemed necessary by the Investigator.
If the visit procedures cannot be conducted within the window (eg, the patient is unable to 
attend the study site), then the entire visit will be re-scheduled along with IP dose.
If a dose is significantly delayed, it is recommended to keep at least a 2-week interval before 
the next dose. If a postponed dose overlaps with the next treatment visit window, the 
postponed dose will be skipped, and the next dose of IP given at the regularly scheduled visit. 
The visit schedule will always be calculated from randomisation visit date.
If a patient misses more than 2 doses of IP (consecutively or non-consecutively) at any time 
within a calendar year, it is strongly recommended that a conversation between the 
Investigator and the AstraZeneca study physician takes place to review the patient's adherence 
to treatment and decide on the patient's further disposition.
The date and time of all IP administrations, as well as any delayed or missed doses, should be 
recorded in the appropriate section of the eCRF.
6.5
Concomitant Therapy
The Investigator must be informed as soon as possible about any medication(s) 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
For corticosteroids (prednisolone/prednisone) and immunosuppressive therapy, the dose must 
be recorded as well as all dose changes (see Appendix K for Belgium). Specific guidance on 
the dose /adjustment of dose of OCS is provided in Section 6.5.1. Patients will be required to 
record the dose of prednisolone/prednisone taken each day during the DB period on an 
electronic diary (ePRO device). During the first year of the OLE, the frequency of recording 
OCS use in the electronic diary will be reduced to weekly recall.
The following medication(s) are restricted as indicated in Table 12:

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Table 12
Restricted Medications
Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which it is allowed )
Inactive/killed vaccinations (eg, inactive influenza)
Not allowed within the 7 days before or within 7 days after 
any IP dosing study visit
Allergen immunotherapy
Allowed if on stable therapy started 30 days prior to V1; 
no change during the treatment period
Immunosuppressive therapy (see Section 6.5.2)
Patients who have received a methotrexate, azathioprine, or 
mycophenolate mofetil induction regimen may be included 
if on a stable dose for at least 4 weeks prior to baseline 
(V2). If on immunosuppressive therapy, the dosage must 
be stable for the 4 weeks prior to baseline (V2) until the 
end of the double-blind period (if the patient does not enter 
the OLE), or until completion of the first 6 months of the 
OLE period (if the patient continues into the OLE). Dose 
reductions for safety reasons will be permitted). Note: The 
dose of immunosuppressive therapy must not exceed the 
maximal doses used in clinical practice. 
The following maximal doses are allowed:
Azathioprine: 250 mg/day
Methotrexate: 25 mg/week (PO or SC)
Mycophenolate mofetil: 3000 mg/day
Mycophenolic acid: 1440 mg/day
Therapy with oral corticosteroids
Patient must be on stable dose of oral prednisolone or 
prednisone of ≥7.5 mg/day (but not > 50 mg/day for at 
least 4 weeks prior to baseline (V 2). Tapering may occur 
starting at Week 4 as detailed in Section 6.5.1 and 
Appendix H.
Live attenuated vaccines
Not allowed from 30 days prior to screening (V1), during 
the treatment period, and for 12 weeks after the last dose of 
the IP
Blood products 
Not allowed from 30 days prior to screening until 
randomisation. May be allowed during the study for the 
treatment of co-morbidities for which no alternative 
treatment is available.
Marketed biologic products
Generally disallowed with the exception for the treatment 
of co-morbidities for which no alternative treatment is 
available. The patient must be on stable therapy at the start 
of and throughout the study. A discussion with the 
AstraZeneca study physician should take place before 
including the patient in the study.
IP, investigational product; OLE, open-label extension; PO, oral; SC, subcutaneous(ly); V, visit (number).
The following medications are not permitted prior to Screening (Visit 1) or during the study in 
accordance with the following specified washout periods (Table 13):

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Table 13
Prohibited Medications With Defined Washout Periods before Screening 
(Visit 1)
Prohibited medication/class of drug
Washout period
Mepolizumab, benralizumab, dupilumab and 
reslizumab
Previous receipt either as a marketed or investigational 
biologic at any time prior to Visit 1
Omalizumab
130 days 
Rituximab
6 months prior to screening (in addition, the patient must 
have shown recovery of peripheral B-cell count to above 
the lower level for the normal reference limit or above pre-
rituximab [first treatment] level). 
IV or SC immunoglobulin
30 days
Interferon-α
6 months 
Anti-tumour necrosis factor therapy
12 weeks
Anti-CD52 (alemtuzumab)
6 months
IV, intravenous; SC, subcutaneous.
In addition, the following medications are also prohibited during the study (with washout 
period noted below as applicable):
∀
IV, IM, or SC corticosteroid therapy: Prohibited during the 4 weeks prior to baseline 
(Visit 2). Applicable for DB only.
∀
CYC: Patients who have received CYC induction regimen may be included a minimum 
of 2 weeks after the last dose of daily oral CYC, or 3 weeks after the last dose of pulsed 
IV CYC prior to baseline (Visit 2), if their total WBC is ≥4 × 109/L (tested at local 
laboratory if necessary) prior to randomisation.
∀
Other investigational agents (biologic or non-biologic): Investigational applies to any 
drug not approved for sale in the country in which it is being used.
∀
Acetaminophen: Prohibited in patients with acute viral hepatitis.
∀
Receipt of any non-biologic investigational product within 30 days or 5 half-lives prior to 
screening, whichever is longer
In the event a prohibited medication is used, a conversation between the Investigator and the 
AstraZeneca study physician should take place to determine whether continuation on IP or 
discontinuation of IP is in the best interest of the patient.
6.5.1
Oral Corticosteroids and Tapering
The background medication OCS (prednisolone/prednisone) is not regarded as an IP but may 
be provided/reimbursed by AstraZeneca according to local regulations, in order to ensure 
access to this concomitant therapy:

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∀
Patients already on prednisone/prednisolone at screening (Visit 1) can continue their 
current background prednisone/prednisolone (patients may be reimbursed according to 
local regulations), OR 
∀
Patients not already taking prednisone/prednisolone at screening (Visit 1) (ie, patients 
taking another OCS for management of EGPA) must switch to an equivalent 
prednisone/prednisolone dose (may be provided by the study site/AstraZeneca or 
reimbursed according to local regulations) and remain on a stable dose for 4 weeks prior 
to baseline (Visit 2). Oral corticosteroids other than prednisolone or prednisone may be 
acceptable but must be discussed with the AstraZeneca study physician.
Protocol requirements specified in Section 5.1 and Section 5.3.1 must be adhered to, 
regardless of the source of prednisone/prednisolone (see Appendix K for Belgium).
Between baseline (Visit 2) and Week 4 (Visit 4), patients will be required to continue their 
stable OCS dose (if necessary, upward adjustments are permitted for clinical management of 
the patient). From Week 4 post-baseline (Visit 4) onwards if the patient’s BVAS = 0 their oral 
prednisolone/prednisone dose should be tapered downwards according to standard of care 
practice. If the BVAS ≠0, the Investigator may taper the patient’s OCS downwards at his/her 
clinical discretion. Use of daily or alternate-day dosing with prednisolone/prednisone is 
acceptable. For alternate-day dosing the daily dose will be considered to be equivalent to half 
the alternate-day dose (eg, 5 mg taken on alternate days is equivalent to a 2.5 mg/day daily 
dose). A recommended tapering schedule, as provided in Appendix H, enables a reduction in 
OCS every 2 weeks, with the intention of achieving a prednisolone/prednisone dose of 
4 mg/day or less. 
Once a patient has achieved a dose of 4 mg/day prednisolone/prednisone, the Investigator 
should continue tapering downwards, if clinically warranted at dose increments of 0.5 to 
1.0 mg every 2 weeks. However, upward adjustment in the dose of OCS is permitted within 
the 0 to 4.0 mg range without necessarily being defined as a relapse. This approach recognises 
that some patients on long-term OCS are relatively resistant to complete discontinuation of 
therapy and are vulnerable to precipitation of Addisonian symptoms. 
The possibility of acute adrenal insufficiency should be considered, according to the guidance 
in Appendix I, in any acutely unwell patient undergoing withdrawal of chronic systemic 
corticosteroid treatment. Assessment of hypothalamic-pituitary-adrenal axis integrity may be 
performed, according to standard of care, at the discretion of the Investigator.
The minimally effective dose of OCS in each patient will be defined as the dose of 
prednisolone/prednisone one step above the dose at which the first relapse occurs. Where the 
patient has achieved a dose of OCS of 0 to 3.5 mg, the minimally effective dose will be 
defined as 4.0 mg/day prednisolone/prednisone. The intention of defining the minimally 
effective OCS dose is to provide information to the Investigator for use during any subsequent 

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tapering. This will reduce the likelihood that a patient will experience a second relapse during 
the study, and therefore balances the efficacy objectives of the study with patient safety.
6.5.2
Other Concomitant Treatment
Use of immunosuppressive therapy (eg, methotrexate, azathioprine, mycophenolate mofetil) 
will be permitted during the study as long as the dosage remains stable from screening until 
the end of the DB period (if the patient does not enter the OLE), or from screening until 
completion of the first 6 months of the OLE period (if the patient continues into the OLE). 
Reduction in the dose for safety reasons, with a return to the original dose, where possible, is 
permitted. After completion of the first 6 months of the OLE, a decrease in dose or 
discontinuation of immunosuppressant is allowed at the Principal Investigator’s discretion. 
In the event immunosuppressive therapy for EGPA is initiated or the dose increased during 
the study, then study treatment should be discontinued and, where possible, the patient 
continue to be followed up as per protocol until the end of DB period as per Section 7.1.1.
Use of inhaled and topical steroids will be permitted throughout the study. 
In case of acute illness, medication other than that described above, which is considered 
necessary for the patient’s safety and well-being, may be given at the discretion of the 
Investigator and recorded in the appropriate sections of the CRF.
It is recommended that patient should not receive allergen immunotherapy on the same day as 
the IP administration.
6.6
Dose modification
Modification of the dose (benralizumab or mepolizumab) is not permitted. Management of 
missed doses is covered in Section 6.4.
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.
7
DISCONTINUATION OF TREATMENT AND PATIENT 
WITHDRAWAL
7.1
Discontinuation of Study Treatment
Discontinuation from IP does NOT automatically lead to a complete withdrawal from the 
study. Patients discontinuing from IP are strongly encouraged to continue in the study up to 
the study completion as described in Section 7.1.1. Patients may be discontinued from IP in 
the following situations:

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1
Patient decision. The patient is at any time free to discontinue treatment, without 
prejudice to further treatment. The patient should always be asked about the reason(s) and 
presence of any AEs.
2
AE that in the opinion of the Investigator contraindicates further dosing
3
Severe non-compliance with the CSP
4
Risk to the patient as judged by the Investigator or AstraZeneca
5
IP unblinding
6
Development of any study specific criteria for discontinuation:
#
Anaphylactic reaction to the IP requiring administration of epinephrine
#
Development of helminth parasitic infestations requiring hospitalisation
#
A respiratory-related event requiring invasive mechanical ventilation
#
Increasing the dose of, or initiating, immunosuppressive therapy for EGPA
#
Patient experiences one organ-threatening or life-threatening EGPA relapse
If any of the following criteria are met, IP should be withheld, and a conversation between the 
investigator and Sponsor study physician/ designee is to take place to determine whether 
continuation on IP or discontinuation of IP will be in the best interest of the patient, and 
whether the issue can be mitigated by postponing or skipping the dose.
See the SoAs (Table 1, Table 2, Table 3, Table 4, Table 5, and Table 6) and Section 7.1.1
(IPD visit) for data to be collected at the time of IP discontinuation and for any further 
evaluations that need to be completed.
7.1.1
Procedures for Early Discontinuation of Study Treatment and at End 
of Study
A patient that decides to discontinue IP should always be asked about the reason(s) and the 
presence of any AEs. The reason for discontinuing treatment and the date of last IP 
administration should be recorded in the eCRF. Patients permanently discontinuing IP 
administration should be given locally available standard of care therapy, at the discretion of 
the Investigator. 
Discontinuation of IP will be registered in IRT/RTSM system.
See the SoA (Table 1, Table 2, Table 3, Table 4, Table 5, and Table 6) for data to be collected 
at the time of treatment discontinuation and for any further evaluations that need to be 
completed.

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Note: The EOT visit is only used following the last dose of IP when AstraZeneca declares the 
end of the study (Section 4.4). The IPD visit is used in all other cases when a patient 
discontinues IP.
7.1.1.1
Early Discontinuation of Study Treatment
All patients who prematurely discontinue IP (during either the DB period or OLE period) 
should return to the study site for an IPD visit within 4 weeks (± 7 days) after the last dose of 
IP for procedures described in Table 1, Table 2, Table 3, Table 4, Table 5, and Table 6. The 
IPD visit replaces the nearest scheduled visit after IP discontinuation. Reasons for patients not 
electing to go into the OLE will be collected.
After the IPD visit, the prohibited medications in Section 6.5 will no longer apply.
IPD during double-blind treatment period
At the IPD visit, the patient will be offered the following options for further FU:
∀
Patients are encouraged to return for all scheduled site visits, but without IP 
administration. For patients who are willing to continue with scheduled visits, the next 
visit after IPD will be conducted as per SoA until the last DB period visit at Week 52 
(Visit 17). 
∀
If the patient is unwilling/unable to attend the scheduled clinic visits until end of the DB 
period, he/she will be offered monthly telephone contact instead and will be encouraged 
to attend the last DB period visit (Visit 17) at the study site, if feasible. During telephone 
contact, the Investigator will collect information about concomitant medications, 
including OCS use, EGPA relapse, and AE/SAEs (Section 8.3). During this time, all 
ePRO assessments will continue at home.
IPD during OLE period
∀
Patients who prematurely discontinue IP during the OLE period of the study will attend 
an IPD visit at 4 weeks (± 7 days) after last dose of IP, after which the patient exits the 
study. The ePRO device will be returned at the IPD visit.
7.1.1.2
Discontinuation of Treatment on Notification of Closure of Study
The following visit should be performed (Table 2, Table 3, Table 4, Table 5, and Table 6, 
dependent on when notification of study closure occurs) for all ongoing patients within 
3 months of notification from AstraZeneca of closure of the study (Section 4.4):
∀
EOT visit: within 4 weeks (± 7 days) after the last dose of IP

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7.1.2
Procedures for Handling Incorrectly Enrolled or Randomised Patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
randomised or receive IP. 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 randomised and must 
be withdrawn (screen failed) from the study.
Where a patient does not meet all the eligibility criteria, but is randomised in error, or 
incorrectly started on IP, the Investigator should inform the AstraZeneca study physician 
immediately, and a discussion should occur between the AstraZeneca study physician and the 
Investigator regarding whether to continue or discontinue the patient from IP. 
If the agreed decision is to discontinue IP, patients should be encouraged to complete an IPD 
visit (Section 7.1.1.1).
The decision to discontinue/continue IP must be appropriately documented, including 
rationale, particularly if the agreed decision is to continue IP treatment.
7.2
Lost to Follow-up
A patient will be considered potentially lost to FU if he or she fails to return for scheduled 
visits and is unable to be contacted by the study site.
To prevent patients being lost to FU, it is recommended that the study sites maintain up-to-
date patients’ contact details, including next of kin or other emergency contacts (if allowed by 
national regulation).
The Investigator should educate the patient on the importance of maintaining contact with the 
Investigator study site throughout the study. 
The following actions must be taken if a patient fails to return to the clinic for required study 
visits:
∀
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.
∀
Repeated attempts must be made to regain contact with the patient or next of kin by, eg, 
repeat telephone calls, emails, and certified letter. 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.
A patient will be classified as lost to FU only if he/she has failed to return for the required 
study visits and his/her vital status remains unknown at the end of the study, despite all above 

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listed efforts. For the primary analysis purposes, a patient will be classified as lost to FU if 
he/she has failed to return for the required study visits and his/her vital status remains 
unknown at the time of primary database lock.
7.3
Withdrawal From the Study
A patient may withdraw from the study (eg, withdraw consent), at any time (IP and
assessments) at his/her own request, without prejudice to further treatment. 
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AE. It is the Investigator’s responsibility to evaluate the patient fully upon discontinuation 
or withdrawal to ensure that the patient receives appropriate treatment according to his/her 
clinical status/condition. An IPD visit is essential to collect as much data as possible for the 
patient as per IPD visit described in SoA (Table 1, Table 2, Table 3, Table 4, Table 5, and 
Table 6). The withdrawal visit (IPD assessments) should take place as soon as the patient 
notifies the Investigator/delegate of intent to withdraw consent, without the need to wait until 
4 weeks after the last dose. The patient will return all study supplied equipment including the 
ePRO device.
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.
If the patient only withdraws consent for the retention of biological samples (blood, nasal, 
sputum, urine, etc.) for future exploratory use (eg, DNA, study of biomarkers of EGPA, 
identifying potential new drug targets for EGPA, or for assay development purposes), the 
patient will not be withdrawn from the study.
Withdrawal of consent from the study must be ascertained and documented by the Investigator 
and recorded in the eCRF.
7.3.1
Discontinuation or Suspension of the Whole Study Program
If AstraZeneca decides to prematurely terminate or suspend the study, the Investigator and 
regulatory authorities should receive written notification of the reasons for the premature 
termination or suspension. The Investigator will immediately notify the decision to the 
patients and, if relevant, give appropriate medical treatment, take necessary measures, and 
document these in the source notes.

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8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA (Table 1, Table 2, Table 3, 
Table 4, Table 5, and Table 6).
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 (Table 1, 
Table 2, Table 3, Table 4, Table 5, and Table 6), 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.
8.1
Efficacy Assessments
8.1.1
Clinical Outcome Assessments
Investigators will complete clinician-reported outcome assessments during site visits in 
accordance with the SoA (Table 1, Table 2, Table 3, Table 4, Table 5, and Table 6). 
The following assessments will be completed by the Investigator: BVAS, EGPA 
relapse/remission, and VDI (Sections 8.1.1.1, 8.1.1.2, and 8.1.1.3, respectively).
Patient-reported outcome assessments (Sections 8.1.1.4 to 8.1.1.11) will be completed by the 
patients using a handheld ePRO device. The ePRO device will be given to patients at 
screening (Visit 1) and must be returned at the end of the first year of the OLE period (Visit 
30) or at the patient’s final study visit if it occurs before Visit 30.
Patients and sites will be trained on the use of the ePRO device. Sites should be aware of the 
guidelines for ePRO administration as provided to the sites in a separate manual. Sites and 
Investigators should be aware that the ePRO device is the only acceptable source of PRO data; 
paper questionnaires are not acceptable.

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The site staff should check ePRO completion and compliance at each visit.
If compliance with the Corticosteroid Medication Usage ePRO assessment completion drops 
below 80%, or if the overall compliance with completion of any of the other ePRO 
assessments (ACQ-6, SSQ, SNOT-22, SF-36v2, PGIS, PGIC, or WPAI-GH) drops below 
80%, it is highly recommended that the study site has a discussion with the patient to ask if 
they are having difficulties and to remind them of the importance of completing ePRO 
assessments.
8.1.1.1
Birmingham Vasculitis Activity Score
The BVAS is a validated, clinician-completed tool used for the comprehensive multisystem 
clinical assessment of disease activity in systemic vasculitis (Luqmani et al 1994, Luqmani et 
al 1997, Mukhtyar et al 2009b). A copy of the BVAS questionnaire will be provided to the site 
separately.
The Investigator will be required to complete the paper BVAS form and transfer data to eCRF 
BVAS module at screening (Visit 1), baseline (Visit 2) and Q4W until the end of the first year 
of the OLE (Visit 30), withdrawal from the study, or the EOT visit (Table 1 and Table 2).
During subsequent years of the OLE (if applicable), the Investigator is only required to 
complete BVAS at unscheduled visits (eg, in the event of a relapse) and at the IPD/EOT visit 
(Table 3, Table 4, and Table 5). The requirement for monthly BVAS assessment is replaced 
with a clinical assessment of relapse/remission based on the Investigators’ overall clinical 
assessment. In case of clinically suspected relapse, an unscheduled visit should be performed.
The BVAS form is divided into 9 organ-based systems, with each section including 
symptoms/signs that are typical of that particular organ involvement in systemic vasculitis. 
The form is designed to record features that are attributable to current vasculitis, after 
exclusion of other causes such as infection, hypertension etc. The scoring sheet records the 
presence or absence of each item. Each item is weighted, and a maximum total score applied 
to each system. The total score on all 9 organ systems gives an indication of the disease 
activity of each patient at the time of scoring and reflects the need for therapy.
An Outcomes Oversight Committee will be utilised for this study. 
8.1.1.2
EGPA Remission and Relapse
Investigators will be required to assess patients for EGPA relapse and remission from baseline 
(Visit 2) until withdrawal from the study or the EOT visit (Table 1, Table 2, Table 3, Table 4, 
and Table 5).

