A Multicenter, Randomized, Double-blind, Parallel-group, Placebo Controlled Study to Investigate the Use of Benralizumab for Eosinophilic Esophagitis
Phase: PHASE3
Conditions: Eosinophilic Esophagitis
Sponsor: AstraZeneca

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Clinical Study Protocol
Drug Substance
Benralizumab
Study Code
D3255C00001
Version
7.0
Date
01 April 2022
A Multicenter, Randomized, Double-blind, Parallel-group, 
Placebo-controlled Study to Investigate the Use of Benralizumab 
for Eosinophilic Esophagitis (MESSINA)
Sponsor:
AstraZeneca AB, 151 85 Södertälje, Sweden
AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan
Regulatory Agency Identifying Number(s):
EudraCT number: 2019-002871-32
NCT number: [04543409]
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered, and the results will be 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
This submission /document contains trade secrets and 
confidential commercial information, disclosure of 
which is prohibited without providing advance notice 
to AstraZeneca and opportunity to object.

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date of Issue
Amendment 6 (CSP ver 7.0)
01-April-2022
Amendment 5 (CSP ver 6.0)
30-April-2021
Amendment 4 (CSP ver 5.0)
11-Feb-2021
Amendment 3 (CSP ver 4.0)
26-Aug-2020
Amendment 2 (CSP ver 3.0)
31-July-2020
Amendment 1 (CSP ver 2.0) 
01-Nov-2019
Original protocol (Initial creation 1.0)
10-July-2019
Amendment 6 (CSP ver 7.0): 01 April 2022
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale For the Amendment
The rationale for this amendment is to adjust the ordering of endpoints within the multiple 
testing procedure and update the analysis method for treatment failure intercurrent events for 
continuous endpoints. In addition, some minor clarifications were made 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
Section 1.1 Schedule of 
Activities (SoA) Table 2, 
Table 3
Section 8.2.2 Pregnancy 
test
Section 6.1.4.1 Optional  
Remote Visits for 
Patients doing At-Home 
or Remote-Location  IP 
Administration
Updated urine pregnancy testing 
frequency after week 52. 
Removal of ‘and urine dipsticks 
for pregnancy tests (for 
WOCBP)’
For clarification and to reduce 
patient/site burden
Non-
Substantial
Section 1.1 Schedule of 
Activities (SoA
Addition of a footnote and a 
separate row for ‘Benralizumab 
administration’ to confirm the 
start of open-label dosing
For clarification
Non-
Substantial
Section 1.2 Synopsis, 
Table 5, Table 6
Section 3 Objective and 
Endpoints, Table 7, 
Table 8
Section 9.4.1.3Analysis 
methods for secondary 
efficacy variables
Section 9.4.5 Methods 
for multiplicity control
Adjustment of endpoint 
prioritisation including 
promotion of secondary 
endpoints to key secondary 
endpoints, addition of key 
treatment responder endpoint 
and promotion of PEESS to a 
secondary (non-ranked) rather 
than exploratory endpoint
To ensure that clinically 
meaningful endpoints are 
multiplicity-protected and to 
reflect the importance of 
PEESS.
Substantial

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial
/Non-
substantial
Section 1.2 Synopsis
Section 9.4.1.1 General 
principles Statistical 
analyses
Section 9.4.1.2Primary 
analysis method
Updated imputation methods to 
handle treatment failure 
intercurrent events for 
continuous endpoints to use 
return-to-baseline multiple 
imputation rather than worst 
observation carried forwards.
As a result of health authority 
feedback, multiple imputation 
methods using the distribution 
of baseline scores from all 
patients will be used to handle 
treatment failure intercurrent 
events. This is an improved 
method quality of imputation 
than the previously proposed 
single imputation approach as it 
ensures uncertainty around the 
imputed values are included in 
the analysis.
Substantial
Section 2.2 Background
Text added regarding outcome 
measures and remission scores
To reflect recent literature
Non-
Substantial
Section 5.1 Inclusion 
criteria
Removal of systemic steroids 
from IC7
As this is included in EC15
Non-
Substantial
Section 6.1.1 Before IP 
administration
Text adjusted; endoscopy 
added. 
To clarify that all procedures 
must be performed prior to IP 
administration.
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
Section 6.1.5 IP 
administration re-
scheduling
Section 8.2.4 Vital signs 
Simplification of on-site patient 
visit 
For simplification 
Non-
Substantial
Section 6.3.2  Methods 
for ensuring blinding
Text added;
‘Additional biopsies are not to 
be sent to local labs in parallel’ 
‘Week 24 follow-up biopsy 
results will not be reported back 
to the investigative sites due to 
potential risk of unblinding'
For clarification
Non-
Substantial
Section 7.1.1.3
Discontinuation of 
treatment in the OLE 
treatment period
Definition of an EOT visit 
versus an IPD visit during the 
OLE added
For clarification
Non-
Substantial
Section 8.4.7
Management of IP-
related toxicities
Appendix F
Anaphylaxis: Definition, 
Signs, Symptoms and 
Management, F 1
Introduction
Text added regarding the 
analysis of serum tryptase 
For clarification
Non-
Substantial
Throughout
Minor editorial or 
administrative changes that do 
not substantially alter the 
document
For better consistency and 
clarity
Non-
Substantial

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.................................... 2
TABLE OF CONTENTS...................................................................................................... 6
1
PROTOCOL SUMMARY................................................................................ 11
1.1
Schedule of Activities (SoA)............................................................................. 11
1.2
Synopsis ........................................................................................................... 27
1.3
Schema............................................................................................................. 36
2
INTRODUCTION............................................................................................ 37
2.1
Study rationale.................................................................................................. 37
2.2
Background ...................................................................................................... 38
2.3
Benefit/risk assessment..................................................................................... 40
3
OBJECTIVES AND ENDPOINTS................................................................... 41
4
STUDY DESIGN ............................................................................................. 46
4.1
Overall design................................................................................................... 46
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis ................................................ 48
4.2
Scientific rationale for study design .................................................................. 49
4.3
Justification for dose......................................................................................... 51
4.4
End of study definition...................................................................................... 51
5
STUDY POPULATION ................................................................................... 52
5.1
Inclusion criteria............................................................................................... 52
5.2
Exclusion criteria.............................................................................................. 54
5.3
Lifestyle restrictions ......................................................................................... 57
5.3.1
Meals and dietary restrictions............................................................................ 57
5.4
Screen failures .................................................................................................. 57
6
STUDY TREATMENTS.................................................................................. 58
6.1
Treatments administered................................................................................... 58
6.1.1
Before IP administration ................................................................................... 59
6.1.2
IP administration at the study Site..................................................................... 59
6.1.3
Self-administration of IP as Mitigation to Study Disruption .............................. 60
6.1.4
Optional At-home or Remote-Location IP Administration ................................ 60
6.1.4.1
Optional  Remote Visits for Patients doing At-Home or Remote-Location  IP 
Administration.................................................................................................. 61
6.1.5
IP administration re-scheduling......................................................................... 61
6.2
Preparation/handling/storage/accountability...................................................... 62
6.3
Measures to minimize bias: randomization and blinding ................................... 63
6.3.1
Methods for assigning treatment groups............................................................ 63

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6.3.2
Methods for ensuring blinding .......................................................................... 64
6.3.3
Methods for unblinding..................................................................................... 65
6.4
Treatment compliance....................................................................................... 66
6.5
Concomitant therapy......................................................................................... 66
6.5.1
Background medication and related treatments ................................................. 66
6.5.2
Other concomitant treatment............................................................................. 67
6.5.3
Rescue medication............................................................................................ 67
6.5.4
Restrictions....................................................................................................... 67
6.6
Dose modification............................................................................................. 70
6.7
Treatment after the end of the study.................................................................. 70
7
DISCONTINUATION OF TREATMENT AND PATIENT WITHDRAWAL . 70
7.1
Discontinuation of IP........................................................................................ 70
7.1.1
Procedures for early discontinuation of study treatment and at end of study...... 71
7.1.1.1
Early discontinuation of study treatment ........................................................... 71
7.1.1.2
Discontinuation at Week 52 .............................................................................. 72
7.1.1.3
Discontinuation of treatment in the OLE treatment period................................. 72
7.2
Lost to follow-up .............................................................................................. 73
7.3
Withdrawal from the study................................................................................ 73
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 74
8.1
Efficacy assessments......................................................................................... 75
8.1.1
Histopathology and tissue eosinophil counts ..................................................... 75
8.1.2
EoE Endoscopic Reference Score ..................................................................... 75
8.1.3
Patient Reported Outcomes............................................................................... 75
8.1.3.1
Dysphagia Symptom Questionnaire (DSQ)....................................................... 76
8.1.3.2
EoE-3D and additional daily questions.............................................................. 77
8.1.3.3
Adult Eosinophilic Esophagitis Quality of Life Questionnaire (EoE-QoL-A).... 78
8.1.3.4
Pediatric Eosinophilic Esophagitis Symptom Severity Module, Version 2, 
Children and Teens Report (PEESS)................................................................. 78
8.1.3.5
Patient Global Impression of Severity............................................................... 79
8.1.3.6
Patient Global Impression of Change ................................................................ 79
8.1.3.7
SF-36 (Version 2), Acute Recall ....................................................................... 79
8.1.3.8
Work Productivity and Activity Impairment questionnaire plus Classroom 
Impairment Questions (WPAI+CIQ)................................................................. 80
8.1.4
EndoFLIP (esophageal distensibility) – sub-study............................................. 80
8.1.5
Early Time Point Sub-study.............................................................................. 80
8.2
Safety assessments............................................................................................ 81
8.2.1
Clinical safety laboratory assessments............................................................... 81
8.2.1.1
Other laboratory assessments ............................................................................ 82
8.2.2
Pregnancy test................................................................................................... 83
8.2.3
Physical examinations....................................................................................... 83
8.2.3.1
Weight and height............................................................................................. 84
8.2.4
Vital signs......................................................................................................... 84
8.2.5
Electrocardiograms........................................................................................... 84

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8.3
Collection of adverse events ............................................................................. 85
8.3.1
Method of detecting AEs and SAEs .................................................................. 85
8.3.2
Time period and frequency for collecting AE and SAE information.................. 85
8.3.2.1
Regulatory Reporting Requirements for SAEs .................................................. 85
8.3.3
Follow-up of AEs and SAEs ............................................................................. 86
8.3.4
Adverse event data collection............................................................................ 86
8.3.5
Causality collection........................................................................................... 87
8.3.6
Adverse events based on signs and symptoms................................................... 87
8.3.7
Adverse events based on examinations and tests ............................................... 87
8.3.8
Disease-under study (DUS)............................................................................... 88
8.3.9
Disease progression .......................................................................................... 88
8.4
Safety reporting and medical management........................................................ 89
8.4.1
Reporting of serious adverse events .................................................................. 89
8.4.2
Pregnancy......................................................................................................... 89
8.4.2.1
Maternal exposure ............................................................................................ 90
8.4.3
Paternal exposure.............................................................................................. 90
8.4.4
Overdose .......................................................................................................... 90
8.4.5
Device Constituent Deficiencies ....................................................................... 91
8.4.5.1
SADE Reporting............................................................................................... 91
8.4.6
Medication error ............................................................................................... 92
8.4.7
Management of IP-related toxicities.................................................................. 92
8.5
Pharmacokinetics.............................................................................................. 93
8.5.1
Determination of drug concentration................................................................. 93
8.5.2
Storage and destruction of pharmacokinetic samples......................................... 93
8.6
Pharmacodynamics........................................................................................... 93
8.7
Genetics............................................................................................................ 94
8.7.1
Optional exploratory genetic sample ................................................................. 94
8.7.2
Storage and destruction of genetic samples ....................................................... 94
8.9
Immunogenicity................................................................................................ 96
8.10
Healthcare resource utilization.......................................................................... 96
8.11
Other assessments............................................................................................. 97
8.11.2
Diet questionnaire............................................................................................. 98
8.11.3
Patient Testing Due to Public Health Crisis....................................................... 98
9
STATISTICAL CONSIDERATIONS............................................................... 98
9.1
Statistical hypotheses........................................................................................ 99
9.2
Sample size determination ................................................................................ 99
9.3
Populations for analyses.................................................................................. 101

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9.4
Statistical analyses.......................................................................................... 101
9.4.1
Efficacy analyses ............................................................................................ 102
9.4.1.1
General principles........................................................................................... 102
9.4.1.2
Primary analysis method................................................................................. 103
9.4.1.3
Analysis methods for secondary efficacy variables.......................................... 104
9.4.1.4
Sensitivity analyses......................................................................................... 106
9.4.1.5
Subgroup analysis........................................................................................... 106
9.4.2
Safety analyses ............................................................................................... 106
9.4.3
Immunogenicity analyses................................................................................ 108
9.4.4
Other analyses ................................................................................................ 109
9.4.5
Methods for multiplicity control ..................................................................... 109
9.5
Interim analyses.............................................................................................. 110
9.6
Independent Data monitoring committee (IDMC)........................................... 110
10
REFERENCES............................................................................................... 111
11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS...................................................................................... 116
LIST OF TABLES
Table 1
Schedule of Activities – Double-blind and Open-label Treatment Periods 12
Table 2
Schedule of Activities after Week 52 – Open-label extension treatment 
period (Year 1) ........................................................................................ 19
Table 3
Schedule of Activities after Week 104 – Open-label extension treatment 
period (Year 2 +) ..................................................................................... 24
Table 4
Schedule of PRO assessments.................................................................. 26
Table 5
Study Objectives for the 52-week Study Period (DB+OL Treatment 
Periods) ................................................................................................... 28
Table 6
Study Objectives for the OLE Period ....................................................... 31
Table 7
Study Objectives for the 52-week Study Period (DB+OL Treatment 
Periods) ................................................................................................... 42
Table 8
Study Objectives for the OLE Period ....................................................... 45
Table 9
Study Treatments..................................................................................... 58
Table 10
Allowed, restricted, and prohibited concomitant medication and 
treatments................................................................................................ 68
Table 11
Threshold values for the SF-36v2 scale and summary measures............... 80
Table 12
Laboratory safety variables...................................................................... 82

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LIST OF FIGURES
Figure 1 
Study design............................................................................................ 36
Figure 2
Injection sites and examples of rotation scheme ....................................... 60
LIST OF APPENDICES
Appendix A
Regulatory, Ethical and Study Oversight Considerations........................ 117
Appendix B
Adverse Event Definitions and Additional Safety Information............... 123
Appendix C
Handling of Human Biological Samples ................................................ 127
Appendix D
Genetics................................................................................................. 130
Appendix E
Best Practice Guidelines For Completing PRO Assessments.................. 134
Appendix F
Anaphylaxis: Definition, Signs, Symptoms and Management ................ 136
Appendix G
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis ............................ 139
Appendix H
Abbreviations ........................................................................................ 142
Appendix I
Protocol Amendment History................................................................. 145

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1
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)
This study comprises 3 distinct treatment periods: A 24-week double-blind (DB) treatment 
period, a 28-week open-label (OL) treatment period, and an open-label extension (OLE) 
period.
All patients who complete the 52-week treatment period (DB+OL treatment periods) on 
investigational product (IP) will be offered the opportunity to continue into an OLE period on 
benralizumab 30 mg every 4 weeks (Q4W).  The OLE period is intended to allow each patient 
at least 1 year of treatment with OL benralizumab after completion of the 52-week DB+OL 
treatment periods. Patients who do not enroll in the OLE period will have a follow-up visit 12 
weeks after their last dose of IP.
The primary database lock is targeted to occur when the required number of patients have 
been randomised for the primary analysis (170 patients including approximately 130 adults 
and 40 adolescents) and they have completed the 24-week DB treatment period, including 
those who have had the opportunity to complete at least 52 weeks of follow-up (the 24-week 
DB treatment period and the 28-week OL treatment period; DB+OL treatment periods). The 
primary analysis will evaluate the effect of benralizumab on histologic signs and symptoms of 
EoE at Week 24 in patients with symptomatic and histologically active EoE.  An additional 
analysis may be performed after the last patient completes 52 weeks of follow up.  The final 
analysis will occur after the last patient completes the OLE period and FU visit.
The schedule of activities (SoA) for the 52-week study period (DB+OL treatment periods) is 
provided in Table 1. The SoA for the first year of the OLE period is provided in Table 2, the 
SoA for the second year and beyond of the OLE period is provided in Table 3.

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Table 1
Schedule of Activities – Double-blind and Open-label Treatment Periods
Study Procedures
Run-in 
Period
DB Treatment Period
OL Treatment Period
IPD a
FU
Details 
in CSP 
Section
Visit (V)
V1
V2
V3
V4
V5
V6
V7
V8 b
V9
V10
V11
V12
V13
V14
V15/ 
EOT c
Unsch 
Visit d
Week (Wk)
Wk -8 
to -2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
4 wks 
after 
final 
IP dose
12 wks 
after 
last IP 
dose
Visit Window (Days) e
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
General procedures
Informed consent / assent
X
Appx 
A 3
Demography / medical history
X
History of EoE and treatment
X
Height, weight
X
X
X
X
8.2.3.1
Inclusion / exclusion criteria
X
X
5.1, 5.2
Efficacy assessments
PRO assessments
In-office:
Provide handheld device and
instructions
X
8.1.3
Record visit in the handheld 
device; Confirm that all PRO
assessments have been 
completed
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.3
Review compliance of at-home 
PROassessments f
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.3

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Table 1
Schedule of Activities – Double-blind and Open-label Treatment Periods
Study Procedures
Run-in 
Period
DB Treatment Period
OL Treatment Period
IPD a
FU
Details 
in CSP 
Section
Visit (V)
V1
V2
V3
V4
V5
V6
V7
V8 b
V9
V10
V11
V12
V13
V14
V15/ 
EOT c
Unsch 
Visit d
Week (Wk)
Wk -8 
to -2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
4 wks 
after 
final 
IP dose
12 wks 
after 
last IP 
dose
Visit Window (Days) e
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
At-home g:
Daily:

Daily Diary (including 
DSQ, EoE-3D) 
Weekly: 

EoE-QoL-A 
Every two weeks:

PGI-S
Monthly: 

PEESS h
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.3.1, 
8.1.3.2, 
8.1.3.3, 
8.1.3.4, 
8.1.3.5
PGI-C
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.1.3.6
SF-36 (Version 2) and 
WPAI+CIQ
X
X
X
X
X
X
8.1.3.7,
8.1.3.8
Other assessments in office
Diet questionnaire
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.11.2
Healthcare resource utilization
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.10
 
 
Procedures

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Table 1
Schedule of Activities – Double-blind and Open-label Treatment Periods
Study Procedures
Run-in 
Period
DB Treatment Period
OL Treatment Period
IPD a
FU
Details 
in CSP 
Section
Visit (V)
V1
V2
V3
V4
V5
V6
V7
V8 b
V9
V10
V11
V12
V13
V14
V15/ 
EOT c
Unsch 
Visit d
Week (Wk)
Wk -8 
to -2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
4 wks 
after 
final 
IP dose
12 wks 
after 
last IP 
dose
Visit Window (Days) e
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
Endoscopy
•
Esophageal biopsies
•
EREFS
X
X j
X j
X
X
X k
8.1.1, 
8.1.2, 
Endoscopy
•
EndoFLIP (sub-study 
[selected sites])
X
X
X
X k
8.1.4

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Table 1
Schedule of Activities – Double-blind and Open-label Treatment Periods
Study Procedures
Run-in 
Period
DB Treatment Period
OL Treatment Period
IPD a
FU
Details 
in CSP 
Section
Visit (V)
V1
V2
V3
V4
V5
V6
V7
V8 b
V9
V10
V11
V12
V13
V14
V15/ 
EOT c
Unsch 
Visit d
Week (Wk)
Wk -8 
to -2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
4 wks 
after 
final 
IP dose
12 wks 
after 
last IP 
dose
Visit Window (Days) e
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
Safety assessments
AEs / SAEs
X
X
X
X
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
X
X
X
X
6.5
Complete physical exam
X
X
X
X
8.2.3
Brief physical exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X l
8.2.3
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2.4
ECG
X
8.2.5
Laboratory assessments
Hematology, WBC w/ 
differential
X
X j
X
X j
X
X
X
X
X 
X l, m
8.2.1
Serum chemistry
X
X
X
X
X
X
X
8.2.1
Serology (hepatitis B and C) n
X
8.2.1.1
HIV-1 and HIV-2
X
8.2.1.1
Urinalysis
X
X
X
X
X
X
8.2.1
FSH o
X
8.2.2
Serum pregnancy test in 
WOCBP
X
8.2.2

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Table 1
Schedule of Activities – Double-blind and Open-label Treatment Periods
Study Procedures
Run-in 
Period
DB Treatment Period
OL Treatment Period
IPD a
FU
Details 
in CSP 
Section
Visit (V)
V1
V2
V3
V4
V5
V6
V7
V8 b
V9
V10
V11
V12
V13
V14
V15/ 
EOT c
Unsch 
Visit d
Week (Wk)
Wk -8 
to -2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
4 wks 
after 
final 
IP dose
12 wks 
after 
last IP 
dose
Visit Window (Days) e
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
Urine pregnancy test in 
WOCBP p
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.2.2
PK q
X
X i
X
X i
X
X
X
X
X
X l
8.5
ADA / nAb q
X
X
X
X
X
X
X
X l
8.9
 
 
 
 
 
 
 
 
 
Investigational product administration
Randomization  
X
6.3.1
Benralizumab or placebo 
administration u
X
X
X
X
X
X
6.1
Benralizumab administration
X
X
X
X
X
X
X
X t
6.1

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Table 1
Schedule of Activities – Double-blind and Open-label Treatment Periods
Study Procedures
Run-in 
Period
DB Treatment Period
OL Treatment Period
IPD a
FU
Details 
in CSP 
Section
Visit (V)
V1
V2
V3
V4
V5
V6
V7
V8 b
V9
V10
V11
V12
V13
V14
V15/ 
EOT c
Unsch 
Visit d
Week (Wk)
Wk -8 
to -2
0
4
8
12
16
20
24
28
32
36
40
44
48
52
4 wks 
after 
final 
IP dose
12 wks 
after 
last IP 
dose
Visit Window (Days) e
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
Telephone contact for patients who discontinue early from IP and unwilling/unable to continue with clinic visits
Telephone contact v
Telephone contact every 4 weeks from the date of last clinic visit, and to continue until 
the end of the DB + OL treatment period
7.1.1.1
a
Details regarding procedures for patients who discontinue treatment but remain in the study are described in Section 7.1, for patients who discontinue from 
the study are described in Section 7.3, and for patients lost to follow up are described in Section 7.2.
b
Visit 8 is the last visit of the DB period and the first visit of the OL period. During this visit the first dose of the OL treatment will be administered.
c
For patients continuing in the OLE period, Visit 15 is the first treatment of the OLE period. If a patient chooses not to continue to the OLE period, then the 
patient will be considered to have completed the study; the site will perform an EOT visit at Week 52, and the patient will return for a FU visit 12 weeks (±7
days) after the last dose of IP, after which the patient exits the study.
d
These are the minimum procedures that should be performed at an unscheduled visit. Other assessments may be performed at discretion of the Investigator.
e
Visit windows are calculated from Visit 2.
f
Compliance with the assessment schedule should be completed weekly. 
g
PROs will be administered at home on the handheld device according to the schedule in Table 4.
h
The PEESS is only for patients aged 18 years and under at Visit 1.
 
k
To be completed at the discretion of the Sponsor.  Endoscopy at the IPD Visit should only be performed if ≥12 weeks have elapsed since the prior 
endoscopy. If a patient discontinues prior to Week 24, the patient should be asked to return for the endoscopy at Week 24 (rather than at the IPD visit).
l
These assessments/procedures will only be performed on patients who attend the FU visit at the study site.
m
Only WBC w/ differential will be measured at the FU visit.
n
For patients that are HBsAg positive or anti-HBc positive at Visit 1, HBeAg, anti-HDV and HBV DNA testing will be performed. For these subjects that 
are HBsAg positive or anti-HBc positive, ALT and HBV DNA will be drawn to monitor for hepatitis B reactivation, see section 8.2.1.1
o
FSH test done only to confirm postmenopausal status in women <50 years of age who have been amenorrheic for ≥12 months.
p
A positive urine test (dipstick) result must be confirmed with a serum beta-HCG.

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q
All samples for PK and ADA/nAb must be taken prior to IP administration.
 
t
IP will be administered at Visit 15 (Week 52) only for patients entering the OLE period.
u
Patient training of self-administration of IP procedures may be offered at Visits 2 and 3.
v
For patients using the phone follow-up option instead of attending the scheduled clinic visits, the handheld device will be returned at the IPD visit and no 
further PRO assessments will be collected.
ADA  anti-drug antibody; AEs  adverse events; ALT  alanine aminotransferase; anti-HDV  hepatitis D antibody; Appx Appendix; CSP  Clinical Study Protocol; 
DB Double-blind; DNA  deoxyribonucleic acid; DSQ Dysphagia Symptom Questionnaire; ECG  electrocardiogram; EGD  esophagogastroduodenoscopy; 
EoE  eosinophilic esophagitis; EoE-3D Eosinophilic Esophagitis - Daily Dysphagia Diary; EoE-QoL-A  Adult Eosinophilic Esophagitis Quality of Life 
Questionnaire; EndoFLIP Endolumenal Functional Lumen Imaging Probe; EOT  End of Treatment; EREFS  Endoscopic Reference Score; FSH  follicle 
stimulating hormone; FU  follow up; HBc  hepatitis B core; HBeAg  hepatitis B e-antigen; HBsAg  hepatitis B surface antigen; HBV  hepatitis B-virus;
HCG human chorionic gonadotropin; HIV-1/2  human immunodeficiency virus-1/2; IgE immunoglobulin E; IP investigational product; IPD  investigational 
product discontinuation (visit); nAb  neutralizing antibody; OL  Open-label; OLE  open-label extension; PEESS  Pediatric Eosinophilic Esophagitis Symptom 
Severity Module, Version 2.0, Children and Teens Report; PGI-C Patient Global Impression of Change; PGI-S Patient Global Impression of Severity; PK  
pharmacokinetics; PRO  Patient Reported Outcome; Q4W every 4 weeks; RNA ribonucleic acid; SAEs  serious adverse events; SF36v2 Short Form-36 
Version 2.0; Unsch Unscheduled; V  visit; Wk  week; WBC white blood cell (count); WOCBP  women of childbearing potential; WPAI+CIQ  Work 
Productivity and Activity Impairment questionnaire plus Classroom Impairment Questions.

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Table 2
Schedule of Activities after Week 52 – Open-label extension treatment period (Year 1)
Study Procedures
Treatment Period
Unsch 
Visit b
IPD / 
EOT c
FU
Details in 
CSP 
Section
Visit (V)
V16a
V17a
V18
V19a
V20a
V21
V22 a
V23 a
V24
V25a
V26 a
V27
V28
Week (Wk)
56
60
64
68
72
76
80
84
88
92
96
100
104
4 wks 
after 
final IP 
dose 
12 
wks 
after 
final 
IP 
dose
Visit Window (Days)d
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
General procedures
Height, weight
X
X
X
8.2.3.1
Efficacy assessments
PRO assessments
In office:
Record visit in the handheld 
device; Confirm that all 
PRO assessments have been 
completed
X
X
X
X
X
X
X 
X
8.1.3
Review compliance of 
at-home PROassessments
X
X
X
X
X
X
X
X
8.1.3
At-home:
Daily:
Daily Diary (including 
DSQ, EoE-3D)
Weekly:
EoE-QoL-A 
Monthly:
PEESS e
X
X
X
X
X
X
8.1.3.1, 
8.1.3.2
8.1.3.3
8.1.3.4
PGI-S (by interview)
X
X
X
8.1.3.5

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Table 2
Schedule of Activities after Week 52 – Open-label extension treatment period (Year 1)
Study Procedures
Treatment Period
Unsch 
Visit b
IPD / 
EOT c
FU
Details in 
CSP 
Section
Visit (V)
V16a
V17a
V18
V19a
V20a
V21
V22 a
V23 a
V24
V25a
V26 a
V27
V28
Week (Wk)
56
60
64
68
72
76
80
84
88
92
96
100
104
4 wks 
after 
final IP 
dose 
12 
wks 
after 
final 
IP 
dose
Visit Window (Days)d
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
Other assessments
Diet questionnaire
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.11.2
Healthcare resource 
utilization
X
X
X
X
X
X
X
X
X
X
X
X
X
X
8.10
 
 
 
 

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Table 2
Schedule of Activities after Week 52 – Open-label extension treatment period (Year 1)
Study Procedures
Treatment Period
Unsch 
Visit b
IPD / 
EOT c
FU
Details in 
CSP 
Section
Visit (V)
V16a
V17a
V18
V19a
V20a
V21
V22 a
V23 a
V24
V25a
V26 a
V27
V28
Week (Wk)
56
60
64
68
72
76
80
84
88
92
96
100
104
4 wks 
after 
final IP 
dose 
12 
wks 
after 
final 
IP 
dose
Visit Window (Days)d
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
Procedures
Endoscopy
•
biopsies
•
EREFS 
•
EndoFLIP (sub-study 
[selected sites])
X
X g
8.1.1, 
8.1.2
8.1.4
Safety assessments
AEs / SAEs
X
X
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
X
X
6.5
Complete physical exam
X
8.2.3
Brief physical exam
X
X
X
X
X
X
X
8.2.3
Vital signs
X
X
X
X
X
X
X
8.2.4
Laboratory assessments
Hematology, WBC w/ 
differential h
X
X
X
X i
8.2.1
Serum chemistry
X
X
X
8.2.1
Urinalysis
X
X
X
8.2.1
Urine pregnancy test in 
WOCBP j
X
X
X
X
X
X
X
8.2.2

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Table 2
Schedule of Activities after Week 52 – Open-label extension treatment period (Year 1)
Study Procedures
Treatment Period
Unsch 
Visit b
IPD / 
EOT c
FU
Details in 
CSP 
Section
Visit (V)
V16a
V17a
V18
V19a
V20a
V21
V22 a
V23 a
V24
V25a
V26 a
V27
V28
Week (Wk)
56
60
64
68
72
76
80
84
88
92
96
100
104
4 wks 
after 
final IP 
dose 
12 
wks 
after 
final 
IP 
dose
Visit Window (Days)d
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
PK k
X
X
X
X
8.5
ADA / nAb k
X
X
X
X
8.9
 
Investigational product
Benralizumab 
administration
X
X
X
X
X
X
X
X
X
X
X
X
X
6.1
a
These visits are designed to support self-administration at home/remotely but patients may opt to complete the visits at the study site. 
b
These are the minimum procedures that should be performed at an Unscheduled Visit. Other assessments may be performed at the discretion of the 
Investigator.
c
The IPD/EOT visit replaces the nearest regular visit: IPD visit procedures should be performed as soon as possible after the decision to discontinue IP has 
been made, and at the latest 4 weeks ±3 days after the last dose of IP.
d
Visit windows are calculated from Visit 2.
e
The PEESS is only for patients age 18 years and under at Visit 1.
g
Endoscopy at the IPD Visit should only be performed if ≥24 weeks have elapsed since the prior endoscopy. Endoscopy is not required at the IPD/EOT visit 
if it occurs after week 104.
h
For patients that are HBsAg positive or anti-HBc positive at Visit 1, HBeAg, anti-HDV and HBV DNA testing will be performed.  For these subjects that 
are HBsAg positive or anti-HBc positive, ALT and HBV DNA will be drawn to monitor for hepatitis B reactivation, see section 8.2.1.1 Other laboratory 
assessments
i
Only WBC w/ differential will be measured at the FU visit
j
A positive urine test (dipstick) result must be confirmed with a serum beta-HCG test.

