A Randomized, Double-Blind, Placebo-controlled Clinical Trial to Evaluate the Efficacy of Benralizumab (Anti-IL5RA) in Subjects With Eosinophilic Gastritis
Phase: PHASE2
Conditions: Eosinophilic Gastritis or Gastroenteritis
Sponsor: Children's Hospital Medical Center, Cincinnati

1 
 
A Randomized, Double-Blind, Placebo-Controlled Clinical Trial 
to Evaluate the Efficacy of Benralizumab (Anti-ILRA) in 
Subjects with Eosinophilic Gastritis 
 
Protocol Date: 04/03/2020 
NCT03473977 
 
 
 
 
 
 

2 
 
Clinical Study Protocol  
Drug Substance 
Benralizumab 
Study Code 
2017-1701 
Edition Number 
8 
Date 
03 Apr 2020 
A 
RANDOMIZED, 
DOUBLE-BLIND, 
PLACEBO-CONTROLLED 
CLINICAL 
TRIAL 
TO 
EVALUATE 
THE 
EFFICACY 
OF 
BENRALIZUMAB (ANTI-IL5RA) IN SUBJECTS WITH EOSINOPHILIC 
GASTRITIS  
Sponsor: Dr. Marc Rothenberg 
The following Amendment(s) and Administrative Changes have been made to this protocol since the date of 
preparation: 
Amendment No. 
Date of Amendment 
Local Amendment No: 
Date of Local Amendment 
2 
11 November 2017 
3 
17 January 2018 
4 
23 Oct 2018 
5 
25 Feb 2019 
6 
30 Apr 2019 
7 
18 Mar 2020 
8 
03 Apr 2020 
Administrative 
Change No. 
Date of Administrative 
Change 
Local Administrative 
Change No. 
Date of Local 
Administrative Change 
 
 

3 
 
PROTOCOL SYNOPSIS 
 
 
A 
RANDOMIZED, 
DOUBLE-BLIND, 
PLACEBO-CONTROLLED 
CLINICAL 
TRIAL 
TO 
EVALUATE 
THE 
EFFICACY 
OF 
BENRALIZUMAB (ANTI-IL5RA) IN SUBJECTS WITH EOSINOPHILIC 
GASTRITIS  
 
Principal Investigator 
Marc Rothenberg, MD, PhD 
Study site(s) and number of subjects planned 
Cincinnati Children’s Hospital Medical Center, 26 subjects planned 
Study period 
 
Phase of development 
Estimated date of first subject enrolled 
August 2017 
II/III 
 
Estimated date of last subject completed 
March 2022 
II/III 
 
Study Design 
 
Note: OLEII injections will take place every 4 or 8 weeks, based on clinical relevance per PI. 
In the double blind and OLE periods, participants affected by postponed EGDs due to 
COVID-19 may receive additional injections (every 4 or 8 weeks) until the EGDs can be 
performed. 

4 
 
Objectives 
Primary Objective: 
To assess the efficacy of repeat subcutaneous 
(SC) doses of benralizumab, compared with 
placebo, to reduce eosinophilic inflammation in 
the gastrointestinal tract of patients with EG. 
Outcome Measure: 
Induction of disease remission defined by the 
percentage of patients that achieve histological 
remission in the stomach as defined by peak eosinophil 
counts less than 30/hpf. Comparison between drug vs 
placebo will be the primary measurement endpoint. 
 
Secondary Objective: 
Outcome Measure : 
To assess changes in endoscopic score before 
and after treatment with benralizumab 
Change in endoscopic score from pre- to post-
treatment with benralizumab or placebo as measured 
by EREFS for EoE and Lanza Score for EG. 
To assess changes in histologic features before 
and after treatment with benralizumab 
Change in histologic score from pre- to post-treatment 
with benralizumab or placebo as measured by HSS for 
EoE and EG and ED Biopsy Evaluation Forms for EG 
or EGE 
To assess changes in blood eosinophil counts 
before and after treatment with benralizumab 
Change in blood eosinophil count before and after 
treatment with benralizumab or placebo as measured 
by CBC with differential. 
To assess changes in clinical symptoms before 
and after treatment with benralizumab 
Change in symptoms from pre- to post-treatment with 
benralizumab or placebo as measured by PROs 
-SODA (for EG) 
-PEESSv2, PedsQL 3.0, EESAI, EoE-QOL-A, 
PROMIS (for EoE) 
To evaluate esophageal, gastric, and duodenal 
tissue 
transcriptome 
changes 
following 
benralizumab treatment. 
Baseline predictors and changes in expression of genes 
as assessed by whole genome RNA sequencing  
To assess changes in peak eosinophil counts in 
biopsies before and after treatment with 
benralizumab 
Change in peak eosinophil count in biopsies 
(esophageal, gastric, and/or duodenal, as applicable) 
pre- vs. post-treatment with benralizumab or placebo 
 
 
Safety Objective: 
Outcome Measure : 
To evaluate the safety and tolerability of 
Benralizumab in subjects with EG 
AEs/SAEs 
Vital signs 
Physical exam 
Collection of blood chemistry and hematology 
Urinalysis 
Pregnancy testing 
 
 

5 
 
Target subject population 
Male and female subjects between the ages of 12-60 with histologically active EG. 
 
Duration of study 
3 months during the double blind treatment and up to 20 months during the open label 
extensions. Due to COVID-19, some participants may remain in the study up to an additional 
3 months. 
 
Investigational product, dosage and mode of administration 
Benralizumab 30 mg or placebo 
Subcuteaneous injection 
Statistical methods 
The planned total sample size of 24 subjects is justified based on previously published studies. 
Based on trials of other therapies in EoE, it is reasonable to assume that an eosinophil count at 
or below 30 eos/hpf for the stomach is considered an adequate response. It is estimated that a 
response rate in the placebo group will be no more than 10%. The estimated benralizumab 
response rate is 70%. To detect a difference between these two response rates, we need a total 
of 24 completed patients, or 12 patients per arm, to reach 80% statistical power. To account 
for possible dropouts, we will enrol at least 26 patients. At the end of OLE, we will use 
descriptive statistics to analyze the OLE data including histology, eosinophil counts, PROs 
etc. 
 
 
 

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SUMMARY OF CHANGES 
Page no. 
Sections 
Change description 
17 
27 
33  
35 
37 
1.3 Study design 
4.  Study plan 
4.2 Treatment period 
4.4 OLE I 
4.5 OLE II 
Due to COVID-19 travel restrictions, investigational 
product injections and some safety procedures may occur 
for double blind and open label visits at the patient’s local 
provider. Local providers may administer injections at 
visits 4,6,7,9 and 12-23 per PI discretion. Safety 
procedures that may occur at local provider or local lab 
include urine pregnancy test, urinalysis, vitals, and CBC 
with differential per PI discretion 
 
When IP administration and safety procedures occur at 
local providers, lab results and date/time of injection and 
other records will be provided to study staff post visit.    
25 
3.8 Post injection monitoring 
Post injection monitoring will occur at local providers 
who are medically trained to perform this monitoring 
including monitoring for hypersensitivity reactions. Study 
staff will confirm that local providers have standard 
treatments for hypersensitivity reactions in stock. 
Reactions related to injections will be logged by local 
providers. 
50 
7.4 Storage of IP 
Local providers who receive and store IP for local 
administration will confirm IP storage temperatures for 
study staff. To minimize risk and monitoring burden, IP 
will be shipped 1-2 days before injection. 
50 
7.6 Accountability 
Date and quantity of IP dispensed for shipment to local 
providers will be maintained in drug accountability 
records. Local providers will provide study staff with 
date/time of IP injection.  
53 
9.1 Training of study staff and 
local providers 
Local providers must show competency in subcutaneous 
injections and post injection monitoring (e.g., currently 
providing injections in clinical practice). 

7 
 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ........................................................................................................... 2 
PROTOCOL SYNOPSIS ......................................................................................... 3 
                TABLE OF CONTENTS ......................................................................................... 7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................... 11 
1. 
INTRODUCTION ................................................................................................. 13 
1.1 
Background and rationale for conducting this study ............................................. 13 
1.2 
Rationale for study design, doses and control groups ............................................ 14 
1.2.1 
Risks of Investigational Product as cited in Investigator Brochure ....................... 14 
1.2.2 
Risks of Study Procedures ..................................................................................... 16 
1.3 
Study Design .......................................................................................................... 18 
2. 
STUDY OBJECTIVES .......................................................................................... 19 
2.1 
Primary objective ................................................................................................... 19 
2.2 
Secondary objectives ............................................................................................. 19 
2.3 
Safety objectives .................................................................................................... 20 
3. 
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL ...................... 21 
3.1 
Inclusion criteria .................................................................................................... 21 
3.2 
Exclusion criteria ................................................................................................... 22 
3.3 
Subject enrollment and randomization .................................................................. 24 
3.4 
Procedures for handling incorrectly enrolled or randomized subjects ................... 25 
3.5 
Methods for assigning treatment groups ................................................................ 25 
3.6 
Methods for ensuring blinding ............................................................................... 25 
3.7 
Methods for unblinding .......................................................................................... 25 
3.8 
Restrictions ............................................................................................................ 26 
3.9 
Discontinuation of investigational product ............................................................ 26 
3.9.1 
Procedures for discontinuation of a subject from investigational product ............ 26 
3.10 
Criteria for withdrawal ........................................................................................... 27 
3.10.1 
Screen failures ........................................................................................................ 27 
3.10.2 
Withdrawal of the informed consent ...................................................................... 27 
3.10.3 
Early withdrawal .................................................................................................... 28 
3.11 
Discontinuation of the study .................................................................................. 28 
4. 
STUDY PLAN AND TIMING OF PROCEDURES ............................................. 28 
4.1 
Enrollment/Screening period ................................................................................. 33 
4.2 
Treatment period .................................................................................................... 33 
4.3 
Follow-up period .................................................................................................... 35 
4.4 
Open Label Extension I (OLE I) ............................................................................ 35 
4.5            Extended Open Label Extension (OLE II) ............................................................ 37 
5. 
STUDY ASSESSMENTS ..................................................................................... 38 

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5.1 
Efficacy assessments .............................................................................................. 38 
5.2 
Safety assessments ................................................................................................. 39 
5.2.1 
Laboratory safety assessments ............................................................................... 39 
5.2.2 
Physical examination ............................................................................................. 40 
5.2.3 
Vital signs .............................................................................................................. 40 
5.2.3.1 
Pulse and blood pressure ........................................................................................ 40 
5.2.3.2 
Body temperature ................................................................................................... 40 
5.2.4 
Other safety assessments ........................................................................................ 40 
5.3 
Other assessments .................................................................................................. 41 
5.3.1 
Patient reported outcomes ...................................................................................... 41 
5.3.1.1 
EESAI: for subjects with EoE and EG .................................................................. 41 
5.3.1.2 
EoE-QOL-A: for subjects with EoE and EG ......................................................... 41 
5.3.1.3 
PEESS®v2.0: For pediatric subjects (≤ 18 years old) ............................................ 41 
5.3.1.4 
PedsQL 3.0: for pediatric subjects (≤ 18 years old) with EoE and EG.................. 41 
5.3.1.5 
PROMIS: Patient Reported Outcomes Measurement Information System ........... 41 
5.3.2 
Other ...................................................................................................................... 42 
5.3.2.1 
Diet Questionnaire ................................................................................................. 42 
5.3.2.2 
Complete Blood Count (CBC) with differential .................................................... 42 
5.3.2.3 
GI Symptoms and Pain Interference ...................................................................... 42 
5.4 
Pharmacokinetics ................................................................................................... 42 
5.4.1 
Collection of samples ............................................................................................. 42 
5.4.2 
Determination of drug concentration ..................................................................... 42 
5.4.3 
Storage and destruction of pharmacokinetic samples ............................................ 42 
5.5 
Pharmacodynamics ................................................................................................ 42 
5.5.1 
Collection of samples ............................................................................................. 42 
5.5.2 
Storage, re-use and destruction of pharmacodynamic samples ............................. 42 
5.6 
Pharmacogenetics .................................................................................................. 42 
5.6.1 
Collection of pharmacogenetic samples ................................................................ 42 
5.6.2 
Storage, re-use and destruction of pharmacogenetic samples ............................... 43 
5.7 
Biomarker analysis ................................................................................................. 43 
5.7.1 
Storage, re-use and destruction of biological samples ........................................... 43 
5.7.2 
Labelling and shipment of biological samples ....................................................... 43 
5.7.3 
Chain of custody of biological samples ................................................................. 43 
5.7.4 
Withdrawal of Informed Consent for donated biological samples ........................ 43 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT .............................. 44 
6.1 
Definition of adverse events .................................................................................. 44 
6.2 
Definition of Serious Adverse Event (SAE) .......................................................... 44 
6.3 
Causality assessment .............................................................................................. 45 
6.4 
Recording of adverse events .................................................................................. 45 
6.4.1 
Time period for collection of adverse events ......................................................... 45 
6.4.2 
Follow-up of unresolved adverse events ................................................................ 45 