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EGPA Remission
Remission at any visit is defined as a BVAS score of 0 with OCS dose of 
prednisolone/prednisolone ≤4 mg/day (see Appendix K for Belgium). This is main definition 
of remission utilised in the primary endpoint derivation (Table 7).
In the event a patient has achieved remission and at any subsequent visit has a BVAS = 1 
which does not require an increase in corticosteroid dose above 4 mg/day or 7.5 mg/day (in 
accordance with the relevant remission definition), or any other significant clinical 
intervention or investigation, the patient will be considered to be in continued remission.
EGPA Relapse
EGPA relapse will be defined as worsening or persistence of active disease since the last visit 
characterised by:
∀
Active vasculitis (BVAS > 0); OR
∀
Active asthma symptoms and/or signs with a corresponding worsening in Asthma Control 
Questionnaire (6-item version) (ACQ-6) score (compared to the most recent previous 
score); OR
∀
Active nasal and/or sinus disease, with a corresponding worsening in at least one of the 
sino-nasal symptom questions (compared to the most recent previous assessment); 
warranting any of the following:
#
An increased dose of OCS therapy to > 4 mg/day prednisolone total daily dose; OR
#
An increased dose or addition of immunosuppressive therapy; OR
#
Hospitalisation related to EGPA worsening
In the event of a suspected EGPA relapse, the patient should attend an unscheduled visit 
(Table 1, Table 2, Table 3, Table 4, and Table 5). A BVAS evaluation will be conducted at the 
time of the relapse, or as soon as possible afterwards.
The time of onset of a relapse will be defined as:
∀
The time of increase in dose of OCS therapy, and/or
∀
Increase in dose or addition of immunosuppressive therapy, and/or
∀
Hospitalisation in association with the worsening in BVAS, asthma, or sino-nasal 
symptoms
Investigators will be required to record details pertaining to each relapse event in the eCRF 
from baseline (Visit 2) until withdrawal from the study or the EOT visit (Table 1, Table 2, 
Table 3, Table 4, and Table 5), eg, details regarding the BVAS item, asthma or nasal/sinus 

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disease resulting in the relapse with detail of the required intervention(s), eg, OCS dose 
increase, use or change in immunosuppressive therapy or requirement for hospitalisation. For 
consenting patients participating in the mechanistic sub-study, where possible (only during the 
DB period and first year of the OLE), a blood and sputum sample should be collected in the 
event of relapse. In addition, where possible, (ie, as part of standard of care management), a 
tissue (biopsy) sample should be collected. 
Note: in the event a patient has achieved remission (ie, BVAS = 0 and 
prednisolone/prednisone dose ≤4 mg/day) and at a subsequent visit has a BVAS = 1, which 
does not require an increase in corticosteroid dose above 4 mg/day, or any other significant 
clinical intervention or investigation, this will not be considered a relapse.
A major relapse (a sub-set of the total relapse events) will be defined as: any organ or life-
threatening EGPA event; OR BVAS ≥6 (involving at least two organ systems in addition to 
any general symptoms where present [myalgia, arthralgia/arthritis, fever > 38°C or weight 
loss > 2 kg]); OR an asthma relapse requiring hospitalisation; OR sino-nasal relapse requiring 
hospitalisation.
The minimally effective dose of OCS (prednisolone/prednisone) for each patient will be 
defined as the dose of OCS one step above the OCS dose at which the first relapse occurred. 
Where the patient has achieved a dose of OCS of 0 to 3.5 mg prednisolone/prednisone, the 
minimally effective dose will be defined as 4.0 mg/day. Upwards dose adjustments within the 
0 to 4.0 mg range are permitted without being considered a relapse.
The management of patients who relapse will be according to standard of care and may 
involve increasing the dose of corticosteroids or adjustment in immunosuppressive therapy.
If the patient's first relapse is managed with the use of an increase in corticosteroid dose, 
tapering should be recommended as soon as the relapse has been appropriately controlled, as 
per standard of care practice. As stated above, the recommended tapering schedule is provided 
in Appendix H, although after the first relapse the Investigator may opt to use larger dose 
increments and shorter dose intervals than outlined in the schedule, if clinically indicated. 
Once a minimally effective dose of OCS is achieved, any down-tapering below this dose level 
will be at the discretion of the Investigator, based on the clinical condition of the patient. In 
the event of a second or subsequent relapse, any further OCS tapering, post-relapse, will be 
conducted at the discretion of the Investigator.
If a relapse is managed by increasing the dose of or initiating immunosuppressive therapy, the 
patient must be withdrawn from receiving further study treatment and where possible, 
continued to be followed up as per protocol.

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If a patient experiences an organ threatening or a life-threatening relapse he/she will be 
withdrawn from receiving further study treatment and where possible, continue to be followed 
up as per protocol.
8.1.1.3
Vasculitis Damage Index
Vasculitis Damage Index (Exley et al 1998) will be used to document those features of 
vasculitis, which are due to persistent damage, where there is no current disease activity. 
Damage is defined as the presence of non-healing scars and does not give any indication of 
current disease activity. The VDI is divided into 11 organ systems and records items of 
damage, due to vasculitis, treatment or unrelated, that have occurred since the onset of 
vasculitis. Completion of the form provides a numerical score. A copy of the VDI 
questionnaire will be provided to the site separately.
The Investigator will be required to complete the paper VDI form and transfer data into the 
eCRF VDI module as specified in Table 1, Table 2, Table 3, Table 4, and Table 5.
8.1.1.4
Corticosteroid Medication Usage
The patient will be asked to report the daily dosage of OCS taken over the past 24 hours 
throughout the 52-week DB period. The daily OCS usage assessment will be completed by the 
patient each evening prior to going to sleep using an ePRO device as indicated in the SoA 
(Table 6). In the OLE period (after Visit 17), patients will complete the OCS usage assessment 
once weekly until Visit 30 (end of year 1 of the OLE; Table 6) using the ePRO device. Any 
within-window assessment that has not been completed prior to the site visit will be 
completed at the site prior to other study procedures.
The ePRO device will be returned at Visit 30 or at the patient’s final study visit, if it occurs 
before Visit 30. After Visit 30, the Investigator will record the patient’s prescribed 
corticosteroid usage in the eCRF at regularly scheduled monthly clinic visits or telephone 
contact visits (Table 3 Table 4, and Table 5). 
Patient-reported corticosteroid use and dosage will be checked at each clinic visit/telephone 
contact visit. This check should include a review of ePRO compliance (Section 8.1.1) as well 
as compliance with the prescribed OCS dose between each visit and/or tapering of dose, as 
described in Section 6.5.1.
8.1.1.5
Asthma Control Questionnaire (6-Item Version)
The ACQ-6 was developed for self-administration by adults and adolescents by omitting the 
FEV1 % predicted question (Juniper et al 1999). Patients are asked to record their experience 
with 5 symptoms (night-time waking, symptoms on waking, activity limitation, shortness of 
breath, and wheezing) and use of SABA over the previous week using a 7-point scale (0 = no 
impairment; 6 = maximum impairment). The ACQ-6 score is calculated by taking the mean of 
the 6 equally weighted items. The ACQ-6 score range is 0 (well controlled) to 6 (extremely 

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poorly controlled). Individual score change of at least 0.5 is meaningful and is used to support 
the responder definition (Juniper et al 2005, Juniper et al 2006). Mean ACQ scores ≤0.75 
indicate well-controlled asthma, scores between 0.75 and 1.5 indicate partly controlled 
asthma, and a score ≥1.5 indicates poorly controlled asthma (Juniper et al 2006).
The patient will complete the ACQ-6 on the ePRO device as described in Table 6. Any 
within-window assessment that has not been completed prior to the site visit will be 
completed at the site prior to other study procedures.
8.1.1.6
Sino-nasal Symptom Questionnaire
The SSQ asks patients to report the severity of their symptoms over the previous week: 
“Considering your sinus and nasal symptoms over the last week, rate each symptom against 
the following categories: very severe, severe, moderate, mild, none.” Symptoms include runny 
nose, post-nasal discharge (sensation of liquid in your throat), facial pain/pressure, loss or 
reduction in sense of taste/smell, and blockage/congestion of nose. Higher scores indicate 
greater severity (0 = none to 4 = very severe). 
The patient will complete the SSQ on the ePRO device as specified in Table 6. Any within-
window assessment that has not been completed prior to the site visit will be completed at the 
site prior to other study procedures.
8.1.1.7
Sino-Nasal Outcome Test-22
The Sino-Nasal Outcome Test-22 (SNOT-22) is a condition-specific HRQoL assessment 
which captures patient-reported physical problems, functional limitations, and emotional 
consequences of sino-nasal 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 of 8.90 has been established for individual score 
change (Hopkins et al 2009).
The patient will complete the SNOT-22 on the ePRO device as specified in Table 6. Any 
within-window assessment that has not been completed prior to the site visit will be 
completed at the site prior to other study procedures.
8.1.1.8
Short Form-36 Version 2 (Acute Recall)
The Short Form-36 version 2 (acute recall) (SF-36v2) is a 36-item, self-report survey of 
functional health and well-being, with a 1-week recall period (Lincoln 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 one week ago, and is not 
used to calculate domain scores. The 8-domain profile consists of the following subscales: 

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physical functioning, role limitations due to physical health, bodily pain, general health 
perceptions, vitality, social functioning, role limitations due to emotional problems, and 
mental health. Psychometrically-based PCS and MCS are computed from subscale scores to 
give a broader metric of physical and mental HRQoL.
The SF-36v2 threshold is suitable for interpreting change at the individual level and is referred 
to as the responder threshold (Table 14) or responder definition (Lincoln 2011).
Table 14
Threshold Values for the SF-36v2 Scale and Summary Measures
SF-36v2 score
Threshold
PCS
MCS
PF
RP
BP
GH
VT
SF
RE
MH
Individual change
3.4
4.6
4.3
3.4
6.2
7.2
6.2
6.9
4.5
6.2
BP, bodily pain; GH, general health perceptions; MCS, mental health component summary; MH, mental health; 
PCS, physical health component summary; PF, physical functioning; RE, role limitations due to emotional 
problems; RP, role limitations due to physical health; SF, social functioning; SF-36v2, Short Form 36-Item 
Health Survey (version 2, acute recall); VT, vitality.
The patient will complete the SF-36v2 on the ePRO device as specified in Table 6. Any 
within-window assessment that has not been completed prior to the site visit will be 
completed at the site prior to other study procedures.
8.1.1.9
Patient Global Impression of Severity 
The PGIS is a single item designed to capture the patient’s perception of overall symptom 
severity over the past week using a 6-point categorical response scale (0 = no symptoms to 
5 = very severe symptoms).
The patient will complete the PGIS on the ePRO device as described in Table 6. Any within-
window assessment that has not been completed prior to the site visit will be completed at the 
site prior to other study procedures.
8.1.1.10
Patient Global Impression of Change
The PGIC instrument captures the patient’s overall evaluation of response to treatment. The 
patient is asked to report the degree to which they have changed since entering the treatment 
period using a 7-point scale (1 = much better to 7 = much worse).
The patient will complete the PGIC on the ePRO device as described in Table 6. Any within-
window assessment that has not been completed prior to the site visit will be completed at the 
site prior to other study procedures.
8.1.1.11
Work Productivity and Activity Impairment questionnaire
The WPAI general health version 2.0 is a self-administered tool comprised of 6 questions 
which address absenteeism, presenteeism (reduced effectiveness while working), overall work 
productivity loss (absenteeism plus presenteeism), and activity impairment. This validated 

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tool captures data from the past 7 days. WPAI outcomes are scored as impairment
percentages, with a higher percentage indicating greater impairment and less productivity 
(Reilly Associates 2012). 
The patient will complete the WPAI on the ePRO device as described in Table 6. Any within-
window assessment that has not been completed prior to the site visit will be completed at the 
site prior to other study procedures.
8.1.1.12
Spirometry
General requirements
Lung function (FEV1 and forced vital capacity) will be measured by spirometry using 
equipment provided by a central vendor. Spirometry will be performed by the Investigator or 
authorised delegate according to American Thoracic Society/European Respiratory Society 
guidelines (Miller et al 2005).
The vendor providing central spirometry will ensure that the spirometer meets American 
Thoracic Society/European Respiratory Society recommendations and that the study site 
personnel who will be performing the testing are properly certified. Spirometry calibration 
will be detailed in a separate spirometry procedures manual.
∀
Patients should avoid engaging in strenuous exertion for at least 30 minutes prior to all 
lung function assessments at the study site.
∀
Patients should avoid eating a large meal for at least 2 hours prior to all lung function 
assessments at the site. 
∀
Patients should withhold their usual maintenance therapies (if applicable) on the day(s) 
when lung function testing is being performed as below:
#
SABA and short-acting muscarinic antagonist should be withheld at least 6 hours 
prior to scheduled spirometry at site. 
#
Twice daily LABA- or LAMA-containing therapies should be withheld for at least 
12 hours prior to scheduled spirometry at site.
#
Once daily LABA- or LAMA-containing therapies should be withheld for at least 
24 hours prior to scheduled spirometry at site.
#
Twice daily theophylline should be withheld for at least 12 hours prior to scheduled 
spirometry at site.
#
Once daily theophylline for at least 24 hours prior to scheduled spirometry at site. 
Note: If any of the above restrictions are not met, the spirometry assessment should be 
rescheduled within the allowed visit window if possible.

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Order of Administration for any Asthma Maintenance Medication (if Applicable) and IP 
Relative to the Scheduled Pre- and Post-bronchodilator Spirograms
For patients that are taking any asthma maintenance therapies, they should not take their 
morning maintenance therapy until after the pre- and post-BD spirograms are complete. The 
patient’s usual asthma medications may be administered following completion of the pre/post-
BD spirograms, and (if applicable) should be taken prior to IP dosing.
Investigational product dosing should also be withheld until pre- and post-BD spirometry is 
complete.
Time of Day for Scheduled Site Visit Spirometry
Spirometry testing should be done according to the SoA (Table 1) (Table 2), (Table 3), and 
(Table 4). Spirometry testing must be initiated in the morning between 0600 and 1100 at the 
baseline visit (Visit 2).
All post-randomisation spirometry assessments should be performed within ± 2 hours of the 
time of day that the baseline (Visit 2) spirometry is performed, if possible.
Spirometry Technique
Detailed procedures for performing spirometry will be described in a separate instruction 
manual. Details regarding assessment of the quality of spirometry and the best test review 
process will also be detailed in the manual. 
Record Keeping
A signed and dated copy of the pre- and post-BD printout must be kept at study site for source 
data verification. The printout must be marked with the study code, enrolment code, date and 
time of measurement, visit number. If a printout cannot be printed, the mean value of the 
measurements will be recorded in the patient’s charts.
Spirometry References
The Global Lung Function Initiative equations will be used to determine the PNV and are pre-
programmed into the spirometer. 
Forced expiration volume in 1 second, expressed as percent of the PNV, will be calculated as 
follows:
FEV1% of PNV = (FEV1 measured/FEV1PNV) × 100
Percent reversibility will be calculated as follows:
Percent reversibility = (post-BD FEV – pre-BD FEV1) × 100%/pre-BD FEV1

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Reversibility Test and Post-Bronchodilator FEV1 Efficacy Assessment
The procedure described in this section refers to the reversibility test and post-BD spirometry 
that should be performed only at baseline (Visit 2).
Endpoint maximal bronchodilation will be induced using albuterol (90 μg metered dose), 
salbutamol (100 μg metered dose), or levalbuterol (45 μg metered dose) 4 inhalations within 
30 ± 15 minutes of the final pre-BD spirometry measurement. Post-BD spirometry should be 
performed 15 to 30 minutes after SABA dosing. It is highly recommended to use a spacer 
device for this procedure. A nebuliser should not be used.
The algorithm for reversibility testing is outlined in Figure 4.
Figure 4
Reversibility Testing Algorithm
BD, bronchodilator; FEV1, forced expiration volume in 1 second; SABA, short acting β2 agonist.
8.1.2
Patient Qualitative Interview Sub-study
Up to 45 patients will be invited to participate in a set of concept elicitation interviews to 
characterise their experience during the DB portion of the study. Interviews will be non-
interventional and will collect data on HRQoL and patients’ experiences with the study 
treatment. Interviews will be performed by an AstraZeneca vendor via telephone contact on a 
one-to-one basis and interview duration will be approximately 60 minutes. Please refer to a 
separate Patient Qualitative Interview Manual describing interview processes.
Patients will be introduced to the sub-study during the informed consent process described in 
Appendix A 3 using patient communication materials and the sub-study patient handout 
provided in a separate Patient Qualitative Interview Manual. Interested patients will indicate 
their willingness to participate via the master ICF and will provide consent to participate in the 
Wait 30 ± 15 minutes
Wait 15 to 30 minutes

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sub-study via a sub-study ICF addendum. Patients will be contacted and interviews scheduled 
by research staff using communication materials provided in a separate Patient Qualitative 
Interview Manual.
Each participating patient will be interviewed twice. The first hour-long interview will take 
place at least 7 and up to 21 days after Visit 2. The second interview will take place at 
least 7 and up to 21 days after Visit 16 (or IPD within the DB portion of the study). With the 
patient’s permission (ascertained via the consent form and confirmed verbally prior to the start 
of the interview), the interviews will be audio recorded.
During the interview, patients will be asked a set of open-ended questions with probes to 
explore their experiences with study treatment. They will be asked about their experience of 
the condition, how their experience may have changed over time, and current signs, 
symptoms, and impacts of the condition and study treatment. Interview discussion guides are 
provided in a separate Patient Qualitative Interview Manual.
Interview transcripts will be completed for each interview in the language in which they are 
conducted, and translated into English (if necessary). Translated transcripts will be coded 
using qualitative data analysis software.
All sub-study data (including interview transcripts and translations, ATLAS.ti codebooks, and 
other analyses) will be de-identified and stored in the vendor’s secure server in a password-
protected file. Aggregated results and summary analyses will be prepared in English. Due to 
the qualitative nature of the data and the analysis, the results will be presented in a separate 
report (not in the CSR) and the data (transcriptions) will not be entered into the study 
database. No identifiable data will be reported.
In the event that any study patient or potential study patient reports or is noted to have 
experienced an AE involving study treatment, information about the AE will be reported to 
the AstraZeneca. AstraZeneca will follow standard procedures for handling AEs reporting 
involving these patients.
8.2
Safety Assessments 
Planned time points for all safety assessments are provided in the SoA (Table 1, Table 2, 
Table 3, Table 4, and Table 5).
8.2.1
Clinical Safety Laboratory Assessments
See Table 15 for the list of clinical safety laboratory tests to be performed and the SoA 
(Table 1, Table 2, Table 3, Table 4, and Table 5) for the timing and frequency. All protocol-
required laboratory assessments, as defined in the table, must be conducted in accordance with 
the separate laboratory manual and the SoA.

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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 information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.6.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.
The clinical chemistry and haematology analyses will be performed at a central laboratory. 
Urinalysis will be performed at a central laboratory only at Visit 1; subsequent analyses will 
be performed locally using a dipstick provided centrally.
Erythrocyte sedimentation rate will be performed at a local laboratory.
As described in Section 6.3.2.1, from baseline (Visit 2) until Visit 18, the eosinophil, basophil, 
and monocyte counts will be redacted from central laboratory reports to prevent the site 
staff/AstraZeneca from possibly deducing the 'eosinophil + basophil + monocyte' contribution 
to the complete blood count. 
Table 15
Laboratory Safety Variables 
Haematology a
Clinical chemistry
Haemoglobin (Hb)
Creatinine
Leukocyte count (white blood cell [WBC] count)
Bilirubin, total
Leukocyte differential count (absolute count)
Bilirubin, direct
Platelet count
Bilirubin, indirect
Red cell count (red blood cell [RBC] count)
Alkaline phosphatise (ALP)
Reticulocytes
Aspartate aminotransferase (AST)
Mean Corpuscular Volume (MCV)
Alanine aminotransferase (ALT)
Mean Corpuscular Haemoglobin (MCH)
Albumin
Mean Corpuscular Haemoglobin Concentration 
(MCHC)
Potassium
Neutrophil (absolute and differential [%])
Calcium, total
Lymphocytes (absolute and differential [%])
Sodium
Monocytes (absolute and differential [%])
Creatine kinase (CK)
Eosinophils (absolute and differential [%])
Chloride

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Table 15
Laboratory Safety Variables 
Basophils (absolute and differential [%])
Phosphorous inorganic
Glucose
Urinalysis 
Protein, total
U-Hb/erythrocytes/blood 
Urea nitrogen
U-Protein/albumin 
Lactic dehydrogenase (LD)
U-Glucose 
Cholesterol, total
U-Ketones
Gamma glutamyl transaminase (GGT)
Microscopic: WBC and RBC (screening [Visit 1] 
only)
Lipoproteins (fasting)
Urine human chorionic gonadotropin (HCG)
Troponin
Other laboratory parameters
Hepatitis B Surface Antigen
Hepatitis C antibody
anti-neutrophil cytoplasmic antibodies (ANCA) 
(myeloperoxidase [MPO] and PR3 [proteinase-3])
Total immunoglobulin E (IgE), fluoroenzyme 
immunoassay (FEIA)
C-reactive protein (CRP)
human immunodeficiency virus (HIV)-1 and 
HIV-2
erythrocyte sedimentation rate (ESR)
follicle stimulating hormone (FSH)
Serum pregnancy test
a
Eosinophils, basophils, and monocytes counts and percentage will be redacted from central laboratory 
reports from Visit 2 (Week 0) to Visit 18 (Week 56) (Section 8.8.1).
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.
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 (Table 1, Table 2, Table 3, Table 4, and Table 5).
∀
Serum beta-human HCG: To be performed for all females at screening (Visit 1) except 
for those who are NOT of child-bearing potential as defined in inclusion criterion 9 
(Section 5.1). This test is to be sent to and analysed 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 amenorrhoeic for 
> 12 months;

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∀
Urine HCG: To be performed at the study site for all WOCBP at each treatment visit 
before IP administration using a dipstick, defined in exclusion criterion 19. A positive 
urine test result must be confirmed with serum beta-HCG. 
8.2.1.2
Serology
Hepatitis B surface antigen and hepatitis C antibody: To be performed at screening and Visit 
16; test to be performed at central laboratory.
In case of positive result of HBsAg or hepatitis C virus antibody, additional testing (eg, 
hepatitis C RNA polymerase chain reaction test) may be performed to confirm eligibility, 
please see exclusion criterion #9 for full details (hepatitis status Section 5.2). 
Human immunodeficiency virus-1 and HIV-2 antibodies (along with p24 antigen): To be 
performed at screening and Visit 16; 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.
8.2.2
Physical Examinations
Physical examination will be performed at timelines as specified in the SoA (Table 1, Table 2, 
Table 3, Table 4, and Table 5). Investigators should pay special attention to clinical signs 
related to previous serious illnesses; new or worsening abnormalities may qualify as AEs 
(Section 8.3.6 for details).
For the physical examination, only information on whether the assessment was performed or 
not is to be recorded in the eCRF.
8.2.2.1
Complete Physical Examination
A complete physical examination will be performed at visits indicated in the SoA (Table 1, 
Table 2, Table 3, Table 4, and Table 5) and includes an assessment of the following: general 
appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, 
nose and throat), lymph nodes, thyroid, musculoskeletal (including spine and extremities) and 
neurological systems.
8.2.2.2
Brief Physical Examination
The brief physical examination will be performed at visits indicated in the SoA (Table 1, 
Table 2, Table 3, Table 4, and Table 5) and includes an assessment of the general appearance, 
abdomen, cardiovascular and respiratory system.
8.2.3
Vital Signs
Pre-dose vital signs are to be obtained in accordance with the SoA (Table 1, Table 2, Table 3, 
Table 4, and Table 5).