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k
All samples for PK and ADA/nAB must be taken prior to IP administration.
ADA  anti-drug antibody; AEs  adverse events; ALT  alanine aminotransferase; anti-HDV  hepatitis D antibody; CSP  Clinical Study Protocol; DNA  
deoxyribonucleic acid; DSQ Dysphagia Symptom Questionnaire;  EoE  eosinophilic esophagitis; EoE-3D Eosinophilic Esophagitis - Daily Dysphagia Diary; 
EoE-QoL-A  Adult Eosinophilic Esophagitis Quality of Life Questionnaire; EOT  End of Treatment (visit); EREFS  Endoscopic Reference Score; FU  Follow 
Up; HBc  hepatitis B core; HBeAg  hepatitis B e-antigen; HBsAg  hepatitis B surface antigen; HBV  hepatitis B-virus; HCG human chorionic gonadotropin; 
IP investigational product; IPD  investigational product discontinuation (visit); nAb  neutralizing antibody; OLE open-label extension; PEESS  Pediatric 
Eosinophilic Esophagitis Symptom Severity Module, Version 2.0, Children and Teens Report; PGI-S Patient Global Impression of Severity; PK  
pharmacokinetics; PRO  Patient Reported Outcome; SAEs  serious adverse events; V  visit; WBC white blood cell; Wk week; WOCBP  women of 
childbearing potential.

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Table 3
Schedule of Activities after Week 104 – Open-label extension treatment period (Year 2 +)
Study Procedures
Treatment Period
Unsch 
Visit b
IPD / 
EOT c
FU
Details 
in CSP 
Section
Visit (V)
V29a 
/41a
V30a
/42a
V31
/43
V32 a 
/44a
V33a 
/45a
V34 
/46
V35a 
/47a
V36a 
/48a
V37 
/49
V38a 
/50a
V39a 
/51a
V40    
/52
Week (Wk)
108/1
56
112/
160
116/
164
120/
168
124/
172
128/
176
132/
180
136/
184
140/
188
144/
192
148/
196
152 
/200
4 wks 
after 
final 
IP 
dose 
12 
wks 
after 
final 
IP 
dose
Visit Window (Days)d
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
Diet questionnaire
X
X
X
X
X
X
8.11.2
Healthcare resource 
utilization
X
X
X
X
X
8.10
Safety assessments
AEs / SAEs
X
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
6.5
Complete physical exam
X
8.2.3
Brief physical exam
X
X
X
X
X
X
8.2.3
Vital signs
X
X
X
X
X
X
8.2.4
Laboratory assessments
Hematology, WBC w/ 
differential e
X
X
X
X f
8.2.1
Serum chemistry
X
X
X
8.2.1
Urinalysis
X
X
X
8.2.1
Urine pregnancy test in 
WOCBP g
X
X
X
X
X
X
8.2.2
PK h
X
X
X
X
8.5
ADA / nAb h
X
X
X
X
8.9

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Table 3
Schedule of Activities after Week 104 – Open-label extension treatment period (Year 2 +)
Study Procedures
Treatment Period
Unsch 
Visit b
IPD / 
EOT c
FU
Details 
in CSP 
Section
Visit (V)
V29a 
/41a
V30a
/42a
V31
/43
V32 a 
/44a
V33a 
/45a
V34 
/46
V35a 
/47a
V36a 
/48a
V37 
/49
V38a 
/50a
V39a 
/51a
V40    
/52
Week (Wk)
108/1
56
112/
160
116/
164
120/
168
124/
172
128/
176
132/
180
136/
184
140/
188
144/
192
148/
196
152 
/200
4 wks 
after 
final 
IP 
dose 
12 
wks 
after 
final 
IP 
dose
Visit Window (Days)d
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 7
 
Investigational product
Benralizumab administration
X
X
X
X
X
X
X
X
X
X
X
X
6.1
a
These visits are designed to support self-administration at home/remotely but patients may opt to complete the visits at the study site.
b
These are the minimum procedures that should be performed at an Unscheduled Visit. Other assessments may be performed at the discretion of the 
Investigator.
c
The IPD/EOT visit replaces the nearest regular visit: IPD visit procedures should be performed as soon as possible after the decision to discontinue IP has 
been made, and at the latest 4 weeks ±3 days after the last dose of IP.
d
Visit windows are calculated from Visit 2.
e
For patients that are HBsAg positive or anti-HBc positive at Visit 1, HBeAg, anti-HDV and HBV DNA testing will be performed.  For these subjects that 
are HBsAg positive or anti-HBc positive, ALT and HBV DNA will be drawn) to monitor for hepatitis B reactivation, see section 8.2.1.1 Other laboratory 
assessments
f
Only WBC w/ differential will be measured at the FU visit
g
A positive urine test (dipstick) result must be confirmed with a serum beta-HCG test.
h
All samples for PK and ADA/nAB must be taken prior to IP administration.
ADA  anti-drug antibody; AEs  adverse events; ALT  alanine aminotransferase; anti-HDV  hepatitis D antibody; CSP  Clinical Study Protocol; DNA  
deoxyribonucleic acid; EoE  eosinophilic esophagitis; FU  Follow Up; HBc  hepatitis B core; HBeAg  hepatitis B e-antigen; HBsAg  hepatitis B surface 
antigen; HBV  hepatitis B-virus; HCG human chorionic gonadotropin; IP investigational product; IPD  investigational product discontinuation (visit); nAb  
neutralizing antibody; OLE open-label extension; PK  pharmacokinetics; SAEs  serious adverse events; V  visit; WBC white blood cell; Wk week; WOCBP  
women of childbearing potential.

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Please note; 
For patients continuing in the study beyond visit 52 (week 200), continue the pattern that is outlined in Table 3, starting with visit 53 
(week 204) which instructs the investigator to apply assessments under Visit 29/41 (Week 108/156).
Table 4
Schedule of PRO assessments
Instruments
Schedule
Daily Diary (including DSQ, EoE-3D, 
and other symptom questions)
Every evening (between 17:00 on Day n and 4:59 on Day n+1). First administration at home on the day of Visit 1. 
Assessments stop after Visit 21 is confirmed. 
PEESS
Only for patients age 18 years and under at Visit 1. First administration at home on the day of Visit 1, then every 
28±3 days thereafter. Assessments stop after Visit 21 is confirmed.
EoE-QoL-A
First administration at home on the day of Visit 1, then every 7±3 days thereafter until Visit 2 is confirmed. Then, 
administration will occur every 7±3 days thereafter. Assessments stop after Visit 21 is confirmed.
PGI-S
First administration on the device at home on the day of Visit 1, then every 14±3 days thereafter until Visit 2 is 
confirmed. Then, administration will occur on the device every 14±3 days from Visit 2 until Visit 15 is confirmed. 
Thereafter administration will occur by interview and entered into the eCRF at Visit 21 and Visit 28 (or at IPD/EOT 
if before Visit 28).
PGI-C
First administration at home 7±3 days after Visit 2, then every 7±3 days thereafter. Assessments stop after Visit 15 is 
confirmed.
SF-36 v2, WPAI+CIQ
First administration at home on the day of Visit 2, then every 84±3 days thereafter. Assessments stop after Visit 15 is 
confirmed.
DSQ Dysphagia Symptom Questionnaire; EoE  eosinophilic esophagitis; EoE-3D  Eosinophilic Esophagitis - Daily Dysphagia Diary; EoE-QoL-A  Adult 
Eosinophilic Esophagitis Quality of Life Questionnaire; PEESS  Pediatric Eosinophilic Esophagitis Symptom Severity Module, Version 2.0, Children and 
Teens Report; PGI-C Patient Global Impression of Change; PGI-S Patient Global Impression of Severity; PRO  Patient Reported Outcome; SF36v2 Short 
Form-36 Version 2.0; WPAI+CIQ  Work Productivity and Activity Impairment questionnaire plus Classroom Impairment Questions

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1.2
Synopsis
International Co-ordinating Investigator:
Protocol Title: A Multicenter, Randomized, Double-blind, Parallel-group, Placebo controlled 
Study to Investigate the Use of Benralizumab for Eosinophilic Esophagitis (MESSINA)
Short Title: A Study of Benralizumab in Patients with Eosinophilic Esophagitis
Rationale:
Benralizumab is a humanized, afucosylated, monoclonal antibody (mAb) that binds 
specifically to the human interleukin-5 (IL-5) receptor alpha subunit (IL-5Rα) on the target 
cell and directly depletes eosinophils through antibody-dependent cell-mediated cytotoxicity 
(ADCC). The direct eosinophil-depleting ability of benralizumab has been shown to be 
effective in eosinophilic asthma, and preliminary results suggest that benralizumab is effective 
in treating hypereosinophilic syndrome (HES), which shares clinical and histologic features 
with eosinophilic esophagitis (EoE). The prominent accumulation and activation of 
pro-inflammatory eosinophils in the esophagus of EoE patients and their pathogenic role in 
pre-clinical modelling suggests that a direct eosinophil-depleting approach may prove 
beneficial in depleting eosinophils from gastrointestinal (GI) tissue(s), improve the symptoms 
of dysphagia, and improve endoscopy scores as well as other markers of disease activity.
The aim of this Phase 3 study is to investigate the use of benralizumab as a treatment for 
patients with EoE.  The effect of doses of benralizumab 30 mg every 4 weeks (Q4W) on EoE 
histologic signs and symptoms will be assessed over a 52-week treatment period (including a 
24-week DB placebo-controlled treatment period and a 28-week OL treatment period).  It is 
proposed that benralizumab will deplete eosinophils from GI tissue(s), improve the symptoms 
of dysphagia, and improve endoscopy scores as well as other markers of disease activity.

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Table 5
Study Objectives for the 52-week Study Period (DB+OL Treatment 
Periods)
The following objectives/endpoints are for the 52-week study period (DB+OL treatment periods):
Primary Objective:
Dual-primary Endpoints/Variables:
To evaluate the effect of benralizumab 30 mg Q4W 
on histologic signs and symptoms of EoE in patients 
with symptomatic and histologically active EoE
•
Proportion of patients with a histologic response 
at Week 24, defined as a peak esophageal 
intraepithelial eosinophil count ≤6 eos/hpf
•
Changes from baseline in DSQ score at Week 24
Secondary Objectives:
Endpoints/Variables:
To evaluate the effect of benralizumab 30 mg Q4W 
on clinical features of EoE and disease activity
•
Key secondary endpoint: Percent change from 
baseline in tissue eosinophils at Week 24 
•
Key secondary endpoint:  Change from baseline 
in EoE-HSS grade score at Week 24
•
Key secondary endpoint: Change from baseline 
in EoE-HSS stage score at Week 24
•
Key secondary endpoint: Changes from baseline 
in centrally-read EoE EREFS at Week 24
•
Key secondary endpoint Treatment responder 
rate at Week 24, defined as a composite of 
histological response (≤6 eos/hpf) and clinically 
meaningful improvement from baseline in DSQ 
(30% improvement)
•
Centrally-read biopsies for additional 
histopathology including tissue eosinophil 
counts at Week 24
•
Dysphagia-free days as captured by the DSQ  
•
Frequency of dysphagia episodes as captured by 
the EoE-3D 
•
Changes from baseline in dysphagia associated 
pain, discomfort, and overall severity as 
captured by the EoE-3D at Week 24
•
Changes from baseline in abdominal pain and 
nausea as captured by the daily diary at Week 24
•
Changes from baseline in PEESS at Week 24
To evaluate the effect of benralizumab 30 mg Q4W 
on patient reported QOL measures 
•
Changes from baseline in EoE-QoL-A at 
Week 24
•
SF-36 v2 Health Survey at Week 24
To evaluate the effect of benralizumab 30 mg Q4W
on healthcare resource utilization due to EoE
•
Percent of patients with relevant concomitant 
procedures and healthcare resource utilization 
during the study through Week 24
To evaluate the effect of benralizumab 30 mg Q4W 
on patient reported measures of disease severity and 
health status
•
PGI-S at Week 24
•
PGI-C at Week 24
To assess the PK and immunogenicity of 
benralizumab 30 mg Q4W in patients with EoE
•
Serum benralizumab concentration
•
ADA and nAb

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Table 5
Study Objectives for the 52-week Study Period (DB+OL Treatment 
Periods)
Other objectives
Endpoints/Variables:
To describe the longer-term effect of benralizumab 
30 mg Q4W in patients with EoE
•
Proportion of patients with a histologic response 
at Week 52, defined as a peak esophageal 
intraepithelial eosinophil count ≤ 6 eos/hpf
•
Changes from baseline in DSQ score at Week 52
•
Changes from baseline in centrally-read EoE 
EREFS at Week 52
•
Centrally-read biopsies for histopathology and 
tissue eosinophil counts at Week 52
•
Dysphagia-free days as captured by the DSQ  
•
Frequency of dysphagia episodes as captured by 
the EoE-3D 
•
Changes from baseline in dysphagia associated 
pain, discomfort, and overall severity as 
captured by the EoE-3D at Week 52
•
Changes from baseline in abdominal pain and 
nausea as captured by the daily diary at Week 52
•
Changes from baseline in PEESS at Week 52
•
Changes from baseline in EoE-QoL-A at 
Week 52
•
SF-36 v2 Health Survey at Week 52
•
Percent of patients with relevant concomitant 
procedures and healthcare resource utilization 
during the study through Week 52
•
PGI-S at Week 52
•
PGI-C at Week 52
Safety Objective:
Endpoints/Variables:
To assess the safety and tolerability of benralizumab 
30 mg Q4W in patients with EoE
Safety and tolerability will be evaluated in terms of 
AEs, Vital signs, and Clinical laboratory values
Assessments related to AEs cover
•
Occurrence/frequency
•
Relationship to IP as assessed by Investigator
•
Intensity
•
Seriousness
•
Death
•
AEs leading to discontinuation of IP
Vital signs parameters include systolic and diastolic 
blood pressure, and pulse, as well as respiration rate, 
body temperature, body weight, and height
Assessments related to vital signs cover
•
Observed value
•
Absolute and percent change from baseline 
values over time

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Table 5
Study Objectives for the 52-week Study Period (DB+OL Treatment 
Periods)
Exploratory Objectives:
Endpoints/Variables:
 
 
 
 
To evaluate the effect of benralizumab 30 mg Q4W 
on clinical features of EoE and disease activity 
•
Changes from baseline in EndoFLIP 
(esophageal distensibility) assessment at Week 
24 and at Week 52 (sub-study)
To evaluate the effect of benralizumab 30 mg Q4W on 
early histologic signs, clinical features, symptoms and  
 of EoE (sub-study)
•
Replicate histology, EREFS and PRO endpoints 
at weeks 4 and 12
•
 
 
 
 
To evaluate the effect of benralizumab 30 mg Q4W 
on the ability to work, attend classes, and perform 
regular daily activities
•
WPAI+CIQ scores 
ADA  anti-drug antibody; AEs  adverse events; DB Double-blind; DSQ Dysphagia Symptom Questionnaire; 
EndoFLIP Endolumenal Functional Lumen Imaging Probe; EoE  eosinophilic esophagitis; EoE-QoL-A  Adult 
Eosinophilic Esophagitis Quality of Life Questionnaire; eos Eosinophils; EoE-HSS Eosinophilic Esophagitis-
Histology Scoring System; EREFS Endoscopic Reference Score; hpf high power field; nAb  neutralizing 
antibody; OL Open-label; OLE  Open-label Extension; PEESS  Pediatric Eosinophilic Esophagitis Symptom 
Severity Module, Version 2.0, Children and Teens Report; PGI-C Patient Global Impression of Change; PGI-
S Patient Global Impression of Severity; PK  pharmacokinetics; PRO  Patient Reported Outcome; Q4W every 
4 weeks; QoL Quality of Life; SF-36v2 Short Form-36 Version 2.0.; WPAI+CIQ  Work Productivity and 
Activity Impairment questionnaire plus Classroom Impairment Questions.

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Table 6
Study Objectives for the OLE Period
The following objectives/endpoints are for the OLE period of the study:
Safety Objective:
Endpoints/Variables:
To assess the safety and tolerability of benralizumab 
30 mg Q4W in patients with EoE
Safety and tolerability will be evaluated in terms of 
AEs, Vital signs, Clinical laboratory values
Assessments related to AEs cover
•
Occurrence/frequency
•
Relationship to IP as assessed by Investigator
•
Intensity
•
Seriousness
•
Death
•
AEs leading to discontinuation of IP
Vital signs parameters include systolic and diastolic 
blood pressure, and pulse, as well as respiration rate, 
body temperature, body weight, and height
Assessments related to vital signs cover
•
Observed value
•
Absolute and percent change from baseline 
values over time
Other Objectives:
Endpoints/Variables:
To describe the longer-term effect of benralizumab 
30 mg Q4W in patients with EoE
•
Changes from baseline in DSQ; frequency of 
dysphagia episodes (EoE-3D), dysphagia-free 
days (DSQ), and associated pain, discomfort, 
overall severity; abdominal pain and nausea 
(daily diary); EoE-QoL-A up to Week 76
•
Changes from baseline in PEESS up to Week 76
•
Percent of patients with relevant concomitant 
procedures and healthcare resource utilization 
during the study
•
Centrally-read biopsies for histopathology and 
tissue eosinophil counts at Week 104
•
Changes from baseline in centrally-read EoE 
EREFS at Week 104
•
PGI-S at Week 104
To describe the effect of benralizumab on the use of 
background EoE medications and related therapies 
and diet restrictions
•
Changes in concomitant medications and diet 
regimens
•
Changes in patient experience as reported by 
PROs
To describe the PK and immunogenicity of 
benralizumab 30 mg Q4W in patients with EoE
•
Serum benralizumab concentration
•
ADA and nAb

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Table 6
Study Objectives for the OLE Period
Exploratory Objectives:
Endpoints/Variables:
 
 
 
To evaluate the effect of benralizumab 30 mg Q4W 
on clinical features of EoE and disease activity
•
Changes from baseline in EndoFLIP 
(esophageal distensibility) assessment at Week 
at Week 104 (sub-study)
 
 
ADA  anti-drug antibody; AEs  adverse events; DSQ Dysphagia Symptom Questionnaire; 
EndoFLIP Endolumenal Functional Lumen Imaging Probe; EoE  eosinophilic esophagitis; EoE-QoL-A  Adult 
Eosinophilic Esophagitis Quality of Life Questionnaire; EREFS  Endoscopic Reference Score; nAb  
neutralizing antibody; OLE  Open-label Extension; PEESS  Pediatric Eosinophilic Esophagitis Symptom 
Severity Module, Version 2.0, Children and Teens Report; PGI-S Patient Global Impression of Severity;  PK  
pharmacokinetics; Q4W every 4 weeks; PRO  Patient Reported Outcome
Overall design:
This is a randomized, placebo-controlled, DB, parallel-group, multicenter, Phase 3 study to 
compare the efficacy and safety of repeat dosing of benralizumab versus placebo in male and 
female patients 12 to 65 years of age with symptomatic and histologically active EoE.
The clinical study consists of 4 periods:

a 2- to 8-week run-in period

a 24-week placebo-controlled, DB, parallel-group treatment period (DB period)

a 28-week OL benralizumab treatment period (OL period)

an additional OLE treatment period (OLE period)
Following informed consent (or assent, if applicable), all patients will enter a run-in period of 
2 to 8 weeks during which inclusion/exclusion criteria are assessed, medical history taken, 
endoscopy with biopsies performed, and patient reported outcomes (PROs), clinical 
laboratories, and diet questionnaires administered.  Patients may be on background medication 
for EoE and related treatments during the study as long as the background medications have 
been stable for at least 4 weeks (8 weeks for PPI) prior to screening, and there is an agreement 
not to change type of background medication or dosage during the run-in period and for the 
first 52 weeks of the study unless a change is medically indicated. If a medication for EoE 
(including swallowed steroids, systemic steroids and PPI) is discontinued prior to screening, 
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changes to the background medication for EoE and related treatments should be documented 
in the eCRF.  Additionally, patients should remain on a stabilized diet for treatment of their 
EoE for at least 6 weeks prior to the run-in period throughout the run-in period and the first 52 
weeks of the study unless medically indicated.  Diet will be tracked and assessed by the diet 
questionnaire.
Eligible patients with symptomatic and histologically active EoE before randomization will be 
randomized in a 1:1 ratio to receive either 30 mg of benralizumab or placebo at 4-week 
intervals for a 24-week treatment period (DB period).  The randomization for adults will be 
stratified by region (North America vs Rest of World [ROW]) and use of swallowed steroids 
at baseline (categorical, Yes/No). Adolescents will be randomized in a separate stratum with 
no other factors included.
Patients who complete the DB, placebo-controlled treatment period on investigational product 
(IP) will continue into an OL treatment period with benralizumab 30 mg Q4W until Week 52 
(OL period).
All patients who complete the 52-week treatment period (the 24-week DB treatment period 
and the 28-week OL treatment period; DB+OL treatment periods) on IP will be offered the 
opportunity to continue into an OLE period on benralizumab 30 mg Q4W (OLE).  The OLE 
period is intended to allow each patient at least 1 year of treatment with OL benralizumab 
after completion of the 52-week DB+OL treatment periods. The Sponsor may choose to 
extend the OLE period beyond one year and reserves the right of terminating the OLE early 
(eg, if development in this indication is terminated or marketing authorisation is obtained).  
Patients who do not enroll in the OLE period will have a follow-up visit 12 weeks after their 
last dose of IP.  
The primary database lock is targeted to occur when the required number of patients have 
been randomised for the primary analysis (170 patients including approximately 130 adults 
and 40 adolescents) and they have completed the 24-week DB treatment period, including 
those who have had the opportunity to complete at least 52 weeks of follow-up (the 24-week 
DB treatment period and the 28-week OL treatment period; DB+OL treatment periods).  The 
primary analysis will evaluate the effect of benralizumab on histologic signs and symptoms of 
EoE at Week 24 in patients with symptomatic and histologically active EoE.  An additional 
analysis may be performed after the last patient completes 52 weeks of follow up.  The final 
analysis will occur after the last patient completes the OLE period.
Study Period:
First patient enrolled:
Estimated date of last patient completed: 

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Number of Patients:
Approximately 170 eligible patients are planned to be randomized.  Recruitment of adolescent 
patients is targeted to be broadly in line with expected prevalence rates of adolescents in the 
overall patient population.  Approximately 20 adolescent patients (12 to 17 years of age) per 
arm are targeted for inclusion in the study.  
Treatments and treatment duration:
Following the run-in period, patients confirmed to be eligible will be randomized in a 1:1 ratio 
to receive 30 mg of benralizumab or placebo at 4-week intervals for a 24-week treatment 
period (DB period).  Patients who complete the DB, placebo-controlled treatment period on IP 
will continue into an OL treatment period with benralizumab 30 mg Q4W until Week 52 (OL 
period).  All patients who complete the 52-week treatment period (the 24-week DB treatment 
period and the 28-week OL treatment period; DB+OL treatment periods) on IP will be offered 
the opportunity to continue into an OLE period on benralizumab 30 mg Q4W (OLE period).  
The OLE period is intended to allow each patient at least 1 year of treatment with OL 
benralizumab after completion of the 52-week DB+OL treatment periods.
The IP will be administered subcutaneously (SC) as a single injection via an accessorized 
prefilled syringe (APFS). All doses of IP during the 52-week treatment period will be 
administered at the study site by the investigator/authorised delegate. After week 52, IP will 
be administered as scheduled in the SoA, either at the site during the visit by a healthcare 
professional or at home/remotely by the patient or caregiver, see section 6.1.4. No dose 
changes are allowed.  If a patient presents with a condition that contraindicates dosing, 
administration of IP will be withheld and resumed as soon as the condition resolves.  If a 
patient misses 2 or more doses (consecutively or non-consecutively) of IP within a 1-year 
period, a conversation between the Investigator and the AstraZeneca study physician should 
take place to review the patient's adherence to treatment and decide on the patient's further 
disposition (see Section 7.1 for details).  All patients, regardless of whether they remain on IP 
treatment or not, will be encouraged to remain in the study and be followed to study 
completion (see Section 7.1).
Data Monitoring Committee:
An independent data monitoring committee (IDMC) will be utilized for this study.  
Section A 5 provides more details on the rationale for and the remit of the committee.
Statistical methods
Approximately 170 patients will be randomized in a 1:1 ratio to benralizumab or matching 
placebo.  This will provide >95% power for the first primary endpoint of proportion of 
patients achieving histological response to demonstrate an increase from 20% or less on 
placebo to 50% on benralizumab at the 2-sided 5% significance level.  The power calculation 

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for the second primary endpoint of the change from baseline in Dysphagia Symptom 
Questionnaire (DSQ) score at Week 24 is based on detecting similar effect sizes (mean 
difference in change from baseline of the PRO / standard deviation) as seen in previous 
studies.  Assuming an effect size of 0.6, which equates to a 7.2-point difference in change in 
the DSQ, 85 patients per arm will allow >95% power for statistical significance at the 5% 
2-sided level.  The high level of power for the primary endpoints will ensure stronger 
statistical evidence can be demonstrated in this single Phase 3 study.  
Efficacy analyses will be performed using the full analysis set (FAS), which will include all 
patients randomized who receive at least 1 dose of IP. The treatment arms will be compared 
on the basis of randomized treatment, regardless of treatment actually received.
The primary efficacy analyses will be based on the DB placebo-controlled first 24 weeks of 
the study (DB period).  A composite estimand strategy will be used for the primary analyses, 
whereby any patients with intercurrent events of randomized therapy discontinuation, an 
increase of background therapy or addition of a new therapy to treat their EoE, or having
dilation procedures prior to week 24 will be considered as treatment failures at week 24. For 
the first dual primary endpoint of proportion of patients achieving a histological response at 
Week 24, defined as a peak esophageal intraepithelial eosinophil count ≤6 eos/hpf on 
centrally-read esophagogastroduodenoscopy (EGD) biopsies, any patient experiencing these 
intercurrent events will be considered non-responders at week 24. The endpoint will be 
compared between benralizumab and placebo using a Cochran-Maentel-Haenszel (CMH) test 
stratified by region, use of swallowed steroids at baseline (categorical, Yes/No), and presence 
of strictures at baseline.  For the second dual-primary endpoint of change from baseline in 
DSQ score at Week 24, any patient experiencing the described intercurrent events will have 
their week 24 value imputed using a return to baseline multiple imputation method.  The 
change at week 24 will then be analysed for each imputation dataset by analysis of covariance 
(ANCOVA) including covariates for treatment, region, use of swallowed steroids at baseline 
(categorical, Yes/No), and presence of strictures at baseline. Results will be combined across 
the datasets using Rubin's rule (Rubin et al 1986, Rubin et al 1987). Hypothesis testing for the 
primary analyses will be performed at the 2-sided 5% significance level.  
Descriptive summary statistics and graphical data displays will be used for Week 52 efficacy 
data and all analyses of data in the OLE period; no formal statistical analyses will be 
performed.