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6.4.3 
Variables ................................................................................................................ 45 
6.5 
Reporting of serious adverse events....................................................................... 47 
6.6 
Overdose ................................................................................................................ 48 
6.7 
Pregnancy ............................................................................................................... 48 
6.7.1 
Maternal exposure .................................................................................................. 49 
6.7.2 
Paternal exposure ................................................................................................... 49 
6.8 
Management of toxicities ....................................................................................... 49 
6.9 
Study governance and oversight ............................................................................ 49 
6.9.1 
Steering Committee ............................................................................................... 49 
6.9.2 
Data Monitoring Committee .................................................................................. 50 
6.9.3 
Scientific Advisory Committee .............................................................................. 50 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS .................... 50 
7.1 
Identity of investigational product(s) ..................................................................... 50 
7.2 
Dose and treatment regimens ................................................................................. 50 
7.3 
Labelling ................................................................................................................ 51 
7.4 
Storage ................................................................................................................... 51 
7.5 
Compliance ............................................................................................................ 51 
7.6 
Accountability ........................................................................................................ 51 
7.7 
Concomitant and other treatments ......................................................................... 52 
7.7.1 
Other concomitant treatment .................................................................................. 52 
8. 
STATISTICAL ANALYSES ................................................................................ 52 
8.1 
Statistical considerations ........................................................................................ 52 
8.2 
Sample size estimate .............................................................................................. 53 
8.3 
Definitions of analysis sets .................................................................................... 53 
8.3.1 
Efficacy analysis set ............................................................................................... 53 
8.3.2 
Safety analysis set .................................................................................................. 53 
8.3.3 
PK analysis set ....................................................................................................... 53 
8.3.4 
PRO analysis set .................................................................................................... 53 
8.4 
Outcome measures for analyses ............................................................................. 53 
8.5 
Methods for statistical analyses ............................................................................. 54 
8.5.1 
Analysis of the primary variable(s) ........................................................................ 54 
8.5.2 
Analysis of the secondary variable(s) .................................................................... 54 
8.5.3 
Subgroup analysis (if applicable) ........................................................................... 54 
8.5.4 
Interim analysis ...................................................................................................... 54 
8.5.5 
Sensitivity analysis (if applicable) ......................................................................... 54 
8.5.6 
Exploratory analysis (if applicable)) ...................................................................... 54 
9. 
STUDY AND DATA MANAGEMENT ............................................................... 55 
9.1 
Training of study site personnel and local provider ............................................... 55 
9.2 
Monitoring of the study ......................................................................................... 55 
9.2.1 
Source data ............................................................................................................. 55 
9.2.2 
Study agreements ................................................................................................... 55 

10 
 
9.2.3 
Archiving of study documents ............................................................................... 55 
9.3 
Study timetable and end of study ........................................................................... 56 
9.4 
Data management ................................................................................................... 56 
10. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 56 
10.1 
Ethical conduct of the study ................................................................................... 56 
10.2 
Subject data protection ........................................................................................... 56 
10.3 
Ethics and regulatory review.................................................................................. 57 
10.4 
Informed consent ................................................................................................... 57 
10.5 
Changes to the protocol and informed consent form ............................................. 57 
10.6 
Audits and inspections ........................................................................................... 58 
LIST OF REFERENCES ....................................................................................................... 59 
ADDENDUM NUMBER 1: GI SYMPTOMS AND PAIN INTERFERENCE .................... 62 
 
LIST OF TABLES 
Table 1 
 Study Plan detailing the procedures ........................................................ 31 
Table 2 
Laboratory Safety Variables ..................................................................... 39 
Table 3 
Benralizumab (MEDI-563) composition .................................................. 50 
 
LIST OF FIGURES 
Figure 1 
Study flow chart ........................................................................................ 18 
 
LIST OF ADDENDUMS 
ADDENDUM NUMBER 1: GI SYMPTOMS AND PAIN INTERFERENCE .................... 62 

11 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
ADA 
Anti-drug Antibodies 
ADCC 
Antibody-Dependent Cell-mediated Cytotoxicity 
AE 
Adverse event 
ANOVA 
Analysis of variation 
CBC 
Complete blood count 
CCHMC 
Cincinnati Children’s Hospital Medical Center 
CFR 
Code of Federal Regulations 
COVID-19 
Coronavirus Disease 2019 
(e)CRF 
Case Report Form (electronic/paper) 
CSA 
Clinical Study Agreement 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Event 
ED 
Eosinophilic Duodenitis 
EGE 
Eosinophilic Gastroenteritis 
EGD 
Esophagogastroduodenoscopy 
EGID 
Eosinophilic Gastrointestinal Disorder 
EoE 
Eosinophilic Esophagitis 
EoE-QOL-A 
Adult Esophagitis Quality of Life Questionnaire 
EOT 
End of Treatment 
EREFS 
Endoscopic Reference Score 
EESAI 
EoE Adult Symptom Score Activity Index 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HPF 
High power field 
HSS 
Histology Scoring System 
ICH 
International Conference on Harmonisation 
ICS 
Inhaled corticosteroids 

12 
 
Abbreviation or 
special term 
Explanation 
IP 
Investigational Product  
IRB 
Institutional Review Board 
IUD 
Intrauterine Device 
IUS 
Intrauterine system (levonogestrel) 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
LABA 
Long-Acting β2-Agonists 
LSLV 
Last Subject Last Visit 
MRO 
Medical Review Officer 
MTA 
Material Transfer Agreement 
NCI-CTCAE 
National Cancer Institute’s Common Terminology Criteria for 
Adverse Events 
OLE 
Open Label Extension 
PEESSv2 
Pediatric EoE Symptom Score, version 2 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PGx 
Pharmacogenetic research 
PHI 
Protected Health Information 
PI 
Principal Investigator  
PPI 
Proton Pump Inhibitor 
PROs 
Patient reported outcome metrics 
QOL 
Quality of Life 
SAE 
Serious adverse event  
SAR 
Serious adverse reaction 
SODA 
Severity of Dyspepsia Assessment 
TEAEs 
Treatment-emergent adverse events 
UGI 
Upper Gastrointestinal series 
WOCBP 
Woman of child bearing potential 
 

13 
 
1. 
INTRODUCTION 
1.1 
Background and rationale for conducting this study 
Eosinophilic gastrointestinal diseases (EGID) include eosinophilic esophagitis (EoE), 
eosinophilic gastritis (EG), eosinophilic duodenitis (ED) and eosinophilic colitis (EC).  
Symptoms of EGID include vomiting, abdominal pain, dysphagia, food impactions, and 
diarrhea, and generally dependent upon which gastrointestinal segment is involved. Patients 
with gastrointestinal eosinophilia in multiple gastrointestinal segments are referred to as 
eosinophilic gastroenteritis (EGE) patients and typically complain of upper abdominal pain, 
nausea and vomiting. Commonly-reported symptoms of EoE include dysphagia, vomiting, 
reflux, food aversion, and food impaction [1-3]. Preliminary studies suggest that most patients 
with EoE do not have extra-esophageal eosinophilia whereas most patients with EG also have 
involvement of the esophagus. There are no FDA approved drugs for any of these disorders. 
Diagnostically, EoE is defined by consensus criteria that requires esophageal-specific 
inflammation of  ≥ 15 eosinophils per high power field (hpf), as obtained from two to four 
biopsies from either the proximal or distal esophagus, that is not mitigated by the use of proton 
pump inhibitor (PPI) therapy [2]. The diagnosis of eosinophilic gastritis (EG) requires ≥ 30 
eosinophils per hpf in at least 5 hpfs, and eosinophilic duodenititis (ED) requires >52 
eosinophils/hpf.  
EGID are complex clinical entities requiring coordinated care within the fields of both Allergy 
and Gastroenterology. Current treatment modalities involve either elimination diet therapy, 
swallowed topical corticosteroid therapy, or a combination of both. These treatments are 
efficacious, but require continuous use, as a majority of patients recrudesce if treatment is not 
maintained. Concerns about the potential risks of chronic steroid use, as well as a desire to find 
more tolerable and/or convenient methods of treatment, have driven the search for other 
potential therapies. 
Interleukin 5 (IL-5) is a cytokine produced by type-2 T helper cells, innate lymphocyte type 2 
cells, and mast cells that serves as a key mediator in eosinophil activation. Drugs, such as the 
monoclonal antibodies against IL-5, mepolizumab and reslizumab, have been evaluated as 
potential therapies for eosinophilic disorders, due to their ability to reduce eosinophilic 
inflammation [4]. These two drugs are now FDA approved for eosinophilic asthma but not other 
eosinophil-associated diseases [5]. Significant numbers of eosinophils have been found to 
remain in the tissue after neutralization or experimental genetic deletion of IL-5 [6], suggesting 
the need for therapies that target other potential pathways for eosinophil activation. 
Benralizumab is a monoclonal antibody that binds to the alpha chain of the IL-5 receptor (IL-
5Ra) [7]. This receptor is expressed not only by mature eosinophils, but also by eosinophil 
progenitor cells and basophils. Benralizumab is a humanized, recombinant IgG1 monoclonal 
antibody. Benralizumab has been engineered to be afucosylated, or without a fucose sugar 
residue, which enhances the interaction of benralizumab with its binding site. This results in 
heightened antibody-dependent cell-mediated cytotoxicity (ADCC) function [8]. Benralizumab 
targets eosinophils and other cells expressing IL-5R in the circulation and residing in tissues 
for ADCC and results in depletion of eosinophils in the circulation, bone marrow and tissues. 

14 
 
Benralizumab also targets eosinophil precursors in the bone marrow for ADCC. Thus, 
benralizumab may potentially be more effective than the monoclonal antibodies against IL-5 
itself. 
IL-5 is one of several cytokine mediators involved in eosinophil development, activation, 
proliferation, and survival.  The concentration of this cytokine in affected tissues is increased in 
patients with asthma and in other diseases such as EGIDs. Findings from clinical trials have 
shown eﬃcacy and safety of treatment with monoclonal antibodies against IL-5 in patients with 
asthma and have led to the approval of mepolizumab and reslizumab in the USA and Europe as 
add-on maintenance treatment for patients with severe asthma aged 18 years (reslizumab) or 12 
years and older (mepolizumab) with an eosinophilic phenotype [5]. Benralizumab induces 
direct, rapid, and nearly complete depletion of eosinophils by lysis through enhanced ADCC 
involving natural killer cells [9]. This mechanism is in contrast to current treatments, which 
target IL-5 directly and act through a passive (i.e. indirect) mechanism that ultimately results in 
eosinophil reduction but not depletion. Benralizumab has a broad eﬃcacy proﬁle for patients 
with severe, uncontrolled asthma with eosinophilic inﬂammation [10]. In a phase 2b study, 
benralizumab 100 mg SQ every 8 weeks for 1 year seemed to reduce exacerbation rates 
compared with placebo (0.34 vs 0.57; 41% reduction, 80% CI 11–60; p=0.096) for patients with 
uncontrolled asthma treated with medium-dosage or high-dosage inhaled corticosteroids (ICS) 
and long-acting β2-agonists (LABA) (ICS plus LABA). A lower 20 mg dosage was also 
eﬃcacious in reducing exacerbation rates (0.30 vs 0.68 in placebo, 57% reduction, 80% CI 33–
72; p=0.015) in patients with blood eosinophil counts of at least 300 cells per mcL [11]. Results 
from this study prompted the decision to investigate a 30 mg dosage in phase 3 trials. A double-
blind, double-dummy designed study (ages 12-75) conﬁrmed the eﬃcacy and safety of 
benralizumab for patients with severe asthma and elevated eosinophils, which were 
uncontrolled by high-dosage ICS plus LABA, and provided support for benralizumab to be an 
additional option to treat this disease in this patient population. Indeed, usage of benralizumab 
has recently been approved by the FDA for eosinophilic asthma in 12 year olds and older [12]. 
1.2 
Rationale for study design, doses and control groups 
Benefit/risk and ethical assessment 
1.2.1 
Risks of Investigational Product as cited in Investigator Brochure 
Risk of serious infection 
Nonclinical pharmacology studies show that benralizumab binds to eosinophils through the IL-
5Rα, and blocks the binding of the ligand, IL-5, to the receptor. Benralizumab, through Fc 
engagement exhibits increased ADCC, resulting in depletion of eosinophils. In two reports, 
strains of transgenic mice that were deficient in eosinophils were created and both had normal 
immunological and hematological profiles except for the absence of eosinophils in their blood 
and tissues. Neither report indicated an increase in susceptibility to viral or bacterial infections 
for these gene-manipulated mice [13-15].  
Observations of eosinophil-deficient, gene-modified mice including (1) IL-5 knockout; (2) IL-
5Rα knockout mice; and (3) normal mice treated with anti-IL-5 mAb, demonstrated that 

15 
 
disruption of eosinophil function or elimination of the eosinophil itself did not cause 
perturbation of the animal’s normal immunological constitution.  
To mitigate the potential risk of serious infections (defined as infections that are life threatening, 
requiring IV antibiotics or hospitalization) eligibility criteria will be included in clinical study 
protocols to exclude vulnerable subjects, and subjects in studies will be monitored with 
complete blood counts including differential white cell count throughout the study; and through 
standard AE/SAE monitoring in clinical studies. 
Risk of helminth infection 
A theoretical risk of depleting eosinophils is interference with expulsion of helminthic 
parasites. A report in the literature showed that ablation of eosinophils with anti-IL-5 antibody 
in mice enhanced the survival of Trichinella spiralis [16]. On the other hand, depletion of 
eosinophils in other murine T spiralis infection models have shown no effect [17] or even a 
detrimental effect [18] on the ability to clear helminth infections. The importance of 
eosinophils in the control of helminth infections in humans is also uncertain. To mitigate the 
potential risk of helminth infections, eligibility criteria will be included in clinical study 
protocols to exclude vulnerable subjects and subjects in studies will be monitored through 
standard AE/SAE monitoring in clinical studies. If patients become infected while receiving 
treatment with Benralizumab and do not respond to anti-helminth treatment, treatment with 
Benralizumab will be discontinued until infection resolves. 
 