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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 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 utilising 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.
∀
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 one minute.
8.2.4
Electrocardiograms 
Triplicate 12-lead ECGs are to be performed at screening (Visit 1) to assess eligibility for this 
study, and then as indicated in the SoA (Table 1, Table 2, Table 3, Table 4, and Table 5) 
during the treatment period using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS complex, QT, and QTc intervals.
Each of the three 12-lead ECGs at each timepoint 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, spirometry, blood draw).
An independent reader at the central EGC vendor will provide overall interpretation as normal 
or abnormal. The Investigator will assess the clinical significance of any potential ECG 
findings. A reassessment ECG may support evaluation of clinical significance, when 
uncertain. Further details are provided in a separate ECG user manual.
8.2.5
Other Safety Assessments
8.2.5.1
Weight and Height and Body Mass Index
Weight and height will be measured in accordance with schedules provided in the SoA 
(Table 1, Table 2, Table 3, Table 4, and Table 5).
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.
Body mass index will be automatically calculated in the eCRF. 
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.

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The definitions of an AE or SAE can be found in Appendix B.
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorised 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 8.3.2.
8.3.1
Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information 
Adverse events will be collected from randomisation throughout the treatment period up to the 
end of OLE Year 3 and including the FU period last contact with patient. 
Serious adverse events will be recorded from the time of signing of the ICF. During OLE Year 
4 onwards, only SAEs or significant medical/adverse events that lead to an intervention 
should be captured and recorded in the eCRF.
All SAEs will be recorded and reported to AstraZeneca or designee within 24 hours of 
awareness, as indicated in Appendix B. The Investigator will submit any updated SAE data to 
AstraZeneca within 24 hours of it being available.
Investigators are not obligated to actively seek AE or SAE in patients after completion of the 
study or after the final visit after early withdrawal from the study. 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.
8.3.2
Follow-up of Adverse Events and Serious Adverse Events
After the initial AE/SAE report, the Investigator is required to follow each patient proactively 
at subsequent visits/contacts. All AEs, will be followed until resolution, stabilisation, the 
event is otherwise explained, or the patient is lost to FU.
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 CRF. 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.

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8.3.3
Adverse Event Data Collection
The following variables will be collected for each AE:
∀
AE (verbatim)
∀
Date when the AE started and stopped
∀
Maximum intensity 
∀
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 description
∀
AE is serious due to
∀
Date of hospitalisation
∀
Date of discharge
∀
Probable cause of death
∀
Date of death
∀
Autopsy performed
∀
Causality assessment in relation to study procedure(s)
∀
Causality assessment to other medication
8.3.4
Causality Collection
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the investigational product?’
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the clinical 
study protocol.

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8.3.5
Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the patient or care provider, or reported in response to the 
open question from the study site staff: ‘Have you had any health problems since the previous 
visit/you were last asked?’, or revealed by observation will be collected and recorded in the 
CRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 
recording a list of signs and symptoms. However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately.
8.3.6
Adverse Events Based on Examinations and Tests
The results from the CSP-mandated laboratory tests and vital signs will be summarised in the 
CSR. Deterioration as compared to baseline in protocol-mandated laboratory values and vital 
signs should, therefore, only be reported as AEs if they fulfil any of the SAE criteria or are the 
reason for discontinuation of treatment with the 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 
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
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 (Section 8.3.7).
8.3.7
Disease Under Study
Symptoms of the disease under study are those which might be expected to occur as a direct 
result of EGPA. Events which are unequivocally due to EGPA should not be reported as an 
AE during the study unless they meet the criteria below.
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms. EGPA symptoms or signs, such as wheeze, cough, dyspnoea, 
allergic rhinitis, abdominal pain, symptoms of vasculitis will be recorded as AEs only when:
∀
The sign or symptom is serious according to definitions, see Appendix B
∀
The patient discontinues the study due to the sign or symptom.

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∀
The sign or symptom is new to the patient or not consistent with the patient’s preexisting 
EGPA history (defined as within one year of Visit 1) as judged by the Investigator.
If an EGPA relapse fulfils any of the above criteria, the sign or symptom should also be 
recorded as an AE.
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(s), or to the 
study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
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, 
ie, immediately but no later than 24 hours of when he or she becomes aware of it.
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 patient has received any study drug.
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, and 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 temporarily 
withheld and a conversation between the Investigator and a Study Physician has to take place 
to determine whether continuation on IP or discontinuation of IP is in the best interest of the 
patient.

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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.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within one day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 
one or 5 calendar days for SAEs (Section 8.3.2) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The pregnancy report form in the eCRF is used to report the pregnancy and the paper-based 
pregnancy outcome report is used to report the outcome of the pregnancy.
8.4.3
Overdose
8.4.3.1
Benralizumab Overdose
No clinical data regarding overdose are available. Single doses of up to 200 mg were 
administered SC in clinical trials to patients with eosinophilic disease without evidence of 
dose-related toxicities. For management of IP-related toxicities, see Section 8.4.7.
For this study, any dose of benralizumab greater than 200 mg will be considered an overdose. 
There is currently no specific treatment in the event of overdose with benralizumab and 
possible symptoms of an overdose are not established.
8.4.3.2
Mepolizumab Overdose
Single doses of up to 1500 mg have been administered IV to patients in a clinical trial with 
eosinophilic disease without evidence of dose-related toxicities. For management of IP-related 
toxicities, see Section 8.4.7.
There is no specific treatment for an overdose with mepolizumab. If overdose occurs, the 
patient should be treated supportively with appropriate monitoring as necessary.

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8.4.4
Medical Device Deficiencies
Combination products with a device constituent are being provided for use in this study. In 
order to fulfil regulatory reporting obligations worldwide, the investigator is responsible for 
the detection and documentation of events meeting the definition of a medical device 
deficiency that occur during the study with the device constituent of the benralizumab 
combination product. 
Medical device deficiencies from this study will be collected and monitored to ensure the 
safety of patients and improve the safety and performance of the device.
Medical device deficiencies will not be presented in the CSR, but where required by local 
regulations, deficiencies will be summarised in the relevant periodic report.
The definition of a medical device deficiency is an inadequacy of a medical device/device 
constituent with respect to its identity, quality, durability, reliability, safety, or performance. 
Medical device deficiencies include malfunctions, use errors, and information supplied by the 
manufacturer.
NOTE: Deficiencies fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Appendix F.
The AstraZeneca Clinical Study Medical Device/Device Constituent Report Form and/or 
Product Complaint Intake Form will be used to collect the deficiency. For third-party medical 
devices, the deficiency will be reported to the manufacturer, who will be responsible for 
fulfilling their regulatory obligations.
8.4.4.1
Time Period for Detecting Medical Device Deficiencies
∀
Medical device incidents or malfunctions of the medical device will be detected, 
documented, and reported during all periods of the study in which the medical device is 
used.
∀
If the investigator learns of any medical device deficiency at any time after a patient has 
been discharged from the study, and such incident is considered reasonably related to a 
medical device provided for the study, the investigator will promptly notify AstraZeneca.
The method of documenting medical device deficiencies is provided in Appendix F.
8.4.4.2
Follow-up of Medical Device Deficiencies
∀
Follow-up applies to all patients, including those who discontinue study intervention.
∀
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.
∀
New or updated information will be recorded on the original form used to report the 
deficiency, with all changes signed and dated by the investigator.

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8.4.4.3
Prompt Reporting of Medical Device Deficiencies to Sponsor
∀
Medical device deficiencies will be reported to AstraZeneca within 24 hours after the 
investigator determines that the event meets the protocol definition of a medical device 
deficiency.
∀
The AstraZeneca Clinical Study Medical Device/Device Constituent Report Form and/or 
Product Complaint Intake Form will be sent to AstraZeneca by email. 
∀
Where an SAE has occurred in addition to the malfunction, the SAE will be recorded in 
the eCRF as detailed in Section 8.4.1.
∀
AstraZeneca will be the contact for the receipt of medical device deficiency reports.
8.4.4.4
Regulatory Reporting Requirements for Device Deficiencies
∀
The investigator will promptly report all medical device deficiencies occurring with any 
medical device provided for use in the study in order for AstraZeneca to fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about certain 
safety information relating to medical devices being used in clinical studies.
∀
The investigator, or responsible person according to local requirements (eg, the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of medical device deficiencies to the IRB/IEC.
∀
For further guidance on the definition of an SAE, see Appendix F.
8.4.4.5
SADE Reporting
Note: There are additional reporting obligations for device constituent deficiencies that are 
potentially related to SAEs that must fulfill the legal responsibility to notify appropriate 
regulatory authorities and other entities about certain safety information relating to device 
constituents being used in clinical studies.
Any device constituent deficiency that is associated with an SAE must be reported to the 
sponsor within 24 hours after the investigator determines that the event meets the definition of 
a device constituent deficiency. The sponsor will review all device constituent deficiencies 
and determine and document in writing whether they could have led to an SAE. These device 
constituent deficiencies will be reported to the regulatory authorities and IRBs/IECs as 
required by national regulations.
8.4.5
Medication Error, Drug Abuse, and Drug Misuse
8.4.5.1
Timelines
If an event of medication error, drug abuse, or drug misuse occurs during the study, then the 
Investigator or other site personnel informs the appropriate AstraZeneca representatives 
within one calendar day, ie, immediately but no later than 24 hours of when they become 
aware of it.

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The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within one (initial fatal/life-threatening or follow up 
fatal/life-threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error, drug abuse, or misuse (Section 8.3.1) and within 
30 days for all other events.
8.4.5.2
Medication Error
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for an IP that either causes harm to the patient or has the potential to 
cause harm to the patient.
The full definition and examples of medication error can be found in Appendix B.
8.4.5.3
Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IP for a 
perceived reward or desired non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix B.
8.4.5.4
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study patient) of IP for medicinal 
purposes outside of the authorised product information, or for unauthorised IPs, outside the 
intended use as specified in the protocol and includes deliberate administration of the product 
by the wrong route.
The full definition and examples of drug misuse can be found in Appendix B.
8.4.6
Reporting of Overdose
Refer to Section 8.4.3 for definition and treatment of overdose.
∀
An overdose with associated AEs should be 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 should be only reported on the overdose eCRF 
module.
If an overdose on an IP occurs in the course of the study, the investigator or other site 
personnel inform appropriate AstraZeneca representatives immediately, but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 

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or 5 calendar days for overdoses associated with an SAE (see Section 8.3.1) and within 
30 days for all other overdoses.
8.4.7
Management of IP-related Toxicities
Appropriate drugs, such as epinephrine, H1 and H2 antihistamines, and corticosteroids, as 
well as medical equipment to treat acute anaphylactic reactions, should be available when IP 
is administered and study site personnel must be trained to recognise and treat anaphylaxis 
(Lieberman et al 2010). Details on anaphylaxis management are provided in Appendix E.
Anaphylaxis will be defined as a serious reaction that is rapid in onset and may cause death 
(Sampson et al 2006). Anaphylaxis typically manifests as 1 of 3 clinical scenarios:
1
The acute onset of a reaction (minutes to hours) with involvement of the skin, mucosal 
tissue, or both and at least one of the following: a) respiratory compromise or b) reduced 
blood pressure or symptoms of end-organ dysfunction; or
2
Two or more of the following that occur rapidly after exposure: involvement of the 
skin/mucosal tissue, respiratory compromise, reduced blood pressure or associated 
symptoms, and/or persistent gastrointestinal symptoms; or
3
Reduced blood pressure after exposure
Further details on the clinical criteria for defining anaphylaxis and immune complex disease 
are provided in Appendix E 2.
Patients will have had a pre-assessment (ie, vital signs and lung function) prior to IP 
administration. Patients should be observed (or contacted when participating in the self-
administration programme) after each IP administration for the appearance of any acute drug 
reactions in line with clinical practice.
Serum tryptase or other blood or urine testing relevant to the diagnosis of anaphylaxis may be 
obtained at a local laboratory at the discretion of the Investigator.
8.5
Pharmacokinetics
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
Pharmacokinetic analysis will only be done on samples from patients who received 
benralizumab. 
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
AstraZeneca and site study files, but will not constitute a protocol amendment. The IRB/IEC 

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will be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICF. 
For the PK analysis, it is important that the date and time of each SC injection is recorded for 
each patient.
Instructions for sample collection, processing, storage, and shipment can be found in the 
separate laboratory manual provided to the study sites.
All serum samples, except for samples collected at Week 1 and Week 25, will be collected 
pre-dose according to the schedule of study procedures (Table 1, Table 2, Table 3, Table 4, 
and Table 5).
A summary of PK analysis 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 a 
central laboratory on behalf of AstraZeneca, using a validated bioanalytical method.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The result from the evaluation will not be reported in the CSR but 
separately in a bioanalytical report.
8.5.2
Storage and Destruction of Pharmacokinetic Samples
The PK samples will be retained for a period of 6 months from bioanalytical report 
finalisation. 
8.6
Pharmacodynamics
Relevant information for blood eosinophils and other biomarkers including serum, RNA, nasal 
secretions, sputum, tissue biopsy (optional) and whole blood for cell phenotyping and PBMC 
isolation are described in Section 8.8.
8.7
Genetics
8.7.1
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.

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The results of the analyses will be reported separately from the CSR in a scientific report or 
publication.
8.7.2
Storage and Destruction of Genetic Samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. Samples may be stored for a maximum of 
15 years or as per local regulations from the date of the Last Patient’s Last Visit, after which 
they will be destroyed. DNA is a finite resource that may be used up during analyses.
No personal details identifying the individual will be available to AstraZeneca or designated 
organisations working with the DNA. For further details, see Appendix D.
8.8
Biomarkers
Biomarkers that may be analysed in both mandatory and mechanistic sub-study sample 
collections include, but are not limited to, sputum differential leukocyte counts; whole blood 
gene expression; blood and tissue leukocyte phenotypic markers; serum/sputum/nasal 
secretion proteins including, but not limited to, eosinophil granule proteins, cytokines, 
chemokines, and inflammatory mediators associated with EGPA; eosinophil activation; 
immunological function; and the pharmacology of benralizumab and mepolizumab.
8.8.1
Blood Eosinophils
Table 1Table 2, Table 3, Table 4, and Table 5).Note that the eosinophil, basophil and 
monocyte counts will be redacted from the haematology report sent to the investigative site in 
order to maintain the study blinding from baseline (Visit 2) until Week 56 (Visit 18).
8.8.2
Mandatory Biomarker Samples
Mandatory collection of samples for exploratory biomarker research is part of this study. The 
following samples for exploratory biomarker research are required and will be collected pre-
dose from all patients in this study, as specified in the SoA:
∀
Blood (serum, whole blood PAXgene RNA tube)
Serum samples will be collected according to the SoA (Table 1, Table 2, Table 3, Table 4, and 
Table 5), and whole blood PAXgene RNA tube samples will be collected according to the 
SoA (Table 1), in order to evaluate the effect of benralizumab compared to mepolizumab on 
biomarkers of eosinophil recruitment, activation, and survival (eg, IL-5, eosinophil-derived 
neurotoxin, and eotaxin), inflammation and immunological mechanisms related to EGPA, as 
well as to identify baseline biomarkers predicting response to benralizumab or mepolizumab.
Additional samples will be collected and analysed as part of the mechanistic sub-study 
(Section 8.8.4). 

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Instructions for sample collection, processing, storage, and shipment can be found in the 
separate laboratory manual provided to the sites.
8.8.3
Nasal Secretions (Mandatory at Selected Sites)
Collection of nasal secretions for exploratory biomarker research is required only for those 
sites with the necessary equipment to process the samples. The Investigator or study staff will 
collect samples from all study patients at that site. 
Samples will be collected pre-dose according to the SoA (Table 1). For biomarkers to be 
evaluated, see Section 8.8.2. 
Instructions for sample collection, processing, storage, and shipment can be found in the 
separate laboratory manual provided to the sites.
8.8.4
Mechanistic Sub-study Sampling (Induced Sputum, Tissue Biopsy, and 
Whole Blood Cells)
Additional exploratory biomarker research will be performed at sites participating in the 
mechanistic sub-study. The purpose of the sub-study is to more extensively evaluate the effect 
of benralizumab compared to mepolizumab on biomarkers of eosinophil recruitment, 
activation, and survival (eg, IL-5, eosinophil derived neurotoxin, and eotaxin); inflammation 
and immunological mechanisms related to EGPA; as well as to identify baseline biomarkers 
predicting response to benralizumab or mepolizumab. The following additional samples will 
be collected pre-dose at the time points shown in the SoA (Table 1, Table 2, Table 3, Table 4, 
and Table 5) only from patients who have consented to participate in this sub-study: 
∀
Induced sputum (for inflammatory cell counts, protein biomarkers, and transcriptomics)
∀
Tissue biopsy (for histology, immunohistochemistry, and transcriptomics)
∀
Whole blood for cell phenotyping and PBMC isolation
Sputum will be induced, collected, and processed using a modification of a previously 
published method (McCormick et al 2007, Pizzichini et al 1998). The sputum, tissue biopsies 
and whole blood will be collected and processed locally at the clinical sites according to the 
process detailed in separate laboratory manuals provided to the sites. Spirometry will be 
performed as part of the sputum induction procedure as described in the separate laboratory 
manual. All planned sample analyses will be performed at a central laboratory.
Tissue biopsies from the nose should be collected from patients with chronic rhinosinusitis 
with or without nasal polyps. Biopsies from other sites may be taken as per clinical judgment 
(unscheduled visit); these biopsies must remain blinded. Instructions for the collection and 
processing of the tissue biopsies are described in a separate laboratory manual.

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Sampling of whole blood for cell phenotyping and PBMC isolation will occur only for 
patients participating at North American mechanistic sub-study sites.
8.8.5
Storage, Reuse, and Destruction of Biomarker Samples
AstraZeneca or a designee will retain biomarker samples for a maximum of 15 years 
following the Last Patient’s Last Visit, after which they will be destroyed.
8.8.6
Reporting of Biomarker Research
The results of the biomarker research will be reported separately from the DB CSR in separate 
scientific reports or publications as appropriate. The results of the biomarker research may be 
pooled with biomarker data from other studies with the study drug to generate hypotheses to 
be tested in future research.
8.9
Immunogenicity
Instructions for immunogenicity (ADA and nAb) sample collection, processing, storage, and 
shipment can be found in the separate laboratory manual provided to the sites.
Anti-drug antibodies/nAb analysis will only be done on samples from patients who received 
benralizumab. 
The immunogenicity samples will be retained at AstraZeneca or designee for a maximum of 
5 years following the final CSR or publication associated with the study in order to properly 
address potential questions from regulatory authorities.
A summary of the analysis will be presented in the primary analysis CSR, and subsequent 
analyses in addendum to the primary analysis CSR and/or a separate OLE period CSR. Details 
of the analytical method used will be described in a bioanalytical report.
8.9.1
Anti-drug Antibodies
Serum samples for analysis of ADA will be collected pre-dose at selected visits according to 
the SoA (Table 1, Table 2, Table 3, Table 4, and Table 5).
The presence or absence of ADA will be determined in the serum samples using validated 
bioanalytical methods.
8.9.2
Benralizumab Neutralising Antibodies
In vitro benralizumab nAb activity testing will occur for all samples that are ADA positive. 
Samples that are ADA negative will not be tested for benralizumab nAb.
The presence or absence of neutralising ADA will be determined using a validated 
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8.10
Medical Resource Utilisation and Health Economics
At visits when health care use is being collected, as specified in the SoA (Table 1, Table 2, 
Table 3, Table 4, and Table 5) the Investigator should ask the patient if they have had any 
need to seek medical treatment for EGPA or an EGPA-related episode since the previous 
scheduled visit. 
Details of all healthcare resource utilisation related to treatment for EGPA or an EGPA-related 
episode will be recorded by the Investigator on paper or designee in the eCRF.
8.11
Other Assessments and Procedures
8.11.1
Patient Testing Due to Public Health Crisis
If patient testing is performed due to the public health crisis, the results may be documented 
for this study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
9.1.1
Primary Endpoint Hypothesis
The primary efficacy endpoint is the proportion of patients who achieve remission at both 
Week 36 and Week 48. EGPA remission is defined as having a BVAS = 0 and OCS 
dose ≤4.0 mg/day. The primary analysis is to demonstrate NI of benralizumab versus 
mepolizumab based on the primary endpoint of remission. 
The null hypothesis is that the proportion of patients achieving remission on benralizumab is 
inferior to that of patients on mepolizumab by a NI margin of -25%. The alternative 
hypothesis is that benralizumab is not inferior to mepolizumab. 
For the null hypothesis to be rejected, the lower 95% confidence limit for the absolute 
difference between benralizumab and mepolizumab remission rates needs to be above the NI 
margin of -25%. The primary endpoint will be tested at the 0.025 one-sided level. The primary 
endpoint will be evaluated using logistic regression, as outlined in Section 9.4.1.2 below. If NI 
is demonstrated for the primary endpoint, the same logistic regression model used to evaluate 
NI will be used to test superiority of benralizumab compared to mepolizumab at the one-sided 
0.025 level. In this case, the null hypothesis is that the benralizumab remission rate is not 
higher than the mepolizumab remission rate, and the alternative hypothesis is that the 
remission rare is greater on benralizumab compared to mepolizumab.
The external validity of the study will be assessed using an approach which compares the 
observed benralizumab rate in this study with the historical placebo remission rate of 
2 of 68 patients (2.9%) observed within the MIRRA study (Wechsler et al 2017). The null 

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hypothesis is that of patients achieving remission on benralizumab is equal to placebo. The 
alternative hypothesis is that patients achieving remission on benralizumab is greater than 
placebo. Superiority of the remission rate of benralizumab within this trial over the historical 
placebo remission rate observed in the mepolizumab trial will be evaluated with a two-sample 
test for binomial proportions and one-sided, 0.025 level test.
9.2
Sample Size Determination
Assuming that benralizumab and mepolizumab each have a remission rate of 32%, 
140 patients will provide approximately 90% power to demonstrate NI with a NI margin 
of -25% at the 2.5% one-sided significance level. For the study to be positive, the lower 
95% confidence limit for the difference between benralizumab and mepolizumab needs to be 
above the NI margin of -25%. The external validity of the study will be assessed using an 
indirect comparison to placebo. Assuming rates of 32% for benralizumab and 2 of 68 (2.9%) 
for historic placebo and sample sizes of 70 and 68, respectively, it is expected there will be 
> 90% power to demonstrate benralizumab has an improved remission rate over historical 
placebo with a one-sided alpha of 0.025. Power at the 2.5% one-sided significance level for 
comparison of benralizumab to historic placebo was evaluated with a two-sample test for 
binomial proportions using a placebo rate of 3%. This method accounts for the uncertainty in 
the historical placebo estimate as well as uncertainty in the current trial.
Patients will be randomised in a 1:1 ratio to benralizumab or mepolizumab treatment.
9.3
Populations for Analyses
For purposes of analysis, the following populations are defined in Table 16.
Table 16
Description of Populations for Analyses
Population
Description
Enrolled 
All patients who sign the ICF
Randomly assigned to study 
treatment
All patients who sign the ICF and are randomised to an investigation 
product regardless of whether they receive a dose of an IP or exit prior to 
receiving the first dose.
Full analysis set
All patients randomised and receiving at least 1 dose of IP will be included 
in the full analysis set, irrespective of their protocol adherence and 
continued participation in the study. Patients will be analysed according to 
their randomised treatment irrespective of whether or not they have 
prematurely discontinued, according to the ITT principle. Patients who 
withdraw consent to participate in the study will be included up to the date 
of their study termination. All efficacy analyses will be analysed using the 
full analysis set.