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1.3
Schema
The general study design is summarized in Figure 1. 
Figure 1
Study design
Q4W every 4 weeks; V Visit; EoT  End of Treatment; FU  Follow up, *Only for patients in the the Early Time 
Point Sub-study (see Section 8.1.5)

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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 directly depletes eosinophils through ADCC.  The mechanism of 
action of benralizumab makes it a potential treatment option for the high unmet need in 
patients with symptomatic and histologically active EoE.
Benralizumab has been or is being investigated in patients with asthma, chronic obstructive 
pulmonary disease (COPD), HES, nasal polyposis, eosinophilic granulomatosis with 
polyangiitis (EGPA), eosinophilic chronic rhinosinusitis, and eosinophilic 
gastritis/gastroenteritis.  The present study (D3255C00001 [MESSINA]) represents the first 
clinical study dedicated to the assessment of benralizumab in patients with EoE.
2.1
Study rationale
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 

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2.2
Background
Eosinophilic esophagitis is a chronic allergic inflammatory disorder of the esophagus, defined 
histologically by esophageal inflammation of ≥15 eosinophils per high power field (eos/hpf) 
as obtained from 2 to 4 biopsies from either the proximal, mid, and/or distal esophagus and 
exclusion of secondary causes of esophageal eosinophilia.  In addition, a response to treatment 
(selective dietary elimination; swallowed topical corticosteroids; proton pump inhibitor [PPI] 
therapy) supports, but is not required for, diagnosis (Dellon et al 2013).  Typical symptoms 
include dysphagia and food impaction in adolescents and adults (Dellon et al 2017).
There is a clinical unmet need for new therapies for use in patients with EoE.  There are no 
products indicated for the treatment of the disease in the US.  Jorveza® (orodispersible 
budesonide tablet) was approved in the EU for the treatment of EoE in adults in 2018, and 
there are no approved products for the treatment of EoE in the paediatric population.  
Additionally, most current treatment approaches are either burdened with compliance 
problems, and/or limited efficacy, or reserved for the treatment of complications.
Current treatment approaches include swallowed topical corticosteroids (asthma preparations 
that are swallowed rather than inhaled so that the medication coats the lining of the esophagus 
[fluticasone or budesonide]), though these are suboptimal for use in EoE (Dellon et al 2013a, 
Dellon et al 2014).  There is evidence that PPIs can also be used to treat EoE when response is 
measured by histological improvement; however, clinical responses have been less frequently 

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studied and it is difficult to draw conclusions about symptom benefit.  In addition, only a 
portion of patients with EoE are PPI responders (Dellon et al 2018).  Dietary elimination of all 
food allergens can be effective, but the evidence for this is shorter term and can present 
challenges with longer term compliance and effectiveness over time.  In addition, esophageal 
dilation, approached conservatively, may be used as an effective therapy in symptomatic 
patients with strictures that persist despite medical or dietary therapy.  Because EoE is chronic 
and symptoms recur when treatments are discontinued, maintenance therapy should be 
considered in all patients (Dellon et al 2013).  The limitations of currently available 
therapeutic approaches have led to the search for alternate potential therapies.
Because eosinophilic inflammation is a central finding in EoE, safe and effective therapies 
that target eosinophils will likely be beneficial for treatment of EoE.  The mechanism of 
action of benralizumab suggests it may potentially be effective in EoE and eosinophilic-driven 
gastrointestinal diseases.  In the aforementioned clinical study in patients with platelet-derived 
growth factor receptor alpha (PDGFRA) negative- HES by Kuang et al (described in 
Section 2.1), a subset of patients with symptoms of dysphagia or a diagnosis of EoE was 
identified (n=5).  Four of the patients in Kuang et al had elevated eosinophil counts in the 
proximal, mid, and/or distal esophagus at baseline.  The remaining patient did not have a 
formal diagnosis of EoE but had a history of dysphagia.
Following 24 weeks of treatment with benralizumab 30 mg Q4W, near complete depletion of 
eosinophils in the proximal/mid esophagus and the distal esophagus were observed for all 
4 patients with elevated esophageal eosinophil concentrations at baseline.  Among all 
5 patients with EoE or dysphagia symptoms, eosinophils were also depleted in all other GI 
tissues at Week 24.  Improvement in GI symptoms was observed in all 5 patients.
A core set of outcome measures for clinical trials in EoE has been developed through a 
multidisciplinary collaboration (The COREOS Collaborators 2022). Comprehensive literature 
reviews, patient surveys and experienced clinicians in this field contributed to build a 
framework of outcome domains. Several of the recommendations are relevant to the 
MESSINA study, including the concept of histologic remission. There was consensus that the 
proportion of patients with <15 eos/hpf in all esophageal locations should be considered for 
histologic remission, while there was no consensus on using a more stringent threshold of ≤6 
eos/hpf. The MESSINA study will apply this more stringent FDA EoE Guidance cut-off of ≤ 
6 eos/hpf (FDA 2020). Use of the EoEHSS was encouraged, specifically with both the grade 
and stage of each component item reported, with EoEHSS remission score of ≤ 3 for grade 
AND ≤ 3 for stage. Recommendations for endoscopic EREFS outcome was also provided and 
defined as an EREFS score ≤ 2. Endoscopic inflammatory EREFS-based remission should be 
defined as the inflammation-associated components (exudate, edema, furrows) score ≤ 2, 
while endoscopic fibrotic EREFS-based remission should be defined as absence of strictures, 
moderate and severe rings. Applying this outcome terminology will support the analyses of 

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data in the context of an evolving understanding of the disease.
A detailed description of the chemistry, pharmacology, efficacy, and safety of benralizumab is 
provided in the Investigator’s Brochure.
2.3
Benefit/risk assessment
In order to evaluate the clinical benefit/risk balance for benralizumab, preclinical and clinical 
data have been taken into consideration.  The key goals of treatment in EoE are to decrease 
the signs and symptoms of EoE, ideally with histologic improvement in esophageal 
eosinophilia, and improve patient quality of life.  By depleting eosinophils, one of the 
presumed key effector cells in the pathogenesis of EoE, benralizumab is likely to improve 
outcomes in patients with EoE.  Expected benefits of benralizumab over placebo include 
clinically significant improvements in symptoms of dysphagia, histologic response, and 
endoscopy scores, as well as other markers of disease activity.
Benralizumab has been well tolerated with the most frequently observed adverse events (AEs) 
from the asthma and COPD Phase 3 controlled studies being generally reflective of each 
study’s respective patient population.  Potential risks of benralizumab are as follows:

Serious infections have been reported for benralizumab.  A relationship between 
eosinophil depletion and serious infection has not been established.

Malignancies have been reported at a low incidence in the completed and ongoing studies 
of benralizumab.  Eosinophils have been found in association with 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 (i.e. pro-tumorigenic versus anti-tumorigenic) of eosinophil 
recruitment and accumulation into tumors are unclear (Jacobsen et al 2012).

Serious hypersensitivity reactions (including anaphylaxis) are an identified risk of 
biologic therapy, including benralizumab.  Anaphylaxis may be life-threatening.  Risk 
minimization includes observation of the patient at the study site following IP 
administration for the appearance of any acute drug reactions in line with clinical 
practice. For patients who select to do the optional/remote location IP administration 
during the OLE, the first dose of IP during the OLE should be given on-site. In the 
instructions for remote/at-home administration of IP, the patient will be informed about 
what symptoms to watch for and to seek medical care in the event of such symptoms. 
When IP is administered at the patient’s home/remotely, it is strongly recommended that 
the patient is contacted by the Investigator or qualified designee after the dose is 
administered in line with clinical practice (see Section 6.1.4 for details).

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
Development of anti-drug antibodies (ADA) to benralizumab has been documented.  
Theoretical risks of developing ADA may include decreased effective drug 
concentrations and hypersensitivity reactions (e.g. anaphylaxis or immune complex 
disease).  There was no impact of ADA on overall benralizumab safety or efficacy in the 
previous Phase 3 studies in asthma.

Eosinophils are a prominent feature of the inflammatory response to helminthic parasitic 
infections, and the presence of infiltrating eosinophils has been circumstantially
associated with a positive prognosis in certain solid tumors.  Therefore, there is a 
theoretical risk that prolonged eosinophil depletion may diminish the ability to defend 
against helminthic parasites or negatively impact the natural history of certain malignant 
tumors.  Risk minimization measures include exclusion of patients with untreated 
parasitic infection and active or recent malignancy, in conjunction with the performance 
of routine pharmacovigilance activities.
Risk of study participation may also include those associated with protocol-mandated study 
procedures and essential components of the diagnosis and follow-up assessments for patients 
with EoE.  This study of EoE involves baseline and follow-up endoscopies with biopsies.  
Potential AEs associated with this procedure include bleeding complications, infection, and 
tears of the GI tract.  Patients will be informed of the risks associated with endoscopy and 
EGD before entering the study.
The benefit/risk assessment for benralizumab in patients with EoE based on previous clinical 
experience in other indications appears favorable.  Risk minimization measures include the 
exclusion of patients with allergy or reaction to any component of the IP formulation, 
untreated helminth parasitic infection, and active or recent malignancy, in conjunction with 
the performance of routine pharmacovigilance activities.  An IDMC will be used for this study 
who will have the responsibility of evaluating cumulative safety and other clinical trial data at 
regular intervals and making appropriate recommendations based on the available data. See 
Section 9.6 and Appendix A 5 for information regarding the IDMC.
More detailed information about the known and expected benefits and risks and safety profile 
of benralizumab may be found in the Investigator’s Brochure.
3
OBJECTIVES AND ENDPOINTS
The objectives and endpoints for the 52-week study period (DB+OL treatment periods) are 
presented in Table 7; the objectives and endpoints for the OLE period of the study are 
provided in Table 8.

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Table 7
Study Objectives for the 52-week Study Period (DB+OL Treatment 
Periods)
The following objectives/endpoints are for the 52-week study period (DB+OL treatment periods):
Primary Objective:
Dual-primary Endpoints/Variables:
To evaluate the effect of benralizumab 30 mg Q4W 
on histologic signs and symptoms of EoE in patients 
with symptomatic and histologically active EoE

Proportion of patients with a histologic response 
at Week 24, defined as a peak esophageal 
intraepithelial eosinophil count ≤6 eos/hpf

Changes from baseline in DSQ score at Week 24
Secondary Objectives:
Endpoints/Variables:
To evaluate the effect of benralizumab 30 mg Q4W 
on clinical features of EoE and disease activity

Key secondary endpoint: Percent change from 
baseline in tissue eosinophils at Week 24 

Key secondary endpoint:  Change from baseline 
in EoE-HSS grade score at Week 24

Key secondary endpoint: Change from baseline 
in EoE-HSS stage score at Week 24

Key secondary endpoint: Changes from baseline 
in centrally-read EoE EREFS at Week 24

Key secondary endpoint Treatment responder 
rate at Week 24, defined as a composite of 
histological response (≤6 eos/hpf) and clinically 
meaningful improvement from baseline in DSQ 
(30% improvement)

Centrally-read biopsies for additional 
histopathology including tissue eosinophil counts 
at Week 24

Dysphagia-free days as captured by the DSQ  

Frequency of dysphagia episodes as captured by 
the EoE-3D 

Changes from baseline in dysphagia associated 
pain, discomfort, and overall severity as captured 
by the EoE-3D at Week 24

Changes from baseline in abdominal pain and 
nausea as captured by the daily diary at Week 24

Changes from baseline in PEESS at Week 24
To evaluate the effect of benralizumab 30 mg Q4W 
on patient reported QOL measures 

Changes from baseline in EoE-QoL-A at Week 
24

SF-36 v2 Health Survey at Week 24
To evaluate the effect of benralizumab 30 mg Q4W
on healthcare resource utilization due to EoE

Percent of patients with relevant concomitant 
procedures and healthcare resource utilization 
during the study through Week 24

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Table 7
Study Objectives for the 52-week Study Period (DB+OL Treatment 
Periods)
Secondary Objectives:
Endpoints/Variables:
To evaluate the effect of benralizumab 30 mg Q4W 
on patient reported measures of disease severity and 
health status

PGI-S at Week 24

PGI-C at Week 24
To assess the PK and immunogenicity of 
benralizumab 30 mg Q4W in patients with EoE

Serum benralizumab concentration
ADA and nAb
Other objectives:
Endpoints/Variables:
To describe the longer-term effect of benralizumab 
30 mg Q4W in patients with EoE 
•
Proportion of patients with a histologic response 
at Week 52, defined as a peak esophageal 
intraepithelial eosinophil count ≤ 6 eos/hpf
•
Changes from baseline in DSQ score at Week 52
•
Changes from baseline in centrally-read EoE 
EREFS at Week 52
•
Centrally-read biopsies for histopathology and 
tissue eosinophil counts at Week 52
•
Dysphagia-free days as captured by the DSQ  
•
Frequency of dysphagia episodes as captured by 
the EoE-3D 
•
Changes from baseline in dysphagia associated 
pain, discomfort, and overall severity as 
captured by the EoE-3D at Week 52
•
Changes from baseline in abdominal pain and 
nausea as captured by the daily diary at Week 52
•
Changes from baseline in PEESS at Week 52
•
Changes from baseline in EoE-QoL-A at 
Week 52
•
SF-36 v2 Health Survey at Week 52
•
Percent of patients with relevant concomitant 
procedures and healthcare resource utilization 
during the study through Week 52
•
PGI-S at Week 52
•
PGI-C at Week 52

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Table 7
Study Objectives for the 52-week Study Period (DB+OL Treatment 
Periods)
Safety Objective:
Endpoints/Variables:
To assess the safety and tolerability of benralizumab 
30 mg Q4W in patients with EoE
Safety and tolerability will be evaluated in terms of 
AEs, Vital signs, and Clinical laboratory values
Assessments related to AEs cover
•
Occurrence/frequency
•
Relationship to IP as assessed by Investigator
•
Intensity
•
Seriousness
•
Death
•
AEs leading to discontinuation of IP
Vital signs parameters include systolic and diastolic 
blood pressure, and pulse, as well as respiration rate, 
body temperature, body weight, and height
Assessments related to vital signs cover
•
Observed value
•
Absolute and percent change from baseline 
values over time
Exploratory Objectives:
Endpoints/Variables:
 
 
 
To evaluate the effect of benralizumab 30 mg Q4W 
on clinical features of EoE and disease activity 
(sub-study)
•
Changes from baseline in EndoFLIP 
(esophageal distensibility) assessment at Week 
24 and at Week 52 (sub-study)
To evaluate the effect of benralizumab 30 mg Q4W 
on early histologic signs, clinical features, symptoms 
and 
 of EoE (sub-study)
•
Replicate histology, EREFS and PRO endpoints 
at weeks 4 and 12
•
 
 
 
 
 
 
To evaluate the effect of benralizumab 30 mg Q4W 
on the ability to work, attend classes, and perform 
regular daily activities
•
WPAI+CIQ scores
ADA  anti-drug antibody; AEs  adverse events; DB Double-blind; DSQ Dysphagia Symptom Questionnaire; 
EndoFLIP Endolumenal Functional Lumen Imaging Probe; EoE  eosinophilic esophagitis; 
EoE-HSS Eosinophilic Esophagitis- Histology Scoring system; EoE-QoL-A  Adult Eosinophilic Esophagitis 
Quality of Life Questionnaire; eos eosinophils; EREFS  Endoscopic Reference Score; hpf high-power field; 
IP investigational product;  nAb  neutralizing antibody;  OL  Open-label; PEESS  Pediatric Eosinophilic 
Esophagitis Symptom Severity Module, Version 2.0, Children and Teens Report;  PGI-C Patient Global 
Impression of Change; PGI-S Patient Global Impression of Severity; PK  pharmacokinetics; Q4W every 

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4 weeks; QOL Quality of Life; SF-36v2 Short Form-36 Version 2.0; WPAI+CIQ  Work Productivity and 
Activity Impairment questionnaire plus Classroom Impairment Questions.
Table 8
Study Objectives for the OLE Period
The following objectives/endpoints are for the OLE period of the study:
Safety Objective:
Endpoints/Variables:
1
To assess the safety and tolerability of 
benralizumab 30 mg Q4W in patients with EoE
Safety and tolerability will be evaluated in terms of 
AEs, Vital signs, Clinical laboratory values
Assessments related to AEs cover
•
Occurrence/frequency
•
Relationship to IP as assessed by Investigator
•
Intensity
•
Seriousness
•
Death
•
AEs leading to discontinuation of IP
Vital signs parameters include systolic and diastolic 
blood pressure, and pulse, as well as respiration rate, 
body temperature, body weight, and height
Assessments related to vital signs cover
•
Observed value
•
Absolute and percent change from baseline 
values over time
Other Objectives:
Endpoints/Variables:
To describe the longer-term effect of benralizumab 
30 mg Q4W in patients with EoE
•
Changes from baseline in DSQ; frequency of 
dysphagia episodes (EoE-3D), dysphagia-free 
days (DSQ), and associated pain, discomfort, 
overall severity; abdominal pain and nausea 
(daily diary); EoE-QoL-A up to Week 76
•
Changes from baseline in PEESS up to Week 76
•
Percent of patients with relevant concomitant 
procedures and healthcare resource utilization 
during the study
•
Centrally-read biopsies for histopathology and 
tissue eosinophil counts at Week 104
•
Changes from baseline in centrally-read EoE 
EREFS at Week 104
•
PGI-S at Week 104
To describe the effect of benralizumab on the use of 
background EoE medications and related therapies 
and diet restrictions
•
Changes in concomitant medications and diet 
regimens
•
Changes in patient experience as reported by 
PRO
To describe the PK and immunogenicity of 
benralizumab 30 mg Q4W in patients with EoE
•
Serum benralizumab concentration
•
ADA and nAb

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Table 8
Study Objectives for the OLE Period
Exploratory Objectives:
Endpoints/Variables:
 
 
To evaluate the effect of benralizumab 30 mg Q4W 
on clinical features of EoE and disease activity
•
Changes from baseline in EndoFLIP 
(esophageal distensibility) assessment at Week 
at Week 104 (sub-study)
 
 
ADA  anti-drug antibody; AEs  adverse events; DSQ Dysphagia Symptom Questionnaire; 
EndoFLIP Endolumenal Functional Lumen Imaging Probe;  EoE  eosinophilic esophagitis; EoE-QoL-A  Adult 
Eosinophilic Esophagitis Quality of Life Questionnaire; EREFS  Endoscopic Reference Score; nAb  neutralizing 
antibody; OLE  Open-label Extension; PEESS  Pediatric Eosinophilic Esophagitis Symptom Severity Module, 
Version 2.0, Children and Teens Report; PGI-S Patient Global Impression of Severity; PK  pharmacokinetics; 
Q4W every 4 weeks; PRO  patient reported outcome.
4
STUDY DESIGN
4.1
Overall design
This is a randomized, placebo-controlled, DB, parallel-group, multicenter, Phase 3 study to 
compare the efficacy and safety of repeat dosing of benralizumab versus placebo in male and 
female patients 12 to 65 years of age with symptomatic and histologically active EoE.
The clinical study consists of 4 periods:

a 2- to 8-week run-in period

a 24-week placebo-controlled, DB, parallel group treatment period (DB period)

a 28-week OL benralizumab treatment period (OL period)

an additional OLE treatment period (OLE period)
Approximately 170 eligible patients are planned to be randomized.  Recruitment of adolescent 
patients is targeted to be broadly in line with expected prevalence rates of adolescents in the 
overall patient population.  Approximately 20 adolescent patients (12 to 17 years of age) per 
arm will be targeted for inclusion in the study.  
Following informed consent or assent (if applicable), all patients will enter a run-in period of 
2 to 8 weeks during which inclusion/exclusion criteria are assessed, medical history taken, 
endoscopy with biopsies performed, and PROs, clinical laboratories, and a diet questionnaire 
are administered.  Patients may be on background medications for EoE and related treatments 

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as long as the background medications have been stable for at least 4 weeks (8 weeks for PPI) 
prior to screening and there is an agreement not to change type of background medication or 
dosage during the run-in period and for the first 52 weeks of the study unless a change is 
medically indicated. If a medication for EoE (including swallowed steroids, systemic steroids 
and PPI) is discontinued  prior to screening, there should be a washout period of a least 8 
weeks. The justification and rationale for changes to the background medication for EoE and 
related treatments should be documented in the eCRF.  Additionally, patients should remain 
on a stabilized diet for treatment of their EoE for at least 6 weeks prior to the run-in period 
throughout the run-in period and the first 52 weeks of the study unless a change is medically 
indicated.  Diet will be tracked and assessed by the diet questionnaire. 
Eligible patients with symptomatic and histologically active EoE before randomization will be 
randomized in a 1:1 ratio to receive either 30 mg of benralizumab or placebo at 4-week 
intervals for a 24-week treatment period (DB period).  The randomization for adults will be 
stratified by region (North America vs ROW) and use of swallowed steroids at baseline 
(categorical, Yes/No).  Adolescents will be randomized in a separate stratum with no other 
factors included.
Adult patients at participating sites will also be offered the opportunity to participate in an 
Early Time Point Sub-study (section 8.1.5).  Approximately 20 patients are targeted to 
participate in this sub-study aiming to generate early time point evidence and demonstrate the 
impact of eosinophil depletion in tissue and to understand its relationship with endoscopic 
findings and symptom response.
Patients who complete the DB, placebo-controlled treatment period on investigational product 
(IP) will continue into an OL treatment period with benralizumab 30 mg Q4W until Week 52 
(OL period).
Patients who prematurely discontinue from IP during the first 52 weeks of the study for any 
reason should return to the study site for the investigational product discontinuation (IPD) 
visit.  It is recommended that the IPD visit is performed within 4 weeks (±3 days) after the last
dose of IP, and the Follow-up (FU) visit 12 weeks (±7 days) after the last dose of IP.  Patients 
are encouraged to return for all scheduled site visits, but without IP administration, following 
the IPD visit, and to continue with data collection according to the study protocol.
All patients who complete the 52-week treatment period (the 24-week DB treatment period 
and the 28-week OL treatment period; DB+OL treatment periods) on IP will be offered the 
opportunity to continue into an OLE period on benralizumab 30 mg Q4W (OLE).  The OLE 
period is intended to allow each patient at least 1 year of treatment with OL benralizumab 
after completion of the 52-week DB+OL treatment periods. The Sponsor may choose to 
extend the OLE period  beyond one year and reserves the right of terminating the OLE early 
(eg, if development in this indication is terminated or marketing authorisation is obtained). For 

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patients who enter the OLE period, background medications and diet for treatment of EoE 
may be adjusted. Patients who do not enroll in the OLE period will have a follow-up visit 12 
weeks after their last dose of IP.  
All patients recruited up to and including the date when the required number of patients have 
been achieved for the primary analysis (minimum of 170 patients including approximately 40 
adolescents and 130 adults) will contribute to the primary analysis. If at this time sufficient 
patients have not been recruited to the Early Time Point Sub-study, recruitment may be 
extended for sub-study patients only. Sub-study patients recruited after recruitment to the 
primary analysis population is completed will not be included in the primary efficacy 
analyses, and will be reported in a later analysis. The primary database lock is targeted to 
occur when all patients randomised for the primary analysis have completed the 24-week DB 
treatment period, including those who have had the opportunity to complete at least 52 weeks 
of follow-up (the 24-week DB treatment period and the 28-week OL treatment period; 
DB+OL treatment periods) Additional analyses may be performed after the last patient 
completes 52 weeks of follow up and/or when sufficient patient numbers and follow up in the 
Early Time Point Sub-study are achieved, if this was not available in the primary analysis.
The final database lock will occur after the last patient completes the OLE period and FU 
visit.  Data reported at this analysis will be presented in an addendum to the primary analysis 
Clinical Study Report (CSR).
For an overview of the study design see Figure 1
Study design, Section 1.3.  For details on 
treatments given during the study, see Section 6.1 Treatments Administered.
For details on what is included in the efficacy and safety endpoints, see Section 3, Objectives 
and Endpoints.
4.1.1
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this CSP and should 
be implemented only during cases of civil crisis, natural disaster, or public health crisis (e.g., 
during quarantines and resulting site closures, regional travel restrictions, and considerations if 
site personnel or study patients become infected with SARS-CoV-2 or similar pandemic 
infection) which would prevent the conduct of study-related activities at study sites, thereby 
compromising the study site staff or the patient’s ability to conduct the study. The investigator 
or designee should contact the study Sponsor to discuss whether the mitigation plans below 
should be implemented.  
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study patients, maintain 
compliance with Good Clinical Practice, and minimize risks to study integrity. 

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Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(e.g., hospital policies) or local government, these changes may include the following options:

Obtaining consent/reconsent /assent/reassent for the mitigation procedures (note, in the 
case of verbal consent/reconsent/assent/reassent , the Informed Consent Form (ICF)  or  
Assent Form( if applicable) should be signed at the patient’s next contact with the study 
site).

Rescreening: Additional rescreening for screen failure and to confirm eligibility to 
participate in the clinical study can be performed in previously screened patients. The 
investigator should confirm this with the designated study physician. 

Home or Remote visit: Performed by a site qualified Health Care Professional (HCP) or 
HCP provided by a third-party vendor (TPV).

Telemedicine visit: Remote contact with the patients using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices.

At-home Investigational Product (IP) administration: Performed by a site qualified HCP, 
HCP provided by a TPV, or by the patients or the patient’s caregiver, if possible. 
Additional information related to the visit can be obtained via telemedicine. 
For further details on study conduct during civil crisis, natural disaster, or public health crisis, 
refer to APPENDIX G. 
4.2
Scientific rationale for study design
 
 
 
 
 
 

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4.3
Justification for dose
The pharmacokinetics (PK) of benralizumab are well-characterized (Wang et al 2017), and it 
is expected to demonstrate consistent PK across different disease populations. In adult and 
adolescent patients with severe asthma (SIROCCO [Bleecker et al 2016] and CALIMA 
[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 HES, where patients have higher 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 GI tissue) in patients with varied clinical 
subtypes of HES (Kuang et al 2019).  For the planned clinical study of patients with EoE, 
which is similar to HES 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 PK 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 PK/pharmacodynamic profiles of benralizumab 
(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 patients who received benralizumab 30 mg Q4W, the incidence of 
treatment-emergent adverse events (TEAEs) 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.
As patients will be offered the opportunity to participate in an OLE period of at least 1 year 
after completing the first 52 weeks of the study (DB+OL treatment periods) on IP, the end of 
study is planned to be when the last randomized patient completes 1 year in the OLE period.  
However, AstraZeneca may choose to extend the OLE period (Section 4.1), this decision will 

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determine when the end of the study is declared. Notification of closure of the study will be 
communicated to sites at least 3 months in advance of the end of study, unless faster 
termination is warranted (eg, emergence of a safety concern).
After the end of the study, patients should be given standard-of-care therapy, which may 
include on label benralizumab, at the discretion of their treating physician, per local practice.
See Appendix A 6 for guidelines for the dissemination of study results.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study in order to be assigned/randomized to a study intervention.  Under no circumstances can 
there be exceptions to this rule.  Patients who do not meet the entry requirements are screen 
failures; refer to Section 5.4.
In this protocol, “enrolled” patients are defined as those who sign informed consent or assent 
(if applicable).  “Randomized” patients are defined as those who undergo randomization and 
receive a randomization number.
5.1
Inclusion criteria
Patients are eligible to be included in the study only if all of the following inclusion criteria 
and none of the exclusion criteria apply:
Informed consent or assent (if applicable)
1
Provision of signed and dated, written informed consent form or assent form (if 
applicable) prior to any mandatory study specific procedures, sampling, and analyses.
2
Provision of signed and dated written Genetic informed consent prior to collection of 
2
sample for genetic analysis for adult patients.
The Informed Consent Form (ICF)/assent form process is described in Appendix A 3.
Age
3
Patients 12 to 65 years of age, inclusive, at the time of signing the informed consent or 
assent (if applicable) form.

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Type of patient and disease characteristics
4
Documented previous diagnosis of EoE by endoscopy (documented diagnosis defined as 
an esophageal count of ≥15 eos/hpf on at least 1 esophageal level) and confirmed 
diagnosis by a centrally-read esophageal biopsy for the purposes of this study (confirmed 
diagnosis defined as an esophageal count of ≥15 eos/hpf at 2 or more esophageal levels).  
Two to 4 biopsies should be obtained from both the proximal and distal esophagus. 
Biopsies can be taken from the mid-esophagus for additional evaluation.
5
Must be symptomatic at Visit 1 (screening) and Visit 2 (randomization):
(a) A patient reported average of at least 2 days per week with an episode of dysphagia 
over the 4 weeks prior to Visit 1 
(a) AND
(b) An average of at least 2 days per week with an episode of dysphagia (Daily DSQ 
≥2) between Visit 1 and Visit 2, and at least 2 days per week with an episode of 
dysphagia (Daily DSQ ≥2) in each of the 2 weeks immediately prior to 
randomization
6
Must be adherent to daily diary assessments: 
(a) Must complete 70% of daily DSQ diaries between Visit 1 and Visit 2; 
(b)AND
(b) Must have completed at least 8 of 14 daily DSQ diaries in the 14 days prior to 
randomization
7
May be on background medications for EoE and related treatments during the study as 
long as the background medications have been stable for at least 4 weeks (8 weeks for 
PPI) prior to screening and there is agreement not to change type of background 
medication or dosage during the run-in period and for the first 52 weeks of the study 
unless a change is medically indicated. If a medication for EoE (including swallowed 
steroids and PPI) is discontinued prior to screening, there should be a washout period of 
at least 8 weeks. See Section 6.5.1 for details regarding background medications.
Reproduction
8
Negative serum pregnancy test for women of childbearing potential (WOCBP) at Visit 1. 
3
9
WOCBP must agree to use a highly effective form of birth control (confirmed by the 
Investigator) from randomization throughout the study duration and for at least 12 week 
after last dose of IP.  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.  
Highly effective forms of birth control include:

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(a) Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation- oral, intravaginal, or transdermal
(b) Progestogen-only hormonal contraception associated with inhibition of ovulation-
(oral, injectable, or implantable)
(c) Intrauterine device (IUD)
(d) Intrauterine hormone-releasing system (IUS)
(e) Bilateral tubal occlusion
(f) Sexual abstinence, i.e. 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.)
(g) Vasectomized sexual partner (provided that partner is the sole sexual partner of the 
WOCBP study patient and that the vasectomized partner has received medical 
assessment of the surgical success) 
10 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 
amenorrheic for ≥12 months prior to the planned date of randomization without an 
alternative medical cause.  The following age-specific requirements apply:

Women <50 years old will be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatment and follicle stimulating hormone (FSH) levels in the postmenopausal range.  
Until FSH is documented to be within menopausal range, treat the patient as 
WOCBP.

