A Multi-center, Randomized, Double-blind, Parallel-group, Placebo-controlled 3-Part Phase 3 Study to Demonstrate the Efficacy and Safety of Benralizumab in Patients With Eosinophilic Gastritis and/or Gastroenteritis (The HUDSON GI Study)
Phase: PHASE3
Conditions: Eosinophilic Gastritis, Eosinophilic Gastroenteritis
Sponsor: AstraZeneca

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Clinical Study Protocol 
Study Intervention
Benralizumab
Study Code
D3258C00001
Version
5
Date
29 March 2023
A Multi-center, Randomized, Double-blind, Parallel-group, 
Placebo-controlled 3-Part Phase 3 Study to Demonstrate 
the Efficacy and Safety of Benralizumab in Patients with 
Eosinophilic Gastritis and/or Gastroenteritis 
(The HUDSON GI Study)
Sponsors: 
AstraZeneca AB
151 85 Södertälje, Sweden
AstraZeneca KK
3-1 Ofuka-cho, Kita-ku, Osaka 530-011, Japan
Regulatory Agency Identifier Number
EudraCT number: 2021-000085-14
ClinicalTrials.gov number: NCT05251909
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered, and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

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Protocol Version Number: 5
Study Intervention: Benralizumab
Study Phase: 3
Short Title: Efficacy and Safety of Benralizumab in Patients with Eosinophilic Gastritis 
and/or Gastroenteritis (HUDSON GI)
Study Physician Name and Contact Information will be provided separately.
International coordinating investigator:
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
Document History
Document
Date of Issue
Amendment 4 (CSP version 5.0)
28-Mar-2023
Amendment 3 (CSP version 4.0)
15-Sept-2021
Amendment 2 (CSP version 3.0)
04-Mar-2021
Amendment 1 (CSP version 2.0) 
23-Feb-2021
Original protocol (Initial creation 1.0)
26-Jan-2021
Amendment 4 (CSP version 5.0): 28-Mar-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.
Overall Rationale for the Amendment.
Following the decision to close recruitment to this study early, the primary rationale for this 
amendment is to fulfill a commitment to participants as they enrolled in the trial, of open-label 
access to benralizumab following double-blind treatment. This amendment will make 
available a streamlined 24-week open-label trial of benralizumab with the addition of a Part D, 
contingent on the Investigator's clinical judgement and the potential for benefit. 

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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 Synopsis, 
Rationale
Emerging evidence added to Rationale
Provide justification for Amendment 
4
Substantial
1.1 Synopsis, 
Objectives and 
Endpoints
Note that original Part A objectives will not 
be assessed due to enrollment stop and 
small number of patients added.
Part B objectives removed.
Updates synopsis to be consistent 
with changes made to protocol body 
due to Amendment 4
Substantial
1.1 Synopsis, 
Design
Part B removed.  New design with Part A 
and Part C patients moving to Part D added
Substantial
1.1 Synopsis, 
Participants
Part B removed.  New design with Part A 
and Part C patients moving to Part D added
Substantial
1.1 Synopsis, 
Intervention
Part B removed.  New design with Part A 
and Part C patients eligible for 24 weeks of 
open-label benralizumab in Part D added.
Substantial
1.1 Synopsis, 
IDMC
Statement that IDMC will not be used 
during Part D added
Substantial
1.1 Synopsis, 
Statistical 
Methods
Part B analysis removed.  Note that 
population is only 12 patients added.   
Analysis methods deleted and replaced with 
descriptive summaries and patient listings.
Substantial
1.2 Schema
New study schema, with deletion of Part B 
and addition of Part D, added (Figure 2).
To reflect the new design.
Substantial
1.3 Schedule of 
activities
Note added to Table 1 and 2 that all Part A 
and Part C patients will advance to Part D 
(V20) at next visit.
Part B removed from Table 1.
Part C after Week 76 SoA (Table 3) 
deleted.
Part D SoA with reduced assessments 
added as new Table 3.
Follow-up visit reduced from 12 to 8 weeks 
post last dose.
Table 4 PRO SoA revised with last PRO at 
V20 and no IP discontinuation assessments.
Part B cancelled as not recruited.
Part C will not extend into after Week 
76
New Part D requires an SoA.
Substantial
2.1 Rationale
2.1.1 added with rationale for Amendment 
4 and information on Part D as an extended 
closure segment.
To update the study rationale
Substantial
2.2 Background
2.2.1 added with emerging scientific 
evidence, closure of study recruiting, and 
addition of Part D
To update background with emerging 
scientific information supporting the 
change in study design
Substantial

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2.3 Benefit/Risk 
Assessment
Note that following the approval of 
Amendment 4, there are no protocol-
mandated endoscopy procedures added to 
2.3.1.
Text on expected benefits deleted from 
2.3.2
Amendment specific text for overall 
benefit:risk conclusion added to 2.3.3 
New Part D requires a statement on 
its benefit:risk
Substantial
3 Objectives and 
Endpoints
Note that original Part A objectives will not 
be assessed due to enrollment stop and 
small number of patients added.
Part B objectives removed.
Part D objective added. 
Part B cancelled as not recruited.
New Part D requires an objective
Substantial
4.1 Overall 
Design
Part B and the post-52-week extension in 
Part C deleted. 
Part D added.
Due to closure of enrollment and 
addition of extended study closure.
Substantial
4.2 Scientific 
Rationale for 
Study Design
Note that medication and dietary 
restrictions will not apply to Part D added.
Reduce patient burden and allowing 
real world clinical management
Substantial
4.4 End of Study 
Definition
Text for open-label extension deleted.
Open-label extension cancelled with 
closure of enrollment
Substantial
5.3 Lifestyle 
Considerations
Note that medication and dietary 
restrictions will not apply to Part D added.
Reduce patient burden and allowing 
real world clinical management.
Substantial
6.1 Investigational 
Products
Text on termination of open-label extension 
deleted from 6.1.2.
Dosing for Part D added to 6.1.2.
Requirement for urine pregnancy test prior 
to every IP administration deleted from 
6.1.3.1
Due to closure of enrollment and 
addition of extended study closure.
Align with current product safety 
requirements.
Substantial
Substantial
Non-
substantial
6.3 Measures to 
Minimize Bias
Note on open-label treatment in Part D and 
unblinding added to 6.3.2.  
Text on breaking the blind allowed after 
Amendment 4 added to 6.3.3
Due to closure of enrollment, blinding 
restrictions relaxed.
Substantial
6.5 Concomitant 
Therapy
Text on relaxing background medication 
restriction in Part D added to 6.5.1 and 
Table 8 in 6.5.3.
Text on relaxing dietary restriction in Part 
D added to 6.5.2.
Due to closure of enrollment, blinding 
restrictions relaxed.
Reduce patient burden.
Substantial
7.1 
Discontinuation 
of Study 
Intervention
Text encouraging IP discontinued patients 
to continue trial participation deleted in 
7.1.1.
End of study text deleted from 7.1.2.
Due to closure of enrollment, text is 
no longer needed.
Substantial
Substantial
7.2 Participant 
Withdrawal from 
the Study
Text referring to Part A or Part B 
withdrawals should be informed about 
modified follow-up options (7.1.2) has been 
deleted.
Request for discontinued patients to return 
for biopsy has been deleted.
Due to closure of enrollment, text is 
no longer needed (ie, no modified 
follow-up options and no need for 
post-withdrawal endoscopies).
Substantial
Substantial

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8.1 Efficacy 
Assessment
Note stating biopsies and endoscopies not 
required at any clinic visit after 
implementation of Amendment 4 added to 
8.1.1 and 8.1.2 respectively.
Note stating PROs will not be collected 
after implementation of Amendment 4 
added to 8.1.3.
CGIS assessments in Part D added to 8.1.4
Note that CGIC assessments will not be 
collected after implementation of 
Amendment 4 added to 8.1.5.
Note that Qualitative Patient Interview Sub-
study has been discontinued added to 8.1.7.
Note that handheld devices will be returned 
at next visit added to 8.1.8.
Clarification that due to closure of 
enrollment, these efficacy 
assessments will not be done. 
Substantial
8.2 Safety 
Assessments
Note that patients should be strongly 
encouraged to monitor for pregnancy 
during the study and report a pregnancy to 
the site as soon as possible added to 8.2.5 
and 8.3.9.
Align with current product safety 
requirements.
Substantial
8.3 Adverse 
Events and 
Serious Adverse 
Events
8.3.9.2 text on paternal exposure has been 
deleted.
Align with current product safety 
requirements.
Substantial
8.3.10 Medication 
Error, Drug 
Abuse, and Drug 
Misuse
Section amended with addition of Drug 
Abuse and Drug Misuse and Reporting of 
Overdose
Update required due to CT-3^ 
Regulation and corporate safety 
CAPA
Non-
substantial
8.5 Human 
Biological 
Samples
Note stating no further biological samples 
will be collected after implementation of 
Amendment 4 added.
Due to closure of enrollment.
Substantial
8.6 Human 
Biological Sample 
Biomarkers
Note stating no further biological samples 
will be collected after implementation of 
Amendment 4 added.
Due to closure of enrollment.
Substantial
9 Statistical 
Considerations
All text on planned statistical analysis has
been deleted.
Due to closure of enrolment meaning 
original objectives will not be 
assessed and so analysis plans have 
been modified accordingly.
Substantial

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9.1 Statistical 
Hypotheses
Text on hypotheses has been deleted and 
replaced with statement “No hypothesis 
testing will be performed given the decision 
to terminate recruitment to the study, 
resulting in the intended sample sizes 
required not being recruited”.  
PK analysis set deleted from 
Text in 9.4.1 General Considerations and 
9.4.2 Efficacy have been deleted and 
replaced with text appropriate for the 
revised design and low number of patients.  
Text specifying output for related events 
and most common events in 9.4.3.1 
Adverse Events has been deleted. 
Due to closure of enrolment meaning 
original objectives will not be 
assessed and so analysis plans have 
been modified accordingly.
Substantial
9.2 Sample Size 
Determination
Text concerning missing data and Part B 
sample size have been deleted. 
A statement that the sample size will be 
limited to 12 patients has been added.
Due to closure of enrollment.
Substantial
9.3 Populations 
for Analyses
PK analysis set deleted.
Due to closure of enrolment meaning 
original objectives will not be 
assessed and so analysis plans have 
been modified accordingly.
Substantial
9.4 Statistical 
Analysis
Statement that personnel will remain 
blinded until DBL has been deleted
Text in 9.4.1 General Considerations and 
9.4.2 Efficacy have been deleted and 
replaced with text appropriate for the 
revised design and low number of patients.  
Text specifying output for related adverse 
events and most common adverse events in 
9.4.3.1 has been deleted.
Other analyses (9.4.4) have been deleted.
9.4.5 Methods for multiplicity control has 
been deleted.
Due to closure of enrolment meaning 
original objectives will not be 
assessed and so analysis plans have 
been modified accordingly.
Substantial
9.6 Data 
Monitoring 
Committed
Note stating with the approval of 
Amendment 4, the open-label dosing in Part 
D will not require the use of an IDMC has 
been added.
Communicating decision by 
AstraZeneca, endorsed by IDMC, that 
the open-label dosing in a small 
cohort of adults does not require the 
IDMC.
Substantial
Appendix A1
Added sub-heading “Regulatory Reporting 
Requirements for Serious Breaches”
Update required to comply with 
regulatory requirement (e.g. EU CTR) 
and global company requirement
Non-
substantial
Appendix A3
Note that patients who participate in Part D 
will be required to sign a supplemental ICF 
specific for Part D added.
As Part D was not part of the original 
study to which patients consented, 
supplemental consent will be required 
for patient participation in Part D.
Substantial

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Appendix A5
Note that with the approval of Amendment 
4, the open-label dosing in Part D will not 
require the use of an IDMC added.
Communicating decision by 
AstraZeneca, endorsed by IDMC, that 
the open-label dosing in a small 
cohort of adults does not require the 
IDMC.
Substantial
Appendix A7
Updated information about retention 
timelines of records and documents to [25 
years after study archiving or as required by 
local regulations]
Update required to comply with EU 
CTR and global company 
requirement 
Non-
substantial
Appendix B4
Added detailed Drug Abuse and Drug 
Misuse definition and examples
Update required due to CT-3^ 
Regulation and corporate safety 
CAPA
Non-
substantial
10 References
Added:
Allakos Press Release 2021
Kliewer et al 2023
Kuang et al 2022
Updated
Non-
substantial

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3
TABLE OF CONTENTS ...................................................................................................... 9
1
PROTOCOL SUMMARY ................................................................................ 14
1.1
Synopsis ........................................................................................................... 14
1.2
Schema............................................................................................................. 19
1.2.1
Previous Schema (Protocol versions 1-4) .......................................................... 19
1.2.2
Current schema (Amendment 4, Protocol version 5) ......................................... 20
1.3
Schedule of Activities ....................................................................................... 21
2
INTRODUCTION............................................................................................ 28
2.1
Study Rationale ................................................................................................ 28
2.1.1
Protocol Amendment 4 (Version 5) ................................................................... 28
2.2
Background ...................................................................................................... 29
2.2.1
Emerging scientific evidence and closure of study recruitment.......................... 30
2.3
Benefit/Risk Assessment................................................................................... 31
2.3.1
Risk Assessment ............................................................................................... 31
2.3.2
Benefit Assessment........................................................................................... 33
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 33
3
OBJECTIVES AND ENDPOINTS................................................................... 34
4
STUDY DESIGN ............................................................................................. 37
4.1
Overall Design.................................................................................................. 37
4.1.1
Study Conduct Mitigation During Study Disruption.......................................... 37
4.2
Scientific Rationale for Study Design ............................................................... 38
4.2.1
Participant Input into Design............................................................................. 39
4.2.1.1
Participant Input into Study Design................................................................... 39
4.2.1.2
Participant Input into Patient-Reported Outcomes............................................. 39
4.3
Justification for Dose........................................................................................ 40
4.4
End of Study Definition.................................................................................... 40
5
STUDY POPULATION.................................................................................... 40
5.1
Inclusion Criteria .............................................................................................. 40
5.2
Exclusion Criteria ............................................................................................. 43
5.3
Lifestyle Considerations ................................................................................... 45
5.4
Screen Failures ................................................................................................. 45
6
STUDY INTERVENTION ............................................................................... 46
6.1
Study Interventions Administered ..................................................................... 46
6.1.1
Investigational Products.................................................................................... 46
6.1.2
Duration and Frequency of Treatment with Investigational Products................. 47
6.1.3
Administration of Investigational Products ....................................................... 47

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6.1.3.1
Before Investigational Product Administration.................................................. 47
6.1.3.2
In-Clinic Investigational Product Administration .............................................. 47
6.1.3.3
Investigational Product Administration Re-scheduling ...................................... 48
6.1.3.4
Self-administration of Investigational Product as Mitigation to Disruption........ 50
6.1.3.5
Optional At-home or Remote Location Self-administration............................... 50
6.1.3.6
Optional Remote Visits for Patients Doing At-Home or Remote-Location 
Investigational Product Administration ............................................................. 51
6.2
Preparation/Handling/Storage/Accountability ................................................... 51
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 52
6.3.1
Methods for Assigning Treatment Groups......................................................... 52
6.3.2
Maintaining Blind to the Investigational Product .............................................. 52
6.3.3
Maintaining Blind to the Participant’s Eosinophil Counts ................................. 53
6.4
Study Intervention Compliance......................................................................... 54
6.5
Concomitant Therapy........................................................................................ 55
6.5.1
Background Medication.................................................................................... 55
6.5.2
Dietary Restrictions .......................................................................................... 55
6.5.3
Restricted Medication....................................................................................... 56
6.5.4
Rescue Medicine............................................................................................... 58
6.6
Dose Modification (not applicable)................................................................... 58
6.7
Intervention after the End of the Study.............................................................. 58
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 58
7.1
Discontinuation of Study Intervention............................................................... 58
7.1.1
Reasons for Discontinuation of Investigational Product .................................... 58
7.1.2
Procedures for Early Discontinuation of Investigational Product....................... 59
7.1.2.1
Early discontinuation of study treatment ........................................................... 59
7.1.3
Procedures for Handling Incorrectly Enrolled or Randomized Patients.............. 59
7.2
Participant Withdrawal from the Study.............................................................. 60
7.3
Lost to Follow up.............................................................................................. 60
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 61
8.1
Efficacy Assessments........................................................................................ 62
8.1.1
Histopathology and Tissue Eosinophil Counts................................................... 62
8.1.2
Endoscopic Reference System Scores ............................................................... 62
8.1.3
Patient Reported Outcomes............................................................................... 63
8.1.3.1
Symptom Assessment for Gastrointestinal Eosinophilic Diseases...................... 64
8.1.3.2
Bristol Stool Form Scale................................................................................... 64
8.1.3.3
Dysphagia Symptom Questionnaire .................................................................. 65
8.1.3.4
Patient Assessment of Gastrointestinal Disorders Symptom Severity Index....... 65
8.1.3.5
Patient-Reported Outcome Measurement Information System Short Form –
Fatigue 7a......................................................................................................... 66
8.1.3.6
Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life ........... 66
8.1.3.7
Short Form 36-item Health Survey, Version 2, Acute Recall.............................. 66
8.1.3.8
Work Productivity and Activity Impairment Questionnaire plus Classroom 

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Impairment Questions....................................................................................... 67
8.1.3.9
Patient Global Impression of Severity............................................................... 67
8.1.3.10
Patient Global Impression of Change ................................................................ 68
8.1.3.11
Patient Global Impression of Benefit-Risk ........................................................ 68
8.1.4
Clinical Global Impression of Severity.............................................................. 68
8.1.5
Clinical Global Impression of Change............................................................... 68
8.1.6
Diet Questionnaire............................................................................................ 69
8.1.7
Qualitative Patient Interview Sub-study............................................................ 69
8.1.8
Eosinophilic Gastrointestinal Disease Diary...................................................... 70
8.2
Safety Assessments........................................................................................... 70
8.2.1
Physical Examinations...................................................................................... 70
8.2.2
Vital Signs ........................................................................................................ 71
8.2.3
Electrocardiograms........................................................................................... 71
8.2.4
Clinical Safety Laboratory Assessments............................................................ 71
8.2.5
Pregnancy Testing............................................................................................. 73
8.2.6
Other Safety Assessments ................................................................................. 73
8.3
Adverse Events and Serious Adverse Events..................................................... 73
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 74
8.3.2
Follow-up of AEs and SAEs ............................................................................. 74
8.3.3
Causality Collection.......................................................................................... 75
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 75
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 76
8.3.6
Disease Progression.......................................................................................... 76
8.3.7
Disease Under Study......................................................................................... 76
8.3.8
Reporting of Serious Adverse Events ................................................................ 77
8.3.9
Pregnancy......................................................................................................... 77
8.3.9.1
Maternal Exposure............................................................................................ 77
8.3.10
Medication Error, Drug Abuse, and Drug Misuse.............................................. 78
8.3.11
Device Constituent Deficiencies ....................................................................... 79
8.3.11.1
SADE Reporting............................................................................................... 80
8.3.12
Management of investigational product-related toxicities.................................. 80
8.4
Overdose .......................................................................................................... 81
8.5
Human Biological Samples............................................................................... 81
8.5.1
Pharmacokinetics.............................................................................................. 82
8.5.1.1
Determination of Drug Concentration ............................................................... 82
8.5.2
Immunogenicity Assessments ........................................................................... 83
8.5.3
Pharmacodynamics........................................................................................... 83
8.6
Human Biological Sample Biomarkers ............................................................. 83
8.6.1
Collection of mandatory samples for biomarker analysis................................... 83
8.6.1.1
Serum............................................................................................................... 83
8.6.1.2
Tissue Histology and Immunostaining .............................................................. 84
8.6.1.3
RNA Transcriptome Research........................................................................... 84
8.7
Optional Genomics Initiative Sample................................................................ 85
8.8
Healthcare Resource Utilization........................................................................ 85
9
STATISTICAL CONSIDERATIONS................................................................ 85

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9.1
Statistical Hypotheses....................................................................................... 86
9.2
Sample Size Determination............................................................................... 86
9.3
Populations for Analyses................................................................................... 86
9.4
Statistical Analyses ........................................................................................... 87
9.4.1
General Considerations..................................................................................... 87
9.4.2
Efficacy ............................................................................................................ 87
9.4.3
Safety ............................................................................................................... 88
9.4.3.1
Adverse Events................................................................................................. 88
9.4.3.2
Clinical Safety Laboratory Assessments............................................................ 89
9.4.3.3
Vital Signs and Weight...................................................................................... 89
9.4.4
Other Analyses.................................................................................................. 89
9.4.5
Methods for multiplicity control ....................................................................... 89
9.5
Interim Analyses............................................................................................... 89
9.6
Data Monitoring Committee ............................................................................. 89
10
REFERENCES............................................................................................... 120

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LIST OF FIGURES
Figure 1
Previous Study Design............................................................................. 19
Figure 2
Current Study Design............................................................................... 20
Figure 3
Injection sites and examples of rotation scheme ....................................... 48
LIST OF TABLES
Table 1
Schedule of Activities – Part A................................................................ 21
Table 2
Schedule of Activities – Part C ................................................................ 23
Table 3
Schedule of Activities – Part D................................................................ 26
Table 4
Schedule of Activities – Patient-Reported Outcomes ............................... 27
Table 5
Risk Assessment...................................................................................... 31
Table 6
Objectives and Endpoints......................................................................... 34
Table 7
Investigational Products........................................................................... 46
Table 8
Concomitant Medication and Treatments................................................. 56
Table 9
Laboratory Safety Values......................................................................... 72
Table 10
Populations for Analysis .......................................................................... 86
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 90
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 96
Appendix C
Handling of Human Biological Samples ................................................ 102
Appendix D
Optional Genomics Initiative Sample..................................................... 104
Appendix E
Best Practice Guidelines for Completing PRO Assessments................... 107
Appendix F
Anaphylaxis: Definition, Signs, Symptoms and Management ................ 109
Appendix G
Changes Related to Mitigation of Study Disruptions.............................. 112
Appendix H
Abbreviations ........................................................................................ 115
Appendix I
Protocol Amendment History................................................................. 116

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Multi-center, Randomized, Double-blind, Parallel-group, Placebo-controlled 
3-Part Phase 3 Study to Demonstrate the Efficacy and Safety of Benralizumab in Patients with 
Eosinophilic Gastritis and/or Gastroenteritis (HUDSON GI)
Short Title: Efficacy and Safety Benralizumab in Patients with Eosinophilic Gastritis and/or 
Gastroenteritis (HUDSON GI)
Regulatory Agency Identifier Number:
EudraCT number: 2021-000085-14
ClinicalTrials.gov number: NCT05251909
Rationale: Eosinophilic gastritis and gastroenteritis (EG/EGE) are inflammatory disorders 
characterized by eosinophilic infiltration of the stomach (EG) and/or duodenum (EGE) with 
a resultant significant burden of gastrointestinal symptoms (eg, abdominal pain, nausea, and 
bloating). Benralizumab is a humanized, afucosylated, monoclonal antibody that binds 
specifically to the IL-5Rα on target cells, resulting in the depletion of eosinophils through 
antibody-dependent cell-mediated cytotoxicity. This mechanism of action makes 
benralizumab a potential treatment for patients with symptomatic and histologically active 
EG/EGE. This 3-part Phase 3 study was designed to 1) validate a patient-reported outcome 
(PRO) instrument for EG/EGE symptoms while providing preliminary efficacy and safety 
data (24-week Part A), 2) provide pivotal efficacy and safety data for EG/EGE for the 
registration of this indication (24-week Part B), and 3) provide long-term efficacy and safety 
data of benralizumab (Part C) during an open-label extension. 
Based on emerging evidence of eosinophil-independent mechanisms in the pathology of 
eosinophilic upper gastrointestinal disease, including EG/EGE (eg, Kuang et al 2022, Allakos 
Press Release 2021 of the ENIGMA 2 study topline results, and results from the Benralizumab 
for Eosinophilic Gastritis study [NCT03473977, Kliewer et al 2023), recruitment was 
terminated early during the recruitment of Part A.  Subsequently, a decision was made to 
amend the protocol (Amendment 4) with the deletion of the unrecruited Part B and the 
addition of a Part D, which will serve as an extended closure segment of the study.  Following 
approval of Amendment 4, all active participants will advance to Part D at their next clinic 
visit, at which time, investigators may give participants the option of receiving 6 months 
(ie, 6 doses) of open-label benralizumab treatment. 