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Table 16
Description of Populations for Analyses
Population
Description
Safety analysis set
The safety analysis set consists of all patients who have received at least one 
dose of IP. Erroneously treated patients (eg, those randomised to treatment 
A but actually given treatment B) are accounted for in the treatment group 
of the treatment they actually received. A patient who has received active IP 
(benralizumab) on one or several occasions is classified as active 
(benralizumab).
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. All PK summaries will be based on 
this analysis set.
ICF, informed consent form; IP, investigational product; ITT, intent to treat; PK, pharmacokinetics.
9.4
Statistical Analyses
All personnel involved with the analysis of the study will remain blinded until the primary 
database lock, which is after CSP deviations identified for the primary analysis. 
Analyses will be performed by AstraZeneca or its representatives. A comprehensive SAP will 
be developed and finalised before primary database lock and will describe the patient 
populations to be included in the analyses, and procedures for accounting for missing, unused, 
and spurious data. This section is a summary of the planned statistical analyses of the primary 
and secondary endpoints. Any deviations from this plan will be reported in the CSR.
9.4.1
Efficacy Analyses
Efficacy analyses will be performed using the full analysis set. 
All analyses described below apply to the full analysis of all patients, through to the end of the 
DB period (Week 52) unless otherwise stated. Primary database lock will occur when the last 
patient completes 52 weeks of DB treatment. Unblinding and data analysis will occur after 
primary database lock.
9.4.1.1
Calculation or Derivation of Variables for Efficacy Analyses
Remission
Eosinophilic granulomatosis with polyangiitis remission is defined as having a BVAS = 0 and 
OCS dose ≤4.0 mg/day and is calculated at each time point every 4 weeks. The primary 
efficacy endpoint is the proportion of patients who achieve remission at both Week 36 and 
Week 48. For a supportive analysis, remission will also be defined as having a BVAS = 0 and 
OCS dose ≤7.5 mg/day and is calculated at each time point every 4 weeks.

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Total Accrued Duration of Remission
Total accrued duration of remission (defined as a BVAS = 0 and OCS dose ≤4.0 mg/day) will 
be evaluated over the 52-week treatment period. The accrued duration will be assigned with 
the following categories: 0 weeks, > 0 to < 12 weeks, 12 to < 24 weeks, 24 to < 36 weeks, and 
≥36 weeks. For a supportive analysis, remission will also be defined as having a BVAS = 0 
and OCS dose ≤7.5 mg/day.
Time to First EGPA Relapse
Time from randomisation to first relapse will be evaluated over the 52-week treatment period. 
Eosinophilic granulomatosis with polyangiitis relapse will be defined as worsening or 
persistence of active disease since the last visit as specified in Section 8.1.1.2. For patients 
who have not experienced a relapse by Week 52, their time to relapse will be right-censored at 
the last available assessment time. 
Average Daily Prednisolone/Prednisone Dose During the Last 4 Weeks of the 
Double-Blind Treatment Period
Average daily prednisolone/prednisone dose during Weeks 48 through 52 will be calculated 
(see Appendix K for Belgium). The average daily dose will be assigned with the following 
categories:
∀
0 mg/day, > 0 to ≤4 mg/day, > 4 to ≤7.5 mg/day, and > 7.5 mg/day
∀
≤4 mg/day
The percent reduction of average daily prednisolone/prednisone dose from baseline at 
Weeks 48 through 52 will be calculated with categories:
∀
No reduction or premature discontinuation from treatment before Week 48, 
< 25% reduction, 25 to < 50% reduction, 50 to < 75% reduction, 75 to < 100% reduction, 
and 100% reduction.
∀
≥ 50% reduction from baseline.
∀
100% reduction from baseline.
For the endpoints of ≥ 50% and 100% reduction from baseline, patients who prematurely 
discontinue from treatment before Week 48 will be considered non-responders.
Clinical Benefit
Any clinical benefit is a composite endpoint that is defined as any of the following 3 
component endpoints (Steinfeld et al 2019): 
∀
Remission (defined as BVAS = 0 and prednisolone/prednisone dose ≤ 4 mg/day) at any 
time during the DB treatment period.

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∀
≥ 50% reduction in average daily prednisolone/prednisone dose during Weeks 48 through 
52.
∀
EGPA relapse free during the DB treatment period.
The patients who prematurely discontinue from treatment before Week 48 will be considered 
non-responder for the percentage reduction in average daily prednisolone/prednisone dose 
component of the clinical benefit.
Complete response is a composite endpoint and patients meet complete response if all of the 
3 components above are met.
The analyses on any clinical benefit and complete response will be repeated for the supportive 
remission definition.
Remission within 24 Weeks and Remained in Remission for Remainder of the 
Double-Blind Treatment Period 
Remission (defined as a BVAS = 0 and OCS dose ≤4.0 mg/day) over the first 24 weeks and 
remained in remission for remainder of the DB treatment period will be evaluated over the 
52-week treatment period. The proportion of patients who have achieved remission within the 
first 24 weeks and remained in remission for remainder of 52-week treatment period will be 
calculated. For a supportive analysis, remission will also be defined as having a BVAS = 0 
and OCS dose ≤7.5 mg/day.
Asthma Control Questionnaire (6-Item Version)
The ACQ-6 is an assessment of 5 asthma symptoms (night-time waking, symptoms on 
waking, activity limitation, shortness of breath, and wheezing) and short-acting beta-agonist 
use.
Sino-nasal Questionnaire
The SSQ captures the severity of 5 sinus and nasal symptoms. 
Sino-nasal Outcome Test-22
The SNOT-22 is a condition-specific HRQoL assessment, which captures 22 items on patient-
reported physical problems, functional limitations, and emotional consequences of sino-nasal 
conditions (Hopkins et al 2009, Piccirillo et al 2002).
Short Form 36-item Health Survey, Version 2
The SF-36v2 is a 36-item, self-report survey of functional health and well-being, with a 
one-week recall period (Lincoln 2011). The 8-domain profile consists of the following 
subscales: physical functioning, role limitations due to physical health, bodily pain, general 

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health perceptions, vitality, social functioning, role limitations due to emotional problems, and 
mental health. Psychometrically-based PCS and MCS are computed from subscale scores.
Patient Global Impression of Severity
The PGIS is a single item designed to capture the patient’s perception of overall symptom 
severity.
Patient Global Impression of Change
The PGIC is a single item designed to capture the patient’s overall evaluation of response to 
treatment.
9.4.1.2
Methods for Efficacy Analyses
Analyses of the Primary Endpoint
The primary analysis is to demonstrate NI of benralizumab versus mepolizumab based on the 
primary endpoint of remission. For NI of benralizumab compared to mepolizumab to be 
demonstrated for the primary endpoint, the lower 95% confidence limit for the absolute 
difference in remission between benralizumab and mepolizumab needs to be above the NI 
margin of -25%. The primary endpoint of the proportion of patients who achieve remission at 
both Week 36 and Week 48 will be analysed using a logistic regression model. The model will 
include covariates of treatment arm, baseline dose of prednisone, baseline BVAS, and region. 
From this model, the absolute difference in remission rates (benralizumab-mepolizumab) will 
be estimated, with the associated two-sided 95% CI. Results will be presented in terms of 
adjusted response rates and difference in response rates with 95% CIs and p-values. If this 
analysis demonstrates NI, a formal test of superiority between benralizumab and mepolizumab 
will be assessed. 
To assess external validity of the study a direct comparison of benralizumab to historic 
placebo will be evaluated using remission rate. An unadjusted rate for benralizumab from this 
study will be compared to a historic rate of 2 of 68 (~2.9%) for placebo. Superiority of 
benralizumab over historical placebo will be evaluated with a two-sample test for binomial 
proportions using a one-sided test of benralizumab having an improved rate over placebo with 
a 2.5% significance level. This method accounts for the uncertainty assuming the sample size 
of 68 from the historical placebo estimate and a sample size of 70 for the benralizumab arm in 
the current trial. A normal approximation will be used for this comparison of benralizumab to 
historic placebo.
Analysis of Secondary Endpoints
Time to first EGPA relapse will be analysed using a Cox-proportional hazards model. Cox-
proportional hazards model results will be presented in terms of adjusted hazard ratios with 
95% CIs. Treatment arm, baseline dose of prednisone, baseline BVAS, and region will be 
included as covariates in the model. 

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Annualised relapse rate, defined as the number of relapses per year, will be evaluated using a 
negative binomial model. Treatment arm, baseline dose of prednisone, baseline BVAS, and 
region will be included as covariates in the model. The logarithm of the follow-up time will be 
used as an offset in the model. 
The secondary endpoints of accrued duration of remission, the average of daily 
prednisolone/prednisone dose during Weeks 48 through 52 (with categories 0 mg/day, > 0 to 
≤4 mg/day, > 4 to ≤ 7.5 mg/day, and > 7.5 mg/day), and percentage reduction from baseline 
in average prednisolone/prednisone dose at Weeks 48 through 52 (with categories no 
reduction or premature discontinuation from treatment before Week 48, < 25% reduction, 25 
to < 50% reduction, 50 to < 75% reduction, 75 to < 100% reduction, and 100% reduction) will 
be analysed using a proportional odds model, with categories for the dependent variable as 
outlined in Section 9.4.1.1. Treatment arm, baseline dose of prednisone, baseline BVAS, and 
region will be included as covariates in the model. Results from the proportional odds model 
will be presented in terms of adjusted odds ratios with 95% CIs.
The following secondary endpoints will be analysed using a logistic regression model:
∀
Proportion of patients who achieved remission within the 24 weeks and remained in 
remission for remainder of the DB treatment period.
∀
Proportion of patients with ≥ 50% reduction in daily prednisolone/prednisone dose from 
baseline during Weeks 48 through 52. 
∀
Proportion of patients with 100% reduction in daily prednisolone/prednisone dose from 
baseline during Weeks 48 through 52.
∀
Proportion of patients with average daily prednisolone/prednisone dose of ≤ 4 mg/day 
during Weeks 48 through 52.
∀
Proportion of patients who achieved any clinical benefit during DB treatment period.
∀
Proportion of patients who achieved complete response during DB treatment period.
Treatment arm, baseline dose of prednisone, baseline BVAS, and region will be included as 
covariates in all the models.
The supportive remission endpoint will also be defined as a BVAS = 0 and 
prednisolone/prednisone dose ≤7.5 mg/day. The following variables will be evaluated under 
this supportive remission definition and analysed as above: proportion of patients who achieve 
remission at both Week 36 and Week 48, total accrued duration of remission, any clinical 
benefit, complete response, and proportion of patients who have achieved remission within the 
first 24 weeks and remained in remission for remainder of treatment period.
BVAS, VDI, ACQ-6, pulmonary function testing, SNOT-22, SF-36v2 (acute; PCS, MCS, and 
domain scores), and blood eosinophil counts will be assessed as change from baseline over the 
52-week treatment period. The change from baseline in the secondary endpoints will be 

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analysed using a MMRM analysis with treatment arm, baseline dose of prednisone, baseline 
BVAS, visit, endpoint's baseline, visit by treatment, and region as covariates. The variance-
covariance matrix will be assumed to be unstructured. If the procedure does not converge, 
then the Toeplitz variance-covariance matrix will be used instead. The primary analysis will 
fit a MMRM model using the data collected up to and including the Week 52 time point. The 
estimate of the treatment effect at Week 52 will be based on a contrast from this MMRM 
model.
Descriptive statistics will be provided for WPAI observed and change from baseline values 
over time by treatment group. Descriptive statistics will be provided for PGIS responses over 
time and PGIC responses between Visits 2 and 4.
The proportion of patients with an ACQ-6 response (defined as a decrease in score from 
baseline of 0.5) at end of the 52-week DB period will be evaluated. The ACQ-6 responder 
analysis will be performed using a logistic regression model adjusted for treatment group, 
baseline ACQ-6 score, baseline dose of prednisone, baseline BVAS score, and region.
Sensitivity Analysis
Sensitivity analyses may be conducted using an on-treatment analysis where patients are 
assumed to not be in remission if they discontinue IP and also using a per-protocol population 
where patients are excluded based on important protocol deviations related to efficacy. These 
sensitivity analyses will be carried out depending on the extent of treatment discontinuations 
and important protocol deviations related to efficacy. Full details of the sensitivity analyses 
will be prespecified in the SAP. 
Subgroup Analysis
To explore the uniformity of the detected overall treatment effect on the primary efficacy 
variable, subgroup analyses will include, but may not be limited to the following factors: 
eosinophils (< 150, ≥150 cells/μL), OCS use at baseline (< 12, ≥12 mg/day), gender, age 
(≥18 to 65 and > 65 years), BMI (≤30, > 30), geographic region, time since EGPA diagnosis 
(≤4, > 4 years), immunosuppressive therapy usage at baseline (yes/no), baseline VDI score 
(< 5, ≥5), race, and ANCA-positive status. These analyses are to be considered as exploratory 
and will be performed on the full analysis set. 
9.4.2
Safety Analyses
Safety analyses will be performed using the safety analysis set. Adverse events will be coded 
using the most recent version of the Medical Dictionary for Regulatory Activities that will 
have been released for execution at AstraZeneca/designee.
Safety data will be presented using descriptive statistics unless otherwise specified. Adverse 
events will be presented for each treatment group by system organ class and/or preferred term 

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covering number and percentage of patients reporting at least one event and number of events 
where appropriate. An overview of AEs for each treatment group will present the number and 
percentage of patients with any AE, AEs with outcome of death, SAEs, and AEs leading to 
discontinuation of IP. Separate AE tables will be provided taking into consideration 
relationship as assessed by the Investigator, intensity, seriousness, death, and events leading to
discontinuation of IP. An additional table will present the number and percentage of patients 
with most common AEs. In accordance with the requirements of the FDA, a separate table 
will present non-serious AEs occurring in more than 5% of patients in any treatment group.
Key patient information will be presented for patients with AEs with outcome of death, SAEs, 
and AEs leading to discontinuation of IP. An AE listing for the safety analysis set will cover 
details for each individual AE.
Full details of AE analyses will be provided in the SAP.
The following events are considered treatment emergent:
∀
AEs with an onset date on or after first dose of IP
∀
Worsening of preexisting events on or after first dose of IP
9.4.3
Other Analyses
Pharmacokinetics, PD, and biomarker exploratory analyses will be described in the SAP 
finalised before the primary database lock. The population PK analysis and PD analyses will 
be presented separately from the CSR for the DB period.
9.4.4
Interim Analyses 
No interim analyses are planned for this study.
9.4.5
OLE Period Analyses
For the OLE period, descriptive statistics will be presented for safety, ADA, PK, remission, 
relapse, and OCS use. Additional analyses may be performed after the primary database lock 
to analyse the data that were not available in the primary analysis. The final database lock will 
occur after the last patient has completed at least one year in the OLE and when the end of the 
study has been declared. A summary of data from the OLE period will be presented in an 
addendum to the primary analysis CSR, and/or a separate OLE period CSR.

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10
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 CSP and with the following:
∀
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines
∀
Applicable ICH GCP guidelines
∀
Applicable laws and regulations
The CSP, CSP amendments, ICF, Investigator Brochure, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.
Any amendments to the CSP 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.
AstraZeneca will be responsible for obtaining the required authorisations to conduct the study 
from the concerned Regulatory Authority. This responsibility may be delegated to a CRO but 
the accountability remains with AstraZeneca.
The investigator will be responsible for providing oversight of the conduct of the study at the 
site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, European 
Regulation 536/2014 for clinical studies (if applicable), European Medical Device Regulation 
2017/745 for clinical device research (if applicable), and all other applicable local regulations.
Regulatory Reporting Requirements for SAEs
∀
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a 
study intervention under clinical investigation are met.
∀
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

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∀
In the European Union, the Sponsor will comply with safety reporting requirements and 
procedures as described in the European Clinical Trials Regulation (EU) No 536/2014. 
All Suspected Unexpected Serious Adverse Reactions (SUSARs) to investigational 
medicinal product will be reported to the EudraVigilance database within the required 
regulatory timelines.
∀
For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.
#
European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations
∀
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements.
Regulatory Reporting Requirements for Serious Breaches
∀
Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met.
#
A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a patient or the reliability and robustness of the data generated in the 
clinical study.
∀
If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
he or she becomes aware of it.
∀
In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.
#
AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If 
EU Clinical Trials Regulation 536/2014 applies, AstraZeneca is required to enter 
details of serious breaches into the European Medicines Agency CTIS. It is important 
to note that redacted versions of serious breach reports will be available to the public 
via CTIS.
∀
The investigator should have a process in place to ensure that:
#
The site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach.
#
A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by AstraZeneca.

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A 2
FINANCIAL DISCLOSURE
Investigators and sub-investigators will provide AstraZeneca with sufficient, accurate 
financial information as requested to allow AstraZeneca to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course 
of the study and for one 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 or 
his/her legally authorised representative and answer all questions regarding the study. 
Patients must be informed that their participation is voluntary and they are free to refuse to 
participate and may withdraw their consent at any time and for any reason during the study. 
Patients or their legally authorised representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, where 
applicable, and the IRB/IEC or study 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 reconsented 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.
Patients who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that briefly addresses the qualitative patient interview 
sub-study. The Investigator or authorised designee will explain the objectives of the sub-study 
to each patient. 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 sub-study. If patients in the 
countries participating in the qualitative patient interview sub-study indicate that they are 
interested in participating in the sub-study, the patient will then complete a separate sub-study 
ICF addendum. 
If a patient’s partner becomes pregnant during or within 12 weeks after the last dose of IP, the 
partner is asked to sign the "Adult Study Informed Consent Form for Pregnant Partners of 
Study Patients" and provide information about the pregnancy accordingly.