Women ≥50 years old will be considered postmenopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatment.
5.2
Exclusion criteria
Medical conditions
1
As judged by the Investigator, any evidence of a medical illness which in the 
Investigator’s opinion makes it undesirable for the patient to participate in the study.
2
Other GI disorders such as active Helicobacter pylori infection, history of achalasia, 
esophageal varices, Crohn’s disease, ulcerative colitis, inflammatory bowel disease, or 
celiac disease.
3
Any clinical significant abnormal findings in physical examination, vital signs, 
hematology, clinical chemistry, or urinalysis during run-in period, which in the opinion of 

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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.
4
Esophageal stricture that prevents the easy passage of a standard endoscope or any critical 
esophageal stricture that requires dilation during the run-in period.
5
Esophageal dilation performed within 8 weeks prior to screening and prior esophageal 
surgery that would impact the assessments for EoE.
6
Use of a feeding tube, or having a pattern of not eating solid food daily during the run-in 
period.
7
Hypereosinophilic syndrome, defined by multiple organ involvement and persistent blood 
eosinophil count >1500 eos/μL.
8
EGPA vasculitis.
9
Eosinophilic gastritis, gastroenteritis, enteritis, or colitis documented by biopsy.
10 Current malignancy, or history of malignancy, except for:
(a) Patients who have had basal cell carcinoma, localized squamous cell carcinoma of 
the skin, or in situ carcinoma of the cervix are eligible provided that the patient is in 
remission and curative therapy was completed at least 12 months prior to the date 
informed consent, and assent when applicable was obtained.
(b) 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.
11 History of anaphylaxis to any biologic therapy or vaccine.
12 Current active liver disease, please note: 
(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, hypoalbuminaemia, esophageal or gastric varices, or persistent 
jaundice, or cirrhosis.
(b) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level ≥3 times 
the upper limit of normal (ULN), confirmed by repeated testing during the run-in 
period.  Transient increase of AST/ALT level that resolves by 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.
13 Helminth parasitic infection diagnosed within 24 weeks prior to screening that has not 
been treated with or has failed to respond to standard of care therapy.
14 History of known immunodeficiency disorder including a positive human 
immunodeficiency virus (HIV) test.

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Prior/concomitant therapy
15 Use of immunosuppressive medication (including but not limited to: methotrexate, 
cyclosporine, azathioprine, and systemic corticosteroids) within 8 weeks prior to 
screening. 
16 Receipt of immunoglobulin or blood products within 30 days prior to screening.
17 Receipt of live attenuated vaccines 30 days prior to randomization.. 
18 Receipt of inactivated/killed vaccinations (e.g., inactive influenza) within 1 week prior to 
randomisation
19 Receipt of any marketed or investigational biologic (monoclonal or polyclonal antibody) 
within 4 months or 5 half-lives prior to screening, whichever is longer.
20 Receipt of oral and/or  sublingual allergen immunotherapy within 8 weeks prior to 
screening.
21 Initiation or change of a food-elimination diet regimen or re-introduction of a previously 
eliminated food group in the 6 weeks prior to start of and during the run-in period.
Prior/concurrent clinical study experience
22 Previous participation in a benralizumab clinical study.
23 Known history of allergy or reaction to any component of the IP formulation.
24 Receipt of any investigational drug within 30 days or 5 half-lives prior to screening, 
whichever is longer.
Other exclusions
25 Currently pregnant, breastfeeding, or lactating women.
26 A serum pregnancy test will be done for WOCBP at screening, and a urine pregnancy test 
must be performed for WOCBP at randomisation prior to IP administration.  A positive 
urine test result must be confirmed with a serum pregnancy test. If the serum test is 
positive, the patient should be excluded.
27 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site).
4

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5.3
Lifestyle restrictions
Women of childbearing potential must use highly effective contraceptive methods throughout 
the study and at least for 12  weeks (5 half-lives) after last administration of the IP, as stated in 
Section 5.1, inclusion criterion 9.
Patients must abstain from donating blood, plasma, or platelets from the time of informed 
consent or assent (if applicable) and for 12 weeks (5 half-lives) after last dose of IP.
5.3.1
Meals and dietary restrictions
Patients should remain on stabilized diet for treatment of their EoE during the run-in and 
during first 52 weeks of the study, unless a change is clinically indicated. Stable diet is 
defined as no initiation of single or multiple elimination diets or reintroduction of previously 
eliminated food groups.
5.4
Screen failures
Screen failures are defined as patients who signed the informed consent or assent (if 
applicable) form to participate in the clinical study but are not subsequently randomly
assigned to IP/entered in the study.  A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure patients to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities.  Minimal information includes demography, screen failure details, 
eligibility criteria, and any serious adverse event (SAE).
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 AZ study 
physician (e.g. 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 EGD and 
biopsy, which should be completed 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:

Confirming histologically active disease by centrally-read esophageal biopsy for the 
purpose of the study, defined as an esophageal count of ≥15 eos/hpf at 2 or more 
esophageal levels (inclusion criterion #4).

Biopsy in order to exclude eosinophilic gastritis, gastroenteritis, enteritis, or colitis 
(exclusion criterion #9) 

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
Screening in order to confirm a patient-reported average of at least 2 days per week with 
an episode of dysphagia over the 4 weeks prior to visit 1, or to confirm an average of at 
least 2 days per week with an episode of dysphagia (Daily DSQ ≥2) between Visit 1 and 
Visit 2, and at least 2 days per week with an episode of dysphagia (Daily DSQ ≥2) in each 
of the 2 weeks immediately prior to randomization (inclusion criterion #5).
Patients may be considered for re-screening in order to meet all other inclusion/exclusion 
criteria. 
6
STUDY TREATMENTS
Study treatment is defined as any IPs (including marketed product comparator and placebo) or 
medical device(s) intended to be administered to a study patient according to the study 
protocol.  Study treatment in this study refers to benralizumab or placebo.
6.1
Treatments administered
Descriptions of the IPs are provided in Table 9. Benralizumab and placebo administered in the 
study will be a clear to opalescent, colourless to yellow solution.  Benralizumab and placebo 
are formulated in 20 mM histidine/histidine hydrochloride monohydrate, 0.25 M trehalose 
dihydrate, and 0.006% (w/v) polysorbate 20, pH 6.0.
Table 9
Study Treatments
Treatment 1
Treatment 2
Study treatment name:
Benralizumab
Placebo
Dosage formulation:
30 mg/mL solution for injection in 
accessorized prefilled syringe 
(APFS), 1 mL fill volume
Matching placebo solution for injection 
in APFS, 1 mL fill volume
Dosage level
30 mg every 4 weeks
Matching placebo every 4 weeks
Route of administration:
SC
SC
Dosing instructions:
Benralizumab active solution will be 
administered SC to patients by 
healthcare professionals in this 
clinical study using an APFS.  Refer 
to Section 6.2.
Placebo solution will be administered SC 
to patients by healthcare professionals in 
this clinical study using an APFS.  Refer 
to Section 6.2.
Packaging and labelling:
Study treatment will be provided in 
APFS.
Each syringe will be labelled in 
accordance with Good Manufacturing 
Practice (GMP) Annex 13 and per 
country regulatory requirement.  The 
labels will be translated into local 
Study treatment will be provided in 
APFS.
Each syringe will be labelled in 
accordance with GMP Annex 13 and per 
country regulatory requirement.  The 
labels will be translated into local 
languages where applicable and required 
by local regulations.

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Table 9
Study Treatments
Treatment 1
Treatment 2
languages where applicable and 
required by local regulations.
Provider:
AstraZeneca
AstraZeneca
Patients will receive IP (i.e., benralizumab or matching placebo) Q4W. All doses of IP during 
the 52-week treatment period (DB+OL treatment periods) and the first dose of open-label 
extension (Visit 15) will be administered at the study site. After Visit 15, IP will be 
administered as scheduled in the SoA (Section 1.1,  Table 2 and Table 3), either at the site 
during the visit by a healthcare professional or at home/remotely by the patient or caregiver, 
provided that the Investigator has assessed and trained the patient and/or caregiver for 
at-home/remote-location administration (Section 6.1.4). The acceptable visit windows are 
specified in the schedules in Section 1.1, and reasons and procedures for rescheduling 
investigational product administration are detailed in Section 6.1.5
6.1.1
Before IP administration
All applicable visit procedures, including endoscopy, 
 PK, and ADA 
samples and on-site PRO assessments, must be completed prior to IP administration. No 
procedures should be performed after the dosing of IP. 
Prior to each IP administration:

For WOCBP, the urine pregnancy test must be performed; IP will be administered only 
when the result of the test is negative (see Section 8.2.2).

Investigator/authorized delegate will evaluate the patient's condition for potential 
contraindications for dosing (see Section 6.1.5).

Investigator/authorized delegate will assess the injection site as per standards of medical
care.
6.1.2
IP administration at the study Site
The IP will be administered subcutaneously as a single injection via the APFS by the 
Investigator/authorized delegate.  It is advised that the site of injection of IP is rotated such 
that the patient receives IP at a different anatomical site at each treatment visit.  Suggested 
injection site rotation sequence is presented below (see Figure 2).  The injection site must be 
documented in the source at each treatment visit and recorded in the electronic Case Report 
Form (eCRF). If rotation of the injection site is not possible, the reason should be included in 
the source.

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Figure 2
Injection sites and examples of rotation scheme
    
The specific details for IP administration are provided in the IP Handling Instruction.  The IP 
administration must be carried out in line with these instructions.
After IP administration
After IP administration at the study site, the patient should be observed for any acute drug 
reactions in line with clinical practice (Section 8.4.7). 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
Self-administration of IP as Mitigation to Study Disruption
At Visits 2 and 3, appropriate patients and/or their caregiver may be trained in IP 
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 to have patients 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.
6.1.4
Optional At-home or Remote-Location IP Administration
To reduce patient burden and to allow flexibility during the OLE period, patients will have the 
option for at-home or remote-location patient/caregiver administration of IP using the APFS. 
The Investigator will first assess the patient and/or his/her caregiver to ensure they are 
appropriate for administration of IP and will provide appropriate training. All necessary 
supplies and instructions for administration and documentation of IP administration will be 
provided.
If the IP is administered at the patient's home/remotely, the patient should administer the IP 
the same day as the remote 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 

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Investigator or qualified designee will complete the AE eCRF page and additional eCRF 
questions about the injection site reaction or other AEs.
Refer to the Study Instructions for At-home or Remote Location Administration of 
Investigational Product by the Patient and/or His/Her Caregiver for step-by-step guidance, 
including Investigator assessment/training of patient and/or caregiver, drug accountability, and 
reconciliation requirements.
The option of at-home or remote-location administration of IP will only be available in 
countries where allowed according to local regulations.
6.1.4.1
Optional  Remote Visits for Patients doing At-Home or Remote-Location  IP 
Administration
During the OLE, some visits (as specified in the SoA) can optionally be done as remote visits 
by telephone contact for patients who are doing at-home/remote-location IP administration.
During the OLE period mandatory on-site visits will occur at approximately 3-month 
intervals. At these visits the site will dispense up to 3 IP kits at a time. WOCBP should be 
asked if they are pregnant during the telephone visit.
6.1.5
IP administration re-scheduling
Every effort should be taken to keep IP administration within the visit window.
If a patient presents with a condition that contraindicates dosing, IP will be withheld and 
administered as soon as possible when the contraindicating condition resolves.
IP 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 patient.

Signs of a clinically significant infection.  Benralizumab should not be administered to a 
patient with a clinically significant active infection treated with oral or IV 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.

Any event or laboratory abnormality that, in the opinion of the Investigator or the 
Sponsor, contraindicates dosing or could result in complications.

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It is recommended that the AZ study physician/delegate be contacted in case of any questions.
If IP cannot be administered at a scheduled treatment visit (e.g. due to conditions listed 
above), it can be postponed as necessary and administered as soon as possible.
When IP dosing needs to be postponed, it is recommended that all scheduled treatment visit 
procedures (except for pregnancy test and IP administration) are still performed within the 
visit window.  
Re-scheduled IP 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 (e.g. the patient is unable to 
attend the study site), then the entire visit will be re-scheduled along with IP dose.
If a dose is significantly delayed it is recommended to keep at least 2 weeks interval before the 
next dose. If a postponed dose overlaps with the next treatment visit window, the postponed 
dose will be skipped, and the next dose of IP given at the regularly scheduled visit.  The visit 
schedule will be always calculated from randomization visit date.
If 2 or more doses (consecutive or non-consecutive) of IP are missed1 within a 1-year period, a 
conversation between the Investigator and the AstraZeneca study physician should take place
to review the patient's adherence to treatment and decide on the patient's further disposition.  
During the DB+OL treatment periods, all patients, regardless of whether they remain on IP or 
not, will be encouraged to remain in the study through the end of the DB+OL treatment 
periods.  Discontinuation procedures are described in Section 7.1.
6.2
Preparation/handling/storage/accountability
Investigational product will be supplied to the site in a kit with an APFS of either 
benralizumab or placebo.  Each kit will have a unique ID that is printed on all labels within 
the kit (i.e. the outer carton label and the label of each container within the carton).
All shipments of IP include a data logger that will allow the Investigator, or designee, to 
confirm that appropriate temperature conditions have been maintained during transit for all IP 
received.  Any discrepancies must be reported and resolved before use of the IP.
Only patients enrolled in the study may receive IP, and only authorized site staff may supply 
or administer IP, except when self-administration or administration by patient’s caregiver is an 
                                                  
1 A ‘missed’ dose is a dose not administered until the next treatment visit window.

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option (Section 6.1.3 and 6.1.4).  All IP must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area, in the original outer container.  The IP 
must be kept under conditions specified on the label (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.
In the following cases the center staff should not use affected IP 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 IP should be documented using the interactive web response system (IWRS)(please 
refer to IWRS manual for further details).
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IP accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).
An AstraZeneca site monitor will account for all IP received at the site, for unused IP, and for 
appropriate destruction of unused IPs.  Any unused kits will be destroyed locally (for further 
details, refer to the Pharmacy Manual).  Documentation of IP delivery and destruction should 
be maintained according to applicable AstraZeneca and institution procedures. Devices sent to 
a patient’s home must be returned to the site for traceability.
Further guidance and information for the final disposition of unused IP are provided in the 
Pharmacy Manual (provided to the sites).
6.3
Measures to minimize bias: randomization and blinding
6.3.1
Methods for assigning treatment groups
All patients will be centrally assigned to randomized IP using an IWRS.  Randomization 
codes will be assigned strictly sequentially in each stratum as patients become eligible for 
randomization.  Randomization for adults will be stratified by region (North America vs 
ROW) and use of swallowed steroids at baseline (categorical, Yes/No).  Adolescents will be 
randomized in a separate stratum with no other factors included.  Patients who fail to meet the 
inclusion/exclusion criteria should not, under any circumstances, be randomized or receive IP.  
There can be no exceptions to this rule.
If a patient withdraws from the study, then his/her enrollment/randomization code cannot be 
reused.  Withdrawn patients will not be replaced.

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6.3.2
Methods for ensuring blinding
The first 24 weeks of this study is DB design.  During this portion of the study benralizumab 
and placebo will not be visually distinct from each other.  All packaging and labelling of the 
IP will be done in such a way as to ensure blinding for all Sponsor and investigational site 
staff.  Neither the patient nor any of the Investigators or Sponsor staff who are involved in the 
treatment, clinical evaluation and monitoring of the patients will be aware of the treatment 
received during the initial 24-week DB treatment period.  Since benralizumab and placebo are 
not visually distinct, IP will be handled by an appropriately qualified member of the study 
team (e.g. pharmacist, Investigator or qualified designee) at the site.  Following Week 24, all 
patients will be treated with unblinded benralizumab 30 mg administered SC Q4W until Week 
52.
An AstraZeneca site monitor will perform IP accountability.  In the event that the treatment 
allocation for a patient becomes known to the Investigator or other study staff involved in the 
management of study patients or needs to be known to treat an individual patient for an AE, 
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 IP

Those generating the randomization list

The AstraZeneca Supply Chain department
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.
Maintaining the blind to the patient’s eosinophil counts
While not entirely assured, patients on active benralizumab treatment are expected to have 
lower eosinophil and basophil counts than patients on placebo.  Procedures to mitigate 
unblinding on this basis will be in place from randomization (Visit 2/Week 0) during the 
entire DB treatment period, and for the first 8 weeks of the OL treatment period (up to 
Visit 10/Week 32):

Hematology will be run by the central laboratory.  Post-randomization (starting from 
Visit 2 and up to Week 32), eosinophil and basophil counts will be redacted from the full 
hematology reports sent back to the investigative sites.  Because complete knowledge of 

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the remaining cell types could permit deduction of the ‘eosinophil + basophil’ 
compartment, monocyte counts will also be redacted from the full haematology 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.

Site staff who are directly involved in the patient’s management should remain blinded to 
any eosinophil, basophil, and monocyte results included as part of an outside laboratory 
report or electronic medical record.  To help ensure this, each investigational site will
designate an individual (e.g. administrator or another ancillary person) not directly 
involved in patient management, to receive and blind any eosinophil, basophil, and 
monocyte results prior to the report being handed over to the site staff involved in the 
patient’s management and prior to filing the laboratory report as a source document.  
Similarly, eosinophil, basophil, and monocyte results must be redacted from all 
communications with the Sponsor.

Esophageal biopsies will be centrally read. Additional biopsies are not to be sent to local 
labs in parallel. Biopsy results will be reported back to the investigative sites for the
purposes of confirming eligibility criteria following Visit 1. Week 24 follow-up biopsy 
results will not be reported back to the investigative sites due to potential risk of 
unblinding.
6.3.3
Methods for unblinding
Individual treatment codes, indicating the treatment randomization for each randomized 
patient, will be available to the Investigator(s) or pharmacists from the IWRS.  Routines for 
this will be described in the IWRS user manual that will be provided to each site.
The randomization code should not be broken except in medical emergencies when the 
appropriate management of the patient requires knowledge of the treatment randomization.  
The Investigator will document and report the action to AstraZeneca, without revealing the 
patient’s treatment randomization to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to IP and that potentially require expedited reporting to 
regulatory authorities.  Randomization codes will not be broken for the planned analyses of 

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data until all decisions on the evaluability of the data from each individual patient have been 
made and documented.
6.4
Treatment compliance
The administration of all study treatments (both in the DB, OL, and OLE periods of the study) 
should be recorded in the source documents, as well as in  the appropriate section of the 
eCRF.  The study treatment provided for this study will be used only as directed in this 
Clinical Study Protocol (CSP).
The IP will be administered SC at the study site on treatment visits and within visit windows 
as specified in Table 1,  Table 2 and Table 3.  Any change from the dosing schedule, dose 
interruptions, dose discontinuations should be recorded in eCRF; dose modifications are 
prohibited.  PRO compliance will be assessed at scheduled assessments as outlined in Table 1, 
Table 2 and Table 3.
If a patient misses 2 or more doses of IP (consecutively or non-consecutively) within a 1-year 
period, a conversation between the Investigator and the AstraZeneca study physician should 
take place to review the patient's adherence to treatment and decide on the patient's further 
disposition.
The date and time of all IP administrations, as well as any missed doses, should be recorded in 
the appropriate section of the eCRF.
6.5
Concomitant therapy
The Investigator/authorized delegate must be informed as soon as possible about any 
medication(s) taken from the time of screening until the end of the study (final study visit). 
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the patient 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
6.5.1
Background medication and related treatments
Background medications for EoE (e.g. swallowed steroids and PPI) 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.  Patients on PPI 
therapy must report a stable dose for at least 8 weeks prior to the run-in period. If a medication 

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for EoE (including swallowed steroids, systemic steroids and PPI) is discontinued prior to 
screening, there should be a washout period of at least 8 weeks.
Background medication for EoE (and related treatments) should remain stable throughout the 
run-in period and the DB+OL treatment periods (up to Week 52) unless a change is medically 
indicated.  Background medication use will be recorded on the eCRF.  The justification and 
rationale for treatment changes should be documented in the eCRF source notes.
Additionally, patients should remain on a stabilized diet for treatment of their EoE for at least 
6 weeks prior to the run-in period throughout the run-in period and the first 52 weeks of the 
study (see Section 5.3.1) unless medically indicated.  Diet will be tracked using a diet 
questionnaire (see Section 8.11.2).
For patients who enter the OLE period after the first 52 weeks, background medications and 
diet for treatment of EoE may be adjusted.
Background medication is not regarded as IP but may be provided by AstraZeneca according 
to local regulations, in order to maintain access to these concomitant therapies from enrolment 
and throughout the duration of the study until the patient completes or withdraws.
6.5.2
Other concomitant treatment
Medication other than that described above, which is considered necessary for the patient’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the eCRF.
6.5.3
Rescue medication
Rescue medication for EoE is prohibited during the first 52 weeks of the study.  Patients not 
on PPI and/or steroid background medications for EoE at Baseline should not initiate these 
medications during the first 52 weeks of the study.  If such a need arises during the study, the 
Investigator should consult with the Sponsor.
6.5.4
Restrictions
The restrictions that apply during the study are summarized in Table 10.
If, at discretion of the Investigator, a patient needs treatment with any disallowed medication 
or changes in background medications for EoE and related treatments, it is recommended that 
the Investigator contact the AZ study physician to discuss justification.

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Table 10
Allowed, restricted, and prohibited concomitant medication and 
treatments
Unless specifically indicated, all conditions apply from enrolment throughout the study duration.
Medication
Allowed/ Restricted/ 
Prohibited
Details
Background (maintenance) 
medication for EoE (e.g. 
swallowed steroids and PPI), 
leukotriene inhibitors and 
steroid treatments used for 
asthma or allergies that are 
inhaled or administered 
intranasally
Allowed
Continuation of EoE therapies and medications 
prior to randomization are allowed.  Background 
medications for EoE and related treatments
should remain stable within 4 weeks prior to 
screening (8 weeks for PPI). During run-in and 
during the course of the study, these medications 
should remain stable unless a change is 
medically indicated.  If such a need arises during 
the study, the Investigator should consult with 
the Sponsor.
Systemic corticosteroids 
(tablets, suspension, or 
injections; (e.g. prednisone, 
prednisolone or related 
products)
Restricted
Disallowed within 8 weeks prior to screening 
and within 4 weeks prior to endoscopy during 
the study.
Throughout the run-in and the first 52 weeks of 
the study, allowed for treatment of an AE (e.g. 
asthma) where there is no alternative treatment 
available, for no more than 7 days. Allowed at 
clinical discretion after the first 52 weeks of the 
study.
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 AZ 
study physician to decide on the patient’s 
disposition.
Disallowed within 8 weeks prior to screening  
and for other reasons throughout the study.
Immunoglobulin or blood 
products
Prohibited
Disallowed 30 days prior to screening and 
during the study.
Antibiotics
Restricted
Allowed, but should be managed according to 
local standards of care and the Investigator’s 
judgment and discussed with AZ study physician 
based on the potential for a precipitating allergic 
response.
Antitussives and mucolytics
Allowed

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Table 10
Allowed, restricted, and prohibited concomitant medication and 
treatments
Unless specifically indicated, all conditions apply from enrolment throughout the study duration.
Medication
Allowed/ Restricted/ 
Prohibited
Details
Dermal topical steroids, 
topical ophthalmic and otic 
corticosteroids
Allowed
Antihistamines and ephedrine 
containing medications
Allowed
Xanthines
Restricted
Allowed in a dose equivalent to theophylline 
≤400mg q day.  For doses greater than 400 mg, 
the dose has to be stable and blood levels should 
be confirmed to be ≤12 mg/dL, within 8 weeks 
prior to screening or during the run-in period.
Blood levels >12 mg/dL should be managed
according to local standards of care and the 
Investigator’s judgment and discussed with AZ 
study physician.  It is recommended that 
additional increments in dose are evaluated with 
blood levels.
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 IP.
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 IP.
Subcutaneous Allergen 
immunotherapy (SCIT)
Restricted
SCIT is 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 patient does not receive SCIT 
on the same day as IP 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 
IP.
Inactive/killed vaccinations 
(e.g., inactive influenza)
Restricted
Not recommended within the 7 days before or 
within 7 days after any IP dosing study visit.

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Table 10
Allowed, restricted, and prohibited concomitant medication and 
treatments
Unless specifically indicated, all conditions apply from enrolment throughout the study duration.
Medication
Allowed/ Restricted/ 
Prohibited
Details
Injection site for vaccine should be distant to 
preceding and next injection site of IP.
6.6
Dose modification
Modification of the dose of benralizumab is not permitted.
6.7
Treatment after the end of the study
After the end of the study, the patient should be given standard of care therapy, at the 
discretion of the Investigator, per local practice.
7
DISCONTINUATION OF TREATMENT AND PATIENT
WITHDRAWAL
7.1
Discontinuation of IP
Discontinuation from IP does NOT automatically lead to a complete withdrawal from the 
study.  Patients discontinuing from IP are strongly encouraged to continue in the study up to 
the end of the DB+OL treatment periods.
Patients may be discontinued from IP in the following situations.

Patient decision. The patient is at any time free to discontinue treatment, without 
prejudice to further treatment

Adverse event that, in the opinion of the Investigator, contradicts further dosing

Severe non-compliance with the Clinical Study Protocol

Eligibility requirement found not to be fulfilled that in the opinion of the Investigator or 
AstraZeneca may put the patient at risk. 
If a patient does not meet all the eligibility criteria but is randomized in error, the 
Investigator should inform the AZ study physician immediately to discuss potential safety 
concerns and the best interests of the patient and decide on further patient's disposition.

Pregnancy.

Lost to follow up.

Development of any study-specific criteria for discontinuation:

Anaphylactic reaction to the IP requiring administration of epinephrine

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
Development of helminth parasitic infestations requiring hospitalization

Confirmed reactivation of hepatitis B virus

If a patient misses 2 or more doses (consecutively or non-consecutively) of IP within 
a 1-year period, a conversation between the Investigator and the AstraZeneca study 
physician should take place to review the patient's adherence to treatment and decide 
on the patient's further disposition
Before a decision to discontinue a patient from IP is instituted, the AZ study physician should 
be consulted regardless of the reason for discontinuation.  The Investigator should contact the 
patient if a decision to stop IP is taken.  A patient that decides to discontinue IP will always be 
asked about the reason(s) and the presence of any AEs.  The date of last IP dose, the date of IP 
discontinuation decision and the reason(s) for discontinuation should be documented in the 
eCRF.  Conditions that require administration of IP to be temporarily withheld are described 
in Section 6.1.5.
Discontinuation of IP will be registered in the IWRS.
See the SoA for data to be collected at the time of treatment discontinuation and follow-up 
and for any further evaluations that need to be completed.
7.1.1
Procedures for early discontinuation of study treatment and at end of 
study
7.1.1.1
Early discontinuation of study treatment
All patients who prematurely discontinue IP (during either the DB, OL, or OLE periods) 
should return to the study site for an IPD visit within 4 weeks (±3 days) after the last dose of 
IP, and FU visit 12 weeks (±7 days) after the last dose of IP for procedures described in 
(Table 1, Table 2 and Table 3).  The IPD visit replaces the nearest scheduled visit after IP 
discontinuation.  Patients who have discontinued IP prior to Week 52 are not eligible to enter 
the OLE period.
IPD during the DB+OL treatment periods
At the IPD visit, the patient will be offered the following options for further follow-up:

Patients are encouraged to return for all scheduled clinic visits, but without IP 
administration.  During this time data collection should continue according to the study 
protocol.

All PRO assessments should continue at home, otherwise the patient should return 
the handheld device at the IPD visit.

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
An endoscopy with biopsy should be performed at the IPD visit only if ≥12 weeks 
have elapsed since the prior endoscopy.  The endoscopy with biopsy at Week 24 
should be performed.  If a patient discontinues prior to week 24, the patient should be 
asked to return for the endoscopy at Week 24 (rather than at the IPD visit).