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Objectives and Endpoints
The original objectives of Part A are presented below. Given the decision to stop recruitment 
to the study, it will not be possible to assess these objectives with the data collected during 
Part A. A revised analysis plan is presented in Section 9.
Objectives for Part A
Estimands descriptions / endpoints
Primary

Part A: To compare the effect of 
benralizumab 30 mg every 4 weeks (Q4W) 
with placebo on histologic signs and 
gastrointestinal symptoms in patients with 
eosinophilic gastritis and/or gastroenteritis
Dual primary endpoints including histology-based and 
symptom-based endpoints:
Histology-based dual primary endpoint

Population: Full analysis set

Histologic Endpoint: Proportion of patients 
achieving a histological response (defined as 
≤6 eosinophils/high power field (hpf) in the 
stomach and/or, ≤15 eosinophils/hpf in the 
duodenum) at Week 24 

Intercurrent events: A composite approach whereby 
participants who receive restricteda or rescue 
medications, or discontinue randomized therapy 
prior to Week 24 will be considered as histologic 
non-responders at Week 24 

Summary measure: Odds ratio and difference in 
response rates between benralizumab and placebo
Symptom-based dual primary endpoint

Population: Full analysis set

Symptom Endpoint: Absolute change from baseline 
in SAGED score at Week 24

Intercurrent events: A composite approach whereby 
participants who receive restricteda or rescue 
medications or discontinue randomized therapy 
prior to Week 24 will be considered as treatment 
failures at Week 24.  Such patients will have their 
worst observation prior to or at the intercurrent 
event carried forward to week 24.

Summary measure: Difference in least squares 
mean change from baseline in SAGED score at 
Week 24 between benralizumab and placebo

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Secondary

Part A: To compare the effect of 
benralizumab 30 mg Q4W with placebo on 
clinical features of eosinophilic gastritis/ 
gastroenteritis and disease activity

Keyb: Percentage change from baseline in tissue 
eosinophils (stomach and/or duodenum) at Week 24

Keyb: Proportion of patients who achieve treatment 
response: tissue remission (≤ 6 eosinophils/hpf in 
the stomach and/or ≤ 15 eosinophils/hpf in the 
duodenum) and an improvement in symptoms at 
Week 24

Change from baseline in proportion of vomiting-
free days and change from baseline in frequency of 
vomiting episodes at week 24

Change from baseline in proportion of diarrhea-free 
days and change from baseline in frequency of 
diarrhea episodes at week 24

Change from baseline in proportion of days both 
diarrhea- and constipation-free

Time to clinically meaningful improvement in 
SAGED score

Change from baseline in PROMIS Fatigue 7a score 
and PAGI-SYM score at Week 24

Part A: To compare the effect of 
benralizumab 30mg Q4W with placebo on 
rescue corticosteroid use

Keyb: Proportion of patients with no rescue 
corticosteroid use up to Week 24

Part A: To compare the effect of 
benralizumab 30 mg Q4W with placebo on 
health-related quality of life in patients with 
eosinophilic gastritis and/or gastroenteritis

Change from baseline in SF-36v2 PCS and MCS at 
Week 24

Change from baseline in PAGI-QOL at Week 24

To assess the pharmacokinetics and 
immunogenicity of benralizumab in patients 
with EG/EGE

Serum benralizumab concentration over time

Anti-drug antibodies over time
Safety

To assess the safety and tolerability of 
benralizumab in patients with eosinophilic 
gastritis and/or gastroenteritis

Safety and tolerability will be evaluated in terms of 
adverse events, vital signs, physical exam, and 
clinical laboratory parameters.
a
Only restricted medications given that are considered to have a potentially meaningful impact on EG/EGE 
outcomes will be considered intercurrent events.
For Exploratory objectives, see Section 3 of the protocol.

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Overall Design
This is a 3-part study. Part A is a parallel-group, randomized, double-blinded, placebo-
controlled with up to 24-weeks of treatment. Part A was planned to include approximately 
70 participants in total with eosinophilic gastritis (with or without eosinophilic duodenitis) or 
duodenal-only disease, including a minimum of at least 50 with EG (with or without duodenal 
involvement), respectively. After a 4-week to 8-week run-in period, symptomatic participants 
with EG with or without duodenitis and patients with eosinophilic duodenitis only, on stable 
background medications and diet, with histologically-confirmed disease were to be 
randomized 1:1 to benralizumab or placebo treatments. 
Patients that completed Part A prior to the approval of Amendment 4 could choose to continue 
to Part C, an extended open-label benralizumab treatment period. Participants were to remain 
on stable background medication and diet throughout the first 52 weeks of the study 
(including Part A and the first 28 weeks of Part C). 
Following approval of protocol Amendment 4, patients in Part A and Part C will advance to 
Part D at their next clinic visit and may be given the option of discontinuing or receiving
6 months of open-label benralizumab treatment, contingent on the Investigator's clinical 
judgement and the potential for benefit.
Disclosure Statement: This is a parallel-group efficacy and safety study with 2 arms that are 
participant and investigator blinded, with an open-label extension.
Number of Participants:
The study planned to randomize a minimum of approximately 210 and a maximum of 
approximately 230 participants.   (Note: enrollment was terminated after the enrollment of 
34 participants, of which 12 were randomized.)
Intervention Groups and Duration:
After a 4-week to 8-week run-in period, eligible patients were randomized 1:1 to 
24 weeks of subcutaneous treatment with benralizumab 30 mg Q4W or matching placebo 
Q4W, in Part A. Subsequently, all participants were to receive benralizumab 
30 mg Q4W subcutaneously in an open-label period, Part C, which was intended to allow 
patients at least 1 year of treatment with open-label benralizumab treatment. Patients were to 
maintain stable background medication and diet regimen for EG/EGE treatment through Week 
52. 
With the approval of Amendment 4, patients currently in Part A and Part C will advance to 
Part D at their next clinic visit.   These patients may then be given the option of continuing 
with 24 weeks of open-label benralizumab Q4W dosing in Part D.  Investigators may consider 
clinically appropriate adjustments to background medications and dietary restrictions in those 

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patients that continue in Part D.
Independent Data Monitoring Committee: Yes 
Note: With the approval of Amendment 4, it has been agreed with the IDMC chair that the 
open-label dosing in Part D will not require the use of an IDMC.
Statistical Methods
Part A of the study was intended to provide a preliminary assessment of efficacy and safety 
and data to assess the measurement properties and responsiveness of the de novo Symptom 
Assessment for Gastrointestinal Eosinophilic Diseases (SAGED) instrument. 
Sample Size Justification
The sample size calculations for the original study were based on the change from baseline 
in SAGED score at Week 24 dual primary endpoint. Changes in the other dual primary 
histological response rate endpoint required smaller sample sizes as larger relative differences 
are assumed (10% placebo response versus 80% benralizumab response). 
Part A was intended to enroll approximately 50 patients with EG.  Eligible patients with 
duodenal only disease were also included whilst enrolling the required 50 EG patients, with 
no minimum requirement on the number of duodenal only patients.  A minimum of 60 and 
maximum of 80 patients in the overall population (i.e. with either EG or duodenal only 
disease) were to be enrolled in Part A. Thirty patients per arm in the overall population and 
25 patients per arm with EG will provide >85% / >80% power for statistical significance at 
the 10% 2-sided level in each population respectively, if the true treatment effect for the 
change from baseline in SAGED score is a standardized effect size (difference in means/ 
standard deviation) of 0.75. A standardized effect size is used as the variability of the SAGED 
Score is not yet known. An effect size of 0.75 is a similar relative effect size as that observed 
in the lirentelimab (formerly antolimab) Phase 2 trial.  Approximately 20 adolescent patients 
(12 to 17 years of age) with either EG or duodenal only disease were targeted for inclusion in 
Part A.
Note: Only 12 patients were randomized due to closure of enrollment.
Analysis Methods
Analyses will consist of descriptive summaries of safety data for the double-blind placebo-
controlled period (Part A) and the open-label period (Parts C and D) and select patient listings 
of baseline characteristics, safety data, and key efficacy data.   Safety data presentations will 
use the safety analysis set which includes all randomized patients who receive at least one 
dose of investigational product.  No hypothesis testing will be performed due to the small 
sample size.

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1.2
Schema
1.2.1
Previous Schema (Protocol versions 1-4)
Figure 1
Previous Study Design 
Q4W: every fourth week; EoT: end of treatment; FU: follow-up.

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1.2.2
Current schema (Amendment 4, Protocol version 5)
Figure 2
Current Study Design   
Q4W: every fourth week; R: reference visit number of weeks (ie, visit prior to approval of Amendment 4); EoT: end of treatment; FU: follow-up.

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1.3
Schedule of Activities
Table 1 presents the schedule of activities for Part A prior to approval of Amendment 4.  Following approval of Amendment 4, all 
participants in Part A will directly proceed to Visit 20 of Part D (Table 3) at their next clinic visit.
Table 1
Schedule of Activities – Part A
Run-in
Double-blinded treatment period
In case of discontinuationa
CSP Section
Visit (V)
V1
V2
V3
V4
V5
V6
V7
V8 
/EOTb
Unscheduledc
IP 
Discontinuation
Follow-up
Week
-8 to -4
0
4
8
12
16
20
24
-
4 weeks post-
dose
8 weeks post-
dose
Visit Window (Days)
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
General procedures
Informed consent/assent
X
-
-
-
-
-
-
-
-
-
-
Appendix A 3
Demography/medical 
history
X
-
-
-
-
-
-
-
-
-
-
-
Inclusion/exclusion criteria
X
X
-
-
-
-
-
-
-
-
-
5.1, 5.2
Height, Weight
X
-
-
-
-
-
-
X
-
X
-
8.2.1
Efficacy assessments
Provide PRO device and 
instructions
X
-
-
-
-
-
-
-
-
-
-
8.1.3
Site visit PRO assessments 
(see Table 4)
X
X
-
-
-
-
-
X
-
X
-
8.1.3
Review PRO assessment 
compliance
-
X
X
X
X
X
X
X
-
X
-
8.1.3
Clinical Global Impression 
of Severity
X
-
-
-
-
-
X
-
X
X
8.1.4
Clinical Global Impression 
of Change
-
X
X
X
X
X
X
-
X
X
8.1.5
Diet questionnaire
X
X
X
X
X
X
X
X
X
X
X
8.1.6

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Qualitative interview reminder
-
X
-
-
-
-
-
-
-
-
-
8.1.7
Healthcare resource 
utilization
-
X
X
X
X
X
X
X
-
X
X
8.8
Endoscopy: biopsy, EG-
REFS, and EREFS 
Xe
-
-
-
-
-
-
X
-
Xf
-
8.1.1, 8.1.2
Safety assessments
Adverse events
X
X
X
X
X
X
X
X
X
X
X
8.3
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
6.5
Complete/(brief) physical 
exam
X
(X)
(X)
(X)
(X)
(X)
(X)
X
(X)
X
(X)
8.2.1
Vital signs
X
X
X
X
X
X
X
X 
X
X
-
8.2.2
Electrocardiograms
-
X
-
-
-
-
-
-
-
-
-
8.2.3
Laboratory assessments
Hematology/clinical chem
X
-
-
X
-
X
-
X
-
X
X
8.2.4
Serology (hepatitis/HIV)
X
-
-
-
-
-
-
-
-
-
-
8.2.6
Urinalysis
X
-
-
-
-
X
-
X
-
X
-
8.2.4
Post-menopause 
confirmationi
X
-
-
-
-
-
-
-
-
-
-
8.2.5
Serum/(urine) pregnancy 
X
(X)
(X)
(X)
(X)
(X)
(X)
(X)
-
(X)
(X)
8.2.5
Pharmacokinetics 
-
X
-
X
-
X
-
X
-
X
Xh
8.5.1
Immunogenicity
-
X
-
X
-
X
-
X
-
X
Xh
8.5.2
Biological sampling
Serum for total IgE 
X
-
-
-
-
-
-
-
-
-
-
8.6.1.1
Serum for tryptase
X
-
-
-
-
--
X
Blood, serum, plasma for 
biomarkers
X
-
-
X
-
X
-
X
-
-
-
8.6.1.1
Tissue for 
histopathology/biomarkers
X
-
-
-
-
-
-
X
-
Xf
-
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EG-REFS: Eosinophilic Gastritis Endoscopic Reference System; EOT: End of treatment; IP: investigational product; PRO: patient-reported outcomes.
a
For participants who discontinue treatment but remain in study see Section 7.1, for participants who discontinue from study see Section 7.2, and for 
participants lost to follow up see Section 7.3.
b
For patients continuing in PART C, Visit 8 is the first treatment of the PART C period. If a patient chooses not to continue in PART C, then the patient will 
be considered to have completed the study; the site will perform an EOT visit at Week 24, and the patient will return for a FU visit 12 weeks (±7days) after 
the last dose of IP, after which the patient exits the study. 
c
Other assessments may be performed at discretion of the Investigator.
d
At sites in select countries, in adult patients who have consented to the sub-study.
e
H.pylori testing to be performed at first endoscopy (at Screening)
f
To be performed at the discretion of the Sponsor and in accordance with guidance in Section 7.2.
g
To confirm postmenopausal status in women < 50 years of age who have been amenorrhoeic for ≥12 months.
h
Assessments/procedures only performed on discontinued patients who attend the follow-up visit at the study site.
i
Optional. Collected any time from Week 0 (Visit 2) after consent for genetic sample is obtained
j
IP will be administered at Visit 8 (Week 24) only for patients entering the OLE period
Table 2 presents the schedule of activities for Part C prior to approval of Amendment 4.  Following approval of Amendment 4, all 
participants in Part C will directly proceed to Visit 20 in Part D (Table 4) at their next clinic visit.
Table 2
Schedule of Activities – Part C
Open-label treatment period
In case of 
discontinuationa
CSP 
Section
Visit (V)
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
Unscheduledb
IP discon-
tinuation
Follow-up
Week
28
32c
36c
40
44c
48c
52
56c
60c
64
68c
-
4 weeks 
post-dose
8 weeks post-
dose
Visit Window (Days)
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
General procedures
Height, Weight
-
-
-
-
-
-
-
-
-
-
-
-
X
-
8.2.1
Blood for genetic analysis
-
Xk
-
-
-
-
-
-
-
-
-
8.7
Investigational product administration
Randomization 
-
X
-
-
-
-
-
-
-
-
-
6.3.1
Administration
-
X
X
X
X
X
X
Xj
-
-
-
6.1.3

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Table 2
Schedule of Activities – Part C
Open-label treatment period
In case of 
discontinuationa
CSP 
Section
Visit (V)
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
Unscheduledb
IP discon-
tinuation
Follow-up
Week
28
32c
36c
40
44c
48c
52
56c
60c
64
68c
-
4 weeks 
post-dose
8 weeks post-
dose
Visit Window (Days)
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
Efficacy assessments
Site visit PRO 
assessment (See 
Table 4)
X
X
8.1.3
Review compliance 
with PRO assessments
X
X
X
X
X
X
X
X
X
X
X
-
X
-
8.1.3
Clinical Global 
Impression of Change
X
X
X
X
X
X
X
X
X
X
X
-
X
-
8.1.5
Diet questionnaire
X
X
X
X
X
X
X
X
X
X
X
X
X
-
8.1.6
Healthcare resource 
utilization
X
X
X
X
X
X
X
X
X
X
X
-
X
-
8.8
Qualitative interview 
reminderd
X
-
-
-
-
-
-
-
-
-
-
-
-
8.1.7
Endoscopy: biopsy, 
EG-REFS, and EREFS 
-
-
-
-
-
-
X
-
-
-
-
-
-
-
8.1.1, 
8.1.2
Safety assessments
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.3
Concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
6.5
Complete/(brief) 
physical exam
(X)
(X)
(X)
(X)
(X)
(X)
X
-
-
(X)
-
(X)
X
(X)
8.2.1

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Table 2
Schedule of Activities – Part C
Open-label treatment period
In case of 
discontinuationa
CSP 
Section
Visit (V)
V9
V10
V11
V12
V13
V14
V15
V16
V17
V18
V19
Unscheduledb
IP discon-
tinuation
Follow-up
Week
28
32c
36c
40
44c
48c
52
56c
60c
64
68c
-
4 weeks 
post-dose
8 weeks post-
dose
Visit Window (Days)
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
Vital signs
X
X
X
X
X
X
X
-
-
X
-
X
X
-
8.2.2
Laboratory assessments
Hematology/clinical chem -
-
-
X
-
-
X
-
-
-
-
-
X
X
8.2.4
Urinalysis
-
-
-
X
-
-
X
-
-
-
-
-
X
-
8.2.4
Urine pregnancy test 
X
-
-
X
-
-
X
-
-
X
-
-
X
X
8.2.5
Pharmacokinetics 
-
-
-
X
-
-
X
-
-
-
-
-
Xe
X
8.5.1
Immunogenicity
-
-
-
X
-
-
X
-
-
-
-
-
Xe
X
8.5.2
Biomarkers sampling
Blood, serum, and plasma
for biomarker analyses
-
-
-
-
-
-
X
-
-
-
-
-
-
-
8.6.1.1
Tissue for 
histopathology and 
biomarkers
-
-
-
-
-
-
X
-
-
-
-
-
-
-
8.6.1.2
Investigational product administration
Administration
X
X
X
X
X
X
X
X
X
X
X
-
-
-
6.1.3
EG-REFS: Eosinophilic Gastritis Endoscopic Reference System; IP: investigational product; PRO: patient-reported outcomes.
a
For participants who discontinue treatment but remain in the study, see Section 7.1; for patients who discontinue from the study, see Section 7.2.
b
Other assessments may be performed at discretion of the Investigator.
c
For patients who are self-administering IP, these visits can optionally be conducted remotely by telephone contact.
d
In adult participants at select sites.
e
To be completed at the discretion of the Sponsor and in accordance with guidance in Section 7.2.

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Table 3
Schedule of Activities – Part D
CSP Section
Visit (V)
V20
V21a
V22a
V23
V24a
V25a
V26
EOT
Unscheduled
IP discontinuation
(Section 7)
Follow-up b
Week
R+4
R+8
R+12
R+16
R+20
R+24
R+28
-
4 weeks post-dose
8 weeks post-dose
Visit Window (Days)
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
General procedures
Informed consent/assent
X
-
-
-
-
-
-
-
-
-
Appendix A 3
Return PRO device
X
-
-
-
-
-
-
-
-
-
8.2.1
Efficacy assessments
Clinical Global Impression of 
Severity
X
X
X
X
X
X
X
-
X
-
8.1.5
Diet questionnaire
X
-
-
-
-
-
X
X
X
-
8.1.6
Healthcare resource utilization
X
-
-
-
-
-
X
-
X
-
8.8
Safety assessments
Adverse events
X
X
X
X
X
X
X
X
X
X
8.3
Concomitant medication
X
X
X
X
X
X
X
X
X
X
6.5
Complete (brief) physical exam
-
-
-
-
-
-
X
(X)
X
-
8.2.1
Vital signs
-
-
-
-
-
-
X
X
X
-
8.2.2
Laboratory assessments
Hematology/clinical chemistry
-
-
-
-
-
-
X
-
X
X
8.2.4
Urine pregnancy test c
-
-
-
-
-
-
X
-
X
X
8.2.5
Investigational product administration
Administration
X
X d
X d
X
X d
X d
-
-
-
-
6.1.3
EOT: end of treatment; IP: investigational product. R: reference visit number of weeks (ie, number of weeks for the visit prior to approval of Amendment 4).
a
For patients who are self-administering IP, these visits can be conducted remotely by telephone contact.
b
Can be conducted remotely by telephone contact
c
Patients should be strongly encouraged to monitor for pregnancy during the study and report a pregnancy to the site as soon as possible.
d
Optional at-home or remote location self-administration (Section 6.1.3.5).