Potential risks common to any monoclonal antibody 
a. Potential risk of hypersensitivity/allergic reactions 
As with the administration of any foreign protein, acute allergic reactions and hypersensitivity 
reactions may occur, may be severe, and may result in death. Acute allergic reactions and 
hypersensitivity reactions may include hypotension, laryngeal edema, dyspnea, cyanosis, 
respiratory failure, urticaria, pruritus, angioedema, hypotonia, mental status changes, and 
unresponsiveness. 
There is a rare possibility of acute or late drug reaction (mild temporary abnormality of liver 
and renal function tests), kidney stones and reactivation of herpes zoster. 
There are specific requirements within each protocol for observing subjects for AEs and for 
monitoring vital signs before, during, and after administration of benralizumab if 
hypersensitivity or allergic reactions are present. 
b. Potential risk of infusion-related reaction 
Infusion-related reactions may be defined as any signs or symptoms experienced by subjects 
during the infusion of pharmacologic or biologic agents or any event occurring on the first day 
of drug administration. Clinical manifestations of these reactions vary. Anaphylactic or 
anaphylactoid reactions are the most severe forms of infusion-related reactions and may result 
in death. Infusion-related reactions usually develop within 2 hours of the start of investigational 

16 
 
product administration and often resolve within 24 hours after completion of investigational 
product administration. Signs/symptoms may include the following: urticaria, arthralgia, 
bronchospasm, wheeze, cough, dizziness, dyspnea, fatigue, headache, hypertension, 
hypotension, myalgia, and vomiting [19, 20]. 
c. Potential risks associated with immune reactivity 
The administration of a mAb can result in the formation of anti-drug antibodies (ADA). The 
occurrence of ADA could result in immune complex disease or hypersensitivity type III 
(defined as disease resulting from immune-complex formation divided broadly into 3 groups: 
those due to persistent infection, those due to autoimmune disease, and those caused by 
inhalation of antigenic material) with manifestations such as serum sickness, nephritis, and 
vasculitis, or altered benralizumab levels or activity. Therefore, subjects will be monitored for 
clinical manifestations that may be associated with the formation of specific antibodies to 
benralizumab generated during clinical studies. 
To date, no confirmed cases of immune complex disease have been observed and no appearance 
of a relationship between ADA and treatment-emergent adverse events (TEAEs) has been 
established. 
d. Potential risk associated with malignancy 
Since benralizumab targets eosinophils for destruction, it is important to understand what 
physiological impact eosinophil depletion may have in relation to carcinogenicity risk. While 
eosinophils have been found in association with solid tumours, especially tumours of epithelial 
origin (breast and colon) [21], the role eosinophils may have in tumour growth, if any, remains 
unclear. While some clinical studies have suggested the presence of eosinophils may be a 
positive prognostic indicator of cancer patient survival, a definitive link has not yet been 
established [22, 23]. 
To mitigate the potential risk of malignancies, eligibility criteria will be included in clinical 
study protocols to exclude vulnerable subjects and subjects in studies will be monitored through 
standard AE/SAE monitoring in clinical studies. 
1.2.2 
Risks of Study Procedures 
Esophagogastroduodenoscopy (EGD) 
Endoscopy with biopsy is a well-established procedure, with few patients experiencing 
unexpected or serious complications. Biopsies are routinely collected from the esophagus, 
stomach, and duodenum during endoscopy, and biopsies from all of these sites will be collected 
during endoscopic procedures for this study. 
The risks associated with collecting additional esophageal and gastrointestinal biopsies (up to a 
total of four obtained from each of the proximal and/or distal esophagus and stomach and 
duodenum) for research at the time of the endoscopy include: bleeding at the site of tissue 
(biopsy) collection, and a small chance of perforation (hole) of the stomach, duodenum, or 
esophagus. Perforation is the most severe gastrointestinal complication, but generally it is self-

17 
 
resolving and poses no life-threatening risk. Transient bacteremia as a result of diagnostic UGI 
endoscopy has been reported at rates as high as 8%, but the frequency of infectious endocarditis 
and other clinical sequelae is extremely low, such that current American Heart Association and 
American Society for Gastrointestinal Endoscopy guidelines do not recommend antibiotic 
prophylaxis with diagnostic UGI endoscopy solely to prevent infectious endocarditis [24]. The 
risk of aspiration during endoscopy is miniscule. 
To minimize the risks of collecting additional biopsies during endoscopy, the procedure will be 
performed or supervised by a skilled endoscopist, and additional biopsies will only be collected 
if the endoscopist feels it is appropriate to do so. Some samples that are collected during an 
endoscopy for research purposes may be frozen and shipped to other hospitals, institutions, and 
testing companies for analysis. Data may also be shared. The data and/or samples will be de-
identified per the Health Insurance Portability and Accountability Act (HIPAA) and have no 
protected health information (PHI) associated with them. The data and/or samples will be used 
in a collaborative relationship between institutions, or testing companies receiving the data 
and/or samples. All of these samples will be shared under a Material Transfer Agreement 
(MTA), or other applicable agreement. 
Blood Draws 
Risks associated with the collection of blood include bleeding, bruising, swelling, dizziness, 
fainting, and infection at the site of blood draw. Blood draws will be performed by individuals 
with expert skills in phlebotomy. To minimize the additional risks associated with phlebotomy, 
blood will be obtained during the standard placement of intravenous lines when possible. The 
amount of blood drawn will adhere to institutional policy. 
Histologic Scoring Tools 
The histology scoring tools are used to evaluate biopsies containing eosinophils for various 
features (ex: basal layer hyperplasia, dilated intercellular spaces, surface epithelial alteration, 
apoptotic epithelial cells), eosinophilic inflammation (peak count, eosinophil abscess, 
eosinophil surface layering), and lamina propria (fibrosis). There is no risk associated with the 
utilization of the histology scoring tools. 
Patient Reported Outcome (PRO) Metrics 
Participants will be asked to complete several metrics, including disease-specific symptom 
scores and QOL measures in order to address their symptoms and problems / feelings related to 
eating. There are no foreseeable physical discomforts or significant risks related to completing 
the PROs.  However, some questions may be difficult or uncomfortable for participants to 
answer, and participants may refuse to answer any questions that they are uncomfortable with. 
Participants may also feel inconvenienced by completing the questionnaires. The participant 
questionnaires typically take approximately 15 to 20 minutes to complete. All participants will 
be given ample time to complete the questionnaires. 
Other Risks 

18 
 
There is a slight risk that data containing PHI may be inadvertently shared. All data will be 
protected to the greatest extent possible. Electronic data will be maintained only on password-
protected systems on secure networks. Paper data will be kept in locked file cabinets and/or 
storage rooms. All data will be deidentified prior to being shared, and will only be shared with 
necessary parties for study purposes. 
It is possible that there are other unforeseen risks that we are not yet aware of. 
There are no guaranteed benefits associated with study participation.  Subjects may experience 
reduced symptoms as a result of treatment.  Subjects who complete the treatment period, 
whether on study drug or placebo, will be eligible to receive the drug during an open label 
extension. 
 
1.3 
Study Design  
Figure 1
 
 
 
 
OLE II injections will take place every 4 or 8 weeks, based on clinical relevance per 
PI. Due to COVID-19, OLE I injections may also take place every 4 or 8 weeks. 
 
Participants affected by postponed EGDs due to COVID-19 may receive additional 
injections (every 4 or 8 weeks) until the EGDs can be performed. 
 
Participants who are unable to travel due to restrictions and risks related to COVID-19 
may receive injections and safety assessments at a local provider per PI discretion 

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Drug Substance Benralizumab 
Study Code 2017-1701 
Edition Number 6 
Date 30 Apr 2019 
 
 
19 
 
2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
Primary Objective: 
Outcome Measure: 
To assess the efficacy of repeat subcutaneous 
(SC) doses of benralizumab, compared with 
placebo, to reduce eosinophilic inflammation 
in the gastrointestinal tract of patients with EG. 
Induction of disease remission defined by the 
percentage of patients that achieve histological 
remission in the stomach as defined by peak 
eosinophil counts less than 30/hpf. Comparison 
between drug vs placebo will be the primary 
measurement endpoint. 
2.2 
Secondary objectives 
Secondary Objective: 
Outcome Measure : 
To assess changes in endoscopic score before 
and after treatment with benralizumab 
Change in endoscopic score from pre- to post-
treatment with benralizumab or placebo as measured 
by EREFS for EoE and Lanza Score for EG 
To assess changes in histologic features before 
and after treatment with benralizumab 
Change in histologic score from pre- to post-
treatment with benralizumab or placebo as measured 
by HSS for EoE and EG and ED Biopsy Evaluation 
Form for EGE 
To assess changes in blood eosinophil counts 
before and after treatment with benralizumab 
Change in blood eosinophil count before and after 
treatment as measured by CBC 

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Drug Substance Benralizumab 
Study Code 2017-1701 
Edition Number 6 
Date 30 Apr 2019 
 
 
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To assess changes in clinical symptoms before 
and after treatment with benralizumab 
Change in symptoms from pre- to post-treatment with 
benralizumab or placebo as measured by PROs 
-PEESSv2, PedsQL 3.0, EESAI, EoE-QOL-A (for 
EoE) 
-SODA (for EG) 
-PROMIS 
To evaluate esophageal, gastric, and duodenal 
tissue transcriptome changes following 
benralizumab treatment.  
Baseline predictive transcripts and changes in 
expression of genes as assessed by whole genome 
RNA sequencing 
Comparison between peak eosinophil counts 
before and after drug or placebo 
Change in histological features including peak 
eosinophil count in biopsies (esophageal, gastric, 
and/or duodenal, as applicable) pre- vs. post-
treatment with benralizumab or placebo 
 
 
2.3 
Safety objectives 
Safety Objective: 
Outcome Measure : 
To evaluate the safety and tolerability of 
Benralizumab in subjects with EG 
AEs/SAEs 
Vital signs 
Physical exam 
Collection of blood chemistry and hematology, and 
coagulation 
Urinalysis 
Pregnancy testing 

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Drug Substance Benralizumab 
Study Code 2017-1701 
Edition Number 6 
Date 30 Apr 2019 
 
 
21 
 
 
3. 
SUBJECT SELECTION, ENROLLMENT, RANDOMIZATION, RESTRICTIONS, 
DISCONTINUATION AND WITHDRAWAL  
3.1 
Inclusion criteria 
Informed Consent: Able to give written informed consent prior to participation in the study, which will include the ability 
to comply with the requirements and restrictions listed in the consent form. Subjects must be able to read, comprehend, 
and write at a level sufficient to complete study related materials. 
Males and females between the ages of 12-60 years  
Confirmed diagnosis of EG involving stomach; involvement of eosinophilic inflammation in other gastrointestinal 
segments will be allowed but not required or sufficient. 
Histologically active EG at time of screening, with a peak Gastric count of ≥ 30 eos/hpf in at least 5 hpfs. 
Must be symptomatic (defined as having experienced symptoms within 4 weeks prior to enrollment). Clinical symptoms 
(i.e., abdominal pain, bloating, vomiting, diarrhea) must be severe enough to impact daily life (e.g., school/work 
attendance, social activities) ≥ 2 times in 3 of the 4 weeks prior to enrollment despite treatment (such as diet, proton 
pump inhibitors or corticosteroids). See addendum number 1, page 59. 
Blood eosinophilia (defined as having an absolute eosinophil count > 0.5 K/ mcL of blood) at least once during the 6 
months prior to enrollment. 
Must be on baseline anti-EG/EGE therapy as long as there is agreement to not change their dosage unless medically 
indicated; OR, must have failed anti-EG/EGE therapy in the past, including diet therapy. 
Female subjects: Women of childbearing potential (WOCBP) must use an effective form of birth control (confirmed by 
the Investigator). Effective forms of birth control include: true sexual abstinence, a vasectomized sexual partner, 

Clinical Study Protocol 
Drug Substance Benralizumab 
Study Code 2017-1701 
Edition Number 6 
Date 30 Apr 2019 
 
 
22 
 
Implanon, female sterilization by tubal occlusion, any effective IUD intrauterine device/IUS levonogestrel Intrauterine 
system, Depo-Provera(tm) injections, oral contraceptive, and Evra Patch(tm) or Nuvaring(tm). WOCBP must agree to 
use effective method of birth control, as defined above, from enrollment, throughout the study duration and within 16 
weeks after last dose of IP, and have negative serum pregnancy test result on Visit 0. 
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 visit -1 without an alternative medical cause.  The 
following age-specific requirements apply: 
Women <50 years old would 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. 
Women ≥50 years old would be considered postmenopausal if they have been amenorrheic for 12 months or more 
following cessation of all exogenous hormonal treatment. 
All male subjects who are sexually active must agree to use an acceptable method of contraception (condom with or 
without spermicide, vasectomy) from Visit 0 until 16 weeks after their last dose. 
3.2 
Exclusion criteria 
Concurrent H. pylori gastritis or parasitic infection 
Other gastrointestinal disorders such as Crohn’s disease, inflammatory bowel disease, or Celiac disease, eosinophilic 
granulomatosis with polyangiitis (EGPA), drug hypersensitivity or connective tissue rheumatological disorders, 
Esophageal stricture that prevents the easy passage of a standard endoscope 
Use of any investigational biologic drug within 6 months prior to screening 

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Drug Substance Benralizumab 
Study Code 2017-1701 
Edition Number 6 
Date 30 Apr 2019 
 
 
23 
 
Hypereosinophilic syndrome, defined by multiple organ involvement (with the exception of atopic disease or EGID) and 
persistent blood absolute eosinophil count ≥1500/mcL. 
History of cancer: Subjects 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 subject is in remission and curative therapy was completed at least 
12 months prior to the date informed consent, and assent when applicable was obtained. Subjects who have had other 
malignancies are eligible provided that the subject is in remission and curative therapy was completed at least 5 years 
prior to the date informed consent, and assent when applicable, was obtained. 
A helminth parasitic infection diagnosed within 24 weeks prior to the date informed consent is obtained that has not been 
treated with, or has failed to respond to standard of care therapy. 
Pregnant or nursing 
Receipt of any investigational non-biologic within 30 days or 5 half-lives prior to visit 0, whichever is longer. 
A history of known immunodeficiency disorder including a positive human immunodeficiency virus (HIV) test. 
Any other medical illness that precludes study involvement 
Positive hepatitis B surface antigen, or hepatitis C virus antibody serology, or a positive medical history for hepatitis B or 
C. Subjects with a history of hepatitis B vaccination without history of hepatitis B are allowed to be enrolled. 
Patients who are currently receiving or have previously received benralizumab or any other type of anti-interleukin 
therapy (i.e. mepolizumab, reslizumab, lebrikizumab etc.) within the last 6 months or 5 half-lives whichever is longer. 
History of anaphylaxis to any biologic therapy or vaccine. 
Receipt of immunoglobulin or blood products within 30 days prior to the date informed consent is obtained. 

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Drug Substance Benralizumab 
Study Code 2017-1701 
Edition Number 6 
Date 30 Apr 2019 
 
 
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3.3 
Subject enrollment and randomization 
We plan to recruit at least of 26 subjects, between the ages of 12-60 years. Potential subjects will be screened during an 8-week 
screening period. An EGD with biopsies will be performed to determine study eligibility, and subjects will be enrolled based on the 
presence of active disease and their ability to meet the study inclusion and exclusion criteria. 
The screening EGD can be performed up to 8 weeks prior to enrollment. In this case, biopsies collected for clinical purposes in 
Cincinnati Children’s Hospital or University of Cincinnati medical center, will be blinded and re-analyzed by Dr. Margaret Collins, 
to determine study eligibility. In case the EGD is performed in a different site, clinical biopsies will be sent to Dr. Collins for 
evaluation, after authorization of release of medical information and specimens is accepted from the subject. 
Qualifying subjects will be blindly randomized 1:1 to either study drug (benralizumab) or placebo, and will receive monthly 30 mg 
doses of study treatment for 2 months (for a total of 3 injections). Participants affected by postponed EGDs due to COVID-19 may 
receive additional injections (every 4 weeks) until the EGD is performed. Randomization ratio will be kept at 1:1 for users of systemic 
and/or swallowed corticosteroids, compared to non-users.  
During the treatment period, subjects will be monitored for adverse events/reactions and will complete patient reported outcome 
metrics to track their symptoms and general wellbeing. Subjects and study staff will remain blinded to the results of the complete 
blood count (CBC) so that they are not biased by an apparent drop in eosinophil counts. At the end of the treatment period, a repeat 
endoscopy with biopsies will be performed to assess the change in peak eosinophil count from pre- to post-treatment. Subjects and 
research study staff will remain blinded to the endoscopy results until completion of the double blind phase of the study. An Open 
Label Extension (OLE) will include four additional injections of Benralizumab, followed by an end of treatment endoscopy. 
Participants affected by postponed EGDs due to COVID-19 may receive additional injections (every 4 or 8 weeks) until an EGD is 
performed. Extended OLE (OLE II) will allow up to 13 additional injections and a final research endoscopy. Participants affected by 
postponed EGDs due to COVID-19 may receive additional injections (every 4 or 8 weeks) until an EGD is performed. Subjects will 
continue to be monitored for 30 days as a safety follow-up. At the end of the 30 day follow-up period, study participation will 
conclude.  
Given the nonspecific nature of the symptoms in EG and the known dissociation of histology and symptoms in other eosinophilic 
disorders, presence or absence of symptomatic responses alone will not be sufficient to assess therapy effectiveness, and thus 
endoscopy is a necessary part of both clinical care and therapeutic trial monitoring.   

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Drug Substance Benralizumab 
Study Code 2017-1701 
Edition Number 6 
Date 30 Apr 2019 
 
 
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3.4 
Procedures for handling incorrectly enrolled or randomized subjects 
Incorrectly enrolled or randomized subjects will be withdrawn from the study at the direction of the study sponsor. 
3.5 
Methods for assigning treatment groups 
Approximately 26 patients will be randomized in a 1:1 ratio to receive benralizumab or placebo.  Randomization will be accomplished 
via a central randomization scheme provided by the study sponsor/principal investigator, Dr. Marc Rothenberg,  to the study 
pharmacist (or qualified designee). 
3.6 
Methods for ensuring blinding 
The investigators, study staff, pathology review pathologist, and study subjects will all remain blinded to treatment assignment 
throughout the trial. The medical review officer (MRO), study monitor, and any other personnel designated by the sponsor (Dr. 
Rothenberg as PI of the study) who have regular contact with the study site will remain blinded to all treatment assignments.  
Individuals not involved in the conduct of the trial who have been designated by the sponsor (e.g. Data Safety Monitoring Board 
members) may have access to unblinded data as necessary for safety review or other data review. Blinded study drug kits coded with 
a medication numbering system will be used. In order to maintain the blind, lists linking these codes with product lot numbers will 
not be accessible to individuals involved in study conduct.   
Study site personnel will be blinded to the peripheral eosinophil results during the double blind phase of the study so as to prevent 
unintentional bias due to changes in blood eosinophil counts. The MRO will have access to the CBC results for data safety review. 
Beginning in the open label extension, peripheral eosinophil counts from the 3rd dose visit (Visit 7) and subsequent visits will be 
made available to study staff after each visit.  This data will be used to determine dosing intervals in OLE II. 
Study site personnel will be blinded to the post-treatment double blind endoscopy results until the completion of the double blind 
phase of the study. Endoscopy results from the open label extensions will be available to study staff after each OLE EGD. Study 
participants may only receive results of any post – OLE endoscopies and peripheral eosinophil counts upon request.  
3.7 
Methods for unblinding  
In the case of medical emergency or other significant medical event (e.g. pregnancy), unblinding of treatment assignment for a subject 
may be necessary. 

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Drug Substance Benralizumab 
Study Code 2017-1701 
Edition Number 6 
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26 
 
For medical emergencies: 
 Only the investigator may make the decision to unblind the treatment assignment. 
 Unblinding will occur only for the affected subject. 
 The study pharmacist(s)/designee at the study site will provide the treatment assignment to the investigator. 
 The investigator will immediately notify the sponsor that unblinding has occurred. 
Barring true emergencies, site personnel, including the PI, should not be provided the treatment assignment data at any time during 
the conduct of the trial. 
3.8 
Restrictions 
Post injection observation 
All subjects will be observed for 1 hour post injection of investigational product for signs of infusion reaction or anaphylaxis during 
the double blind and OLEI treatment periods. During OLEII, this may be reduced to 30 minutes post injection, if the subject has 
tolerated previous treatments well. Anaphylaxis will be assessed as per standard protocol and treatment will include subcutaneous 
epinephrine, antihistamines and /or systemic corticosteroids such as solumedrol or prednisone as clinically indicated. When drug is 
administered at local providers for patients that cannot travel to the study site due to COVID-19, local providers will follow the above 
post-injection observation procedures including monitoring for hypersensitivity reactions. Standard protocols for treatment of 
hypersensitivity reactions will be reviewed by study staff with local provider. Study staff will confirm local providers have standard 
treatments (epinephrine, antihistamine, corticosteroids) on site and are clinically trained on the administration of treatments for 
hypersensitivity reactions. Local providers will be asked to log all reactions related to injections and provide to study staff to ensure 
adverse reactions are recorded in research records.  
3.9 
Discontinuation of investigational product 
3.9.1 
Procedures for discontinuation of a subject from investigational product  
Study therapy may be prematurely discontinued for any participant for any of the following reasons: 
1. 
At the discretion of the sponsor 
2. 
The PI feels that the study treatment is no longer in the best interest of the participant. 

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Drug Substance Benralizumab 
Study Code 2017-1701 
Edition Number 6 
Date 30 Apr 2019 
 
 
27 
 
3. 
The participant experiences an AE that the PI feels warrants discontinuation of the study therapy. 
3.10 
Criteria for withdrawal  
Participants may be prematurely terminated from the study for the following reasons: 
1. The participant elects to withdraw consent from all future study activities, including follow-up. 
2. Participant develops severe complications from their EoE/EGE (for instance, esophageal strictures). 
3. Participant required EGID rescue medicines that the investigator feels are substantial. 
4. Participant becomes pregnant. 
5. The participant is “lost to follow-up” (i.e., no further follow-up is possible because attempts to reestablish contact with the 
participant have failed). 
6. The participant develops an SAE related to therapy. 
7. The participant dies. 
8. The Investigator no longer believes participation is in the best interest of the participant. 
Enrolled participants who start on the initial intervention protocol and prematurely discontinue/withdraw from the study will be 
replaced if they do not reach the End of Treatment (V5) visit of the study, including the EGD. Additional participants will be 
enrolled in the same manner as all other participants. Participant numbers will not be re-used.  All enrolled participants will be 
included into intent to treat analysis. 
3.10.1 
Screen failures 
If it has been confirmed that a subject does not meet inclusion and/or exclusion criteria, the subject will be considered a screen failure. 
Screen failed subjects cannot be rescreened unless the screen failure was due to a concomitant medication that can be discontinued 
prior to rescreening. Other potential reasons for rescreening (i.e. reasons unrelated to the inclusion/exclusion criteria) must be 
approved by the study principal investigator prior to rescreening the subject. 
3.10.2 
Withdrawal of the informed consent 
Subjects may choose to withdraw consent at any time during study participation. When a participant withdraws permission, they will 
no longer be part of the study and no new information about the subject will be gathered for the study except for information related 
to an adverse event that is related or potentially related to the study. 

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Drug Substance Benralizumab 
Study Code 2017-1701 
Edition Number 6 
Date 30 Apr 2019 
 
 
28 
 
3.10.3 
Early withdrawal 
Subjects may be asked to complete an  EOT/Early withdrawal visit prior to withdrawal per the discretion of the PI.  
3.11 
Discontinuation of the study 
 The principal investigator may discontinue the study, or part of the study, at any time for any reason. If the study is suspended or 
terminated, the principal investigator will notify the drug manufacturer, and regulatory agencies and the IRB will be notified as 
appropriate. Additionally, the study entry on clinicaltrials.gov will be updated to reflect that the study has been discontinued. 
4. 
STUDY PLAN AND TIMING OF PROCEDURES 
Study Procedures 
Screening 
Double-Blind Treatment 
OLE 
  
V1 
V2 
Baseline 
V3 
V4† 
V5 
EOT/EW  
V6 OLE 2nd 
dose 
V7 OLE 3rd 
dose 
V8 (phone 
call) 
V9†† OLE 
4th dose 
V10 
(phone 
call) 
V11 
EOT/EW 
(***1st 
dose OLEII 
OLE 1st 
dose 
Week (Wk) 
Wk -8 to 0 
WK 0 
4 
8 
12  
16 
20 
24 
28 
32 
36 
Visit Window (in days, d)+ 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
Screening/Baseline: 
  
  
  
  
  
  
Informed Consent 
X 
  
  
  
 
  
  
  
  
  
  
Inclusion/exclusion 
X 
X 
  
  
 
  
  
  
  
  
  
Medical History/demographics/height 
X 
  
  
  
  
  
  
  
  
  
  
Randomization/Eligibility 
  
X 
  
  
  
  
  
  
  
  
  
Diet Questionnaire 
  
X 
  
  
X  
  
  
  
  
  
  
Treatment: 
  
  
  
  
  
  
Administer study drug2 
  
X 
X 
X 
X**2 
X** 
X2 
 
X2 
  
 X***2 
Con meds/procedures 
X 
X 
X 
X 
X** 
X** 
X 
X 
X 
X 
X 
Efficacy: 
  
  
  
  
  
  
EESAI1 
X 
X 
X 
X 
X 
X** 
X 
X 
X 
X 
X 
GI symptoms and pain interference 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

Clinical Study Protocol 
Drug Substance Benralizumab 
Study Code 2017-1701 
Edition Number 6 
Date 30 Apr 2019 
 
 
29 
 
Study Procedures 
Screening 
Double-Blind Treatment 
OLE 
  
V1 
V2 
Baseline 
V3 
V4† 
V5 
EOT/EW  
V6 OLE 2nd 
dose 
V7 OLE 3rd 
dose 
V8 (phone 
call) 
V9†† OLE 
4th dose 
V10 
(phone 
call) 
V11 
EOT/EW 
(***1st 
dose OLEII 
OLE 1st 
dose 
Week (Wk) 
Wk -8 to 0 
WK 0 
4 
8 
12  
16 
20 
24 
28 
32 
36 
Visit Window (in days, d)+ 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
EoE-QOL-A2 
X 
X 
X 
X 
X 
X** 
X 
X 
X 
X 
X 
SODA3 
X 
X 
X 
X 
X 
X** 
X 
X 
X 
X 
X 
EREFS4 
X 
  
  
  
X 
  
  
  
  
  
X 
PEESSv25 
X 
X 
X 
X 
X 
X** 
X 
X 
X 
X 
X 
PedsQL 3.06 
X 
X 
X 
X 
X 
X** 
X 
X 
X 
X 
X 
PROMIS7 
X 
X 
X 
X 
X 
X** 
X 
X 
X 
X 
X 
Lanza Score 
X 
  
  
  
X 
  
  
  
  
  
X 
Histology Assessments8 
X 
  
  
  
X 
  
  
  
  
  
X 
Safety: 
  
  
  
  
  
  
Weight 
X 
X 
X  
 X 
X  
 X 
 X 
 
 X 
  
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
X 
  
X 
Physical Exam 
X 
  
  
  
X 
X* 
  
  
  
  
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing: 
  
  
  
  
  
  
Hematology and serum chemistry 
X 
  
X 
  
X 
  
  
  
  
  
X 
CBC with Differential 
 
 
 
 
X** 
X** 
X 
 
X 
 
X 
HBsAG 
X 
 
 
 
 
 
 
 
 
 
 
Hepatitis C Ab 
X 
 
 
 
 
 
 
 
 
 
 
IgE 
X 
  
  
  
X 
  
  
  
  
  
X 
Urinalysis 
X 
  
X 
  
X 
  
X 
  
X 
  
X 
Pregnancy testing - Serum 
X 
  
  
  
  
  
  
  
  
  
  
Pregnancy testing - Urine 
X 
X 
X 
X 
X 
X 
X 
 
X 
  
X 

Clinical Study Protocol 
Drug Substance Benralizumab 
Study Code 2017-1701 
Edition Number 6 
Date 30 Apr 2019 
 
 
30 
 
Study Procedures 
Screening 
Double-Blind Treatment 
OLE 
  
V1 
V2 
Baseline 
V3 
V4† 
V5 
EOT/EW  
V6 OLE 2nd 
dose 
V7 OLE 3rd 
dose 
V8 (phone 
call) 
V9†† OLE 
4th dose 
V10 
(phone 
call) 
V11 
EOT/EW 
(***1st 
dose OLEII 
OLE 1st 
dose 
Week (Wk) 
Wk -8 to 0 
WK 0 
4 
8 
12  
16 
20 
24 
28 
32 
36 
Visit Window (in days, d)+ 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
Endoscopy with biopsies9 
X 
  
  
  
X 
  
  
 
  
  
X 
Research samples (whole blood/serum) 
X 
X 
 X 
X 
X  
X 
X 
 
X 
  
X 
Tissue transcriptome (esophagus, 
stomach, and duodenum) 
X 
  
  
  
X 
  
  
 
  
  
X 
Stool microbiome 
X 
  
  
  
X 
  
  
  
  
  
X 
1EESAI = eosinophilic esophagitis symptom activity index; 2EoE-QOL-A = Adult Esophagitis Quality of Life Questionnaire; 3SODA = severity of dyspepsia assessment; 4EREFS = endoscopic reference 
score; EOT = end of treatment; EW = early withdrawal 5PEESS = Pediatric EoE Symptom Score; 6PedsQL = Pediatric Quality of Life; 7PROMIS = Patient Reported Outcomes Measurement System; 8HSS 
for esophageal biopsies; EG Biopsy Evaluation form for gastric biopsies; ED Biopsy Evaluation form for duodenal biopsies. 9SOC qualifying Endoscopy will be a part of screening. EOT of unscheduled 
endoscopies will be covered by the study. 
2 Study drug administration and related activities= every 4 or 8 weeks, determined ad-lib by the study doctor depending upon symptoms and COVID-19 restrictions 
*= Procedures in Visit 5/6 (F/U) which will only be performed if subject does NOT continue to OLE 1 
**= Procedures in Visit 5/6 (F/U) which will only be performed if subject is to start OLE 1. 
***= drug administration in visit 11 will only be performed if subject chooses to continue to OLE2.  
+ visit window is counted from the previous visit and not from the date of enrollment/randomization. 
† This visit may be repeated until an EGD can be performed for participants whose EGDs are postponed due to COVID-19. 
† † This visit may be repeated until an EGD can be performed for participants whose EGDs are postponed due to COVID-19 
Note: study drug administration may occur at local provider per PI discretion at visits 4, 6, 7, and 9 due to COVID-19 

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Study Procedures 
OLE II 
  
V12 OLE II  
V13 OLE II  
V14 OLE II  
V15 OLE 
II  
V16 OLE II  
V17 OLE 
II  
V18 OLE II  
V19 OLE 
II  
V20 OLE II  
V21 OLE 
II  
V22 OLE 
II  
V23†† 
OLE II  
V24 
EOT/EW 
EGD 
V25 
Safety F/U 
Week (Wk) 
40 
44 
48 
52 
56 
60 
64 
68 
72 
76 
80 
84 
88 or 92 
96 
Visit window in days (d) + 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
Diet Questionnaire 
 
 
X 
 
 
X 
 
 
 
 
 
 
X 
X 
Administer study drug1 
X1 
X 
X1 
X 
X1 
X 
X1 
X 
X1 
X 
X1 
X 
  
  
Con meds/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EESAI2 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
  
EoE-QOL-A3 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
  
GI symptoms and pain 
interference 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
SODA4 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
  
EREFS5 
 
 
 
 
 
 
 
 
 
 
 
 
X 
  
PEESSv26 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
  
PedsQL 3.07 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
  
PROMIS8 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
  
Lanza Score 
  
 
  
 
  
 
  
 
  
 
  
 
X 
  
Histology Assessments9 
  
 
  
 
  
 
  
 
  
 
  
 
X 
  
Safety: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
  
Vital signs 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X 
  
Physical Exam 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
  
Adverse events 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X 
  
Lab testing: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology and serum 
chemistry 
 
 
 
 
 
 
 
 
 
 
 
 
X 
  
CBC with Differential 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
  

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Drug Substance Benralizumab 
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Edition Number 6 
Date 30 Apr 2019 
 
 
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Study Procedures 
OLE II 
  
V12 OLE II  
V13 OLE II  
V14 OLE II  
V15 OLE 
II  
V16 OLE II  
V17 OLE 
II  
V18 OLE II  
V19 OLE 
II  
V20 OLE II  
V21 OLE 
II  
V22 OLE 
II  
V23†† 
OLE II  
V24 
EOT/EW 
EGD 
V25 
Safety F/U 
Week (Wk) 
40 
44 
48 
52 
56 
60 
64 
68 
72 
76 
80 
84 
88 or 92 
96 
Visit window in days (d) + 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
IgE 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
  
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
X 
  
Pregnancy testing – Urine 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X 
  
Endoscopy with biopsies10 
 
 
 
 
 
 
 
 
 
 
 
 
X 
  
Research samples (whole 
blood/serum) 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X* 
X 
X 
  
Tissue transcriptome 
(esophagus, stomach, and 
duodenum) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
  
Stool microbiome 
  
 
  
 
  
 
  
 
  
 
  
 
  
1 Study drug administration and related activities= every 4 or 8 weeks, determined ad-lib by the study doctor depending upon symptoms, CBC and discussion with patients.; 2EESAI = eosinophilic esophagitis symptom 
activity index; 3EoE-QOL-A = Adult Esophagitis Quality of Life Questionnaire; 4SODA = severity of dyspepsia assessment; 5EREFS = endoscopic reference score;  6PEESSv2 = Pediatric EoE Symptom Severity; 7PedsQL = 
Pediatric Quality of Life; 8PROMIS = Patient Reported Outcomes Measurement System; 9HSS for esophageal biopsies; EG Biopsy  
Evaluation form for gastric biopsies; ED Biopsy Evaluation form for duodenal biopsies. 10Endoscopy with biopsies in visit 24 will be performed at week 88 or week 92, depending on the treatment interval.  
* assessments to be done if subjects are in cchmc  
+ visit window is counted from the previous visit and not from the date of enrollment/randomization. 
† † This visit may be repeated until an EGD can be performed for participants whose EGDs are postponed due to COVID-19. 
Note: study drug administration may occur at local provider per PI discretion at visits 12-23 due to COVID-19 

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4.1 
Enrollment/Screening period 
Visit 1 
 Informed Consent 
 Inclusion/Exclusion 
 Medical history/demographics/height 
 Concomitant medications/procedures GI symptoms and pain interference 
 endoscopy with biopsies (Standard of care if performed prior to consent) 
 PROs (EESAI, EoE-QOL-A, SODA, PedsQL, PEESS, PROMIS) 
 Endoscopic and Histologic metrics (EREFS, HSS, Lanza Score, EG Biopsy Evaluation 
Form, ED Biopsy Evaluation Form) 
 Physical Exam, Vital Signs, Weight 
 Clinical labs (hematology and serum chemistry, urinalysis, IgE, HBsAg, Hepatitis C 
Ab) 
 Pregnancy testing: serum and urine  
 Adverse Events 
 Research samples (whole blood/serum, plasma, endoscopic biopsies, stool 
microbiome) 
4.2 
Treatment period 
Visit 2 (Baseline Week 0) 
 Administer study drug 
 Inclusion/Exclusion 
 Randomization 
 Concomitant medications/procedures 
 GI symptoms and pain interference 
 PROs (EESAI, EoE-QOL-A, SODA, PedsQL, PEESS, PROMIS) 
 Vital Signs, Weight 
 Diet Questionnaire 
 Adverse Events 
 Pregnancy Testing: urine  
 Research samples (whole blood/serum/plasma) 
 
 
 

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Edition Number 6 
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Visit 3 (Week 4) 
 Administer study drug 
 Concomitant medications/procedures 
 GI symptoms and pain interference 
 PROs (EESAI, EoE-QOL-A, SODA, PedsQL, PEESS, PROMIS ) 
 Vital Signs, Weight 
 Adverse Events 
 Pregnancy Testing: urine  
 Clinical labs (hematology and serum chemistry, urinalysis) 
 Research samples (whole blood/serum/plasma) 
Visit 4 (week 8)† 
 Administer study drug 
 Concomitant medications/procedures 
 GI symptoms and pain interference 
 PROs (EESAI, EoE-QOL-A, SODA, PedsQL, PEESS, PROMIS) 
 Vital signs, weight 
 Adverse Events 
 Pregnancy Testing: urine  
 Research samples (whole blood/serum/plasma) 
† This visit may be repeated until an EGD can be performed for participants whose EGDs are 
postponed due to COVID-19. Participants may have study drug administered by their local 
providers due to COVID-19 travel restrictions and travel risks. In these cases, adverse events 
and concomitant meds will be assessed by study team via telephone/telemedicine prior to the 
visit to local provider. Pregancy testing and vitals will occur by local provider or local lab per 
PI discretion. Results from testing will be provided to the study staff directly from the local 
provider (via medical record release when necessary). Date and time of study drug injection 
and post injection monitoring results will also be provided to study staff from the local 
provider.  
Visit 5 (Week 12 - End of Treatment/Early Withdrawal) 
 Concomitant medications/procedures 
 GI symptoms and pain interference 
 PROs (EESAI, EoE-QOL-A, SODA, PedsQL, PEESS, PROMIS) 
 Physical Exam, Vital Signs, Weight 
 Diet Questionnaire 
 Adverse Events 

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Edition Number 6 
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 Pregnancy Testing: urine 
 Endoscopy with biopsies 
 Endoscopic and Histologic metrics (EREFS, HSS, Lanza score, EG Biopsy Evaluation 
Form, ED Biopsy Evaluation Form) 
 Clinical labs (hematology and serum chemistry, urinalysis, pregnancy testing, IgE) 
 Research samples (whole blood/serum, plasma, stool microbiome) 
4.3 
Follow-up period 
Visit 6 (Week 16 Follow-Up) 
 Physical Exam, Vital Signs, weight 
 Adverse Events 
 Pregnancy testing: urine  
 Clinical labs (hematology and serum chemistry, urinalysis, IgE) 
4.4 
Open Label Extension I (OLE I) 
Study subjects who complete the 12 week treatment phase (whether on drug or placebo) will 
be allowed into an extension study, where 3 doses of Benralizumab will be administered every 
four weeks, and 1 more dose will be administered at an 8 week interval. Study drug may be 
administered at 8 week intervals due to COVID-19 restrictions or PI discretion depending 
upon symptoms. General laboratory studies and patient reported outcomes will be measured 
regularly. Endoscopy will be performed four weeks after the last dose of the study drug. The 
first dose in the OLE phase will be administered at visit 5 of the double treatment phase, for 
subjects who choose to do so.  
Visit 5 (OLE I Week 12, 1st dose) 
 Administer study drug 
 Concomitant medications/procedures 
 GI symptoms and pain interference 
 PROs (EESAI, EoE-QOL-A, SODA, PedsQL, PEESS, PROMIS) 
 Adverse Events 
 Research samples (whole blood/serum, plasma) 
Visit 6 (OLE I Week 16, 2nd dose) 
 Administer study drug 
 Concomitant medications/procedures 
 GI symptoms and pain interference 
 PROs (EESAI, PEESSv2, PedsQL3.0, EoE-QOL-A, SODA, PROMIS) 

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 Vital signs 
 Clinical labs (CBC with differential, pregnancy testing) 
 Adverse Events 
 Research samples (whole blood/serum, plasma) 
Visit 7 (OLE I Week 20, 3rd dose) 
 Administer study drug 
 Concomitant medications/procedures 
 GI symptoms and pain interference 
 PROs (EESAI, PEESSv2, PedsQL3.0, EoE-QOL-A, SODA, PROMIS) 
 Adverse Events 
 Research samples (whole blood/serum, plasma) 
 Clinical labs (CBC with differential, urinalysis, pregnancy testing) 
Visit 8 (OLE I Week 24, safety follow up phone call) 
 Concomitant medications/procedures 
 GI symptoms and pain interference 
 PROs (EESAI, PEESSv2, PedsQL3.0, EoE-QOL-A, SODA, PROMIS) 
 Adverse Events 
 Visit 9†† (OLE I Week 28 – 4th dose ) 
 Administer study drug 
 Concomitant medications/procedures 
 GI symptoms and pain interference 
 PROs (EESAI, PEESSv2, PedsQL3.0, EoE-QOL-A, SODA, PROMIS) 
 Adverse Events 
 Research samples (whole blood/serum, plasma) 
 Clinical labs (CBC with differential, urinalysis, pregnancy testing) 
 
†† This visit may be repeated until an EGD can be performed for participants whose EGDs 
are postponed due to COVID-19 
At visits 6, 7, and 9 participants may have study drug administered by their local providers 
due to COVID-19 travel restrictions and travel risks. In these cases, adverse events and 
concomitant meds will be assessed by study team via telephone/telemedicine prior to the visit 
to local provider. Pregancy testing, vitals, urinalysis, and CBC with differential will occur by 
local provider/lab per PI discretion. Results from testing will be provided to the study staff 
directly from the local provider (via medical record release if necessary). Date and time of 

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Study Code 2017-1701 
Edition Number 6 
Date 30 Apr 2019 
 
 
37 
 
drug injection and post injection monitoring results will also be provided to study staff from 
the local provider. 
Visit 10 (OLE I Week 32, safety follow up phone call) 
 Concomitant medications/procedures 
 PROs (EESAI, PEESSv2, PedsQL3.0, EoE-QOL-A, SODA, PedsQL, PEESS) 
 GI symptoms and pain interference 
 Adverse Events 
Visit 11 (OLE I Week 36 - End of treatment EGD or Early Withdrawal) 
 Concomitant medications/procedures 
 GI symptoms and pain interference 
 PROs (EESAI, PEESSv2, PedsQL3.0, EoE-QOL-A, SODA, PROMIS) 
 Adverse Events 
 Endoscopy with biopsies 
 Endoscopic and Histologic metrics (EREFS, HSS, Lanza score, EG Biopsy Evaluation 
Form, ED Biopsy Evaluation Form) 
 Clinical labs (CBC with differential, urinalysis, pregnancy testing) 
 Research samples (whole blood/serum) 
4.5 Extended Open Label Extension (OLE II) 
Study subjects may choose to extend the OLE period, and receive up to 7 additional injections 
of benralizumab (every8 weeks) or 13 additional injections (every 4 weeks dosing), based on 
clinical considerations by the treating physician. The default dosing will be every 8 weeks.  A 
research endoscopy will occur in visit 24 (end of treatment). Any other endoscopies will be 
performed clinically as needed, per the discretion of the PI. Medications will be modified ad 
lib during the  OLE II period. 
 Visit 11 (Week 36) through Visit 25 (Week 92) 
During OLE II, study drug will be administered at either 4 or 8 week intervals, which will be 
determined ad-lib by the study doctor, depending upon the symptoms, CBC results and 
discussion with patients. Additional unscheduled clinical tests such as  CBC with differential 
tests (for peripheral eosinophil counts) may be drawn to determine dosing frequency and 
assess patient wellbeing.  If the study drug is given at 8 week interval, then telephone 
encounter and surveys will be completed remotely every four weeks. For participants whose 
EGDs are postponed due to COVID-19, additional injections may be given until an EGD can 
be performed. 

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Edition Number 6 
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The below activities are done when indicated in the study plan table (section 4): 
 Concomitant medications/procedures 
 GI symptoms and pain interference 
 PROs (EESAI, EoE-QOL-A, SODA, PedsQL, PEESS, PROMIS) 
 Vital Signs, Weight 
 Adverse Events 
 Pregnancy Testing: urine 
 Endoscopy with biopsies 
 Endoscopic and Histologic metrics (EREFS, HSS, Lanza score, EG Biopsy Evaluation 
Form, ED Biopsy Evaluation Form) 
 Physical exam (Due to COVID-19, physical exams not associated with EGDs may be 
conducted via telephone or telemedicine) 
 Clinical labs (hematology and serum chemistry, urinalysis, pregnancy testing, IgE) 
 Research samples (whole blood/serum, plasma, stool microbiome) 
 
At visits 12 - 23 participants may have study drug administered by their local providers due to 
COVID-19 travel restrictions and travel risks. In these cases, adverse events and concomitant 
medications will be assessed by study team via telephone/telemedicine prior to the visit to 
local provider. Pregancy testing, vitals, and CBC with differential will occur by local 
provider/lab per PI discretion. Results from testing will be provided to the study staff directly 
from the local provider (via medical record release if necessary). Date and time of drug 
injection and post injection monitoring results will also be provided to study staff from the 
local provider. 
5. 
STUDY ASSESSMENTS   
5.1 
Efficacy assessments 
Severity of Dyspepsia Assessment (SODA) 
Since instruments are not available to date for adult EG, this study will use the Severity of 
Dyspepsia Assessment (SODA) scale as a validated instrument to assess dyspepsia related 
health [25]. 
EREFs 
The EREFs measures EoE esophageal mucosal inflammatory and remodeling features as 
identified during endoscopy. The score includes a total of 17 items related to the presence and 

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Study Code 2017-1701 
Edition Number 6 
Date 30 Apr 2019 
 
 
39 
 
severity of esophageal features. Specific esophageal features assessed include: rings (absent, 
mild, moderate, severe, not applicable); stricture (yes, no, not applicable); diameter of the 
stricture (if applicable); exudates (absent, mild, severe), furrows (absent, present); edema, 
(absent, present); crêpe paper esophagus (absent, present); overall general appearance 
incorporating all endoscopically identified EoE findings (ie, fixed rings, strictures, whitish 
exudates, furrowing, edema, and crêpe paper mucosa). Mucosal changes associated with 
gastroesophageal reflux disease will also be recorded using the Los Angeles classification 
system for erosions (No Erosions or LA Classification A, B, C, D). The EREFS is a validated 
scoring system for the assessment of inflammatory and remodeling features of disease using 
both overall scores and scores for each individual characteristic [26]. The EoE-EREFS should 
be performed by the physician who performs the endoscopy procedure. 
Lanza Score 
The Lanza score is an endoscopic grading system used to evaluate for gastritis. It has been used 
in therapeutic trials and is based on the 0-7 scale with 0=no lesions and 7= >3mm ulcer scale. 
Since no system has been developed/used to date for EG, this score will be used to assess adult 
EG [27]. 
HSS (EoE) 
The HSS is a scale developed by Collins, et al. [28] to express the severity and extent of 
abnormalities in the gastrointestinal (GI) tract that often accompany eosinophilic inflammation.  
The HSS evaluates esophageal biopsies for various features (e.g. basal layer hyperplasia, dilated 
intercellular spaces, surface epithelial alteration, apoptotic epithelial cells), eosinophilic 
inflammation (peak count, eosinophil abscess, eosinophil surface layering), and lamina propria 
(fibrosis). 
 
Eosinophilic Gastritis (EG) and Eosinophilic Duodenitis (ED) Biopsy Evaluation Forms 
Histological evaluation forms, with the goal of capturing features of eosinophilia relevant to the 
affected tissue as well as other features indicative of mucosal health and inflammation, have 
been developed by expert pathologist Dr. Margaret Collins. These forms will be utilized to 
evaluate the gastric and duodenal biopsies from subjects with extraesophageal eosinophilia. 
5.2 
Safety assessments 
5.2.1 
Laboratory safety assessments 
The following laboratory variables will be measured: 
Table 2 
Laboratory Safety Variables 
 

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Haematology/Haemostasis (whole blood) 
Clinical Chemistry (serum or plasma) with 
Differential 
B-Haemoglobin (Hb) 
S/P-Creatinine 
B-Leukocyte count 
S/P-Bilirubin, total 
B-Leukocyte differential count (absolute count) 
S/P-Alkaline phosphatise (ALP) 
B-Platelet count 
S/P-Aspartate transaminase (AST) 
 
S/P-Alanine transaminase (ALT) 
Urinalysis (dipstick) 
S/P-Albumin 
U-Hb/Erythrocytes/Blood  
S/P-Potassium 
U-Protein/Albumin  
S/P-Calcium, total 
U-Glucose  
S/P-Sodium 
S/P-Creatine kinase (CK) 
Blood urea nitrogen (BUN) 
Differential: Neutrophils, Lymphocytes, 
Monocytes, Basophils, Eosinophils 
5.2.2 
Physical examination 
A thorough physical examination will be performed at the time points indicated in Table 1.  
Any abnormalities that may be present, according to the patient’s medical history, should be 
assessed. Due to COVID-19, physical exams not associated with EGDs may be conducted via 
telephone or telemedicine. 
5.2.3 
Vital signs 
Vital signs, including heart rate, blood pressure, and respiration rate will be measured at the 
time points indicated in Table 1. 
5.2.3.1 
Pulse and blood pressure 
Heart rate and blood pressure will be measured with the patient in sitting position, after the 
patient has been resting for at least 5 minutes. 
5.2.3.2 
Body temperature 
Body temperature will be measured at the time points indicated in Table 1. 
5.2.4 
Other safety assessments 
Pregnancy testing will be performed for all women of childbearing potential. Serum or urine 
pregnancy testing will be performed at the time points indicated in Table 1. A serum FSH test 
will be performed if there is a question regarding menopausal status. 

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5.3 
Other assessments 
5.3.1 
Patient reported outcomes 
5.3.1.1 
EESAI: for subjects with EoE and EG 
The EESAI is a validated index developed at University Hospital Inselspital (Berne, 
Switzerland) [29], which is a part of the international EESAI study group.  The EESAI includes 
items related to the intensity and frequency of dysphagia, the influence of specific food groups 
on dysphagia symptoms, and other symptoms independent of eating or drinking (e.g., heartburn, 
acid regurgitation, and chest pain). The total EESAI PRO score ranges from 0 to 100. The 
EESAI PRO utilizes 24-hour and 1-week recall periods.  In this study, a 1-week recall period 
will be utilized. This questionnaire will be administered to both adolescents and adults. 
5.3.1.2 
EoE-QOL-A: for subjects with EoE and EG 
The EoE-QOL-A is a validated disease-specific questionnaire used to assess health-related 
quality of life in patients with EoE [30]. The instrument that will be used in this study, the EoE-
QOL-A v.3.0, includes 30 items related to established domains such as social functioning, 
emotional functioning, and the impact of disease on daily life experiences. The EoE-QOL-A 
has a 1-week recall period. Items are graded on a 5-point scale: ‘Not at All,’ ‘Slightly,’ 
‘Moderately,’ ‘Quite a bit,’ and ‘Extremely’. This questionnaire will be administered to both 
adolescents and adults.  
5.3.1.3 
PEESS®v2.0: For pediatric subjects (≤ 18 years old) 
The PEESS® v2.0 is a content-validated metric that seeks to capture EoE-specific symptoms 
directly from children with EoE (8–18 years of age) and from their parents (2–18 years of age) 
[31]. From parent/participant interviews, four domains were established: dysphagia, 
gastroesophageal reflux disease (GERD), nausea/vomiting and pain. The range for these 
PEESS® v2.0 scores is 0 to 100, with a higher score being indicative of more frequent and/or 
severe symptoms for total score, and the dysphagia, GERD, nausea/vomiting and pain domains.  
A 30 day recall will be used. This questionnaire will be administered to all pediatric patients. 
5.3.1.4 
PedsQL 3.0: for pediatric subjects (≤ 18 years old) with EoE and EG 
The PedsQL 3.0 is a disease-specific measure of health-related quality of life for pediatric 
patients diagnosed with EoE [32]  . This questionnaire will be administered to all pediatric 
patients. 
5.3.1.5 
PROMIS: Patient Reported Outcomes Measurement Information System 
The PROMIS assessments selected for this study are multi-purpose, short-form health surveys 
with 29 (for adults) and 25 (for peds) questions, that will be used with EG patients. It yields a 
high profile of general well being.  

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5.3.2 
Other 
5.3.2.1 
Diet Questionnaire 
The diet questionnaire is a tool used to track participants’ diets before and after treatment.  Since 
participants are asked not to change their diet during trial participation, this questionnaire allows 
for an evaluation of whether or not a participant’s diet did change during the trial. 
5.3.2.2 
Complete Blood Count (CBC) with differential 
CBCs will be performed to measure changes in participants’ blood eosinophil counts pre- and 
post-treatment. 
5.3.2.3 
GI Symptoms and Pain Interference  
The GI symptoms and pain interference tool is a series of questions administered to patients to  
quantify symptoms. The tool is used to determine eligibility at screening and to track clinical 
symptoms during the study. 
5.4 
Pharmacokinetics 
5.4.1 
Collection of samples 
Not applicable  
5.4.2 
Determination of drug concentration 
Not applicable  
5.4.3 
Storage and destruction of pharmacokinetic samples 
Not applicable  
5.5 
Pharmacodynamics 
Not applicable  
5.5.1 
Collection of samples 
Not applicable  
5.5.2 
Storage, re-use and destruction of pharmacodynamic samples 
Not applicable  
5.6 
Pharmacogenetics 
Not applicable  
5.6.1 
Collection of pharmacogenetic samples 
Not applicable  

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5.6.2 
Storage, re-use and destruction of pharmacogenetic samples 
Not applicable  
5.7 
Biomarker analysis  
5.7.1 
Storage, re-use and destruction of biological samples 
Tissue samples for transcriptome evaluation will be stored in RNAlater reagent (Qiagen) in 
individual tubes at -80oC until RNA or protein isolation is performed; isolated RNA and protein 
will then be stored at -80oC. Tissue samples for eosinophil counts will be collected in tubes 
containing 10% formalin and will be stored at room temperature until they are embedded in 
paraffin using routine procedures; paraffin blocks will then be stored at room temperature. 
Serum samples will be aliquoted into several tubes and stored at -80oC until proteomic and/or 
biomarker analysis is performed. Stool samples will be stored in individual tubes at -80oC in a 
freezer until DNA is isolated from such samples; DNA will then be stored at -20oC. Research 
blood cell samples will be aliquoted into several tubes and stored at -80oC until used for 
biomarker analysis and/or reprogramming into induced pluripotent stem cells. Re-use of 
samples may occur if the entire sample or material isolated or derived from the sample is not 
depleted during a particular analysis. In this case, the remainder of the sample or material 
derived from the sample will be stored at the appropriate temperature until additional analysis 
is performed. Samples or material isolated or derived from samples will be destroyed only if a 
subject withdraws consent and gives written notice of his/her request for destruction of samples 
collected prior to the withdrawal of consent. 
5.7.2 
Labelling and shipment of biological samples 
Unique biological samples will be stripped of protected health information and labeled with a 
unique barcode linked to the protected health information of the corresponding patient. Any 
material derived or isolated from the original sample will be labeled with the same barcode as 
the original sample. Shipment of biological samples, if necessary, will be performed in 
accordance with federal guidelines for shipment of biological materials and will be coordinated 
by personnel who are trained to comply with these guidelines. The shipping conditions (e.g., 
temperature of shipment) will be chosen according to the most appropriate storage conditions 
for the given samples being shipped. 
5.7.3 
Chain of custody of biological samples  
Biological samples obtained by the study physician or other qualified medical professional will 
be delivered to clinical research coordinators. The clinical research coordinators will deidentify 
the samples and then deliver them to designated laboratory personnel, who will then process 
and store the samples. All personnel in the chain of custody will be qualified to handle the 
designated tasks and will have successfully completed any required appropriate training. 
5.7.4 
Withdrawal of Informed Consent for donated biological samples  
If a subject withdraws consent for donated biological samples, any existing samples provided 
by the subject will be retained unless notified otherwise by the subject. The subject must provide 

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written notice of this withdrawal of consent and include their request for destruction of existing 
samples. 
6. 
SAFETY REPORTING AND MEDICAL MANAGEMENT 
Safety will be evaluated throughout the study. Evaluation for AEs, review of concomitant 
medications, and review of protocol restrictions will occur at the beginning of each visit. 
6.1 
Definition of adverse events 
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to benralizumab or placebo, whether 
or not considered causally related to the product. An undesirable medical condition can be 
symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the abnormal results 
of an investigation (eg, lab findings). In clinical studies, an AE can include an undesirable 
medical condition occurring at any time, including run-in or washout periods, even if no study 
treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. An AE does not include the 
following: 
 Medical or surgical procedures such as surgery, endoscopy, tooth extraction, and 
transfusion. The condition that led to the procedure may be an AE and must be reported. 
 Preexisting diseases, conditions, or laboratory abnormalities present or detected before the 
Visit 1 that do not worsen 
 Situations where an untoward medical occurrence has not occurred (eg, hospitalization for 
elective surgery, social and/or convenience admissions) 
Any medical condition or clinically significant laboratory abnormality with an onset date before 
the consent form is signed and not related to a protocol-associated procedure is not an AE. It is 
considered to be preexisting and should be documented on the medical history CRF. 
6.2 
Definition of Serious Adverse Event (SAE) 
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
 Results in death 
 Is immediately life-threatening 
 Requires in-patient hospitalization or prolongation of existing hospitalization  
 Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
 Is a congenital abnormality or birth defect 
 Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
 

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The causality of SAEs (their relationship to all study treatment/procedures) will be assessed 
by the investigator(s) and communicated to AstraZeneca. 
 
6.3 
Causality assessment 
The Investigator will assess causal relationship between Benralizumab 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 a causal relationship will also be assessed for other concomitant medications, study 
procedures, and comparator study drugs.  Note that for SAEs that could be associated with any 
study procedure the causal relationship is implied as ‘yes’. 
6.4 
Recording of adverse events 
6.4.1 
Time period for collection of adverse events 
Adverse events (including SAEs) will be collected from the time of consent until a subject 
completes study participation, or until 30 days after he/she prematurely withdraws (without 
withdrawing consent) or is withdrawn from the study. 
Adverse events (including SAEs) may be discovered through any of these methods: 
 Observing the participant. 
 Interviewing the participant  
 Receiving an unsolicited complaint from the participant. 
In addition, an abnormal value or result from a clinical or laboratory evaluation can also indicate 
an adverse event, as defined in Definition of adverse events. 
Throughout the study, the investigator will record adverse events and serious adverse events on 
the appropriate AE/SAE CRF, regardless of the relationship to study therapy regimen or study 
procedure. 
6.4.2 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the subject’s last AE assessment in the study will be 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 subject with ongoing 
AE(s)/SAE(s) at the end of study, if judged necessary 
6.4.3 
Variables  
 The following variables should be collected for each AE; 
 
AE (verbatim) 

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 
The date when the AE started and stopped 
 
CTCAE grade (Grade 1 = mild adverse event, Grade 2 = moderate adverse event, Grade 
3 = severe and undesirable adverse event, Grade 4 = life-threatening or disabling 
adverse event, Grade 5 = death.) 
 
Whether the AE is serious or not 
 
Investigator causality rating against the Investigational Product 
 
Action taken with regard to investigational product 
 
AE caused subject’s withdrawal from study (yes or no) 
 
Outcome 
In addition, the following variables should be collected for SAEs: 
 
Date AE met criteria for serious AE 
 
Date Investigator became aware of serious AE 
 
AE is serious due to... 
 
Date of hospitalisation 
 
Date of discharge 
 
Probable cause of death 
 
Date of death 
 
Autopsy performed 
 
Causality assessment in relation to Study procedure(s) 
 
Description of AE. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of intensity 
whereas seriousness is defined by the criteria in Section 6.2.  An AE of severe intensity need 
not necessarily be considered serious.  For example, nausea that persists for several hours may 
be considered severe nausea, but not a SAE. On the other hand, a stroke that results in only a 
limited degree of disability may be considered a mild stroke but would be a SAE. 
Adverse Events based on signs and symptoms 
All AEs spontaneously reported by the subject or reported in response to the open question from 
the study personnel: ‘Have you had any health problems since the previous visit/you were last 
asked?’, or revealed by observation will be collected and recorded in the CRF. When collecting 
AEs, the recording of diagnoses is preferred (when possible) to recording a list of signs and 
symptoms. However, if a diagnosis is known and there are other signs or symptoms that are not 
generally part of the diagnosis, the diagnosis and each sign or symptom will be recorded 
separately. 
 
Adverse Events based on examinations and tests 
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report (CSR). Deterioration as compared to baseline in protocol-mandated 

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laboratory values and vital signs should therefore only be reported as AEs if they fulfil any of 
the SAE criteria or are the reason for discontinuation of treatment with the 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 (eg, anaemia versus low haemoglobin value). In the 
absence of clinical signs or symptoms, clinically relevant deteriorations in nonmandated 
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. 
 
Since the most common adverse effects previously noted for Benralizumab has been breathing 
difficulty, nasopharyngitis, upper respiratory infection, headache, bronchitis, sinusitis, 
influenza and pharyngitis, surveillance for these events will be undertaken. Any of these events 
that fulfil the criteria of an AE as judged by the investigator should be reported using the 
standard procedures for assessing severity, causality and seriousness. 
6.5 
Reporting of serious adverse events 
All SAEs have to be reported to AstraZeneca, whether or not considered causally related to 
benralizumab, or to the study procedure(s). The reporting period for SAEs is the period 
immediately following the time that written informed consent is obtained through 60 days after 
the last dose of benralizumab. The investigator is responsible for informing the IRB as per local 
requirements.  
The investigator and other site personnel must inform the FDA, via a MedWatch/AdEERs form, 
of any serious or unexpected adverse events that occur in accordance with the reporting 
obligations of 21 CFR 312.32, and will concurrently forward all such reports to AZ. A copy of 
the MedWatch/AdEERs report must be faxed or email to AstraZeneca at the time the event is 
reported to the FDA. It is the responsibility of the investigator to compile all necessary 
information and ensure that the FDA receives a report according to the FDA reporting 
requirement timelines and to ensure that these reports are also submitted to AstraZeneca at the 
same time. 
When reporting to AstraZeneca, a cover page should accompany the MedWatch/AdEERs form 
indicating the following: 
• 
Investigator Sponsored Study (ISS) 
• 
The investigator IND number assigned by the FDA 
• 
The investigator’s name and address 

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• 
The trial name/title and AstraZeneca ISS reference number (ESR- 16-12419) 
Investigative site must also indicate, either in the SAE report or the cover page, the causality of 
events in relation to all study medications and if the SAE is related to disease progression, as 
determined by the principal investigator. 
Send SAE report and accompanying cover page to AstraZeneca by email to AE Mailbox 
Clinical Trial (TCS) <AEMailboxClinicalTrialTCS@astrazeneca.com> or by fax to 1-302-886-
4114 (US Fax number). Email is the preferred method. 
Serious adverse events that do not require expedited reporting to the FDA need to be reported 
to AstraZeneca preferably using the MedDRA coding language for serious adverse events at 
least on a monthly basis. 
6.6 
Overdose 
Overdose in itself is not considered to be an AE or SAE.   
Investigator/site staff are responsible for recording and reporting overdose in accordance with 
the clinical study protocol instructions. All overdoses with AstraZeneca product are collected 
and reported to AstraZeneca.  Overdoses associated with SAEs will be reported according to 
SAE reporting described in section 6.5.  All other overdoses can be sent to AstraZeneca at least 
on a monthly basis.  
The following information should be provided in the event of an Overdose (Overdose Report 
Form can be provided upon request):  
 Details of the Patient who was dispensed study medication (Randomization code) 
 Details of the Patient who took the overdose (demographic information, was patient a 
study participant?) 
 Details of the  drug overdose (total daily dose, route, formulation, Overdose start and 
stop dates) 
 Was the overdose accidental or intentional?  
 Was the overdose associated with an adverse event (serious or non-serious) 
 Provide an Adverse Event description (use same wording as in CRF). Provide start and 
stop dates of the event, or indicate if the event is ongoing. 
 Provide Investigator’s signature and date. 
 
6.7 
Pregnancy 
All female patients of child-bearing potential should receive blood and urine pregnancy 
screening tests during the baseline assessment and should receive a urine test at each study visit. 
If any female patient is found to be pregnant during the study she should be withdrawn and 
study medication should be immediately discontinued. If the pregnancy occurs during 

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administration of active study drug the pregnancy should be reported immediately to the study 
investigators. 
Should the pregnancy occur during or after administration of the study drug the investigator 
must inform the subject of their right to receive treatment information. Healthy controls do not 
need follow-up.  
Pregnancy in itself is not considered to be an AE or SAE. However, if the subjects become 
pregnant during the study, Investigator/site staff are responsible for recording and reporting 
pregnancies and their pregnancy outcomes until pregnacy resolution in accordance with the 
clinical study protocol instructions.  
6.7.1 
Maternal exposure 
All reports of pregnacy with benralizumab (with or without associated SAE, AE or no 
symptoms) are collected and reported to AstraZeneca. If the pregnancy is accompanied by an 
SAEs (e.g. events of congenital abnormality/birth defect, spontaneous miscarriage or ectopic 
pregnancy, or any complications in the subject which meet the criteria for a serious adverse 
event), it should be reported according to the SAE reporting requirement. All other maternal 
exposure reports can be sent to AstraZeneca at least on a monthly basis.  
Normal births and elective abortions without complications are not considered to be SAEs.  
6.7.2 
Paternal exposure  
If paternal exposure pregnancy occurs in the course of the study, the the investor/site staff 
should inform AstraZeneca within the same timeframe as the maternal exposure. The female 
partner of the patient will be asked to consent to allow collection of information and follow-up 
on the pregnancy. The outcome of the pregnancy is also followed and reported in accordance 
with the processes written in maternal exposure section.   
6.8 
Management of toxicities  
The study is designed to administer uniform dose of 30mg of benralizumab. In the event of 
SAEs, the subject will be discontinued from the study and the event reported as mentioned 
above. Continued enrolment at reduced dosage is not applicable. 
Dose Reductions: Not applicable. 
6.9 
Study governance and oversight 
An unblinded medical review officer (MRO) will review all AE data in order to make 
determinations regarding subject safety and trial continuation. 
6.9.1 
Steering Committee 
Not applicable  

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6.9.2 
Data Monitoring Committee 
At least biannually, a data safety monitoring board will review and evaluate the accumulated 
study data for participant safety, and make recommendations to the study investigators and 
regulatory agencies (CCHMC IRB, CCHMC IBC, FDA, etc.) concerning the continuation, 
modification, or termination of the trial.  
 
6.9.3 
Scientific Advisory Committee 
Not applicable  
 
 
7. 
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS 
7.1 
Identity of investigational product(s) 
Investigational product 
Dosage form and strength 
Manufacturer 
Benralizumab 
30 mg SC 
AstraZeneca 
Placebo 
Same as benralizumab, without 
the active substance 
AstraZeneca 
7.2 
Dose and treatment regimens 
Benralizumab Drug Product is a sterile liquid solution presented in an accessorized prefilled 
syringe (APFS) for subcutaneous injection.  Each syringe contains 10 mg of benralizumab in a 
0.5 volume (nominal) or 30 or 100 mg of benralizumab in a 1.0 mL volume (nominal).  The 
Drug Product is formulated in 20 mM histidine/histidine-HCl, 0.25 M trehalose dihydrate, and 
0.006% (w/v) polysorbate 20, pH 6.0 (Table 3). 
Table 3 
Benralizumab (MEDI-563) composition 
Ingredient 
Concentration 
Unit formula per 10 mg, 30 mg, or 
100 mg syringe (nominal) 
Active ingredient 
Benralizumab 
20 
mg/mL 
30 
mg/mL 
100 
mg/mL 
10 mg 
30 mg 
100 mg 
Other ingredients 
L-Histidine 
9 mM 
9 mM 
9 mM 
0.7 mg 
1.4 mg 
1.4 mg 
L-Histidine HCl 
monohydrate 
11 mM 
11 mM 
11 mM 
1.2 mg 
2.3 mg 
2.3 mg 
Trehalose dehydrate 
0.25 M 
0.25 M 
0.25 M 
47 mg 
95 mg 
95 mg 
Polysorbate 20 
0.006% 
(w/v) 
0.006% 
(w/v) 
0.006% 
(w/v) 
0.03 mg 
0.06 mg 
0.06 mg 

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Benralizumab will be administered as a 30 mg SC injection at V3 and once every 4 weeks for 
2 months (for a total of 3 injections) during the double blind portion of the study. 
Benralizumab will be administered as a 30 mg SC injection at V5 and once every 4 or 8 weeks 
during the open label extensions. 
  
7.3 
Labelling 
A numbering system will be used to label the blinded IP.  A list linking the label number with 
the product lot number will be maintained by the groups (or companies) responsible for study 
drug packaging. In order to maintain the blind, the list will not be accessible to individuals 
involved in study conduct. 
7.4 
Storage 
The investigational product must be stored refrigerated at 2-8°C (36-46°F) and must not be 
frozen. The investigational product will be allowed to warm to room temperature prior to 
administration. Due to COVID-19, drug may be shipped to local providers using cold transport 
shipping or courier. Local providers will confirm IP is stored at 2-8°C (36-46°F) until the IP is 
administered. To minimize storage risks, the investigational product will be shipped to local 
providers 1-2 days prior to the patient’s planned local injection. 
7.5 
Compliance 
Drug compliance records must be kept current and must be available for inspection by the 
sponsor and regulatory authorities. 
7.6 
Accountability 
Drug accountability records must be kept current at all times.  The investigator must be able to 
account for all opened and unopened study drug. Records should contain the following: 
Dates, quantity, and study medication 
 
dispensed to each patient (if applicable) including drug shipped to local provider 
for patients that cannot travel to the study site due to COVID-19  
 
returned from each patient (if applicable), and 
 
disposed of at the site or returned to the manufacturer or designee. 
Accountability records must be available for inspection by the AstraZeneca and regulatory 
authorities. Photocopies must be provided to the sponsor at the conclusion of the study. 

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7.7 
Concomitant and other treatments  
Prohibited Medication/Class of drug: 
Washout Period Prior to Study Screening (i.e. 
Study Entry) 
Anti-immunoglobulin E [IgE] mAb 
6 months 
Anti-tumor necrosis factor [TNF] mAb) 
6 months 
Other investigative biologic 
6 months 
Anti-IL 5 agents 
6 months 
Anti-IL 4/13 agents including anti-IL4Ra 
6 months 
Other investigative drugs or device 
1 month 
 
Rescue/Supportive Medication/Class of drug: 
Usage: 
Study participants should continue their baseline medications and dietary 
therapy.  Rescue medicines for EGID exacerbations are not allowed and 
will lead to study withdrawal. 
N/A 
During study visits, participants will be allowed to have EMLA or topical 
analgesic (Pain Ease or Spray & Stretch) for the purpose of 
venepuncture/IV insertion 
As needed during 
study visits 
 
7.7.1 
Other concomitant treatment 
Throughout the study duration, all participants are expected to maintain medications such as a 
PPI, oral or nasal allergy medications (such as antihistamines and any asthma-related 
medications) as well as special diets including elimination diets that were prescribed prior to 
study entry. 
8. 
STATISTICAL ANALYSES  
8.1 
Statistical considerations 
Pertaining to the primary objective of this study, the primary efficacy endpoint is the eosinophil 
count response rate to the treatments. The comparison of response rates between the 
benralizumab and placebo groups will be made with a Fisher’s exact test of binomial 
distributions. For secondary endpoints, continuous variables comparisons between the two 
groups, e.g. change in peak eos counts, change in blood eosinophil count, change in symptom 
scores from pre- to post-treatment, and change in endoscopic scores from pre- to post-treatment 
at each study visit (e.g. Weeks 4, 8 and the end of treatment) will be made in a repeated measure 
ANOVA model, where serial correlation within patients will be accounted for. Proper 
transformation of data, e.g. logarithmic, or non-parametric methods may be applied to satisfy 
statistical assumptions. Categorical responses, e.g. response rate will also be compared using a 
Fisher’s exact test, by visit if applicable. Additional exploratory analysis to investigate other 

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factors’ effect on response may also be performed, with generalized linear models with 
appropriate link functions. 
All comparisons are two-sided, and p-value < 0.05 is considered statistically significant. No 
multiplicity adjustment will be made for this analysis. 
Safety measurements, including adverse events will be summarized by descriptive statistics. 
The total numbers of AE’s as well as number of patients with an AE will be summarized via N 
and percent.   
8.2 
Sample size estimate 
The planned total sample size of 24 subjects is justified based on previously published studies. 
Based on trials of other therapies in EoE and EGID, it is reasonable to assume that an eosinophil 
count at or below 15, 30 and 52 eos/hpf in esophagus, stomach and duodenum, respectively, 
after treatment, is considered an adequate response. It is estimated that in the placebo group, the 
response rate will be no more than 10%. We assume that the benralizumab group response rate 
will be about 70%. To detect a difference between these two response rates, we need a total of 
24 completed subjects, or 12 subjects per arm to reach 80% statistical power. This is based on 
a two-sided Fisher’s exact test at 0.05 level. We will enroll 26 subjects to account for possible 
dropouts. 
8.3 
Definitions of analysis sets 
8.3.1 
Efficacy analysis set 
There will be one efficacy analysis set. That is the intention-to-treat (ITT) set. This comprises 
all enrolled patients who took at least one dose of study medication.  
8.3.2 
Safety analysis set 
Safety analysis set comprises all patients enrolled in the study. 
8.3.3 
PK analysis set 
N/A 
8.3.4 
PRO analysis set 
PRO analysis sets are the same as Efficacy analysis sets. 
8.4 
Outcome measures for analyses 
The primary efficacy endpoints are the eosinophil count response rate to the treatments. A 
disease remission is defined by peak eosinophil counts less than 15 for esophagus, less than 30 
for stomach, and less than 52 for duodenum. A patient is considered in remission if all applicable 
counts are in remission range. The rate of remission among all patients is the primary efficacy 
measure for both treatment groups. 

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Secondary outcome measures include individual disease remission rate, changes in endoscopic 
scores from pre to post-treatment as measured by EREFS for EoE and Lanza score for EGE, 
changes in histologic scores from pre to post-treatment,  changes in blood eosinophil count pre 
and post-treatment, changes in symptom scores from pre to post-treatment measured by EESAI, 
EoE-QoL-A (for EoE), and SODA (for EGE), and changes in peak eosinophil counts in biospies 
from pre to post-treatment. 
8.5 
Methods for statistical analyses 
8.5.1 
Analysis of the primary variable(s) 
The comparison of primary response/remission rates between the benralizumab and placebo 
groups will be made with a Fisher’s exact test of binomial distributions. 
8.5.2 
Analysis of the secondary variable(s) 
For secondary endpoints, continuous variables, e.g. change in peak eos counts, change in blood 
eosinophil count, change in symptom scores from pre- to post-treatment, and change in 
endoscopic scores from pre- to post-treatment at each study visit will be analysed and compared 
in a repeated measure ANOVA model. Proper transformation of data, e.g. logarithmic, or non-
parametric methods may be applied to satisfy statistical assumptions. Categorical responses, 
e.g. response rate will also be compared using a Fisher’s exact test.  
Safety endpoints, i.e. adverse events (by organ system and preferred terms), SAEs, as well as 
demographic variables will be summarized by treatment groups. The total numbers of AE’s as 
well as number of patients with an AE will be summarized via N and percentages. 
8.5.3 
Subgroup analysis (if applicable) 
No subgroup analysis is planned, other than a per-protocol analysis of efficacy. 
8.5.4 
Interim analysis 
No interim analysis is planned. 
8.5.5 
Sensitivity analysis (if applicable) 
Logistic regression models will be explored in the primary efficacy endpoint analysis, namely 
the remission rate. In addition to treatment groups, other terms may be included in the regression 
model, e.g. gender, age, and baseline eosinophil count, to assess the sensitivity of the primary 
results. 
8.5.6 
Exploratory analysis (if applicable))  
Additional exploratory analysis may be conducted for the exploratory objective measures. 

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9. 
STUDY AND DATA MANAGEMENT  
9.1 
Training of study site personnel and local providers 
All study staff listed on the site delegation log must be trained on the conduct of the study prior 
before engaging in any study-related activities 
Due to COVID-19, drug may be administered by local providers to some patients. Local 
providers medically trained to administer subcutaneous injections (RNs, MDs, PharmD) will 
provide the study injections. Local providers will be asked to provide evidence of competency 
in subcutaneous injections and/or injection certification to the study staff. Local providers must 
show competency in monitoring for post injection reactions.   
9.2 
Monitoring of the study 
The Principle Investigator will designate a study monitor who will visit the study site prior to 
enrollment of the first patient, and periodically throughout the study. The monitor will compare 
CRF entries with the corresponding source documents, as outlined in the ICH guidelines. The 
study monitor may also review subject ICFs, patient recruitment and follow-up documentation, 
AEs, SAEs, and concomitant therapy; along with records of dispensation of study drug, 
compliance, and accountability. A copy of the drug dispensing log must be provided to the 
sponsor upon request. 
9.2.1 
Source data 
Study staff must prepare and maintain adequate and accurate records of each subject’s study 
participation (i.e. source documents). All source documents must be kept on file with the CRFs. 
(CRFs may be either paper or electronic [eCRF]). CRFs and source documents must be available 
at all times for inspection by authorized representatives of the Principle Investigator regulatory 
agencies. 
9.2.2 
Study agreements 
If the PI chooses to close out the study site (for example, due to lack of subject enrollment 
within a reasonable period of time, violation of the study agreement, breach of protocol, early 
attainment of study enrollment targets, etc.), the PI will notify involved individuals in writing. 
The appropriate regulatory agencies must be informed according to applicable requirements, 
and adequate consideration must be given to the protection of the subjects’ interests. 
9.2.3 
Archiving of study documents 
All essential study documents must be retained by the investigator for at least 3 years after the 
conclusion or discontinuation of the trial.  Prior to destroying any essential documents, the 
investigator must consult with the PI.  If and when destruction is authorized, records must be 
destroyed in a manner that ensures confidentiality.  If an investigator can no longer ensure 

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archiving, the sponsor and the investigator will agree upon a suitable designation for transferring 
the essential records. 
9.3 
Study timetable and end of study 
The end of study will be at a follow up visit at Week 16 ±3 days. For subjects who are remote, 
the follow up visit can be performed at a local site, in which vital signs, physical exam, urine 
pregnancy and lab work will be performed. Results will be released to CCHMC upon 
authorization of release of medical information/specimen by the subject.  
9.4 
Data management  
Serious Adverse Event (SAE) Reconciliation 
SAEs will be followed until they are resolved, with or without sequlae, or until the end of study 
participation, or until 30 days after the subject prematurely withdraws from the study (without 
withdrawing consent)/or is withdrawn from the study, whichever occurs first. 
Data Management of genotype data 
N/A 
Data associated with human biological samples 
N/A 
Management of external data 
N/A 
10. 
ETHICAL AND REGULATORY REQUIREMENTS 
10.1 
Ethical conduct of the study 
This study will be conducted using good clinical practice (GCP), as delineated in Guidance for 
Industry: E6 Good Clinical Practice Consolidated Guidance, and according to the criteria 
specified in this study protocol. 
10.2 
Subject data protection 
Participant’s privacy and confidentiality will be respected throughout the study.  Each 
participant will be assigned a unique identification number and these numbers will be used to 
collect, store, and report participant information instead of the participant’s name. Site 
personnel will not transmit documents containing personal health identifiers (PHI) to the study 
sponsor or their representatives. 

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10.3 
Ethics and regulatory review 
Before study initiation, the protocol and the informed consent documents will be reviewed and 
approved by the Cincinnati Children’s Hospital Medical Center IRB (CCHMC IRB). 
10.4 
Informed consent 
The Principal Investigator will designate appropriate study staff for performing the informed 
consent process. 
During the consent process, study staff will provide information about the study to a prospective 
participant and will allow adequate time for review and discussion prior to his/her decision.  The 
principal investigator or designee listed on the delegation log will review the consent and answer 
questions. The consent designee must be listed on the delegation log, have knowledge of the 
study and received training (from the local IRB, PI, or study coordinator) in the consent process.  
The prospective participant will be told that being in the trial is voluntary and that he or she may 
withdraw from the study at any time, for any reason.  All participants (or their legally authorized 
representative) will read, sign, and date a consent form before undergoing any study procedures.  
Consent materials will be presented in participants’ primary language. A copy of the signed 
consent form will be given to the participant. 
This study will be conducted in compliance with ICH E6 GCP: Consolidated Guidelines 
pertaining to informed consent.  At the first visit, prior to initiation of any study-related 
procedures, participants will give their written consent to participate in the study after having 
been informed about the nature and purpose of the study, participation/termination conditions, 
and risks and benefits.  If the participant is unable to provide written informed consent, the 
participant’s legally acceptable representative may provide written consent as approved by 
institutional specific guidelines. The informed consent document must be signed and dated by 
the participant, or the participant’s legally authorized representative, prior to study participation.  
A copy of the informed consent document must be provided to the participant or the 
participant’s legally authorized representative.  Signed consent forms must remain in the 
participant’s study file and be available for verification by the monitor, IRB, and/or regulatory 
authorities at any time.  If participant’s legally acceptable representative provides written 
consent, participants will also give their written assent to participate in the study as approved 
by institutional specific guidelines for obtaining assent. 
The consent form will be revised when important new safety information is available, the 
protocol is amended, and/or new information becomes available that may affect participation in 
the study. 
10.5 
Changes to the protocol and informed consent form 
Any amendments to the protocol or consent materials will be approved by the CCHMC IRB 
before they are implemented. 

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10.6 
Audits and inspections 
The study PI or CCHMC representative may subject this trial to quality assurance audits or 
inspections at any time. In the case of an audit or inspection, the investigator is responsible for 
the following: 
 
Informing the sponsor of a planned inspection by regulatory agencies as soon 
as they become aware of the inspection, and authorizing the sponsor to 
participate in the inspection 
 
Providing access to all necessary facilities, study data, and documents for the 
inspection or audit 
 
Immediately communicating any information arising from inspection by 
regulatory agencies to the sponsor 
 
Taking all appropriate measures requested by the sponsor to resolve any 
problems discovered during audit or inspection 
Documents subject to audit or inspection include, but are not limited to: 
 
all source documents, CRFS, and ICFs 
 
medical records 
 
correspondence 
 
IRB/EC files 
 
documentation of certification and quality control of supporting laboratories 
 
records relevant to the study maintained in any supporting pharmacy facilities. 
Study material storage data are also subject to inspection. Representatives of CCHMC may 
observe the conduct of any aspect of the trial or its supporting activities both within and outside 
of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
 
 

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Ward CK, Wu YP, Wang B, Khatry DB, van der Merwe R, Kolbeck R, Molfino NA and Raible 
DG (2014) Benralizumab, an anti-interleukin 5 receptor alpha monoclonal antibody, versus 
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inhaled corticosteroids and long-acting beta 2-agonists (SIROCCO): a randomised, multicentre, 
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Birrell C and van der Merwe R (2014) Benralizumab for chronic obstructive pulmonary disease 
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Endoscopic assessment of the oesophageal features of eosinophilic oesophagitis: validation of 
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Kim SG, Kim N, Shin SK, Sung IK, Hong SJ and Park HJ (2016) Efficacy of Albis for 
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ADDENDUM NUMBER 1: GI SYMPTOMS AND PAIN INTERFERENCE 
Inclusion criteria “patient must be symptomatic” will be determined by the following 
assessment of symptoms and pain interference  to a subject’s daily life: 
IRB# 2017-1701 Benralizumab Study 
Subject number:________________ 
Date of visit:___________________ 
 
In the past 4 weeks, how have pain and symptoms affected your daily life? 
GI symptoms may include Nausea, pain, abdominal discomfort, diarrhea, heartburn, burping, 
constipation and others.  
 
Ability to Participate in Social Roles and Activities  
Never  
1 time per 
week  
2-3 times 
per week  
4-5 times 
per week  
6-7 times 
per week  
How often did pain/symptoms interfere with 
your regular leisure activities with others, such 
as playing sports or participating in your 
hobbies? 
 
 
 
 
 
How often did pain/symptoms interfere with 
your day to day activities?  
 
 
 
 
 
How often did pain/symptoms interfere with 
your ability to go to work/ school and participate 
in classes, doing school work at home, 
chores/tasks you usually do around the 
home/place of work? 
 
 
 
 
 
How often did pain/symptoms interfere with 
your ability to participate in social activities, 
such as spending time with friends, attending 
events or parties, or going on dates? 
 
 
 
 
 
How many times have your symptoms 
interfered with your daily life in any way? 
 
 
 
 
 
 
For inclusion: At least 1 question must be answered with 2-3 time per week and up.  
OR, 
At least 2 questions must be answered with 1 time per week and up.  
Inclusion criteria Pass/Fail (circle) 
 
PI signature:______________________  Date:_________________