If the FU visit (12 weeks after the last dose of IP) overlaps with a scheduled visit, the 
procedures for the scheduled visit should be performed

If the patient is unwilling/unable to attend the scheduled clinic visits until end of the 
DB+OL period, he/she will be offered a follow-up option that includes monthly telephone 
contact instead.  The patient will be encouraged to attend the FU visit at the study site, if 
feasible.

During telephone follow-up contact(s), the Investigator will collect information about 
concomitant medications, AE/SAEs, diet, and healthcare resource utilization.

The handheld device will be returned at the IPD visit, and no further PRO 
assessments will be collected.
The approach taken should be recorded in the medical records.  A patient that agrees to phone 
follow-up is not considered to have withdrawn consent or assent (if applicable) or to have 
withdrawn from the study.
Permanently discontinuing IP shall prompt no further changes regarding EoE therapy; patients 
should remain on stable background medications and stable diet for EoE during the first 
52 weeks of the study, even without IP.  If a patient requires initiating a background 
medication for EoE or related treatment during the study following discontinuation of IP, the 
Investigator should consult with the Sponsor (Section 6.5.3).  Following discontinuation of IP, 
restrictions and prohibitions on concomitant medications or treatment other than background 
medications for EoE or related treatments no longer apply.
7.1.1.2
Discontinuation at Week 52
All patients who complete the 52-week treatment period (DB+OL treatment periods) on IP 
will be offered the opportunity to continue into the OLE period.  If a patient chooses not to 
continue to the OLE period, then the patient will be considered to have completed the study; 
the site will perform an End of Treatment (EOT) visit at Week 52, and the patient will return 
for a FU visit 12 weeks (±7 days) after the last dose of IP, after which the patient exits the 
study.  The reason for not entering the OLE period will be recorded in the eCRF.
7.1.1.3
Discontinuation of treatment in the OLE treatment period
During the OLE treatment period, a visit will be defined as an EOT visit when the study is 
closed at the site for any reason, including when AstraZeneca declares the end of the study 
(Section 4.4). When a patient discontinues IP for other reasons during the OLE, the visit will 
be defined as an IPD visit.

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The following visits should be performed (Table 2 and Table 3) for all patients who 
discontinue during the OLE period:

IPD/EOT visit – within 4 weeks (±3 days) after the last dose of IP 

Follow-Up visit – within 12 weeks (±7 days) after last dose of IP
7.2
Lost to follow-up
A patient will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit:

The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule.

Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient or next of kin by repeat telephone calls, 
certified letter to the patient´s last known mailing address or local equivalent methods.  
These contact attempts should be documented in the patient’s medical record.

Efforts to reach the patient should continue until the end of the study.  Should the patient 
be unreachable at the end of the study the patient should be considered to be lost to follow 
up with unknown vital status at end of study and censored at latest follow up contact.
7.3
Withdrawal from the study
A patient may withdraw from the study (e.g., withdraw consent or assent), at any time 
(investigational product and assessments) at his/her own request, without prejudice to further 
treatment.
A patient who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (e.g., telephone contact, a contact with a relative or treating 
physician, or information from medical records).
If the patient and/or legal representative withdraws consent or assent (if applicable) for 
disclosure of future information, the Sponsor may retain and continue to use any data 
collected before such a withdrawal of consent/assent.
If a patient withdraws from the study, he/she may request destruction of any samples taken, 
and the Investigator must document this in the site study records.

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A patient and/or legal representative who withdraws consent/assent will always be asked 
about the reason(s) and the presence of any AE.  The Investigator will follow up patients as 
medically indicated.  The patient will return the handheld device.
AstraZeneca or its delegate will request Investigators to collect information on patients’ vital 
status (dead or alive; date of death when applicable) at the end of the study from publicly 
available sources, in accordance with local regulations.  Knowledge of the vital status at study 
end in all patients is crucial for the integrity of the study (end of study is defined in 
Section 4.4).
See SoA, Table 1, Table 2 and Table 3, for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (Table 1, Table 2 and Table 3).
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 patient should continue or discontinue IP.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations during the run-in period must be completed and reviewed to confirm 
that potential patients meet all eligibility criteria.  The Investigator will maintain a screening 
log to record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the patient’s routine clinical management (e.g., 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 the SoA.

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8.1
Efficacy assessments
8.1.1
Histopathology and tissue eosinophil counts
One of the dual-primary endpoints in the study is the proportion of patients with a histologic 
response at 24 weeks defined as ≤6 eos/hpf across all available esophageal levels.
During the study, EGD biopsies will be conducted as per the schedule provided in Table 1, 
Table 2 and Table 3.  EGD will be performed according to local medical practice.  The 
biopsies will be sent to the central lab for slide preparation and for central, blinded pathology 
review of tissue eosinophil counts and histopathology.  Centralized slide assessments and 
scoring from independent physician review will be performed for all biopsies.
Details pertaining to EGD biopsy collection are provided in the laboratory manual.
To confirm eligibility at Visit 2, the Visit 1 results of the central biopsy review will be 
communicated to the site.
The EoE Histology Scoring System (EoE-HSS) may be determined and recorded 
independently for all available esophageal levels by central, blinded pathology review.
8.1.2
EoE Endoscopic Reference Score
The EoE Endoscopic Reference Score (EREFS) is a scoring system for assessing the presence 
and severity of the major endoscopic signs of EoE, including esophageal edema, rings, 
exudates, furrows, and stricture.
The EREFS will be evaluated at the time of each EGD as per the schedule provided in 
Table 1, Table 2 and Table 3.
The EREFS will be centrally-read from video recordings and Investigator-read during the 
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 EREFS 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
Between Visit 1 and Visit 21, patients will complete all PRO assessments using a handheld 
device. The handheld device (or web-based back-up, in case of device failure) will be the only 
accepted source of PRO data in this protocol (except for PGI-S, see section 8.1.3.5). The 

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Investigator will ensure that patients 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 diary.  
Study site staff will be able to adjust alarms for specific patient needs as required.  The patient 
will be required to complete a training module before taking the device home.
The Investigator or designee will be responsible for monitoring patient adherence with the 
daily diary and follow-up as necessary to minimize missing data.  Patient compliance should 
be checked weekly (at a minimum) to ensure that the patient is completing the assessments as 
scheduled.  Monitoring of patient adherence to the diary is critical between Visit 1 and Visit 2 
to ensure that the patient meets applicable criteria for randomization.  If the patient does not 
meet the randomization requirements, the device will be deactivated and retained at the site 
for future use.
Review of patient compliance with the assessment schedule, completion of any available 
assessments, and logging of the visit on the handheld device should be completed prior to 
other study procedures.
Compliance with the assessment schedule should be reviewed weekly throughout the study. 
Patients 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 outlined in Table 4.  The schedule used in the 
DB+OL periods is also used for the first 24 weeks of the OLE period, though fewer PROs are 
assessed in the OLE period. The handheld device will be returned to the study site at Week 76.
8.1.3.1
Dysphagia Symptom Questionnaire (DSQ)
The DSQ is a PRO measure validated for patients age 12 and older with dysphagia related to 
EoE (Dellon et al 2013).  The presence and severity of dysphagia symptoms in the past day 
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). Please note, if the patient reports not eating solid food, 
then the DSQ is considered missing for that day. 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]).

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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 (MCID) and clinically important difference (CID) 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 assessments will be completed by patients daily starting at Visit 1 as described in 
Table 4. 
8.1.3.2
EoE-3D and additional daily questions
The Eosinophilic Esophagitis Daily Dysphagia Diary (EoE-3D) is a daily diary focused on the 
patient experience of EoE.  The diary is episode-based and uses reporting over the past 
24 hours.
The EoE-3D consists of 6 items and focuses on components of an episode of dysphagia. In the 
EoE-3D, respondents are asked to first report on whether they experienced episodes of 
difficulty swallowing in the past 24 hours and if so, how many.  Patients are asked to report 
the time at which the episode occurred to facilitate recall and subsequently respond to 
3 questions on the pain, discomfort, and overall severity of the event using an 11-point 
numeric rating scale (0 [no] to 10 [worst]).  These items are repeated for each episode reported 
by the respondent.  Therefore, the EoE-3D allows for an assessment of the frequency count of 
episodes over time as well as a characterization of the severity of the episode experience over 
time.
Patients are also asked several additional questions to characterize their daily experience. 
These items will be scored separately from EoE-3D.  Patients reporting no solid food 
consumption will be asked to report if this is due to their eosinophilic esophagitis or due to 
other reasons.  Patients will be asked to report, via two separate questions, the severity of 
abdominal pain and the severity of nausea at their worst over the past 24 hours using similar 
11-point numeric rating scales.
Dysphagia episode frequency will be summarized as the total number of dysphagia episodes 
occurring over each 28-day period following randomization. Calculation of the 28-day 
dysphagia episode frequency will require at least 16 days of evaluable data in the period; 
otherwise, the period will be set to missing.

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Dysphagia related pain, discomfort and overall episode severity will be recorded for each 
episode. The severity of these episode characteristics (pain, discomfort, overall severity) will 
be summarized as 14-day mean scores. The 3 separate 14-day means will be calculated as the 
sum of episode response(s) divided by the number of episodes in the same 14-day period.
Calculation of the 14-day mean scores will require at least 8 days of evaluable data during the 
period; otherwise, the mean scores will be set to missing. 
Abdominal pain severity and nausea severity will be summarized individually as 14-day mean 
scores. Each 14-day mean score will be calculated as the sum of daily NRS responses divided 
by the number of days with evaluable data in the same 14-day period. Calculation of the 
14-day means will require at least 8 out of 14 days of evaluable data; otherwise, the mean 
score will be set to missing. 
The daily diary assessments, including EoE-3D, will be completed by patients daily starting at 
Visit 1 as described in Table 4.
8.1.3.3
Adult Eosinophilic Esophagitis Quality of Life Questionnaire (EoE-QoL-A)
The Adult Eosinophilic Esophagitis Quality of Life (EoE-QoL-A) questionnaire is a 30-item 
assessment developed specifically to capture health-related quality of life (HRQoL) in patients 
with EOE (Taft et al 2011).  The assessment is divided into 5 domains: eating/diet impact, 
social impact, emotional impact, disease anxiety and swallowing anxiety.  Patient response is 
captured via a 5-point rating scale.  Overall and domain scores are calculated by taking the 
mean of item responses.
The EoE-QoL-A assessments will be completed by patients weekly (ie., every 7 days) starting 
from Visit 1 as described in Table 4.
8.1.3.4
Pediatric Eosinophilic Esophagitis Symptom Severity Module, Version 2, 
Children and Teens Report (PEESS) 
The Pediatric Eosinophilic Esophagitis Symptom Severity Module, Version 2, Children and 
Teens Report (PEESS) is an 18-item assessment of EoE symptom severity and frequency 
validated for use in patients age 8 to 18 years. The recall period is one month. The first 
18 questions alternate between a question about a given symptom’s frequency (never, almost 
never, sometimes, often, almost always) and a question about the symptom’s severity (face 
rating scale with drawings representing not bad at all, a little bad, kind of bad, bad, very bad). 
The remaining two questions ask about frequency of eating less food than others and 
frequency of needing more time to eat than others. The overall score ranges from 0 to 80, with 
higher scores representing more severe and frequent EoE symptoms.
The PEESS will be completed only by patients who are age 18 years or under at Visit 1. The 
assessment will be completed monthly as described in Table 4 and as per the schedule 
provided in Table 1, Table 2 and Table 3.

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8.1.3.5
Patient Global Impression of Severity
Patient Global Impression of Severity (PGI-S) is a single item designed to capture the 
patient’s perception of overall symptom severity over the past 14 days using a 6-point 
categorical response scale (no symptoms to very severe symptoms).
The PGI-S assessment will be completed by patients on the device every two weeks (i.e., 
every 14 days) starting from Visit 1 as described in Table 4. At Visit 21 and Visit 28 (or 
IPD/EOT visit if before Visit 28), PGI-S will be administered by interview and the data will 
be entered into the eCRF.   
8.1.3.6
Patient Global Impression of Change
Patient Global Impression of Change (PGI-C) is a single item assessment to capture the 
patient’s perception of change in health status.  The patient is asked to report the degree to 
which they 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, 
Much worse).
The PGI-C assessment will be completed by patients weekly (i.e., every 7 days) starting 
7 days after Visit 2 as described in Table 4.
8.1.3.7
SF-36 (Version 2), Acute Recall
The Short Form 36-item Health survey, Version 2 (acute recall) (SF-36v2) is a 36-item, self-
report survey of functional health and well-being, with a 1-week recall period.  Responses to 
35 of the 36 items are used to compute an 8-domain profile of functional health and 
well-being scores.  The remaining item, referred to as the ‘Health Transition’ item, asks 
patients to rate how their current state of health compared to their state of health 1 week ago 
and is not used to calculate domain scores.  The 8-domain profile consists of the following 
subscales: Physical Functioning (PF), Role Limitations due to Physical Health (RP), Bodily 
Pain (BP), General Health Perceptions (GH), Vitality (VT), Social Functioning (SF), Role 
Limitations due to Emotional Problems (RE), and Mental Health (MH). Psychometrically-
based physical and mental health component summary scores (PCS and MCS, respectively) 
are computed from subscale scores to give a broader metric of physical and mental HRQoL.
Two types of thresholds have been developed for interpretation of SF-36v2 scores.  The first 
type is suitable for comparing group mean scores and is generally referred to as the MCID.  
The second type is suitable for interpreting change at the individual level and is referred to as 
the responder threshold or responder definition (QualityMetric 2011).  Threshold values for 
the SF-36v2 scale and summary measures are provided in Table 11.
The SF-36v2 assessment should be completed using the handheld device as described in 
Table 4.  If the SF-36v2 is not complete by the time the patient arrives at the site, the patient 

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will complete the SF-36v2 at the site using the handheld device prior to other study 
procedures.
Table 11
Threshold values for the SF-36v2 scale and summary measures
SF-36v2 score
Threshold
PCS
MCS
PF
RP
BP
GH
VT
SF
RE
MH
Group 
difference
2
3
3
3
3
2
2
3
4
3
Individual 
change
3.4
4.6
4.3
3.4
6.2
7.2
6.2
6.9
4.5
6.2
BP Bodily Pain; GH General Health Perceptions; MCS mental health component summary; MH Mental Health; 
PCS physical component summary; PF Physical Functioning; RE Emotional Problems; RP Role Limitations 
due to Physical Health; SF Social Functioning; VT Vitality.
8.1.3.8
Work Productivity and Activity Impairment questionnaire plus Classroom 
Impairment Questions (WPAI+CIQ)
The 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.  The questionnaire will be completed using the handheld device.
The WPAI+CIQ assessment should be completed using the handheld device as described in 
Table 4.  If the WPAI+CIQ is not complete by time the patient arrives at the site, the patient 
will complete the WPAI+CIQ at the site using the handheld device prior to other study 
procedures.
8.1.4
EndoFLIP (esophageal distensibility) – sub-study
EndoFLIP (Endolumenal Functional Lumen Imaging Probe) is an imaging tool utilizing 
high-resolution impedance planimetry to investigate pressure and cross-sectional area 
relationships during serial volumetric distention, thereby measuring both esophageal 
distensibility and compliance.
At select sites, EndoFLIP will be performed by an EndoFLIP expert at the time of endoscopy  
as per the schedule provided in Table 1.  The data obtained from the EndoFLIP measurements 
will be analysed with a FLIP analytic software and reviewed by an EndoFLIP expert.
Details on the procedure will be available in a separate EndoFLIP Guide provided to the sites.
8.1.5
Early Time Point Sub-study 
In asthmatic patients, the enhanced ADCC 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 as early as 4 weeks post dose (Busse et al 2013, 

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Kolbeck et al 2010, Laviolette et al 2013). Rapid depletion of eosinophils in esophageal tissue  
has also been observed (Freeman et al 2020). 
To generate early time point evidence and demonstrate the impact of eosinophil depletion in 
tissue and to understand its relationship with endoscopic findings and symptom response, 
additional endoscopies will be performed in an Early Time Point Sub-study according to the 
SoA (Table 1). Additional blood samples will also be collected (see Table 1).
Adult patients at participating sites will be offered the opportunity to participate in the Early 
Time Point Sub-study.  Approximately 20 patients are targeted to participate in this sub-study.
All patients recruited up to and including the date when the required number of patients have 
been achieved for the primary analysis (minimum of 170 patients including approximately 40 
adolescents and 130 adults) will contribute to the primary analysis, including any patients 
already recruited to the Early Time Point Sub-study. If at this time sufficient patients have not 
been recruited to the Early Time Point Sub-study, recruitment may be extended for sub-study 
patients only. Sub-study patients recruited after recruitment to the primary analysis population 
is completed will not be included in the primary efficacy analyses, and will be reported in a 
later analysis.
8.2
Safety assessments
Planned time points for all safety assessments are provided in the SoA (Table 1, Table 2 and 
Table 3).
8.2.1
Clinical safety laboratory assessments
See Table 12 for the list of clinical safety laboratory tests to be performed and see the SoA 
(Table 1, Table 2 and Table 3) for the timing and frequency.  All protocol-required laboratory 
assessments, as defined in the table, must be conducted in accordance with the laboratory 
manual and the SoA.
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 8.3.7.
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 in the patient’s medical records.

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The clinical chemistry, haematology and urinalysis will be performed at a central laboratory.
Table 12
Laboratory safety variables
Clinical chemistry
Hematology
Urinalysis
Alkaline phosphatase
Gamma-GT (gamma-
glutamyl 
transpeptidase)
Hematocrit
Appearance
ALT (alanine 
aminotransferase)
Glucose
Hemoglobin
Blood
AST (aspartate 
aminotransferase)
Phosphorus
Mean corpuscular volume 
(MCV)
Color
BUN (blood urea 
nitrogen)
Potassium
Platelet count
Ketones
Calcium
Sodium
Red blood cell (RBC) 
count
Microscopy including 
WBC/high power field 
(HPF), RBC/HPF
Chloride
Total bilirubin
WBC count (absolute and 
differential)a
pH
CO2 (carbon dioxide)b
Uric acid
Specific gravity
Creatinine
Creatine kinase
Cholesterol, total
a
Eosinophil, basophil, and monocyte counts and differentials will be redacted from the central laboratory 
reports starting from Visit 2 (see Section 6.3.2).
b
Measured as bicarbonate.
8.2.1.1
Other laboratory 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 the SoA (Table 1, Table 2 and Table 3).  The analysis will be performed at 
the central laboratory.  Any low-positive or indefinite results must be confirmed prior to 
determining the patient's eligibility.
For patients that are HBsAg positive or anti-HBc positive at Visit 1, hepatitis B e-antigen 
(HBeAg), hepatitis D antibody (anti-HDV) and hepatitis B-virus (HBV) DNA testing will be 
performed. For these subjects that are HBsAg positive or anti-HBc positive, ALT and HBV 
DNA will be drawn monthly at on-site visits to monitor for hepatitis B reactivation. Similarly, 
if patient is using self-administration option, this assessment will be performed at on-site 
visits.

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Instructions for sample collection, processing, storage, and shipment will be found in the 
central laboratory manual.
8.2.2
Pregnancy test
A serum pregnancy test will be done for WOCBP during the run-in period. A urine pregnancy 
test will be performed for WOCBP at each on-site treatment visit prior to IP administration. 
The frequency of urine pregnancy testing is adjusted after week 52 according to the SoA. A 
positive urine test result must be confirmed with a serum pregnancy test. If a serum test is 
positive, the patient should be excluded.
The following tests are applicable to female patients only and will be conducted as per the 
schedule provided in Table 1, Table 2 and Table 3, as applicable.

FSH:  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 analysed at the central laboratory. 

Serum beta- human chorionic gonadotropin (HCG): The test will be performed at Visit 1 
for WOCBP (defined in inclusion criterion 10). This test is to be sent to and analysed at 
the central laboratory.

Urine HCG:  The dipstick test will be performed at the study site for WOCBP as per the 
schedule provided in Table 1, Table 2 and Table 3.  At each on-site treatment visit, the 
test will be performed before IP administration. This kit is to be provided by the central 
laboratory and analysed locally at the sites. Between on-site pregnancy tests, WOCBP 
should be encouraged to follow contraceptive measures and to carefully monitor for 
pregnancy. If the urine test result is positive, the patient should contact the site and should 
not administer IP. 
8.2.3
Physical examinations
Physical examinations (complete or brief) will be done in accordance with the schedule 
provided in Table 1, Table 2 and Table 3.  Baseline data will be collected at the randomization 
visit (Visit 2) before first dose of IP.  Any new findings or aggravated existing abnormalities, 
judged as clinically significant by the Investigator, will be reported as an AE as described in 
Section 8.3.7.
The complete physical examination will include an assessment of the following: general 
appearance, skin, head and neck (including eyes, ears, nose, mouth, and throat), lymph nodes, 
abdomen, musculoskeletal (including spine and extremities), cardiovascular, respiratory, and 
neurological systems.

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The brief physical examination will include an assessment of the general appearance, 
abdomen, cardiovascular, and respiratory system.  
8.2.3.1
Weight and height
The patient's height and weight will be measured in accordance with the schedule provided in
Table 1, Table 2 and Table 3.  The patient's weight will be recorded in kilograms and height 
will be recorded in centimetres.
Weight and height measurements will be performed in light clothing and without shoes.
8.2.4
Vital signs
Pre-dose vital signs, including pulse rate, blood pressure, respiratory rate will be assessed in 
accordance with the schedule provided in Table 1, Table 2 and Table 3.
It is recommended that vital signs are assessed before any interventional study procedures 
(blood test collection, IP administration), and prior to administration of EoE 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 patient has been 
resting for at least 5 minutes in a quiet setting without distractions (e.g., television, cell 
phones). The pulse rate will be obtained before blood pressure.
The respiration rate will be obtained after the patient has been resting for at least 5 minutes, by 
counting the number of breaths (how many times the chest rises) for 1 minute.
8.2.5
Electrocardiograms
Single 12-lead electrocardiograms (ECG) will be obtained in accordance with the schedule 
provided in Table 1 using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, and QT intervals. 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.
ECG will be taken in the supine position, after the patient has been resting for at least 
5 minutes.  The assessment should be performed before interventions with the patient 
(e.g. IP).

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8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section
The definitions of an AE or SAE can be found in Appendix B.
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative).
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow up on AEs 
see Section 8.3.2.1.
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.
8.3.2
Time period and frequency for collecting AE and SAE information 
Adverse Events will be collected from time of signature of informed consent or assent (if 
applicable) form, throughout the treatment period and including the follow-up period/last 
contact with the patient (including the phone follow-up period).
SAEs will be recorded from the time of signing of informed consent form.
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as 
indicated in Appendix B.  The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available.
Investigators are not obligated to actively seek AEs or SAEs in former study patients. 
However, if the Investigator learns of any SAE, including a death, at any time after a patient’s 
last visit and he/she considers the event to be reasonably related to the IP or study 
participation, the Investigator may notify the Sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
8.3.2.1
Regulatory Reporting Requirements for SAEs
Prompt notification by the Investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of patients and the safety of a study 
intervention under clinical investigation are met.

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The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), and Investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to Investigators as necessary.
An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the sponsor will review and then 
file it along with the Investigator’s Brochure or and will notify the IRB/IEC, if appropriate 
according to local requirements.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each patient 
at subsequent visits/contacts.  All AEs/SAEs will be followed until resolution, stabilization, 
the event is otherwise explained, or the patient is lost to follow-up.
Any AEs that are unresolved at the end of the study (database lock) are followed up by the 
Investigator for as long as medically indicated, but without further recording in the CRF.  
AstraZeneca retains the right to request additional information for any patient with ongoing 
AEs/SAEs at the end of the study, if judged necessary.
8.3.4
Adverse event data collection
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

The maximum NCI CTCAE grade 

Whether the AE is serious or not

Investigator causality rating against the IP (yes or no)

Action taken with regard to IP

Administration of treatment for the AE

Outcome
In addition, the following variables will be collected for SAEs:

Date the AE met criteria for serious AE

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
Date Investigator became aware of serious AE

Seriousness criteria

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Causality assessment in relation to study procedure(s)

Description of the SAE
The grading scales found in NCI CTCAE version 5.00 will be utilized for all events. For those 
events without assigned CTCAE grades, the Investigator should assign the CTCAE criteria 
based on the CTCAE definitions. A copy of the CTCAE version 5.00 can be downloaded from 
the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).
8.3.5
Causality collection
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’
For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure, the causal relationship 
is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B.
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or guardian (if applicable) 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 CRF.  When collecting AEs, the recording of diagnoses is 
preferred (when possible) to recording a list of signs and symptoms.  However, if a diagnosis 
is known and there are other signs or symptoms that are not generally part of the diagnosis, 
the diagnosis and each sign or symptom will be recorded separately.
8.3.7
Adverse events based on examinations and tests
The results from the Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarized in the CSR.  Deterioration as compared to baseline in protocol-mandated 
laboratory values and vital signs should therefore only be reported as AEs if they fulfill any of 

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the SAE criteria or are the reason for discontinuation of treatment with the investigational 
product.
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 (e.g., anaemia versus low hemoglobin value).  
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study, see Section 8.3.8 and Section 8.3.9.
8.3.8
Disease-under study (DUS)
Symptoms of DUS are those which might be expected to occur as a direct result of EoE. 
Events which are unequivocally due to EoE should not be reported as an AE during the study 
unless they meet the criteria below.
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms. Outcomes associated with EoE, such as food impaction, and 
symptoms or signs, such as dysphagia, vomiting, heartburn, and abdominal pain will be 
recorded as AEs only when:

The event is serious according to definitions, see Appendix B.

The patient discontinues IP due to the event.

The sign or symptom is new to the patient or not consistent with the patient’s pre-existing 
EoE history (defined as within 1 year of Visit 1) as judged by the Investigator.
Outcomes associated with EoE that do not fulfil any of the above criteria will be captured 
under healthcare resource utilization (see Section 8.10).
8.3.9
Disease progression
Disease progression can be considered as a worsening of a patient’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 a stricture that requires dilatation 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. Interventions that occur due to disease progression will be 
collected and analysed as healthcare resource utilization measures (see Section 8.10).

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8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s).  All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately.  Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
If the electronic data capture system is not available, then the Investigator or other study site 
staff reports a SAE to the appropriate Sponsor representative by telephone.
The Sponsor representative will advise the Investigator/study site staff how to proceed.
The reference document for definition of expectedness/listedness is the Investigator's 
Brochure for benralizumab.
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study 
Protocol.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study patient has received any IP
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy.
Abnormal pregnancy outcomes (eg, spontaneous abortion, foetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.

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8.4.2.1
Maternal exposure
If a patient becomes pregnant during the course of the study, IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an adverse event 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/birth defects) should be 
followed up and documented even if the patient was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
8.4.3
Paternal exposure
Pregnancy of a patient’s partner will not be considered an AE. However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, 
or congenital anomaly) should be followed up and documented for conceptions occurring 
from the date of the first administration of IP until 12  weeks (5 half-lives) after the last 
administration of IP.
8.4.4
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 
patient should be treated supportively with appropriate monitoring as necessary.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the CRF and on the Overdose CRF module.

An overdose without associated symptoms is only reported on the Overdose CRF module

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If an overdose on an AstraZeneca IP occurs in the course of the study, then the Investigator or 
other site personnel inform appropriate AstraZeneca representatives immediately, or no later 
than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see 
Section 8.3.2.  For other overdoses, reporting must occur within 30 days.
8.4.5
Device Constituent Deficiencies
In a combination drug-device IP (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 incorrect 
information supplied by the manufacturer.
SADE (Serious Adverse Device Effect ) 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.
8.4.5.1
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 

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constituent deficiencies will be reported to the regulatory authorities and IRBs/IECs as 
required by national regulations.
8.4.6
Medication error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.2) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B.
8.4.7
Management of IP-related toxicities
Appropriate drugs, such as epinephrine, H1 and H2 antihistamines, corticosteroids, etc, and 
medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis (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 
(Sampson et al 2006).  Anaphylaxis typically manifests as 1 of 3 clinical scenarios:
1
The acute onset of a reaction (minutes to hours) with involvement of the skin, mucosal 
tissue, or both, and at least 1 of the following: a) respiratory compromise; b) reduced 
blood pressure or symptoms of end-organ dysfunction; or
2
Two or more of the following that occur rapidly after exposure: involvement of the 
skin/mucosal tissue, respiratory compromise, reduced blood pressure or associated 
symptoms and/or persistent gastrointestinal symptoms; or
3
Reduced blood pressure after exposure.
Further details on the clinical criteria for defining anaphylaxis and immune complex disease 
are provided in Appendix F 2.
Patients will have had a pre-assessment (i.e. vital signs) prior to IP administration and should 
be observed after IP administration for any acute drug reactions in line with clinical practice.