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Table 4 presents the schedule of activities for patient-reported outcomes prior to approval of Amendment 4.  There will be no further 
collection of patient-reported outcome data following Visit 20 of Part D.
Table 4
Schedule of Activities – Patient-Reported Outcomes
During scheduled clinic visits
At home
CSP Section
Run-in
Treatment period
Run-in, double-blinded and open-label
Visit (V) (if applicable)
V1
V2
V8
V15
Weeka/Frequency
-8 to -4
0
24
52
Every 
evening from 
V1 until V20b
Every 
2 weeks from 
V1 until V20c
Every 
4 weeks after 
V2 until V20c
Symptom Assessment for Gastrointestinal Eosinophilic Diseases 
(SAGED)
-
-
-
-
X
-
-
8.1.3.1
Bristol Stool Form Scale
-
-
-
-
X
-
-
8.1.3.2
Dysphagia Symptom Questionnaire (DSQ)
-
-
-
-
X
-
-
8.1.3.3
Patient Assessment of Gastrointestinal Disorders Symptom Severity 
Index (PAGI-SYM)
X
X
-
-
-
-
X
8.1.3.4
Patient-Reported Outcome Measurement Information System (PROMIS) 
Short Form – Fatigue 7a
X
X
-
-
-
-
X
8.1.3.5
Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life 
X
X
-
-
-
X
8.1.3.6
Short Form Health Survey Version 2, Acute Recall (SF-36v2)
X
X
-
-
-
-
X
8.1.3.7
Work Productivity and Activity Impairment Questionnaire plus 
Classroom Impairment Questions: SHP, Version 2 (WPAI+CIQ)
X
X
-
-
-
-
X
8.1.3.8
Patient Global Impression of Severity (PGI-S)
X
X
-
-
-
X
-
8.1.3.9
Patient Global Impression of Change (PGI-C)
-
-
-
-
-
X
-
8.1.3.10
Patient Global Impression of Benefit-Risk (PGI-BR)
-
-
X
X
-
-
-
8.1.3.11
a
Scheduled Visit 8 at Week 24 and Visit 14 at Week 52 should occur within a window of +3 days; discontinuation visit may occur within a window of +7 days.
b
Evening defined as 17:00 to 23:59.
c
2 weeks defined as 14 ± 3 days. 4 weeks defined as 28 ± 3 days. 

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2
INTRODUCTION
Benralizumab is a humanized, afucosylated, monoclonal antibody that binds specifically to the 
IL-5Rα on the target cell and thus directly depletes eosinophils through antibody-dependent 
cell-mediated cytotoxicity. Benralizumab has been widely approved for treatment of asthma 
and also has been or is being investigated in patients with asthma, chronic obstructive 
pulmonary disease, hypereosinophilic syndrome, nasal polyposis, eosinophilic granulomatosis 
with polyangiitis, eosinophilic chronic rhinosinusitis, and eosinophilic esophagitis. This 
AstraZeneca-sponsored clinical trial investigates the use of benralizumab in patients with 
eosinophilic gastritis and/or gastroenteritis.
2.1
Study Rationale
In patients with asthma, the enhanced antibody-dependent cell-mediated cytotoxicity activity 
of benralizumab results in the rapid and nearly complete depletion of eosinophils in the blood 
as well as depletion of eosinophils in the lung tissue, sputum, and bone marrow (Busse et al 
2013, Kolbeck et al 2010, Laviolette et al 2013). The direct eosinophil-depleting ability of 
benralizumab has been shown to be effective in eosinophilic asthma (Bleecker et al 2016, 
FitzGerald et al 2016) and steroid-dependent asthma (Nair et al 2017), and preliminary results 
suggest that benralizumab is effective in treating hypereosinophilic syndrome (Kuang et al 
2018, Kuang et al 2019), which shares clinical and histologic features with EG/EGE. Based 
upon the above, benralizumab is a potentially safe and effective treatment for EG/EGE.
The central role of eosinophil inflammation in the pathophysiology of EG/EGE strongly 
suggests that a direct eosinophil depleting approach, as provided by benralizumab, may prove 
beneficial in reducing/eliminating eosinophils from gastrointestinal tissues and improve 
gastrointestinal symptoms and outcomes. This Phase 3 study originally had 3 overall aims: 
1) Part A will validate an EG/EGE symptom PRO instrument, as no fit-for-purpose instrument 
is available, and provide a preliminary assessment of efficacy and safety, 2) Part B will 
provide pivotal efficacy and safety data to support registration of benralizumab for this 
indication, and 3) Part C will provide longer term efficacy and safety data.
2.1.1
Protocol Amendment 4 (Version 5)
Based upon an emergent body of evidence (see Section 2.2.1), AstraZeneca has elected to 
close recruitment of the HUDSON study, with Part A only partially enrolled.  
Subsequently, the protocol has been amended to allow investigators to offer participants who 
elect to continue in the study at least 6 months of open-label benralizumab in a Part D, which 
serves as an extended closure segment of the study.

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2.2
Background
Eosinophilic gastritis and eosinophilic gastroenteritis (EG/EGE) are rare chronic allergic 
inflammatory disorders of the gastrointestinal tract characterized by increased infiltration 
of eosinophils in the stomach and duodenum tissues and accompanying gastrointestinal 
symptoms, such as nausea, vomiting, abdominal pain, and diarrhea. Although these disorders 
have been increasingly recognized and diagnosed in both adults and adolescents, there are 
currently neither established diagnostic criteria nor treatment guidelines and no approved 
treatments. 
The etiology of EG/EGE has not been fully characterized, but there is some evidence to 
support an allergic cause of eosinophilic gastrointestinal diseases (Rothenberg 2004). Food 
allergy, immune-dysregulation in response to an allergic reaction, and intestinal dysbiosis 
have been suggested or implicated in the pathogenesis (Sunkara et al 2019). A strong type 
2 immune response has been shown to occur systemically and locally, with marked 
overproduction of eosinophil chemoattractant and activating factors including eotaxins and 
IL-5 (Caldwell 2014, Shoda et al 2020).  Murine models of EG/EGE have demonstrated a 
role for eosinophils in eliciting gastrointestinal pathology, including motility problems and 
neurotoxicity (Hogan et al. 2001). A history of atopic conditions is common in patients, 
including rhinitis, asthma, food allergies, eczema and atopic dermatitis (Jensen et al 2016). 
Histopathology of affected tissue demonstrates high numbers of eosinophils and evidence 
of eosinophilic degranulation. This increase, especially when associated with aggregation, 
degranulation and infiltration of squamous epithelium along with architectural changes in the 
mucosa, indicates a pathologic process, and the histopathology of affected tissue demonstrates 
high numbers of eosinophils and evidence of eosinophilic degranulation (Egan and Furuta 
2018). 
Currently there are no established treatment guidelines and no approved treatments for 
EG/EGE. Dietary elimination therapy and corticosteroids (systemic and topical) are the most 
common treatments but are suboptimal and have limitations. 
Food elimination diets may be considered as an initial therapy. Diets used in EG/EGE include 
elemental diets, a 6- or 7-food empiric elimination diet, and empiric avoidance of specific 
foods (eg, milk). However, determination of the type of food to eliminate can be challenging, 
and elimination diets have variable results, and data evaluating this strategy is limited for 
EG/EGE compared to eosinophilic esophagitis. Empirical dietary elimination can be 
burdensome on patients, as it may require numerous attempts of trial and error, including 
follow-up endoscopies, and each error can cause significant relapse of symptoms. 
Elemental/amino acid-based diets may be more effective but have not been proven for long-
term efficacy; cost and compliance can also be problematic, and these are not feasible for 
long-term use in adults as the sole-source of nutrition.

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Corticosteroids, which suppress eosinophilic growth factors IL-3, IL-5, and GM-CSF, and 
various other chemokines, are currently the most effective pharmacological treatment for 
EG/EGE. Systemic corticosteroids are typically used for severe disease or when dietary 
changes have failed to achieve adequate response or were impractical. A low-dose 
maintenance corticosteroid treatment may be necessary in some patients. Swallowed 
budesonide, a corticosteroid formulation that has limited systemic exposure due to high first-
pass metabolism, is a treatment option, including an enteric-coated formulation of budesonide 
developed for inflammatory bowel disease (ie, Entocort); this is considered a relatively local 
or topical treatment compared with systemic prednisone. 
There is an unmet medical need for new therapies for patients with EG/EGE.
Nomenclature of eosinophilic gastrointestinal diseases (EGIDs) is evolving, especially in the 
area of the GI tract distal to the esophagus.  Although Eosinophilic Gastroenteritis suggests 
involvement of the stomach and the small intestine, there are literature references that utilize 
Eosinophilic Enteritis (Gurkan et al 2021) and Eosinophilic Duodenitis (Dellon et al 2020) to 
specify small intestine involvement.  Where necessary in this protocol, precise segment of the 
gastrointestinal tract will be identified for clarity.
A detailed description of the chemistry, pharmacology, efficacy, and safety of benralizumab is 
provided in the Investigator’s Brochure.
2.2.1
Emerging scientific evidence and closure of study recruitment
There is a growing body of emergent evidence of eosinophil independent mechanisms in the 
pathology of eosinophilic upper gastrointestinal (GI) disease, including eosinophilic 
esophagitis and EG/EGE. The results of the ENIGMA II trial of lirentelimab, first 
communicated in a press release (Allakos Press Release 2021), showed that while the 
histologic endpoint of eosinophil depletion was met, the symptom co-primary endpoint was 
not. In addition, an in-depth open-label analysis of a 7-patient eosinophil GI subgroup among 
the 20 patient hypereosinophilic syndrome Phase 2 trial of benralizumab showed that despite 
durable eosinophil depletion in the GI tract, prolonged clinical response was heterogeneous 
and that residual symptoms may reflect persistent epithelial inflammation (Kuang et al 2022). 
AstraZeneca has recently announced high-level results from the Phase 3 MESSINA study in 
eosinophilic esophagitis, in which the histologic endpoint was met, but not the symptomatic 
endpoint. Most recently, new clinical data generated in the investigator-sponsored 
Benralizumab for Eosinophilic Gastritis study (NCT03473977, in press) raises further 
questions regarding the role of eosinophils in disease of the upper GI tract.  
Given the scientific evidence referenced above that has accrued since HUDSON was initiated, 
AstraZeneca elected to close recruitment of the HUDSON study. There is no new data to 
warrant any changes to the benralizumab safety profile in this patient population, more that 

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eosinophil independent mechanisms may work to maintain previously considered eosinophilic 
gastrointestinal diseases, even when eosinophils are robustly depleted.
Participants may be given the option of receiving 6 months (ie, 6 doses) of open-label 
benralizumab treatment in Part D, which will serve as an extended closure segment of the 
study.
2.3
Benefit/Risk Assessment
In order to assess the benefit/risk for participation in this benralizumab study, preclinical and 
clinical data for the investigational product have been taken into consideration as well as the 
risks associated with the study procedures. 
More detailed information about the known and expected benefits and potential risks 
associated with benralizumab may be found in the Investigator’s Brochure.
2.3.1
Risk Assessment
Benralizumab is approved for severe asthma with an eosinophilic phenotype and has a well-
established safety profile. Benralizumab has been well tolerated with the most frequently 
observed adverse events (AEs) from the asthma and chronic obstructive pulmonary disease 
Phase 3 controlled studies being generally reflective of each study’s respective patient 
population. Additionally, benralizumab is approved for use in asthma with an eosinophilic 
phenotype in many areas of the world.  Potential risks that may be associated with the use of 
benralizumab are presented in Table 5.  Note: following the approval of Amendment 4, 
there are no protocol-mandated endoscopy/biopsy procedures. 
Table 5
Risk Assessment
Potential risk of clinical 
significance
Summary of data/rationale for risk
Mitigation strategy
Study intervention (benralizumab or matching placebo)
Serious infections
Serious infections have been reported 
for benralizumab. A relationship 
between eosinophil depletion and 
serious infection has not been 
established.
In addition to routine 
pharmacovigilance activities and 
an Independent Data Monitoring 
Committee, benralizumab will not 
be administered to a patient with a 
clinically significant active 
infection until the infection has 
resolved (see Section 6.1.3.3).
Malignancies
Malignancies have been reported at a 
low incidence in the completed and 
ongoing studies of benralizumab.
Eosinophils have been circumstantially 
In addition to routine 
pharmacovigilance activities and 
an Independent Data Monitoring 
Committee, risk minimization 

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Potential risk of clinical 
significance
Summary of data/rationale for risk
Mitigation strategy
associated with a positive prognosis in 
certain solid tumors, especially tumors 
of epithelial origin (breast and colon) 
and may play an active role in tumor 
defense by modulating host defenses or 
may be a bystander effect. However, 
the cause and consequences (ie, pro-
tumorigenic versus anti-tumorigenic) of 
eosinophil recruitment and 
accumulation into tumors are unclear.
measures include exclusion of 
patients with active or recent 
malignancy (see exclusion criteria 
14).
Serious hypersensitivity 
reactions (including 
anaphylaxis)
Serious hypersensitivity reactions 
(including anaphylaxis) are an 
identified risk of biologic therapy, 
including benralizumab. Anaphylaxis 
may be life-threatening. 
Risk minimization includes 
exclusion of patients with known 
hypersensitivity to investigational 
product (exclusion criteria 17) 
and observation following 
administration for the appearance 
of any acute drug reactions, in 
line with clinical practice.
Development of anti-drug 
antibodies
Development of anti-drug antibodies to 
benralizumab has been documented. 
Theoretical risks of developing anti-
drug antibodies may include decreased 
effective drug concentrations and 
hypersensitivity reactions (eg, 
anaphylaxis or immune complex 
disease). There was no impact of anti-
drug antibodies on overall 
benralizumab safety or efficacy in the 
previous Phase 3 studies in asthma.
Helminth infection
Eosinophils are a prominent feature of 
the inflammatory response to 
helminthic parasitic infections. 
Therefore, there is a theoretical risk that 
prolonged eosinophil depletion may 
diminish the ability to defend against 
helminthic parasites. 
In addition to routine 
pharmacovigilance activities, risk 
minimization measures include 
exclusion of patients with 
untreated parasitic infection (see 
exclusion criteria 17).
Study procedures
Esophagogastroduodenoscopy 
with biopsy
Beside risks associated with routine 
clinical practice (eg, blood draw), study 
procedures include endoscopies with 
biopsies. Potential AEs associated with 
this procedure include bleeding 
complications, infection, and tears of 
the gastrointestinal tract. 
Procedures will be performed by 
specialist physicians at centers 
where this procedure is routinely 
performed. 

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2.3.2 Benefit Assessment
The goals of treatment for EG/EGE are to decrease its gastrointestinal signs and symptoms, 
with histologic improvement in gastrointestinal eosinophilia, and improve patient quality of 
life. By depleting eosinophils, benralizumab might still improve clinical outcomes in patients 
with EG/EGE. 
This amendment adds an open label extended closure for patients who feel, along with their 
investigator, that they are receiving or may receive benefit from treatment with benralizumab.
2.3.3 Overall Benefit: Risk Conclusion
Taking into account the purpose and design of this trial, the well-established safety profile of 
benralizumab, and the measures taken to minimize potential risks to participants participating 
in this study, the benefit: risk for participation in this trial is deemed to be acceptable.
Protocol V5 (Amendment 4): Given the well-established safety profile of benralizumab, the 
perceived benefit of benralizumab treatment by patients along with their physician, and the 
measures taken to minimize potential risks to participants participating in the extended 
closure, the benefit: risk for continued participation is deemed to be acceptable.

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3
OBJECTIVES AND ENDPOINTS
Note: Given the small number of patients randomized at the time of decision to stop 
recruitment to the study, it will not be possible to assess of these objectives with the data 
collected during Part A.  A revised analysis plan is presented in Section 9.
Table 6
Objectives and Endpoints
Objectives
Estimand description/Endpoint
Primary

Part A: To compare the effect of benralizumab 
30 mg every 4 weeks (Q4W) with placebo on 
histologic signs and gastrointestinal symptoms 
in patients with eosinophilic gastritis and/or 
gastroenteritis
Dual primary endpoints including histology-based and 
symptom-based endpoints:
Histology-based dual primary endpoint

Population: Full analysis set

Histologic Endpoint: Proportion of patients 
achieving a histological response (defined as 
≤6 eosinophils/hpf in the stomach and/or, 
≤15 eosinophils/hpf in the duodenum) at Week 24

Intercurrent events: A composite approach 
whereby participants who receive restricteda or 
rescue medications, or discontinue randomized 
therapy prior to Week 24 will be considered as 
histological non-responders at Week 24

Summary measure: Odds ratio and difference in 
response rates between benralizumab and placebo
Symptom-based dual primary endpoint

Population: Full analysis set

Symptom Endpoint: Absolute change from 
baseline in SAGED Score at Week 24

Intercurrent events: A composite approach 
whereby participants who receive restricteda or 
rescue medications or discontinue randomized 
therapy prior to Week 24 will be considered as 
treatment failures at Week 24.  Such patients will 
have their worst observation prior to or at the 
intercurrent event carried forwards to Week 24.

Summary measure: Difference in least squares 
mean change from baseline in SAGED score at 
Week 24 between benralizumab and placebo

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Table 6
Objectives and Endpoints
Objectives
Estimand description/Endpoint
Secondary

Part A: To compare the effect of benralizumab 
30 mg Q4W with placebo on clinical features 
of eosinophilic gastritis/ gastroenteritis and 
disease activity

Keyb: Percentage change from baseline in tissue 
eosinophils (stomach and/or duodenum if 
applicable) at Week 24

Keyb: Proportion of patients who achieve 
treatment response: tissue remission (≤6 
eosinophils/hpf in the stomach and ≤15 
eosinophils/hpf in the duodenum, if applicable) 
and improvement in symptoms at Week 24

Change from baseline in proportion of vomiting-
free days, and change from baseline in frequency 
of vomiting episodes at Week 24

Change from baseline in proportion of diarrhea-
free days, and change from baseline in frequency 
of diarrhea episodes at Week 24

Change from baseline in proportion of days both 
diarrhea and constipation free at Week 24

Time to clinically meaningful improvement in 
SAGED score

Change from baseline in PROMIS Fatigue 7a 
score and PAGI-SYM score at Week 24

Part A: To compare the effect of benralizumab 
30mg Q4W with placebo on rescue 
corticosteroid use

Keyb: Proportion of patients with no rescue 
corticosteroid use up to Week 24

Part A: To compare the effect of benralizumab 
30 mg Q4W with placebo on health-related 
quality of life in patients with EG/EGE

Change from baseline in SF-36v2 PCS and MCS 
at Week 24

Change from baseline in PAGI-QoL at Week 24

To assess the pharmacokinetics and 
immunogenicity of benralizumab in patients 
with EG/EGE

Serum benralizumab concentration over time

Anti-drug antibodies over time
Safety

To assess the safety of benralizumab in 
patients with eosinophilic gastritis and/or 
gastroenteritis

Adverse Events, vital signs, physical exam, and 
laboratory parameters

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Table 6
Objectives and Endpoints
Objectives
Estimand description/Endpoint
Exploratory

Part A:  To describe the effect of 
benralizumab on clinical features of EG/EGE 
and disease activity

Change from baseline in vomiting severity at 
Week 24

Change from baseline in diarrhea severity at 
Week 24

Change from baseline in endoscopic measures of 
inflammation and remodeling, EG-REFS, by 
central reader at Week 24

Change from baseline in PAGI-SYM, DSQ, 
PGIS, PGI-C, CGI-S, and CGI-C

Part D: To collect more information on the 
safety and clinical response of benralizumab 
in EG/EGE.

Adverse Events, vital signs, physical exam, and 
laboratory parameters

Change from baseline in CGI-S
a
Only restricted medications given that are considered to have a potentially meaningful impact on EG/EGE 
outcomes will be considered intercurrent events.

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4
STUDY DESIGN
4.1
Overall Design


The study will be performed in patients ages 12 and above with EG/EGE that are 
symptomatic and histologically active on stable background medication and diet.

Following screening to confirm eligibility, an initial double-blinded, randomized placebo-
controlled, parallel-group 24-week treatment period aimed to validate a PRO instrument 
for EG/EGE symptoms and provide preliminary efficacy and safety data (Part A). 

Participants completing Part A may continue to a subsequent exploratory open-label Part 
C which will provide further efficacy and safety data.

Following approval of Amendment 4, patients in both Part A and Part C may proceed to 
Part D in which they may be offered 24 weeks of open-label benralizumab treatment.
contingent on the Investigator's clinical judgement and the potential for benefit.
4.1.1
Study Conduct Mitigation During Study Disruption
The guidance given below supersedes instructions provided elsewhere in this clinical study 
protocol and should be implemented only during cases of civil crisis, natural disaster, or 
public health crisis (eg, during quarantines and resulting site closures, regional travel 
restrictions, and considerations if site personnel or study participants become infected with 
SARS-CoV-2 or similar pandemic infection) which would prevent the conduct of 
study-related activities at study sites, thereby compromising the study site staff or the 
participant’s ability to conduct the study. The investigator or designee should contact the study 
Sponsor representative to discuss whether the mitigation plans below should be implemented. 
The study participants will be required to complete the screening and randomization visits on 
site prior to having the option to participate in the mitigation plans. 
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with Good Clinical Practice, 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: 

Obtaining [consent/reconsent] for the mitigation procedures (note, in the case of verbal 
[consent/reconsent], the informed consent form (ICF) should be signed at the participant’s 
next contact with the study site).

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
Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened participants. 
The investigator should confirm this with the designated study physician.

Home or Remote visit: Performed by a site-qualified Health Care Professional or a Health 
Care Professional provided by a third-party vendor.

Telemedicine visit: Remote contact with the participants using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices. 