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The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The Investigator or authorised designee will 
explain to each patient the objectives of the 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 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 analysed at the time of the request, AstraZeneca 
will not be obliged to destroy the results of this research.
The ICF will contain a separate sub-study addendum that addresses mechanistic sub-study 
procedures. The Investigator or authorised designee will explain to each patient the objectives 
of the mechanistic sub-study. 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 additional specimens to be used for the 
mechanistic sub-study. 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 analysed at the time of the request, AstraZeneca will not be obliged to 
destroy the results of this research.
A 4
DATA PROTECTION
Each patient will be assigned a unique identifier (ID) (E-code) 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 and use of 
their data must also be explained to the patient in the informed consent. 
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 regulatory authorities.
The patient must be informed that data will be collected only for the business needs. We will 
only collect and use the minimum amount of personal data to support our business activities 
and will not make personal data available to anyone (including internal staff) who is not 
authorised or does not have a business need to know the information.
The participant must be informed that in some cases their data may be pseudonymised. The 
General data Protection Regultaion (GDPR) defines pseudonymisation as the processing of 

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personal data in such a way that the personal data can no longer be attributed to a specific 
individual without the use of additional information, provided that such additional information 
is kept separately and protected by technical and organisational measures to ensure that the 
personal data are not attributed to an identified or identifiable natural person.
Personal Data Breaches
A ‘personal data breach’ means a breach of security leading to the accidental or unlawful 
destruction, loss, alteration, unauthorised disclosure of, or access to, personal data transmitted, 
stored or otherwise processed.
∀
In compliance with applicable laws, the Data Controller4 for the processing activity 
where the personal data breach occurred (AstraZeneca or respectively the site), will 
notify the data protection authorities without undue delay within the legal terms 
provided for such notification and within the prescribed form and content.
∀
Whilst AstraZeneca has processes in place to deal with personal data breaches it is 
important that investigators that work with AstraZeneca have controls in place to 
protect patient data privacy.
The Investigator should have a process in place to ensure that:
∀
Allow site staff or service providers delegated by the investigator/institution to identify 
the occurrence of a (potential) personal data breaches.
∀
Any (potential) personal data breach is promptly reported to AstraZeneca or delegated 
party, through the contacts (e-mail address or telephone number) provided by 
AstraZeneca.
AstraZeneca and the site must demonstrate that they:
∀
Have taken all necessary steps to avoid personal data breaches and
∀
Have undertaken measures to prevent such breaches from occurring in the first place 
and to mitigate the impact of occurred data breaches (eg, applying encryption, 
maintaining and keeping systems and IT security measures up-to-date, regular reviews 
and testing, regular training of employees, and developed security policies and 
standards).
                                               
4 The data controller determines the purposes for which and the means by which personal data is processed, as 
defined by the European Commission

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∀
Where possible, have developed an internal data breach reporting and investigation 
process and internal protocols with guidance on how to respond swiftly and diligently 
to the occurrence of a personal data breach.
∀
Where it has not been possible to develop an internal data breach reporting and 
investigation process, the site follows AstraZeneca’s instructions.
Notification of personal Data Breach to participants:
∀
Notification to participants is done by the site for the data breaches that occurred 
within the processing activities for which the site is the Data Controller and for data 
breaches occurred within the processing activities of AstraZeneca as the Data 
Controller, the notification is done in collaboration with the site and is performed by 
the site and/or Principal Investigator, acting on behalf of AstraZeneca, so that 
AstraZeneca has no access to the identifying personal information of the participants. 
The site and/or Principal Investigator shall conduct the notification by contacting the 
participants using the information that they gave for communication purposes in 
clinical research.
∀
If a personal data breach occurs in a processor’s systems, engaged by AstraZeneca, the 
processor under contractual obligations with AstraZeneca promptly and in due course 
after discovering the breach notifies AstraZeneca and provides full cooperation with 
the investigation. In these cases, to the extent AstraZeneca is the Data Controller for 
the processing activity where the breach occurred, it will be responsible for the 
notification to data protection authorities and, if applicable, to participants. If the 
personal data breach needs to be notified to the participants, the notification to 
participants is done in collaboration with the site and is performed by the site and/or 
Principal Investigator, acting on behalf of the Sponsor, so that AstraZeneca has no 
access to the identifying personal information of the participants.
∀
If a personal data breach involving an AstraZeneca's representative device (i.e Study 
Monitor laptop), AstraZeneca representative will provide AstraZeneca with all of the 
information needed for notification of the breach, without disclosing data that allows 
AstraZeneca directly or indirectly to identify the participants. The notification will be 
done by AstraZeneca solely with the information provided by the Study Monitor and 
in no event with access to information that could entail a risk of re-identification of the 
participants. If the data breach must be notified to the data subjects, the notification 
will be done directly by the Study Monitor in collaboration with the site and/or 
Principal Investigator, acting on behalf of the Sponsor, so that AstraZeneca has no 
access to the identifying personal information of the participants. The contract between 
AstraZeneca and the Study Monitor shall expressly specify these conditions.

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∀
The contract between the site and AstraZeneca for performing the clinical research 
includes the provisions and rules regarding who is responsible for coordinating and 
directing the actions in relation to the breaches and performing the mandatory 
notifications to authorities and participants, where applicable.
A 5
DISSEMINATION OF CLINICAL STUDY DATA
Any results both technical and lay summaries for this trial, will be submitted to EU CTIS 
within a year from global End of Trial Date in all participating countries, due to scientific 
reasons, as otherwise statistical analysis is not relevant.
A description of this clinical trial will be available on www.astrazenecaclinicaltrials.com, 
http://www.clinicaltrials.gov and https://euclinicaltrials.eu, as will the summary of the 
main/sub-study results when they are available. The clinical trial and/or summary of 
main/sub-study results may also be available on other websites according to the regulations of 
the countries in which the main/sub-study is conducted.
A 6
DATA QUALITY ASSURANCE
All patient data relating to the study will be recorded on printed or eCRF unless transmitted to 
AstraZeneca or designee electronically (eg, laboratory data). The Investigator is responsible 
for verifying that data entries are accurate and correct or electronically signing the CRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Monitoring details describing strategy, including definition of study-critical data items and 
processes (eg, risk-based initiatives in operations and quality such as Risk Management and 
Mitigation Strategies and Analytical Risk-based Monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are included in the Monitoring Plan(s).
AstraZeneca or designee is responsible for medical oversight throughout the conduct of the
study which includes clinical reviews of study data in accordance with the currently approved 
protocol. Monitoring details describing clinical reviews of study data from a medical 
perspective are included in more detail in the Monitoring Plan(s).
AstraZeneca or designee is responsible for the data management of this study including 
quality checking of the data.

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AstraZeneca assumes accountability for actions delegated to other individuals (eg, CROs).
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete, and verifiable from source 
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 a minimum of 25 years after study archiving or as required 
by local regulations, according to the AstraZeneca Global retention and Disposal (GRAD) 
Schedule. No records may be destroyed during the retention period without the written 
approval of AstraZeneca. No records may be transferred to another location or party without 
written notification to AstraZeneca. 
A 7
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 entered in the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available.
Definitions of what constitutes source data can be found in the Monitoring Plan.
A 8
STUDY AND SITE START AND CLOSURE
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. 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.

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In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the subjects’ interests.
Study sites will be closed upon study completion. A study site is considered closed when all 
required documents and study supplies have been collected and a study-site closure visit has 
been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:
∀
Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines
∀
Inadequate recruitment of patients by the investigator
∀
Discontinuation of further study intervention development
A 9
PUBLICATION POLICY
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to AstraZeneca before 
submission. This allows AstraZeneca to protect proprietary information and to provide 
comments.
AstraZeneca will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, AstraZeneca will generally support publication of 
multicentre studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.

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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 (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a preexisting 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
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-
up), that fulfils one or more of the following criteria:
∀
Results in death
∀
Is immediately life-threatening
∀
Requires in-patient hospitalisation or prolongation of existing hospitalisation 
∀
Results in persistent or significant disability or incapacity.
∀
Is a congenital 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
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 fulfil the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumour as an AE is valid and should occur. Also, 
some types of malignant tumours, which do not spread remotely after a routine treatment that 
does not require hospitalisation, may be assessed as non-serious; examples include Stage 1 
basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.

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Life threatening
Life-threatening means that the 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).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a SAE, although the reasons for it 
may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical operations 
planned before or during a study are not considered AEs if the illness or disease existed before 
the patient was enrolled in the study, provided that it did not deteriorate in an unexpected way 
during the study.
Important medical event or medical treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise the 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.
Examples of such events are:
∀
Angioedema not severe enough to require intubation but requiring IV hydrocortisone 
treatment
∀
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine
∀
Intensive treatment in an emergency room or at home for allergic bronchospasm
∀
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalisation
∀
Development of drug dependency or drug abuse
Intensity rating scale
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).

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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 3
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?
∀
Dechallenge experience: Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?
∀
No alternative cause: The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.
∀
Rechallenge experience: Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a 
rechallenge.
∀
Laboratory tests: A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
∀
Is this a recognised feature of overdose of the drug?
∀
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.

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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 4
MEDICATION ERROR, DRUG ABUSE, AND DRUG MISUSE
Medication Error
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for an IP that either causes harm to the patient or has the potential to 
cause harm to the patient.
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 patient.
Medication error includes situations where an error:
∀
Occurred
∀
Was identified and intercepted before the patient received the drug
∀
Did not occur, but circumstances were recognising that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
∀
Drug name confusion
∀
Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the patient
∀
Drug not administered as indicated, for example, wrong route or wrong site of 
administration
∀
Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a 
solid tablet 
∀
Drug not stored as instructed, eg, kept in the fridge when it should be at room temperature 
∀
Wrong patient received the medication (excluding IRT/RTSM errors)
∀
Wrong drug administered to the patient (excluding IRT/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:
∀
Errors related to or resulting from IRT/RTSM - including those which lead to one of the 
above listed events that would otherwise have been a medication error 
∀
Patient accidentally missed drug dose(s), eg, forgot to take medication
∀
Accidental overdose (will be captured as an overdose)

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∀
Patient failed to return unused medication or empty packaging
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IP a perceived reward or desired non therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded 
to the Data Entry Site (DES) using the Drug Abuse Report Form. This form should be used 
both if the drug abuse happened in a study patient or if the drug abuse involves a person not 
enrolled in the study (such as a relative of the study patient).
Examples of drug abuse include but are not limited to:
∀
The drug is used with the intent of getting a perceived reward (by the study patient or a 
person not enrolled in the study)
∀
The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study patient) of IP for medicinal 
purposes outside of the authorised product information, or for unauthorised IPs, outside the 
intended use as specified in the protocol and includes deliberate administration of the product 
by the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study patient or if the drug misuse regards a person not enrolled in the 
study (such as a relative of the study patient).
Examples of drug misuse include but are not limited to:
∀
The drug is used with the intention to cause an effect in another person
∀
The drug is sold to other people for recreational purposes 
∀
The drug is used to facilitate assault in another person
∀
The drug is deliberately administered by the wrong route
∀
The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole

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∀
Only half the dose is taken because the study patient feels that he/she is feeling better 
when not taking the whole dose
∀
Someone who is not enrolled in the study intentionally takes the drug

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Appendix C
HANDLING OF HUMAN BIOLOGICAL SAMPLES
C 1
CHAIN OF CUSTODY 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.
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 AstraZeneca-assigned biobanks and will 
be registered by the AstraZeneca Biobank Team during the entire life cycle.
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 analysed,
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 patient’s 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 organisation(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 organisations 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.

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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 
(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, eg, 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, eg, Hepatitis A, B, C, D, and E viruses, 
HIV 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 subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to contain 
any risk of infection or contamination by using approved couriers and 
packaging/containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.

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Appendix D
OPTIONAL GENOMICS INITIATIVE SAMPLE
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 IRB/IEC 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, ie, the 
entire genome. 
The results of genetic analyses may be reported in the CSR 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 benralizumab continues, but no longer than 
15 years or other period as per local requirements.
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 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 of the main 
CSP and Appendix C 2.
Collection of Samples for Genetic Research
The blood sample for genetic research will be obtained from the patients at baseline (Visit 2), 
or at any other visit if not collected at randomisation. Although DNA is stable, early sample 
collection is preferred to avoid introducing bias through excluding patients who may withdraw 
due to an AE, such patients would be important to include in any genetic analysis. If for any 
reason the sample is not drawn at baseline (Visit 2), 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 last patient’s last visit, after which they will be destroyed. DNA is a 
finite resource that is used up during analyses. Samples will be stored and used until no further 
analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable only by the second, unique number. This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
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/randomisation code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organisations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, 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 centre. 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 organisations to analyse the samples.
AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organisations or health insurance companies. This can 
be done by placing the results in scientific databases, where they can be combined with the 
results of similar studies to learn even more about health and disease. The researchers can 

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

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Appendix E
ANAPHYLAXIS: DEFINITION, SIGNS, SYMPTOMS AND 
MANAGEMENT
E 1
INTRODUCTION
As with any antibody, allergic reactions to dose administration are possible. The World Health 
Organisation has categorised anaphylaxis into 2 subgroups, which are clinically 
indistinguishable: immunologic (IgE-mediated and non-IgE-mediated [eg, IgG and immune 
complex-mediated]) and non-immunologic (Johansson et al 2004). The clinical criteria for 
defining anaphylaxis for this study are listed in Section E 2 of this Appendix. A guide to the 
signs and symptoms and management of acute anaphylaxis is provided in Section E 3 of this 
Appendix. Appropriate drugs, such as epinephrine, antihistamines, corticosteroids, etc, and 
medical equipment to treat anaphylactic reactions should be available at study sites, and study 
personnel should be trained to recognise and treat anaphylaxis according to local guidelines. 
If an anaphylactic reaction occurs, a blood sample for serum tryptase should be collected as 
soon as possible after the event, at 90 ± 30 minutes after the event, and at discharge; analysis 
for serum tryptase will be performed at a local laboratory. Other blood or urine testing 
relevant to the diagnosis of anaphylaxis may be obtained at a local lab at the discretion of the 
Investigator.
E 2
CLINICAL CRITERIA FOR DEFINING ANAPHYLAXIS AND 
IMMUNE COMPLEX DISEASE
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 (eg, generalised hives, pruritus or flushing, swollen lips-tongue-uvula) and 
at least one of the following:
(a) Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow [PEF], hypoxemia).
(b) Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence).
2
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours):
(a) Involvement of the skin-mucosal tissue (eg, generalised hives, itch-flush, swollen 
lips-tongue-uvula).
(b) Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia).

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(c) Reduced blood pressure or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence).
(d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting).
3
Reduced blood pressure after exposure to known allergen for that patient (minutes to 
several hours). For adults, this corresponds to a systolic blood pressure of less than 
90 mm Hg or a greater than 30% decrease from that patient’s baseline. 
Immune Complex Disease
Immune complex disease or hypersensitivity type III is evoked by the deposition of antigen-
antibody or antigen antibody-complement complexes on cell surfaces, with subsequent 
involvement of breakdown products of complement, platelets, and polymorphonuclear 
leukocytes, and development of vasculitis; serum sickness and nephritis are common.
E 3
SIGNS AND SYMPTOMS AND MANAGEMENT OF ACUTE 
ANAPHYLAXIS
Anaphylaxis is an acute and potentially lethal multi-system allergic reaction in which some or 
all of the following signs and symptoms occur: 
∀
Diffuse erythema
∀
Pruritus
∀
Urticaria and/or angioedema
∀
Bronchospasm
∀
Laryngeal oedema
∀
Hypotension
∀
Cardiac arrhythmias
∀
Feeling of impending doom
∀
Unconsciousness
∀
Shock
Other earlier or concomitant signs and symptoms can include:
∀
Itchy nose, eyes, pharynx, genitalia, palms, and soles
∀
Rhinorrhoea
∀
Change in voice
∀
Metallic taste
∀
Nausea, vomiting, diarrhoea, abdominal cramps, and bloating
∀
Light headedness
∀
Headache

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∀
Uterine cramps
∀
Generalised warmth
E 4
MANAGEMENT OF ACUTE ANAPHYLAXIS
E 4.1
IMMEDIATE INTERVENTION
1
Assessment of airway, breathing, circulation, and adequacy of mentation.
2
Administer epinephrine IM every 5 to 15 minutes, in appropriate doses, as necessary, 
depending on the presenting signs and symptoms of anaphylaxis, to control signs and 
symptoms and prevent progression to more severe symptoms such as respiratory distress, 
hypotension, shock and unconsciousness.
E 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
E 4.3
SPECIFIC MEASURES TO CONSIDER AFTER EPINEPHRINE 
INJECTIONS, WHERE APPROPRIATE
(a) Consider epinephrine infusion 
(b) Consider H1 and H2 antihistamines
(c) Consider nebulised β2 agonist (eg, albuterol [salbutamol]) for bronchospasm resistant 
to epinephrine
(d) Consider systemic corticosteroids
(e) Consider vasopressor (eg, dopamine)
(f) Consider glucagon for patient taking β-blocker
(g) Consider atropine for symptomatic bradycardia
(h) Consider transportation to an emergency department or an intensive care facility
(i)
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and prolonged 
resuscitation efforts are encouraged, if necessary
Adapted from Kemp et al 2008.

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Appendix F
MEDICAL DEVICE AEs, ADEs, SAEs, SADEs, USADEs, 
AND MEDICAL DEVICE DEFICIENCIES: DEFINITIONS 
AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW-UP, AND REPORTING
∀
The definitions and procedures detailed in this appendix are in accordance with 
International Organization for Standardization 14155 and European Medical Device 
Regulation 2017/745 for clinical device research (if applicable). 
∀
Both the investigator and AstraZeneca will comply with all local reporting requirements 
for medical devices.
∀
The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices/combination products provided for use in the study. See Section 
6.1.2 for the list of sponsors combination products.
F 1
DEFINITION OF MEDICAL DEVICE AE AND ADE
Medical Device AE and ADE Definition
∀
A medical device AE is any untoward medical occurrence in a clinical study patient, 
users, or other persons, temporally associated with the use of study intervention, whether 
or not considered related to the medical device. An AE can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease 
(new or exacerbated) temporally associated with the use of a medical device. This 
definition includes events related to the medical device or comparator and events related 
to the procedures involved except for events in users or other persons, which only include 
events related to medical devices.
∀
Adverse Device Effect is defined as an AE related to the use of a medical device. This 
definition includes any AE resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the medical 
device as well as any event resulting from use error or from intentional misuse of the 
medical device. 
F 2
DEFINITION OF MEDICAL DEVICE SAE, SADE AND USADE
A Medical Device SAE is any AE that:
∀
Led to death.
∀
Led to serious deterioration in the health of the patient, that either resulted in:
#
A life-threatening illness or injury. The term ‘life-threatening’ in the definition of 
‘serious’ refers to an event in which the patient was at risk of death at the time of the 
event. It does not refer to an event, which hypothetically might have caused death if it 
were more severe.
#
A permanent impairment of a body structure or a body function.

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#
Inpatient or prolonged hospitalisation. Planned hospitalisation for a pre-existing 
condition, or a procedure required by the protocol, without serious deterioration in 
health, is not considered an SAE.
#
Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function.
#
Chronic disease (European Medical Device Regulation 2017/745).
∀
Led to foetal distress, foetal death, or a congenital anomaly or birth defect.
A Medical Device SADE is:
∀
Any ADE that has resulted in any of the consequences characteristic of an SAE.
∀
Any medical device deficiency that might have led to an SAE if appropriate action had 
not been taken, intervention had not occurred, or circumstances had been less fortunate.
USADE Definition
∀
A USADE (also identified as UADE in 21 CFR 812.3) is defined as a SADE that by its 
nature, incidence, severity, or outcome has not been identified in the current version of 
the risk analysis report (see Section 2.3).
F 3
DEFINITION OF MEDICAL DEVICE DEFICIENCY
Medical Device Deficiency Definition
∀
A device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. Device deficiencies include 
malfunctions, use errors, and inadequacy of the information supplied by the manufacturer.
F 4
RECORDING AND FOLLOW-UP OF MEDICAL DEVICE AE 
AND/OR SAE AND MEDICAL DEVICE DEFICIENCIES
AE, SAE, and Medical Device Deficiency Recording
∀
When an AE/SAE/medical device deficiency occurs, it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory reports, 
and diagnostics reports) related to the event.
∀
The investigator will then record all relevant AE/SAE/medical device deficiency 
information in the patient’s medical records, in accordance with the investigator’s normal 
clinical practice and on the appropriate form.
∀
It is not acceptable for the investigator to send photocopies of the patient’s medical 
records to sponsor in lieu of completion of the AE/SAE/medical device deficiency form.

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∀
There may be instances when copies of medical records for certain cases are requested by 
sponsor. In this case, all patient identifiers, except for the patient number, will be redacted 
on the copies of the medical records before submission to the sponsor.
∀
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
∀
For medical device deficiencies, it is very important that the investigator describes any 
corrective or remedial actions taken to prevent recurrence of the deficiency.
#
A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of a medical 
device deficiency. This includes any protocol revision to the medical device design to 
prevent recurrence.
Assessment of Intensity
The investigator will assess intensity for each AE/SAE/medical device deficiency reported 
during the study and assign it to one of the following categories: 
∀
Mild (awareness of sign or symptom, but easily tolerated)
∀
Moderate (discomfort sufficient to cause interference with normal activities)
∀
Severe (incapacitating, with inability to perform normal activities)
Other measures to evaluate AEs and SAEs may be used (eg, National Cancer Institute 
CTCAE).
Assessment of Causality
∀
The investigator is obligated to assess the causal relationship between study intervention 
and each occurrence of AE/SAE/medical device deficiency.
∀
A ‘reasonable possibility’ of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship.
∀
The investigator will use clinical judgment to determine the relationship.
∀
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.
∀
The investigator will also consult the IB and/or Product Information for marketed 
products in their assessment. 
∀
For each AE/SAE/medical device deficiency, the investigator must document in the 
medical notes that they have reviewed the AE/SAE/medical device deficiency and have 
provided an assessment of causality.
∀
There may be situations in which an SAE has occurred, and the investigator has minimal 
information to include in the initial report to sponsor. However, it is very important that 

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the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to sponsor.
∀
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
∀
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.
Medical Device Coordination Group 2020 Guidance 
For the purpose of harmonising reports, each SAE will be classified according to 5 different 
levels of causality. AstraZeneca and the investigators will use the following definitions to 
assess the relationship of the SAE to the investigational device5 or procedures.
1
Not related: Relationship to the device or procedures can be excluded when:
(a) The event has no temporal relationship with the use of the investigational device or 
the procedures;
(b) The serious event does not follow a known response pattern to the investigational 
device (if the response pattern is previously known) and is biologically implausible;
(c) The discontinuation of investigational device application or the reduction of the level 
of activation/exposure - when clinically feasible - and reintroduction of its use (or 
increase of the level of activation/exposure), do not impact the serious event;
(d) The event involves a body-site or an organ not expected to be affected by the device 
or procedure;
(e) The serious event can be attributed to another cause (eg, an underlying or concurrent 
illness/clinical condition, an effect of another device, drug, treatment, or other risk 
factors);
(f) The event does not depend on a false result given by the investigational device used 
for diagnosis, when applicable.
In order to establish the non-relatedness, not all the criteria listed above might be met at the 
same time, depending on the type of device/procedures and the serious event.
2
Unlikely: The relationship with the use of the device seems not relevant and/or the event 
can be reasonably explained by another cause, but additional information may be 
obtained.
3
Possible: The relationship with the use of the investigational device is weak but cannot be 
ruled out completely. Alternative causes are also possible (eg, an underlying or 
concurrent illness/clinical condition or/and an effect of another medical device, drug, or 
                                               
5 Investigational device: Any device object of the clinical investigation, including the comparators.

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treatment). Cases where relatedness cannot be assessed, or no information has been 
obtained should also be classified as possible.
4
Probable: The relationship with the use of the investigational device seems relevant 
and/or the event cannot be reasonably explained by another cause, but additional 
information may be obtained.
5
Causal relationship: the serious event is associated with the investigational device or with 
procedures beyond reasonable doubt when:
(a) The event is a known side effect of the product category the investigational device 
belongs to or of similar devices and procedures;
(b) The event has a temporal relationship with investigational device use/application or 
procedures;
(c) The event involves a body-site or organ that
(d) the investigational device or procedures are applied to;
(e) the investigational device or procedures influence;
(f) The serious event follows a known response pattern to the investigational device (if 
the response pattern is previously known);
(g) The discontinuation of investigational device application (or reduction of the level of 
activation/exposure) and reintroduction of its use (or increase of the level of 
activation/exposure) impact the serious event (when clinically feasible);
(h) Other possible causes (eg, an underlying or concurrent illness/ clinical condition 
or/and an effect of another device, drug or treatment) have been adequately ruled out;
(i)
Harm to the patient is due to error in use;
(j)
The event depends on a false result given by the investigational device used for 
diagnosis, when applicable.
In order to establish the relatedness, not all the criteria listed above might be met at the same 
time, depending on the type of device/procedures and the serious event.
Follow-Up of AE/SAE/Medical Device Deficiency
∀
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sposnor to 
elucidate the nature and/or causality of the AE/SAE/medical device deficiency as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other healthcare professionals.
∀
If a patient dies during participation in the study or during a recognised follow-up period, 
the investigator will provide sponsor with a copy of any post mortem findings including 
histopathology. 
∀
New or updated information will be recorded in the original form used to report the 
deficiency.

