Efficacy of Dupilumab on Facilitated Food Introduction in Eosinophilic Esophagitis
Phase: PHASE4
Conditions: Eosinophilic Esophagitis
Sponsor: Children's Hospital of Philadelphia

 
Protocol version: October 6, 2022 
  
Title: 
Efficacy of dupilumab on facilitated food introduction in 
Eosinophilic Esophagitis 
Short Title 
Dupilumab Food Introduction in Eosinophilic Esophagitis 
Drug or Device 
Name(s): 
Dupilumab 
FDA IND 
Not applicable 
Regulatory Sponsor: 
Children’s Hospital of Philadelphia 
eIRB Number 
19416 
Protocol Date: 
December 29, 2022 
Amendment 1 Date:  June 6, 2022 
Amendment 3 Date: October 6, 2022 
Amendment 2 Date:  August 3, 2022 
Amendment 4 Date: 
 
Sponsor CHOP 
 
Site Principal Investigator 
Jonathan M. Spergel, MD, PhD 
The Children’s Hospital of Philadelphia 
The HUB for Clinical Collaboration, Rm 13521 
Philadelphia, PA, 19104 
Phone 215-590-2549 
email: spergel@chop.edu 
NCT Number: NCT05247866

 
 
  
 
 
 
 
 
 
ii
TABLE OF CONTENTS 
Table of Contents ................................................................................................................................................................................. ii 
Abstract .................................................................................................................................................................................................. vii 
Protocol Synopsis ............................................................................................................................................................................ viii 
Table 1: Schedule of Study Procedures.................................................................................................................................... xii 
Figure 1: Study Diagram ................................................................................................................................................................ xiv 
1 
BACKGROUND INFORMATION AND RATIONALE ............................................................. 1 
1.1 Introduction ...................................................................................................................................................................... 1 
1.2 Name and Description of Investigational Product or Intervention ............................................................. 1 
1.3 Findings from Non-Clinical and Clinical Studies ................................................................................................. 1 
1.3.1 
Clinical Studies ........................................................................................................................................................................ 1 
1.4 Selection of Drugs and Dosages ................................................................................................................................. 3 
1.5 Relevant Literature and Data ..................................................................................................................................... 3 
1.6 Compliance Statement .................................................................................................................................................. 5 
2 
STUDY OBJECTIVES ......................................................................................................... 5 
2.1 Primary Aim ...................................................................................................................................................................... 5 
3 
INVESTIGATIONAL PLAN ................................................................................................. 6 
3.1 General Schema of Study Design ............................................................................................................................... 6 
3.1.1 
Disease Control ....................................................................................................................................................................... 6 
3.1.2 
Food Introduction.................................................................................................................................................................... 7 
3.1.3 
Follow-up Phase ..................................................................................................................................................................... 7 
3.2 Allocation to Treatment Groups and Blinding ..................................................................................................... 7 
3.3 Study Duration, Enrollment and Number of Sites............................................................................................... 8 
3.3.1 
Duration of Subject Study Participation ...................................................................................................................... 8 
3.3.2 
Total Number of Study Sites/Total Number of Subjects Projected .............................................................. 8 
3.4 Study Population ............................................................................................................................................................. 8 
3.4.1 
Inclusion Criteria ..................................................................................................................................................................... 8 
3.4.2 
Index/Case Subject Inclusion Criteria ......................................................................................................................... 8 
3.4.3 
Exclusion Criteria .................................................................................................................................................................... 8 
3.4.4 
Individual stopping rules ................................................................................................................................................... 10 
4 
STUDY PROCEDURES .................................................................................................... 10 
Eosinophilic Esophagitis History ............................................................................................ 10 

 
 
  
 
 
 
 
 
 
iii
Esophagogastroduodenoscopy with biopsy with conscious sedation: ..................................... 10 
4.1 Study Treatment Phase: EoE disease control .................................................................................................... 11 
4.1.1 
Visit 1 .......................................................................................................................................................................................... 11 
4.1.2 
Visit 2 .......................................................................................................................................................................................... 11 
4.1.3 
Visit 3 .......................................................................................................................................................................................... 11 
4.1.4 
Visit 4 .......................................................................................................................................................................................... 11 
4.2 Phase 2: Food Introduction ...................................................................................................................................... 12 
4.2.1 
Visit 5, 9, 13 ............................................................................................................................................................................. 12 
4.2.2 
Visit 6, 10, 14 .......................................................................................................................................................................... 12 
4.2.3 
Visit 7, 11, 15 .......................................................................................................................................................................... 12 
4.2.4 
Visit 8, 12, 16 .......................................................................................................................................................................... 12 
4.3 Follow-up Phase ........................................................................................................................................................... 13 
4.3.1 
Visit 17: End of Study ......................................................................................................................................................... 13 
4.4 Unscheduled Visits ...................................................................................................................................................... 13 
4.5 Concomitant Medication ........................................................................................................................................... 13 
4.6 Subject Completion/Withdrawal ........................................................................................................................... 13 
4.6.1 
Early Termination Study Visit ......................................................................................................................................... 13 
5 
STUDY EVALUATIONS AND MEASUREMENTS ................................................................ 14 
5.1 Screening and Monitoring Evaluations and Measurements ........................................................................ 14 
5.1.1 
Medical Record Review .................................................................................................................................................... 14 
5.1.2 
Medical History ...................................................................................................................................................................... 14 
5.1.3 
Physical Examination ......................................................................................................................................................... 14 
5.1.4 
Vital Signs................................................................................................................................................................................. 14 
5.1.5 
Eosinophilic Esophagitis Quality of Life ................................................................................................................... 14 
5.1.6 
Upper Endoscopy with Biopsy ....................................................................................................................................... 15 
5.1.7 
Histological Evaluation ...................................................................................................................................................... 15 
5.1.8 
Endoflip ...................................................................................................................................................................................... 16 
5.1.9 
Diet Diary .................................................................................................................................................................................. 16 
5.1.10 
Pregnancy testing ........................................................................................................................................................... 17 
5.1.11 
Pregnancy ............................................................................................................................................................................ 17 
5.1.12 
Research Laboratory Tests ....................................................................................................................................... 17 
5.2 Safety Evaluation.......................................................................................................................................................... 18 
5.3 STATISTICAL CONSIDERATIONS ............................................................................................................................ 18 
5.3.1 
Primary Endpoint .................................................................................................................................................................. 18 
5.3.2 
Secondary Endpoints ......................................................................................................................................................... 18 
5.4 Statistical Methods ...................................................................................................................................................... 18 
5.4.1 
Analysis Populations .......................................................................................................................................................... 18 
5.4.2 
Demographics and Baseline Characteristics Analysis ..................................................................................... 19 
5.4.3 
Efficacy Analysis ................................................................................................................................................................... 19 
5.4.4 
Pharmacokinetic Analysis ................................................................................................................................................ 20 
5.4.5 
Safety Analysis ...................................................................................................................................................................... 20 

 
 
  
 
 
 
 
 
 
iv
5.5 Significance level and alpha allocation ................................................................................................................ 21 
5.6 Sample Size and Power .............................................................................................................................................. 21 
5.7 Interim Analysis ........................................................................................................................................................... 21 
6 
STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) ....................... 22 
6.1 Description ..................................................................................................................................................................... 22 
6.1.1 
Labeling ..................................................................................................................................................................................... 22 
6.1.2 
Dosing ........................................................................................................................................................................................ 22 
6.1.3 
Treatment Compliance and Adherence.................................................................................................................... 23 
6.1.4 
Drug Accountability ............................................................................................................................................................. 23 
7 
SAFETY MANAGEMENT ................................................................................................ 24 
7.1 Clinical Adverse Events.............................................................................................................................................. 24 
7.2 Adverse Event Reporting .......................................................................................................................................... 24 
7.3 Definition of an Adverse Event ............................................................................................................................... 24 
7.4 Causality .......................................................................................................................................................................... 25 
7.5 Definition of a Serious Adverse Event (SAE) ...................................................................................................... 26 
7.5.1 
Relationship of SAE to study drug or other intervention ................................................................................. 26 
7.6 IRB/IEC Notification of SAEs and Other Unanticipated Problems ............................................................. 26 
7.6.1 
Follow-up report .................................................................................................................................................................... 27 
7.7 STUDY ADMINISTRATION ......................................................................................................................................... 28 
7.7.1 
Treatment Assignment Methods .................................................................................................................................... 28 
7.7.2 
Randomization ....................................................................................................................................................................... 28 
7.7.3 
Blinding ...................................................................................................................................................................................... 28 
7.8 Data Collection and Management .......................................................................................................................... 28 
7.9 Confidentiality .............................................................................................................................................................. 28 
7.10 
Regulatory and Ethical Considerations .......................................................................................................... 28 
7.10.1 
Data and Safety Monitoring Plan ........................................................................................................................... 28 
7.10.2 
Risk Assessment ............................................................................................................................................................ 29 
7.10.3 
Potential Benefits of Trial Participation ............................................................................................................... 33 
7.10.4 
Risk-Benefit Assessment ........................................................................................................................................... 33 
7.11 
Recruitment Strategy ............................................................................................................................................ 33 
7.12 
Informed Consent/Assent and HIPAA Authorization ............................................................................... 33 
7.12.1 
Screening ............................................................................................................................................................................ 34 
7.12.2 
Main Study ......................................................................................................................................................................... 34 
7.12.3 
Consent/HIPAA Authorization Plan for Subjects Who Reach Age of Majority .............................. 34 
7.13 
Payment to Subjects/Families ........................................................................................................................... 34 

 
 
  
 
 
 
 
 
 
v
7.13.1 
Reimbursement for travel, parking, and meals ............................................................................................... 34 
8 
PUBLICATION ............................................................................................................... 34 
9 
REFERENCES ................................................................................................................. 35 
 

 
 
  
 
 
 
 
 
 
vi
Abbreviations and Definitions of Terms 
 
 
°C 
Degrees centigrade 
AE 
EGD 
EoE 
EREFS 
Eos 
GCP 
HPF 
ICH 
IgE 
PEESS 
PPI 
QOL 
SAE 
Adverse event 
Esophagogastroduodenoscopy  
Eosinophilic Esophagitis 
EoE Endoscopy Reference Score 
Eosinophils 
Good Clinical Practice 
High Power Field 
International Conference on Harmonization 
Immunoglobulin E 
Pediatric Eosinophilic Esophagitis Symptom Score 
Proton Pump Inhibitor 
Quality of Life 
Serious Adverse Event 
SAP 
SOC 
T2 
TCS 
Statistical analysis plan 
Standard of Care 
Type 2 
Topical corticosteroids 
TEAE 
Treatment-emergent adverse event 
 
 
 
 
 
 
 
 

 
 
  
 
 
 
 
 
 
vii 
ABSTRACT 
Context:   
Eosinophilic Esophagitis is a food driven non-IgE mediated disease involving eosinophils and 
type 2 inflammation.  Current therapies include diet and the off-label use of medications 
including proton pump inhibitors, topical steroids, or biologics.  Food elimination creates a 
decrease quality of life in many children.  The goal of the study is to examine a T2 inhibitor 
(dupilumab) can allow successful reintroduction of allergic EoE foods into the diet.  
Objectives:  
Evaluate the efficacy of Dupilumab, a humanized anti-IL4 receptor alpha monoclonal antibody to 
allow Eosinophilic Esophagitis trigger foods into a diet based on symptoms and histologic 
endpoints 
Study Design:  
Open label pilot exploratory study 
Setting/Participants: 
This will be a single outpatient site at Children’s Hospital of Philadelphia.  
There will be 30 patients ages 6 to 25 years of age with food induced Eosinophilic Esophagitis. 
Study Interventions and Measures:  
Study drug: Dupilumab 
Main study outcome measures: 
Primary Efficacy Endpoint: The primary efficacy endpoint will be the change in peak eosinophil 
counts on esophageal biopsies between 1st and 2nd endoscopy after food introduction in the 
same patient 
• 
Eosinophils per high power field in the esophagus after food introduction 
• 
Eosinophilic Esophagitis symptom score measured by validated measure 
• 
Esophageal compliance measured by Endoflip 
 
 

 
 
  
 
 
 
 
 
 
viii 
PROTOCOL SYNOPSIS 
Study Title 
Dupilumab for Facilitated food introduction in Eosinophilic 
Esophagitis 
Funder 
Development funds (Donated medication from Regeneron and 
Sanofi-Pasteur) 
Clinical Phase 
Not applicable 
Study Rationale 
Eosinophilic esophagitis (EoE) is a chronic, debilitating, 
allergic/immune-mediated disease due to chronic esophageal 
inflammation with the development of dysphagia that affects food 
intake and quality of life. The disease is characterized by symptoms 
related to esophageal dysfunction and by eosinophil-predominant 
inflammation of the esophageal mucosa. While eosinophils are 
present in specific regions of the gastrointestinal (GI) tract, they are 
not normally found in the esophagus. Patients with EoE 
demonstrate esophageal tissue infiltration of significant numbers of 
eosinophils and other pro-inflammatory cells characterized by an 
enrichment of CD4+ T regulatory and type 2 cytokine producing 
effector type 2 T helper (Th2) cells. This infiltrating cellular profile 
along with over expression of cytokines, particularly interleukin-13 
(IL-13) and interleukin-5 (IL-5), strongly suggests that EoE is a type 
2 cell-mediated inflammatory disease.  
The treatment options for EoE include diet avoidance, and off-label 
use of topical steroids or proton pump inhibitors. Diet avoidance 
can be successful in eliminating symptoms and leading to 
normalization of the esophageal eosinophilia.  However, six-food 
elimination diet which has success rate of 70% and elemental diet 
with a success rate of 90% have a tremendous amount of patient 
and family burden.  Patients have a very restricted diet with 
increased costs to the family and reduced quality of life.  The new 
biologics, in particular, dupilumab has shown to high rate of clinical 
and histologic remission in 2/3 of patients in treatment of EoE in 
adolescents and adults. Dupilumab is approved for the treatment of 
atopic dermatitis and asthma for children greater than or equal to 6 
years of age.   
The goal of this study is to show that foods can be safely added to 
diet when on dupilumab without exacerbation of Eosinophilic 
Esophagitis when on standard of care treatment for EoE. 
 
Study Objective 
To determine if dupilumab can allow EoE trigger foods without 
inducing flares of EoE (histological or symptomatic) 

 
 
  
 
 
 
 
 
 
ix
Study Endpoint(s) 
Primary  
- 
The primary efficacy endpoint will be the change in peak 
eosinophil counts on esophageal biopsies between 1st and 
2nd endoscopy after food introduction in the same patient.   
Secondary 
- 
Maintenance of resolution (<15 eosinophils/HPF on peak 
measurements) of eosinophilia observed on esophageal 
biopsies   
- 
Maintenance of remission (<6 eosinophils/HPF on peak 
measurements)  
- 
Change in mean esophageal eosinophil count from baseline 
to the end of treatment. 
- 
Change in symptoms scores at the end of treatment 
compared to baseline 
- 
Interval change on a validated endoscopic scoring system, 
EREFS 
- 
Interval change on esophageal compliance and distensibility 
measured by EndoFlip 
- 
Interval change in mRNA transcriptome profile (esophageal 
tissue), Th2 phenotype (peripheral blood), blood 
eosinophilia, and total serum IgE. 
- 
Change in the Eosinophilic Esophagitis Quality of Life Score 
from baseline to the end of treatment 
Test Article(s) 
(If Applicable) 
Dupilumab (anti-IL4 receptor alpha) 
Study Design 
 
Open label exploratory pilot study 
Subject Population 
key criteria for Inclusion 
and Exclusion: 
Inclusion Criteria 
1) Subjects age 6 – 25 years of age 
2) Diagnosis of Eosinophilic Esophagitis 
3) History of endoscopy with a peak count of >15 eosinophils per 
high powered field meeting consensus criteria for Eosinophilic 
Esophagitis1 
4) History of either milk, egg, soy, or wheat induced EoE based on 
the following criteria in the last two years 

 
 
  
 
 
 
 
 
 
x
a) Addition of a single food lead to exacerbation of esophageal 
eosinophilia (increase of greater than 15 eos/hpf) or 
b) Removal of a single food lead to normalization of biopsy 
(esophageal eosinophilia showed less than 6 eos/hpf) 
AND 
c) History of either milk, egg, soy, or wheat induced EoE 
based on introduction of the food and symptoms in the last 
12 months 
5) Maintained on stable dose of PPI throughout the trial 
Exclusion Criteria 
1. Patients with other Eosinophilic Gastrointestinal disease 
2. Tracheo-esophageal fistulas, inflammatory bowel disease, 
Barrett’s disease, or other significant inflammatory disease of 
the gastrointestinal tract 
3. Biopsy evidence of eosinophilic infiltration in any other organ 
system 
4. History of significant esophageal procedures e.g., sclerotherapy 
or esophagectomy 
5. Systemic immunosuppressant usage in prior 3 months 
6. Narrow caliber esophagus defined as the inability to pass a 9.5 
mm endoscopy into the esophagus 
7. IgE mediated reaction to food (milk, egg, soy, or wheat) being 
introduced in the last 12 months 
8. No change in the dose of swallowed steroids for Eosinophilic 
Esophagitis for 2 months prior to starting the study and 
throughout the study (their current standard of care EoE 
treatments) 
 
Number Of Subjects  
 
30 patients 
Study Duration 
Each subject’s participation will last 52 weeks 
Study Phases 
Disease Control 
Food introduction 
 
1) The first phase is the initial disease control in patients with 
Eosinophilic Esophagitis. Subjects will be treated with 
dupilumab for 12 weeks (per current proposed dosing in 
EoE clinical trials) 

 
 
  
 
 
 
 
 
 
xi
a. At the end of the 12 weeks, subjects will have 
endoscopy showing resolution of EoE 
2) Food introduction: If subjects do not have active 
esophageal biopsies (defined by greater than 15 eos/hpf) 
and have decreased symptoms per EoE symptom score, 
the subjects will continue dupilumab at current dosing 
regiment 
a. They will introduce one food (per food introduction 
guideline) for 12 weeks, then, upper endoscopy with 
biopsy will be done to examine EoE disease status 
b. If biopsies are normal, second food can be added, 
final endoscopy will be performed at week 51 to 
determine the stability of food introduction on 
dupilumab 
i. If a 3rd food was shown to be causative, it 
can be added at week 38. 
Efficacy Evaluations 
Esophageal Biopsy (Eosinophils/high power field) 
Esophageal Symptom Scores  
Pharmacokinetic 
Evaluations 
Not applicable 
Safety Evaluations 
Safety measures including symptom score, adverse events from 
dupilumab and endoscopies will be collected at each visit. 
Statistical And Analytic 
Plan 
The primary statistical efficacy endpoint will be tested using a 
Paired T-test on the change in peak eosinophil counts on 
esophageal biopsies between 1st and 2nd endoscopy after food 
introduction in the same patient. 
If peak eosinophil counts do not satisfy the assumption of normality, 
instead the Wilcoxon Signed-Rank test will be used for the primary. 
DATA AND SAFETY 
MONITORING PLAN 
The principal investigator will be responsible for the safety and 
monitoring of the study and data validation of the study. 

 
xii  
 
 
 
 
 
 
 
TABLE 1: SCHEDULE OF STUDY PROCEDURES  
Study Phase 
Disease Control 
Food introduction 
Follow-
up 
Visit Number 
1 
2 
3 
4 
5 
6* 
7* 
8 
9 
10* 
11* 
12 
13 
14* 
15* 
16 
17 
Study weeks 
1 
3 
8 
12 
13 
15 
20 
25 
26 
28 
33 
38 
39 
41 
46 
51 
52 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics/Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
Vital Signs: BP, HR, RR 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Height and Weight 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
EGD and biopsy 
 
 
 
X 
 
 
 
Xa 
 
 
 
Xa 
 
 
 
Xa 
 
EREFS 
 
 
 
X 
 
 
 
Xb 
 
 
 
Xb 
 
 
 
Xb 
 
EoE Symptom Score 
X 
X 
X 
X 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
Xb 
X 
EoE QOL 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
Food Introduction# 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
Pregnancy Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant 
Medications 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research laboratory  
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
  CBC (safety) 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 

 
xiii  
 
 
 
 
 
 
 
T cell phenotype, PBMC 
RNAseq 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Dispense Study Drug 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
 
Drug Compliance 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
 
Adverse Event Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
EREFS-EoE Endoscopy Reference Score 
EoE QOL-Eosinophilic Esophagitis Quality of Life measure 
*Visits can be done via remote research visit  
a-EGDs are standard of care biopsies for food introduction 
b-SOC procedures 
# Food Introduction 
Foods in phase 1 will be introduced as one serving size at week 13.  If biopsy at week 25 are less than 6 eosinophils/HPF, the subjects will 
have one of 2 options 
• 
Increase the serving size to 2 servings a day or 
• 
Add an additional EoE trigger food 
If the week 25 biopsy show 6-15 eosinophils/hpf, the diet will remain the same 
If the week 25 biopsy show >15 eosinophils, the diet will decrease to ½ serving size a day 
For the week 38 endoscopy with biopsy, the three scenarios are 
 
If the biopsy show < 6 eosinophils/hpf, the three options are 
• 
Increase the serving size to ad lib (if one food) or 
• 
Add a 3rd EoE trigger food or 
• 
Increase the serving size of 1st and 2nd foods to 2 serving size a day 
If the biopsy shows 6-15 eosinophils/hpf, the plan is to remain at the current diet 
If the biopsy show >15 eosinophils/hpf, the plan is to decrease the serving size by 50% 

 
  
 
 
 
xiv
FIGURE 1: STUDY DIAGRAM 
 
 
Week 12 
Endoscopy 
 
Week 51 
Endoscopy 
 
 
 
Week  
0 
Initial Disease Control 
Food introduction* 
Week 25 
Endoscopy 
Follow-
up 
Week 38 
Endoscopy 
Food  
Introduction-2# 
Food  
Introduction-3# 

 
 
 
 
 
 
1
1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 
Introduction 
Eosinophilic esophagitis (EoE) is a chronic, debilitating, allergic/immune-mediated disease due 
to chronic esophageal inflammation with the development of dysphagia that affects food intake 
and quality of life1. The disease is characterized by symptoms related to esophageal dysfunction 
and by eosinophil-predominant inflammation of the esophageal mucosa. EoE is a food allergy 
as removal of the foods can resolve the symptoms and histology.2  But, it is not IgE mediated 
food allergy3 and appears to be more driven by T cell mediated food allergy.4, 5  The pathology 
of EoE is driven by eosinophils isolating to the esophagus. While eosinophils are present in 
specific regions of the gastrointestinal (GI) tract, they are not normally found in the esophagus. 
Patients with EoE demonstrate esophageal tissue infiltration of significant numbers of 
eosinophils and other pro-inflammatory cells, including mast cells and B and T lymphocytes6, 
the latter characterized by an enrichment of CD4+ T regulatory and type 2 cytokine producing 
effector type 2 T helper (Th2) cells 7. This infiltrating cellular profile along with over expression of 
cytokines, particularly interleukin-13 (IL-13) and interleukin-5 (IL-5), strongly suggests that EoE 
is a type 2 cell-mediated inflammatory disease. Many patients with EoE have other atopic 
diseases including asthma and food allergies, supporting the view that EoE likely represents a 
disease in which type 2 cells and eosinophils play key pathogenic roles8. 
The treatment options for EoE include diet avoidance, and off-label use of topical steroids or 
proton pump inhibitors9. Diet avoidance can be successful in eliminating symptoms and leading 
to normalization of the esophageal eosinophilia.  However, six-food elimination diet which has 
success rate of 70% and elemental diet with a success rate of 90% have a tremendous amount 
of patient and family burden.  Patients have a very restricted diet with increased costs to the 
family and reduced quality of life (QOL).  The new biologics dupilumab has shown to high rate 
(67%) of clinical and histologic remission in treatment of EoE in adolescents and adults10, 11.  
The goal of this study is to show that foods can be safely added to diet when on dupilumab 
without exacerbation of Eosinophilic Esophagitis. 
 
1.2 
Name and Description of Investigational Product or Intervention 
Dupilumab is an interleukin-4 receptor alpha antagonist  It is approved for 6 years and above for 
the treatment of atopic dermatitis and asthma and approved for chronic rhinosinusitis with nasal 
polys for 18 years and above.  
1.3 
Findings from Non-Clinical and Clinical Studies  
1.3.1 Clinical Studies 
1.3.1.1 Eosinophilic Esophagitis 
Dupilumab has been studied in Eosinophilic Esophagitis in phase 2 and 3 clinical trials. In the 
phase 2 clinical trial, subjects were randomly assigned to groups that received weekly 
subcutaneous injections of dupilumab (300 mg, n = 23) or placebo (n = 24) for 12 weeks.  
Dupilumab reduced the peak esophageal intraepithelial eosinophil count by a mean 86.8 
eosinophils per high-power field (reduction of 107.1%; P < .0001 vs placebo), the EoE-histologic 
scoring system (HSS) severity score by 68.3% (P < .0001 vs placebo), and the endoscopic 

 
 
 
 
 
 
2
reference score by 1.6 (P = .0006 vs placebo). Dupilumab increased esophageal distensibility 
by 18% vs placebo (P < .0001).11  
In the phase 3 clinical trial, 81 subjects (12 years and older) were randomized 1:1 to dupilumab 
300 mg weekly versus placebo.  At 12 weeks, 64% of subjects treated with dupilumab versus 
8% of the placebo subjects had less 15 eosinophils/hpf in the esophageal biopsies.  Both 
groups had a similar adverse event profile with no serious adverse events in either group and 
86% having adverse events in the active group and 84% in the placebo group. 12   
Dupilumab was approved for the treatment of EoE in patients greater than 12 years of age on 
May 24, 2022.  We will be using the approved doses in this study. 
In our published data of 45 children13 (6-18) with eosinophilic esophagitis that were being 
treated with dupilumab for asthma or atopic dermatitis per approved indications.  39/41 patients 
(95%) had clinical improvement and 22/26 (85%) with follow-up endoscopies with biopsies had 
complete remission with esophageal eosinophil count of less 6 eosinophils/HPF.  
1.3.1.2 Clinical Studies in Children 
The drug is approved for clinical use in children with atopic dermatitis down to 6 years of age.  It 
has been studied down to 1 year of age in atopic dermatitis and Eosinophilic Esophagitis and 
asthma to 6 years of age. 
In the pivotal phase 3 study for the treatment of atopic dermatitis, 367 patients 6-11 years of age 
were randomized 1:1:1 to 300 mg dupilumab every 4 weeks (300 mg q4w), a weight-based 
regimen of dupilumab every 2 weeks (100 mg q2w, baseline weight <30 kg; 200 mg q2w, 
baseline weight ≥30 kg), or placebo.  In both the q4w and q2w dupilumab + topical 
corticosteroid (TCS) regimens resulted in clinically meaningful and statistically significant 
improvement in signs,  and symptoms of atopic dermatitis versus placebo + TCS in all 
prespecified endpoints. For q4w, q2w, and placebo, 32.8%, 29.5%, and 11.4% of patients, 
respectively, achieved Investigator's Global Assessment scores of 0 or 1; 69.7%, 67.2%, and 
26.8% achieved ≥75% improvement in Eczema Area and Response to therapy was weight-
dependent: optimal dupilumab doses for efficacy and safety were 300 mg q4w in children <30 
kg and 200 mg q2w in children ≥30 kg.14  
In the pediatric trial of 6 months to 6 years, 40 children were given open label dosing. At week 3, 
treatment with 3 and 6 mg/kg dupilumab reduced scores of mean Eczema Area and Severity 
Index by -44.6% and -49.7% (older cohort) and -42.7% and -38.8% (younger cohort) and mean 
Peak Pruritus NRS scores by -22.9% and -44.7% (older cohort) and -11.1% and -18.2% 
(younger cohort), respectively. At week 4, improvements in most efficacy outcomes diminished 
in both age groups, particularly with the lower dose. The safety profile was comparable to that 
seen in adults, adolescents, and children.15 
In the asthma phase 3 trials for dupilumab in children 6-11 years of age, it was a randomized, 
double-blind, placebo-controlled trial of 408 children aged 6 to <12 years old with uncontrolled 
moderate-to-severe asthma.  They were given dupilumab versus placebo plus their standard 
care of therapy.  The population was split into two arms  with  259 patients with baseline 

 
 
 
 
 
 
3
(peripheral blood eosinophil count ≥300 cells/µl) and 350 patients with markers of type 2 
inflammation (baseline peripheral blood eosinophil count ≥150 cells/μl or FeNO ≥20 ppb). 
During the 52-week treatment period, patients received subcutaneous injections of dupilumab 
100 mg or 200 mg every two weeks, based on weight (100 mg for ≤30 kg, 200 mg for >30 kg), 
or placebo every two weeks. The primary endpoint assessed the annualized rate of severe 
asthma attacks.  Dupilumab arm had reduced rate of severe asthma attacks, with a 65% 
(p<0.0001) and 59% (p<0.0001) average reduction over one year compared to placebo (0.24 
and 0.31 events per year for dupilumab vs. 0.67 and 0.75 for placebo, respectively). The 
dupilumab arm had improved lung function at 12 weeks compared to baseline by 10.15 and 
10.53 percentage points for Dupixent vs. 4.83 and 5.32 percentage points for placebo (least 
squares mean difference for Dupixent vs. placebo of 5.3 and 5.2 percentage points, p=0.0036 
and p=0.0009), respectively, as measured by percent predicted FEV1.16  
1.3.1.3 Package Inserts 
Package inserts for dupilumab for asthma eosinophilic Esophagitis and atopic dermatitis are in 
separate appendix. 
1.4 
Selection of Drugs and Dosages 
We use the current dosing used in the phase 3 Eosinophilic Esophagitis clinical trials (see 
section 6.1.1-6.1.3).  We are using the approved doses for 12 years and older and if a specific 
dose for EoE is approved during the trial for 6-11 yo, we will transition all patients to the FDA 
approved dose. 
1.5 
Relevant Literature and Data 
The diagnosis of Eosinophilic Esophagitis will be made by the current international guidelines, 
where patients have symptoms of esophageal dysfunction and greater than 15 eosinophils/hpf 
isolated to the esophagus.1  Other causes of esophageal eosinophilia will be ruled out.  
The current consensus treatment options for EoE were based on peer reviewed and expert 
opinion and include diet elimination and medication use (topical corticosteroids (CS) and proton 
pump inhibitors (PPI)10.  For diet elimination therapy, the most common foods are milk, egg, 
soy, and wheat based on multiple clinical trials (retrospective and prospective studies).17, 18  Diet 
therapies have been successful in 40-70% depending on whether 1 or 4 foods were removed.  
When, patients are placed on elemental diets, the response rate with normalization of biopsies 
and symptoms in >95% of patients.19  
For medical therapy, dupilumab is the first approved medication for EoE patients greater than 
12 yo as in phase 2 and 3 trials with the use of dupilumab in adolescents in adults in 12 year 
and old found that 67% of the patients showed resolution of their EoE.11 There are several 
phase 2 and 3 clinical trials examining the use of biologics and swallowed steroids for the use in 
EoE.  Recent completed phase 3 clinical trial in patients in 12 years and old with EoE showed 
that swallowed budesonide is effective in about 50% of the patients.20     
In our cohort of 3500 patients seen at Children’s Hospital of Philadelphia, 70% are treated with 
a combination of two or three of the current therapies of diet elimination, topical steroids, or PPI.   

 
 
 
 
 
 
4
Families have strong desire for simple therapy and improved quality of life with expansion of 
foods into their diet.  
In preliminary data for this study13, we performed a retrospective chart review of patients with 
EoE using dupilumab for approved indications (asthma or atopic dermatitis).  We identified 45 
patients age 6 to 19 years of age and we have follow-up data for 41 patients.  39/41 patients 
showed improvement in EoE symptoms and we have follow-up endoscopies in 26 endoscopies 
showing normalization of histology in 22 patients and maintenance of normal endoscopy and 
histology in one additional patient while stopping their other medications to treat their EoE.   
However, 80% of the patients were still on a combination of medications and diet to treat their 
EoE.  This current study will examine if the use of dupilumab for the treatment of Eosinophilic 
Esophagitis will allow expansion of their diet.  The goal of expansion of diet will improve quality 
of life, nutrition without negatively affecting their EoE.  We will examine EoE using validated EoE 
measures for disease activity and nutrition status by weight (z-scores).  
The validated measures for endpoints in Eosinophilic Esophagitis to be used include 
• 
Pediatric Eosinophilic Esophagitis Symptom Score21 
• 
EoE Endoscopy Reference Score22 
• 
EoE Quality of Life23 
• 
EoE Histology Scale24 
• 
Esophageal Compliance (Endoflip)25 
• 
Height and Weight, calculated z-scores 
We would also examine if the use of dupilumab will normalize the esophageal transcriptome by 
examining esophageal biopsy mRNA transcriptome.  In EoE, there is an altered esophageal 
transcriptome with an increase expression of specific esophageal and T2 cytokines.26  Both T 
cell profile and peripheral blood eosinophilia and eosinophil progenitors have shown correlation 
with esophageal biopsy and maybe a non-invasive marker of disease.4, 27  We will examine 
these research bloods to explore potential non-invasive markers of disease and/or mechanism 
of dupilumab on disease activity.    
The goal of this study is to see if dupilumab can facilitate food introduction while patients on 
standard of care EoE therapies. They will maintain their EoE therapies, which can include PPIs, 
swallowed steroids, or diet elimination. throughout the study except for food introduction as 
indicated by the protocol. 
We are examining food introduction in this age group for the following reasons. 
1) Dupilumab is approved for children 6 years and above for asthma and atopic dermatitis 
2) Dupilumab has been shown to be clinical effective in phase 2 and 3 clinical trials for 12 
years and above and recently approved in May 24, 2022 
3) Dupilumab has been shown to be effective in our published observational study looking 
at patients 6 years and older being treated with dupilumab for their co-existing asthma 
and/or atopic dermatitis.  We found that their EoE had improvements in both clinical 
symptoms and histology.  In addition, many patients were able to add foods into their 
diet. 

 
 
 
 
 
 
5
4) Foods triggers have been primarily identified in pediatrics as almost all the dietary trials 
were done in pediatrics.  The proposed biomarker studies have only been done in 
pediatrics.  
Therefore, the study medication is safe and effective in this age group of 6 years and above.  
There are insufficient patients in the adult group with identified food triggers to complete this 
trial. 
 
1.6 
Compliance Statement 
This study will be conducted in full accordance all applicable Children’s Hospital of Philadelphia 
Research Policies and Procedures and all applicable Federal and state laws and regulations 
including 45 CFR 46, and the Good Clinical Practice: Consolidated Guideline approved by the 
International Conference on Harmonization (ICH) and all relevant FDA regulations.  All episodes 
of noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain consent and 
assent, and will report unanticipated problems involving risks to subjects or others in 
accordance with The Children’s Hospital of Philadelphia IRB Policies and Procedures and all 
federal requirements. Collection, recording, and reporting of data will be accurate and will 
ensure the privacy, health, and welfare of research subjects during and after the study.  
2 
STUDY OBJECTIVES 
The purpose of the study is to determine if dupilumab can allow introduction of EoE triggered 
foods to be added reintroduced back into the diet without causing exacerbation of disease. 
2.1 
Primary Aim 
1) Evaluate the efficacy of Dupilumab, a humanized anti-IL4 receptor alpha monoclonal 
antibody, to allow successful food introduction into diet 
2) Assess changes in clinical (symptoms, QOL) and biologic parameters after food 
introduction. 
The secondary Endpoint: 
- 
Maintenance of resolution (<15 eosinophils/HPF on peak measurements) of eosinophilia 
observed on esophageal biopsies   
- 
Maintenance of remission (<6 eosinophils/HPF on peak measurements)  
- 
Change in mean esophageal eosinophil count from baseline to the end of treatment. 
- 
Change in symptoms scores at the end of treatment compared to baseline 
- 
Interval change on a validated endoscopic scoring system, EREFS 
- 
Interval change on esophageal compliance and distensibility measured by EndoFlip 
- 
Interval change in mRNA transcriptome profile (esophageal tissue), Th2 phenotype 
(peripheral blood), blood eosinophilia, and total serum IgE. 

 
 
 
 
 
 
6
- 
Change in the Eosinophilic Esophagitis Quality of Life Score from baseline to the end of 
treatment 
3 
INVESTIGATIONAL PLAN 
3.1 
General Schema of Study Design 
This study is an open label exploratory study to examine if patients controlled with dupilumab 
can successful introduce EoE trigger foods back into their diet.   
In the initial 12-week period, patients will be start on dupilumab on the doses used in the phase 
3 trials to control disease.  If disease is controlled based on histologic and symptom control at 
week 12 endoscopy, patients will be start on EoE trigger food.  The trigger foods will be based 
on both a combination of history and histology results.  The food will have trigger EoE by 
histology in the last 2 years and symptoms in the last year when reintroduced into the diet.  The 
study will focus on the four most common foods that trigger EoE: milk, egg, wheat, and soy.  For 
the initial food introduction, the subjects will add one serving size of the food daily for 12 weeks.  
After 12 weeks, the subjects will have a 2nd endoscopy if the 2nd endoscopy is normal, the 
subjects will increase the trigger food to 2 serving sizes a day or add an additional trigger food.  
A 3rd endoscopy will be done if the patients increase the food amount or adds a new food at 
week 38 (12 weeks after adding the new food).  If the subject does not increase or add new 
foods at week 25, the 3rd endoscopy will not be obtained.  All subjects will have end of study 
endoscopy at week 51. 
If the subjects have abnormal endoscopy or increase in symptoms, the amount food will be 
reduced by 50% and repeat endoscopy will be obtained at the same time schedule-12 weeks 
later.  (See Figure 1 and Table 1) 
Screening Phase 
Potential subjects will be screened using the protocol inclusion and exclusion criteria based on 
review of their medical records.  
Parental/guardian permission (informed consent) and, if applicable, child assent, will be 
obtained prior to any study related procedures being performed. After consent is obtained, 
research blood samples will be drawn to confirm eligibility based on clinical laboratory 
parameters.  Females of child bearing potential will have an urine pregnancy test. 
3.1.1 Disease Control  
At the initial phase, research subjects will start on dupilumab based on the dosage used in the 2 
phase 3 clinical trials.   Based on previous data, patients respond within 12 weeks, therefore, a 
baseline endoscopy showing a clinical and histologic response will be obtained at week 12. If 
patients show clinical response with dupilumab as defined as esophagus biopsy with less 6 
eosinophils/hpf.  If the biopsy does not improve such that eosinophil count is still greater than 15 
eosinophils/hpf, the subject will exit the study.  If the biopsy is between 6-15 eosinophils/hpf, the 
subject will be treated for an additional 12 weeks on dupilumab.  If the biopsy is still not less 
than six eosinophils/hpf, the subject will exit the study.   If the subjects have biopsy have less 
than six eosinophils/hpf (FDA definition of remission), the subjects will advance to food 
introduction phase of the study.  

 
 
 
 
 
 
7
 
3.1.2 Food Introduction  
If research subjects have a clinical response to dupilumab, they will introduce an EoE trigger 
food at one serving size per day. After 12 weeks, repeat EGD and symptoms score will be 
obtained.  12 weeks is being used as determined clinical and histologic responses can be seen 
at that time point in previous clinical studies18.  
The foods (milk, egg, soy, and wheat) to be introduced after having caused exacerbation of their 
EoE by standard definitions: 
- 
Addition of a single food lead to exacerbation of esophageal eosinophilia 
(increase of greater than 15 eos/hpf) or 
- 
Removal of a single food lead to normalization of biopsy (esophageal 
eosinophilia showed less than 6 eos/hpf) 
- 
AND 
- 
History of either milk, egg, soy, or wheat induced EoE based on introduction of 
the food and symptoms in the last 12 months 
Foods in phase 1 will be introduced as one serving size at week 13.  If biopsy at week 25 are 
less than 6 eosinophils/HPF, the subjects will have one of 2 options 
• 
Increase the serving size to 2 servings a day or 
• 
Add an additional EoE trigger food 
If the week 25 biopsy show 6-15 eosinophils/hpf, the diet will remain the same 
If the week 25 biopsy show >15 eosinophils, the diet will decrease to ½ serving size a day 
For the week 38 endoscopy with biopsy, the three scenarios are 
 
If the biopsy show < 6 eosinophils/hpf, the three options are 
• 
Increase the serving size to ad lib (if one food) or 
• 
Add a 3rd EoE trigger food or 
• 
Increase the serving size of 1st and 2nd foods to 2 serving size a day 
If the biopsy shows 6-15 eosinophils/hpf, the plan is to remain at the current diet 
If the biopsy show >15 eosinophils/hpf, the plan is to decrease the serving size by 50% 
 
3.1.3 Follow-up Phase 
The follow-up phase will continue for up to 14 days to monitor for adverse events.   
3.2 
Allocation to Treatment Groups and Blinding 
All patients will receive active drug. 

 
 
 
 
 
 
8
3.3 
Study Duration, Enrollment and Number of Sites 
3.3.1 Duration of Subject Study Participation 
If subjects complete all phases, the study will last 52 weeks. 51 weeks of treatment and 1 week 
of follow-up. If the subject does not meet study criteria (response to dupilumab), they will exit 
the study at week 13. 
3.3.2 Total Number of Study Sites/Total Number of Subjects Projected 
The study will be conducted at approximately 1 investigative site in the United States.  
3.4 
Study Population 
Children, adolescent, and adults with Eosinophilic Esophagitis 
3.4.1 Inclusion Criteria 
3.4.2 Index/Case Subject Inclusion Criteria 
1) Males or females age 6 to 25 years   
2) Diagnosis of Eosinophilic Esophagitis based on the most recent international consensus 
definition (Dellon et al, Gastroenterology 2019) 
a) History of endoscopy with a peak count of >15 eosinophils per high powered field 
meeting consensus criteria for Eosinophilic Esophagitis1 
3) History of either milk, egg, soy, or wheat induced EoE based on the following criteria in the 
last two years  
a) Addition of a single food lead to exacerbation of esophageal eosinophilia (increase of 
greater than 15 eos/hpf) or 
b) Removal of a single food lead to normalization of biopsy (esophageal eosinophilia 
showed less than 6 eos/hpf) 
AND 
c) History of either milk, egg, soy, or wheat induced EoE based on introduction of the food 
and symptoms in the last 12 months 
4) Weight ≥ 10 kg 
5) Ability to remain on stable dose of PPI therapy throughout the study 
6) Women with child bearing potential must have a negative urine/serum pregnancy test. 
7) Parental/guardian permission (informed consent) and if appropriate, child assent. 
 
3.4.3 Exclusion Criteria 
1. Tracheo-esophageal fistulas, inflammatory bowel disease, Barrett’s disease, or other 
significant inflammatory disease of the gastrointestinal tract 
2. Biopsy evidence of eosinophilic infiltration in any other organ system 

 
 
 
 
 
 
9
3. History of significant esophageal procedures e.g., sclerotherapy or esophagectomy 
4. Systemic immunosuppressant usage in prior 3 months and throughout the study 
5. Narrow caliber esophagus defined as the inability to pass a 9.5 mm endoscopy into the 
esophagus 
6. IgE mediated reaction to food (milk, egg, soy, or wheat) being introduced in the last 12 
months 
7. Therapy with biologic molecule (e.g., omalizumab, infliximab) in prior 12 months 
8. Any factors that may pose a significant risk for undergoing anesthesia/sedation 
9. Subjects undergoing any type of immunotherapy to any food (oral immunotherapy, 
sublingual immunotherapy, specific oral tolerance induction) within 3 months prior to Visit 1. 
10. Active IgE- mediated milk, egg, wheat, or soy allergy based on skin test or history (if those 
foods are being introduced back into the diet).  
11. Allergy or known hypersensitivity to the dupilumab.  
12. Subjects (or parents of subjects) with obvious excessive anxiety and unlikely to cope with the 
conditions of an upper Endoscopy and biopsy. 
13. No change in the dose of swallowed steroids for Eosinophilic Esophagitis for 2 months prior 
to starting the study and throughout the study (their current standard of care EoE treatments 
14. Past or current disease(s), which in the opinion of the Investigator or the Sponsor, may 
affect the subject’s participation in this study, including but not limited to active autoimmune 
disorders, immunodeficiency, malignancy, uncontrolled diseases (hypertension, psychiatric 
(especially anxiety), cardiac), or other disorders (e.g., liver, gastrointestinal, kidney, 
cardiovascular, pulmonary disease, or blood disorders). 
15. Participation in another clinical intervention study in the three months prior to Visit 1. 
16. Subjects unable to follow the protocol and the protocol requirements. 
17. Subjects on any experimental drugs or treatments. 
18. Subjects unable to read/understand English or follow the protocol and the protocol 
requirements. 
19. Treatment with a live (attenuated) vaccine within 4 weeks before the baseline visit or 
throughout the trial 
20. Major elective surgeries are prohibited during the study 
21. Female patients who are pregnant, breastfeeding, or planning to become pregnant or 
breastfeed during the study 
 
22. Women of children bearing potential (WOCBP) who are unwilling to practice highly effective 
contraception prior to the initial dose/start of the first treatment, during the study, and for at 
least 12 weeks after the last dose. This includes female patients who experience menarche 
during the study duration and who are unwilling to follow the precautions for WOCBP. 

 
 
 
 
 
 
10 
23. Chronic or acute infection requiring treatment with systemic antibiotic, antivirals, or 
antifungal within 2 weeks of baseline visits 
a. Patients maybe rescreened after infection resolves 
24. Participants with active or suspected parasitic infection are excluded.  
3.4.4 Individual stopping rules 
Subjects may withdraw from the study/schedule of assessments for any of the following reasons: 
• 
Patients will be stopped if they have severe adverse reaction from a serious 
adverse event from injection reaction 
• 
The Investigator decides that it is the subject’s best interest to be withdrawn from 
the study.  
• 
The subject is unwilling to continue in the study (consent withdrawal). 
• 
Lack of compliance with protocol requirements and procedures. 
• 
The Sponsor- Investigator or Regulatory Authorities, for any reason, stops the 
study. 
• 
The subject fails to return to the clinic for scheduled visits and does not respond to 
telephone or written attempts at contact (lost to follow-up).  
• 
Subject’s death 
The reason for withdrawal will be recorded in the clinical records and the electronic Case Report 
Form (eCRF). All subjects who are withdrawn or discontinue should be provided with alternative 
medical care, if applicable. 
 
4 
STUDY PROCEDURES 
Eosinophilic Esophagitis History 
Physical examination 
Esophagogastroduodenoscopy with biopsy with conscious sedation: 
Eosinophilic Esophagitis Symptom Score: 
Pediatric Eosinophilic Esophagitis Symptom Score 
Pediatric Eosinophilic Esophagitis Symptom Questionnaire 
Eosinophilic Esophagitis Quality of Life Measures 
o PedsQL™ Eosinophilic Esophagitis Module Version 3 Teen Report (ages 13-18) 
o PedsQL™ Eosinophilic Esophagitis Module Version 3 Child Report (ages 8-12) 
o PedsQL™ Eosinophilic Esophagitis Module Version 3 Parent Report for Child 
(ages 8-12) 
o PedsQL™ Eosinophilic Esophagitis Module Version 3 Parent Report for Young 
Child (ages 5-7) 
Esophageal Compliance measured by Endoflip 
Research esophageal biopsies-6 additional esophageal biopsies 
Blood draws for exploratory markers (RNAseq transcriptome of blood, T cell proliferation, 
peripheral blood eosinophils and progenitors)-15 ml per blood draw 

 
 
 
 
 
 
11 
Diet records 
Study Drug administration 
 
4.1 
Study Treatment Phase: EoE disease control 
4.1.1 Visit 1 
Visit 1: Baseline Visit, Study enrollment 
• 
Informed consent obtained,  
• 
Inclusion and exclusion criteria reviewed,  
• 
Medical Records reviews 
• 
Physical exam including vital signs with height and weight  
• 
Eosinophilic Esophagitis Symptom Score-Pediatric Eosinophilic Esophagitis Symptom 
Score (PEESS and PESQ) 
• 
EoE Quality of life (QOL) 
• 
Research labs (T cell phenotype, PBMC RNAseq, peripheral blood eosinophils and 
progenitors, proteomics)-15 ml 
• 
First dose of Dupilumab 
4.1.2 Visit 2 
2 weeks from visit 1 (+/- 3 days) 
• 
EoE Symptom Score-PEESS and PESQ 
• 
Drug disposition 
• 
Monitor drug compliance 
• 
AE assessment 
• 
Physical Examination including vital signs with height and weight 
4.1.3 Visit 3 
5 weeks from visit 2 (+/- 4 days) 
• 
EoE Symptom Score-PEESS and PESQ 
• 
Drug disposition 
• 
Monitor drug compliance 
• 
AE assessment 
• 
Physical Examination including vital signs with height and weight 
4.1.4 Visit 4 
4 weeks from visit 3 (+/- 4 days)  
• 
Upper Endoscopy with biopsy with 4 esophageal biopsies for histology 
• 
EoE Symptom Score-PEESS and PESQ 
• 
EoE QOL 
• 
Drug disposition 
• 
Monitor drug compliance 

 
 
 
 
 
 
12 
• 
AE assessment 
• 
Physical Examination including vital signs with height and weight 
• 
Endoflip and/or esophageal impedance 
• 
Research bloods (T cell phenotype, PBMC RNAseq. peripheral blood eosinophils and 
progenitors, proteomics)-15 ml of blood 
• 
Research Biopsies (esophageal RNAseq)-6 esophageal biopsies for research samples 
4.2 
Phase 2: Food Introduction 
4.2.1 Visit 5, 9, 13 
1 week (+/- 3 days) after visit 4, 8 and 12 
• 
EoE Symptom Score-PEESS and PESQ (SOC procedure) 
• 
Drug disposition 
• 
New food introduction 
• 
Monitor drug compliance 
• 
AE assessment 
• 
Physical Examination including vital signs with height and weight 
4.2.2 Visit 6, 10, 14 
2 weeks (+/- 4 days) after preceding visit. This visit can be done by remote research visit. 
• 
EoE Symptom Score-PEESS and PESQ (SOC procedure) 
• 
Drug disposition 
• 
Review food diary 
• 
Monitor drug compliance 
• 
AE assessment 
• 
Physical Examination including vital signs with height and weight 
 
4.2.3 Visit 7, 11, 15 
5 weeks (+/- 4 days) after preceding visit. This visit can be done by remote research visit.  
• 
EoE Symptom Score-PEESS and PESQ (SOC procedure) 
• 
Review food diary 
• 
Monitor drug compliance 
• 
AE assessment 
4.2.4 Visit 8, 12, 16 
• 
Upper Endoscopy with biopsy-4 esophageal biopsies (SOC procedure) 
• 
EoE Symptom Score-PEESS and PESQ 
• 
EoE QOL 
• 
Review food diary 
• 
Drug disposition (except for visit 16) 
• 
Monitor drug compliance 

 
 
 
 
 
 
13 
• 
AE assessment 
• 
Physical Examination including vital signs with height and weight 
• 
Endoflip and/or esophageal impedance 
• 
Research bloods: (T cell phenotype, PBMC RNAseq. peripheral blood eosinophils and 
progenitors, proteomics)-15 ml of blood 
• 
Research Biopsies: Esophageal biopsy RNAseq-6 esophageal biopsies 
• 
AE assessment 
4.3 
Follow-up Phase  
4.3.1 Visit 17: End of Study 
• 
AE assessment 
• 
Physical Examination including vital signs with height and weight 
4.4 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for 
any other reasons as warranted.  
 
4.5 
Concomitant Medication 
All prior and concomitant medications used within 14 days prior to the screening visit and 
through the end of the study will be recorded. The dates of administration, dosage, and reason 
for use will be included.  
4.6 
Subject Completion/Withdrawal 
Subjects may withdraw from the study at any time without prejudice to their care.  They may 
also be discontinued from the study at the discretion of the Investigator for lack of adherence to 
study treatment or visit schedules, AEs, or due to lack of response to dupilumab as defined by 
esophageal biopsy greater than 15 eosinophils/high power field at week 12. The Investigator 
may also withdraw subjects who violate the study plan, or to protect the subject for reasons of 
safety or for administrative reasons.  It will be documented whether or not each subject 
completes the clinical study. If the Investigator becomes aware of any serious, related adverse 
events after the subject completes or withdraws from the study, they will be recorded in the 
source documents and on the CRF. 
4.6.1 Early Termination Study Visit 
Subjects who withdraw from the study will have all procedures enumerated for Visit 8 as the 
early termination visit.  

 
 
 
 
 
 
14 
5 
STUDY EVALUATIONS AND MEASUREMENTS 
5.1 
Screening and Monitoring Evaluations and Measurements 
5.1.1 Medical Record Review 
Prior to screening visit, previous upper endoscopy and biopsy results and diet history will be 
reviewed.  This information will be collected as part of routine clinical care.  
5.1.2 Medical History 
Complete medical history will include history and duration of all allergies (including milk. Egg, 
soy, or wheat allergy) and current medical conditions, number of allergic reactions and 
treatments in the previous 12 months, past or present cardiovascular, respiratory, 
gastrointestinal, renal, hepatic, neurological, endocrine, lymphatic, hematologic, immunologic, 
dermatological, psychiatric, and genitourinary disorders, drug and surgical history and any other 
diseases or disorders. 
5.1.3 Physical Examination 
Physical examinations will be performed by a physician or nurse practitioner and will include 
examination of the following: general appearance, head, ears, eyes, nose and throat, neck, complete 
skin examination, cardiovascular system, respiratory system, abdominal system, and nervous 
system. For each body system an assessment of normal or abnormal will be recorded in the eCRF 
at screening and the abnormality will be documented. During the study, any clinically relevant 
changes observed during physical examinations will be reported as AEs. 
 
Physical examinations must be performed before the upper endoscopy/biopsy.  
 
5.1.4 Vital Signs 
Vital signs will include sitting systolic and diastolic blood pressure, heart rate, respiratory rate, and 
temperature. Systolic blood pressure and diastolic blood pressure will be measured on the same 
arm after the subject has been in a sitting position for 5 minutes. Heart rate will be recorded 
simultaneously with blood pressure measurements, followed by respiratory rate and body 
temperature. 
Body weight (kg) will be measured without shoes or jacket. Height (cm) will be determined at 
without shoes. 
During the study, the measurement of vital signs may be repeated at the discretion of the Investigator 
for safety reasons. Clinically relevant abnormal findings will be reported as AEs. 
 
Vital signs must be performed before the upper endoscopy/biopsy.  
5.1.5 Eosinophilic Esophagitis Quality of Life 
Quality of life is a measurement of a subject’s overall well-being. QOL will be measured by the 
validated age specific Eosinophilic Esophagitis tool for 5-7 years of age, 8-12 years of age, and 13- 
18 years of age developed by Franciosi and colleagues based on the age of the subject at Visit 1.   

 
 
 
 
 
 
15 
The subjects will complete the same questionnaire throughout the study. 
 
5.1.6 Upper Endoscopy with Biopsy 
All subjects will undergo a maximum of six upper endoscopies with biopsies during their 
participation in the study (biopsies will include three each of proximal and distal, plus any inflamed 
areas) as per standard clinical practice).  The samples will be processed by the Department of 
Pathology at The Children’s Hospital of Philadelphia and the number of eosinophils will be 
counted using hematoxylin and eosin stain.  The handling of samples will be done following ASGE 
Standard on Endoscopic Mucosal Tissue Sampling.28    
Six research biopsies will be obtained in addition to the clinical biopsies.  The biopsies will be 
taken from other areas of the esophagus compared to the clinical biopsies. 
Upper endoscopy will be scored using a validated standardized measure. 22  The measure 
examines four major esophageal features (rings, furrows, exudates, and edema) and the 
presence of minor features of narrow caliber esophagus, feline esophagus, stricture, and crepe 
paper esophagus. The features are graded: 
• 
Rings (0-none, 1 mild, 2-moderate, 3-severe)  
• 
Exudates (0-none, 1-mild, 2-severe) 
• 
Furrows- (0-none, 1-present) 
• 
Edema- (0-none, 1-present) 
• 
Stricture (0-none, 1-present) 
• 
Crepe paper esophagus (0-none, 1-present) 
Endoscopy and biopsy are standard of care after food introduction. 
The endoscopy will be done under moderate conscious sedation.   Moderate sedation is defined 
as a drug-induced depression of consciousness during which patients respond purposefully to 
verbal command that is accompanied by light tactile stimulation. No interventions are required to 
maintain a patent airway and spontaneous ventilation is adequate. Cardiovascular function is 
usually maintained. 
Conscious sedation will be done by CHOP standard protocol: Policy: Protocol Sedation: 
http://intranet.chop.edu/patcare/patcarman/tx-5-01.pdf 
5.1.7 Histological Evaluation 
Esophageal biopsy samples will be evaluated to confirm eligibility. Biopsy samples will be stained 
with hematoxylin and eosin stain. Intraepithelial eosinophils will be counted in all HPFs using 
400X light microscopy. A HPF will be counted only if at least half of the field is occupied by tissue. 
The maximum eosinophil count per HPF will be reported for each esophageal biopsy site (at each 

 
 
 
 
 
 
16 
of 2 levels) with a minimum of 2 biopsies at each level. In addition to the evaluation for 
eosinophilia, all biopsy samples will be assessed for other histologic changes including epithelial 
hyperplasia, intercellular edema, and fibrosis.   
Specimens will be examined with respect to the maximum eosinophil counts and other histologic 
changes. Together with the EoE Clinical Symptom Score, the maximum eosinophil count per HPF 
for each specimen (from the total of all specimens) will be used to determine response to 
treatment. 
The maximum eosinophil count will be defined as the highest number of eosinophils observed in 
any single HPF from an esophageal specimen. All specimens from all esophageal sites will be 
considered in determining the resolution of eosinophilia. A maximum eosinophil count will be 
recorded for the esophagus. The highest peak counts at a given timepoint will be referred to as 
the maximum eosinophil count for that timepoint. 
5.1.8 Endoflip 
Esophageal distensibility utilizing the endolumenal functional lumen imaging 
probe (EndoFLIP, Medtronic, USA) will be performed with measurements taken as part of the 
esophagogastroscopy procedure. The EndoFLIP procedure must be performed before biopsies 
are collected. Procedural order should be: EREFS/imaging, EndoFLIP, then biopsies. The 
EndoFLIP device is a catheter-based procedure that measures the cross-sectional area at 
multiple sites along the esophagus with simultaneous intraluminal pressure recordings during 
volumetric distension of the esophagus. The analyses of cross-sectional area versus pressure 
relationships of the esophagus allow for determination of esophageal compliance as well as the 
distensibility plateau. The distensibility plateau has been shown to be significantly reduced in 
adult patients with EoE compared to healthy controls29. Moreover, the esophageal distensibility 
has been associated with outcomes of both food impaction and need for esophageal dilation25. 
Endoflip has also been shown to correlate with symptoms in pediatric cohorts.30 
 
Endoflip are standard of care at the time of endoscopy to measure esophageal function. 
 
Esophageal epithelial integrity is affected by the presence of dilated intercellular spaces (DIS), 
or spongiosis (intercellular edema), which affects paracellular permeability of the esophageal 
lumen. DIS is an important histologic feature in GERD and EoE which inversely correlates with 
MI measurements (i.e., lower impedance values with increasing DIS). 
 
Patients with EoE have shown to decreased impedance compared to GERD or achalasia.31  
Esophageal impedance will be measured by MiVu.   
 
5.1.9 Diet Diary 
Subjects will indicate the duration and amount of food taken on a daily basis during the food 
reintroduction period.  
 

 
 
 
 
 
 
17 
5.1.10 Pregnancy testing 
A urine pregnancy test will be performed for female subjects who are physically capable of 
becoming pregnant. 
 
5.1.11 Pregnancy 
If a subject becomes pregnant during the trial, they will immediate stop receiving dupilumab.  They 
will not be followed as there no published reports of adverse events from pregnancy, fetus and 
dupilumab. 
 
If the subject becomes pregnant, we will enroll them in a pregnancy exposure registry for women 
who take DUPIXENT during pregnancy. The purpose of this registry is to collect information about 
the health of subject and her baby. The registry is https://mothertobaby.org/ongoing-study/dupixent/. 
 
5.1.12 Research Laboratory Tests 
The differential gene expression profiles of esophageal biopsies of EoE patients shows a 
marked difference compared to healthy controls and is the EoE disease transcriptome32. This 
disease gene expression signature was further refined to a smaller gene set to be used as an 
EoE diagnostic panel (EDP)33. A gene signature representing type 2 inflammation has been 
curated from the literature, preclinical experiments performed at Regeneron, and dupilumab 
response signatures from atopic dermatitis and a phase 2 and 3 study of EoE (Regeneron 
unpublished data).  
 
In a phase 2 study of EoE (R668-EE-1324), dupilumab significantly decreased the disease, 
EDP, and type 2 transcriptome signatures. Normalized Enrichment Score (NES) reflects the 
degree to which the activity level of a set of transcripts is overrepresented at the extremes (top 
or bottom) of the entire ranked list of transcripts within a sample and is normalized by 
accounting for the number of transcripts in the set34, 35. 
 
The research bloods that will be collect include: 
T cell phenotyping for T1/T2/Th17 expression, blood eosinophilia (CBC) and eosinophilic 
progenitor cells measured by flow cytometry in peripheral blood. 
We will collect patient 6 biopsies and 15 ml peripheral blood at the time of study 
endoscopy.  Patient samples will be provided to laboratory and CAG staff using the deidentified 
study code. Biopsy tissue will be dissociated in media containing RNAse inhibitors and single 
cell RNA expression libraries will be generated following 10x genomics manufacturer protocols. 
Peripheral blood mononuclear cell samples will be isolated from patient blood samples 
and single cell RNA expression libraries will be generated following 10x genomics manufacturer 
protocols. Single cell RNA libraries will be pooled and sequenced to a minimum depth of 20,000 
reads per cell using next generation sequencing (Illumina) at CHOP Center for Applied 
Genomics (CAG).  
 
Patient sequencing data will be stored using deidentified study codes and will not be associated 
with patient names or any protected health information. Sequencing data will be transferred 

 
 
 
 
 
 
18 
from the CAG to study staff for analysis and stored using CHOP IT managed laboratory data 
drives (i.e.: SMB://ressmb ). Sequencing data will not be stored on personal devices.  Data 
analysis will be performed on CHOP managed devices and on the CHOP high performance 
computing cluster.  
 
Research blood will be done at the following visits 1, 4, 8, 12, and 16 
 
Research esophageal biopsies will be collected at visit 4, 8, 12 and 16. 
 
5.2 
Safety Evaluation 
Subject safety will be monitored by adverse events, vital signs, physical examinations and 
endoscopy and biopsy.  
If a public health emergency is declared that limits or prevents on-site study visits, regular 
phone call or virtual calls can occur for safety monitoring and discussion of the patient’s health 
until it is safe for the participant to visit the site again.  
5.3 
STATISTICAL CONSIDERATIONS 
5.3.1 Primary Endpoint 
The primary efficacy endpoint will be the change in peak eosinophil counts on esophageal 
biopsies between 1st and 2nd endoscopy after food introduction in the same patient.   
5.3.2 Secondary Endpoints 
Secondary endpoints will include the following: 
• 
Maintenance of resolution (<15 eosinophils/HPF on peak measurements) of eosinophilia 
observed on esophageal biopsies   
• 
Maintenance of remission (<6 eosinophils/HPF on peak measurements)  
• 
Change in mean esophageal eosinophil count from baseline to the end of treatment. 
• 
Change in symptoms scores at the end of treatment compared to baseline 
• 
Interval change on a validated endoscopic scoring system, EREFS 
• 
Interval change on esophageal compliance and distensibility measured by EndoFlip 
• 
Interval change in mRNA transcriptome profile (esophageal tissue), Th2 phenotype 
(peripheral blood), blood eosinophilia 
• 
Change in the Eosinophilic Esophagitis Quality of Life Score from baseline to the end of 
treatment 
5.4 
Statistical Methods 
5.4.1 Analysis Populations 
An Intent to Treat population (ITTP) will be used as the primary analysis population.  This will 
include all patients that were enrolled in the study. 
A Per Protocol population (PPP) will be used as a sensitivity analysis population.  This will 
include all patients that did not have a major protocol violation. 

 
 
 
 
 
 
19 
5.4.2 Demographics and Baseline Characteristics Analysis 
Demographic and baseline characteristics will be described descriptively.  For continuous 
(including age, height, weight, and maximum Esophageal Eosinophil Count), means, standard 
deviations, medians, and ranges and for categorical (including race, ethnicity, medical history) 
frequency counts and percentages. 
All individual subject demographic and baseline characteristic data will be listed. 
5.4.3 Efficacy Analysis 
The efficacy analysis will focus on changes from baseline measure to follow-up measures.   
5.4.3.1 Primary Efficacy Analysis 
The primary statistical efficacy endpoint will be tested using a Paired T-test on the change in 
peak eosinophil counts on esophageal biopsies between 1st and 2nd endoscopy after food 
introduction in the same patient. 
If peak eosinophil counts do not satisfy the assumption of normality, instead the Wilcoxon 
Signed-Rank test will be used for the primary. 
5.4.3.2 Descriptive analysis 
Descriptive statistics will be presented by time point, and changes from baseline.  Tables will use 
means, standard deviations, medians, and ranges for continuous variables and frequency counts 
and percentages for the categorical variables.  Graphs will use box plots for continuous variables, 
and barplots for categorical variables. 
All individual subject data will be listed. 
Biostatistical core of Westat will help with the analysis. 
5.4.3.3 Univariate testing 
For measures with multiple time points, Paired statistical tests will be used with Baseline being 
compared to the other time points.  Specifically, the statistical method will be the most 
appropriate of paired T-test, Wilcoxon Sign-Rank, or McNemar’s tests.   
5.4.3.4 Statistical Modeling 
Modeling using categorical time points as the explanatory variable will be conducted with 
baseline as the reference category.  The model will be estimated using generalized estimating 
equations with a covariance structure assumed for time points from the same subject.  The 
appropriate distribution and covariance structure will be selected based on the data. 
5.4.3.5 Operationalization of Variables 
Distribution of the continuous outcomes will be evaluated using density and histograms. 
Transformation and categorization of some of these continuous variables will be performed wherever 
deemed more appropriate.   
Re-categorization of categorical variables will be considered when appropriate. 
5.4.3.6 Eosinophilic Esophagitis Symptom Score 
Improvement in symptom scores will be defined as a decrease in total symptom scores of two or 

 
 
 
 
 
 
20 
more from baseline to end of treatment. Subjects will be categorized based on whether they 
improved their symptoms. Subjects who improved their symptom scores were considered as 
responders and patients who did not improve their symptom scores were considered as non-
responders.  
 
The responses will be divided into three categories as suggested:  Poor <30% improvement, good 
30-70% improvement and excellent >70% improvement from baseline. 
 
5.4.3.7 Vital Signs 
The analysis of vital signs will focus on the incidence of clinically relevant abnormalities.  
 
5.4.4 Pharmacokinetic Analysis 
Not applicable, no pharmacokinetic assessments will be performed during this study. 
5.4.5 Safety Analysis 
All AEs will be coded by system organ class and preferred term using MedDRA. 
Treatment-emergent AEs (TEAEs) will be defined as any AEs, regardless of relationship to study 
drug, which occur during AE collection period of study drug or any event already present that worsens 
in either intensity or relationship to study drug following exposure to the dupilumab. If relationship 
information is missing, the TEAE will be considered drug related.  
An overall summary of TEAEs will be provided showing the number and percentage of subjects in 
each treatment group with any TEAE, any potentially drug related TEAE, any severe TEAE, any 
serious TEAE, any TEAE leading to discontinuation, and any TEAE leading to death. The number of 
events will also be presented.  
The number of AEs as well as the number and percentage of subjects who experienced at least one 
AE will be summarized by system organ class, preferred term, and time period. The incidence of the 
following events will be summarized: 
• TEAEs: incidence, severity, and duration. 
• Potentially drug related TEAEs 
• Discontinuations due to TEAEs 
• Physical examinations, and vital signs  
• SAEs 
• Potentially drug-related SAEs 
In addition, TEAEs will be summarized by relationship to study drug and by severity. If a subject has 
more than one occurrence of the same TEAE with different severities or relationship to study drug, 
then the TEAE will be assigned to the highest severity category and/or most related relationship 
category. If the intensity or relationship is missing, then the ‘worst case’ will be assumed (i.e., severe 
for intensity and drug-related for relationship). 
Time period of an AE will be determined based on the start time of the AE. 

 
 
 
 
 
 
21 
5.5 
Significance level and alpha allocation 
The significance level for all statistical testing in this study will be 0.05, and the alpha of 0.05 will 
all be allocated entirely to the primary efficacy endpoint.  All other statistical testing will be 
considered exploratory. 
5.6 
Sample Size and Power 
In the phase 2 clinical trial, 67% of the active treated with dupilumab had less 6 eosinophils per 
high power field compared to zero in the placebo group.11 In phase 3 trial, 59.5% of the 
dupilumab had less 6 eos/hpf and only 5% of the placebo treated group had less than 6 
eos/hpf.36, 37 
Therefore, we would assume 64% efficacy rate (average between the 2 studies) from the initial 
enrollment allowing 19 evaluable subjects.  A sample size of 20 with alpha of 0.05 and power 
80% would allow detection of difference in eosinophil count of 11 (effect size of 0.7 based on 15 
eosinophils/high power field being abnormal). 
  
5.7 
Interim Analysis 
No interim analysis is planned. 

 
 
 
 
 
 
22 
6 
STUDY MEDICATION (STUDY DEVICE OR OTHER STUDY INTERVENTION) 
6.1 
Description 
Dupilumab, an interleukin-4 receptor alpha antagonist, is a human monoclonal antibody of the 
IgG4 subclass that binds to the IL-4Rα subunit and inhibits IL-4 and IL-13 signaling. Dupilumab 
has an approximate molecular weight of 147 kDa.  
Dupilumab is produced by recombinant DNA technology in Chinese Hamster Ovary cell 
suspension culture.  
DUPIXENT (dupilumab) Injection is supplied as a sterile, preservative-free, clear to slightly 
opalescent, colorless to pale yellow solution for subcutaneous injection. DUPIXENT is provided 
as either a single-dose pre-filled syringe with needle shield or a single dose pre-filled pen in a 
siliconized Type-1 clear glass syringe. The needle cap is not made with natural rubber 
latex.Available dupilumab dosing: 
• 
Injection: 300 mg/2 mL solution in a single-dose pre-filled syringe with needle shield.  
• 
Injection: 200 mg/1.14 mL solution in a single-dose pre-filled syringe with needle shield.  
• 
Injection: 100 mg/0.67 mL solution in a singled-dose pre-filled syringe with needle shield 
• 
Injection: 300 mg/2 mL solution in a single-dose pre-filled pen.  
• 
Injection: 200 mg/1.14 mL solution in a single-dose pre-filled pen.  
Pre-filled pen will be used in adults and pediatric patients aged 12 and older and the pre-filled 
syringe will be used for adults and pediatrics patients aged 6 years and older.  
6.1.1 Labeling 
Description of product label 
6.1.2 Dosing 
Dosing will be done based on current doses in phase 3 clinical trials for EoE.  The dose will not 
be adjusted based on changes in weight during the study protocol.  
Dupilumab Dosing Scale: per the current Eosinophilic Esophagitis trials (R668-EE-1877 
and R668-EE-1774) and approved dosage for 12 yo > 40 kg:  
 
 
Weight 
>12 years of age 
> 40 kg 
300 mg SQ weekly 
 
30-39.9 kg 
300 mg SQ Q2W 
 
15-29.9 kg 
200 mg SQ Q2W 
6-11 years of age 
10-14.9 kg 
100 mg SQ Q2W 
 
> 15-29.9 kg 
200 mg SQ Q2W 
 
≥ 30-60 kg 
300 mg SQ Q2W 
 
≥ 60.1 kg 
300 mg SQ Q2W 

 
 
 
 
 
 
23 
 
6.1.3 Treatment Compliance and Adherence 
It is the Investigators’ responsibility to ensure that subjects are correctly instructed on how to take 
their study medication. Records of study medication used and intervals between visits will be kept 
during the study.  Subjects will be asked to return their unused medication (box(es)) when they come 
back for their study visits. All unused medication (boxes) should be returned at each study visit and 
the end of the study. The study drug will be dispensed by the Investigator, or by a qualified individual 
under the Investigator’s supervision.  
 
At each visit, prior to dispensing trial medication, previously dispensed trial medication will be 
retrieved by the Investigator and compliance assessed. A compliance of > 80% over the treatment 
period is sought. Subjects exhibiting poor compliance as assessed by counts and response to the 
question “Did you take your dupilumab regularly?” will be counseled on the importance of good 
compliance to the study dosing regimen. 
 
Non-compliance is defined as taking less than 80% of trial medication during any evaluation period 
(visit to visit). Subjects who are persistently non-compliant may be withdrawn from the study. 
 
6.1.4 Drug Accountability 
All supplies of dupilumab will be accounted for in accordance with GCP. There will be an individual 
study drug accountability record for each subject and the Investigator will maintain accurate records 
of the disposition of all trial medication supplies received during the study. These records will include 
the amounts and dates that clinical drug supplies were received, dispensed to the subject, returned 
by the subject, and returned to the Investigator or destroyed on site.  The unused dupilumab will be 
returned on subsequent study visits.  The excessive and used study drug will be destroyed by The 
Children’s Hospital of Philadelphia Research Pharmacy using standard protocols.  The research 
pharmacist will provide a corresponding certificate of destruction. 
 

 
 
 
 
 
 
24 
7 
SAFETY MANAGEMENT 
7.1 
Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
7.2 
Adverse Event Reporting 
Unanticipated problems related to the research involving risks to subjects or others that occur 
during this study (including SAEs) will be reported to the IRB in accordance with CHOP IRB 
SOP 408: Unanticipated Problems Involving Risks to Subjects. AEs that do not meet prompt 
reporting requirements will be summarized in narrative or other format and submitted to the IRB 
at the time of continuing review (if continuing reviews are required) or will be tracked and 
documented internally by the study team but not submitted to the IRB (if continuing reviews are 
not required).  
7.3 
Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a subject who has received an 
intervention (drug, biologic, or other intervention).  The occurrence does not necessarily have to 
have a causal relationship with the treatment.  An AE can therefore be any unfavorable or 
unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product, whether or not considered related to 
the medicinal product. 
All AEs (including serious AEs) will be noted in the study records and on the case report form 
with a full description including the nature, date and time of onset, determination of non-serious 
versus serious, intensity (mild, moderate, severe), duration, causality, and outcome of the event. 
The severity of AEs will be graded according to the following scale: 
 
Mild: Does not interfere in a significant manner with the patient’s normal functioning level. It 
may be an annoyance. Prescription drugs are not ordinarily needed for relief of symptoms but 
may be given because of personality of the patient. 
 
Moderate: Produces some impairment of functioning but is not hazardous to health. It is 
uncomfortable or an embarrassment. Treatment for symptoms may be needed. 
 
Severe: Produces significant impairment of functioning or incapacitation and is a definite hazard 
to the patient’s health. Treatment for symptom may be given and/or patient hospitalized. 
 
Injection Site Reactions 
The severity of injection site reactions will be graded according to the following scale (semi-
colon indicates “or” within description of grade: 
 
Mild: Pain that does not interfere with activity; mild discomfort to touch; <5 cm of erythema or 
induration that does not interfere with activity 
 

 
 
 
 
 
 
25 
Moderate: Pain that requires repeated use of non-narcotic pain reliever >24 hours or interferes 
with activity; discomfort with movement; 5.1 cm to 10 cm erythema or induration or induration 
that interferes with activity 
 
Severe: Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; >10 cm erythema or induration; prevents daily activity; requires 
emergency room visit or hospitalization; necrosis or exfoliative dermatitis 
 
7.4 
Causality 
The investigator must provide causality assessment as to whether or not there is a reasonable 
possibility that the drug caused the AE, based on evidence or facts, his/her clinical judgment, 
and the following definitions. The causality assessment must be made based on the available 
information and can be updated as new information becomes available. 
 
The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset versus time drug was administered 
• Nature of the reactions: immediate versus long term 
• Clinical and pathological features of the events 
• Existing information about the drug and same class of drugs 
• Concomitant medications 
• Underlying and concurrent illnesses 
• Response to dechallenge (drug discontinuation) or dose reduction 
• Response to rechallenge (re-introduction of the drug) or dose increase, when applicable 
• Patient’s medical and social history 
 
Causality to the study drug (including study drug administration): 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
state (e.g., disease under study, concurrent diseases, concomitant medications), or 
other external factors. 
 
Or 
 
− The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its class of drugs, or is predicted 
by known pharmacology. 
 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(e.g., disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
 
Causality to the study conduct (protocol-specified procedure): 
 

 
 
 
 
 
 
26 
• Related: 
− The AE follows a reasonable temporal sequence from a protocol-specified 
procedure, and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical state (e.g., disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
 
• Not Related: 
− The AE does not follow a reasonable sequence from a protocol-specified procedure, 
or can be reasonably explained by the nature of the reaction, patient’s clinical state 
(e.g., disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
 
7.5 
Definition of a Serious Adverse Event (SAE) 
An SAE is any adverse drug experience occurring at any dose that results in any of the 
following outcomes:  
• 
death, 
• 
a life-threatening event (at risk of death at the time of the event),  
• 
requires inpatient hospitalization or prolongation of existing hospitalization, 
• 
a persistent or significant disability/incapacity, or 
• 
a congenital anomaly/birth defect in the offspring of a subject.   
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug event when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
A distinction should be drawn between serious and severe AEs.  A severe AE is a major event 
of its type.  A severe AE does not necessarily need to be considered serious.  For example, 
nausea which persists for several hours may be considered severe nausea but would not be an 
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 an SAE.  
7.5.1 Relationship of SAE to study drug or other intervention 
The relationship of each SAE to the study intervention should be characterized using one of the 
following terms in accordance with CHOP IRB Guidelines: definitely, probably, possibly, 
unlikely, or unrelated.  
7.6 
IRB/IEC Notification of SAEs and Other Unanticipated Problems 
The Investigator will promptly notify the IRB of all on-site unanticipated, serious Adverse Events 
that are related to the research activity. Other unanticipated problems related to the research 
involving risk to subjects or others will also be reported promptly. Written reports will be filed 
using the eIRB system and in accordance with the timeline below. External SAEs that are both 
unexpected and related to the study intervention will be reported promptly after the investigator 
receives the report.   

 
 
 
 
 
 
27 
Type of Unanticipated 
Problem 
Initial Notification  
(Phone, Email, Fax) 
Written Report 
Internal (on-site) SAEs 
Death or Life 
Threatening  
24 hours 
Within 2 calendar days 
Internal (on-site) SAEs 
All other SAEs 
7 days 
Within 7 business days 
Unanticipated Problems 
Related to Research 
7 days  
Within 7 business days 
All other AEs 
N/A 
Brief Summary of important 
AEs may be reported at time 
of continuing review 
7.6.1 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that 
changes the investigator’s assessment of the event, a follow-up report including all relevant new 
or reassessed information (e.g., concomitant medication, medical history) should be submitted 
to the IRB. The investigator is responsible for ensuring that all SAE are followed until either 
resolved or stable.  

 
 
 
 
 
 
28 
7.7 STUDY ADMINISTRATION 
7.7.1 Treatment Assignment Methods 
7.7.2 Randomization 
Not applicable, all patients are receiving active therapy 
7.7.3 Blinding 
Not applicable, all patients are receiving active therapy 
7.8 
Data Collection and Management 
An eCRF will be used for the current study, and a data management plan will be prepared by the 
BDMC (Biostatistics and Data management Core) at CHOP managed by Westat.  The data will be 
entered in REDCap (prepared by Westat). 
 
Previous and concomitant medications will be coded using the latest available World Health 
Organization (WHO) Drug Reference Dictionary. Coexistent diseases and AEs will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA). 
 
When the database has been declared to be complete and accurate, the database will be locked. 
Any changes to the database after that time can only be made by written agreement between the 
investigator and the Westat BioStat unit. 
 
7.9 
Confidentiality 
No identifiable data will be used for future study without first obtaining IRB approval or 
determination of exemption. The investigator will obtain a data use agreement between the 
provider (the PI) of the data and any recipient researchers (including others at CHOP) before 
sharing a limited dataset (PHI limited to dates and zip codes).  
7.10 Regulatory and Ethical Considerations 
7.10.1 Data and Safety Monitoring Plan 
The principal investigator (PI) will monitor adverse events and other safety concerns during the 
study.  As the drug is approved for this age group and has been studied in this indication, little 
new adverse events are expected.   The main novel adverse event will be with food introduction 
while on dupilumab.  The symptoms and side effects will be monitored at regular study visits for 
worsening EoE symptoms.  In addition, the endoscopies at week 12 after the introduction will 
examine if active disease has returned and the food introduction will be adjusted. 
The PI will ensure the accuracy, security, and validity of the data via oversight of data storage, 
integrity, and laboratory methodology including statistical analysis. The PI will provide oversight 
of study personnel to ensure the safety of enrolled subjects by enforcing the protections and 
safeguards outlined in the protocol.  

 
 
 
 
 
 
29 
7.10.2 Risk Assessment 
7.10.2.1 Risks from Upper Endoscopy and Biopsy. 
The safety of multiple biopsies is supported by studies on adult patients with Barrett’s esophagus 
that have shown that multiple esophageal biopsies (as many as 35 to 120 esophageal biopsies 
in an individual patient) do not produce esophageal perforation or bleeding when performed by 
an experienced team of physicians, nurses, and technicians38.  In addition, a recent NIH study 
demonstrated that obtaining multiple mucosal biopsies for research purposes during elective 
endoscopy is well-tolerated and appears to have no more than minimal risk without appreciably 
increasing the risk of otherwise routine endoscopy39. Importantly, there was no statistically 
significant association between the number of biopsies, type of procedure, anatomic location of 
research biopsies, endoscopist, or the use of nonsteroidal anti-inflammatory drugs and the risk of 
complications. 
The incidence of perforation associated with upper endoscopy was recently reviewed in an 11-
year retrospective study at CHOP. A total of 21,345 esophagogastroduodenoscopy (EGD) were 
performed between February 1998 and November 2008 including patients with esophageal 
strictures or crepe-paper esophagus. Three perforations occurred with EGD (0.02%, 95% CI 0-
0.04%), and 2 with colonoscopy (0.04%, 95% CI 0-0.11%). Two of the three EGD-related 
perforations occurred after therapeutic EGD (foreign body removal, and dilatation of a proximal 
esophageal stricture and esophageal web removal), for an incidence of 0.18% (95% CI 0-0.47%). 
None of the EGD-related perforations was the result of esophageal mucosal biopsies.  The 
presence of crepe-paper esophagus or strictures does not increase the risk for EGD-related 
perforations based on this review, thus these patients were not excluded from our proposed 
cohort.  Identified risk factors for perforation on diagnostic (non-therapeutic) endoscopy were 
Crohn’s disease (2 colonoscopy perforations) and severe hemorrhagic gastritis (1 EGD 
perforation of the stomach). The incidence of perforation associated with pediatric gastrointestinal 
endoscopy performed by pediatric gastroenterologists in this case series from CHOP was low 
and less than that previously reported in adults. Based upon this retrospective study, the 
estimated incidence of perforation from EGD at CHOP is 1 in 7,115 EGD procedures.40, 41  
There are standard risks from moderate intravenous sedation or general anesthesia for  research 
biopsy.  To minimize the risks, all anesthesia will be done by pediatric anesthesiologist. For the 
intravenous sedation, the risk of assisted ventilation is 0.1-0.2% and no patients have required 
intubation and no history of permanent injury based on current literature. For general anesthesia, 
the overall risk for a serious adverse event is 1/250,000. Total adverse events with nausea and 
vomiting being the most common are seen in 1/29 cases42-44.    
Since the EGD procedure with biopsy is conducted under conscious sedation only, this needs to 
be considered for the total risk assessment. The investigative team considers the overall risk of 
the single research EGD procedure with biopsy under conscious sedation to be at most a minor 
increase above minimal risk45.   
7.10.2.2 Endoscopies after food introduction 
For EoE, patients have standard care of endoscopies when foods are reintroduced into the diet.   
Routinely, patients have endoscopies 3-4 months after adding a new food into the diet and this is 
considered best practice.  Therefore, it is not uncommon that patients have 3-4 standard of care 
(SOC) upper endoscopy with biopsies a year when food(s) are introduced into the diet.  Patients 
in this study will have endoscopies that are no different in frequency than SOC endoscopies when 
foods are introduced into their diet. 

 
 
 
 
 
 
30 
Therefore, only the first endoscopy is research.  The remaining endoscopies with biopsies are 
standard of care. 
7.10.2.3 Risks from food introduction 
The main risk from food introduction is exacerbation of Eosinophilic Esophagitis symptoms.  
Subjects will be monitored one week by phone for increasing symptoms and study visits for 
worsening symptoms by validated EoE questionnaires.  In addition, the other risk is worsening 
esophageal histology and possible long-term fibrosis with untreated disease.  Therefore, we 
monitor for worsening disease at 12 weeks after food introduction by upper endoscopy with 
biopsy.  
7.10.2.4 Risk from dupilumab 
Dupilumab is approved for asthma and atopic dermatitis at this age at Q2 week interval.  The 
dosing from both Q1 and Q2 week were similar in atopic dermatitis pivot trial.46    
Adverse Events (AE) 
 
Placebo 
N=222 
Dupilumab 
QOW 
N=229 
Dupilumab 
QW 
N=218 
Any AE 
145 (63%) 
167 (73%) 
150 (69%) 
Injection 
reaction 
13 (6%) 
19 (8%) 
41(19%) 
Infections 
63(28%) 
80(35%) 
74(34%) 
     Conjunctivitis 
2(1%) 
12(5%) 
7(3%) 
Headache 
13 (6%) 
21 (9%) 
11(5%) 
The adverse event profile was from the pediatric clinical trials show a low AE rate: 
For pediatric asthma 
Adverse Reaction 
 
Dupixent 200 mg Q2W + SOC 
N=779 
Dupixent 300 mg Q2W + SOC 
N=788 
Placebo 
N=792 
Injection site reactions 
111 (14) 
144 (18) 
50 (6) 
Oropharyngeal pain 
13 (2) 
19 (2) 
7 (1) 
Eosinophilia 
17 (2) 
16 (2) 
2 (<1) 
For pediatric atopic dermatitis: 
Adverse Reaction 
 
DUPIXENT 200 mg or 300 mg 
Q2W 
(n=82) 
PLACEBO  
(n=85) 
Conjunctivitis 
10% 
5% 
Injection site reaction 
9% 
4% 
Gastroenteritis viral 
4% 
1% 
Pharyngitis streptococcal 
2% 
0% 
Viral upper respiratory tract 
infection 
2% 
1% 
Bronchitis 
2% 
0% 
Sinusitis bacterial 
2% 
0% 
Fatigue 
2% 
0% 

 
 
 
 
 
 
31 
Oropharyngeal pain 
2% 
1% 
Nausea 
2% 
1% 
Abdominal pain upper 
2% 
1% 
Ligament sprain 
2% 
0% 
Procedural pain 
2% 
0% 
For the concern of Qweek vs Q2week dosing as the study will be using Qweek dosing instead 
of Q2 week approved dosing.  Both dupilumab 300 mg QW and Q2W have a well understood 
and favorable safety profile. Approximately 2500 atopic dermatitis patients were exposed to 
dupilumab in clinical trials; 645 atopic dermatitis patients have been exposed to 300 mg QW for 
≥364 days, and 58 have been exposed to 300 mg Q2W for ≥364 days as of the 27 April 2016 
biologics license application cut-off. In completed/unblinded Phase 2/3 studies of dupilumab in 
asthma patients (as of 30 September 2017), 2649 asthma patients were exposed to dupilumab; 
1035 of these patients have been exposed to 300 mg Q2W for ≥1 year, 662 have been exposed 
for ≥1.5 years, and 473 have been exposed for ≥2 years.  
From the Dupilumab investigator brochure-AD clinical trials comparing Q2 week to Qw showed 
similar AE rates: 
 
Overall, a higher incidence of injection site reactions has been observed in the dupilumab-
treated subjects, consistent with the SC injection of a protein biologic. Most injection site 
reactions were mild to moderate in intensity, and less than 2% were severe or led to treatment 
discontinuation. The proportion of patients experiencing injection site reactions diminished over 
time during the treatment period.  
The only known adverse event that has been seen is conjunctivitis, allergic conjunctivitis, 
bacterial conjunctivitis, blepharitis, dry eye, eye pruritus, herpes simplex (primarily 
mucocutaneous in nature), and oral herpes but only for the atopic dermatitis indication. These 
eye-related disorders and mucocutaneous herpes infections appear to be atopic dermatitis 
specific, as no increase in incidence of these events has been observed in clinical studies of 
other indications including EoE. Most events were mild in intensity and transient in nature and 
did not necessitate treatment discontinuation.  

 
 
 
 
 
 
32 
In the 52-week phase 3 clinical trial for EoE, 81 pts were randomized in Part A 1:1 to dupilumab 
(42) or placebo(39) for 24 weeks; 77 pts continued into Part C to dupilumab for a further 28 
weeks (40 from dupilumab/dupilumab, 37 from placebo/placebo). The most common treatment-
emergent adverse events for dupilumab/dupilumab arm and placebo/dupilumab arm were 
injection-site reactions (10.0% and 21.6%) and injection site erythema (10.0% and 13.5%). In 
part B of the phase 3 clinical trial, patients were randomized 1:1:1 to placebo, q weekly or q2 
weekly dosing with 115 patients in each arm.  There were no significant differences in adverse 
event rates. The overall rates of treatment-emergent adverse events were similar for 
dupilumab/placebo (83.8%/70.5%), the most common being injection-site reactions (MedDRA 
High-Level Term, 37.5%/33.3%).11, 12   
The dosing from the 52 weeks clinical trial for EoE showed no novel adverse events compared 
to the adverse event for asthma or atopic dermatitis.  There were lower rates of conjunctivitis in 
the EoE clinical trial compared to the atopic dermatitis clinical trial and similar rate to the asthma 
clinical trial. 
To summarize, the most common risks that have identified in pediatric trials of dupilumab are 
injection site reaction, and conjunctivitis and there are no significant differences between Qweek 
and Q2week dosing.  
It is also not predicted to be any difference in adverse events between patients 6-12 with 
asthma, atopic dermatitis or EoE based on  
1) No difference was detected in subjects > 12 years of age in published phase 3 
trials in asthma, atopic dermatitis and EoE 
2) No difference in adverse events was seen in our patients > 6 years of age treated 
for asthma or atopic dermatitis with or without Eosinophilic Esophagitis 
3) There are no biologic reasons to predict an increased risk of adverse events in 
patients with EoE at any age.  
7.10.2.5 Risk from blood draws 
The risks associated with drawing blood include discomfort, bleeding, bruising, or swelling 
where the needle is inserted, local infection, and, in rare cases, syncope. A local skin anesthetic 
(i.e., topical lidocaine/prilocaine cream) may be placed on the skin before the blood draw to 
reduce the pain of the stick. Side effects from this agent (mainly skin rash) may occur, including 
allergic reactions. The 
7.10.2.6 Risk for Research laboratories 
The risk from research laboratories are minimal.  We are not collecting genetic data.  We are 
only collecting lymphocyte function, expression, and eosinophil expression.  
7.10.2.7 Risk from Questionnaires: 
There is a possibility that the participant and/or parent/legal guardian too personal.  A participant 
and/or parent/legal guardian may refuse to answer any questions that make them 
uncomfortable. There is also a possibility that answers may be read by others; however, the 
participants’ records are carefully protected so this is very unlikely.  

 
 
 
 
 
 
33 
7.10.3 Potential Benefits of Trial Participation 
Potential benefits for the subject include clinical and histologic improvement with the use of 
dupilumab.  In addition, subjects may be able to add additional foods into their diet with 
improvement in quality of life, and nutritional status.  
In the phase 2 clinical trial, 65.2% of active treated patients had less than 6 eosinophils per high 
power field compared to zero in the placebo group11. In the phase 3 clinical trial of dupilumab for 
EoE, at Week 24 endpoint, 58.8% of dupilumab- vs 6.3% placebo-treated patients achieved 
histological remission of less 6 eosinophils per hpf(P<0.0001).12  Therefore, we would assume 
that over 50% will respond in the initial screening phase and benefit from dupilumab.  In the 
previous EoE clinical trials, the patients were not allowed to add new foods into their diet.  This 
proposed clinical trial will address an important family question and goal of adding foods back 
into their diet.  In addition, patients’ nutritional issue will improve as foods are added into their 
diet and patients benefit from improved quality of life. 
7.10.4 Risk-Benefit Assessment 
All subjects will have active therapy and therefore the risks are from three inventions: 
endoscopy, food introduction and dupilumab compared to the benefit of expansion of the foods 
into the diet are lower than the benefit of improved quality of life and nutritional status. The risk 
from endoscopy which is identical to standard of care endoscopy with food introduction is 
equivalent to SOC. The risk of food introduction is minimal and will be monitor closely by repeat 
clinical visits and endoscopy to ensure patient safety. The assumption of expanded diet will 
enhance nutritional status of patients and improve their quality of life.   Dupilumab has low 
adverse event profile with minimal serious side effects.  Therefore, the benefit of the study 
(adding new foods) significantly outweighs the risk of endoscopy, food introduction and 
dupilumab.  
7.11 Recruitment Strategy 
Subjects will be recruited from Children’s Hospital of Philadelphia Eosinophilic Esophagitis 
Program.  The program has over 3000 subjects in its clinical data base. All the information that 
is needed captured as routine standard of care.   
7.12 Informed Consent/Assent and HIPAA Authorization 
The Investigator is responsible for and will obtain informed consent from each subject in the study, 
in accordance with the ICH-GCP Guidelines, the Declaration of Helsinki, and applicable regulatory 
requirements. 
 
Subjects will be informed of the nature of the study, its aim, possible risks and restrictions, its 
duration, and the compensation that they might receive. The protocol will be explained during a 
meeting prior to study enrollment, and each subject must be informed that participation in the study 
is voluntary and that he/she may withdraw from the study at any time. The subject should read the 
ICF before signing and dating it and a copy of the signed document should be given to the subject. 
No subject can enter the study before his/her informed consent has been obtained. Children if able  
will sign assent. The parents or legal representative(s) of all children and adolescents regardless of 

 
 
 
 
 
 
34 
age must also sign the ICF.  
 
The consent form may need to be revised during the study should important new information become 
available that may be relevant to the safety of the subject. In this instance approval should always 
be given by the CHOP IRB and existing subjects informed of the changes and re-consented. This is 
documented in the same way as previously described. 
 
The Investigator should keep a copy of the consent of the subject, inform the subject’s primary 
physician about participation in the clinical study. 
 
The study physician will be available to explain the medical aspects of the study, risks and benefits 
of the intervention, and answer questions during the consent process 
 
7.12.1 Screening  
Patients will be screen through chart review for diagnosis of Eosinophilic Esophagitis and foods 
to be introduced.  Patients will be approached during Allergy, Gastroenterology or Center for 
Pediatric Eosinophilic Disease Clinics. 
7.12.2 Main Study 
The consent will be completed in person to allow sufficient time to review the consent and 
answer all questions and concerns.   Subjects and their families will also be emailed the consent 
prior to screening visit if requested by the family.  All consent procedure will follow CHOP SOP 
and Division of Allergy and Immunology Research SOP.  Obtaining and reviewing consents will 
be done in separate visits not part of standard of care visits.  The visits will be done in the 
dedicated Allergy research room. 
7.12.3 Consent/HIPAA Authorization Plan for Subjects Who Reach Age of Majority 
At the next study visit after the subject turns 18 (age of majority), the subject will review the 
written consent/HIPPA authorization for their continued participation in the trial. The subject will 
continue in the study if they sign the consent. 
7.13 Payment to Subjects/Families 
7.13.1 Reimbursement for travel, parking, and meals 
Subjects will be paid $35 per visit for travel, parking, and time.  Subjects will be $125 for each 
endoscopy due to extended time.  
8 
PUBLICATION 
We will publish the data upon completion of the study and finalization of the data basis and 
statistical plans.  The data will be presented in national/international medical meetings and 
submitted for peer review publications. 
 

 
 
 
 
 
 
35 
9 
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