At-home investigational product administration: Performed by a site qualified Health 
Care Professional, Health Care Professional provided by a third-party vendor, or by the 
participant or the participant’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, 
see Appendix G.
4.2
Scientific Rationale for Study Design
As a registration trial, this study was designed to evaluate benralizumab’s effect on both the 
signs and symptoms of EG/EGE and the underlying eosinophilic inflammation, with dual 
primary outcome variables, in a double-blinded, randomized, placebo-controlled fashion. 
With regard to the symptoms, as no suitable clinical outcome assessment was available, 
AstraZeneca has performed initial activities to develop such a tool to be used in this study, 
the SAGED PRO instrument, including identifying the symptoms that are most important to 
this patient population. The first part of this study, Part A, will evaluate the measurement 
properties of this PRO instrument and demonstrate whether the SAGED score is fit for 
purpose as one of the dual primary endpoints for this indication and patient population.  
This was to be done in a population separate from the population in which pivotal efficacy 
data was to subsequently generated, Part B.
This symptom-based endpoint will be supported by a histology endpoint, the number of 
eosinophils present in the stomach and duodenal biopsy samples, to document whether or not 
a histological response to treatment, ie, eosinophil depletion, underlies improvement in 
symptoms. The histological cut-off to be used for patient entry into the study 
(≥30 eosinophils/hpf in 5hpf) (Collins MH 2014) is higher than established clinical guidelines 
recommend for eosinophilic esophagitis diagnosis, which is ≥15 eosinophils/hpf (with 2 to 4 
biopsies obtained) (Dellon et al 2013a). Normally, eosinophils do not occur in the esophagus, 
whereas they are normally present in the remainder of the gastrointestinal tract tissue, 
including the stomach and small intestine. As such, a higher threshold will be used for 
diagnosing EG/EGE in this study compared with eosinophilic esophagitis guidelines.

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Patients will be eligible for this study if they have been diagnosed by a clinician with EG/EGE 
at least 3 months prior to screening. This duration serves several purposes. Firstly, it works to 
support the persistence of the disease, and with it decreases the likelihood for spontaneous 
remission and similarly decreases the potential for a higher than expected placebo response 
in patients spontaneously remitting. In addition, this time period enables assessment for diet 
modification and medication strategies to be considered prior to enrollment in the study.
While the conditions of EG/EGE are rare, the gastric and duodenal pathophysiology, 
symptomatology and diagnostic evaluation of EG/EGE are sufficiently consistent between 
adolescents and adult patients, supporting the study of both populations in the same study 
and utilizing the same measures. The available data and safety profile from studies with 
benralizumab in adolescents in addition to robust PK modelling support the inclusion of 
adolescent patients (12 to 17 years of age) in this EG/EGE study. Modelling also supports the 
use of the 30mg dose in these adolescent patients in order for exposure to be commensurate to 
that of adult patients.
Variability in background medications and diet could have confounding effects on the 
outcomes being measured for EG/EGE; stable medications and dietary restrictions are thus 
required to show the benefit of benralizumab. Prior to screening, patients’ background 
medication must be stable for at least 4 weeks and diet restrictions must be stable for at least 
6 weeks, and patients were to agree that there will be no changes during Part A and until Week 
52 of the study (unless medically indicated).  These medication and dietary restrictions will 
not apply to Part D of the study. 
4.2.1 Participant Input into Design
4.2.1.1
Participant Input into Study Design
The study team sought input from patients on the proposed study design and discussed patient 
experiences with key experts in the field and their clinical staff. Input on aspects of the study 
design such as the use of endoscopy, the use of injectable medications, the presence of a 
placebo treatment arm, and the potential for self-administration was provided.
4.2.1.2
Participant Input into Patient-Reported Outcomes
The primary data source for the development of the SAGED instrument was semi-structured 
concept elicitation interviews with EG/EGE patients, in which concepts (ie, symptoms and 
their impacts) that are important to patients emerge spontaneously through open-ended 
questions. Patients’ responses were the basis of the conceptual framework. The wording of 
the questions in the instrument was directly adapted from language patients used in the 
interviews. Drafts of the SAGED instrument were cognitively debriefed with patients to 
ensure the instrument captured all concepts of interest and used language and response options 
that were meaningful to patients.

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4.3
Justification for Dose
The pharmacokinetics of benralizumab are well-characterized (Wang et al 2017), and it is 
expected to demonstrate consistent pharmacokinetics across different disease populations. 
In adult and adolescent patients with severe asthma (CALIMA [Bleecker et al 2016] and 
SIROCCO [FitzGerald et al 2016]) treated with benralizumab 30 mg every 8 weeks (Q8W) 
or Q4W, near complete blood eosinophil depletions were observed for both dosing regimens. 
In a study of benralizumab in hypereosinophilic syndrome, where patients have high blood 
eosinophils and significant organ manifestations of eosinophilic inflammation, a dosing 
regimen of 30 mg Q4W was effective in reducing blood and tissue eosinophilia (including 
gastrointestinal tissue) in patients, with an associated improvement in gastrointestinal 
symptoms (Kuang et al 2019). For the planned clinical study of patients with eosinophilic 
esophagitis, which is similar to hypereosinophilic syndrome in that the disease is characterized 
by significant eosinophilic inflammation of tissues that are thicker and less vascular than lung 
tissue, the Sponsor is proposing a dosing regimen of 30 mg Q4W as it is believed that a higher 
concentration is necessary to generate meaningful eosinophil reduction in the tissues of the 
esophagus and resolution of associated clinical symptoms.
In the CALIMA/SIROCCO studies, the pharmacological profiles of benralizumab in blood 
(30 mg Q4W and 30 mg Q8W) were consistent between adolescents and adults, and the safety 
profile of benralizumab was similar to that of placebo in both adolescents and adults. Among 
adolescent participants who received benralizumab 30 mg Q4W, the incidence of 
treatment-emergent AEs and the most commonly reported preferred terms were similar to the 
Q8W group.
4.4
End of Study Definition
The end of study is defined as the last expected visit/contact of the last patient undergoing the 
study.
A patient is considered to have completed the study when he/she has completed his/her last 
scheduled visit/telephone contact. 
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waiver or exemption, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:

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Age
1
Participant must be at least 12 years of age at the time of signing the ICF or informed 
assent form.
Type of Participant and Disease Characteristics
2
Clinician confirmed diagnosis of EG/EGE for at least 3 months prior to screening.
3
Participants who have documented previous diagnosis of eosinophilic gastritis, with or 
without duodenitis, or eosinophilic duodenitis alone. This will be confirmed by biopsy for 
the purpose of this study, defined as a gastric count of ≥30 eosinophils/hpf in 5 hpfs 
and/or duodenal eosinophil count ≥30 eosinophils/hpf in at least 3 hpfs without any other 
cause for the gastrointestinal eosinophilia (eg, parasitic or other infection or malignancy). 
Participants can have duodenal only disease and be enrolled in the duodenal only subject 
population. See Section 8.1.1 for details regarding endoscopy and biopsy.
4
At Visit 1 (screening), participants who in the investigator’s judgement have a history of 
symptoms of abdominal pain, nausea, bloating, early satiety, and/or loss of appetite to an 
extent that they would meet criteria 5 at Visit 2.
5
At Visit 2 (randomisation), participants who are symptomatic, defined as having a mean 
SAGED score >12 (on a 0 to 50 point scale) over the last 14 days of the run-in period.  
6
Must be adherent to daily PRO assessments: 
(a) Must complete 70% SAGED, DSQ, and Bristol Stool Form Scale assessments 
between Visit 1 and Visit 2 AND
(b) Must have completed at least 8 of 14 SAGED assessments in the 14 days prior to 
randomization
7
If on background medications for EG/EGE during the study, background medications 
have been stable for at least 4 weeks prior to the run-in period.
(a) Patient must agree not to change type of background medication or dosage during the 
study unless medically indicated or allowed by protocol during Part C OL after Week 
52 as clinically indicated. If a medication for EG/EGE (including swallowed steroids, 
systemic steroids and PPI) is discontinued prior to screening, there should be a 
washout period of at least 8 weeks prior to screening. See Section 6.5 for details 
regarding background medications. 
Reproduction
8
Negative serum pregnancy test for women of childbearing potential (WOCBP) at Visit 1 
(enrollment).
9
Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
Female participants:

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Women not of childbearing potential are defined as women who are either 
permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy), or who are postmenopausal. Women will be considered postmenopausal 
if they have been amenorrhoeic for 12 months prior to the planned date of randomisation 
without an alternative medical cause. The following age-specific requirements apply:

Women <50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatment and have follicle stimulating hormone levels in the postmenopausal range. 
Until FSH is documented to be within menopausal range, she should be treated as a 
WOCBP

Women ≥50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of all exogenous hormonal 
treatment.
Female participants that are WOCBP must use one highly effective form of birth 
control. A highly effective method of contraception is defined as one that can achieve a 
failure rate of less than 1% per year when used consistently and correctly. WOCBP who 
are sexually active with a non-sterilized male partner must agree to use one highly 
effective method of birth control, as defined below, from enrollment throughout the study 
and until at least 12 weeks after last dose of study intervention. Cessation of contraception 
after this point should be discussed with a responsible physician. Periodic abstinence 
(calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhea method are not acceptable methods of 
contraception. Female condom and male condom should not be used together. All women 
of childbearing potential must have a negative serum pregnancy test result at Visit 1.
Highly effective birth control methods include: 

Combined (estrogen and progestogen) 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)

Vasectomized sexual partner provided that partner is the sole sexual partner of 
the WOCBP study patient and that the vasectomized partner has received medical 
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Informed Consent
10 Capable of giving signed informed consent/assent as described in Appendix A which 
includes compliance with the requirements and restrictions listed in the ICF and in this 
protocol
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
Any disorder, including, but not limited to, cardiovascular, renal, neurological, 
musculoskeletal, infectious, endocrine, metabolic, hematological, psychiatric, or major 
physical impairment that is not stable in the opinion of the investigator and could:
- Affect the safety of the patient throughout the study
- Influence the findings of the studies or their interpretations
- Impede the patient’s ability to complete the entire duration of study.
2
Other gastrointestinal disorders such as active Helicobacter pylori infection, history of 
achalasia, esophageal varices, Crohn's disease, ulcerative colitis, inflammatory bowel 
disease, or celiac disease.
3
Hypereosinophilic syndrome or eosinophilic granulomatosis with polyangiitis.
4
Current malignancy, or history of malignancy, except for patients who have had basal 
cell, localized 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 the date of informed consent, and assent when applicable was 
obtained. 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, and assent when applicable, was obtained.
5
History of anaphylaxis to any biologic therapy or vaccine.
6
Current active liver disease:
(a)
Chronic stable hepatitis B and C (including positive testing for hepatitis B surface 
antigen [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, 
hypoalbuminemia, esophageal or gastric varices, or persistent jaundice, or cirrhosis.
(b) Alanine aminotransferase or aspartate aminotransferase level > 3 times the upper 
limit of normal, confirmed by repeated testing during the run-in period. Transient 
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the time of randomization is acceptable if in the Investigator's opinion the patient 
does not have an active liver disease and meets other eligibility criteria.
7
Helminth parasitic infection diagnosed within 24 weeks prior to the date informed 
consent or assent (if applicable) is obtained that has not been treated with or has failed to 
respond to standard of care therapy.
8
Any clinically significant abnormal findings in physical examination, vital signs, 
hematology, clinical chemistry, or urinalysis during 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.
9
Known immunodeficiency disorder including testing positive for HIV.
Prior/Concomitant Therapy
10 Concomitant use of immunosuppressive medication (including but not limited to: 
methotrexate, cyclosporine, and azathioprine (see Table 8).
11 Receipt of immunoglobulin or blood products within 30 days prior to the date informed 
consent or assent is obtained.
12 Receipt of live attenuated vaccines 30 days prior to date of informed consent or assent.
13 Receipt of inactive vaccines within 7 days of informed consent or assent.
14 Receipt of any marketed or investigational biologic (monoclonal or polyclonal antibody) 
within 4 months or 5 half-lives prior to the date informed consent or assent (if applicable), 
is obtained, whichever is longer, and during the study period.
Prior/Concurrent Clinical Study Experience
15 Previous participation in a benralizumab clinical study.
16 Participation in another clinical study with an investigational product administered in the 
last 30 days or 5 half-lives prior to randomization, whichever is longer.
17 Participants with a known hypersensitivity to benralizumab or any of the excipients of the 
product.
Other Exclusions
18 Initiation or change of a food-elimination diet regimen or re-introduction of a previously
eliminated food group from 6 weeks prior to start of the run-in period and unable or 
unwilling to remain on a stable diet until the completion of Week 52.
19 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
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20 Judgment by the investigator that the participant is unlikely to comply with study 
procedures, restrictions, and requirements.
21 For women: currently pregnant confirmed with positive pregnancy test or breast-feeding.
5.3
Lifestyle Considerations
Patients must abstain from donating blood, plasma, or platelets from the time of informed
consent or assent (if applicable) and for 12 weeks after last dose of investigational product.
WOCBP must use highly effective contraceptive methods throughout the study and 12 weeks 
after last dose of the investigational product (see also inclusion criterion 8 in Section 5.1).
Prior to Amendment 4, patients were to remain on stabilized diet for treatment of their 
EG/EGE during the first 52 weeks of the study (stable diet is defined as no initiation of single 
or multiple elimination diets or reintroduction of previously eliminated food groups).  For 
participants in Part D, there will be no such restrictions.  
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized to treatment. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the Consolidated 
Standards of Reporting Trials publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE).
Individuals who do not meet criteria for participation in this study (screen failure) may be 
re-screened after careful consideration by the Investigator and in agreement with the 
AstraZeneca study physician (eg, if a patient needs a long-term follow up to rule out an 
exclusory condition). Patients cannot be re-screened more than one time. Re-screened patients 
should sign new ICF form. In case of re-screening, all medical events that have occurred since 
the first enrollment will be recorded as part of medical history. All study procedures scheduled 
for Visit 1 (Table 1) should be repeated at the re-screening visit, with the exception of the 
endoscopy and biopsy, which may be performed again at the discretion of the Investigator. 
Re-screened patients should be assigned the same patient number as for the initial screening. 
Re-screening will be documented so that its effect on study results, if any, can be assessed. 
Re-screening a patient after failing the following inclusion/exclusion criteria is not allowed:

Biopsy in order to confirm diagnosis of EG/EGE (inclusion criterion #3)

Establishing the patient is symptomatic prior to randomization (inclusion criterion #5)

Non-adherence to daily PRO assessments (inclusion criterion #6)

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Patients may be considered for re-screening in order to meet all other inclusion/exclusion 
criteria. 
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention, marketed product, or placebo 
intended to be administered to or medical devices utilized by a study participant according to 
the Clinical Study Protocol.
Only patients randomized in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention, except when self-administration or 
administration by the patient’s caregiver is an option (Section 6.1.3.4).
6.1
Study Interventions Administered
6.1.1
Investigational Products
Descriptions of the investigational products are provided in Table 7..
Table 7
Investigational Products
Arm name
Benralizumab
Placebo
Intervention name
Benralizumab
Placebo
Type 
Combination Product
Combination Product
Dose formulation
Solution for injection
Solution for injection
Unit dose strengths
30 mg/ml 
-
Dosage level
30 mg every 4 weeks
-
Administration route
Subcutaneous injection
Subcutaneous injection
Use
Experimental
Placebo comparator
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the sponsor
Packaging and labelling
Investigational product will be supplied to the site in a kit with an accessorized 
pre-filed syringe of either benralizumab or placebo. Each kit will have a unique 
ID number that is printed on all labels within the kit (ie, the outer carton label and 
the label of each container within the carton). Each syringe will be labelled in 
accordance with Good Manufacturing Practice Annex 13 and per country 
regulatory requirement. The labels will be translated into local languages where 
applicable and required by local regulations.
Former/current names 
in earlier clinical development. 
Marketed under the brand name 
Fasenra.
-
CCI

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6.1.2
Duration and Frequency of Treatment with Investigational Products
Patients will receive investigational product (ie, benralizumab or matching placebo) Q4W. 
The investigational product will be administered on-site or, optionally, at home (see Sections 
6.1.3.4 and 6.1.3.5). The acceptable visit windows are specified in the schedule in Section 1.3, 
and reasons and procedures for rescheduling investigational product administration are 
detailed in Section 6.1.3.3.
Prior to the approval of Amendment 4, patients who complete the 24-week double-blind 
treatment period are eligible to continue receiving benralizumab 30 mg Q4W in the open-label 
extension starting at Visit 8. The open-label extension treatment period was intended to allow 
patients at least 1-year treatment with open-label benralizumab 30 mg Q4W. 
Following the approval of the protocol Amendment 4, patients in both Part A and Part C that 
are offered and choose to continue in Part D will be offered 24 weeks of open-label 
benralizumab Q4W treatment (ie, patients will not complete their current treatment period).
6.1.3
Administration of Investigational Products
Only participants enrolled in the study may receive study intervention and only authorized site 
staff may supply or administer study intervention, except when self-administration or 
administration by the patient’s caregiver is an option (see Sections 6.1.3.4 and 6.1.3.5). 
6.1.3.1
Before Investigational Product Administration
All applicable visit procedures, including biological sample collection, should be completed 
prior to investigational product administration. If the participant does not undergo a particular 
visit procedure during the visit, investigational product can be administered, and the procedure 
should be re-scheduled for a different date, preferably within the visit window. No procedures 
should be performed after the dosing on the day of investigational product administration. 
Pharmacokinetic and anti-drug antibody samples must always be collected before 
investigational product administration.
Prior to each investigational product administration:

Investigator/authorized delegate will evaluate the participant's condition for potential 
contraindications for dosing (see investigational product administration rescheduling, 
below).

Investigator/authorized delegate will assess the injection site as per standards of medical 
care.
6.1.3.2
In-Clinic Investigational Product Administration
The investigational product will be administered subcutaneously as a single injection via the 
accessorized pre-filled syringe by the Investigator/authorized delegate. It is advised that the 
site of injection of investigational product is rotated such that the participant receives 

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investigational product at a different anatomical site at each treatment visit. Suggested 
injection site rotation sequence is presented below. Investigational product should not be 
administered into areas where the skin is tender, bruised, erythematous, or hardened.
The injection site must be documented in the source at each treatment visit and recorded in the 
electronic Case Report Form (eCRF).
Figure 3
Injection sites and examples of rotation scheme
                  
If rotation of the injection site is not possible, the reason for this must be documented in the 
source.
Further details on investigational product administration are provided in the Pharmacy 
Manual. Investigational product administration must be carried out in line with these 
instructions and clinical practice.
After investigational product administration
Participants should be observed after investigational product administration for the appearance 
of any acute drug reactions, in line with clinical practice (Section 8.3.12). If the patient reports 
an injection site reaction or other AEs, the Investigator or qualified designee will complete the 
AE eCRF page and additional eCRF questions about the injection site reaction or other AEs.
6.1.3.3
Investigational Product Administration Re-scheduling
Every effort should be taken to keep investigational product administration within the visit 
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If a participant presents with a condition that contraindicates dosing, investigational product 
will be withheld and administered as soon as possible when the contraindicating condition 
resolves.
Investigational product should not be administered, and the dosing is to be re-scheduled in the 
presence of the following conditions:

An intercurrent illness that, in the opinion of the Investigator, may compromise the safety 
of the participant.

Signs of a clinically significant infection. Benralizumab should not be administered to a
participant with a clinically significant active infection treated with oral or intravenous 
antimicrobials, antivirals, or antifungals until it is confirmed by the Investigator that the 
infection has resolved.

An acute or emerging condition requiring systemic steroids. Benralizumab should not be 
administered until it is confirmed by the Investigator that the condition has clinically 
resolved.

Fever (≥38°C; ≥100.4°F) within 72 hours prior to investigational product administration.