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Serum tryptase or other blood or urine testing relevant to the diagnosis of anaphylaxis may be 
obtained at a local lab at the discretion of the Investigator. If local analysis of serum tryptase 
is unavailable, there will be an option to have the sample analysed at the central lab.
8.5
Pharmacokinetics
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
AstraZeneca and site study files, but will not constitute a protocol amendment.  The IRB/IEC 
will be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICF.
For the PK analysis it is important that the date and time of each SC injection is recorded for 
each patient.
Instructions for sample collection, processing, storage, and shipment can be found in the 
separate laboratory manual provided to the study sites.
Serum will be collected pre-dose in accordance with the schedule provided in Table 1, Table 2
and Table 3.
8.5.1
Determination of drug concentration
Samples for determination of benralizumab concentration in serum will be analysed for all 
patients receiving benralizumab at an appropriate contract laboratory on behalf of 
AstraZeneca, using a validated bioanalytical method.
A summary of PK analysis results will be reported in the CSR.
8.5.2
Storage and destruction of pharmacokinetic samples
Samples may be stored for a maximum of 5 years from the date of the last patient’s last visit 
(end of study is defined in Section 4.4), after which they will be destroyed.
Guidance regarding handling, transport, and destruction of human biological samples is 
provided in Appendix C.
8.6
Pharmacodynamics
Blood eosinophil levels are an important marker of the pharmacodynamic effect of 
benralizumab and will be assessed as part of the hematology safety testing, see Section 8.2.1. 
 

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8.7
Genetics
8.7.1
Optional exploratory genetic sample
A blood sample for DNA isolation will be collected at one time point only from patients who 
have consented to participate in the genetic analysis component of the study.  Participation is 
optional.  Patients who do not wish to participate in the genetic research may still participate 
in the study.
Samples can be collected at any time after the genetic consent form is signed.  The blood 
sample should be collected at randomization (Week 0); however, it may be taken at any visit 
until the last study visit.  In the event of DNA extraction failure, a replacement genetic blood 
sample may be requested from the patient.
Adolescent patient samples will not be collected for optional genetic research.
See Appendix D for Information regarding genetic research.  Details on processes for 
collection and shipment and destruction of these samples can be found in Appendix D or in 
the Laboratory Manual.
8.7.2
Storage and destruction of genetic samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. Samples may be stored for a maximum of 
15 years or as per local regulations from the date of the Last Patient’s Last Visit, after which 
they will be destroyed.  Deoxyribonucleic acid (DNA) is a finite resource that may be used up 
during analyses.  The results of any further analyses will be reported either in the CSR itself or 
as an addendum, or separately in a scientific report or publication.
No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA.
8.8
  
 
 
 
 

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8.9
Immunogenicity
Blood samples for determination of ADA in serum will be assayed at the discretion of 
AstraZeneca by bioanalytical test site 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. ADA samples may also be further tested for characterization of 
the ADA response. Neutralizing antibodies (nAb) may be assessed on ADA positive samples. 
Samples will be collected according to the SoA (Table 1, Table 2 and Table 3), labelled, 
stored and shipped as detailed in the Laboratory manual. 
8.10
Healthcare resource utilization 
Healthcare resource utilization data, associated with medical encounters related to EoE, will 
be collected in the eCRF by the Investigator or designee for all patients throughout the study.  
The data may be used as input to cost analyses for example cost utility analysis or cost 
effectiveness analysis.  Protocol-mandated procedures, tests, and encounters are excluded.
At visits when healthcare use is being collected, as specified in the SoA (Table 1, Table 2 and 
Table 3) the Investigator should ask the patient if they have had any need to seek medical 
treatment for EoE or an EoE-related episode (e.g., an intervention for food impaction or 
stricture requiring dilatation) since last healthcare resource utilization assessment during the 
previous scheduled visit.

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8.11
Other assessments
8.11.1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8.11.2
Diet questionnaire
A diet questionnaire will be completed at Visit 1, monthly between Visit 2 and Visit 28 (Week 
104), and thereafter at 3-month intervals in accordance with the schedule provided in Table 1, 
Table 2 and Table 3. The Investigator or designee will interview the patient and enter the 
information via a web portal.
The diet questionnaire is a tool to capture patient-reported diet and eating behaviors related to 
EoE. The questionnaire will consist of sections related to initiation or discontinuation of 
elimination diets and the defining parameters of these diets. Further, the questionnaire will ask 
patients to characterize EoE-related eating behaviours or self-initiated symptom management 
techniques.
8.11.3
Patient Testing Due to Public Health Crisis
If patient testing is performed due to the public crisis, the results may be documented for this 
study. 
9
STATISTICAL CONSIDERATIONS
All patients recruited up to and including the date when the required number of patients have 
been achieved for the primary analysis (minimum of 170 patients including approximately 40 
adolescents and 130 adults) will contribute to the primary analysis. If at this time sufficient 
patients have not been recruited to the Early Time Point Sub-study, recruitment may be 
extended for sub-study patients only. Sub-study patients recruited after recruitment to the 
primary analysis population is completed will not be included in the primary efficacy
analyses, and will be reported in a later analysis.
The primary database lock is targeted to occur when all patients randomised for the primary 
analysis have completed the 24-week DB treatment period, including those who have had the 
opportunity to complete at least 52 weeks of follow-up (i.e., DB+OL treatment periods). The 
primary CSR for the study will be written based on this analysis and all data reported up to the 
primary database lock will be included.  Additional analyses may be performed after the last 
patient completes 52 weeks of follow up and/or when sufficient patients numbers and follow 

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up in the Early Time Point Sub-study is achieved, if this was not available at the primary 
analysis.
The final database lock will occur after the last patient completes the OLE period and FU 
visit.  Data reported at this analysis will be presented in an addendum to the primary analysis 
CSR.
9.1
Statistical hypotheses
For the first primary endpoint of proportion of patients achieving a histological response at 
Week 24, the null hypothesis is that the odds of responding on benralizumab 30mg Q4W is 
equal to the odds of responding on placebo (this can be interpreted as the proportion of 
responders on benralizumab 30 mg Q4W is equal to the proportion of responders on placebo).  
The alternative hypothesis is that the odds of responding on benralizumab 30 mg Q4W is not 
equal to the  odds of responding on placebo, i.e.:
H0: Odds ratio (benralizumab 30 mg / Placebo) = 1
H1: Odds ratio (benralizumab 30 mg / Placebo) ≠ 1
For the second primary endpoint of change from baseline in DSQ score at Week 24, the null 
hypothesis is that the change in DSQ for patients on benralizumab 30 mg Q4W is equal to the 
change in DSQ for patients on placebo.  The alternative hypothesis is that the change in DSQ 
for patients on benralizumab 30 mg Q4W is not equal to the change in DSQ for patients on 
placebo, i.e.:
H0: Difference in change from baseline in DSQ at Week 24 (benralizumab 30 mg –
Placebo) = 0
H1: Difference in change from baseline in DSQ at Week 24 (benralizumab 30 mg –
Placebo) ≠ 0
Hypothesis testing for the primary analyses will be performed at the 2-sided 5% significance 
level.  If the p-value is less than 0.05 and the treatment effect favors benralizumab, reject H0
and accept H1.
A multiple testing procedure will be applied to the primary endpoints and key secondary 
endpoints; details are provided in Section 9.4.5.
9.2
Sample size determination
Approximately 170 patients will be randomized in a 1:1 ratio to benralizumab or matching 
placebo.  This will provide >95% power for the first primary endpoint of proportion of 
patients achieving histological response to demonstrate an increase from 20% or less on 

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placebo, to 50% on benralizumab at the 2-sided 5% significance level.  This is a conservative 
estimate of the likely placebo histological response rate as lower placebo rates have been 
reported in previous EoE studies (Hirano et al 2017, Dellon et al 2017).  The power 
calculation for the second primary endpoint of the change from baseline in DSQ score at 
Week 24 is based on detecting similar effect sizes (mean difference in change from baseline of 
the PRO / standard deviation) as seen in previous studies (Hirano et al 2017, Hudgens et al 
2017, Lucendo et al 2017).  Assuming an effect size of 0.6, which equates to a 7.2-point 
difference in change in the DSQ, 85 patients per arm will allow >95% power for statistical 
significance at the 5% 2-sided level.  The high level of power for the primary endpoints will 
ensure stronger statistical evidence can be demonstrated in this single Phase 3 study. 
The amount of missing data for the histological response rate endpoint is expected to be low, 
based on rates previously reported; 96% of patients in Hirano et al 2017 had peak eosinophil 
counts available at Week 12; 94% of patients in Dellon et al 2017 had evaluable 
post-treatment DSQ and biopsy data at Week 12.  There is some uncertainty in the amount of 
missing data for the DSQ endpoint at Week 24 given the limited data available to date on this 
tool and differences in length of follow-up between this study and the referenced trials.  
However measures are in place in the protocol to limit missing data by excluding 
non-compliance during the run-in period and monitoring overall compliance with the PRO on 
an ongoing basis.  In addition, patients who discontinue randomised therapy are accounted for 
in the analyses using a composite estimand strategy. Given this estimand strategy which 
imputes outcomes for the most likely potential source of missing data, it is considered un-
likely that there will be much remaining missing data in the analyses, but with missing data 
rates at Week 24 as high as 25%, the study still maintains >90% power for statistical 
significance under the assumptions highlighted above.
Success in the adolescent population will be dependent on demonstrating broadly consistent 
results with the overall population. With 20 adolescents per arm there is a high chance of 
demonstrating consistent effects, if they truly exist. For the histological response rate at 
Week 24 endpoint, there is a 99% chance of observing an adolescent treatment difference that 
is at least half of the overall population effect, assuming the true histological response rates 
are 65% on benralizumab and 10% on placebo. For the change in DSQ endpoint at Week 24 
there is an 86% chance of observing an adolescent treatment difference that is at least half of 
the overall population effect, assuming the true treatment effect for the DSQ endpoint is as 
outlined in the sample size justification above.
The focus of the Early Time Point Sub-study is to characterise the time profile of tissue 
eosinophil depletion with benralizumab, with contextualisation versus the placebo control 
arm.  Therefore the sample size of this sub study has been chosen to adequately characterise 
the changes in tissue eosinophils over time. For example, 10 patients per arm provides >80% 
power for statistical significance at the 2-sided 5% level to detect a difference between 

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benralizumab and placebo in the % change from baseline in tissue eosinophils of at least 80% 
(eg 20% increase on placebo versus 60% reduction on benralizumab). A pooled standard 
deviation of 60 is assumed in these calculations based on the dupilumab phase 2 data on % 
tissue eosinophil reduction at week 12, where a 14% increase on placebo versus 93% 
reduction on dupilumab was observed (Hirano et al 2017).
9.3
Populations for analyses
For purposes of analysis, the following populations are defined:
Population
Description
All patients analysis set
All patients screened for the study, to be used for reporting of disposition and 
screening failures.
Full analysis set
All randomized patients who received at least 1 dose of IP, irrespective of 
their protocol adherence and continued participation in the study.  Patients will 
be analysed according to their randomized treatment irrespective of whether or 
not they have been prematurely discontinued, according to the ITT principle.  
Patients who withdraw consent or assent to participate in the study will be 
included up to the date of their study termination.
Safety analysis set
The Safety analysis set consists of all patients who have received at least one 
dose of IP.
Erroneously treated patients (e.g., those randomized to treatment A but 
actually given treatment B) are accounted for in the treatment group of the 
treatment they actually received.
A patient who has on one or several occasions received active IP is classified 
as active.
Safety summaries and ADA data will be based on this analysis set and for 
whom any post-dose data are available.
Pharmacokinetic analysis set
All patients who received benralizumab and from whom PK blood samples 
are assumed not to be affected by factors such as protocol violations (e.g. 
received wrong dose) and who had at least 1 quantifiable serum PK 
observation post first dose.  All PK summaries will be based on this analysis 
set.
OL benralizumab analysis 
set
All patients who start or carry on receiving at least 1 dose of benralizumab 
after the end of the Week 24 DB treatment period.
OLE benralizumab analysis 
set
All patients who carry on receiving at least 1 dose of benralizumab after the 
end of the Week 52 DB + OL treatment periods.
ADA  Anti-drug antibodies; DB  Double-blind; IP  Investigational product; ITT  Intent-to-Treat; OL Open-label; 
OLE Open-label extension period ; PK  Pharmacokinetic
9.4
Statistical analyses
All personnel involved with the analysis of the study will remain blinded until the primary 
database lock and Clinical Study Protocol deviations identified.

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Analyses will be performed by AstraZeneca or its representatives. A comprehensive statistical 
analysis plan (SAP) will be developed and finalised before database lock and will describe the 
patient populations to be included in the analyses, and procedures for accounting for missing, 
unused, and spurious data.  This section is a summary of the planned statistical analyses of the 
primary and secondary endpoints.  Any deviations from this plan will be reported in the CSR.
In general, the baseline value for statistical analysis is the last non-missing value prior to 
administration of the first dose of IP. Details are described in the SAP.
9.4.1
Efficacy analyses
9.4.1.1
General principles
The primary efficacy analyses will be based on the DB placebo-controlled first 24 weeks of 
the study (DB period).  In this part of the study all efficacy analyses will use the full analysis 
set (FAS) as defined above, and patients will be analysed according to their randomized 
treatment, following the Intention-to-Treat principle.
A composite estimand strategy will be used for the primary analyses of endpoints at week 24, 
whereby any patient with intercurrent events of IP discontinuation, an increase of background 
therapy or addition of a new therapy for EoE, or having a dilation procedure will be 
considered as treatment failures at week 24. For the histologic response rate endpoint, patients 
with these intercurrent events prior to week 24 will be considered non-responders at week 24; 
for the change in DSQ at week 24 endpoint, and for other change from baseline continuous 
endpoints, any patient experiencing the described intercurrent events will have their week 24 
value imputed using return to baseline multiple imputation methods.
All patients who prematurely discontinue from IP or have any changes to background 
therapies for EoE are asked to come in for all visits and study assessments up to week 52. 
Therefore, sensitivity analyses can be performed to assess the robustness of the efficacy 
results to these estimand approaches and missing data assumptions as described in individual 
endpoint analysis methods and Section 9.4.1.2 below.
Analyses will include factors or strata (as appropriate) for each of region, use of swallowed 
steroids at baseline (categorical, Yes/No), and presence of strictures at baseline, to ensure any 
imbalances in these factors are adjusted for in the treatment effects estimated. However, in the 
instance of convergence issues/small strata for stratified analyses, presence of strictures at 
baseline may be removed if necessary. 
All analyses of Week 52 endpoints will be descriptive as no placebo control is available at that 
timepoint and so no hypothesis testing will be performed.  Week 52 analyses will primarily be 
presented on the FAS, but a repeat of key analyses may also be produced on the OL 
benralizumab analysis set to ensure only patients who switched to receive benralizumab after 
24 weeks are included in the denominator for that group and to ensure a meaningful 

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interpretation of the placebo-to-benralizumab patients.  Full details of the Week 52 analysis 
groupings and methods will be provided in the SAP.
Demography and baseline characteristics will be summarized by treatment group for the FAS.  
In the event that there are major differences between the FAS and safety analysis set, these 
summaries will also be repeated for the safety analysis set.
9.4.1.2
Primary analysis method
Histological response rate
The first of the primary dual endpoints, the proportion of patients achieving a histological 
response at Week 24, will be compared between benralizumab and placebo using a CMH test 
stratified by region, use of swallowed steroids at baseline (categorical, Yes/No), and presence 
of strictures at baseline.  The results of the analysis will be presented using an odds ratio, 
together with its associated 95% confidence intervals (CIs) and 2-sided p-value.  Results will 
also be transformed into a difference in proportions for ease of interpretation.  The number 
and percentage of histological responders will also be summarized by randomized treatment 
with confidence intervals around the proportions.
A sensitivity analysis to the CMH test may be performed using a logistic regression with 
covariates.
The analysis of histological response rate at Week 24 will include data collected at the 
Week 24 visits including a window of +/-2 weeks.  Patients with no biopsy data at Week 24 
will be considered non-responders.  Sensitivity analyses may be performed including all 
post-baseline biopsy data to assess the impact of any additional data collected that may have 
been outside of the Week 24 window.
Change from baseline in Dysphagia Symptom Questionnaire (DSQ)
The second of the dual-primary endpoints, the change from baseline in DSQ score at 
Week 24, will be compared between the benralizumab and placebo treatment groups using a 
composite estimand strategy where subjects with the intercurrent events described above at or 
before week 24 will have their change from baseline value imputed at each timepoint from the 
time of the intercurrent events occurring onwards using return-to-baseline multiple 
imputation.  This method will impute values multiple times for the change from baseline 
drawing from a normal distribution with mean 0 and variance as a function of the number of 
completers and variance of the completers, Vimp = (1 + 1/Nc)*Vc. For each imputation 

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dataset, the change from baseline in DSQ score at Week 24 will then be analyzed using an 
analysis of covariance (ANCOVA) model. 
The model will include change from baseline in DSQ score at Week 24 as the dependent 
variable, baseline DSQ score as a continuous covariate, and region, swallowed steroids used at 
baseline (categorical, Yes/No), and presence of strictures at baseline as categorical covariates. 
The model will be used to estimate the mean change from baseline at Week 24 for each 
treatment group and the difference versus placebo, with corresponding 95% confidence limits. 
A p-value, corresponding to a 2-sided test, will be presented to compare the benralizumab and 
placebo treatment groups. Results will be combined across the imputations using Rubin's rule
(Rubin et al 1986, Rubin et al 1987).
Descriptive statistics to summarize reasons for non-evaluable daily DSQ score data due to the 
patient reporting no solid food consumption will be provided.  Full details will be defined in 
the SAP.
To support the change from baseline in DSQ results, clinically meaningful within patient 
change responder categories will be defined and proportion of responders summarized by 
visit.  The threshold used to define responder categories will be explored using the data 
generated in this study using anchor based methods supplemented with empirical cumulative 
distribution functions and probability density functions; results will also be presented using 
the MCID of -6.5 points presented in the literature (Hudgens 2017).  Additional analyses to 
characterize patient dysphagia experience and correlations between the two primary endpoints 
may also be explored.  Full details will be defined in the SAP.
9.4.1.3
Analysis methods for secondary efficacy variables
Analyses of the secondary variables will follow the same treatment failure approach to handle 
intercurrent events as described above for the primary endpoints (non responder imputation 
for binary endpoints, return to baseline multiple imputation for continuous endpoints).
The key secondary endpoint of percent change from baseline in tissue eosinophils at Week 24 
will be compared between the benralizumab and placebo treatment groups using an analysis of 
covariance (ANCOVA) model. The dependent variable will be percent change from baseline 
eosinophils at Week 24, and baseline eosinophils along with treatment, region, use of 
swallowed steroids at baseline (categorical, Yes/No), and presence of strictures at baseline as 
covariates.
The key secondary endpoints of change from baseline in EoE-HSS grade and stage scores at 
Week 24 will be compared between benralizumab and placebo treatment groups using 
ANCOVA models similarly as above.

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The key secondary endpoint of change from baseline in centrally-read EREFS at Week 24 will 
be compared between the benralizumab and placebo treatment groups using an ANCOVA 
model.  The dependent variable will be the change from baseline in centrally-read EREFS 
score at Week 24, baseline centrally-read EREFS score and treatment will be included as 
covariates along with region, use of swallowed steroids at baseline (categorical, Yes/No), and 
presence of strictures at baseline.  The primary analysis of change in centrally-read EREFS at 
Week 24 will include centrally-read data collected at the Week 24 visit including a window of 
±2 weeks.  In addition, exploration into the concordance between site recorded and centrally-
read data may be performed.  Full details will be specified in the SAP.
The key secondary endpoint of treatment responder rate at Week 24 is a composite endpoint 
of histological response and clinically meaningful improvement from baseline in DSQ (30% 
improvement) (Hudgens et al 2017Dellon et al 2014). The endpoint will be analyzed using 
logistic regression with treatment response as the dependent variable, and covariates of 
treatment, region, use of swallowed steroids at baseline, and presence of strictures at baseline. 
The results of the analysis will be presented using an odds ratio, together with its associated 
95% confidence intervals (CIs) and 2-sided p-value.  Results will also be transformed into a 
difference in proportions for ease of interpretation.
To support the primary histological response rate endpoint, further summaries and analyses of 
tissue eosinophil counts and EoE-HSS from centrally-read biopsies will be performed.  These 
will include summaries of number of patients achieving histological response to certain levels 
will be produced (<1, 1 to ≤6, 7 to <15 eos/hpf, etc.).
Other continuous secondary endpoints collected by visit up to Week 24 including changes 
from baseline in PEESS, EoE QoL-A, changes in SF-36v2 scores, and changes in EoE-3D and 
daily assessments will be analysed using ANCOVA in a similar way to that described for the 
change in DSQ primary endpoint.  For these analyses the dependent variable will be the 
change from baseline in the respective continuous endpoint at Week 24, and each will include 
the relevant baseline score as a covariate. Additional responder analyses and descriptive 
summaries of the PRO assessments will be produced to further characterize patient 
symptomatology and health status.
Categories of PGI-C, PGI-S and percentage of patients with relevant procedures and 
healthcare resource utilization during the study will be summarized by visit and during the 
study.  No formal analyses will be performed.
Change from baseline in EndoFLIP scores at Week 24 will be analysed using an ANCOVA 
model with change in EndoFLIP score as the dependent variable and baseline score along with 
treatment and other covariates (region, use of swallowed steroids at baseline (categorical, 
Yes/No), and presence of stricture at baseline) as explanatory variables.

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Descriptive summary statistics and graphical data displays will be used for Week 52 efficacy 
data and all analyses of data in the OLE, no formal statistical analyses will be performed.  
Details will be provided in the SAP.
9.4.1.4
Sensitivity analyses
Sensitivity analyses for the primary and key secondary endpoints based on different estimand 
strategies and different missing data mechanism assumptions including those expected to 
more conservative, will be used to explore the robustness of any treatment effect including 
other multiple imputation approaches and tipping point analyses.  Full details of sensitivity 
analyses will be pre-specified in the SAP and documented prior to database lock of the study.
Sensitivity analyses may also be considered to explore the effect of extreme outliers on 
individual endpoints, such as rank based methods.  Full details of these will be pre-specified in 
the SAP.
9.4.1.5
Subgroup analysis
Analyses of the primary endpoints will be performed to explore the consistency of the 
treatment effect across key pre-defined subgroups.  These will include but are not limited to 
explorations into background medications at baseline and prior response to background 
medications, presence of strictures at baseline, dietary restrictions, and duration of EoE.  Full 
details of all subgroup analyses and statistical modelling including possible testing of 
interaction between treatment group and covariates will be described in the SAP.
9.4.2
Safety analyses
Safety analyses will be performed using the safety analysis set.
The first analysis of safety data will include only data from the DB, placebo-controlled first 24 
weeks of the study (DB period).  Patients will be analysed according to the treatment they 
received (benralizumab or placebo).  A second analysis of safety data will include all data 
reported in the study for patients receiving benralizumab from the start of treatment.  Safety 
data from patients’ entire duration on benralizumab during the DB period, along with the 
benralizumab OL period and OLE period will be summarized.  Additional safety data 
presentations based on the OL benralizumab set will be included to summarise safety data 
from patients who switched from placebo to receive benralizumab after 24 weeks, with only 
their safety data while receiving benralizumab included.  If there is considerable drop out 
between the first 52 weeks of the study and the OLE, additional safety summaries may be 
produced on the OLE benralizumab analysis set to avoid any concern around rollover bias 
between parts of the study.  Full details of the groupings and analysis periods will be provided 
in the SAP.

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In general, the baseline value for statistical analysis is the last non-missing value prior to 
administration of the first dose of IP. Details are described in the SAP.
Adverse events
Adverse events will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA) that will have been released for execution at AZ/designee.
Safety data will be presented using descriptive statistics unless otherwise specified in the SAP.
Adverse events will be presented for each treatment group by system organ class and 
preferred term, including the number and percentage of patients 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 patients with any AE, AEs with outcome of death, serious AEs, and AEs 
leading to discontinuation of IP.
Separate AE tables will be provided taking into consideration the relationship as to IP 
assessed by the Investigator, maximum intensity, seriousness, death and events leading to 
discontinuation of IP, as well as other action taken related to IP.
An additional table will present number and percentage of patients with most common AEs 
(frequency of ≥3%).
In accordance with the requirements of the FDA, a separate table will present non-serious AEs 
occurring in more than 5% of patients in any treatment group.
Key patient information will be presented for patients with AEs with outcome of death, 
serious AEs, and AEs leading to discontinuation of IP.
An AE listing for the safety analysis set will cover details for each individual AE.
Plot of frequencies and risk differences (forest plots) between treatment arms will be 
presented for the most common AEs and other specific events of interest. Estimates and 
confidence intervals based on the Miettinen-Nurminen method will also be presented for the 
most common AEs and any other specific events of interest included in the structured 
assessment of benefit risk.
Full details of AE analyses will be provided in the SAP.

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Treatment emergent
The following events are considered treatment emergent:

Adverse events with an onset date on or after the first dose of IP

Worsening of pre-existing events on or after first dose of IP
Clinical laboratory safety assessments
Laboratory data for hematology and clinical chemistry will be summarized.  The frequency of 
changes with respect to normal ranges between baseline and each post-treatment time point 
will be tabulated.  Frequencies of clinically noteworthy values (defined in the SAP) occurring 
during the clinical study will also be given.  Shifts from normal to abnormal between baseline 
and each post-baseline time point will be evaluated for urinalysis.
Vital signs and weight
Vital sign parameters will be presented for each treatment group. Summary statistics for 
continuous variables cover n, mean, SD, Minimum, Q1, median, Q3, and Maximum. 
Frequency tables cover number and percentage of patients in the respective category.
For each scheduled post-baseline visit, descriptive statistics for all vital sign parameters 
(systolic and diastolic blood pressure, pulse, respiration rate, oral temperature) and body 
weight will be presented for observed values and change from baseline.
Changes in vital signs and weight will be examined according to Table 1. Table 2 and Table 3. 
Frequencies of clinically noteworthy values (defined in the SAP) occurring during the clinical 
study will be presented.
Details of vital sign analyses will be provided in the SAP.
Shifts from normal to abnormal between baseline and follow-up will be evaluated for the 
physical examination.
9.4.3
Immunogenicity analyses
Anti-drug antibodies to benralizumab will be summarized using descriptive statistics at each 
visit. The impact of ADA on PK and eosinophil level may be assessed.  The potential 
association of ADA with safety and efficacy may be evaluated.  Further details will be 
provided in the SAP.

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9.4.4
Other analyses
Pharmacokinetic and pharmacodynamic exploratory analyses will be described in the SAP 
finalized before database lock.
The focus of the Early Time Point Sub-study is to characterise the time profile of tissue 
eosinophil depletion with benralizumab, with contextualisation versus the placebo control 
arm. Analyses will focus on summarising and plotting the tissue eosinophils and change in 
eosinophils over time, any statistical testing performed will be considered exploratory.  
Exploration into the relationship between tissue eosinophil depletion and symptom 
improvements will be performed using scatterplots and time profile plots of absolute values 
and changes from baseline in these measures together on a patient level if appropriate.  Full 
details of these analysis, and those of other exploratory endpoints will be pre-defined in an 
analysis plan which will be finalized before the primary database lock.
9.4.5
Methods for multiplicity control
To account for multiplicity testing for the primary endpoints (histological response rate and 
changes from baseline in DSQ at Week 24) and the key secondary endpoints listed below, a 
hierarchical testing strategy will be used to strongly control the overall type 1 error rate at the 
0.05 level.
If the null hypothesis for the first primary endpoint of histological response rate at 24 weeks is 
not rejected (i.e. p-value >0.05), no null hypotheses will be rejected for any other endpoint in 
the study.  If the null hypothesis is rejected for the first dual-primary endpoint, then 
hierarchical fixed-sequence testing will continue at the α=0.05 level moving to the second 
dual-primary endpoint of change from baseline in DSQ at Week 24 and subsequently to the 
key secondary endpoints in the following order:

Percent change from baseline in tissue eosinophils at Week 24

Change from baseline in EoE-HSS grade score at Week 24

Change from baseline in EoE-HSS stage score at Week 24

Change from baseline in EREFS at Week 24

Treatment responder rate at Week 24
At any time that a null hypothesis cannot be rejected (i.e. p-value >0.05), further testing will 
stop and no subsequent null hypothesis in the testing hierarchy will be rejected. It is noted that 
for the purpose of US marketing approval both primary endpoints would need to be 
statistically significant.

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9.5
Interim analyses
No formal interim analysis is planned for this study.
9.6
Independent Data monitoring committee (IDMC)
An IDMC will be utilized for this study.  Section A 5 provides more details on the rationale 
for and the remit of the committee.

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10
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Bleecker et al 2016
Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and 
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11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS

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

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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 and will notify the IRB/IEC, if 
appropriate according to local requirements.
A 2
Financial Disclosure
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process
The Investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorized representative and answer all questions regarding the study.
Patients must be informed that their participation is voluntary for the entire study and they are 
free to refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Patients or their legally authorized representative will be required to sign a 
statement of informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, 
where applicable, and the IRB/IEC or study site.
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date and time the written consent was 
obtained.  The authorized person obtaining the informed consent must also sign the ICF.
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
A copy of the ICF(s) (or assent forms, if applicable) must be provided to the patient and/or 
legal representative.
If a patient declines to participate in any voluntary exploratory research component of the 
study, there will be no penalty or loss of benefit to the patient and he/she will not be excluded 
from other aspects of the study.
Patients who are re-screened are required to sign a new ICF.
The ICF will contain a separate section that addresses the use of remaining samples for future 
research projects. Adult patients will give a separate agreement to allow any remaining 
specimens to be used for future research. Patients will be told that they are free to refuse to 

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participate and may withdraw their consent at any time and for any reason during the storage 
period.  Patients who decline to participate in this optional research will indicate this in the 
ICF.  If a patient withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed, and the action documented.  If samples already have been analysed 
at the time of the request, AstraZeneca will not be obliged to destroy the results of this 
research.  
At sites selected for the EndoFlip and/or 
sub-studies, and/or the 
Early Time Point Sub-study, the ICF will contain separate sections  with additional 
information on those sub-studies.  If a patient’s partner becomes pregnant during or within 12 
weeks after the study, the partner is asked to sign the "Adult Study Informed Consent Form 
for Pregnant Partners of Study Patients" and provide information about the pregnancy 
accordingly. 
A 4
Data Protection
Each patient will be assigned a unique identifier by the Sponsor (eCode).  Any patient records 
or data sets transferred to the Sponsor will contain only the identifier; patient names or any 
information which would make the patient identifiable will not be transferred.
The patient must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law.  The level of disclosure and use of their 
data must also be explained to the patient in the informed consent .
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Independent Data Monitoring Committee
An independent DMC consisting of 2 clinicians (including at least 1 EoE expert) and a 
statistician will be used for this study to monitor overall patient safety. The IDMC will receive 
patient profiles including safety data and unblinded patient laboratory results on a regular 
basis and will meet to discuss the data as needed. Based on their review, the IDMC may 
recommend changes to the study design or conduct or that individual patients be discontinued 
from the study for safety reasons. 
The IDMC 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 IDMC requests and will communicate back their actions and 
justification to the IDMC.

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Further details, composition and operation of the IDMC are described in the separate IDMC 
charter.
The safety of all Sponsor clinical studies is closely monitored on an ongoing basis by the 
Sponsor representatives in consultation with Patient Safety.
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.clinicaltrialsregister.eu, as will the summary of the main study results when they 
are available. The clinical study and/or summary of main study results may also be available 
on other websites according to the regulations of the countries in which the main study is 
conducted.
A 7
Data Quality Assurance
All patient data relating to the study will be recorded on a printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (e.g., laboratory data).  The Investigator 
is responsible for verifying that data entries are accurate and correct by electronically signing 
the CRF.
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the Sponsor.  No records may be 
transferred to another location or party without written notification to the Sponsor.

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A 8
Source Documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected.  Source documents are filed at the Investigator’s site.
Data 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.
Definitions of what constitutes source data can be found in the data monitoring plan.
A 9
Study and Site Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
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 
with sufficient notice and approval is given in advance of the intended termination.
Reasons for the early closure of a study site by the Sponsor or Investigator may include, but 
are not limited to:

Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines

Inadequate recruitment of patients by the Investigator

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.

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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.  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 Event Definitions and Additional Safety Information
B 1
Definition of Adverse Events
An adverse event is the development of any untoward medical occurrence in a patient or 
clinical study patient administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (e.g. an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product.
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence.  An AE may occur at any time, including 
run-in or washout periods, even if no IP has been administered.
B 2
Definitions of Serious Adverse Event
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability or incapacity

Is a congenital anomaly or birth defect

Is an important medical event that may jeopardize the patient 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 judgement on an individual event basis 
should be applied to clarify that the malignant tumour event should be assessed and reported as a 
Non-Serious AE. For example, if the tumour is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumour, the AE may not fulfill the attributes for being assessed as Serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumours, which do not spread remotely after a routine treatment that does 
not require hospitalization, may be assessed as Non-Serious; examples include Stage 1 basal cell 
carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.

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B 3
Life Threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (e.g. hepatitis that resolved without hepatic failure).
B 4
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g. 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 patient was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
B 5
Important Medical Event or Medical Treatment
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the patient or may require 
medical treatment to prevent one or more outcomes listed in the definition of serious.  These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring intraveous 
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (e.g. neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse
B 6
Intensity Rating Scale:
The grading scales found in NCI CTCAE version 5.00 will be utilized for all events. For those 
events without assigned CTCAE grades, the Investigator should assign the CTCAE criteria 
based on the CTCAE definitions. A copy of the CTCAE version 5.00 can be downloaded from 
the Cancer Therapy Evaluation Program website (http://ctep.cancer.gov).

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B 7
A Guide to Interpreting the Causality Question
When making an assessment of causality, consider the following factors when deciding if 
there is a ‘reasonable possibility’ that an AE may have been caused by the drug:

Time Course.  Exposure to suspect drug.  Has the patient actually received the suspect 
drug?  Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience.  Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?

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 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.

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B 8
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the patient or 
has the potential to cause harm to the patient.
A medication error is not lack of efficacy of the drug, but rather a human- or process-related 
failure while the drug is in control of the study site staff or patient.
Medication error includes situations where:

An error occurred

An error or situation that could have led to an error was identified and intercepted before 
the patient received the drug
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error e.g. medication prepared incorrectly, even if it was not actually given to 
the patient

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as a 
solid tablet

Drug not stored as instructed e.g. kept in the fridge when it should be at room temperature

Wrong patient received the medication (excluding IWRS errors)

Wrong drug administered to patient (excluding system IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IWRS - including those which lead to one of the above 
listed events that would otherwise have been a medication error

Patient accidentally missed drug dose(s) e.g. forgot to take medication

Accidental overdose (will be captured as an overdose)

Errors related to background and rescue medication, or standard of care medication in OL 
studies, even if an AZ product
Medication errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.

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Appendix C
Handling of Human Biological Samples
C 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Investigator at each study site keeps full traceability of collected biological samples from 
the patients while in storage at the site until shipment or disposal (where appropriate).
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers.
Samples retained for further use will be stored in the AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.
C 2
Withdrawal of informed consent/assent for donated biological 
samples 
If a patient and/or legal representative withdraws consent/assent to the use of donated 
biological samples, the samples will be disposed of/destroyed, and the action documented.  If 
samples are already analysed, AstraZeneca is not obliged to destroy the results of this 
research.
As collection of the biological sample(s) is an integral part of the study where mandatory 
sampling conforms with the clinical safety laboratory test requirements, then the patient is 
withdrawn from IP.  In the case where a patient and/or legal representative allows for 
collection and analysis of biological samples (for clinical safety laboratory tests) but 
specifically withdraws his/her consent/assent for the use of samples for exploratory research 
or retention of samples for exploratory research after the end of the study, the patient does not 
need to be discontinued from IP and will be allowed to continue participation in the study.
The Investigator or designee:

Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca

Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of/destroyed, and the action documented

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

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
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable

Samples routinely transported by road or rail are patient to local regulations which require 
that they are also packed and transported in a safe and appropriate way to contain any risk 
of infection or contamination by using approved couriers and packaging/containment 
materials at all times. The IATA 650 biological sample containment standards are 
encouraged wherever possible when road or rail transport is used

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Appendix D
Genetics
D 1
Use/Analysis of DNA
Genetic variation may impact a patient’s response to therapy, susceptibility to, and severity 
and progression of disease.  Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease etiology; and/or molecular subtype of the disease being treated.  Therefore, 
where local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis from consenting patients.
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications.  Genetic research may lead to better understanding of diseases, better diagnosis 
of diseases or other improvements in healthcare and to the discovery of new diagnostics, 
treatments or medications.
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the patient´s DNA, i.e. the 
entire genome.
The results of genetic analyses may be reported in the CSR or 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
Study selection record
All adult patients will be asked to participate in this genetic research.  Participation is 
voluntary and if a patient declines to participate there will be no penalty or loss of benefit.  
The patient will not be excluded from any aspect of the main study.
Inclusion criteria
For inclusion in this genetic research, patients must fulfill all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and provide informed consent for 
the genetic sampling and analyses.

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Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample 
collection

Age <18 years
Withdrawal of consent for genetic research:
Patients may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study.  Voluntary withdrawal will not 
prejudice further treatment.  Procedures for withdrawal are outlined in Section 7.3 of the main 
Clinical Study Protocol and Appendix C 2.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the patients at randomization 
(Week 0).  Although DNA is stable, early sample collection is preferred to avoid introducing 
bias through excluding patients who may withdraw due to an adverse event (AE); such 
patients would be important to include in any genetic analysis.  If for any reason the sample is 
not drawn at Week 0, it may be taken at any visit until the last study visit.  Only 1 sample 
should be collected per patient for genetics during the study.  Samples will be collected, 
labelled, stored, and shipped as detailed in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 
15 years from the date of last patient last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube.  Thereafter, the sample will be 
identifiable only by the second, unique number.  This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organization.  No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organizations working with the DNA).

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The link between the patient enrollment/randomization code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organizations.  The link will be used to identify the relevant DNA samples for 
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.
Informed consent
The genetic component of this study is optional and the patient may participate in other 
components of the main study without participating in the genetic component.  To participate 
in the genetic component of the study the patient must give separate consent for this. The 
consent will be covered in Addendum to the main ICF.  The Investigator is responsible for 
ensuring that consent is given freely and that the patient understands that they may freely 
withdrawal from the genetic aspect of the study at any time.
Patient data protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient.  For example, in the case of 
a medical emergency, an AZ study physician or an Investigator might know a patient’s 
identity and also have access to his or her genetic data. In addition, Regulatory Authorities 
may require access to the relevant files, though the patient’s medical information and the 
genetic files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyse the samples.
AstraZeneca and its designated 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 

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only use this information for health related research purposes.  Researchers may see summary 
results but they will not be able to see individual patient data or any personal identifiers.
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical methods and determination of sample size
The number of patients that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A Statistical 
Analysis Plan may be prepared where appropriate.

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Appendix E
Best Practice Guidelines For Completing PRO Assessments
Patients 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

Patients 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 patients. Reinforce that these 
are standardized questions designed to capture the patient experience in the study.

Inform patients 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 patient 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 patients will ask site staff to clarify the meaning of a question or 
response.  To avoid introducing any bias, politely tell the patient that you cannot 
clarify items.  Remind them that there are no right or wrong answers.  Inform the 
patient that they should select the response that best answers the question as they 
understand it.

If a patient becomes unable to independently use the handheld device during the 
treatment period of the study (e.g. unable to read due to vision problems), then the 
patient should be exempted from completing PRO questionnaires used for efficacy 
endpoints (DSQ, EoE-3D, PGI-C/S, EoE-QoL-A, SF-36) and may continue in the 
study with external help for symptom severity and background/rescue medication use 
questionnaires completion.  Patient’s exemption in this regard must be pre-approved 
by an AZ study physician/delegate and appropriately documented.

No time limits

Although most PRO assessments require only a few minutes to complete, the patient 
should be given as much time as is needed.

Train the patient on handheld device usage

Train patients on how to use the handheld device using the materials and training 
provided by the device vendor.

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
Provide guidance on whom the patient 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 patient is 
completing the assessments as scheduled.  Follow-up with patients 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 [e.g. 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, etc, and medical equipment to treat 
anaphylactic reactions must be immediately available at study sites, and study personnel 
should be trained to recognize and treat anaphylaxis according to local guidelines.
If an anaphylactic reaction occurs, a blood sample for serum tryptase should be collected at 90 
minutes ± 30 minutes after the event; analysis for serum tryptase may be performed at a local 
laboratory. If local analysis of serum tryptase is unavailable, there will be an option to have 
the sample analysed at the central lab. 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 (e.g. generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
AND AT LEAST 1 OF THE FOLLOWING:
(a) Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia).
(b) Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g. 
hypotonia [collapse], syncope, incontinence).
2
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours):
(a) Involvement of the skin-mucosal tissue (e.g. generalized hives, itch-flush, swollen 
lips-tongue-uvula).
(b) Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia).

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(c) Reduced BP or associated symptoms (e.g. hypotonia [collapse], syncope, 
incontinence).
(d) Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting).
3
Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
Adults: systolic BP 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:

Diffuse erythema

Pruritus

Urticaria and/or angioedema

Bronchospasm

Laryngeal edema

Hypotension

Cardiac arrhythmias

Feeling of impending doom

Unconsciousness

Shock
Other earlier or concomitant signs and symptoms can include:

Itchy nose, eyes, pharynx, genitalia, palms, and soles

Rhinorrhea

Change in voice

Metallic taste

Nausea, vomiting, diarrhea, abdominal cramps and bloating

Lightheadedness

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
Headache

Uterine cramps

Generalized warmth
F 4
Management of Acute Anaphylaxis
F 4.1
Immediate intervention
1
Assessment of airway, breathing, circulation, and adequacy of mentation.
2
Administer epinephrine 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.
F 4.2
Possibly appropriate, subsequent measures depending on response to 
epinephrine
(a) Place patient in recumbent position and elevate lower extremities.
(a) Establish and maintain airway.
(b) Administer oxygen.
(c) Establish venous access.
(d) Normal saline IV for fluid replacement.
F 4.3
Specific measures to consider after epinephrine injections, where 
appropriate
(a) Consider epinephrine infusion.
(b) Consider H1 and H2 antihistamines.
(c) Consider nebulized β2 agonist (e.g. albuterol [salbutamol]) for bronchospasm 
resistant to epinephrine.
(d) Consider systemic corticosteroids.
(e) Consider vasopressor (e.g. dopamine).
(f) Consider glucagon for patient taking β-blocker.
(g) Consider atropine for symptomatic bradycardia.
(h) Consider transportation to an emergency department or an intensive care facility.
(i)
For cardiopulmonary arrest during anaphylaxis, high-dose epinephrine and prolonged 
resuscitation efforts are encouraged, if necessary.
Adapted from Kemp et al 2008.

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Appendix G
Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
patients become infected with SARS-CoV-2 or similar pandemic infection) during which 
patients may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
notification from the Sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation.
Please note that during civil crisis, natural disaster, or public health crisis, some study 
assessments and procedures may not be conducted due to international or local policies or 
guidelines, hospital or clinic restrictions and other measures implemented to ensure the 
patient’s safety. If in doubt, please contact the AZ Study Physician. If patient testing is 
performed as a result of the public health crisis, results may be documented for this study.
G 1
Consent/Reconsent/Assent/Re-assent of Study Patients During 
Study Interruptions
During study disruptions, it may not be possible for the patients to complete study visits and 
assessments on site and alternative means for carrying out the visits and assessments may be 
necessary, eg, remote visits. Consent/reconsent/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 2 to G 66. Local and regional regulations 
and/or guidelines regarding reconsent of study patients should be checked and followed. 
Consent/Reconsent may be verbal if allowed by local and regional guidelines (note, in the 
case of verbal consent/reconsent the ICF should be signed at the patient’s next contact with 
the study site). Visiting the study sites for the sole purpose of obtaining reconsent should be 
avoided. 
G 2
Rescreening of Patients To Reconfirm Study Eligibility 
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened patients. The investigator should confirm this with the designated study 
physician.
In addition, during study disruption there may be a delay between confirming eligibility of a 
patient and either enrolment into the study or commencing of dosing with IP. If this delay is 
outside the screening window specified in Table 1 the patient will need to be rescreened to 
reconfirm eligibility before commencing study procedures. This will provide another 

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opportunity to re-screen a patient in addition to that detailed in Section 5.4. The procedures 
detailed in Section 8 must be undertaken to confirm eligibility using the same 
screening/enrolment number as for the patient.
G 3
Home or Remote Visit to Replace On-site Visit (where applicable)
A qualified HCP from the study site or TPV service will visit the patients home / or other 
remote location as per local standard operating procedures (SOPs), as applicable. Supplies 
will be provided for a safe and efficient visit. The qualified HCP will be expected to collect 
information per the clinical study protocol (CSP). 
G 4
Telemedicine Visit to Replace On-site Visit (where applicable)
In this appendix, the term telemedicine visit refers to remote contact with the patients using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices.
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the patients will allow adverse events, 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 patient can safely attend subsequent site visit. 
G 5
At-home or Remote Location IP Administration Instructions
If a site visit is not possible, at-home or remote location administration of IP may be 
performed by a qualified HCP, provided this is acceptable within local regulation/guidance, or 
by the patient or his/her caregiver. The option of at-home or remote location IP administration 
ensures patients safety in cases of a pandemic where patients may be at increased risk by 
traveling to the site/clinic. This will also minimize interruption of IP administration during 
other study disruptions, eg, site closures due to natural disaster. 
G 5.1
At-home or Remote Location IP Administration by a Qualified HCP or 
TPV Service
A qualified HCP from the study site or TPV service should administer the IP at the patient’s
home or other remote location according to the CSP. All necessary supplies and instructions 
for administration and documentation of IP administration will be provided. Additional 
information related to the visit can be obtained via a telemedicine or home visit.

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G 5.2
At-home or Remote Location IP Administration by the Patient or 
His/Her Caregiver
Prior to at-home or remote location IP administration the investigator must assess the patient
or his/her caregiver to determine whether they are appropriate for at-home or remote location 
administration of IP. Once the patient or his/her caregiver is deemed appropriate for at-home 
or remote location administration, he/she must receive appropriate training. All necessary 
supplies and instructions for administration and documentation of IP administration will be 
provided. More information related to the visit can be obtained via a telemedicine or home / 
remote visit.
G 6
Data Capture During Telemedicine or Home / Remote Visits
Data collected during telemedicine or home / remote visits will be captured by the qualified 
HCP from the study site or TPV service, or by the patient themselves e.g., details of self-
administration, PRO, signs and symptoms.

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Appendix H
Abbreviations
Abbreviation or special 
term
Explanation
ADA
anti-drug antibody
ADCC
antibody-dependent cell-mediated cytotoxicity
AE
adverse event
AEC
absolute eosinophil count
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
anti-HCV
hepatitis C antibody
anti-HDV
hepatitis D antibody
APFS
accessorized prefilled syringe
AST
aspartate aminotransferase
CI
confidence interval
CID
clinically important difference
CMH
Cochran-Maentel-Haenszel
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
CSP
Clinical Study Protocol
CSR
clinical study report
DB
double-blind
DNA
deoxyribonucleic acid 
DSQ
Dysphagia Symptom Questionnaire
DUS
disease under study
EC
ethics committee, synonymous to institutional review board (IRB) and independent 
ethics committee (IEC)
ECG
electrocardiogram
eCRF
electronic case report form 
EDP
EoE Diagnostic Panel
EGID
eosinophilic gastrointestinal disease
EGD
esophagogastroduodenoscopy
EGPA
eosinophilic granulomatosis with polyangiitis
EndoFLIP
Endolumenal Functional Lumen Imaging Probe
EoE
eosinophilic esophagitis
EoE-3D
Eosinophilic Esophagitis - Daily Dysphagia Diary

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Abbreviation or special 
term
Explanation
EoE-HSS
Eosinophilic Esophagitis - Histology Scoring System
EoE-QoL-A
Adult Eosinophilic Esophagitis Quality of Life Questionnaire;
eos
eosinophils
EREFS
Endoscopic Reference Score
FAS
full analysis set
FSH
follicle stimulating hormone
FU
follow up
GCP
Good Clinical Practice
GI
gastrointestinal
HBc
hepatitis B core
HBeAg
hepatitis B e-antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B-virus
HCG
human chorionic gonadotropin
HCP
Health Care Professional  
HES
hypereosinophilic syndrome
HIV-1/2
human immunodeficiency virus-1/2
hpf
high power field
HRQoL
health-related quality of life
HSS
histology scoring system
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IDMC
independent data monitoring committee
IEC
Independent Ethics Committee
IgE
immunoglobulin E
IL-5
interleukin-5
IL-5Rα
IL-5 receptor alpha subunit
International 
Co-ordinating Investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the Investigators and/or activities 
internationally.  
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IPD
investigational product discontinuation (visit)
IP
investigational product
IRB
Institutional Review Board

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Abbreviation or special 
term
Explanation
IWRS
interactive web response system
mAb
monoclonal antibody
MCID
minimal clinically important difference
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed effect models for repeated measures
nAb
neutralizing antibody
OL
open-label
OLE
open-label extension
PDGFRA
platelet-derived growth factor receptor alpha
PEESS
Pediatric Eosinophilic Esophagitis Symptom Severity Module, Version 2, Children 
and Teens Report
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
PK
pharmacokinetics
PPI
proton pump inhibitor
PRO
Patient Reported Outcome
PT
preferred term
Q4W
every 4 weeks
Q8W
Every 8 weeks
RNA
ribonucleic acid
ROW
Rest of World
SAE
serious adverse event 
SADE
serious adverse device effect
SAP
statistical analysis plan
SC
subcutaneous(ly)
SF-36v2
Short Form-36 Version 2.0
SoA
schedule of activities
SOC
system organ class
TEAEs
treatment-emergent adverse events
TPV
Third Party Vendor 
ULN
upper limit of normal
WBC
white blood cell (count)
WOCBP
women of childbearing potential
WPAI+CIQ
Work Productivity and Activity Impairment questionnaire plus Classroom 
Impairment Questions

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Appendix I
Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 5 (CSP ver 6.0): 30-April-2021
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall rationale for the amendment
The primary rationale for this amendment is to add the early time point sub-study. The sub-
study aims to generate early time point evidence of eosinophil depletion in tissue and to 
understand its relationship with endoscopic findings and symptom response. In addition, some 
minor clarifications were made to ensure correct interpretation of the protocol.
Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial
/Non-
substantial
Section 1.1 Schedule of 
Activities (SoA) Table 1
SoA updated with additions of: 
-endoscopies (with 
esophageal biopsies and 
EREFS)
- PK
- Hematology, WBC w/ 
differential, and blood 
sampling 
 
 
- Esophageal tissue for 
histopathology and 
 
analyses
at week 4 and week 12, and a 
footnote to clarify that this 
applies only for patients in the 
Early Time Point Sub-study.
To indicate assessments added 
for the Early Time Point Sub-
study.
Substantial

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial
/Non-
substantial
Section 1.1 Schedule of 
Activities (SoA) Table 2
Section 1.2 Synopsis, 
Table 6
Section 3 Objective and 
Endpoints, Table 8
Addition of EndoFLIP 
procedure at selected sites at 
Week 104
EndoFLIP added as an endpoint 
at week 104
To evaluate the longer-term 
effect of benralizumab on 
esophageal distensibility.
Non-
Substantial
Section 1.2 Synopsis, 
Table 5
Section 3 Objective and 
Endpoints, Table 7 Table 
8
Study Objectives 
for the OLE Period
Addition of the objective and 
endpoints for the Early Time 
Point Sub-study.
The Early Time Point Sub-study 
was added to the study since the 
previous amendment.
Substantial
Section 5.1 Inclusion 
criteria #5b
Wording added:  An average of
at least 2 days per week with an 
episode of dysphagia (Daily 
DSQ ≥2) between Visit 1 and 
Visit 2 and at least 2 days per 
week with an episode of 
dysphagia in the 2 weeks prior 
to randomization
For clarification
Substantial
Section 5.1 Inclusion 
criteria #6
Wording added:
(a) Must complete 70% of daily 
DSQ diaries between Visit 1 and 
Visit 2;
AND 
(b) Must have completed at least 
8 of 14 daily DSQ diaries in the 
14 days prior to
randomization
For clarification
Substantial

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial
/Non-
substantial
Section 5.2 Exclusion 
criteria #27
Addition of an exclusion 
criterion; ‘Involvement in the 
planning and/or conduct of the 
study (applies to both 
AstraZeneca staff and/or staff at 
the study site)’  
To align with the protocol 
template 
Substantial
Section 8.1.5 Early time 
point  sub-study
Section 9 Statistical 
considerations
Section 9.2  Sample size 
determination 
Section 9.4.4  Other 
analyses
Appendix A 3
New section added for the Early 
Time Point Sub-study.
New paragraph added regarding 
the Early Time Point Sub-study.
Text added: and/or the Early 
Time Point Sub-study
Sub-study added to generate 
early time point evidence of 
eosinophil depletion in tissue 
and to understand its 
relationship with symptom 
response.
Substantial
Section 8.4.2.1, 8.4.3 and 
Appendix  B 2
’Congenital abnormality’ 
updated to ’Congenital 
anomaly’.
To align with regulatory 
requirements
Non-
Substantial
Throughout
Minor editorial or 
administrative changes that do 
not substantially alter the 
document. 
For better consistency and 
clarity
Non 
Substantial
Amendment 4 (CSP ver 5.0): 11-Feb-2021
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.

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Overall rationale for the amendment.
The primary rationale for this amendment is to update the duration of the OLE-period to at 
least 1 year (variable duration) and to include the option of at-home or remote location self-IP 
administration after week 52. Inclusion/exclusion criteria were clarified, the primary estimand 
approach for the analyses of study data was updated to a composite strategy to more 
accurately account for the occurrence of the described intercurrent events which are 
considered to reflect a treatment failure outcome. In addition, some minor clarifications were 
made to ensure correct interpretation of the protocol.
Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial
/Non-
substantial
Section 1.1 Schedule of 
Activities (SoA)
Reference to compliance as a 
specific criterion for eligibility 
to the OLE period was taken out 
to emphasize that all patients 
who complete the 52-week 
treatment period on IP may 
continue into the OLE period.
To align with changes made in 
amendment 2.
Section 1.1 Schedule of 
Activities (SoA)
Section 1.2 Synopsis 
Section 4.1 Overall 
design
Section 4.4 End of study 
definition
Text revised regarding duration 
of the OLE period.
To clarify that the OLE period 
is intended to allow each patient 
at least 1 more year of OL 
treatment and that the duration 
of the OLE period is flexible.
Non-
Substantial
Section 1.1 Schedule of 
Activities (SoA)
Table 1
The schedule of activities was 
updated to include references to 
CSP section for ‘Serum for total 
IgE’ and ‘serum tryptase’.
Updates to serology footnote 
regarding monitoring of patients 
who are HBsAg positive or 
anti-HBc positive.
Corrected reference section.
To clarify how this would occur 
if the patient are using self-
administration option.
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
Section 1.1 Schedule of 
Activities (SoA)
Table 2
Heading adjusted, V28 with 
assessments and a footnote with 
a subsequent footnote 
renumbering added. Brief 
physical exam and vital signs 
were removed from some visits 
and PGI-S (via interview) was 
added to Visit 21, 28 and 
EOT/IPD (if before Visit 28). 
Some assessments were moved 
from visit 27 to visit 28. 
Updates to serology footnote 
regarding monitoring of patients 
who are HBsAg positive or 
anti-HBc positive.
To have first year of the OLE in 
a separate table and the fourth 
endoscopy scheduled at V28 
and not at EOT, since the OLE 
will continue. Footnote was 
added to indicate which visits 
that can be conducted remotely 
with self IP admin, and at these 
visit brief PE and vital signs 
were removed. PGI-S was 
added to have a measure of the 
patient’s perception of overall 
symptom severity.  Update to 
serology footnote to clarify how 
this would occur if the patient 
are using self-administration 
option.
Non-
Substantial
Section  1.1
Schedule of Activites 
(SoA) Table 3
A new table was added, Table 
3; therefore all subsequent table 
numbers have been updated.
To have OLE from week 104 
(the second year of the OLE 
period and beyond) in a 
separate table.
Non-
Substantial
Section 1.1 Schedule of 
Activities (SoA)
Table 4
Section 1.2 Synopsis, 
Table 6
Section 3 Objective and 
Endpoints, Table 8
Section 8.1.3.5 Patient 
Global Impression of 
Severity
PGI-S schedule updated.
PGI-S administration was added 
to Visit 21 and Visit 28 (or at 
IPD/EOT if before Visit 28) and 
will at these visits occur by 
interview ( i.e. Not via the 
device) and be entered into the 
eCRF. 
PGI-S was entered as an 
endpoint in the OLE
To include PGI-S as an 
endpoint in the OLE  measuring 
the patient’s perception of 
overall symptom severity after 
the handheld PRO device is 
returned, and to clarify when 
PGI-S will be administered on 
the device and when it will be 
administered by interview.
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
Section 1.2 Synopsis, 
Table 5 and Table 6
Section 3 Objective and 
Endpoints, Table 7 and  
Table 8
Study 
Objectives for the OLE 
Period
Addition of the objective and 
endpoint for;  the
 