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∀
The investigator will submit any updated SAE data to sponsor within 24 hours of receipt 
of the information.
F 5
REPORTING OF MEDICAL DEVICE SAES AND SADES
∀
All medical device SAEs will be reported in accordance with Section 8.4.1.
NOTE: There are additional reporting obligations for SADEs that must fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about certain 
safety information relating to medical devices being used in clinical studies.
∀
Any medical device deficiency that is associated with an SAE must be reported to 
AstraZeneca within 24 hours after the investigator determines that the event meets the 
definition of a medical device deficiency.
∀
In addition to the reporting process described in Section 8.4.1, the AstraZeneca Clinical 
Study Medical Device/Device Constituent Report Form will be used to capture details of 
the device and related deficiency.
∀
Email transmission of the AstraZeneca Clinical Study Medical Device/Device Constituent 
Report Form is the preferred method to transmit this information to the Study Clinical 
Lead/SAE coordinator.
∀
Initial notification via telephone does not replace the need for the investigator to complete 
and sign the AstraZeneca Clinical Study Medical Device/Device Constituent Report Form 
within the designated reporting time frames.
∀
AstraZeneca will review all medical device deficiencies and determine and document in 
writing whether they could have led to an SAE. These medical device deficiencies will be 
reported to the regulatory authorities and IRBs/IECs as required by national regulations.

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Appendix G
CHANGES RELATED TO MITIGATION OF STUDY 
DISRUPTIONS DUE TO CASES OF CIVIL CRISIS, 
NATURAL DISASTER, OR PUBLIC HEALTH CRISIS
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
patients become infected with SARS-CoV-2 or similar pandemic infection) 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 and instructions on how to perform these procedures will be 
provided at the time of implementation.Please note that during civil crisis, natural disaster, or 
public health crisis, some study assessments and procedures may not be conducted due to 
international or local policies or guidelines, hospital or clinic restrictions and other measures 
implemented to ensure the patient’s safety. If in doubt, please contact the AZ Study Physician. 
If patient testing is performed as a result of the public health crisis, results may be documented 
for this study. 
G 1
CONSENT/RECONSENT OF STUDY PATIENTS DURING 
STUDY INTERRUPTIONS
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, eg, remote visits. Consent/reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Sections F2 to F5. Local and regional regulations and/or guidelines regarding 
consent/reconsent of study patients should be checked and followed. Consent/reconsent may 
be verbal if allowed by local and regional guidelines (note, in the case of verbal reconsent the 
ICF should be signed at the patient’s next contact with the study site). Visiting the study sites 
for the sole purpose of obtaining consent/reconsent should be avoided. 
G 2
RESCREENING OF PATIENTS TO RECONFIRM STUDY 
ELIGIBILITY
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened patients. The investigator should confirm this with the designated study 
physician.
In addition, during study disruption there may be a delay between confirming eligibility of a 
patient and either enrolment into the study or commencing of dosing with IP. If this delay is 
outside the screening window specified in SoA (Table 1) the patient will need to be rescreened 
to reconfirm eligibility before commencing study procedures. This will provide another 

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opportunity to re-screen a patient in addition to that detailed in Section 5.5.1 (Rescreening).
The procedures detailed in Section 5.3 (Criteria to be Confirmed/Reconfirmed at Baseline) 
must be undertaken to confirm eligibility using the same screening/ enrolment number as for 
the patient.
G 3
HOME OR REMOTE VISIT TO REPLACE ON-SITE VISIT 
(WHERE APPLICABLE)
A qualified HCP from the study site or TPV service will visit the patients home / or other 
remote location as per local Standard Operating Procedures (SOPs), as applicable. Supplies 
will be provided for a safe and efficient visit. The qualified HCP will be expected to collect 
information per the clinical study protocol (CSP).
G 4
TELEMEDICINE VISIT TO REPLACE ON-SITE VISIT 
(WHERE APPLICABLE)
In this appendix, the term telemedicine visit refers to remote contact with the patients using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the patients will allow assessments such as adverse events, concomitant medications, 
BVAS/VDI, OCS usage to be reported and documented. 
G 5
AT-HOME OR REMOTE LOCATION IP ADMINISTRATION 
INSTRUCTIONS
If a site visit is not possible, at-home or remote location administration of IP may be 
performed by a qualified HCP, provided this is acceptable within local regulations/guidance, 
or by the patient or his/her caregiver. The option of at-home or remote location IP 
administration ensures patient safety in cases of a pandemic where patients may be at 
increased risk by traveling to the site/clinic. This will also minimize interruption of IP 
administration during other study disruptions, eg, site closures due to natural disaster. 
G 5.1
AT-HOME OR REMOTE LOCATION IP ADMINISTRATION BY A 
QUALIFIED HCP OR TPV SERVICE
A qualified HCP from the study site or TPV service may administer the IP at the patient’s
home or other remote location according to the CSP. All necessary supplies and instructions 
for administration and documentation of IP administration will be provided. Additional 
information related to the visit can be obtained via a telemedicine or home visit.

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G 5.2
AT-HOME OR REMOTE LOCATION IP ADMINISTRATION BY 
THE PATIENT OR HIS/HER CAREGIVER
Prior to at-home or remote location IP administration the investigator must assess the patient
or his/her caregiver to determine whether they are appropriate for at-home or remote location 
administration of IP. Once the patient or his/her caregiver is deemed appropriate for at-home 
or remote location administration, he/she must receive appropriate training. All necessary 
supplies and instructions for administration and documentation of IP administration will be 
provided. More information related to the visit can be obtained via a telemedicine or home / 
remote visit.
G 6
DATA CAPTURE DURING TELEMEDICINE OR HOME / 
REMOTE VISITS
Data collected during telemedicine or home / remote visits will be captured by the qualified 
HCP from the study site or TPV service, or by the patient themselves.

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Appendix H
RECOMMENDED PREDNISOLONE/PREDNISONE 
TAPERING SCHEDULE FROM WEEK 4 (VISIT 4)

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Appendix I
ADRENAL CRISIS GUIDELINES
Management of Acute Adrenal Insufficiency Secondary to Glucocorticoid Withdrawal
National or local guidelines for the management of acute adrenal insufficiency (adrenal crisis), 
where they exist, should be followed. The following guidelines have been adapted from the 
guidelines of the Society for Endocrinology6. They are intended for guidance subject to 
clinical judgement only.
The possibility of acute adrenal insufficiency should be considered in any acutely unwell 
patient undergoing withdrawal of chronic systemic corticosteroid treatment.
Recognition
∀
Clinical signs and symptoms:
#
Fatigue, lack of energy, weight loss
#
Low blood pressure, postural dizziness and hypotension (≥20 mmHg drop in systolic 
blood pressure from supine to standing position), dizziness, collapse, and in severe 
cases hypovolaemic shock
#
Abdominal pain, tenderness and guarding, nausea, vomiting
#
Fever
#
Confusion, somnolence, in severe cases delirium or coma
#
Back and leg cramps/spasms may be reported
∀
Lab findings:
#
Hyponatraemia
#
Pre-renal failure (increased serum creatinine due to hypovolaemia)
#
Normochromic anaemia, sometimes also lymphocytosis and eosinophilia
#
Hypoglycaemia
Management
∀
Hydrocortisone (immediate bolus injection of 100 mg hydrocortisone IV or IM followed 
by continuous IV infusion of 200 mg of hydrocortisone per 24 hours (alternatively 50 mg 
of hydrocortisone per IV or IM injection every 6 hours)
∀
Rehydrate with IV 0.9% sodium chloride in hypotensive patients. The rate and total 
volume of infusate must be decided on an individual patient basis with continuous 
                                               
6 Arlt W. Society for Endocrinology Clinical Committee. Society for Endocrinology Endocrine Emergency 
Guidance: Emergency management of acute adrenal insufficiency (adrenal crisis) in adult patients. Endocr 
Connect 2016;(5):G1-G3

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monitoring for fluid overload. Correction of hyponatremia must be according to relevant 
local guidelines
∀
Consider any other potential precipitating factors (in addition to corticosteroid 
withdrawal), eg, infection; investigate and treat as appropriate.
Contact an endocrinologist at an early stage to advise on ongoing management.

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Appendix J
ABBREVIATIONS
Abbreviation or special 
term
Explanation
ACQ-6
Asthma Control Questionnaire (6-item version)
ADA
Anti-drug antibodies
AE(s)
Adverse event(s)
ALT
Alanine aminotransferase
ANCA(s)
Anti-neutrophil cytoplasmic antibody (ies)
APFS
Accessorised prefilled syringe
AST
Aspartate aminotransferase
BD
Bronchodilator
BMI
Body mass index
BVAS
Birmingham Vasculitis Activity Score
CI
Confidence interval
CRF
Case report form
CSP
Clinical study protocol
CSR
Clinical study report
CTIS
Clinical Trial Information System
CYC
Cyclophosphamide
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic case report form
EGPA
Eosinophilic granulomatosis with polyangiitis
EOT
End of treatment
ePRO
Electronic patient-reported outcome
EU
European Union
Fc
Fragment crystallizable
FDA
Food and Drug Administration 
FEV1
Forced expiration volume in 1 second
FSH
Follicle stimulating hormone
FU
Follow-up
GCP
Good Clinical Practice
HBsAg
Hepatitis B surface antigen
HCG
Human Chorionic Gonadotropin
HCP
Health Care Professional
HES
Hypereosinophilic syndrome

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Abbreviation or special 
term
Explanation
HIV
Human immunodeficiency virus
HRQoL
Health-related quality of life
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
International Coordinating 
Investigator
If a study is conducted in several countries the International Coordinating 
Investigator is the Investigator coordinating the Investigators and/or activities 
internationally
Ig
Immunoglobulin
IgE
Immunoglobulin E
IgG1
Immunoglobulin G, subclass 1
IgG1κ
Immunoglobulin G1, kappa isotype
IL
Interleukin
IL-5Rα
Interleukin-5 receptor alpha 
IM
Intramuscular
IP
Investigational product
IPD
Investigational product discontinuation
IRB
Institutional review board
IV
Intravenous(ly)
IRT
Interactive response technology
LABA
Long-acting β2 agonist
LAMA
Long-acting muscarinic antagonist
mAb
Monoclonal antibody
MCS
Psychometrically-based mental health component summary score (in SF-36v2 
questionnaire)
MMRM
Mixed-effect model for repeated measures
MoA
Mechanism of action
MPO
Myeloperoxidase
nAb
Neutralising antibodies
NI
Non-inferiority
NYHA
New York Heart Association
OCS
Oral corticosteroids
OLE
Open-label extension
PBMC(s)
Peripheral blood mononuclear cell(s)
PCS
Psychometrically-based physical health component summary score (in SF-36v2 
questionnaire)

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Abbreviation or special 
term
Explanation
PD
Pharmacodynamic(s)
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PNV
Predicted normal value
PK
Pharmacokinetic(s)
PR3
Proteinase 3
PRO(s)
Patient-reported outcome(s)
Q4W
Every 4 weeks
Q8W
Every 8 weeks
QTc
QT interval corrected
QTcF
QT interval corrected by Fredericia’s
RNA
Ribonucleic acid
RoW
Rest of World
RTSM
Randomisation and trial supply system management
SABA
Short acting β2 agonist
SAE(s)
Serious adverse event(s) 
SAP
Statistical analysis plan
SADE
Serious adverse device effect
SC
Subcutaneous(ly)
SF-36v2
Short Form 36-Item Health Survey (version 2)
SNOT-22
Sino-Nasal Outcomes Test 22
SoA
Schedule of assessments
SOP
Standard Operating Procedure
SSQ
Sino-nasal Symptoms Questionnaire
SUSAR
Suspected unexpected serious adverse reactions
TPV
Third Party Vendor
ULN
Upper limit of normal
US
United States
VDI
Vasculitis Damage Index
WBC
White blood cells
WOCBP
Women of child-bearing potential
WPAI
Work Productivity and Activity Impairment Questionnaire
WPAI-GH
Work Productivity and Activity Impairment Questionnaire - General Health

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Appendix K
COUNTRY-SPECIFIC REQUIREMENTS
K 1
FRANCE (VERSION 1.0, 29 JULY 2019)
Reason for Addendum: 
A local EGPA cohort was initiated in France meeting the definition of “interventional clinical 
study” without any administration of investigational product.
In order to give a chance to patient participating to this cohort to be included in D3253C00001 
clinical trial, an exception needs to be added to the current exclusion criterion #18.
Centres Affected by the Addendum
All French sites 
Change text is indicated in bold italic underlined where applicable.
Section of Protocol Affected 
Section 5.2 - Exclusion Criterion #18
Previous Text:
18. Patient is currently participating in any other interventional clinical study.
Revised Text: 
18. Patient is currently participating in any other interventional clinical study (with the 
exception of “registry”/ “cohort” trials which may include periodic biological sampling 
and/or patient questionnaires but in which no other un-licenced investigational product is 
administered).
K 2
BELGIUM (VERSION 1.0, 31 OCTOBER 2019)
Centres Affected by the CSP Country Addendum:
This Local Addendum affects all Centres in Belgium.
Reason for Use of CSP Country Addendum:
The global CSP requires that the background standard of care corticosteroid treatment consists 
of either prednisone or prednisolone for all patients. In addition, the OCS doses should be 
tapered as described in the CSP and the study protocol provides a tapering scheme for 
guidance of tapering steps. 
The primary endpoint as described in the global study protocol is the proportion of patients 
with relapsing or refractory EGPA, achieving remission, defined as BVAS=0 and OCS dose 
≤4 mg/day (Main Remission definition) at both weeks 36 and 48. 

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Prednisone and prednisolone are not commercially available in Belgium (unless in magistral 
preparation) and are therefore not usually used in Belgium as OCS treatment in EGPA 
patients. Therefore, the use of methylprednisolone as background OCS treatment will be 
allowed for Belgian sites. Methylprednisolone is the standard of care used in Belgium to treat 
EGPA patients who require OCS.
The conversion factor for prednisone/prednisolone to methylprednisolone is 0.8 (Source: The 
online conversion calculator https://clincalc.com/corticosteroids/ for conversion of other OCS 
doses or other OCS products):
Estimated OCS Dose Therapy Equivalence:
Oral Corticosteroid
Approximate equivalence dose
Prednisone
10 mg
Prednisolone
10 mg
Methylprednisolone
8 mg
Conversion table based on above-mentioned ‘Estimated OCS Dose Therapy Equivalence’:
Prednisone/Prednisolone 
Approximate equivalence dose 
methylprednisolone 
50 mg
40 mg
45 mg
36 mg
40 mg
32 mg
35 mg
28 mg
30 mg
24 mg
25 mg
20 mg
20 mg
16 mg
17.5 mg
14 mg
15 mg
12 mg
12.5 mg
10 mg
10 mg
8 mg
8 mg
6.4 mg
5 mg
4 mg
4 mg
3.2 mg
2.5 mg
2 mg
2 mg
1.6 mg
1 mg
0.8 mg
0.5 mg
0.4 mg

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As per the Clinical Study Protocol (section 6.5.1), patients will be required to continue their 
stable OCS dose (if necessary, upward adjustments are permitted for clinical management of 
the patient) between baseline (Visit 2) and Week 4 (Visit 4). Week 4 post-baseline (Visit 4) 
onwards if the patient’s BVAS=0 their OCS dose should be tapered downwards according to 
standard of care practice. If the BVAS ≠0, the Investigator may taper the patient's OCS 
downwards at his/her clinical discretion. A recommended tapering schedule is provided in 
Appendix H. The tapering schedule provided in Appendix H has reductions of:
#
10 mg prednisone/prednisolone (equivalence dose of 8 mg methylprednisolone)
#
5 mg prednisone/prednisolone (equivalence dose of 4 mg methylprednisolone)
#
2.5 mg prednisone/prednisolone (equivalence dose of 2 mg methylprednisolone)
#
2 mg prednisone/prednisolone (equivalence dose of 1.6 mg methylprednisolone)
#
1 mg prednisone/prednisolone (equivalence dose of 0.8 mg methylprednisolone)
#
0.5 mg prednisone/prednisolone (equivalence dose of 0.4 mg methylprednisolone)
Current presentations in Belgium include methylprednisolone 32 mg, 16 mg & 4 mg tablets. 
The 2 mg, 0.8 mg, and 0.4 mg tablets methylprednisolone are not available. The 4 mg tablet 
methylprednisolone can be divided in four equal pieces. Local practice and guidelines will be 
used for the lower doses of methylprednisolone.
In all sections of the CSP please replace the previous text by the revised text below:
Previous text:
Prednisone/prednisolone
0.5 mg / 1 mg / 2 mg / 2.5 mg / 4 mg / 5 mg / 8 mg / 10 mg / 12.5 mg / 15 mg / 17.5 mg / 20 
mg / 25 mg / 30 mg / 35 mg / 40 mg / 45 mg / 50 mg
Revised text:
Methylprednisolone
0.4 mg / 0.8 mg / 1.6 mg / 2 mg / 3.2 mg / 4 mg / 6.4 mg / 8 mg / 10 mg /12 mg / 14 mg / 16 
mg / 20 mg / 24 mg / 28 mg / 32 mg / 36 mg / 40 mg

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Appendix L
PROTOCOL VERSION HISTORY
The Summary of Changes Table for the current version is located directly before the Table of 
Contents.
L 1
AMENDMENT 4 (VERSION 5.0): 11 APRIL 2023
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union,
because it may affect the safety or physical/mental integrity of patients or the scientific value 
of the study.
Overall Rationale for the Amendment
The primary rationale for this protocol amendment is to extend the intended duration of the 
open-label extension (OLE), to add an additional objective of clinical benefit rate, consistent 
with that reported in Steinfeld et al 2019 to the objectives table, and to add additional steroid 
reduction endpoints to the existing oral corticosteroid objective. Furthermore, the protocol has 
been amended to comply with the requirements/legislation due to changes in EU Clinical Trial 
Regulation, regulatory requirements, inspection outcomes, and protocol template and to 
incorporate changes due to local requirements. Minor editorial changes have also been made 
throughout the protocol. 
Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
1.1 Schedule of 
Assessments (Table 2)
Reduced frequency of assessments 
for weight and urine pregnancy test 
(dipstick) and removed brief 
physical examination from all visits 
except from unscheduled visits.
To reduce patient/site 
burden.
Non-substantial
1.1 Schedule of 
Assessments (Table 3) 
and (Table 4)
Increased visits that can be done 
remotely, reduced frequency of 
assessments for vital signs, serum 
chemistry, and urine pregnancy test 
(dipstick), removed assessments for 
weight from all visits except 
unscheduled and IPD/EOT visits, 
removed assessments for health 
resource use and complete physical 
examination from all visits except 
IPD/EOT visit, and removed 
assessments for spirometry, brief 
physical examination, ESR, and 
To reduce patient/site 
burden. Spirometry, 
health resource use, ESR, 
and CRP are not part of 
the OLE Year 2 and 3
objectives.
Non-substantial

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
CRP from all visits except 
unscheduled visits.
1.1 Schedule of 
Assessments (Table 5)
Added a new Schedule of 
Assessments presenting the 
assessments to be performed during 
Year 4 onwards in the OLE.
To ensure continuity of 
treatment for patients 
who would end Year 3 of 
the OLE before all 
patients have been 
allowed at least one year 
of treatment with open-
label benralizumab. 
Substantial
1.2 Synopsis (Table 7) 
and Statistical Methods
3 Objectives and 
Endpoints (Table 9)
9.4.1 Efficacy 
Analyses
Changed one secondary objective 
and clarified one corresponding 
secondary endpoint and added 
corresponding secondary endpoints:
Changed objective:
To assess the effect of 
benralizumab on average daily dose 
of corticosteroid dose required 
during Weeks 48 through 52 in 
patients receiving benralizumab 
compared to mepolizumab
Clarified and added new endpoints:
Based on the average daily 
prednisolone/prednisone dose 
during Weeks 48 through 52:
Proportion of patients in each 
category of average daily 
prednisolone/prednisone dose
during Weeks 48 through 52 using 
the following categories: 0 mg; > 0 
to ≤ 4 mg; > 4 to ≤ 7.5 mg, and > 
7.5 mg (clarified).
Proportion of patients in each 
category of percent reduction from 
baseline: no reduction or 
withdrawal from treatment; < 25% 
reduction; 25 to < 50% reduction; 
50 to < 75% reduction; 75 to < 
100% reduction; 100% reduction 
(new).
Proportion of patients with ≥ 50% 
reduction from baseline (new).
To assess the steroid 
sparing effect of 
treatment.
Substantial

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
Proportion of patients with 100% 
reduction from baseline (new).
Proportion of patients with ≤ 4 mg 
in average daily dose (new).
1.2 Synopsis (Table 7) 
and Statistical Methods
3 Objectives and 
Endpoints (Table 9)
Added a secondary objective:
To assess the clinical benefit of 
benralizumab compared to 
mepolizumab.
AND
Added corresponding endpoints:
Proportion of patients who have 
achieved any clinical benefit when 
meeting any of the criteria below.
Proportion of patients who have 
achieved complete response when 
meeting all of the criteria below.
Remission (defined as BVAS = 0 
and prednisolone/prednisone dose ≤ 
4 mg/day) at any time during the 
double-blind treatment period
≥ 50% reduction in average daily 
prednisolone/prednisone dose 
during Weeks 48 through 52
EGPA relapse free during the 
double-blind treatment period.
Analysis will be repeated for the 
supportive remission definition.
To combine current 
endpoints to assess 
clinical benefit in a 
clinically relevant way 
(Steinfeld et al 2019).
Substantial
1.1 Schedule of 
Assessments (Table 2)
1.2 Synopsis (Table 8) 
and Statistical Methods
3 Objectives and 
Endpoints (Table 10)
8.8.2 Mandatory 
Biomarker Samples
8.8.3 Nasal Secretions 
(Mandatory at Selected 
Sites)
Removed ‘nasal secretions’ from 
the SoA Year 1 of OLE.
Removed whole blood for 
PAXgene RNA, nasal secretions, 
and tissue biopsies and sputum 
(mechanistic sub-study only) from 
the exploratory biomarker 
endpoints in the OLE.
Updated the sections which 
describes the collection of these 
samples.
These biomarkes are 
only collected during the 
double-blind period.
Non-substantial
1.2 Synopsis, Study 
Period
Updated the estimated date of last 
patient completed from first quarter 
2024 to third quarter of 2024.
This is the current 
estimate of when the last 
randomised patient will 
Non-substantial

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
4.4 End of Study 
Definition
complete one year of 
treatment with open-
label benralizumab in the 
OLE.
1.2 Synopsis, 
Statistical Methods
4.1 Overall Design
Clarified which data will be 
included in the primary analysis 
and updated definition of final 
database lock.
Clarifications.
Non-substantial
4.4 End of Study 
Definition 
Clarified definition of the end of 
study according to EU and FDA 
requirements.
To comply with 
regulatory requirement(s) 
(eg, EU CTR) and global 
company requirement.
Non-substantial
5.2 Exclusion Criteria
Added an exception to exclusion 
criterion #18 per local CSP 
addendum in France.
To consolidate local 
protocol addendum with 
global study protocol.
Non-substantial.
6.1.2 Medical Devices 
Including Combination 
Products with a Device 
Constituent
8.4.4 Medical Device 
Deficiencies
Appendix F Medical 
Device AEs, ADEs, 
SAEs, SADEs, 
USADEs, and Medical 
Device Deficiencies: 
Definitions and 
Procedures for 
Recording, Evaluating, 
Follow-up, and 
Reporting
Added section regarding device 
constituents.
Updated current section regarding 
device deficiencies.
Added a new Appendix describing 
the processes to follow if device 
deficiencies fulfill definition of an 
AE/SAE.
To comply with 
regulatory requirement(s) 
(eg, EU CTR) and global 
company requirement.
Non-substantial
6.2.1 Preparation and 
Handling of IP
8.2.1.1 Pregnancy Test
Clarified that no urine pregnancy 
test (dipstick) will be performed 
during those visits in the OLE 
which can be done remotely.
To reduce patient/site 
burden.
Non-substantial
6.2.4 Conditions 
Requiring 
Investigational Product 
Administration 
Rescheduling
The requirement regarding patient 
being febrile within 72 hours prior 
to the IP administration has been 
deleted.
This is not a requirement 
anymore and has been 
removed from the 
Sponsor’s Project 
Specific Safety 
Requirements 
Non-substantial

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
6.5 Concomitant 
Therapy (Table 12)
Removed the words ‘or 
investigational’ from the last row.
Investigational products 
are prohibited without 
exeptions, according to 
Exclusion criterion 18.
Non-substantial
8.3.1 Method of 
Detecting Adverse 
Events and Serious 
Adverse Events
Removed the section.
Section 8.3.1 is 
redundant as the process 
for collecting adverse 
events in AstraZeneca 
clinical studies is 
described in Section 
8.3.5 Adverse Events 
Based on Signs and 
Symptoms
Non-substantial
8.4.3 Overdose
Moved text regarding reporting of
overdose to Section 8.4.6.
To align with current 
Transcelerate unified 
protocol template.
Non-substantial
8.4.5 Medication Error, 
Drug Abuse, and Drug 
Misuse
Appendix B4 
Medication Error, Drug 
Abuse, and Drug 
Misuse
Added subheadings covering 
timelines and definitions of 
medication error, drug abuse, and 
drug misuse.
To comply with CT-3 
Regulation and corporate 
safety CAPA.
Non-substantial
8.5.2 Storage and 
Destruction of 
Pharmacokinetic 
Samples
Updated the retention of PK 
samples to a period of 6 months 
from bioanalytical report 
finalisation.
To comply with 
regulatory requirement(s) 
(eg, EU CTR) and global 
company requirement.
Non-substantial
9.4.1.1 Calculation or 
Derivation of Variables 
for Efficacy Analyses
Added derivation of the new 
endpoints.
To present how the new 
endpoints will be 
derived.
Substantial
9.4.1.2 Methods for 
Efficacy Analyses
Added the new endpoints to the 
secondary endpoint statistical 
analyses.
To present how the new 
endpoints will be 
analysed.
Substantial
9.4.1.2 Methods for 
Efficacy Analyses
Added two factors (ie, BMI and 
ANCA-positive status) to the 
exploratory subgroup analyses.
These factors have been 
specified in the SAP.
Non-substantial
Appendix A1 
Regulatory and Ethical 
Considerations
Added sub-heading “Regulatory 
Reporting Requirements for Serious 
Breaches”.
To comply with 
regulatory requirement(s) 
(eg, EU CTR) and global 
company requirement.
Non-substantial

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
Appendix A6 Data 
Quality Assurance
Updated information about 
retention timelines of records and 
documents to 25 years after study 
archiving or as required by local 
regulations.
To comply with 
regulatory requirement(s) 
(eg, EU CTR) and global 
company requirement.
Non-substantial
Appendix K Country-
specific Requirements
Added a new appendix to present 
changes as per local CSP 
addendums in France and Belgium 
and added references to the 
appendix where applicable in the 
protocol.
To consolidate local 
protocol addendums with 
global study protocol.
Non-substantial
Appendix L Protocol 
Version History
Moved previous amendment details 
to a new protocol version history 
appendix.
To align with current 
Transcelerate unified 
protocol template.
Non-substantial
Throughout
Minor editorial changes
To clarify text, improve 
consistency and 
organization, and align 
with current 
Transcelerate unified 
protocol template and 
Sponsor style 
conventions.
Non-substantial
AE, adverse event; ANCA, anti-neutrophil cytoplasmic antibody; BMI, body mass index; BVAS, Birmingham 
Vasculitis Activity Score; CAPA, corrective and preventive action; CRP, C-reactive protein; CSP, clinical study 
protocol; CTR, Clinical Trial Regulation; EGPA, eosinophilic granulomatosis with polyangiitis; EOT, end of 
treatment; ESR, erythrocyte sedimentation rate; EU, European Union; FDA, Food and Drug Administration; IP, 
investigational product; IPD, IP discontinuation; OCS, oral corticosteroids; OLE, open-label extension; PK, 
pharmacokinetics; RNA, ribonucleic acid; SAE, serious adverse event; SoA, Schedule of Assessments; SAP, 
statistical analysis plan.
L 2
AMENDMENT 3 (VERSION 4.0): 24 FEBRUARY 2021
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
patients nor the scientific value of the study.
Overall Rationale for the Amendment
The primary rationale for this amendment is to introduce the possibility of self/at-home 
administration of benralizumab during the OLE of the study.

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Section # and Name
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Brief Rationale
Substantial 
/ Non-
substantial
1.1 Schedule of 
Assessments (Table 2, 
Table 3, and Table 4)
6.1.1 Investigational 
Products
8.2.1.1 Pregnancy Test
6.2.1 Preparation and 
Handling of IP
6.2.3 Optional At-
home or Remote-
location 
Investigational Product 
Administration 
Introduced the option of IP self-
administration (or administration by a 
caregiver) during the OLE.
Introduced the option of remote visits 
during the OLE for patients who opt for IP 
self-administration (optional remote visits: 
V24, V25, V27, V28, V31, V32, V34, 
V35, V37, V38, V40, V41, V44, V45, 
V47, V48, V50, V51, V53, V54).
Frequency of some on-site safety and 
laboratory assessments changed to 
quarterly and some assessments moved to 
adjacent visits to accommodate the new 
option for remote visits and self-
administration of IP.
Instructions on pregnancy test before IP 
administration and observation after IP 
administration revised to accommodate 
the option of IP self-administration.
To reduce patient burden 
and allow flexibility during 
the OLE.
Non-
substantial
1.1 Schedule of
Assessments (Table 1, 
Table 2, Table 3, and 
Table 4)
1.3 Schema
4.1 Overall Design
6.5.2 Other 
Concomitant 
Treatment
7.1 Discontinuation of 
Study Treatment 
(including all 
subsections)
7.1.1.2 
Discontinuation of 
Treatment on 
Notification of Closure 
of Study
7.3 Withdrawal From 
the Study
Removed the FU visit 8 weeks after last 
dose of IP.
To decrease patient burden 
by removing the additional 
FU visit; patients will have 
a follow-up visit 4 weeks 
after last dose of IP (IPD 
visit) and will be followed 
until the end of the DB 
period regardless of whether 
they continue IP
Non-
substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial 
/ Non-
substantial
1.1 Schedule of 
Assessments –
Double-blind 
Treatment Period 
(Table 1)
Added visit window of ± 3 days to Visit 2, 
Visit 9, and Visit 10.
Visit windows had 
mistakenly been
deleted/omitted.
Non-
substantial
Added footnote that at Visit 17, IP will 
only be administered to patients who are 
entering the OLE.
To clarify.
Non-
substantial
Footnote stating that "Spirometry is 
required as part of the sputum induction 
procedure as described in the separate 
laboratory manual" moved from the 
induced sputum assessment at V15 to the 
induced sputum row header.
Correction as footnote 
applies to all induced 
sputum assessments.
Non-
substantial
Added row “Administer open-label
benralizumab at the site (first dose of 
OLE)” with X at V17. Renamed “IP 
administration row” to “Administer 
blinded IP at the site” and removed X at 
V17.
To clarify that the IP dose 
on V17 is only for patients 
entering the OLE.
Non-
substantial
Added spirometry assessment to IPD visit. To ensure spirometry is 
performed if patient 
discontinues IP.
Non-
substantial
Removed troponin assessment from 
unscheduled visit.
Troponin had been 
mistakenly been added to 
the unscheduled visit during 
the DB period.
Non-
substantial
Revised footnote regarding ePRO at Visit 
2 to “Visit 2 must be confirmed on the 
handheld device by a trained site 
personnel prior to baseline ePRO 
questionnaires completion by the patient. 
Sites should ensure patients complete all 
baseline ePRO assessments. For 
subsequent visits, the site should confirm 
the visit either on the web portal Study 
Works or on the device.”
For clarification.
Non-
substantial
1.1 Schedule of 
Assessments (Table 1, 
Table 2, Table 3, and 
Table 4)
Brief physical examination, vital signs, 
and ePRO assessments changed to only be 
mandatory if the unscheduled visit is to 
assess a potential EGPA relapse.
To reduce patient burden; 
these assessments may not 
be required if the 
unscheduled visit is not to 
assess a relapse.
Non-
substantial

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial 
/ Non-
substantial
1.1 Schedule of 
Assessments (Table 1, 
Table 6)
Added “and confirm compliance” to the 
row “Administer/(re)train /review ePRO 
assessments” to Table 1.
Added a footnote to this assessment at 
Visit 2 stating that “It should be ensured at 
Visit 2 that the visit is confirmed in the 
handheld device and that baseline ePRO 
questionnaires are filled out by the 
patient” to Table 1.
Deleted row “Return ePRO device” to 
Table 1.
Deleted footnote “Only if the patient 
discontinues use of ePRO device at the 
IPD visit” from Table 3.
To ensure ePRO 
compliance is confirmed 
and encourage continued 
ePRO assessements 
throughout the study.
Non-
substantial
1.1 Schedule of 
Assessments (Table 2)
Removed mandatory assessments of 
serum for biomarkers, nasal secretions, 
tissue sample, induced sputum from 
unscheduled visits
To reduce patient burden.
Non-
substantial
Added haematology assessments to Visits 
19 and 21.
To better characterise PD 
parameters in the beginning 
of the OLE period. 
Non-
substantial
Removed CRP assessments from Visits 20 
and 22.
To reduce patient burden by 
reducing the number of 
blood draws needed.
Non-
substantial
Deleted row “Return ePRO device”.
Redundant.
Non-
substantial
1.1 Schedule of 
Assessments (Table 3 
[formerly Table 14 in 
Appendix H], Table 4 
[formerly Table 15 in 
Appendix H])
Moved tables from Appendix H to Section 
1.1 Schedule of Assessments
To keep all schedules of 
assessments in one place 
and improve navigability
Non-
substantial
1.2 Synopsis
Section 4.4 End of 
Study Definition
Revised estimated date or last patient 
completed to first quarter 2024.
To update the estimated 
date following delays in 
patient enrolment due to the 
Covid-19 pandemic.
Non-
substantial
1.2 Synopsis (Table 8)
3 Objectives and 
Endpoints (Table 10)
Added footnote to the variable 
“Remission, relapse (as defined in Table 
6/8), OCS use” stating that the definition 
in Table 6/8 is only applicable during the 
first year of the OLE. From the second 
To clarify the definitions of 
remission and relapse 
during the OLE.
Non-
substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial 
/ Non-
substantial
year, the definitions of remission and 
relapse will be based on the Investigator’s 
overall clinical assessment.
4.1.1 Study Conduct 
Mitigation During 
Study Disruptions Due 
to Cases of Civil 
Crisis, Natural 
Disaster, or Public 
Health Crisis
Added clarification that at-home IP 
administration would only be applicable 
during the OLE period.
At-home IP administration 
not be possible during the 
DB period.
Non-
substantial
5.2 Exclusion Criteria
Removed the text “A positive urine test 
result must be confirmed with a serum 
pregnancy test, before proceeding with 
further IP dosing. If serum test is positive, 
the patient should be excluded.”
Redundant; covered in 
inclusion criterion 8 and in 
instructions for pre-IP 
administration pregnancy 
tests in Section 6 and 
Section 8.
Non-
substantial
5.3.3 Criteria to be 
Confirmed Prior to 
Commencing OLE at 
Visit 17
Revised “Patients that enter the OLE must 
not have been randomised into the trial in 
error” to “If a patient had been 
randomised in error but the Investigator 
considers participation in the OLE to be 
safe and in the best interests of the patient, 
the Investigator should discuss the 
potential entry of the patient into the OLE 
with the AstraZeneca study physician”.
To introduce the possibility 
of patients randomised in 
error to enter the OLE when 
considered safe and in the 
best interests of the patient.
Non-
substantial
6.2.2.5 After 
Investigational Product 
Administration
8.4.6 Management of 
investigational 
product-related drug 
reactions
Appendix E 
Anaphylaxis: 
Definition, Signs, 
Symptoms, and 
Management
Changed from a minimum of 1 hour of 
observation on site after IP administration 
to state that the patient should be observed 
in line with clinical practice.
Changed guidance on treatment of acute 
anaphylactic reactions to state that 
appropriate drugs should be available at 
study sites rather than must be 
immediately available.
To align with clinical 
practice. 
Non-
substantial
6.3.1Patient 
Enrolment and 
Randomisation -
Double-blind Period
Added to the Visit 2 subsection to confirm 
Visit 2 on the handheld device prior to 
ePRO questionnaire completion by the 
To ensure that the baseline 
ePRO questionnaires are 
filled out.
Non-
substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial 
/ Non-
substantial
patient and to ensure patients complete all 
baseline ePRO assessments.
6.5 Concomitant 
Therapy
Blood products and marketed or 
investigational biologic products redefined 
from prohibited to restricted medications.
To make it possible for 
patients who have to use 
such therapies to treat co-
morbidities (if medically 
indicated with no alternative 
treatment available) to 
continue on IP in some 
specific cases.
Non-
substantial
Revised the instructions regarding the use 
of prohibited medications to state that “In 
the event a prohibited medication is used, 
a conversation between the Investigator 
and the AstraZeneca study physician 
should take place to determine whether 
continuation on IP or discontinuation of IP 
is in the best interest of the patient.”
To remove the requirement 
that IP must be withdrawn if 
a prohibited medication is 
used for cases when 
continuing IP may be in the 
best interest of the patient.
Non-
substantial
7.1 Discontinuation of 
Study Treatment
Revised “Patients will be discontinued 
from IP in the following situations” to 
“Patients may be discontinued from IP in 
the following situations”.
Revised “Increasing the dose of, or 
initiating, immunosuppressive therapy” to 
“Increasing the dose of, or initiating, 
immunosuppressive therapy for EGPA”.
Deleted “Use of prohibited concurrent 
medication (ie, as noted in Section 6.5) 
including CYC” as a study-specific 
criterion for discontinuation.
To alignment with the 
changes made to Section 
6.5.
Non-
substantial
7.1.1.1 Early 
Discontinuation of 
Study Treatment
Removed the following text from the 
information on patients who are willing to 
continue with scheduled visits after IPD 
during the DB period: “Ideally, during this 
time, all ePRO assessments should 
continue at home, otherwise, return ePRO 
device at the IPD visit”
To ensure ePRO 
assessments are continued 
even if IP has been 
discontinued and are not 
considered optional.
Non-
substantial
Added the following text from the 
information on patients who are 
unwilling/unable to continue with 
scheduled visits after IPD during the DB 

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Section # and Name
Description of Change
Brief Rationale
Substantial 
/ Non-
substantial
period: “During this time, all ePRO 
assessments should continue at home.”
8.1.1 Clinical Outcome 
Measures 
8.1.1.4 Corticosteroid 
Medication Usage
Revised both sections to state that the 
ePRO device must be returned at the end 
of the first year of the OLE period or the 
patient’s final study visit if it occurs 
before Visit 30 (rather than “at an earlier 
IPD visit”).
Added text to Section 8.1.1: “The site staff 
should check ePRO completion and 
compliance at each visit.
If compliance with the Corticosteroid 
Medication Usage ePRO assessment 
completion drops below 80%, or if the 
overall compliance with completion of 
any of the other ePRO assessments (ACQ-
6, SSQ, SNOT-22, SF-36v2, PGIS, PGIC, 
or WPAI-GH) drops below 80%, it is 
highly recommended that the study site 
has a discussion with the patient to ask if 
they are having difficulties and to remind 
them of the importance of completing 
ePRO assessments.”
To ensure the ePRO device 
is not returned to the site too 
early and to provide 
instructions to help ensure 
ePRO assessment 
compliance.
Non-
substantial
8.1.1.1 Birmingham 
Vasculitis Activity 
Score
Section 8.1.1.2 EGPA 
Remission and Relapse
Removed IPD visit and added 
“withdrawal from the study” in the 
description of until when these 
assessments should be made.
To ensure these assessments 
are only stopped early if a 
patient withdraws from the 
study and not if the patient
merely discontinues IP, 
since patients are 
encouraged to continue 
attending study visits even 
if IP has been discontinued.
Non-
substantial
8.1.2Patient 
Qualitative Interview 
Sub-study
Revised description of interview 
transcripts to “Interview transcripts will be 
completed for each interview in the 
language in which they are conducted, and 
translated into English (if necessary). 
Translated transcripts will be coded using 
qualitative data analysis software.”
Clarification and change in 
qualitative analysis
methodology for interview 
transcripts,
Non-
substantial

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial 
/ Non-
substantial
8.2.2 Physical 
Examinations
8.2.2.2 Brief Physical 
Examination
Added sentence “For the physical 
examination, only information on whether 
the assessment was performed or not is to 
be recorded in the eCRF” to Section 8.2.2 
and removed sentence “For the brief 
physical examination only information on 
whether the assessment was performed or 
not is to be recorded” from Section 
8.2.2.2.
To clarify how physical 
examinations (both brief 
and full) should be recorded 
in the eCRF.
Non-
substantial
9.4.1.2 Methods for 
Efficacy Analyses –
Analyses of Secondary 
Endpoints
Revised “The primary analysis will fit a 
MMRM model using the data collected up 
to and including the Week 52/IPD 52 time 
point” to “The primary analysis will fit a 
MMRM model using the data collected up 
to and including the Week 52 time point.”
Typo; corrected for clarity 
and consistency with the 
rest of the CSP and SAP.
Non-
substantial
Throughout
“IVRS/IWRS” revised to “IWRS”
IVRS not used in this study. Non-
substantial
Throughout
Minor editorial changes
To clarify text, improve 
consistency and 
organization, and align with 
current templates and style 
conventions.
Non-
substantial
L 3
AMENDMENT 2 (VERSION 3.0): 04 AUGUST 2020
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment
The primary rationale for this amendment is to add study mitigation language which will 
provide sites with measures that may be implemented if a patient is not able to visit a study 
site to ensure that the clinical trial can continue whilst minimizing risk to the patient, 
maintaining compliance with GCP, and minimizing risks to the study integrity. The protocol 
has also been amended to modify spirometry frequency, revise recommendations on 
investigational product rescheduling, align with current sponsor safety recommendations in 
studies with benralizumab, clarify exclusion criteria, and revise, add, or remove minor text as 
needed to increase clarity or correct interpretation of the protocol.

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
Section 4.1.1 Study 
conduct mitigation 
during study 
disruptions due to cases 
of civil crisis, natural 
disaster, or public 
health crisis. 
New wording was added which 
would give guidance on how the 
study could continue in the event of 
a serious disruption with details of 
mitigations that could be employed 
to ensure study continuity.
The impact of COVID-
19 has highlighted the 
risk to continuity of 
clinical trials during 
times of study disruption, 
whether by civil crisis, 
natural disaster or public 
health crisis. This section 
details the measures that 
may be implemented if a 
patient is not able to visit 
a study site to ensure that 
the clinical trial can 
continue whilst 
minimizing risk to the 
patient, maintaining 
compliance with GCP, 
and minimizing risks to 
study integrity. These 
changes will only be 
initiated at a time of 
study disruption.
Substantial
Section 1.1 Schedule of 
Assessments (Table 1
and Table 2); Appendix 
H (Table 14 and Table 
15)
Reduced the frequency of 
spirometry assessments to 12 week 
intervals (visit 2, 6, 9, 13, 16, 17 ) 
in the double blind treatment 
period. 
Spirometry is not required at 
IPD/EOT visit.
To decrease patient and 
HCP exposure to 
potential pathogens 
given COVID-19 
pandemic. 
Substantial
Section 1.1 Schedule of 
Assessments in OLE 
(Table 2); Appendix H 
(Table 14 and Table 
15)
Additional Chemistry assessments 
added: V21, V26, V31, V33, V39, 
V44, V46, V52
Chemistry frequency 
adjusted to monitor 
disease under study 
(EGPA). 
Non-substantial
Section 1.1 Schedule of 
Assessments in OLE 
(Table 2); Appendix H 
(Table 14 and Table 
15)
Align OLE years two and three 
with OLE year one by removing 
required troponin assessments at 
unscheduled visits. 
Troponin assessments 
changed for consistency 
within the CSP.
Non-substantial
Section 1.1 Schedule of 
Assessments (Table 1
and Table 2); Appendix 
Efficacy assessment: “Record 
prescribed OCS dose and check 
compliance “
Modified to match the 
activity description in the 
CSP.
Non-substantial

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
H (Table 14 and Table
15) and corresponding 
footnote
Section 5.2 (Exclusion 
criteria # 14 & 22), 
Table 13
Added a bullet to #14: “- Receipt of 
any other marketed or 
investigational biologic products 
within 4 months or 5 half-lives 
prior to screening, whichever is 
longer”
Modified #22: “Other 
investigational non-biologic
product: receipt of any 
investigational non-biologic 
product drug within 30 days or 5 
half-lives prior to screening (Visit 
1) whichever is longer. ”
Modified bullets beneath Table 10
to align with changes to exclusion 
criteria #14 & #22.
These changes were 
implemented to align 
with updated safety 
recommendations based 
on accumulated safety 
data.
Substantial
Section 5.5.1 
Rescreening
“If the reason for screen failure was 
transient (including but not limited 
to study-supplied equipment failure, 
unforeseen personal events that 
mandate missed screening visits, 
etc), patients may potentially be 
rescreened. These cases must be 
discussed with the AstraZeneca 
study physician prior to 
randomisation rescreening and 
documented in the Investigator 
study file.”
Timing updated to ensure 
eligibility discussions 
occur prior to re-
screening
Non-substantial
Section 6.2.6 
(Conditions Requiring 
Investigational Product 
Administration 
Rescheduling) and 
Section 6.4 (Treatment 
Compliance)
In cases of IP re-scheduling, 
guidance modified to postpone, 
where possible, rather then than 
skip IP
Guidance revised to try 
to prevent missed doses 
of IP and align with other 
studies with 
benralizumab conducted 
by the sponsor.
Non-substantial
Section 1.2 (Statistical 
Methods) and Section 
9.4.1.2 (Analysis of 
Secondary Endpoints) 
Removed MMRM analysis for 
PGIS and WPAI to evaluate change 
from baseline. 
The MMRM analysis 
was erroneously included 
in the original CSP, and 
the revised descriptive 
analysis aligns the 
Non-substantial

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
Added descriptive statistics for 
PGIS and WPAI to evaluate change 
from baseline 
analysis approach with 
other benralizumab 
studies using these 
instruments
Section 8.2.1.2 
Serology
Text added:
Hepatitis B surface antigen and 
hepatitis C antibody: To be 
performed only at screening and 
Visit 16
Human immunodeficiency virus-1 
and HIV-2 antibodies (along with 
p24 antigen): To be performed only
at screening and Visit 16
Text revised to clarify 
that, as per SoA, HBsAg, 
hepatitis C antibody and 
HIV-1 and HIV-2 
antibody testing should 
also occur at Visit 16.
Non-substantial
Section 8.4.2.1 
(Maternal Exposure); 
Section 7.1
(Discontinuation of 
Study Treatment) 
Section 8.4.2.1: Modified text, “If a 
patient becomes pregnant during 
the course of the study, IP should 
be discontinued immediately
temporarily withheld and a 
conversation between the 
Investigator and a Study Physician 
has to take place to determine 
whether continuation on IP or 
discontinuation of IP is in the best 
interest of the patient”
Section 7.1 Patients will be 
discontinued from IP in the 
following situations: Removed 
bullet “Pregnancy”
These changes were 
implemented to follow 
current sponsor safety 
recommendations in 
studies with 
benralizumab 
Substantial
Section 8.4.3.1 
Benralizumab 
Overdose
Sentence added: “For this study, 
any dose of benralizumab greater 
than 200 mg will be considered an 
overdose. “
Sentence was added to 
follow current sponsor 
safety recommendations 
in studies with 
benralizumab.
Non-substantial
Section 8.4.4 Devie 
Constituent 
Deficiencies
Text revised for:
changed title and section contents 
from “Malfunctions of APFS “ to 
“Device Constituent Deficiencies’
Sub-section 8.4.4.1 about SADE 
reporting added 
To ensure compliance 
with new regulatory 
guidance.
Non-substantial
Section 8.8.4 
Mechanistic Sub-study 
Sampling
Sentence added: “Spirometry will 
be performed as part of the sputum 
Sentence was added to 
clarify that separate 
spirometry is part of the 
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
induction procedure as described in 
the separate laboratory manual.”
sputum collection 
procedure in the sub-
study.
Section 8.11 (Other 
Assessments and 
Procedures); Section 
8.11.1 (Patient Testing 
Due to Public Health 
Crisis) 
Section included if patient testing is 
performed due to public health 
crisis, the results may be 
documented for this study.
Section added for test 
results secondary to 
public health crisis to be 
collected allowing for an 
evaluation of the public 
health crosis on the 
study, 
Non-substantial
Section 9.4.1.1 
Calculation or 
Deriviation of 
Variables for Efficacy 
Analyses
Deleted Baseline section
Detailed definitions of 
baseline for efficacy and 
safety endpoints are 
specified in SAP Section 
3.1.2
Non-substantial
Appendix A1 
Regulatory and Ethical 
Considerations
Regulatory and Ethical 
Considerations text was updated for 
Regulatory Reporting Requirements 
for SAEs’
Provision of appropriate 
statements that describe 
Regulatory Reporting 
Requirements for SAEs 
in AZ studies.
Correction to align with 
CSP template 5.0
Non-substantial
Appendix A5 
Dissemination of 
Clinical Study Data 
Text revision: A description of this 
clinical study will be available on 
http://
astrazenecaclinicaltrialsastrazeneca
grouptrials.pharmacm.com
Section updated with 
correct weblink
Non-substantial
Appendix F 
Appendix F “Medical device 
incidents: definition and procedures 
for recording, evaluating, follow-up 
and reporting” was removed.
Appendix was not 
applicable as 
Benralizumab is not 
considered a medical 
device. It is considered a 
drug device combination 
and subject to different 
reporting guidelines
Non-substantial
Appendix F 
New wording was added which 
would give guidance on how the 
study could continue in the event of 
a serious disruption with details of 
mitigations that could be employed 
to ensure study continuity.
The impact of COVID-
19 has highlighted the 
risk to continuity of 
clinical trials during 
times of study disruption, 
whether by civil crisis, 
natural disaster or public 
Substantial

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial / 
Non-substantial
health crisis. This section 
details the measures that 
may be implemented if a 
patient is not able to visit 
a study site to ensure that 
the clinical trial can 
continue whilst 
minimizing risk to the 
patient, maintaining 
compliance with GCP, 
and minimizing risks to 
study integrity. These 
changes will only be 
initiated at a time of 
study disruption.
Change to the Clinical Study Protocol- Amendment 1: 27 March 2020. Added change which was not 
documented in the summary of changes with CSP Amendment 1 
Section # and 
Name
Description of Change
Brief Rationale
Substantial/Non-
substantial
Table 8 
Match placebo text modified 
from solutions for injections 
2mL or 3mL syringes (3 
syringes will be used on each 
dosing occasion) to Matching 
Placebo: solutions in 1 mL 
polypropylene syringes (3 
syringes will be used on each 
dosing occasion). Injection 
volume per syringe is 1 mL. 
and 3x100 mg vials of powder 
for solution for injection 
reconstituted into 3 separate 
2mL or 3mL syringes for 
administration on each dosing 
occasion. Into 3 × 100 mg vials 
of powder for solution for 
injection reconstituted into 
3 separate 1 mL polypropylene 
syringes for administration on 
each dosing occasion. 
Injection volume per 
syringe is 1 mL to correct 
inconsistencies in the CSP 
and mepolizumab leaflet
Non-substantial

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L 4
AMENDMENT 1 (VERSION 2.0): 27 MARCH 2020
This amendment is considered to be non-substantial based on the criteria set forth in 
Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union because it neither significantly impacts the safety or physical/mental integrity 
of patients nor the scientific value of the study. 
Overall Rationale for the Amendment
This protocol (study D3253C00001) has been amended to correct and/or clarify 
inclusion/exclusion criteria, clarify that nasal secretions will be collected from selected sites, 
correct text on capping, correct typos, and revise, add, or remove minor text as needed to 
increase clarity or correct interpretation of the protocol. 
Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
General (throughout)
•
Minor editorial and document 
formatting revisions 
•
Corrected typos and spelling
•
Defined, fixed, removed, and added 
abbreviations as needed
•
Added or fixed hyperlinks as needed
•
Added footnotes to several tables to 
clarify information related to the study 
protocol 
•
Added numeric scales for patients’ 
scores as needed
•
Minor; therefore, these have not 
been summarised.
Protocol amendment 
Summary of changes
•
Summary of changes in CSP 
(amendment #1) added in a new 
section and table
•
New section added to 
summarise amendment #1.
Section 1.1 Schedule 
of assessments 
(Table 1, Table 2, and 
Table 3)
•
Updated the SoA for the OLE period, 
including wording clarifications 
•
Revisions were made to clarify 
type of visit and visit location.
Section 1.2 Synopsis 
(Table 7); 
Section 3 Objective 
and endpoints 
(Table 9);
Section 8.1.1.2 EGPA 
remission and relapse
•
Formatted bullets for EGPA relapse:
“warranting any of the following: 
!
An increased dose of OCS …; OR
!
An increased dose …; OR
!
Hospitalisation related …”
•
Formatting was corrected to 
align with EGPA relapse 
definition in Section 8.1.1.1 and 
the rest of the CSP.
Section 4.1 Overall 
design
Section 5.5.2 
Withdrawal from 
•
Text revision: “The number of 
patients with ANCA-positive status or 
an eosinophil count < 150 cells/μL 
will be restricted to approximately 
•
Anti-neutrophil cytoplasmic 
antibodies status and eosinophil 
capping should be 10% and 40 
%, respectively, of total study 

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
study due to 
recruitment cap
10% and 40%, respectively, of the 
total number of randomised patients.”
population instead of per-
treatment arm.
Section 5.1 Inclusion 
criteria
Text revisions:
•
#4, #4 Japan-only: Added 
“Investigator-initiated”
•
#5: Added “Stable doses of OCS other 
than prednisolone or prednisone may 
be acceptable, but must be discussed 
with the AstraZeneca study 
physician.”
•
#6: Additional text moved here from 
exclusion criterion #14
•
#9 Text added: “WOCBP must agree 
to use a highly effective method of 
birth control (confirmed by the 
Investigator) from randomisation 
throughout the study duration and 
within 16 for at least 12 weeks after 
last dose of IP. Highly effective forms 
of birth control (those that can achieve 
a failure rate of less than 1% per year 
when used consistently and correctly)
include: 
•
#4, #4 Japan-only: An orally 
reported temporary increase of 
the OCS dose by a patient due to 
feeling worse is not a 
“confirmed” relapse. To be 
confirmed, the relapse must 
require an increase of the 
physician-initiated OCS dose (or 
require initiation/increased dose 
of immunosuppressive therapy 
or hospitalisation).
•
#5: Text was added for 
particular cases not involving 
prednisolone or prednisone to 
clarify that the AstraZeneca 
study physician should be 
contacted in all such cases.
•
#6: Text clarifies requirements 
for immunosuppressive therapy 
prior to baseline.
•
#9: These changes were 
implemented to follow current 
sponsor safety recommendations 
in studies with benralizumab 
and to ensure compliance with 
the Clinical Trial Facilitation 
Group guidance.
Section 5.2 Exclusion 
criteria
Text revisions:
•
#2, #3, and #6: revised to “within 
3 months prior to screening (Visit 1) 
and through randomisation (Visit 2)
•
#8: Parasitic infection: revised to 
“within 6 months prior to screening 
(Visit 1) and through randomisation
(Visit 2)
•
#9: Remove information related to 
Japanese requirements
•
#14: Abbreviation NB was changed to 
“Note” and bullet moved to inclusion 
criterion #6
•
#2, #3, #6, and #8: Time 
window for life or organ-
threatening relapse, angina, and 
parasitic infection prior to study 
was revised to clarify that this 
window also includes the time 
from screening to 
randomisation.
•
#9: Change made to apply 
world-wide consistent criteria
•
#14: Bullet clarifies 
requirements for 
immunosuppressive therapy 
prior to baseline, which applies 
to inclusion criterion #6.
Section 5.3.1 Inclusion 
criteria to be 
confirmed/reconfirmed 
at baseline (Visit 2)
•
Text in bullet “Liver Function Tests” 
revised to “obtained at screening 
(Visit 1) or on repeat testing prior to 
Visit 2 if applicable”
•
Adding “or on repeat testing 
prior to V2” is for cases where 
the screening’s LFTs were 
abnormal and retesting was done 
(this is allowed [see exclusion 
criterion #24]); if LFTs were 

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
retested then the “on repeat 
testing prior to V2” is 
applicable.
Section 5.4 Lifestyle 
restrictions
Text revisions:
•
Women of child-bearing potential 
must use a highly effective 
contraceptive …for at least 16
12 weeks (5 half-lives) after last 
administration of the IP…
•
Patients must abstain from donating 
blood, … for 16 12 weeks (5 half-
lives) after last dose of IP.
•
Both changes were implemented 
to follow current sponsor safety 
recommendations in studies 
with benralizumab.
Section 6.3.2.3 
Maintaining the blind 
to the patient’s 
induced sputum cell 
count analysis - double 
blind period
•
Removed sentence “The sample at 
Visit 1 will only be assessed for 
quality.”
•
Sputum will be quantitatively 
analysed as per analysis plan.
Section 6.5 
Concomitant therapy 
(Table 12)
•
Text revision for live attenuated 
vaccines: “Not allowed from 30 days 
prior to screening (V 1), during the 
treatment period, and for 12 weeks 
after the last dose of IP.”
•
Text was added to clarify time 
period when patients taking an 
IP/benralizumab (OLE) cannot 
be administered live vaccines.
Section 6.5 
Concomitant therapy 
(Table 13)
•
Text revision for Rituximab: “…the 
patient must have shown recovery of 
peripheral B-cell count to above the 
lower level for the normal reference
limit or above pre-rituximab [first 
treatment] level).” 
•
Patients may have lower B-cell 
levels due to their autoimmune 
disease or previous treatment.
Section 6.5.1 Oral 
corticosteroids and 
tapering
•
Text added: “Oral corticosteroids 
other than prednisolone or prednisone 
may be acceptable but must be 
discussed with the AstraZeneca study 
physician.”
•
Patients in countries where 
prednisolone/prednisone is not 
available may be allowed to be 
treated with other 
glucocorticoids.
Section 6.5.2 Other 
concomitant treatment
•
Text revision: “Use of 
immunosuppressive therapy …or 
from screening until completion of the 
first 6 months of the OLE period.” 
•
Text added: “... After completion of 
the first 6 months of the OLE, a 
decrease in dose or discontinuation of 
immunosuppressant is allowed at the 
Principal Investigator’s discretion.”
•
Text was revised to clarify time 
when stable doses of 
immunosuppressive therapy will 
be permitted during the study.
•
Text was revised to 6 months; 
patients will have had ample 
time on open-label 
benralizumab before decreases 
in background 
immunosuppressant are allowed.
Section 7.1.2 
Procedures for 
handling incorrectly 
•
Text revision: “… patients should be 
encouraged to remain in the study and 
continue to be followed up complete 
IPD and FU visits, ie, follow-up for 
•
A patient that has been 
incorrectly enrolled or 
randomised should not be 
encouraged to remain in study 

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
enrolled or randomised 
patients
8 weeks after last IP dose (if received) 
(Section 7.1.1.1).”
but rather to complete the IPD 
and FU visits.
Section 8.1.1.1 
Birmingham 
Vasculitis Activity 
Score
•
Text revision: “The requirement for 
monthly BVAS/VDI assessment is 
replaced with…”
•
Vasculitis Damage Index was 
deleted because this is not done 
monthly. 
Section 8.1.1.8 SF-
36v2 (acute recall) and 
Table 14
Text revisions:
•
“…asks patients to rate how their 
current state of health compared to 
their state of health 1 year ago
one week ago”
•
“Two types of thresholds have been 
developed for interpretation of The 
SF-36v2 threshold 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 (Table 11) or 
responder definition (Lincoln 2011).” 
Table 11 row “Group difference” was 
removed
•
The text should say 1 week ago 
instead of 1 year ago.
•
We will be using only individual 
level threshold for SF-36v2 
responder analysis as described 
further in the SAP. 
Section 8.1.1.12 
Spirometry (Time of 
day for scheduled site 
visit spirometry)
•
Text revision: “Spirometry testing 
must be initiated in the morning 
between 6:00 AM and 11:00 AM
0600 and 1100 during the screening or 
re-screening period and at the baseline 
visit (Visit 2)”
•
Text added: “Post-BD spirometry 
should be performed 15 to 30 minutes 
after SABA dosing.” 
•
Spirometry is not planned at the 
screening period.
•
Text added for clarification and 
consistency within the CSP. 
8.2.1 Clinical safety 
laboratory assessments
•
Text added: “Urinalysis will be 
performed at a central laboratory only 
at Visit 1; subsequent analyses will be 
performed locally using a dipstick 
provided centrally.”
•
Text was revised to clarify that, 
as per SoAs, urinalysis should 
be performed centrally only at 
V1 and then locally using a 
dipstick. 
8.2.1 Clinical safety 
laboratory assessments 
(Table 15)
•
Text removed: Urinary sediment from 
urinalysis safety variables removed 
from list
•
Urinary sediment is not a 
required assessment.
Section 8.8.2 
Mandatory biomarker 
samples
•
Text revisions: Deleted nasal 
secretions from mandatory samples 
and added new subsection: “8.8.3 
Nasal secretions (mandatory at 
selected sites)”
•
Only sites with the required 
equipment will collect nasal 
secretion samples.
8.8.3 Nasal secretions
•
Text added: Describe how and when 
nasal secretions will be collected 
•
New section added to describe 
the mandatory nasal secretions 
at selected sites, collection 

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
times, and reference to 
laboratory manual. 
Section 8.8.4 
Mechanistic sub-study 
sampling (induced 
sputum, tissue biopsy, 
and whole blood cells)
•
Text revisions: Add additional 
information regarding assessments to 
be performed on collected samples 
(induced sputum, tissue biopsy, and 
whole blood) and to add further detail 
on the collection of the tissue 
biopsies”
•
Text revisions added to provide 
information on the purpose of 
the sub-study sample collections 
and to be consistent with the 
sub-study laboratory manual. 
Section 9.4.1.2 
Methods for efficacy 
analyses (ACQ-6 
response analysis) 
•
Text added: New paragraph for the 
ACQ-6 responder analysis
•
This was missing from the CSP, 
and it is part of the planned 
analysis.
Section 9.4.1.2 
Methods for efficacy 
analyses (Analysis of 
secondary endpoints)
•
Text added: Visit, endpoint's baseline, 
and visit by treatment were added as 
covariates
•
Text revision: “The proportion of 
patients with an ACQ-6 response 
(defined as a decrease in score from 
baseline of 0.5) during Weeks 48 
through 52 at end of 52-week double-
blind period will be evaluated.
•
To understand the relationship 
between change from baseline 
and treatment we need to adjust 
for the endpoints' baseline value.
•
Text was revised as per ACQ-6 
responder definition in the SAP.
Appendix A 
•
A1: Subsection added: “Regulatory 
reporting requirement for SAEs”
•
A3: Text revision: “If patients in the 
countries participating in the 
qualitative patient interview sub-study
indicate that they are interested in 
participating in the sub-study, the 
patient …”
•
A3: Text revision: If a patient’s 
partner becomes pregnant during or 
within 16 12 weeks after the study last 
dose of IP, the partner …
•
New A8: Sub-appendix added: “Study 
and site start and closure”
•
A1: The language for regulatory 
requirements for SAEs was 
missing in the CSP.
•
A3: To clarify that an ICF 
addendum will be provided to 
patients joining the sub-study in 
participating countries only.
•
A3: Change implemented to 
follow current sponsor safety 
recommendations in studies 
with benralizumab.
•
New A8: text added as it is a 
requirement to address these 
study aspects in the CSP as per 
the International Conference on 
Harmonisation Good Clinical 
Practice.
Appendix E 
(E1 Introduction)
•
Text revision: “a blood sample for 
serum tryptase should be collected as 
soon as possible after the event, at 
60 minutes 90 ± 30 minutes” 
•
Change made because an 
interval of 60 minutes is too 
short to observe changes in 
tryptase.

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11
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SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d3253c00001-csp-v6
Document Title:
D3253C00001 Clinical Study Protocol version 6
Document ID:
Doc ID-004002269
Version Label:
6.0 CURRENT LATEST APPROVED
Server Date
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18-Mar-2024 13:16 UTC
Management Approval
18-Mar-2024 13:59 UTC
Content Approval
18-Mar-2024 13:03 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
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