Any event or laboratory abnormality that, in the opinion of the Investigator or the 
Sponsor, contraindicates dosing or could result in complications.
It is recommended that the AstraZeneca study physician/delegate be contacted in case of any 
questions.
If investigational product cannot be administered at a scheduled treatment visit (eg, due to 
conditions listed above), it can be postponed as necessary and administered as soon as 
possible.
When investigational product dosing needs to be postponed, it is recommended that all 
scheduled treatment visit procedures (except for pregnancy test and investigational product 
administration) are still performed within the visit window. 
Re-scheduled investigational product dose can be then administered at an unscheduled visit 
along with the pregnancy test. Brief physical exam and vital signs assessment are the 
minimum procedures to 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 participant is unable 
to attend the study site), then the entire visit will be re-scheduled along with investigational 
product dose.
If a dose is significantly delayed it is recommended to keep at least 2 weeks interval before the 

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next dose. If a postponed dose overlaps with the next treatment visit window, the postponed 
dose will be skipped, and the next dose of investigational product given at the regularly 
scheduled visit. The visit schedule will be always calculated from randomization visit date.
A ‘missed’ dose is a dose not administered until the next treatment visit window. If 2 or more 
doses (consecutive or non-consecutive) of investigational product are missed within a 1-year 
period, a conversation between the Investigator and the AstraZeneca study physician should 
take place to review the participant's adherence to treatment and decide on the participant's 
further disposition. During the double-blinded and open-label treatment periods, all 
participants, regardless of whether they remain on investigational product or not, will be 
encouraged to remain in the study through the end of the double-blinded and open-label 
treatment periods. Discontinuation procedures are described in Section 7.1.
6.1.3.4
Self-administration of Investigational Product as Mitigation to Disruption
At Visits 2 and 3, appropriate patients and/or their caregiver may be trained in self-
administration of investigational product administration by the investigator or designee. If not 
possible at Visits 2 and 3 this may occur at later visits. This training will be provided so that 
patients are prepared in case remote visits may be required secondary to study disruptions as 
described in Section 4.1.1. Patients may still participate in the study if they do not 
consent/assent to this training.
6.1.3.5
Optional At-home or Remote Location Self-administration
To reduce participant burden and to allow flexibility during open-label treatments in Part C 
and Part D, patients will have the option for at-home or remote location participant/caregiver 
administration of investigational product. The investigator will first assess the participant 
and/or caregiver to ensure they are appropriate for administration of investigational product 
and ensure they have received appropriate training. Both will be captured in the source 
documentation. 
All necessary supplies and instructions for administration and documentation of 
investigational product administration will be provided. See the ‘Pharmacy Manual’ or the 
'Study Instructions for At-home or Remote Location Administration of Benralizumab by the 
[Participant/Patient] and/or His/Her Caregiver’ for step-by-step guidance including drug 
accountability and reconciliation requirements.
If the investigational product is administered at the participant’s home/remotely, the 
participant should administer the investigational product on the same day as the Visit after the 
visit assessments. It is strongly encouraged that the patient is contacted by the Investigator or 
qualified designee after the dose is administered in line with clinical practice. If the patient 
reports an injection site reaction or other AEs, the Investigator or qualified designee will 
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6.1.3.6
Optional Remote Visits for Patients Doing At-Home or Remote-Location 
Investigational Product Administration
In case of self-administration, some clinic visits (see Table 1 - Table 3) can be done as remote 
visits by telephone contact to reduce participant burden. WOCBP should be asked if they are 
pregnant during the telephone visit. Between on-site pregnancy testing, the patient is 
encouraged to monitor for pregnancy, and, if pregnant, should contact the site and should not 
administer IP.
6.2
Preparation/Handling/Storage/Accountability
The investigator or designee must confirm via the shipment data logger that appropriate 
temperature conditions have been maintained during transit for all study intervention received 
and any discrepancies are reported and resolved before use of the study intervention.
All study intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area, in the original outer container, in accordance with the labelled 
storage conditions (between 2 to 8°C [36 to 46°F], protected from light) with access limited to 
the investigator and authorized site staff. The temperature should be monitored on a daily 
basis and documented in the temperature monitoring log. Further details are provided in the 
separate Pharmacy Manual.
In the following cases the center staff should not use affected investigational product and 
should immediately contact AstraZeneca representative for further guidance:

Temperature excursion upon receipt or during storage at the study

Damaged kit upon receipt

Damaged syringe/cartridge
Damaged investigational product should be documented using the RTSM (please see the 
RTSM manual for further details).
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
An AstraZeneca site monitor will account for all investigational product received at the site, 
for unused investigational product, and for appropriate destruction of unused investigational 
products. 
Any unused kits will be destroyed locally (for further details, see the Pharmacy Manual). 
Documentation of investigational product delivery and destruction should be maintained 
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Devices sent to a patient’s home must be returned to a site for traceability.
Further guidance and information for the final disposition of unused study interventions are 
provided in the Pharmacy Manual
In the case of a malfunctioning benralizumab/matching placebo accessorized pre-filled 
syringe, the site should contact the study monitor to initiate a product complaint process 
according to applicable guidelines.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Methods for Assigning Treatment Groups
In Part A, all eligible participants were centrally assigned to randomized study intervention 
using the Randomisation and Trial Supply Management (RTSM) system. Before the study is 
initiated, the log-in information & directions for the RTSM will be provided to each site. 
The RTSM will provide to the investigators or pharmacists the kit identification number to be 
allocated to the participant at the dispensing visit. Routines for this will be described in the 
RTSM user manual that will be provided to each center.
Randomization codes will be assigned strictly sequentially in each stratum as patients become 
eligible for randomization. Randomization will be stratified by location of disease (EG with or 
without duodenal involvement vs duodenal disease alone) and baseline steroid use (eg, 
patients on a background of systemic or swallowed steroids/enteric-coated corticosteroids vs 
no use of these steroids at baseline). Patients who fail to meet the inclusion/exclusion criteria 
should not, under any circumstances, be randomized or receive investigational product. There 
can be no exceptions to this rule.
If a participant withdraws from the study, then his/her enrollment/randomization code cannot 
be reused. Withdrawn participants will not be replaced.
6.3.2
Maintaining Blind to the Investigational Product
Note: following the approval of Amendment 4 (CSP version 5), only open-label treatment 
is provided in Part D, and in addition, all parties may be unblinded to patient’s 
treatment. The text below concerns maintaining the blind prior to implementation of 
Amendment 4.
Benralizumab and placebo will not be visually distinct from each other. All packaging and 
labelling of the investigational product will be done in such a way as to ensure blinding for 
all Sponsor and investigational site staff during the first 24 weeks of the study. Neither the 
participant nor any of the Investigators or Sponsor staff who are involved in the treatment, 
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during the double-blinded 24-week treatment period. Since benralizumab and placebo are not 
visually distinct, investigational product will be handled by an appropriately qualified member 
of the study team (eg, pharmacist, Investigator, or qualified designee) at the site.
An AstraZeneca site monitor will perform investigational product accountability. In the event 
that the treatment allocation for a participant becomes known to the Investigator or other study 
staff involved in the management of study participants or needs to be known to treat an 
individual participant for an AE, the Sponsor must be notified immediately by the Investigator 
and, if possible, before unblinding.
The following personnel will have access to the randomization list during the study, prior to 
database lock:

Those carrying out the packaging and labelling of investigational product

Those generating the randomization list

The AstraZeneca Supply Chain department

Bioanalytical lab personnel analyzing pharmacokinetic samples.
The information in the randomization 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 Organization handling data, 
will have access to the randomization scheme during the conduct of the study.
6.3.3
Maintaining Blind to the Participant’s Eosinophil Counts
While not entirely assured, participants on active benralizumab treatment are expected to have 
lower eosinophil and basophil counts than participants on placebo. Procedures to mitigate 
unblinding on this basis will be in place from randomization (Visit 2/Week 0) and up to Visit 
12/Week 40.

Hematology will be run by the central laboratory. Post-randomization (starting from 
Visit 2), eosinophil and basophil counts will be redacted from the full hematology reports 
sent back to the investigative sites. Because complete knowledge of the remaining cell 
types could permit deduction of the eosinophil + basophil compartment, monocyte counts 
will also be redacted from the full hematology reports sent back to the investigative sites.

If the Investigator orders any local safety laboratory assessments, the requested tests 
should be restricted to the question at hand. For example, if hemoglobin is desired, the 
Investigator should avoid ordering a complete blood cell count with a differential count.

In cases where the Investigator requires an eosinophil, basophil, or monocyte count for 
managing safety issues, he/she may order these tests as per regular site practice. 
AstraZeneca should be notified of all such cases without absolute eosinophil counts, 
absolute basophil counts or absolute monocyte counts being revealed.

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
Site staff who are directly involved in the participant’s management and participant 
should remain blinded to any eosinophil, basophil, and monocyte results included as part 
of an outside laboratory report or electronic medical record. To help ensure this, each 
investigational site will designate an individual (eg administrator or another ancillary 
person) not directly involved in participant 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 participant’s management and prior to filing the laboratory report 
as a source document. Similarly, eosinophil, basophil, and monocyte results must be 
redacted from all communications with the Sponsor.

Biopsy results will be reported to the investigative sites for the purposes of confirming 
eligibility criteria following Visit 1. Blinded biopsy results through Week 24 will not be 
reported to the investigator sites until the completion and reporting of Part A, as 
appropriate. In addition, biopsy results from after Week 24 may be provided to the 
investigator upon request.
Prior to the approval of Amendment 4, the randomisation code should not have been broken 
except in medical emergencies when the appropriate management of the participant requires 
knowledge of the treatment randomisation. The investigator documents and reports the action 
to AstraZeneca, without revealing the treatment given to participant to the AstraZeneca staff.  
After the approval of Amendment 4, the randomisation code may be broken without a need to 
conceal the unblinding from AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product and that potentially require 
expedited reporting to regulatory authorities. Randomisation codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
participant have been made and documented.
6.4
Study Intervention Compliance
The investigational product will be administered within visit windows as specified in Table 1
through Table 3.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date, and time if applicable, of dose 
administered in the clinic, as well as any missed doses, will be recorded in the source 
documents and recorded in the eCRF. The dose of study intervention and study participant 
identification will be confirmed at the time of dosing by a member of the study site staff other 
than the person administering the study intervention.
When study interventions are administered at home, compliance with study intervention will 
be assessed at subsequent visit. Compliance will be assessed by direct questioning and 
returned investigational product during the site visits and documented in the source documents 

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and eCRF. A record of the number of investigational product kits dispensed to and used by 
each participant must be maintained and reconciled with study intervention and compliance 
records. Intervention start and stop dates, including dates for intervention delays will also be 
recorded in the eCRF.
6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency.
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.5.1
Background Medication
Background medications for EG/EGE (eg, systemic and topical ingested or swallowed 
corticosteroids, PPIs) and steroid treatments used for asthma or allergies that are inhaled or 
administered intranasally should be maintained at the same dose and schedule for at least 4 
weeks prior to the run-in period. 
If a medication for EG/EGE (eg. systemic and topical ingested or swallowed steroids, PPIs, 
and other treatments) are discontinued prior to screening, there should be a washout period of 
at least 8 weeks prior to screening. 
Background medication for EG/EGE (and related treatments) was to remain stable throughout 
the run-in period and the initial 52 weeks of study treatment (ie, 24-week Part A and first 28 
weeks of Part C) unless a change is medically indicated. 
Following approval of Amendment 4, background medication for EG/EGE (and related 
treatments) can be changed at the discretion of the investigator in those patients that choose to 
continue and receive 24 weeks of open-label benralizumab treatment. Background medication 
use will be recorded on the eCRF. The justification and rationale for treatment changes should 
be documented in the eCRF source notes. 
6.5.2
Dietary Restrictions
Participants may have dietary restrictions as part of the clinical management of their EG/EGE 
during the study as long as the diet restrictions have been stable for at least 6 weeks prior to 
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of study intervention, unless medically indicated. The justification and rationale for diet 
changes should be documented in the source notes and diet questionnaire (Section 8.1.6).
Following approval of Amendment 4, investigators may consider relaxing dietary restrictions 
while continuing benralizumab, as clinically indicated, in those patients that continue with 
24 weeks of open-label benralizumab treatment as part of the Part D. 
The reintroduction of previously avoided foods has the potential to trigger an anaphylactic 
reaction (Ho and Chehade 2018). For clearer assessment of causality for any anaphylactic 
reactions that may be reported, foods should not be reintroduced one week before or one week 
after dosing of benralizumab. 
6.5.3
Restricted Medication
The medication restrictions that apply during the study are summarized in Table 8. 
Unless specifically indicated, all conditions apply from enrollment throughout the study 
duration. If, at discretion of the Investigator, a participant needs treatment with any disallowed 
medication or changes in background medications for EG/EGE and related treatments, it is 
recommended that the Investigator contact the AstraZeneca study physician to discuss 
justification.
Table 8
Concomitant Medication and Treatments
Medication
Allowed/ Restricted/ 
Prohibited
Details
Background (maintenance) 
medication for EG/EGE, 
including steroids, proton 
pump inhibitors, and 
antiemetics, and steroid 
treatments used for asthma or 
allergies that are inhaled or 
administered intranasally
Allowed
Maintained at the same dose and schedule for at 
least 4 weeks prior to the run-in period and 
throughout the study 52-week treatment period.  
Following approval of Amendment 4, patients 
continuing with 24-week open-label treatment in 
Part D have no restriction.
Rescue corticosteroid 
medication for EG/EGE
Restricted
A brief course of systemic or enteric-coated 
steroids is allowed, see section 6.5.4. Rescue 
corticosteroid medication for EG/EGE would 
constitute treatment failure in the primary 
analyses.  
Systemic corticosteroids 
(tablets, suspension, or 
injections; (eg prednisone, 
prednisolone or related 
products) for reasons other 
than EG/EGE
Restricted
Not allowed within 8 weeks prior to screening 
and within 4 weeks prior to endoscopy during the 
study. Throughout the treatment period, allowed 
for treatment of an AE (eg, asthma) where there is 
no alternative treatment available, for no more 
than 7 days.

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Table 8
Concomitant Medication and Treatments
Medication
Allowed/ Restricted/ 
Prohibited
Details
Other immunosuppressive 
medication (including but not 
limited to: methotrexate, 
cyclosporine, azathioprine)
Restricted
Allowed for treatment of an AE where there is no 
alternative treatment available for the duration of 
<4 weeks. If longer treatment is required, this 
should be discussed with the study physician to 
decide on the participant’s disposition.
Disallowed within 8 weeks prior to screening and 
for other reasons throughout the study.
Immunoglobulin or blood 
products
Prohibited
Not allowed 30 days prior to screening and during 
the study.
Any other marketed or 
investigational biologic
Prohibited
Disallowed if taken for any reason within 
4 months or 5 half-lives, whichever is longer, 
prior to screening and during the study
Not recommended within 12 weeks (5 half-lives) 
after the last dose of investigational product.
Any investigational non-
biologic drug
Prohibited
Disallowed within 30 days or 5 half-lives 
(whichever is longer) prior to screening, during 
the treatment period, and is not recommended 
within 12 weeks (5 half-lives) after the last dose 
of investigational product
Subcutaneous allergen 
immunotherapy
Restricted
Allowed if on stable therapy started at least 30 
days prior to screening and stable dose is 
maintained during the study
It is recommended that participant does not 
receive SCIT on the same day as investigational 
product administration. 
Oral and/or sublingual 
allergen immunotherapy
Prohibited
Disallowed within 8 weeks prior to screening and 
during the treatment period
Live attenuated vaccines
Prohibited
Disallowed within 30 days prior to 
randomization, during the treatment period and 
for 12 weeks (5 half-lives) after the last dose of 
investigational product
Inactive/killed vaccinations 
(eg, inactive influenza)
Restricted
Not recommended within the 7 days before or 
within 7 days after any investigational product 
dosing study visit. Injection site for vaccine 
should be distant to preceding or next injection 
site of IP.

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6.5.4
Rescue Medicine
In response to severe gastrointestinal symptoms that the participant cannot tolerate, 
corticosteroids, including an increased dose over the participant’s maintenance dose if they 
are receiving maintenance treatment with corticosteroids, can be given as rescue medication, 
but use should be limited to as short a course as possible. If, at discretion of the Investigator, 
a participant needs treatment with any disallowed medication or changes in background 
medications as rescue for EG/EGE, it is recommended that the Investigator contact the 
AstraZeneca study physician to discuss justification. Rescue medication for EG/EGE would 
constitute treatment failure in the primary analyses. Rescue medication will not be provided 
by the sponsor but are obtained locally. The date of rescue administration as well as the name 
and dosage regimen must be recorded.
6.6
Dose Modification (not applicable)
Modification of the dose of benralizumab is not permitted.
6.7
Intervention 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 STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
7.1.1
Reasons for Discontinuation of Investigational Product
Participants may be discontinued from investigational product in the following situations.

Participant decision. The participant is at any time free to discontinue treatment, 
without prejudice to further treatment

An AE that, in the opinion of the Investigator, contradicts further dosing

Severe non-compliance with the Clinical Study Protocol

If it is discovered that a patient does not meet all the eligibility criteria but was 
randomized in error, the Investigator should inform the study physician immediately 
to discuss potential safety concerns and if the investigational product should be 
discontinued.

Pregnancy

Development of any study-specific criteria for discontinuation:

Anaphylactic reaction to the investigational product requiring administration of 
epinephrine

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
Development of helminth parasitic infestations requiring hospitalization

Confirmed reactivation of hepatitis B virus

If a participant misses 2 or more doses (consecutively or non-consecutively) of 
investigational product within a 1-year period, a conversation between the 
Investigator and the AstraZeneca study physician should take place to review 
the participant's adherence to treatment and decide on the participant's further 
disposition.
Before a decision to discontinue a participant from investigational product is instituted, the 
study physician should be consulted regardless of the reason for discontinuation. The 
Investigator should contact the participant if a decision to stop investigational product is 
taken. A participant that decides to discontinue investigational product will always be asked 
about the reasons and the presence of any AEs. The date of last investigational product dose, 
the date of investigational product discontinuation decision and the reasons for discontinuation 
should be documented in the eCRF. Conditions that require administration of investigational 
product to be temporarily withheld are described in Section 6.1.3.3. Discontinuation of 
investigational product will be registered in the RTSM.
See Table 1 to Table 3 for data to be collected at the time of treatment discontinuation and 
follow-up and for any further evaluations that need to be completed.
7.1.2
Procedures for Early Discontinuation of Investigational Product
7.1.2.1
Early discontinuation of study treatment
All patients who prematurely discontinue IP should return to the study site for an IPD visit 
within 4 weeks (±3 days) after the last dose of IP and an FU visit 4 weeks (±7 days) after the 
last dose of IP for procedures described in Table 1 to Table 3. The IPD visit replaces the 
nearest scheduled visit after IP discontinuation. Patients will return the PRO device at the IPD 
visit if applicable. Patients who have discontinued IP during Part A are not eligible to 
enter Part C or Part D.
7.1.3
Procedures for Handling Incorrectly Enrolled or Randomized Patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
randomized or receive IP. There can be no exceptions to this rule. Patients who are enrolled 
but who do not meet all eligibility criteria must not be randomized and must be withdrawn 
(screen failed) from the study. 
When a patient does not meet all the eligibility criteria but is randomized in error or 
incorrectly started on IP, the Investigator should inform the AstraZeneca study physician 
immediately to discuss potential safety concerns and the best interests of the patient and 
decide whether IP should be continued or discontinued. 

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If the agreed decision is to discontinue IP, patients should be encouraged to complete IPD and 
FU visits, ie, follow-up for 4 weeks after last IP dose (if received) (Section 7.1.2). 
The decision to discontinue/continue IP must be appropriately documented, including 
rationale, particularly if the agreed decision is to continue IP treatment.
7.2
Participant Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request or may 
be withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon.

At the time of withdrawal from the study, if possible, an IP Discontinuation visit should 
be conducted, as shown in the schedule of activities. See Table 1 to Table 3 for what to be 
collected at the time of study withdrawal and follow-up and for any further evaluations 
that need to be completed.

The participant will discontinue the study intervention and be withdrawn from the 
study at that time.

Endoscopy should be performed at the discretion of the Sponsor and only if ≥12 
weeks have elapsed since the prior endoscopy. 

If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.

If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests 
withdrawal of consent for use of samples, destruction of any samples taken and not tested 
should be carried out in line with what was stated in the ICF and local regulations. The 
investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team.
7.3
Lost to Follow up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

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
Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 

Efforts to reach the participant should continue until the end of the study. Should the 
participant be unreachable at the end of the study the participant should be considered to 
be lost to follow up with unknown vital status at end of study and censored at latest 
follow up contact.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in Table 1 to Table 3. Protocol waivers 
or exemptions are not allowed.

The Investigator will ensure that data are recorded on the eCRF. The Web Based Data 
Capture (WBDC) system will be used for data collection and query handling.

The Investigator ensures the accuracy, completeness, 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 the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention.

Adherence to the study design requirements, including those specified Table 1 to Table 3, 
is essential and required for study conduct.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in Table 1 to Table 3.

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8.1
Efficacy Assessments
8.1.1
Histopathology and Tissue Eosinophil Counts
Note: following the approval of Amendment 4 (CSP version 5), biopsies are NOT 
required at any clinic visit, although investigators may perform endoscopies and collect 
biopsies as part of their normal standard of care. The text below concern assessments 
prior to implementation of Amendment 4.
One of the dual-primary endpoints in the study is the proportion of participants with a 
histologic response at 24 weeks defined as ≤6 eosinophils/hpf in the stomach gastric levels 
and/or ≤15 eosinophils/hpf across duodenal levels. During the study, biopsies were planned 
to be conducted at Visit 1 (Week -8 to -4), Visit 8 (Week 24), and Visit 15 (Week 52).  
Esophagogastroduodenoscopy will be performed according to local medical practice. Eight 
gastric biopsies should be targeted for collection from separate areas of the gastric antrum 
(four samples) and the gastric corpus (four samples); four duodenal biopsies, with at least two 
from the second part of the duodenum. Additionally, 4 biopsies should be taken from the 
esophagus:  two from the proximal esophagus and two from the distal esophagus.  The 
biopsies will receive blinded pathology review of tissue eosinophil counts and histopathology 
from an independent physician. Details pertaining to biopsy collection are provided in the 
Laboratory Manual. To confirm eligibility at Visit 2, the Visit 1 biopsy results will be 
communicated to the site.
Additional pathology findings will also be captured on biopsy specimens.  A histology scoring 
system may be applied and recorded independently for all available esophageal, gastric, and 
duodenal specimens by blinded pathology review.
Helicobacter pylori will be evaluated on gastric biopsies from Visit 1 (Week -8 to -4) by 
pathology review.
8.1.2
Endoscopic Reference System Scores
Note: following the approval of Amendment 4 (CSP version 5), there are no study-
mandated endoscopy procedures. The text below concern assessments prior to 
implementation of Amendment 4.
During study-mandated endoscopy procedures, the endoscopic manifestations of EG/EGE, 
including erosions/ulcerations, granularity, raised lesions, erythema, friability, fold thickness 
and pyloric stenosis, will be scored by the endoscopist using the Eosinophilic Gastritis 
Endoscopic Reference System (EG-REFS) from three areas of the stomach (antrum, body,
and fundus).  Endoscopic appearance of the duodenum will also be characterized.
The Eosinophilic Esophagitis Endoscopic Reference System (EREFS) is a scoring system for 
assessing the presence and severity of major endoscopic findings in the esophagus, including 

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esophageal edema, rings, exudates, furrows, and stricture.  A global (EREFS) should be 
obtained that scores the most severe esophageal abnormality in the criteria scoring system.  
Each of these GI scoring tools will have an additional separate overall global disease activity 
scoring assessment (0 normal –10 extremely diseased).
The EGREFS including duodenal findings and EREFS will be centrally-read from video 
recordings and Investigator-read during the upper endoscopies. Centralized imaging data 
assessments and scoring from expert physician review will be performed for all endoscopies.  
Standardized methods for training Investigators on the application of these scoring systems to 
ensure the collection of quality data using this measure will be implemented.  Details on the 
scoring will be provided to Investigators in a separate manual.
The sites will remove patient-identifying information from the imaging data header prior to 
sending the imaging data to the central reader.
8.1.3
Patient Reported Outcomes
Note: following the approval of Amendment 4 (CSP version 5), participants will cease 
performing PRO assessment at their next clinic visit (ie, Part D Visit 20) and return their 
handheld PRO devices.  The text below concern PRO assessments prior to 
implementation of Amendment 4.
Participants will complete all PRO assessments using a handheld device. The handheld device 
(or the web-based backup, in case of device failure) will be the only accepted source of PRO 
data. Participants will be required to complete a training module before taking the device 
home. The Investigator will ensure that participants are properly trained on the use of this 
device and the importance of completing assessments as scheduled. The handheld device will 
be programmed at Visit 1 with reminder alarms for the daily PROs. Study site staff will be 
able to adjust alarms for specific participant needs as required. 
The Investigator or designee will be responsible for monitoring participant adherence with the 
daily PROs and follow-up as necessary to minimize missing data. Participant compliance 
should be checked weekly (at a minimum) to ensure that the participant is completing the 
assessments as scheduled. Monitoring of participant adherence to the daily PROs is especially 
critical between Visit 1 and Visit 2 to ensure that the participant meets applicable criteria for 
randomization. If the participant does not meet the randomization requirements, the device 
will be deactivated and retained at the site for future use.
Participants are expected to bring the device to every Part A site visit. To reduce bias, review 
of compliance with the assessments, completion of any available assessments, and logging of 
the visit on the handheld device should be completed prior to any other study procedures. 
Compliance with the assessment schedule should be reviewed weekly throughout the study. 