and 
WPAI+CIQ
It was missing from the tables
Non-
Substantial
Section 1.2 Synopsis, 
Overall design
Section 4.1 Overall 
design
Wording on background 
medications updated 
To align with Inclusion criteria 
#7 on background medications 
Non-
Substantial
Section 1.2 Synopsis, 
Overall design
Section 4.1 Overall 
design
Revised text on how diet will be 
tracked during the study
Correction
Non-
Substantial
Section 1.2 Synopsis
Section 6.1.4 Optional 
At-home or Remote-
Location IP 
administration 
Section 6.1.4.1  Optional 
Remote Visits for 
Patients doing At-Home 
or Remote-Location IP 
administration 
Section 8.2.2 Pregnancy 
test
New text/sections added to 
provide guidance on the 
optional self IP administration 
after week 52 (if allowed by 
local guidance)
Clarified procedure for urine 
pregnancy testing for WOCBP 
in case of IP self-administration
To describe procedures if 
optional self-administration is 
implemented during the OLE
Non-
Substantial
Section 1.3 Schema
Figure updated
To include the fourth 
endoscopy, the variable OLE 
duration and to clarify 
restrictions on background 
medications and diet
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
Section 2.3 Benefit/risk 
assessment
The requirement for observation 
of the patient following IP 
administration was changed 
from 1 hour to be ‘in line with 
clinical practice at the site’.
Wording added regarding self 
IP administration during the 
OLE.
These safety requirements have 
been updated. Wording was 
also added to include risk 
minimisation for patients who 
select to do the optional/remote 
location IP administration 
during the OLE.
Non-
Substantial
Section 4.2 Scientific 
rational for study design
‘During the run-in’ was added 
to the fifth bullet of ‘Key 
features of this study include’.
To clarify that EoE-related diet 
and background medications are 
to be kept stable also during the 
run-in period.
Non-
Substantial
Section 5.1 Inclusion 
criteria # 7
Section 5.2 Exclusion 
criteria # 21
Wording added: ‘during the 
run-in period and’
Wording added: ‘and during’ 
To clarify that background 
medications taken for EoE  and 
related treatments should be 
stable also during the run-in 
period
Non-
Substantial
Section 5.2 Exclusion 
criteria # 5
Revised – text added
‘Esophageal dilation performed 
within 8 weeks prior to 
screening and prior 
esophagaeal surgery that would 
impact the assessments  for 
EoE’
Added as this may impact EoE 
assessments
Substantial
Section 5.2 Exclusion 
criteria # 6
Revised – text added. Use of a 
feeding tube, or having a 
pattern of not eating solid food 
daily during the run-in period
Added for clarification
Non-
Substantial
Section 5.2
Exclusion criteria # 15 
Section 6.5.4
Restrictions, Table 10
Troleandomycin removed
Safety requirements have been 
updated
Non-
Substantial
Section 5.3 Lifestyle 
restrictions
Corrected the number of the 
inclusion criterion referred to in 
the first paragraph, from 4 to 9
Correction
Non-
Substantial
Section 5.3.1 Meals and 
dietary restrictions
Wording updated that patients 
should remain on stabilized diet 
for treatment of their EoE also 
during the run-in period
For clarification 
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
Section 5.4 Screen 
failures
The first criterion for when re-
screening is not allowed was 
reworded
To align with inclusion criteria 
#4
Non-
Substantial
Section 6.1, Table 9
Dosage level added
For clarity
Non-
Substantial
Section 6.1 Treatment 
administered
Paragraph added to inform 
when IP will be administered at 
site and when it may be 
administered at home/remotely 
by the patient
To align with addition of the 
optional self-administration 
during the OLE
Non-
Substantial
Section 6.1.2 IP 
administration 
Section 8.4.7 IP 
administration at the 
study site
Wording revised regarding how 
patients should be monitored 
after IP administration- changed 
from ‘1 hour’ to be ‘in line with 
clinical practice at the site’
Safety requirements have been 
updated 
Non-
Substantial
Section 6.2
Preparation/handling/stor
age/accountability
Wording on where IP will be 
administered was removed
Since wording is included in 
new section  in 6.1
Non-
Substantial
Section 6.2
Preparation/handling/stor
age/accountability
Revised, text added that patient 
or caregiver may administer IP,
and that ‘Devices sent to 
patients home must be returned 
to the  site for traceability’
As IP may be self-administered 
at home or remote location
Non-
Substantial
Section 6.5.4
Restrictions, Table 10
For ‘background medication for 
EoE’  and for ‘Systemic 
corticosteroids’, wording was 
added to the third column 
describing details, to include 
also the run-in period
To clarify that;
-Background medications taken 
for EoE  and related treatments 
should be stable also during the 
run-in period 
-Systemic corticosteroid is 
restricted also during the run-in 
period
Non-
Substantial
Section 8.1.3 Patient 
reported outcomes
Wording on when PRO 
assessments will be performed 
on a handheld device was 
adjusted.
For clarification
Non-
Substantial
Section 8.1.3.1
Dysphagia Symptom 
Questionnaire (DSQ)
Wording added to note that if 
the patient reports not eating 
solid food, then the DSQ is 
considered missing for that day.
For clarification
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
Section 8.2.1.1 Other 
laboratory assessments
Wording was updated and 
added regarding monitoring of 
patients that are HBsAg positive 
or anti-HBC positive.
To clarify how this would occur 
if the patient is using self-
administration option
Non-
Substantial
Section 8.11.2 Diet 
Questionnaire
Wording updated on when the 
diet questionnaire will be 
completed
To clarify how this would occur 
during in the OLE, Year 2 and 
beyond
Non-
Substantial
Section 9.4.1 Efficacy 
Analyses
Section 1.2 Synopsis
Updated estimand strategy to a 
composite strategy where the 
occurrence of intercurrent 
events such as increase of 
background medication or 
addition of a new therapy for 
EOE are considered treatment 
failure events and handled as 
such in the analyses.
To better account for 
intercurrent events considered 
to be a negative outcome in the 
analyses.
Non-
Substantial
Section 9.4.2 Safety 
Analyses, Adverse 
Events
Wording added that information 
on  frequencies and risk 
differences between treatment 
arms will be presented for the 
most common AEs and other 
specific events of interest.
For clarification
Non-
Substantial
A 3Informed consent 
process
Updated wording-
The time period was changed 
based on updated safety 
recommendations
Non-
Substantial
Appendix F
Anaphylaxis: Definition, 
Signs, Symptoms and 
Management
Timing for collection of a blood 
sample to measure serum 
tryptase was changed from ‘as 
soon as possible, at 60 (±30) 
minutes after the event, and at 
discharge’ to at 90 (±30) after 
the event
To optimize timing of sample 
collection for measuring serum 
tryptase
Non-
Substantial
Appendix A.9 Study and 
Site Start and Closure
Modified section heading from 
‘Study and Site Closure’. Added 
Suggested Text for study start 
date
To comply with EU Clinical 
Trials Regulation No 536/2014 
requirements (38) for definition 
of start of recruitment and 
ct.gov definition of study start.
Non-
Substantial

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Summary of Changes to the Clinical Study Protocol
Section # and Name
Description of Change
Brief Rationale
Substantial
/Non-
substantial
Throughout
Updated wording of the 
stratification  factor from 
‘steroids at baseline’ to ‘use of 
swallowed steroids at baseline 
(categorical, Yes/No)’
For clarification
Non 
Substantial
Throughout
Reference to Interactive Voice
Response System (IVRS) was 
removed
Interactive Voice Response 
System (IVRS) will not be used
Non 
Substantial 
Throughout
Minor editorial or 
administrative changes that do 
not substantially alter the 
document have been made 
where applicable are not 
individually listed 
For better consistency and 
clarity
Non 
Substantial
Amendment 3 (CSP ver 4.0): 26-Aug-2020
This amendment includes only corrected numbering of inclusion criteria. 
Amendment 2:  31-July-2020
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment.
The primary rationale for this amendment is to add study mitigation language which will 
provide sites with measures that may be implemented if a patient is not able to visit a study 
site to ensure that the clinical trial can continue whilst minimizing risk to the patient, 
maintaining compliance with GCP, and minimizing risks to the study integrity.  
 
In addition, 

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inclusion/exclusion criteria were clarified, and Table 9 of Restrictions (Section 6.5.4) was 
updated with clarifications regarding medications allowed, restricted and prohibited prior to 
screening. Finally, some minor clarifications were made to ensure correct interpretation of the 
protocol.
Summary of Changes to the Clinical Study Protocol
Section # and 
Name
Description of Change
Brief Rationale
Substantial
/Non-
substantial
Section 4.1.1
Study conduct 
mitigation 
during study 
disruptions 
due to cases of 
civil crisis, 
natural 
disaster, or 
public health 
crisis; 
Appendix G
New wording was added which 
would give guidance on how the 
study could continue in the event of 
a serious disruption with details of 
mitigation that could be employed 
to ensure study continuity.
The impact of COVID-19 has 
highlighted the risk to continuity of 
clinical trials during times of study 
disruption, whether by civil crisis, 
natural disaster or public health crisis. 
This section details the measures that 
may be implemented if a patient is not 
able to visit a study site to ensure that 
the clinical trial can continue whilst 
minimizing risk to the patient, 
maintaining compliance with GCP, 
and minimizing risks to study 
integrity. These changes will only be 
initiated at a time of study disruption.
Substantial
Section 
Schedule of 
Activities 
(SoA)1.1
(Schedule of 
Activities), 
Table 1 and 
Table 2
 
Non-
substantial
Section 1.1
(Schedule of 
Activities), 
Table 1
The schedule of activities was 
updated to include references to 
CSP section for ‘Serum for total 
IgE’ and ‘serum tryptase’.
Corrected reference section.
Non-
substantial
Section 1.1
(Schedule of 
Activities), 
Table 1
Healthcare resource utilization 
removed from V1.
Healthcare resource utilization 
removed from V1 for simplification, 
as V2 is seen as baseline for this 
assessment.
Non-
substantial
Section 1.1 
(Schedule of 
Activities), 
Table 2
•
ADA/nAb was added to the 
EOT/IPD visits. 
•
A footnote was added to 
emphasize that all samples for PK 
and ADA/nAB must be taken prior 
to IP administration.
•
Added for complete analysis of 
ADA/nAb.
•
Added for clarification.
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
Section 1.1
(Schedule of 
Activities), 
Table 1 and 
Table 2
•
Urine pregnancy test added at 
the 12 week Follow-up visit.
•
Text revisions:” Laboratory 
assessments: Hematology, WBC 
w/differential “Only eosinophils 
will be measured at the FU visit”
was replaced with “Only WBC 
w/differential will be measured at 
the FU visit.”
•
Added for final confirmation that 
pregnancy has not occurred during the 
study.
•
Change needed due to limitations 
at the central lab; eosinophils are only 
analyzed as part of the WBC 
w/differential.
Non-
substantial
Section 1.1
(Schedule of 
assessments), 
Table 4
Schedule of ePRO assessment: 
Time for completion of daily diaries 
was extended on Day n+1 from 4:00 
in the previous version to 4:59.
Schedule of ePRO assessment: 
Frequency of PGI-S assessment was 
reduced from weekly to every two 
weeks.
•
Evening completion was 
extended to match ePRO 
specifications  and training 
material.
•
PGI-S frequency was adjusted to 
match recall period.
Non-
substantial
Section 1.2
(Synopsis), 
Overall 
design; 
Section 4.1
(Overall 
design); 
Section 7.1.1.2
(Discontinuati
on at Week 
52)
Reference to compliance as a 
specific criterion for eligibility to 
the OLE period was taken out to 
emphasize that all patients who 
complete the 52-week treatment 
period on IP may continue into the 
OLE period.
Wording was changed to clarify 
eligibility for the OLE period.
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
Section 5.1
(Inclusion 
Criteria)
Text revisions:
•
#5: Must be symptomatic at 
Visit 1 (run-in-period  
screening) and Visit 2 
(randomization):
-
A patient reported average of 
at least 2 days per week with 
an episode of dysphagia over 
the 4 weeks prior to the run-in 
period Visit 1
-
At least 2 days per week with 
an episode of dysphagia (Daily 
DSQ ≥2) per week between 
Visit 1 and Visit 2 
(randomization)
•
#7: May be on background 
medications for EoE ……for 
at least 4 weeks (8 weeks for 
PPI) prior to the run-in period
screening. Patient on PPI 
therapy must report If a a 
stable dose medication for at 
least 8 weeks EoE (including 
swallowed steroids, systemic 
steroids and PPI) is 
discontinued prior to the run-in
screening, there should be a 
washout period of at least 8 
weeks.
•
#8: Body weight of at least 35 
kg (inclusion criterion 
removed)  
•
#9 (previously #10): WOCBP 
must agree to use a highly 
effective form of birth control 
(confirmed by the Investigator) 
from randomization 
throughout the study duration 
and within 16 weeks for at 
least 12 week after last dose of 
IP.  
•
Inclusion criterion #5 was 
updated to clarify the symptom 
criteria.
•
Inclusion criterion #7 was 
updated to add details on a 
washout period for background 
medications for EoE. A washout 
period is needed to ensure that 
discontinuation of the 
medications will not affect 
baseline assessments.
•
Align to approved product 
profile and dosing instructions
•
The time period was changed 
based on updated safety 
recommendations.
Substantial

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Section 5.2
(Exclusion 
Criteria)
Text revisions:
•
#5: Added new exclusion 
criterion: Esophageal dilation 
performed within 8 weeks 
prior to screening.
•
#13 (previously #16) : 
Helminth parasitic infection 
diagnosed within 24 weeks 
prior to screening that has not 
been treated with or has failed 
to respond to standard of care 
therapy. (formerly time of 
consent/assent).
•
#15 (previously #18): A 
prohibition period of 8 weeks 
prior to screening was added 
for immunosuppressive 
medications.
•
#16 (previously #19): Receipt 
of immunoglobulin or blood 
products within 30 days prior 
to screening. (formerly time of 
consent/assent)
•
#17 (previously #20):Receipt 
of live attenuated vaccines 30 
days prior to 
randomization.(formerly time 
of consent/assent). 
•
#18: Added new exclusion 
criterion: Receipt of 
inactivated/killed vaccinations 
(e.g., inactive influenza) 
within 1 week prior to 
randomisation.
•
#19 (previously #21): Receipt 
of any marketed or 
investigational biologic 
…within 4 months or 5 half-
lives prior to screening, 
whichever is longer. (formerly 
time of consent/assent)
•
#20: Added new exclusion 
criterion: Receipt of oral 
and/or sublingual allergen 
immunotherapy within 8 
weeks prior to screening.
•
An 8-week period is needed after 
an esophageal dilation to 
stabilize symptoms and findings 
prior to baseline assessments.
•
Simplification of language.
•
An 8-week period is needed after 
discontinuation of 
immunosuppressive treatment to 
stabilize symptoms and findings 
prior to baseline assessments
•
Simplification of language.
•
The decisive time period is the 
time before randomization, to 
separate the effects of IP from 
effects of the vaccine.
•
Addition made for completeness 
and alignment with the 
instruction already included in 
Table 9.
•
Simplification of language.
•
An 8-week period is needed after 
oral and/or sublingual allergen 
immunotherapy to stabilize 
symptoms and findings prior to 
baseline assessments.
Substantial

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Summary of Changes to the Clinical Study Protocol
Section # and 
Name
Description of Change
Brief Rationale
Substantial
/Non-
substantial
Section 5.3
(lifestyle 
restrictions)
Text revisions: 
Women of childbearing potential 
must use highly effective 
contraceptive methods …for 16 12  
weeks (5 half-lives) after last 
administration of the IP. 
Patients must abstain from donating 
blood, plasma, or platelets from the 
time of informed consent or assent 
(if applicable) and for 16 12 weeks 
(5 half-lives) after last dose of IP.
The time period was changed to 12 
weeks based on updated safety 
recommendations.
Non-
substantial
Section 5.4
(Screen 
failures)
Text revisions: Screening in order to 
confirm a patient-reported average 
of at least 2 days per week with an 
episode of dysphagia over the 4 
weeks prior to the run-in period  
visit 1 or to confirm at least 2 days 
per week with an episode of 
dysphagia (Daily DSQ ≥2)  between 
Visit 1 and  Visit 2. 
Wording was added to clarify that re-
screening is not allowed if patients fail 
to meet inclusion criterion #5.
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
Section 6.1
(Treatments 
administered)
Text revisions:
•
(Before IP administration): 
“All applicable visit 
procedures, including sample 
collection of 
, PK, 
and ADA samples and on-site 
PRO assessments, should be 
completed prior to IP 
administration. If the patient 
cannot tolerate a particular 
visit procedure(s) during the 
visit, IP can be administered, 
and the procedure should be 
re-scheduled for a different 
date, preferably within the visit 
window.” 
•
(IP administration): Added 
wording about training in IP 
administration.  
•
The mentioned visit procedures 
need to be performed before IP 
administration
•
Training in IP administration was 
added to have patients prepared 
for self-administration in case of 
study disruption.
Non-
substantial
Substantial
Section 6.4
(Treatment 
compliance)
Text revisions: "The administration 
of all study treatments (both in the 
DB, OL, and OLE periods of the 
study) should be recorded in the 
source documents, as well as in  the 
appropriate section of the eCRF."
Wording was added to emphasize the 
need to note IP administrations in 
source documents.
Non-
substantial
Section 6.5.1
(Background 
medication 
and related 
treatments)
Added wording about a washout 
period needed after discontinuation 
of a medication for EoE. 
A washout period is needed to ensure 
that discontinuation of the medication 
will not affect baseline assessments.
Substantial

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Summary of Changes to the Clinical Study Protocol
Section # and 
Name
Description of Change
Brief Rationale
Substantial
/Non-
substantial
Section 6.5.4
(Restrictions)
Clarifications were added to Table 9 
regarding allowed, restricted and 
prohibited medications:
•
Immunoglobulins, blood 
products and investigational 
non-biologic drugs were added 
to the table as prohibited.
•
A clarification was added that 
it is allergen immunotherapy 
administered subcutaneously 
that is restricted, whereas oral 
and sublingual allergen 
immunotherapy is prohibited.
•
Additions made for alignment 
with the exclusion criteria. 
•
Allergen immunotherapy may 
have different effects on EoE 
disease depending on the route of 
administration.
Substantial
Section 8.1.3.5
(Patient 
Reported 
Outcome)
The recall period for the Patient 
Global Impression of Severity (PGI-
S) instrument was specified.
Added for clarification.
Non-
substantial
Section 8.1.3.4
(EndoFLIP 
(esophageal 
distensibility) 
– sub-study
Requirement for performing 
EndoFLIP prior to obtaining 
esophagal biopsies was removed.
Update made based on feedback from 
external experts.
Non-
substantial
Section 8.2.3
(Physical 
examination)
Text removed: "For the brief 
physical examination, only 
information on whether the 
assessment was performed or not is 
to be recorded."
A separate instruction for the brief 
physical examination is not needed as 
it is the same as for the complete 
physical examination.
Non-
substantial
Section 8.4.3
(Paternal 
exposure)
The time period required after the 
last IP dose for follow-up and 
documentation of pregnancies was 
changed from 16 to 12 weeks.
The time period was changed based on 
updated safety recommendations.
Non-
substantial
Section 8.4.5
(Device 
Constituent 
Deficiencies)
New Section 8.4.5 added: Device 
Constituent Deficiencies including 
8.4.5.1 SADE reporting
To ensure compliance with new 
regulatory guidance.
Non-
substantial
Section 8.9
(Immunogenic
ity)
Detailed and specific descriptions of 
the collection and analysis of 
immunogenicity samples were 
omitted and other documents 
describing these details were 
referenced.
Language updated to allow for 
evolving approach to immunogenicity 
analyses.
Non-
substantial

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Summary of Changes to the Clinical Study Protocol
Section # and 
Name
Description of Change
Brief Rationale
Substantial
/Non-
substantial
 
8.11.3 (Patient 
Testing Due to 
Public Health 
Crisis)
Section included if patient testing is 
performed due to the public health 
crisis, the results may be 
documented for this study.
Section added for test results 
secondary to public health crisis to be 
collected allowing  for an evaluation 
of the public health crisis on the study.
Non-
substantial 
Section 9.4.3
(Immunogenic
ity analyses)
Text revisions: “Anti-drug 
antibodies to benralizumab will be 
summarized using descriptive 
statistics at each visitby treatment 
group.  The ADA titres time profiles 
of benralizumab by treatment group 
will be generated. The impact of 
ADA on PK and eosinophil level 
will may be assessed.  The potential 
association of ADA with safety and 
efficacy willmay be evaluated.  
Further details will be provided in 
the SAP.”
Updated wording to align with 
evolving AZ process.
Non-
substantial
Appendix A 1
(Regulatory 
and Ethical 
Considerations
)
Text revised and added for   
Regulatory Reporting Requirements 
for SAEs’
Provision of appropriate statements 
that describe Regulatory Reporting 
Requirements for SAEs in AZ studies.
Correction to align with  CSP template 
5.0
Non-
substantial
Appendix 
A 3(Informed 
consent 
Process)
Text revisions:
•
“The ICF will contain a 
separate section that addresses 
the use of remaining samples 
for future projects. Adult 
patients will give a separate 
agreement to allow any 
remaining specimens to be 
used for future research.”
•
 
 
•
The section was updated to 
clarify that future exploratory 
research is relevant for adults 
only. 
 
 
Substantial

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Summary of Changes to the Clinical Study Protocol
Section # and 
Name
Description of Change
Brief Rationale
Substantial
/Non-
substantial
Appendix A 6
(Disseminatio
n of clinical 
study data)
Text revisions: A description of this 
clinical study will be available on 
http://astrazenecaclinicaltrialsastraz
enecagrouptrials.pharmacm.com.
Section updated with correct weblink.
Non-
substantial
Appendix A 7
(Data quality 
assurance)
Section updated to note that the 
eCRF is only signed electronically 
and not physically, as was stated in 
the previous version.
Clarification of the eCRF signature 
process.
Non-
substantial
Version 2.0, 01 November 2019
Changes to the protocol are summarised below: 
Section 1.1 (Schedule of Activities): The schedule of activities was updated to remove IgE 
allergen testing and add assessments for serum tryptase and plasma sampling. The visit 
schedule for the OLE period was updated to have the final dose of benralizumab at Week 
100 with the EOT occurring at Week 104. The specific tests for hepatitis B and C serology 
were clarified.  All visit windows were calculated from Visit 2. The PEESS assessment was 
added to the PRO assessments collected during the 52-week study period (DB+OL) and 
OLE period. An additional table was added to clarify the schedule for all PRO assessments. 
Section 3 (Objectives and Endpoints): The secondary and other endpoint measures were 
updated as follows:

Change from baseline in dysphagia associated pain, and discomfort as captured by the 
EoE-3D

Changes from baseline in abdominal pain and nausea as captured by the daily diary

Dysphagia-free days as captured by the DSQ

Frequency of dysphagia episodes as captured by the EoE-3D 
The exploratory endpoints during the 52-week study period (DB+OL) and the OLE period 
were updated to include EoE-related transcriptomic profile, tissue histology and 
immunohistochemistry, 
 and PEESS. 
Section 4.1 (Overall Design): This section was updated to clarify that patients on PPI 
therapy must report a stable dose for at least 8 weeks prior to the run-in period. 
Stratification by region for adults was clarified as North American vs Rest of World.  

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Target recruitment for adolescents was updated for approximately 20 adolescent patients 
per arm. 
Section 5.1 (Inclusion Criteria): Inclusion criterion #4 was updated to clarify the definitions 
of EoE diagnoses. Inclusion criterion #5 was updated to clarify the definition of 
symptomatic EoE. Inclusion criterion #6 was updated to clarify the definition of daily diary 
adherence. Inclusion criterion #7 was updated to require patients on PPI therapy report a 
stable dose for at least 8 weeks prior to enrolment. Inclusion criterion #10 was updated to 
clarify the definition of a highly effective method of contraception.
Section 5.2 (Exclusion Criteria): Exclusion criterion #5 was updated to exclude patients 
who do not report eating solid food daily during the run-in period. Exclusion criterion #18 
was updated to exclude patients with any concomitant use of systemic corticosteroids. 
Section 5.4 (Screen failures): Study procedures for re-screening were clarified such that all 
study procedures scheduled for Visit 1 should be repeated at the re-screening visit, with the 
exception of the EGD and biopsy, which should be completed at the discretion of the 
Investigator. The inclusion/exclusion criteria that cannot be failed in order to be considered 
for re-screening were added, and it was specified that re-screened patients should sign a 
new ICF.
Section 6.3.1 (Methods for assigning treatment groups): The stratification by region for 
adults was clarified: North America vs Rest of World. 
Section 6.3.2 (Methods for Ensuring Blinding): The text was updated to indicate that in 
instances in which the Investigator requires an eosinophil, basophil, or monocyte count test 
for managing safety issues, AstraZeneca should be notified of all such cases without 
absolute eosinophil counts, absolute basophil counts or absolute monocyte counts being 
revealed.
Section 6.5.1 (Background medication and related treatments): This section was updated to 
indicate that patients on PPI therapy must report a stable dose for at least 8 weeks prior to 
the run-in period.
Section 6.5.4 (Restrictions): Clarifications were added to Table 9 (Allowed, restricted, and 
prohibited concomitant medication and treatments) regarding allowed and restricted steroid 
use.
Section 7.1 (Discontinuation of IP): Confirmed reactivation of hepatitis B virus was added 
as a study-specific criterion for discontinuation.

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Section 8.1.3 (Patient Reported Outcomes): The description of the PRO device was updated 
to be a handheld device. The weekly review of PRO compliance was clarified. 
Section 8.1.3.1 (Dysphagia  Symptom Questionnaire): Calculation of the DSQ score was 
clarified and the assessment of dysphagia-free days over each 28-day period was added. 
Section 8.1.3.2 (EoE-3D and additional daily questions): The text was updated to clarify 
how dysphagia episode frequency will be calculated and summarized. Specifics regarding 
the analyses of dysphagia-related pain/discomfort/overall episode severity and abdominal 
pain/nausea severity were added. 
Section 8.1.3.3 (EoE-QoL-A): The text was updated to reflect that both overall and domain 
scores will be calculated.
Section 8.1.3.4 (PEESS): The PEESS was added for completion only by patients who are 
age 18 or under at Visit 1. The assessment will be completed as per the schedule provided 
in Table 4.
Section 8.1.3.6 (PGI-C): The text was updated to indicate that the PGI-C assessment will be 
completed by patients weekly starting 7 days after Visit 2.
Section 8.2.1 (Clinical safety laboratory measurements): The text was updated to indicate 
that the date, time of collection and results (values, units and reference ranges) of additional 
safety samples will be recorded in the patient’s medical records. The text was clarified to 
include differentials in the eosinophil, basophil, and monocyte counts to be redacted starting 
from Visit 2. 
Section 8.2.1.1 (Other laboratory measurements): The text was updated to indicate that 
blood samples for hepatitis B core antibody testing will be taken during the run-in period 
with additional monitoring as needed. This section was updated to include a description of 
the monitoring requirements for patients that are HBsAg positive or anti-HBc positive at 
Visit 1. The description of the assessments for total IgE and IgE allergen testing was 
removed from this section. 
Section 8.2.2 (Pregnancy test): This section was updated to clarify that FSH and serum 
HCG tests would be sent to and analysed at the central laboratory.
Section 8.2.4 (Vital signs): This section was updated to clarify that oral temperature will be 
measured.
Section 8.3.2.1 (Regulatory Reporting Requirements for SAEs): The section was added to 
describe the regulatory reporting requirements for SAEs. 

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Section 8.3.4 (Adverse event data collection): This section was updated to include 
collection of maximum NCI CTCAE grade and administration of treatment for each AE and 
description of SAEs. 
Section 8.5.1 (Determination of drug concentration): This section was updated to clarify 
that samples will be analysed for all patients receiving benralizumab. 
 
 
 
 
 
 
 
Section 8.9 (Immunogenicity): This section was updated to clarify that samples will be 
analysed for all patients receiving benralizumab.
Section 8.11.1 (Diet Questionnaire): This section was updated to clarify that interview data 
will be entered by the investigator via a web portal. 
Section 9.2 (Sample size determination): This section was updated to clarify the 
assumptions of the sample size calculation.
Section 9.4.1.1 (General principles): The general principles of the analyses that include 
presence of strictures at baseline as a covariate were clarified to indicate that in the instance 
of convergence issues/small strata for stratified analyses, presence of strictures at baseline 
may be removed if necessary.
Section 9.4.1.2 (Primary analysis method): This section was updated to indicate additional 
analyses to characterize patient dysphagia experience and correlations between the two 
primary endpoints may be explored. This section was also updated to indicate that 
sensitivity analyses for missing data will be collected for change from baseline in DSQ 

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score. Sensitivity analyses of the primary endpoint related to non-evaluable daily DSQ 
score data were removed.
Section 9.4.1.3 (Analysis methods for secondary efficacy variables):  The histological 
response levels were revised to <1, 1 to ≤6, 7 to <15 eos/hpf, etc.  This section was also 
updated to indicate that responder analyses and descriptive summaries will be provided for
all PRO assessments.
Section 9.4.1.4 (Sensitivity analyses): This section was updated to describe the sensitivity 
analyses that will be performed for the primary and key secondary endpoints. 
Section 9.4.2 (Safety analyses): The definition of baseline values for the safety analyses was 
added.  The collection of vital sign parameters was clarified to include systolic and diastolic 
blood pressure, pulse, respiration rate, and oral temperature. Collection of body weight was 
also added. 
Section 9.4.5 (Methods for multiplicity control): This section was clarified to note that for 
the purpose of US marketing approval both primary endpoints would need to be statistically 
significant.
Appendix A-5 (Independent Data Monitoring Committee): The description of the IDMC 
was updated.
Appendix B-6 (Intensity Rating Scale): This section was clarified to indicate that grading 
scales NCI CTCAE V5.00 will be utilized for all events with a CTCAE grading.  
Considerations for other AE intensity grading (e.g., mild, moderate, severe) were removed. 
Appendix H (Daily Diary [DSQ, EoE-3D, and other symptom questions]): The PRO 
instruments contained in this appendix were removed.
Appendix I (EoE-Qol-A): The EoE-Qol-A PRO instrument was removed.  
Global:  The word ‘optional’ was removed from the description of the OLE period.  
Participation in the OLE period will be offered to all patients who are eligible.
Version 1.0, 10 July 2019
Original Protocol (Initial creation)

SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d3255c00001-csp-v7
Document Title:
D3255C00001 Clinical Study Protocol version 7
Document ID:
Doc ID-004158106
Version Label:
6.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
05-Apr-2022 14:21 UTC
Content Approval
05-Apr-2022 16:25 UTC
Management Approval
08-Apr-2022 15:55 UTC
Content Approval
06-Apr-2022 14:34 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.