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Participants with low compliance should be reminded to complete their assessments through 
follow-up phone calls and during site visits. Correcting poor compliance is required to ensure 
sufficient data are available for supporting the dual-primary endpoint of this study.
The timing and frequency for each PRO is presented Table 4. PRO assessments end at 
Visit 21 when the handheld device will be returned to the study site. 
8.1.3.1
Symptom Assessment for Gastrointestinal Eosinophilic Diseases
The Symptom Assessment for Gastrointestinal Eosinophilic Diseases (SAGED) instrument 
was developed to measure gastrointestinal symptoms in participants diagnosed with EG/EGE. 
The SAGED instrument, comprising 8 items, measures the severity of abdominal pain, 
nausea, bloating, early satiety, lack of appetite, vomiting, and diarrhea, and frequency of 
vomiting. Severity for each concept is assessed using an 11-point numerical rating scale 
(where 0 = ‘none’ and 10 = ‘worst imaginable’). Frequency of vomiting is reported as number 
of episodes of vomiting within the past 24 hours. 
The SAGED instrument is a daily diary to be completed by participants each evening to 
record their symptoms during the past 24 hours. It will be completed by the participant every 
evening starting on the evening following Visit 1 as described in Table 4.
The SAGED score (range: 0-50) includes the items measuring severity of abdominal pain, 
nausea, bloating, early satiety and lack of appetite. The severity of vomiting and severity of 
diarrhea scores (range: 0-10) are considered separately. Frequency of vomiting is reported as a 
count.
8.1.3.2
Bristol Stool Form Scale
The Bristol Stool Form Scale is a frequently used diagnostic tool designed to evaluate human 
feces based on the shape and consistency of the stool (Lewis and Heaton 1997). There a 7 
stool types, which are dependent upon the amount of time in which it spends in the colon:
1. Separate hard lumps, like nuts (hard to pass)
2. Sausage-shaped, but lumpy
3. Like sausage, but with cracks on its surface
4. Like a sausage or snake, smooth and soft
5. Soft blobs with clear cut edges (passed easily)
6. Fluffy pieces with ragged edges, a mushy stool
7. Watery, no solid pieces.

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Types 3, 4, 5 are considered optimal. Types 1 and 2 indicate constipation, and 
Types 6 and 7 indicate diarrhea.
Participants were to be asked every evening to classify the stool type of each bowel movement 
they have had during the past 24 hours, starting on the evening following Visit 1 until the end 
of study (Visit 15, Week 76).
8.1.3.3
Dysphagia Symptom Questionnaire
The Dysphagia Symptom Questionnaire (DSQ) is a PRO measure validated for patients age 
12 and older with dysphagia related to eosinophilic esophagitis (Dellon et al 2013b). The 
presence and severity of dysphagia symptoms in the past 24 hours are captured in a 4-item 
questionnaire. 
Questions 1 and 2 utilize yes/no response capture if the patient consumed solid food that day 
(yes/no; unscored) and instances of food going down slowly or becoming stuck in the throat or 
chest (scored 0 for no and 2 for yes). Question 3 asks about the severity of dysphagia, based 
on actions the patient took to relieve the dysphagia at its worst point during the day. It ranges 
from 0 (dysphagia cleared up on its own) to 4 (patient sought medical attention for 
dysphagia). Question 4 asks the patient to report the worst pain experienced while swallowing 
food over the past 24 hours (no pain [0] to very severe pain [4]).
The total DSQ score ranges from 0 to 84, with a lower score indicating less severe dysphagia. 
Questions 2 and 3 are the only questions that contribute to the total DSQ score. The score is 
calculated by multiplying the daily scores of questions 2 and 3 by 14 days and dividing by the 
number of days in the past 14 days with no missing data. Question 4 is a standalone item 
intended to be evaluated separately. The DSQ can only be scored if there are at least 8 days 
with no missing data. Using anchor-based methods, the minimal clinically important
differences and clinically important difference in DSQ score (mean absolute change) were 
estimated to be −6.5 points and −13.5 points, respectively (Hudgens et al 2017). Using DSQ 
Question 2, dysphagia-free days over each 28-day period following randomization will also be 
summarized.
The DSQ will be completed by the participant every evening starting on the evening following 
Visit 1, as described in Table 3.
8.1.3.4
Patient Assessment of Gastrointestinal Disorders Symptom Severity Index 
The Patient Assessment of Gastrointestinal Disorders Symptom Severity Index (PAGI-SYM) 
measures symptom severity in patients with upper gastrointestinal disorders. The standard 
recall version used in this study asks the patient to report the severity of symptoms over the 
past two weeks. 
The instrument is composed of 20 items, which form 6 sub-scales: heartburn/regurgitation 

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(7 items), nausea/vomiting (3 items), post-prandial fullness/early satiety (4 items), bloating 
(2 items), upper abdominal pain (2 items), and lower abdominal pain (2 items). Subscale 
scores are calculated by averaging across items comprising the subscale; scores vary from
0 (none or absent) to 5 (very severe). The total PAGI-SYM score is calculated by taking the 
mean of the subscale scores. Higher scores indicate greater symptom severity. 
The PAGI-SYM will be completed initially in the clinic at Visit 1 and Visit 2 and then at home 
every 4 weeks after Visit 2 as described in Table 4.
8.1.3.5
Patient-Reported Outcome Measurement Information System Short Form –
Fatigue 7a
The Patient-Reported Outcome Measurement Information System (PROMIS) Short Form –
Fatigue 7a consists of 7 questions assessing the severity of the patient’s fatigue-related 
symptoms and the impact of these symptoms on health-related quality of life. The questions 
have a 7-day recall period, and the response options are on a 5-point Likert scale ranging from 
1 (never) to 5 (always). 
The standardized T-score (range 0-100) is obtained by rescaling the raw total score using the 
score conversion table. The mean T-score for the reference population of US adults is 50; the 
standard deviation of the reference population is 10. Higher T-scores represent greater fatigue.
The PROMIS Fatigue Short Form 7a assessment will be completed initially in the clinic at 
Visit 1 and Visit 2 and then at home every 4 weeks after Visit 2 as described in Table 4.
8.1.3.6
Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life
The Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life (PAGI-QoL), 
the health-related quality of life counterpart to PAGI-SYM, measures disease-specific health-
related quality of life impacts in patients with upper gastrointestinal disorders. It is comprised 
of 30 items and five sub-scales: daily activities (10 items), clothing (2 items), diet and food 
habits (7 items), relationships (3 items), and psychological well-being and distress (8 items). 
Patients are asked to rate the impacts of their gastrointestinal symptoms over the past two 
weeks on a scale ranging from 0 (none of the time) to 5 (all of the time).
Subscale scores are calculated by averaging across items comprising the subscale after 
reversing all scores. The total PAGI-QoL score is calculated by averaging across subscale 
scores. Lower scores reflect worse health-related quality of life.
The PAGI-QoL assessment will be completed initially in the clinic at Visit 1 and Visit 2 and 
then at home every 4 weeks after Visit 2 as described in Table 4.
8.1.3.7
Short Form 36-item Health Survey, Version 2, Acute Recall
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questionnaire on functional health and well-being. The recall period is 1 week. Responses to 
35 of the 36 items are used to compute 8 domain scores and 2 component summary measures. 
The remaining “Health Transition” item asks participants to rate how their current state of 
health compares to their state of health 1 week ago. The Heath Transition item is not used to 
calculate the domain scores.
The 8 domains are: 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. The component summary measures, Physical 
Component Summary (PCS) and Mental Component Summary (MCS), are computed from 
domain scores to give a broader metric of physical and mental health-related quality of life. 
The transformed score range for each of the 8 domains and for PCS and MCS is 0-100; higher 
scores indicate better health state. The change from baseline in PCS, MCS, and domain scores 
will be calculated.
The SF-36v2 assessment will be completed initially in the clinic at Visit 1 and Visit 2 and then 
at home every 4 weeks after Visit 2 as described in Table 4.
8.1.3.8
Work Productivity and Activity Impairment Questionnaire plus Classroom 
Impairment Questions
The Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment 
Questions Version 2 (WPAI+CIQ) consists of questions about how health and health-related 
issues impact the ability to work, attend classes, and perform regular daily activities. The 
questionnaire relates to the previous 7 days. The WPAI+CIQ will be used to measure self-
reported productivity loss.
This study uses the version of the instrument designed to measure the impact of a specific 
health problem (SHP). All instances of “problem” in the source text are replaced with 
“eosinophilic gastritis and/or eosinophilic gastroenteritis” to specify that the participant should 
respond with EG/EGE symptoms in mind.
The WPAI+CIQ assessment will be completed initially in the clinic at Visit 1 and Visit 2 and 
then at home every 4 weeks after Visit 2 as described in Table 4.
8.1.3.9
Patient Global Impression of Severity
Patient Global Impression of Severity (PGI-S) is a single item designed to capture the 
participant’s perception of overall EG/EGE symptom severity over the past 14 days using a 4-
point categorical response scale (none, mild, moderate, or severe).
The PGI-S assessment will be completed initially in the clinic at Visit 1. It should be repeated 
at home every 2 weeks after Visit 1 until Visit 2 is confirmed. The assessment will be 
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will then be repeated at home every 2 weeks after Visit 2 as described in Table 4. 
8.1.3.10
Patient Global Impression of Change
Patient Global Impression of Change (PGI-C) is a single item assessment to capture the 
participant’s perception of change in their EG/EGE symptoms. The participant is asked to 
report the degree to which their EG/EGE symptoms have changed since entering the treatment 
period using a 7-point scale (much better, moderately better, a little better, about the same, a 
little worse, moderately worse, or much worse).
The PGI-C assessment will be completed by participants every 2 weeks, starting 2 weeks after 
Visit 2 as described in Table 4.
8.1.3.11
Patient Global Impression of Benefit-Risk
The Patient Global Impression of Benefit-Risk (PGI-BR) is a 5-item questionnaire assessing 
the participant’s perception of the overall benefits and risks of treatment. The 5 items assess: 
overall trial experience, efficacy, side effects, convenience and overall assessment of the 
benefits and harms of treatment. Items are rated on 5- or 6-point verbal rating or Likert-type 
scales.
The PGI-BR assessment will be completed by participants Visits 8 (Week 24) and 15 (Week 
52) and after discontinuation if applicable as described in Table 4.
8.1.4
Clinical Global Impression of Severity
Clinical Global Impression of Severity (CGI-S) is a single item designed to capture the 
clinician’s perception of the participant’s overall disease severity at the time of the visit using 
a 6-point categorical response scale (no signs and/or symptoms to very severe signs and/or 
symptoms). 
The answer will be entered in the eCRF at Week 0 and Week 24 of Part A (Table 1) and all 
visits in Part D (Table 3).
8.1.5
Clinical Global Impression of Change
Note: following the approval of Amendment 4 (CSP version 5), investigators will cease 
assessing the Clinical Global Impression of Change.
Clinical Global Impression of Change (CGI-C) is a single item assessment to capture the 
clinician’s perception of change in the participant’s health status. The clinician is asked to 
report the degree to which the participant has changed since entering the treatment period 
during the randomization study period using a 7-point scale (very much improved, much 
improved, minimally improved, no change, minimally worse, much worse, very much worse).  
For the open label extension period, the clinician will report the degree to which the 
participant has changed since entering the open label extension period.

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The answer will be entered in the eCRF at Part A and Part C visits as described in Table 1 and 
Table 2.  
8.1.6
Diet Questionnaire
The Investigator or designee were to interview participants about their current diet restrictions 
at every visit. The information will be entered via a standardized diet questionnaire on a web 
portal.
8.1.7
Qualitative Patient Interview Sub-study
Note: following the decision to close enrollment of this study, it was also decided to 
discontinue the qualitative patient interview sub-study, with no further enrollment or 
interviews.  The text below describes procedures used prior to that decision.
Adult participants who complete the ICF in select languages will be invited to participate in a 
qualitative patient interview sub-study. Up to 45 participants will be enrolled in the sub-study, 
which consist of interviews at three timepoints (baseline, end of double-blind treatment, and 
open label). The interviews will be non-interventional and will collect data on participants’ 
experiences with EG/EGE, the study treatment, and non-pharmacological interventions for 
EG/EGE (eg, diet and lifestyle modifications). Interviews will be performed via telephone 
contact on a one-to-one basis. The duration of each interview is approximately 90 minutes. 
A detailed description of sub-study procedures is available in the Qualitative Patient Interview 
Sub-study Manual.
Participants will be introduced to the sub-study during the informed consent process using the 
participant communication materials attached to the Qualitative Patient Interview Sub-study 
Manual. Interested participants will indicate their willingness to participate via the master ICF. 
Participants will be contacted according to procedures described in the Qualitative Patient 
Interview Sub-study Manual. 
Each participating participant will be interviewed at the following timepoints:

Baseline: between Visit 2 and Visit 3, to capture experiences before starting study 
treatment and/or in the first few months of study treatment

Open-label extension period: between Visit 9 and Visit 11, to capture experiences after at 
least one month of benralizumab treatment

Middle of open-label extension: after Visit 20, to capture experiences after at least 
11 months of benralizumab treatment.
During each interview, participants will be asked a set of open-ended questions with probes to 
explore their symptoms, their experiences with study treatment, and their EG/EGE-related diet 
and lifestyle modifications. The interview discussion guide is provided as an appendix to the 

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Qualitative Patient Interview Sub-study Manual.
The interview will be audio recorded with the participant's permission (confirmed verbally 
prior to the start of the interview). The recordings will be transcribed, and transcripts will be 
coded using qualitative data analysis software. 
Participants’ confidentiality and personal information will be protected throughout the sub-
study to the same standard as all other coded data in the study. 
Due to the qualitative nature of the data and the analysis, the results will be presented in a 
separate report (ie, not in the Clinical Study Report) and the data (transcriptions) will not be 
entered into the study database. No identifiable data will be reported.
AstraZeneca will follow standard procedures for handling AE reporting involving these 
participants (as described in Appendix B). At the beginning and end of each interview, 
participants will be advised to report any AE to the Investigator or designee.
8.1.8
Eosinophilic Gastrointestinal Disease Diary
The Eosinophilic Gastrointestinal Disease Diary is an exploratory free text diary assessing 
participants’ health-related quality of life. Participants may write about their symptoms and 
quality of life impacts using an app on their handheld PRO device. Completion of the diary is 
optional. Though the software will use occasional notifications to encourage the participant to 
enter data, there is no predetermined schedule of assessment. The diary is accessible at any 
time during the study in which participants have the handheld device, and participants may 
write up to once per day. Note: following the approval of Amendment 4 (CSP version 5), 
participants will return their handheld PRO devices at their next clinic visit (ie, Part D 
Visit 20).  
8.2
Safety Assessments
Planned time points for all safety assessments are provided in Table 1 to Table 3.
8.2.1
Physical Examinations

A complete physical examination will be performed in accordance with the schedule of 
activities and include assessments of the following: general appearance, respiratory,
cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose, and throat), 
lymph nodes, thyroid, muscular-skeletal (including spine and extremities) and 
neurological systems. 

A brief physical examination will be performed in accordance with the schedule of 
activities and will include, at a minimum, assessments of general appearance, lungs, 
cardiovascular system, and abdomen (liver and spleen).

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
The participant's height and weight will be measured in accordance with the schedule 
provided in Table 1 through Table 2. The participant's weight will be recorded in 
kilograms and height will be recorded in centimeters.
Any new findings or aggravated existing abnormalities, judged as clinically significant by 
the Investigator, will be reported as an AE as described in Section 8.3.5.
8.2.2
Vital Signs
Pre-dose vital signs (pulse rate, blood pressure, respiratory rate, and temperature) will be 
performed at timelines as specified in the Schedule of Activities. 
It is recommended that vital signs are assessed before any interventional study procedures 
(blood test collection, investigational product administration), and prior to administration of 
maintenance therapy, if possible.
Blood pressure and pulse measurements will be assessed while sitting with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available. The pulse rate and blood pressure should be measured after the participant has been 
resting for at least 5 minutes in a quiet setting without distractions (eg, television, cell 
phones). The pulse rate will be obtained before blood pressure.
The respiration rate will be obtained after the participant has been resting for at least 
5 minutes, by counting the number of breaths (how many times the chest rises) for 1 minute.
Body temperature will be measured in Celsius; oral measurement is preferred, but other 
methods are acceptable as per local standards of care.
8.2.3
Electrocardiograms
A single 12-lead electrocardiogram (ECG) will be obtained at Visit 2 using an ECG machine 
that automatically calculates the heart rate and measures PR, QRS, and QT intervals. The 
ECG will be taken in the supine position, after the participant has been resting for at least 
5 minutes and prior to investigational product administration. The ECG results will be 
interpreted locally.
The Investigator or authorized delegate will be responsible for the overall interpretation and 
determination of clinical significance of any potential ECG findings. The ECG printouts will 
be signed and dated by the Investigator and stored at the study site. Any findings will be 
recorded in the eCRF.
8.2.4
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis 
will be taken at the visits indicated in Table 1 to Table 3. All protocol-required laboratory 

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assessments, as defined in the table, must be conducted in accordance with the Laboratory 
Manual and the schedule of activities indicated in Table 1 to Table 3.
For information on methods of collection, assessment, labelling, storage, and shipment of 
samples, see 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 
center as source data for laboratory variables.
For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 8.3.5.
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF.
The clinical chemistry, hematology and urinalysis will be performed at a central laboratory.
The following laboratory variables will be measured.
Table 9
Laboratory Safety Values
Clinical Chemistry
Hematology
Urinalysis
Alanine 
aminotransferase
Creatine kinase
Hematocrit
Appearance
Albumin
Creatinine
Hemoglobin
Blood
Alkaline 
phosphatase
Gamma-glutamyl 
transpeptidase
Mean corpuscular volume
Color
Aspartate 
aminotransferase
Glucose
Platelet count
Glucose
Blood urea 
nitrogen
Phosphorus
Red blood cell count
Ketones
Calcium
Potassium
White blood cell count 
(absolute and differential)a
Microscopy, including 
white and red blood cells
Chloride
Sodium
pH
Cholesterol, total
Total bilirubin
Protein/Albumin
CO2b
Uric acid
Specific gravity
a
Eosinophil, basophil, and monocyte counts and differentials will be redacted from the central laboratory 
reports starting from Visit 2 (see Section 6.3.3).
b
Measured as bicarbonate.

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8.2.5
Pregnancy Testing
The following tests are applicable to female participants only and will be conducted as per the 
schedule provided in Table 1 through Table 3, as applicable.

Follicle-stimulating hormone: The test will be performed at Visit 1 only to confirm 
postmenopausal status in women <50 years of age who have been amenorrheic for 
≥12 months. This test is to be sent to and analyzed at the central laboratory. 

Serum beta-human chorionic gonadotropin: The test will be performed at Visit 1 for 
WOCBP. This test is to be sent to and analyzed at the central laboratory. Urine human 
chorionic gonadotropin: To be performed at the study site for all females (according to 
the schedule of assessments in Table 1 through Table 3) before investigational product
administration using a dipstick except for those females who are NOT of childbearing 
potential as defined in inclusion criterion 8. This kit is to be provided by the central lab 
and analyzed locally at the sites. A positive urine test result must be confirmed with 
serum beta human chorionic gonadotropin analyzed at the central laboratory. Between 
on-site pregnancy testing, the patient is encouraged to monitor for pregnancy, and, if 
pregnant, should contact the site and should not administer IP.
Note: Patients should be strongly encouraged to monitor for pregnancy during the study and 
report a pregnancy to the site as soon as possible.
8.2.6
Other Safety Assessments
Serology
Blood samples for the hepatitis B surface antigen (HBsAg), hepatitis B core antibody 
(anti-HBc), hepatitis C antibody (anti-HCV), and the HIV-1 and HIV-2 antibodies will be 
taken according to Table 1 through Table 3. The analysis will be performed at the central 
laboratory. Any low-positive or indefinite results must be confirmed prior to determining the 
participant's eligibility.
For participants that are HBsAg positive or anti-HBc positive at Visit 1, hepatitis D antibody 
and hepatitis B virus DNA testing will be performed. For those participants that are HBsAg 
positive or anti-HBc positive, alanine aminotransferase and hepatitis B-virus DNA may be 
analyzed at scheduled on-site visits to monitor for hepatitis B reactivation.
Instructions for sample collection, processing, storage, and shipment will be found in the 
Laboratory Manual.
8.3
Adverse Events and Serious 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.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE. For information on how to follow up on AEs see 
Section 8.3.2.
Care will be taken not to introduce bias when detecting AEs. Open-ended and non-leading 
verbal questioning of the participant is the preferred method to inquire about AE occurrences.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
AEs will be collected from time of signature of the IFC throughout the treatment period and 
including the follow-up period.
SAEs will be recorded from the time of signing of the IFC.
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix B. The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available.
If the investigator becomes aware of an SAE with a suspected causal relationship to the 
investigational medicinal product that occurs after the end of the clinical study in a participant 
treated by him or her, the investigator shall, without undue delay, report the SAE to the 
sponsor.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last AE assessment in the study are followed 
up by the investigator for as long as medically indicated, but without further recording in the 
eCRF. AstraZeneca retains the right to request additional information for any participant with 
ongoing AEs at the end of the study, if judged necessary.
Adverse event variables
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix B. The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available.
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

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
Maximum intensity of the AE

Whether the AE is serious or not

Investigator causality rating against the investigational product (yes or no)

Action taken with regard to investigational product

AE caused participant’s withdrawal from study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date investigator became aware of SAE

Seriousness criteria

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to study procedures

Causality assessment to other medication
8.3.3 Causality Collection
The investigator should assess causal relationship between investigational product and each 
AE and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable 
possibility that the event may have been caused by the investigational product?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or guardian or reported in response to the 
open question from the study site staff: ‘Have you/the child had any health problems since the 
previous visit/you were last asked?’, or revealed by observation will be collected and recorded 
in the eCRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 

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recording a list of signs and symptoms. However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarized in the Clinical Study Report. 
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, are the 
reason for discontinuation of treatment with the investigational product or are considered to be 
clinically relevant as judged by the investigator (which may include but not limited to 
consideration as to whether treatment or non-planned visits were required or other action was 
taken with the study intervention, eg, dose adjustment or drug interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AEs.
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE.
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.
8.3.6 Disease Progression
Disease progression can be considered as a worsening of a participant’s condition attributable 
to the disease for which the investigational product is being studied. It may be an increase in 
the severity of the disease under study and/or increases in the symptoms of the disease. The 
development of new or more severe gastrointestinal symptoms or new gastroduodenal 
endoscopic findings should be considered as disease progression and not an AE. Events, 
which are unequivocally due to disease progression, should not be reported as an AE during 
the study.
8.3.7 Disease Under Study
Symptoms of disease under study are those which might be expected to occur as a direct result 
of EG/EGE. These events may include abdominal pain, nausea, bloating, vomiting severity, 

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early satiety, loss of appetite, and diarrhea. Events which are unequivocally due to disease 
under study should not be reported as an AE during the study unless they meet SAE criteria or 
lead to discontinuation of the investigational product.
8.3.8
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedures. All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, investigators or other site personnel will inform 
the appropriate AstraZeneca representatives within one day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative will work with the investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
one calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day, ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the investigator or other study site staff reports a SAE 
to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the investigator/study site staff how to proceed. 
8.3.9
Pregnancy
Patients should be strongly encouraged to monitor for pregnancy during the study and report a 
pregnancy to the site as soon as possible.
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for if 
the pregnancy is discovered before the study participant has received any study intervention.
8.3.9.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, the investigational product 
should be discontinued immediately and the pregnancy reported to AstraZeneca.

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Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital anomalies/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital anomaly) should be followed up and documented even if the 
participant was discontinued from the study.
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, ie, immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (see Section 8.3.8) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy, and the paper-based 
pregnancy outcome form is used to report the outcome of the pregnancy.
8.3.10
Medication Error, Drug Abuse, and Drug Misuse
8.3.10.1.1 Timeline
If an event of medication error, drug abuse, and drug misuse occurs during the study, then the 
investigator or other site personnel informs the appropriate AstraZeneca representatives within 
1 calendar day, ie, immediately but no later than 24 hours of when he or she becomes 
aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.8) and within 30 days for all other 
events.
8.3.10.1.2 Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for an investigational medicinal product or AstraZeneca non-
investigational medicinal product that either causes harm to the participant or has the potential 
to cause harm to the participant.
The definition of a medication error can be found in Appendix B 4. 

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8.3.10.1.3 Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of 
investigational medicinal product or AstraZeneca non-investigational medicinal product for a 
perceived reward or desired non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix B 4.
8.3.10.1.4 Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of 
investigational medicinal product or AstraZeneca non-investigational medicinal product for 
medicinal purposes outside of the authorised product information, or for unauthorised 
investigational medicinal products or AstraZeneca non-investigational medicinal product, 
outside the intended use as specified in the protocol and includes deliberate administration of 
the product by the wrong route.
The full definition and examples of drug misuse can be found in Appendix B 4.
8.3.10.1.5 Reporting of Overdose
Refer to Section 8.4 for definition and treatment of overdose.
8.3.11
Device Constituent Deficiencies
In a combination drug-device IMP (e.g. APFS), the Device Constituent deficiency is an 
inadequacy of a device constituent with respect to its identity, quality, durability, reliability, 
safety, or performance. These deficiencies include malfunctions, use errors, and information 
supplied by the manufacturer.
SADE is defined as any Device Constituent 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.

For device constituent 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 device 
constituent where such action is necessary to prevent recurrence of a device constituent 
deficiency. This includes any amendment to the device constituent design to prevent 
recurrence.

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature and/or 
causality of the device constituent deficiency as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

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8.3.11.1
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.
8.3.12
Management of investigational product-related toxicities
Appropriate drugs, such as epinephrine, H1 and H2 antihistamines, and corticosteroids, and 
medical equipment to treat acute anaphylactic reactions should be available at the study site, 
and study personnel should be trained to recognize and treat anaphylaxis (see Lieberman et al 
2010). Details on anaphylaxis management are provided in Appendix F 4.
Anaphylaxis will be defined as a serious reaction that is rapid in onset and may cause death. 
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 1 of the following: a) respiratory compromise; b) or 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 F.
Participants will have had a pre-assessment (ie, vital signs) prior to investigational product 
administration and should be observed after investigational product administration for the 
appearance of any acute drug reactions, in line with clinical practice.
Serum tryptase or other blood or urine testing (drawn 90 +/- 30 min after concern for 
anaphylaxis is identified) relevant to the diagnosis of anaphylaxis may be obtained at a local 
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will be an option to have the sample tested centrally.
8.4
Overdose
For this study, any dose of benralizumab greater than 200 mg will be considered an overdose.
There is no specific treatment for an overdose with benralizumab. If overdose occurs, the 
participant should be treated supportively with appropriate monitoring as necessary.

An overdose with associated AEs is recorded as the AE diagnoses/symptoms on the 
relevant AE modules in the CRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose on an investigational product or AstraZeneca non-investigational product 
occurs in the course of the study, the Investigator or other site personnel inform appropriate 
AstraZeneca representatives immediately, but no later than 24 hours of when he or she 
becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within one 
or 5 calendar days for overdoses associated with an SAE (see section 8.3.8) and within 
30 days for all other overdoses.
8.5
Human Biological Samples
Note: following the approval of Amendment 4 (CSP version 5), no further human 
biological samples as described in this section will be collected.
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Samples see Appendix C.
Samples will be stored for a maximum of 15 years from the date of the issue of the Clinical 
Study Report in line with consent and local requirements, after which they will be 
destroyed/repatriated. 

Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or 
6 months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
consented for future analyses. 

Pharmacokinetic samples may be disposed of or anonymized by pooling. Additional 
analyses may be conducted on the anonymized, pooled pharmacokinetic samples to 
further evaluate and validate the analytical method. Any results from such analyses may 
be reported separately from the Clinical Study Report.

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
Remaining anti-drug antibody sample aliquots will be retained at AstraZeneca or its 
designee for a maximum of 5 years following issue of the Clinical Study Report. 
Additional use includes but is not limited to further characterization of any anti-drug 
antibodies, confirmation and/or requalification of the assay as well as additional assay 
development work. The results from future analysis will not be reported in the Clinical 
Study Report.
8.5.1
Pharmacokinetics

Serum samples will be collected for measurement of serum concentrations of 
benralizumab as specified in Table 1. It is important that the date, time, and location of 
each SC injection is recorded for each participant.

Pharmacokinetic samples will be collected before administration of investigational 
product, if applicable. 

Samples may be collected at additional time points during the study if warranted and 
agreed upon between the investigator and the sponsor, eg, for safety reasons. The timing 
of sampling may be altered during the course of the study based on newly available data 
(eg, to obtain data closer to the time of peak or trough matrix concentrations) to ensure 
appropriate monitoring. 

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

Samples collected for analyses of benralizumab concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study.

Samples will be collected, processed, labelled, stored, and shipped as detailed in the 
Laboratory Manual.

The IRB/IEC will be informed of any safety issues that require alteration of the safety 
monitoring scheme or amendment of the ICF.
8.5.1.1
Determination of Drug Concentration
Samples for determination of drug concentration in serum of patients that received 
benralizumab will be assayed by bioanalytical test sites operated by or on behalf of 
AstraZeneca, using an appropriately validated bioanalytical method. Full details of the 
analytical method used will be described in a separate bioanalytical report.
The bioanalytical laboratory will have access to the randomization list. Drug concentration 
information that may unblind the study will not be reported to investigative sites or blinded 
personnel until the study has been unblinded.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
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separate Bioanalytical Report.
8.5.2
Immunogenicity Assessments
Blood samples for determination of anti-drug antibodies in serum will be collected pre-
investigational product administration as detailed in Table 1 and assayed by bioanalytical test 
sites operated by or on behalf of AstraZeneca, using an appropriately validated bioanalytical 
method. Full details of the methods used will be described in a separate report. 
Anti-drug antibodies samples may also be further tested for characterization of the anti-drug 
antibody response.
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
8.5.3
Pharmacodynamics
Blood and urine samples will be collected for pharmacodynamic measurements at timepoints 
specified in Table 1.
For information on storage, re-use, and destruction of pharmacodynamic samples see Section 
8.5 and Appendix C. 
8.6
Human Biological Sample Biomarkers
8.6.1
Collection of mandatory samples for biomarker analysis
Note: following the approval of Amendment 4 (CSP version 5), no further human 
biological samples as described in this section will be collected.
Mandatory collection of samples for exploratory biomarker research is a part of this study. 
Samples for exploratory biomarker research are required and will be collected from all 
participants in this study as specified in Table 1. Blood (whole blood, serum, and plasma) as 
well as stomach and/or intestinal tissue will be collected. Samples will be tested in order to 
evaluate the effect of benralizumab on gene expression (RNA transcript analysis), 
inflammation, and immunological mechanisms related to the pathogenesis of EG/EGE.
Instructions for sample collection, processing, storage, and shipment are provided in the 
Laboratory Manual. Results from the exploratory biomarker analyses, if performed, will be 
reported separately from the CSR. (Investigators will not receive the results.)
8.6.1.1
Serum 
Serum samples will be collected as specified in Table 1 to evaluate the pharmacology of 
benralizumab as well as biomarkers of eosinophil recruitment, activation, and survival (eg, 
absolute eosinophil count,
). Additional markers of cellular inflammation 
and/or activation may be assessed including, but not limited to, those associated with humoral 
CCI

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autoimmunity (total serum IgE), T cell subsets (eg, 
), eosinophil 
granule proteins (eg,
), epithelial cell 
damage (eg,
), or activation of inflammatory cells including
. The results from such studies will not be reported in the CSR but in separate reports 
or publications as appropriate.
Serum samples will be collected according to the schedules presented in Table 1 for analysis 
of serum tryptase levels. The analysis will be performed at the central laboratory.
Instructions for sample collection, processing, storage, and shipment will be found in the 
Laboratory Manual.
8.6.1.2
Tissue Histology and Immunostaining
Biopsies will be collected at screening, Week 24, and Week 52. Biopsies will be taken from 
sites within the stomach and/or small intestine identified during endoscopy by site physicians. 
At the time of each EGD, pts will also have biopsies taken of the esophagus, 2 each proximal 
and distal, for monitoring of esophageal eosinophilia during the trial.
Biopsies will be collected and processed locally at the clinical sites as described in detail in 
the Laboratory Manual.
Staining of the biopsies will be conducted at an appropriate contract lab and/or at 
AstraZeneca. The gastrointestinal biopsies will be stained for chemical markers for the 
detection and enumeration of inflammatory cell types such as eosinophils, mast cells, and 
basophils. Other molecules that may be directly or indirectly involved in the mechanism of 
action of benralizumab (including, but not limited to,
) and/or the pathophysiology of EG/EGE may be investigated.
8.6.1.3
RNA Transcriptome Research
Transcriptome studies (blood and biopsy) will be conducted.  Transcriptomic studies of serum 
and/or biopsies collected from gastrointestinal mucosal tissue will be conducted using 
microarray, RNA-sequencing, and/or alternative equivalent technologies, which facilitate the 
simultaneous measurement of the relative abundances of as many as thousands of RNA 
species, resulting in a transcriptome profile for each tissue sample. This will enable the 
evaluation of transcriptome profiles that will provide molecular insight into mechanisms 
underlying tissue pathology, identification of features associated with pathology conserved 
across subjects or across areas of the GI tract within a given subject, as well as the mechanism
of action of benralizumab and how its clinical efficacy correlates with changes in 
gastrointestinal tissue transcriptome.
Details on biopsy acquisition and processing for transcriptomics will be included in the lab 
manual.  
CCI
CCI
CCI
CCI
CCI

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8.7
Optional Genomics Initiative Sample
Collection of optional samples for Genomics Initiative research is also part of this study and is 
subject to a separate consent in the ICF addendum, and local regulations.
A blood sample for DNA isolation will be collected from adult participants who have 
consented to participate in the genetic analysis component of the study at Visit 2 (Table 1). 
Adolescents are not included in this option. Participation is optional; participants 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 ICF has been signed.
Details on processes for collection, shipment, storage and destruction of these samples are 
provided in Appendix D and in the Laboratory Manual.
8.8
Healthcare Resource Utilization
EG/EGE-related and other GI-disease complications-related healthcare resource utilization 
data will be collected in the eCRF by the Investigator and study-site personnel for all 
participants throughout the study. Protocol-mandated visits, procedures, tests, and encounters 
are excluded.
At visits when healthcare use is being collected, as specified in Table 1 through Table 3, the 
Investigators retrospectively collect any EG/EGE-related and other GI disease complications-
related healthcare resource utilization information. At baseline, healthcare resource utilization 
will be collected with a 6-month recall period. At all subsequent visits, any EG/EGE-related 
and other GI disease complications-related healthcare resource utilization information will be 
collected with a recall period of ‘since last HRU assessment during the scheduled visit’. 
The data collected may be used to conduct exploratory economic analyses and will include:

Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient)

Duration of hospitalization (total days or length of stay, including duration by wards 
[eg, intensive care unit])

Outpatient medical encounters and interventions (including specialist visits, General 
Practitioner visits, home health care visits, and emergency room visits, etc.)

Number and type of diagnostic and therapeutic tests and procedures
9
STATISTICAL CONSIDERATIONS
The analysis of the study will be performed when all patients have completed their last visit in 
the study.  Data from this analysis will be summarized in a synoptic CSR.

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9.1
Statistical Hypotheses
No hypothesis testing will be performed given the decision to terminate recruitment to the 
study, resulting in the intended sample sizes required not being recruited.
9.2
Sample Size Determination
The original sample size calculations for the study were based on the change from baseline in 
SAGED score at Week 24 dual primary endpoint. Changes in the other dual primary 
histological response rate endpoint required smaller sample sizes as larger relative differences 
are assumed (10% placebo response versus 80% benralizumab response). 
Part A intended to enroll approximately 50 patients with EG (with or without duodenal 
involvement). Eligible patients with duodenal only disease were also to be included whilst 
enrolling the required 50 EG patients, with no minimum requirement on the number of 
duodenal only patients.   A minimum of 60 and a maximum of 80 patients in the overall 
population in Part A were targeted. Thirty patients per arm in the overall population, and 25 
patients per arm with gastric disease would provide >85% and >80% power for statistical 
significance at the 10% 2-sided level for each population respectively, if the true treatment 
effect for the change from baseline in SAGED score is a standardized effect size (difference in 
means/ standard deviation) of 0.75. A standardized effect size is used as the variability of the 
SAGED score is not known yet. An effect size of 0.75 is a similar relative effect size as that 
observed in the antolimab Phase 2 trial (Dellon et al 2020). Approximately 20 adolescent 
patients (12 to 17 years of age) with either EG or duodenal only disease were targeted for 
inclusion in Part A.
The final sample size for the study is limited to 12 patients due to closure of recruitment to the 
study.
9.3
Populations for Analyses
The following populations are defined:
Table 10
Populations for Analysis
Population/Analysis set
Description
Enrolled 
All participants who sign the ICF
All patients analysis set
All patients screened for the study, to be used for reporting of disposition 
and screening failures
Safety analysis set
The safety analysis set consists of all patients who have received at least one 
dose of investigational product.
Erroneously treated patients (eg, those randomized to one treatment but 
actually given the other treatment) are accounted for in the treatment group 
of the treatment they actually received.
A patient who has on one or several occasions received active 

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Population/Analysis set
Description
investigational product is classified as active.
Safety summaries will be based on this analysis set and for whom any post-
dose data are available.
Open-label benralizumab 
analysis set
All patients who receive at least 1 dose of benralizumab after the end of the 
double-blind treatment period
9.4
Statistical Analyses
Analyses will be performed by AstraZeneca or its representatives. Any deviations from the 
analyses outlined here will be reported in the CSR.
9.4.1
General Considerations
As recruitment to the study has been terminated and the final sample size is too low to 
perform originally planned analysis, analyses will consist of descriptive summaries and 
figures of safety data for the double-blind placebo-controlled period (Part A) and the open-
label periods (Parts C and D) as well as select patient listings of demographic and baseline 
characteristics, safety and key efficacy data.   No statistical analyses or hypothesis testing will 
be performed. 
All available data will be included in data presentations, regardless of use of rescue therapy, 
restricted medications for EG/EGE or treatment discontinuation.
9.4.2
Efficacy 
All available (from Part A and Part C) peak eosinophil count (eos/hpf) data will be listed by 
patient including whether patients achieved a histological response at available visits, defined 
as ≤6 eosinophils/hpf in the stomach and/or, ≤15 eosinophils/hpf in the duodenum, as 
applicable based on disease area involvement at enrollment. 
All available (from Parts A and C) SAGED score data will be listed by patient including 
individual abdominal pain, nausea, bloating, early satiety and loss of appetite severity item 
scores and the bi-weekly SAGED score calculated as the 14-day mean of the daily sum of the 
item scores.  
Listings of other efficacy endpoints may be produced as required including all available data 
from Parts A, C, and D.  Individual patient data may be presented graphically as appropriate.
Available efficacy data collected in relation to EG-REFs, EoD-REFs, PGI-S/C, CGI-S/C will 
be listed by patient (from the point of protocol amendment onwards only PGI-C data is 
collected during Part D but data already collected from patients in Part C will be included as 
available).  

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9.4.3
Safety
Safety data presentations will be performed using the safety analysis set.
The first presentation of safety data will include only data from the double-blind, placebo-
controlled first 24 weeks of the study (Part A double-blind period). Patients will be 
summarized according to the treatment they received (benralizumab or placebo).
Safety data from the open-label benralizumab parts of the study (Part C and Part D) will be 
reported separately from Part A. 
Safety data will be presented using descriptive statistics, figures, and data listings. Full details 
will be provided in the SAP.
In general, the baseline value for safety analyses is the last non missing value prior to 
administration of the first dose of investigational product.
9.4.3.1
Adverse Events
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.
Adverse events will be presented for each treatment group by system organ class and/or 
preferred term, including the number and percentage of participants reporting at least 1 event, 
number of events and exposure-adjusted rates, where appropriate.
An overview of AEs will be presented for each treatment group, including the number and 
percentage of participants with any AE, AEs with outcome of death, serious AEs, and AEs 
leading to discontinuation of investigational product.
AE listings for the safety analysis set will cover details for each individual AE, including 
information on the relationship to investigational product as assessed by the investigator, 
maximum intensity, seriousness, death and events leading to discontinuation of investigational 
product, as well as other action taken related to investigational product.
Key participant information will be presented for participants with AEs with outcome of 
death, serious AEs, and AEs leading to discontinuation of investigational product.
Full details of AE analyses will be provided in the SAP.
Treatment Emergence
The following events are considered treatment emergent:

AEs with an onset date on or after the first dose of investigational product

Worsening of pre-existing events on or after first dose of investigational product

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9.4.3.2
Clinical Safety Laboratory Assessments
Laboratory data for hematology and clinical chemistry will be Listed. The frequency of 
changes with respect to normal ranges between baseline and each post-treatment time point 
will be tabulated. Frequencies of clinically noteworthy values (defined in the SAP) occurring 
during the clinical study will also be given. Shifts from normal to abnormal between baseline
and each post-baseline time point will be evaluated.
9.4.3.3
Vital Signs and Weight
Vital sign parameters will be listed for all patients during the study.
Shifts from normal to abnormal between baseline and follow-up will be evaluated via a listing 
for the physical examination data.
9.4.4
Other Analyses 
9.4.5
Methods for multiplicity control
As no hypothesis testing will be performed and no statistical comparisons of benralizumab 
versus placebo will be made there is no adjustment for multiplicity necessary.
9.5
Interim Analyses
No interim analyses are planned for this study.
9.6
Data Monitoring Committee
For details on the Independent Data Monitoring Committee, see Appendix A 5.  
Note: With the approval of Amendment 4, the open-label dosing in Part D will not 
require the use of an IDMC.

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Appendix A
Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines

Applicable ICH Good Clinical Practice Guidelines

Applicable laws and regulations

The protocol, protocol 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 protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
contract research organization, but the accountability remains with AstraZeneca.

The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions 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

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

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A 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, the US Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICFs during their 
participation in the study.

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.

Participants who are rescreened are required to sign a new ICF.

The ICF will contain a separate section that addresses and documents the collection and 
use of any mandatory and/or optional human biological samples. The investigator or 
authorized designee will explain to each participant the objectives of the analysis to be 
done on the samples and any potential future use. Participants will be told that they are 
free to refuse to participate in any optional samples or the future use and may withdraw 
their consent at any time and for any reason during the retention period.

Patients who participate in Part D will be required to sign a supplemental ICF 
specific for Part D. 
A 4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.

The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent 

The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.

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A 5
Independent Data Monitoring Committee
An independent DMC consisting of 2 clinicians (including at least 1 EG/EGE expert) and a 
statistician will be used for this study to monitor overall patient safety. The Independent Data 
Monitoring Committee will receive participant profiles including safety data and unblinded 
participant laboratory results on a regular basis and will meet to discuss the data as needed. 
Based on their review, the Independent Data Monitoring Committee may recommend changes 
to the study design or conduct or that individual participants be discontinued from the study 
for safety reasons. 
The Independent Data Monitoring Committee will communicate decisions/recommendations 
to an internal (Sponsor) Executive Committee that will consist of representatives from 
regulatory affairs, clinical development, biostatistics and patient safety and will remain 
blinded to data. The committee will decide on the implementation of the 
decisions/recommendation and will communicate back their actions and justification to the 
Independent Data Monitoring Committee.
Further details, composition and operation of the Independent Data Monitoring Committee are 
described in a separate Independent Data Monitoring Committee charter.
The safety of all Sponsor clinical studies is closely monitored on an ongoing basis by the 
Sponsor representatives in consultation with AstraZeneca’s Patient Safety department.
Note: With the approval of Amendment 4, the open-label dosing in Part D will not 
require the use of an IDMC.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.com, http://www.clinicaltrials.gov, and 
https://www.clinicaltrialsregsiter.eu, as will the summary of the study results when they are 
available. The clinical study and/or summary of study results may also be available on other 
websites according to the regulations of the countries in which the study is conducted.
A 7
Data Quality Assurance

All participant data relating to the study will be recorded on eCRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by electronically 
signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

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
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 (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 provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH Good Clinical Practice, 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 the sponsor. No records may be transferred to another location or 
party without written notification to the sponsor.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data entered in the eCRF that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may 
need to request previous medical records or transfer records, depending on the study. 
Also, current medical records must be available.

Definition of what constitutes source data can be found in the data monitoring plan.
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the first site open, and it’s opening date will be the study start 
date.

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The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or ICH Good Clinical Practice 
guidelines

Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IRB/IECs, the regulatory authorities, and any contract research organizations 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should 
assure appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a patient or clinical study 
participant administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (for example nausea, chest pain), or disease 
temporally associated with the use of a medicinal product, whether or not considered related 
to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered.
B 2
Definition of Serious Adverse Events
A 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-participant hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability or incapacity. 

Is a congenital anomaly or birth defect

Is an important medical event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above.
Adverse Events (AEs) for malignant tumors 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 judgment on an individual 
event basis should be applied to clarify that the malignant tumor event should be assessed and 
reported as a non-serious AE. For example, if the tumor is included as medical history and 
progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumor, the AE may not fulfil the attributes for being assessed as 
serious, although reporting of the progression of the malignant tumor as an AE is valid and 
should occur. Also, some types of malignant tumors, which do not spread remotely after a 
routine treatment that does not require hospitalization, may be assessed as non-serious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
removed via cone biopsy.

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Life-threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself an serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse
Intensity Rating Scale:

Mild (awareness of sign or symptom, but easily tolerated)

Moderate (discomfort sufficient to cause interference with normal activities)

Severe (incapacitating, with inability to perform normal activities)
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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 participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 

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information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
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 investigational medicinal product or AstraZeneca non-
investigational product that either causes harm to the participant or has the potential to cause 
harm to the participant. 
A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or participant.
Medication error includes situations where an error. 

Occurred

Was identified and intercepted before the participant received the drug

Did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error eg, medication prepared incorrectly, even if it was not actually given to 
the participant

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated eg, tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed eg, kept in the fridge when it should be at room temperature 

Wrong participant received the medication (excluding IRT/RTSM errors)

Wrong drug administered to participant (excluding IRT/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT/RTSM - including those which lead to one of the 
above listed events that would otherwise have been a medication error 

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
Participant accidentally missed drug dose(s) eg, forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of investigational medicinal product or AstraZeneca non-
investigational product for a perceived reward or desired non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the Data Entry Site (DES) using the Drug Abuse Report Form. This form should be used both 
if the drug abuse happened in a study participant or if the drug abuse involves a person not 
enrolled in the study (such as a relative of the study participant).
Examples of drug abuse include but are not limited to:

·The dug is used with the intent of getting a perceived reward (by the study participant 
or a person not enrolled in the study)

The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high 
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of investigational 
medicinal product or AstraZeneca NIMP for medicinal purposes outside of the authorised 
product information, or for unauthorised investigational medicinal products or AstraZeneca 
non-investigational medicinal products, outside the intended use as specified in the protocol 
and includes deliberate administration of the product by the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study participant or if the drug misuse regards a person not enrolled in 
the study (such as a relative of the study participant).
Examples of drug misuse include but are not limited to:

The drug is used with the intention to cause an effect in another person

The drug is sold to other people for recreational purposes 

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

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Appendix C
Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each center keeps full traceability of collected biological samples from the 
participants while in storage at the center until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for 
the remainder of the sample life cycle.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analyzed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the ICF.
The investigator:

Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.

Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented.

Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented and study site is notified.

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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) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A Pathogens are, eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to 
UN 2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN 3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content

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Appendix D
Optional Genomics Initiative Sample
D 1
Use/Analysis of DNA

AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response 
to medications. This genetic research may lead to better understanding of diseases, better 
diagnosis of diseases or other improvements in health care and to the discovery of new 
diagnostics, treatments or medications. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting participants.

This optional genetic research may consist of the analysis of the structure of the 
participant´s DNA, ie, the entire genome. 

The results of genetic analyses may be reported in a separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.
D 2
Genetic Research Plan and Procedures
Selection of Genetic Research Population

All adult participants will be asked to participate in this genetic research. Participation is 
voluntary and if a participant declines to participate there will be no penalty or loss of 
benefit. The participant will not be excluded from any aspect of the main study.
Inclusion Criteria
For inclusion in this genetic research, participants must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and provide informed consent for 
the Genomics Initiative sampling and analyses.
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

Healthy Volunteers and pediatric patient samples will not be collected for the 
Genomics Initiative.

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Withdrawal of Consent for Genetic Research

Participants may withdraw from this genetic research at any time, independent of any 
decision concerning participation in other aspects of the main study. Voluntary 
withdrawal will not prejudice further treatment. Procedures for withdrawal are outlined in 
Section 7.2 of the main Clinical Study Protocol.
Collection of Samples for Genetic Research

The blood sample for this genetic research will be obtained from the participants at 
randomization (Visit 2). Although DNA is stable, early sample collection is preferred to 
avoid introducing bias through excluding participants who may withdraw due to an AE. If 
for any reason the sample is not drawn at Visit 2, it may be taken at any visit until the last 
study visit. Only one sample should be collected per participant for genetics during the 
study.
Coding and Storage of DNA Samples

The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum 
of 15 years, from the date of last participant last visit, after which they will be destroyed. 
DNA is a finite resource that is used up during analyses. Samples will be stored and used 
until no further analyses are possible or the maximum storage time has been reached.

An additional second code will be assigned to the sample either before or at the time of 
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 organizations working with the 
DNA).

The link between the participant enrollment/randomisation code and the second number 
will be maintained and stored in a secure environment, with restricted access at 
AstraZeneca or designated organizations. The link will be used to identify the relevant 
DNA samples for 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 A.

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

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Appendix E
Best Practice Guidelines for Completing PRO Assessments
Participants will complete PRO assessments at home using a handheld device. PRO 
assessments must be collected in a systematic way to ensure data integrity. The following best 
practice guidelines should be followed when collecting PRO data via handheld device:

Provide the right environment

Participants should complete the PRO questions in a quiet and private location 
without help from others.

Purpose of the PRO assessments

Discuss the purpose of the PRO assessments with the participants. Reinforce that 
these are standardized questions designed to capture the participant experience in the 
study.

Inform participants that each PRO assessment is independent of the others. Some 
questions may be very similar or seem repeated, but it is important to answer each 
question independently.

Help with procedural questions

Make sure the participant understands how to complete the PRO assessment. 
Assessment instructions are usually self-explanatory, but staff may answer questions 
about procedural issues like what it means to “tick a box”.

Avoid bias: do not clarify the meaning of questions or responses

Sometimes participants will ask site staff to clarify the meaning of a question or 
response. To avoid introducing any bias, politely tell the participant that you cannot 
clarify items. Remind them that there are no right or wrong answers. Inform the 
participant that they should select the response that best answers the question as they 
understand it.

If a participant becomes unable to independently use the handheld device during the 
treatment period of the study (eg, unable to read due to vision problems), then the 
participant should be exempted from completing PRO questionnaires used for 
efficacy endpoints and may continue in the study with external help for symptom 
severity and background/rescue medication use questionnaires completion. 
Participant’s exemption in this regard must be pre-approved by an AstraZeneca study 
physician/delegate and appropriately documented.

No time limits

Although most PRO assessments require only a few minutes to complete, the 
participant should be given as much time as is needed.

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
Train the participant on handheld device usage

Train participants on how to use the handheld device using the materials and training 
provided by the device vendor.

Provide guidance on whom the participant should call if they have problems with the 
device.

Monitor compliance

Minimizing missing data is a key aspect of study success. Compliance with device 
completion must be checked weekly (at a minimum) to ensure that the participant is 
completing the assessments as scheduled. Follow-up with participants via phone and 
at the visits is required to ensure sufficient data are available for supporting the 
dual-primary endpoint of this study.

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Appendix F
Anaphylaxis: Definition, Signs, Symptoms and 
Management
F 1
Introduction
As with any antibody, allergic reactions to dose administration are possible. The World Health 
Organization has categorized anaphylaxis into 2 subgroups, which are clinically 
indistinguishable: immunologic (IgE-mediated and non-IgE-mediated [eg IgG and immune 
complex-mediated]) and nonimmunologic. The clinical criteria for defining anaphylaxis for 
this study are listed in Section F 2 of this Appendix. A guide to the signs and symptoms and 
management of acute anaphylaxis is provided in Section F 3 of this Appendix. Appropriate 
drugs, such as epinephrine, antihistamines, corticosteroids, and medical equipment to treat 
anaphylactic reactions must be immediately available at study sites, and study personnel 
should be trained to recognize and treat anaphylaxis according to local guidelines.
If an anaphylactic reaction occurs, a blood sample for serum tryptase should be collected as at 
90 minutes ± 30 minutes after the event; analysis for serum tryptase will be performed at a 
local laboratory. If local testing of serum tryptase is unavailable, there will be an option to 
have the sample tested centrally. Other blood or urine testing relevant to the diagnosis of 
anaphylaxis may be obtained at a local lab at the discretion of the Investigator.
F 2
Clinical Criteria for Defining Anaphylaxis 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 generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST 1 OF THE FOLLOWING:
(a) Respiratory compromise (eg dyspnea, wheeze-bronchospasm, stridor, reduced 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 generalized hives, itch-flush, swollen 
lips-tongue-uvula).
(b) Respiratory compromise (eg dyspnea, 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): Adults: systolic blood pressure of less than 90 mm Hg or 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.
F 3
Signs and Symptoms and Management of Acute Anaphylaxis
Anaphylaxis is an acute and potentially lethal multi-system allergic reaction in which some or 
all of the following signs and symptoms occur:
Other earlier or concomitant signs and symptoms can include:

Itchy nose, eyes, pharynx, genitalia, palms, and soles

Rhinorrhea

Change in voice

Metallic taste

Nausea, vomiting, diarrhea, abdominal cramps and bloating

Light-headedness

Headache

Uterine cramps

Generalized warmth
F 4
Management of Acute Anaphylaxis
F 4.1
Immediate intervention
1
Assessment of airway, breathing, circulation, and adequacy of mentation.
2
Administer epinephrine intramuscularly every 5-15 minutes, in appropriate doses, as 
necessary, depending on the presenting signs and symptoms of anaphylaxis, to control 
signs and symptoms and prevent progression to more severe symptoms such as 
respiratory distress, hypotension, shock and unconsciousness.

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F 4.2
Possibly appropriate, subsequent measures depending on response to 
epinephrine
(a) Place participant in recumbent position and elevate lower extremities.
(a) Establish and maintain airway.
(b) Administer oxygen.
(c) Establish venous access.
(d) Normal saline intravenous for fluid replacement.
F 4.3
Specific measures to consider after epinephrine injections, where 
appropriate
(a) Consider epinephrine infusion.
(b) Consider H1 and H2 antihistamines.
(c) Consider nebulized β2-agonist (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.

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Appendix G
Changes Related to Mitigation of Study Disruptions
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
participants become infected with SARS-CoV-2 or similar pandemic infection) during which 
participants may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
notification from the Sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation. 
G 1
Consent/Reconsent/Assent/Re-assent of Study Participants During 
Study Interruptions
During study interruptions, it may not be possible for the participants to complete study visits 
and assessments on site and alternative means for carrying out the visits and assessments may 
be necessary, eg, remote visits. Consent/reconsent/assent/re-assent 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 G 2to G 5. Local and regional regulations 
and/or guidelines regarding reconsent of study participants should be checked and followed. 
Reconsent may be verbal if allowed by local and regional guidelines (note, in the case of 
verbal reconsent the ICF should be signed at the participant’s next contact with the study site). 
Visiting the study sites for the sole purpose of obtaining reconsent should be avoided. 
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 enrollment into the study or commencing of dosing with investigational 
product. If this delay is outside the screening window specified in Table 1 the patient will 
need to be rescreened to reconfirm eligibility before commencing study procedures. This will 
provide another opportunity to re-screen a patient in addition to that detailed in Section 5.4. 
The procedures detailed in Section 5 must be undertaken to confirm eligibility using the same 
screening/enrollment number as for the patient.
G 3
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified Health Care Professional from the study site or third-party vendor 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 

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Health Care Professional will be expected to collect information per the Clinical Study 
Protocol. 
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 participants will allow AEs, concomitant medication, diet questionnaire, review 
compliance of PRO assessments, and healthcare resource utilization to be reported and 
documented. Scheduled blood sample collection and endoscopies will be performed as soon as 
the participant can safely attend subsequent site visit. 
G 5
At-home or Remote Location Investigational Product 
Administration Instructions
If a site visit is not possible, at-home or remote location administration of investigational 
product may be performed by a qualified Health Care Professional, provided this is acceptable 
within local regulation/guidance, or by the participant or his/her caregiver. The option of at-
home or remote location investigational product administration ensures patients safety in cases 
of a pandemic where participants may be at increased risk by traveling to the site/clinic. This 
will also minimize interruption of investigational product administration during other study 
disruptions, eg, site closures due to natural disaster. 
G 5.1
At-home or Remote Location investigational product Administration 
by a Qualified Health Care Professional or Third Party Vendor Service
A qualified Health Care Professional from the study site or third party vendor service should 
administer the investigational product at the participant’s home or other remote location 
according to the Clinical Study Protocol. All necessary supplies and instructions for 
administration and documentation of investigational product administration will be provided. 
Additional information related to the visit can be obtained via a telemedicine or home visit.
G 5.2
At-home or Remote Location Investigational Product Administration 
by the Participant or His/her Caregiver
Prior to at-home or remote location investigational product administration the investigator 
must assess the participant or his/her caregiver to determine whether they are appropriate for 
at-home or remote location administration of investigational product. Once the participant 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 

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and documentation of investigational product administration will be provided. More 
information related to the visit can be obtained via a telemedicine or home/remote visit.
G 5.3
Data Capture During Telemedicine or Home / Remote Visits
Data collected during telemedicine or home/remote visits will be captured by the qualified 
Health Care Professional from the study site or third party vendor service, or by the 
participant themselves, eg, details of self-administration, PRO, signs and symptoms.

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Appendix H
Abbreviations
Abbreviation 
Explanation
AE
Adverse event
eCRF
Electronic Case Report Form
DSQ
Dysphagia Symptom Questionnaire
EG
Eosinophilic gastritis
EGE
Eosinophilic gastroenteritis
EG-REFS
Eosinophilic Gastritis Endoscopic Reference System 
hpf
High powered field
IATA
International Airline Transportation Associations
ICF
Informed Consent Form
ICH
International Council for Harmonization
IP
Investigational Product
IRB/IEC
Institutional Review Board/Independent Ethics Committees
PCS
Physical Component Summary of the SF-36v2
PAGI-QoL
Patient Assessment of Upper Gastrointestinal Disorders-Quality of Life 
PAGI-SYM
Patient Assessment of Gastrointestinal Disorders Symptom Severity Index
MCS
Mental Component Summary of the SF-36v2
PGI-C/S/BR
Patient Global Impression of Change/Severity/Benefit-Risk
PRO
Patient-reported outcome
PROMIS
Patient-Reported Outcome Measurement Information System
Q4W
Every 4 weeks 
Q8W
Every 8 weeks
RTSM
Randomisation and Trial Supply Management
SAGED
Symptom Assessment for Gastrointestinal Eosinophilic Diseases
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SoA
Schedule of activities
SF-36v2 
Short Form Health Survey Version Short (Acute Recall)
WOCBP
Women of childbearing capacity
WPAI+CIQ
Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment 
Questions

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Appendix I
Protocol Amendment History
The Summary of Changes Table for the current revision is located directly before the Table of 
Contents.
Amendment 3 (CSP ver 4.0): 15-September-2021
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study.
Overall Rationale for the Amendment.
The primary rationale for this amendment is to include the free text questionnaire 
(Eosinophilic Gastrointestinal Disease Diary) for exploratory descriptive analyses.
Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial
/Non-
substantial
0 Schedule of Activities
Updated Tables 1-4 to reflect 
changes in assessment schedules, as 
applicable 
Consistency with main 
text of CSP and clarity
Non-
substantial
8.1.3.6 Patient 
Assessment of Upper 
Gastrointestinal 
Disorders-Quality of Life
Edited description of PAGI-QoL
Error correction
Non-
substantia
l
8.1.8 Eosinophilic 
Gastrointestinal Disease 
Diary
Added description of new 
assessment
Added new assessment
Non-
substantial
8.2.4 Clinical Laboratory 
Safety Assessments
Added albumin to clinical chemistry 
labs in Table 9
Additional safety 
assessment 
Non-
substantial
8.2.6 Other Safety 
Assessments
Clarified instructions for follow-up 
testing for HBV reactivation
Clarity
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
0 Schedule of Activities
6.1.3.6  Optional Remote 
Visits for Patients Doing 
At-Home or Remote-
Location Investigational 
Product Administration
8.2.5 Pregnancy Testing
Reduced urine pregnancy testing 
requirements to quarterly, rather than 
every visit after Week 24 (during 
open-label treatment). All relevant 
sections updated with new guidance
Updated internal guidance 
for benralizumab
Non-
substantial
8.3.12 Management of 
investigational product-
related toxicities
Appendix F Anaphylaxis: 
Definition, Signs, 
Symptoms and 
Management
Clarified requirements for serum 
tryptase analysis
Clarity
Non-
substantial
8.3.9.1 Maternal 
Exposure
changed wording from "congenital 
abnormality" to "congenital 
anomaly" 
Updated guidance and 
CSP template
Non-
substantial
Throughout
Minor editorial and document 
formatting revisions
Minor, therefore have not 
been summarised
Non-
substantial
Amendment 2 (CSP ver 3.0): 04-Mar-2021
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study.
Overall Rationale for the Amendment.
The primary rationale for this amendment is to include minor clarifications to ensure 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
8.1.1. Histopathology and 
Tissue Eosinophil Counts
8.1.2. Endoscopic 
Reference System Scores
Corrected description of Week 1
To ensure that in-text 
description of assessments 
aligns with Schedule of 
Activities table.  
Non-
substantial
8.1.7. Qualitative Patient 
Interview Sub-study
Number of patients in sub-study 
changed from ‘30’ to ‘up to 45’.  
Correction from previous 
version
Non-
substantial
8.1.1. Histopathology and 
Tissue Eosinophil Counts
Reworded to state that at least two of 
the four required duodenal biopsies 
should be obtained from the lower 
part of the duodenum
Clarification allows for 
obtaining of biopsies from 
the upper duodenum 
according to clinician or 
investigator discretion 
Non-
substantial
8.2.2. Vital Signs
Added language permitting non-oral 
measurements of body temperature
Allows for other methods 
of measuring body 
temperature that may be 
more acceptable per local 
standards of care, and 
aligns with other 
benralizumab studies.
Non-
substantial
Throughout
Minor editorial and document 
formatting revisions
Minor, therefore have not 
been summarised
Non-
substantial
Amendment 1 (CSP ver 2.0): 23-Feb-2021
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union because it neither significantly impacts the safety or physical/mental integrity of 
participants nor the scientific value of the study.
Overall Rationale for the Amendment.
The primary rationale for this amendment is to update the description of the PGI-S tool, which 
has been changed from a 6-point to a 4-point scale. Details of the collection and analysis of 
healthcare research utilization data have also been updated. In addition, some minor 
clarifications were made to ensure correct interpretation of the study protocol. 

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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.Synopsis
The word ‘corticosteroid’ was added 
to the objectives and endpoints table 
Clarification of the rescue 
medication use objective 
and to align with the 
protocol text.  
Non-
substantial
0.Schedule of Activities
Removed the healthcare resource 
utilization assessment, CGI-S, and 
CGI-C from the unscheduled visit 
Streamlining of required 
assessments at the 
unscheduled visits
Non-
substantial
3. Objectives and 
Endpoints
The word ‘corticosteroid’ was added 
to the objective for rescue 
medication use in Table 6
Alignment with protocol 
text
Non-
substantial
3. Objectives and 
Endpoints
Reworded text of healthcare resource 
utilization objective and endpoint 
To provide additional 
clarity and detail around 
the healthcare resource 
utilization data
Non-
substantial
5.4.Screen Failures
Corrected the numbers of the 
inclusion/exclusion criteria that are 
not allowed to be considered for re-
screening.
Correction of a typo in 
previous version
Non-
substantial
8.1.3.9. Patient Global 
Impression of Severity
Changed the PGI-S scale from a 6-
point to a 4-point scale 
(none/mild/moderate/severe), and 
clarified that the PGI-S asks 
participants to consider the severity 
of their EG/EGE symptoms.
Revised scale will help 
participants select 
meaningful responses.
Non-
substantial
Section 8.1.3.10. Patient 
Global Impression of 
Change
Clarified that the PGI-C asks 
participants to consider change in 
their EG/EGE symptoms.
Revised wording will help 
participants select 
meaningful responses.
Non-
substantial
Throughout
Minor editorial and document 
formatting revisions
Minor, therefore have not 
been summarised
Non-
substantial

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10
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04-Apr-2023 11:37 UTC
Content Approval
04-Apr-2023 11:12 UTC
Management Approval
05-Apr-2023 10:30 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD