A Phase 3, Randomized, 3-Part Study to Investigate the Efficacy and Safety of Dupilumab in Adult and Adolescent Patients With Eosinophilic Esophagitis (EoE)
Phase: PHASE3
Conditions: Eosinophilic Esophagitis
Sponsor: Regeneron Pharmaceuticals

IND Number:  136142 
EudraCT number:  2018-000844-25 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A PHASE 3, RANDOMIZED, 3-PART STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF DUPILUMAB IN ADULT AND 
ADOLESCENT PATIENTS WITH EOSINOPHILIC ESOPHAGITIS 
Compound: 
Dupilumab 
Clinical Phase: 
3 
Protocol Number: 
R668-EE-1774 
Protocol Version: 
R668-EE-1774 Amendment 5 
Amendment 5 Date of Issue: 
See appended electronic signature page 
Amendment 4 Date of Issue: 
16 April 2020 
Amendment 3 Date of Issue: 
10 March 2020 
Amendment 2 Date of Issue: 
18 April 2019 
Amendment 1 Date of Issue: 
04 October 2018 
Original Date of Issue: 
21 June 2018 
Medical /Study Director: 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
. 
VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00
NCT Number:  NCT03633617

Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 2 of 113 
 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 5 
The purpose of this protocol amendment is to adjust the sample size for Part B based on the 
results of Part A of the study, and to add an additional database lock after all patients in Part A 
complete study week 52 of Part C. Other changes were made for clarification and consistency. 
The following table outlines the changes made to the protocol and the rationale.  
Description of Change 
Rationale 
Section Changed 
Decreased the required sample size for 
Part B from 345 patients to 210 
patients (70/arm) based on the sample 
size re-estimation for Part B, as 
previously outlined in Section 10.2 
Justification of Sample Size.  
 
This sample size re-
estimation for Part B 
was based on results 
from Part A of the 
study in which a larger 
treatment effect on the 
Dysphagia Symptom 
Questionnaire (DSQ) 
was observed than in a 
phase 2 study with 
budesonide, 
previously used for 
sample size 
estimation. 
Clinical Study Protocol Synopsis: 
Population, Statistical Plan 
Section 5.1 Study Description and Duration 
Figure 2 Study Design 
Section 6.1 Number of Patients Planned 
Section 7.5 Method of Treatment 
Assignment 
Section 10.2 Justification of Sample Size 
Added an additional database lock to 
occur after the last Part A patient has 
completed their week 52 visit of Part 
C, including patients who have 
terminated early in Part C.  
 
To provide safety and 
efficacy data for 
analyses of durability 
of treatment effect 
Section 10.4.9 Timing of Statistical Analysis 
Added a subgroup analysis of the co-
primary and secondary study variables 
in patients with previous swallowed 
topical corticosteroid use. 
 
To assess the 
treatment effects of 
dupilumab in a 
subgroup who 
received topical 
steroid therapy. 
Clinical Study Protocol Synopsis: 
Objective(s), Endpoint(s) 
Section 2.2 Secondary Objectives 
Section 4.2.2 Secondary Endpoints 
 
Revised the adverse events of special 
interest (AESIs) definitions and 
adverse drug reactions (ADRs) for the 
dupilumab clinical development 
program.  
 
For program 
consistency based on 
regulatory authority 
feedback and to align 
with the most recent 
Investigator’s 
Brochure. 
Section 3.2.3.2 Risks 
Section 9.4.3 Other Events that Require 
Accelerated Reporting to Sponsor 
Clarified that any additional analyses 
required to investigate the impact of 
COVID-19 on the safety evaluation 
will be specified in the SAP. 
To address guidance 
from the US and EU 
regarding the conduct 
of clinical trials during 
the COVID-19 
pandemic. 
Section 10.4.4 Safety Analysis 
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Clinical Study Protocol 
 
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Page 3 of 113 
 
CONFIDENTIAL 
Description of Change 
Rationale 
Section Changed 
Added the primary estimand for 
primary and key secondary endpoints 
and clarified the sensitivity analysis 
for co-primary endpoints including 
but not limited to the methods listed in 
protocol. 
 
To implement a 
concept estimand in 
the primary analysis 
approaches for the 
primary and key 
secondary endpoints 
based on ICH E9 (R1). 
Section 10.4.3.1 Primary Efficacy Analysis 
Table 4 Summary of Primary Estimand for 
Co-primary Endpoints  
Section 10.4.3.2.1 Analysis of Secondary 
Efficacy Endpoints in Part A and Part B 
Table 5 Summary of Primary Estimand for 
Key Secondary Endpoints  
Revised the Schedule of Events (SOE) 
to list TARC and Total IgE sample 
collection as separate rows, rather 
than listing in the same row with 
footnotes to clarify differences as 
before. 
 
For clarification only; 
there are no changes to 
sample collection. 
Table 1 Parts A and B Schedule of Events – 
Screening Period and Double-Blind 
Treatment Period 
Section 8.1.1.1 Footnotes for Table 1, 
footnote #17 (removed) 
Table 2 Table 2 Part C Schedule of Events – 
Extended Active Treatment Period 
Section 8.1.1.2 Footnotes for Table 2, 
footnote #14 (removed) 
Made minor clarifications and 
editorial corrections. 
For clarification. 
Throughout the document. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00

Clinical Study Protocol 
 
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Regeneron Pharmaceuticals, Inc. 
 
Page 4 of 113 
 
CONFIDENTIAL 
Amendment 4 
The purpose of this protocol amendment is to protect patient safety and data integrity during the 
COVID-19 pandemic by allowing for certain study procedures to occur at delayed time points 
and/or outside of the clinic environment. All temporary mechanisms utilized, and deviations 
from planned study procedures are to be documented as being related to COVID-19 and will 
remain in effect only for the duration of the public health emergency. The following table 
outlines the changes made to the protocol and the rationale.  
Description of Change 
Rationale 
Section Changed 
Added provisions allowing study 
procedures to occur at delayed 
timepoints and/or outside of the clinic 
environment. 
• 
Biopsy with endoscopies may be 
delayed for visit 11/week 24, visit 
19/week 52, early termination, 
and before initiating rescue 
treatment 
• 
At-home study drug dosing is 
permitted for all visits except for 
visit 3/day 1 and visit 11/week 24 
• 
If the endoscopy with biopsies 
cannot occur due to COVID-19 
restrictions, rescue treatment 
should be initiated without delay 
and these patients will be eligible 
to participate in Part C 
• 
Safety and laboratory procedures 
(vital signs, weight, PK/ADA 
sample collection, hematology 
and chemistry urine sample 
collection) may be delayed or 
occur at-home when possible 
• 
The patient-reported outcome 
questionnaires that are intended to 
be completed during clinic visits 
may be conducted via phone 
interviews after visit 3/day 1 
To protect 
patient safety 
and data 
integrity in 
the context of 
COVID-19 
restrictions. 
Clinical Study Protocol Synopsis: Study Design 
Section 3.2.3 Risk/Benefits of Participating in the 
Study 
Section 3.2.3.2 Risks 
Section 5.1 Study Description and Duration 
Section 5.1.1.3 Placebo-Controlled Double-Blind 
Treatment Period (24 Weeks) 
Section 6.2.3 Exclusion Criteria for Part C (the 
Extended Active Treatment Period), Criterion #5 
Section 7.3 Rescue Treatments 
Table 1 Parts A and B Schedule of Events – 
Screening Period and Double-Blind Treatment Period 
Table 2 Part C Schedule of Events – Extended Active 
Treatment Period 
Section 8.1 Schedule of Events 
Section 8.1.1.1 Footnotes for Table 1, footnote #5, 9, 
10, 11 (edited), footnote #6.a, 7.a, 13.a, 19 (added) 
Section 8.1.1.2 Footnotes for Table 2, footnote #3, 6, 
7, 8 (edited), footnote #2.a, 4.a, 15 (added) 
Section 8.1.1.3 Footnotes for Table 3, footnote #3, 4, 
5, 7.a (edited), footnote # 10 (added) 
Section 8.2.2.3 EoE Impact Questionnaire (EoE-IQ) 
Section 8.2.2.4 EoE Symptom Questionnaire 
Section 8.2.2.5 Patient Global Impression of Change 
(PGIC) 
Section 8.2.2.6 Patient Global Impression of Severity 
(PGIS) 
Section 8.2.2.7 Total Nasal Symptom Score (TNSS) 
Section 8.2.2.8 Standardized Rhinoconjunctivitis 
Quality of Life Questionnaire for ages 12+ 
[RQLQ(s)+12] 
Section 8.2.2.9 Juniper Asthma Control Questionnaire 
(ACQ) 
Section 8.2.2.10 Patient-Oriented Eczema Measure 
(POEM) 
Section 10.4.3.1 Primary Efficacy Analyses 
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Clinical Study Protocol 
 
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Page 5 of 113 
 
CONFIDENTIAL 
Description of Change 
Rationale 
Section Changed 
Added a provision allowing patients to 
extend their current assigned dose 
regimen of study drug (Parts A/B 
and/or C) until the post-baseline 
esophageal biopsy procedure(s) are 
performed.  
 
This change is detailed in the 
Footnotes for the Schedule of Events. 
Additionally, the word 
“approximately” was added 
throughout the protocol for time 
points related to duration of treatment. 
To protect 
patient safety 
and data 
integrity in 
the context of 
COVID-19 
restrictions. 
Section 3.2.1 Rationale for Study Design 
Section 5.1 Study Description and Duration 
Section 5.1.1.3 Placebo-Controlled Double-Blind 
Treatment Period (24 Weeks) 
Section 5.1.2.3 Placebo-Controlled Double-Blind 
Treatment Period (24 Weeks) 
Section 5.1.3 Part C (28-Week Extended Active 
Treatment Period 
Table 1 Parts A and B Schedule of Events – 
Screening Period and Double-Blind Treatment Period 
Table 2 Part C Schedule of Events – Extended Active 
Treatment Period 
Section 8.1.1.1 Footnotes for Table 1, footnote #6a 
(added) 
Section 8.1.1.2 Footnotes for Table 2, footnote #4a 
(added) 
Section 10.4.3.1 Primary Efficacy Analyses 
 
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Regeneron Pharmaceuticals, Inc. 
 
Page 6 of 113 
 
CONFIDENTIAL 
Amendment 3 
The purpose of this amendment is to add transcriptome sequencing for analyzing RNA 
expression of eosinophilic esophagitis (EoE) and type 2 inflammation to the study secondary 
objectives and endpoints, and to add the European Quality of Life 5-dimension 3-level (EQ-5D-
3L) Questionnaire to collect general health status of EoE patients. Additionally, the Eosinophilic 
Esophagitis-Endoscopic Reference Score (EoE-EREFS) procedure for Part B patients was 
revised to allow for centralized reading and scoring. Other minor changes were made to align 
with regulatory authority feedback and for general clarification. The following table outlines the 
changes made to the protocol and the rationale.  
Study status as of Amendment 3: Part A enrollment complete and Part B enrollment ongoing.  
Change 
Rationale 
Section Changed 
Added endpoints for EoE and type 2 
inflammation transcriptome 
signatures to the study secondary 
objectives and endpoints (from 
samples collected as a part of the 
original study procedures).  
Transcriptome sequencing 
was added as an important 
indicator of disease activity. 
Clinical Study Protocol Synopsis: 
Objective(s), Endpoint(s), Procedures 
and Assessments 
Section 2.2 Secondary Objectives 
Section 4.2.2 Secondary Endpoints 
Section 8.2.6.1 EoE Diagnostic Panel 
and Type 2 Inflammation 
Transcriptomics (section added) 
Section 10.4.3.2.1 Analysis of 
Secondary Efficacy Endpoints in Part A 
and Part B 
Section 22 References 
Added the EQ-5D-3L Questionnaire 
for newly screened patients at the 
screening or baseline visit only. 
 
In order to collect general 
health status of EoE 
patients. 
Table 1: Parts A and B Schedule of 
Events – Screening Period and Double-
Blind Treatment Period 
Section 8.1.1.1 Footnotes for Table 1, 
footnote #18 (footnote added) 
Section 8.2.2.11 European Quality of 
Life 5-Dimensional Scale (EQ-5D) 
(section added) 
Section 22 References 
Revised the EoE-EREFS procedure 
for Part B enrolled patients to allow 
for centralized reading and scoring. 
 
To minimize inter-rater 
variability for this endpoint. 
Clinical Study Protocol Synopsis: 
Procedures and Assessments 
Section 8.1.1.1 Footnotes for Table 1, 
footnote #12  
Section 8.1.1.2 Footnotes for Table 2, 
footnote #9 
Section 8.1.1.3 Footnotes for Table 3, 
footnote #6 
Section 8.2.2.1 Endoscopy with EoE-
EREFS and Biopsies, and Photographs 
Section 10.4.3.2.1 Analysis of 
Secondary Efficacy Endpoints in Part A 
and Part B 
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Clinical Study Protocol 
 
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Page 7 of 113 
 
CONFIDENTIAL 
Change 
Rationale 
Section Changed 
Revised the adverse events of special 
interest (AESIs) definitions for the 
dupilumab clinical development 
program.  
For program consistency 
based on regulatory 
authority feedback. 
Section 9.4.3 Other Events that Require 
Accelerated Reporting to Sponsor 
Revised the visit window for visit 
11/week 24 and visit 19/week 52 to 
change ±7 days to +7 days. 
For clarification to ensure 
the full 14 days of 
Dysphagia Symptom 
Questionnaire (DSQ) diary 
entries are collected just 
prior to these visits. 
Table 1: Parts A and B Schedule of 
Events – Screening Period and Double-
Blind Treatment Period 
Table 2: Part C Schedule of Events – 
Extended Active Treatment Period 
Revised an existing secondary 
endpoint to state: Proportion of 
patients achieving peak esophageal 
intraepithelial eosinophil count of 
<15 eos/hpf at week 24 (previously 
stated ≤15 eos/hpf). 
To correct a typographical 
error and thus align with the 
inclusion criteria of 
≥15 eos/hpf.  
Clinical Study Protocol Synopsis: 
Endpoint(s) 
Section 4.2.2 Secondary Endpoints 
 
Clarified exclusion criterion #14 and 
prohibited medications to allow for 
one-time steroid use with the 
anesthetic preparation (not for EoE) 
used during the endoscopy 
procedures.  
For clarification. 
Section 6.2.2 Exclusion Criteria for 
Parts A and B, #14  
Section 7.7.1 Prohibited Medications 
and Procedures 
Clarified the requirement that all pre-
dosing procedures (including 
endoscopy with biopsy) at the 
scheduled visit 11/week 24 must 
occur prior to dosing with Part C / 
Extended Active Treatment study 
drug. 
For clarification. 
Section 8.1.1.2 Footnotes for Table 2, 
footnotes #1 and #4  
 
Clarified the assumption used for 
Part A sample size calculation. 
For clarification. 
Section 10.2 Justification of Sample 
Size 
Minor language changes were made 
to clarify the definition of 
hospitalization. 
For clarification. 
Section 9.3.2 Serious Adverse Event 
Section heading was updated to add 
to word circulating before 
biomarkers. 
For clarification. 
Section 8.2.6.2 Type 2 Inflammatory 
and Disease-Related Circulating 
Biomarkers 
 
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Page 8 of 113 
 
CONFIDENTIAL 
Amendment 2 
The following table outlines the changes made to the protocol and the affected sections: 
Change 
Section Changed 
Per Health Authority request, changed Part C from open-
label to a design with added placebo SC injections 
alternating with dupilumab 300 mg Q2W doses in order to 
mask the dosing regimen for Part B patients during this 
extended active treatment phase of the study. 
Clinical Study Protocol Synopsis – Objectives, Study 
Design, Study Duration, Treatment(s), Endpoint(s), 
Statistical Plan 
Section 3.2.1 Rationale for Study Design 
Section 3.2.3.1 Benefits 
Section 4.2.2 Secondary Endpoints 
Section 5.1 Study Description and Duration 
Figure 1 Study Flow Diagram 
Figure 2 Study Design 
Section 5.1.1.3 Placebo-Controlled, Double-Blind 
Treatment Period (24 Weeks) 
Section 5.1.2.3 Placebo-Controlled, Double-Blind 
Treatment Period (24 Weeks) 
Section 5.1.3 Part C (28-Week Extended Active 
Treatment Period) 
Section 5.2 Planned Interim Analysis 
Section 6.2.3 Exclusion Criteria for Part C (the 
Extended Active Treatment Period) 
Section 7.1 Investigational and Reference Treatments 
Section 7.3 Rescue Treatments 
Section 7.4.2 Study Drug Discontinuation 
Section 7.5 Method of Treatment Assignment 
Section 7.5.1 Blinding 
Section 7.6.1 Packaging, Labeling, and Storage 
Section 8.1 Schedule of Events 
Table 2 Part C Schedule of Events – Extended Active 
Treatment Period 
Section 10.3.1 Efficacy Analysis Sets 
Section 10.3.2 Safety Analysis Set 
Section 10.4.3.2.2 Analysis of Secondary Efficacy 
Endpoints in Part C 
Section 10.4.4.1 Adverse Events 
Section 10.4.4.3 Treatment Exposure 
Added a per protocol set to the defined efficacy analysis 
sets to assess the overall robustness of the analysis results. 
Added that any re-estimation of sample size for Part B 
will be documented in the Part B SAP before its database 
lock. If the re-estimated sample size requires an increase 
of the planned sample size in Part B by more than 86 total 
patients (25%), it will also be documented in a protocol 
amendment so as to inform Has, ECs, and investigators. 
 
Clinical Study Protocol Synopsis – Statistical Plan 
Section 6.1 Number of Patients Planned 
Section 10.2 Justification of Sample Size 
Section 10.3.1 Efficacy Analysis Sets 
Section 10.3.2 Safety Analysis Set 
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Page 9 of 113 
 
CONFIDENTIAL 
Change 
Section Changed 
Clarified safety analyses of the Part C extended active 
treatment period will only include patients who received 
at least 1 dose of Part C study drug. 
Added a substudy which may be performed at select sites 
and a secondary endpoint to the study for the endolumenal 
functional lumen imaging probe (EndoFLIP) procedure to 
measure esophageal distensibility during the 
esophagogastroscopy procedures at selected sites in 
approximately 150 adult patients. 
Clinical Study Protocol Synopsis – Procedures and 
Assessments, Endpoint(s) 
List of Abbreviations 
Section 4.2.2 Secondary Endpoints 
Table 1 Parts A and B Schedule of Events – Screening 
Period and Double-Blind Treatment Period 
Table 2 Part C Schedule of Events – Extended Active 
Treatment Period 
Table 3 Follow-up Period, Early Termination Visit, and 
Unscheduled Visit 
Section 8.1.1.1 Footnotes for Table 1, footnote 2c 
Section 8.1.1.2 Footnotes for Table 2, footnote 10 
Section 8.1.1.3 Footnotes for Table 3, footnote 7 
Section 8.2.2.1 Endoscopy with EoE-EREFS and 
Biopsies, and Photographs 
Section 22 References 
Added additional secondary endpoints for proportion of 
patients who receive rescue medications or procedures 
during the 24-week placebo-controlled treatment period 
and absolute change in EoE Stage Score from the 
EoEHSS from baseline to week 24. 
Clinical Study Protocol Synopsis – Endpoint(s) 
Section 4.2.2 Secondary Endpoints 
Made revisions to sections related to patient screening and 
eligibility criteria to: 
• 
clarify that baseline endoscopy with biopsy and 
EoE-EREFS do not need to be repeated for 
patients eligible for rescreening. 
• 
clarify the requirement that all patients required 
to initiate high-dose PPI therapy prior to baseline 
may change to a different approved PPI 
medication during the study and to clarify the 
requirement for duration of treatment with high-
dose PPI regimen prior to the baseline endoscopy 
to account for patients who present at the 
screening visit already using an acceptable PPI 
regimen. 
• 
specify that exclusion of patients because of 
bleeding disorders or esophageal varices will be 
based on the opinion of the investigator if the 
condition would put the patient at undue risk for 
significant complications from an endoscopy 
procedure. 
Clinical Study Protocol Synopsis – Treatment(s) 
Section 5.1.1.1 Screening (Up to 12 Weeks) 
Figure 3 Endoscopy/Biopsy Procedure Flow Diagram 
Section 6.2.1 Inclusion Criteria for Parts A and B, #2 
Section 6.2.2 Exclusion Criteria for Parts A and B, #8 
Section 7.2 Background Treatment 
Table 1 Parts A and B Schedule of Events – Screening 
Period and Double-Blind Treatment Period 
Section 8.1.1.1 Footnotes for Table 1, footnote 4 
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CONFIDENTIAL 
Change 
Section Changed 
Made the following changes to the Schedule of Events: 
• 
Added a column to the Schedule of Events 
specifying procedures for an Early Termination 
Visit that occurs during the 12-week safety 
follow-up period 
• 
Changed collection of blood samples for FBR 
and DNA and RNA extraction from mandatory 
to optional. 
• 
Changed the Visit Window for Visit 11 (from ±3 
days to ±7 days) for consistency with all other 
study visits requiring an endoscopy procedure. 
• 
Removed TARC analysis at Visit 8, Visit 12, and 
Visit 14 as well as removed Eotaxin-3 collection 
and analysis at Visit 5 
• 
Added respiratory rate to the list of vital signs to 
be collected pre/post dose.  
• 
Specified that the 21-day interval between visit 2 
and visit 3 may be extended for patients whose 
DSQ compliance does not meet eligibility 
criteria (at least 11 daily entries during the 14 
days immediately preceding the planned 
randomization/baseline date), as long as the total 
duration of the screening period does not exceed 
the 85-day maximum. 
• 
Added clarification for the collection of TNSS, 
POEM, ACQ-5 and RQLQ(S)+12 PROs. 
• 
Deleted reference to monthly visits from the 
Study Flow Diagram (Figure 1) for clarity. 
• 
Clarified the visit window for Self-
Administration of Study Drug at Home 
Section 5.1.1.1 Screening (Up to 12 Weeks) 
Figure 1 Study Flow Diagram  
Section 5.1.1.3 Placebo-Controlled Double-Blind 
Treatment Period (24 Weeks) 
Table 1 Parts A and B Schedule of Events – Screening 
Period and Double-Blind Treatment Period 
Table 2 Part C Schedule of Events – Extended Active 
Treatment Period 
Table 3 Follow-Up Period, Early Termination Visit, 
and Unscheduled Visit 
Section 8.1.1.1 Footnotes for Table 1, footnotes 6, 11, 
13, 17 
Section 8.1.1.2 Footnotes for Table 2, footnotes 3, 4, 8, 
11, 14 
Section 8.1.1.3 Footnotes for Table 3, footnote 5 
Section 8.2.3.1 Vital Signs 
Section 8.2.7 Future Biomedical Research (FBR) 
Serum/Plasma (Optional) 
Section 8.2.7.1 Genomics Substudy (Optional) 
Section 10.4.4.2 Other Safety 
 
Editorial changes were made throughout the protocol for 
further clarification, consistency, and completeness, and, 
if appropriate, correction. 
All references to the “study reference manual” have been 
replaced with 'study regulatory binders.’ 
Clinical Study Protocol Synopsis 
– Endpoints, 
Procedures and Assessments 
Section 4.2.2 Secondary Endpoints 
Section 5.1 Study Description and Duration 
Section 5.1.1.3 Placebo-Controlled Double-Blind 
Treatment Period (24 Weeks) 
Section 6.2.1  Inclusion Criteria for Parts A and B  
Section 7.5.1 Blinding 
Section 8.1.1.1  Footnotes for Table 1, footnote 15 
Section 8.2.2.1 Endoscopy with EoE-EREFS and 
Biopsies, and Photographs 
Section 8.2.2.2  Dysphagia Symptom Questionnaire 
(DSQ) - Patient-reported Outcome (PRO) 
Section 8.2.2.3  EoE Impact Questionnaire (EoE-IQ) 
Section 8.2.3.4  Electrocardiogram 
Section 8.2.3.5  Laboratory Testing 
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CONFIDENTIAL 
Change 
Section Changed 
Section 8.2.6 Pharmacodynamic and Exploratory 
Biomarker Procedures 
Section 9.4.1 Adverse Events 
Section 9.4.2 Serious Adverse Events 
Section 9.4.4 Reporting Adverse Events Leading to 
Withdrawal from the Study 
Section 10.4.4.1 Adverse Events 
Section 10.4.4.3 Treatment Exposure 
Section 10.4.6 Analysis of Anti-Drug Antibody Data 
 
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CONFIDENTIAL 
Amendment 1 
The following table outlines the changes made to the protocol and the affected sections: 
Change 
Section Changed 
Added an exclusion criterion:  known systemic 
hypersensitivity to dupilumab or the excipients of the drug 
product 
Section 6.2.2 Exclusion Criteria for Parts A and 
B, #34 (added) 
Section 6.2.3 Exclusion Criteria for Part C (the 
Open-Label Treatment Period), #6 (added) 
Exclusion Criterion # 26:  replaced serum creatinine 
threshold with estimated glomerular filtration rate (eGFR). 
Section 6.2.2 Exclusion Criteria for Parts A and 
B, #26 
Exclusion Criterion #27:  replaced the example for severe 
renal conditions of “patients on dialysis” with “severe 
nephrotic syndrome”. 
Section 6.2.2 Exclusion Criteria for Parts A and 
B, #27 
Exclusion Criterion #33:  Added clarification that the 
reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the patient based on Clinical Trial 
Facilitation Group guideline on contraception. 
Section 6.2.2 Exclusion Criteria for Parts A and 
B, #33 
Clarified criteria for resumption of treatment after study drug 
has been temporarily discontinued because of a severe 
laboratory abnormality.  
Section 7.4.2.2 Reasons for Temporary 
Discontinuation of Study Drug 
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Page 13 of 113 
 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 3, Randomized, 3-Part Study to Investigate the Efficacy and Safety of 
Dupilumab in Adult and Adolescent Patients with Eosinophilic Esophagitis 
(EoE) 
Site Location(s) 
Global 
Objective(s) 
Primary Objectives 
This study consists of three parts:  Part A and Part B are 24-week treatment, 
randomized, double-blind, placebo-controlled study phases and Part C is a 
28-week, extended active treatment phase that will enroll patients from Part A 
and Part B. 
The primary objectives by study part are: 
• 
Part A: To determine the treatment effect of dupilumab compared 
with placebo in adult and adolescent patients with EoE after 24 weeks 
of treatment as assessed by histological and clinical measures and to 
inform/confirm the final sample size determination for Part B. 
• 
Note:  Patients enrolled in Part A may not participate in Part B. 
• 
Part B: To demonstrate the efficacy of dupilumab treatment compared 
with placebo in adult and adolescent patients with EoE after 24 weeks 
of treatment as assessed by histological and clinical measures. 
• 
Part C: To assess the safety and efficacy of dupilumab treatment in 
adult and adolescent patients with EoE after up to 52 weeks of 
treatment as assessed by histological and clinical measures. 
Secondary Objectives 
• 
To evaluate the safety, tolerability, and immunogenicity of 
dupilumab treatment for up to 52 weeks in adult and adolescent 
patients with EoE 
• 
To explore the relationship between dupilumab concentration and 
responses in adult and adolescent patients with EoE, using 
descriptive analyses 
• 
To evaluate the effects of dupilumab on transcriptomic signatures 
associated with EoE and type 2 inflammation  
• 
To demonstrate the efficacy of dupilumab treatment compared to 
placebo after 24 weeks and 52 weeks of treatment in adult and 
adolescent patients with EoE who have previously received 
swallowed topical corticosteroids 
Study Design 
Part A 
Screening (Up to 12 Weeks) 
After obtaining informed consent/assent, patients will initially be assessed for 
study eligibility at visit 1. 
Study participants are required to have a conﬁrmed diagnosis of EoE which 
may be established either by a prior historical biopsy or by biopsies performed 
during the screening period. 
All patients meeting clinical and laboratory eligibility criteria will undergo 
endoscopy with biopsies at visit 2 to establish a baseline reference measure. For 
patients without a historical biopsy, the visit 2 biopsies will serve as both 
confirmation of EoE diagnosis and the baseline reference measure. All biopsies 
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performed during this study will be evaluated by pathologists at a central 
pathology laboratory who will be blinded to treatment assignment. 
After confirmation of EoE diagnosis, patients will be given an electronic diary 
(eDiary) to begin recording dysphagia symptoms on a daily basis. 
Randomization 
At the baseline visit (visit 3), patients who continue to meet eligibility criteria 
will enter the 24-week placebo-controlled, double-blind treatment period and 
will be randomized in a 1:1 ratio to dupilumab 300 mg once weekly (QW) or 
placebo administered subcutaneously (SC). 
Placebo-Controlled Double-Blind Treatment Period (24 Weeks) 
The co-primary endpoints will be assessed at week 24, one week after the last 
dose of study drug during the double-blind treatment period to inform/confirm 
the final sample size determination for Part B. 
At the end of the double-blind treatment visit (week 24), eligible patients in 
Part A may enter a 28-week extended active treatment period (Part C). Patients 
not participating in Part C will enter a 12-week follow-up period. 
Patients enrolled in Part A will not be eligible to participate in Part B. 
Part B 
Enrollment for Part B will begin immediately after the last patient is enrolled 
in Part A. 
Screening (Up to 12 Weeks) 
The screening procedures for Part B are identical to those described above for 
Part A. 
Randomization 
At the baseline visit (visit 3), patients who continue to meet eligibility criteria 
will enter the 24-week double-blind treatment period and will be randomized 
in a 1:1:1 ratio to dupilumab 300 mg QW, dupilumab 300 mg once every two 
weeks (Q2W), or placebo administered SC. 
Placebo-controlled Double-Blind Treatment Period (24 Weeks) 
Procedures for Part B are identical to those for Part A. 
At the end of the double-blind treatment visit (week 24), eligible patients in 
Part B may enter a 28-week extended active treatment period (Part C). Patients 
not participating in Part C will enter a 12-week follow-up period. 
Part C (28-Week Extended Active Treatment Period) 
At the end of the double-blind treatment visit (week 24), eligible patients in 
Part A and Part B may enter a 28-week extended active treatment period where 
all patients will receive active treatment with dupilumab but only patients in 
Part B will be blinded to treatment regimen in Part C. 
Patients from Part A who are randomized to placebo during the double-blind 
treatment period will receive dupilumab 300 mg QW during Part C. Patients 
from Part A who are randomized to dupilumab 300 mg QW during the 
double-blind treatment period will continue to receive dupilumab 300 mg QW 
during Part C. 
Patients from Part B who are randomized to placebo during the double-blind 
treatment period will be re-randomized in a 1:1 ratio to dupilumab 300 mg QW 
or dupilumab 300 mg Q2W.  
Patients randomized to dupilumab 300 mg Q2W will also receive matching 
placebo administered Q2W alternating with dupilumab doses so the injection 
frequency will match the other group for regimen-blinding purposes. All other 
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patients will remain on the same dupilumab dose regimen to which they are 
randomized during the double-blind treatment period. 
Follow-up Period (12 Weeks) 
All patients will be followed up for an additional 12 weeks after completing 
Part C or, if ineligible for Part C, immediately following Part A or B. 
Rescue Treatment  
If medically necessary, rescue medications (systemic and/or swallowed topical 
corticosteroids) or emergency esophageal dilation are allowed in study patients 
in Parts A, B and C. An endoscopy with biopsies will be performed prior to the 
initiation of rescue therapy unless COVID-19 restrictions prohibit this 
procedure. If the endoscopy with biopsies cannot occur due to COVID-19 
restrictions, rescue treatment should not be delayed, and these patients will be 
eligible for Part C. Part C treatment will be initiated per the schedule of events 
and only at an in-clinic visit. Patients receiving rescue therapy may continue to 
receive study drug. They will remain blinded and will be asked to return to the 
clinic for all remaining study treatment visits and participate in all study 
assessments according to the schedule of events. However, they will not 
undergo any scheduled endoscopy/biopsies subsequent to the date of rescue. 
Study Duration 
The duration of the study for a patient (excluding the screening period) is 
approximately 64 weeks. This includes participation in the double-blind and 
extended active treatment part, and the follow-up period. For patients not 
entering Part C, the duration of the study is approximately 36 weeks. 
End of Study Definition 
The end of study is defined as the last visit of the last patient in the study. 
Population 
 
 
Sample Size: 
Part A:  Approximately 80 patients (40 per treatment group). Patients may be 
adults ≥18 years of age or adolescents ≥12 and <18 years of age. 
Part B:  Approximately 210 patients (70 in each treatment group).  
 
Target Population: 
The target population includes adult males and females ≥18 years of age and 
adolescent males and females ≥12 to <18 years of age at the time of study entry 
with EoE. At least 10% of patients enrolled in Part B will be adolescents ≥12 
to <18 years of age. At least 30% of patients enrolled in Part B must have a 
history of prior use of swallowed topical corticosteroids. 
 
Key Eligibility Criteria: 
Key Inclusion Criteria 
• A documented diagnosis of EoE by endoscopic biopsy prior to screening, as 
demonstrated by intraepithelial eosinophilic infiltration (peak cell count 
≥15 eosinophils/high power field [eos/hpf]) from at least one esophageal 
region and performed after at least 8 weeks of treatment with a high dose 
proton pump inhibitor (PPI) regimen. If the patient discontinued PPI 
therapy, the biopsy must have been performed within 2 weeks of the date of 
discontinuation. 
If a prior (historical) endoscopic biopsy meeting these criteria is not 
available (or no prior biopsy is available), patients who meet other clinical 
and laboratory eligibility criteria will undergo treatment with a high dose 
PPI regimen for at least 8 weeks during the screening period before their 
baseline endoscopy/biopsies.  
• Baseline endoscopic biopsies with a demonstration on central reading of 
intraepithelial eosinophilic infiltration (peak cell count ≥15 eos/hpf) in at 
least 2 of the 3 biopsied esophageal regions (proximal, mid, or distal) 
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• History (by patient report) of an average of at least 2 episodes of dysphagia 
(with intake of solids) per week in the 4 weeks prior to screening 
• At least 4 episodes of dysphagia in the 2 weeks prior to baseline, 
documented via eDiary, at least 2 of which require liquids, coughing or 
gagging, vomiting, or medical attention to obtain relief 
• Completed at least 11 of 14 days of the Dysphagia Symptom Questionnaire 
(DSQ) eDiary data entry in the 2 weeks prior to the baseline visit (visit 3) 
• Baseline DSQ score ≥10  
 
Key Exclusion Criteria 
• Body weight ≤40 kg  
• Prior participation in a dupilumab clinical trial, or past or current treatment 
with dupilumab 
• Initiation or change of a food-elimination diet regimen or re-introduction of 
a previously eliminated food group in the 6 weeks prior to screening. 
Patients on a food-elimination diet must remain on the same diet throughout 
the study. 
• Other causes of esophageal eosinophilia or the following conditions:  
hypereosinophilic syndrome and eosinophilic granulomatosis with 
polyangiitis (Churg-Strauss syndrome)  
Note:  Patients with eosinophilic gastroenteritis are eligible, provided they 
meet other eligibility criteria. 
• Active Helicobacter pylori infection 
• History of achalasia, Crohn’s disease, ulcerative colitis, celiac disease, and 
prior esophageal surgery 
• Any esophageal stricture unable to be passed with a standard, diagnostic, 
9 to10 mm upper endoscope or any critical esophageal stricture that requires 
dilation at screening 
• History of bleeding disorders or esophageal varices that, in the opinion of 
the investigator, would put the patient at undue risk for significant 
complications from an endoscopy procedure 
• Treatment with swallowed topical corticosteroids within 8 weeks prior to 
baseline 
Treatment(s) 
 
 
Investigational Drug 
 
Dose/Route/Schedule: 
Part A 
• Dupilumab 300 mg SC QW 
Part B 
• Dupilumab 300 mg SC QW 
• Dupilumab 300 mg SC Q2W 
Part C 
• Dupilumab 300 mg SC QW 
• Dupilumab 300 mg SC Q2W 
 
Placebo 
 
Dose/Route/Schedule: 
• Placebo SC QW (Part A and Part B only) 
• Placebo SC Q2W alternating with Dupilumab Q2W for regimen-blinding 
purposes (Part B and Part C) 
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Background Treatment 
 
Dose/Route/Schedule: 
For both Part A and Part B, patients who present at the initial screening visit 
with current use of PPIs initiated prior to screening or during the screening 
period must remain on the same or similar approved dosage regimen for the 
duration of their respective treatment period. Patients who initiate PPI therapy 
during the screening period must remain on the same or similar approved 
dosage regimen for the duration of the treatment period for their respective 
study part. Patients may change to a different approved PPI medication during 
the study. PPI therapy is prohibited for all other patients. 
Endpoint(s) 
 
 
Primary: 
The co-primary endpoints for both Part A and Part B are: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil 
count of ≤6 eos/hpf at week 24 
• Absolute change in DSQ score from baseline to week 24 
 
Key Secondary: 
The key secondary endpoints for both Part A and Part B of the study are: 
• Absolute change in Eosinophilic Esophagitis-Endoscopic Reference Score 
(EoE-EREFS) from baseline to week 24 
• Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) 
from baseline to week 24 
• Absolute change in EoE Grade Score from the Histology Scoring System 
(EoEHSS) from baseline to week 24 
• Absolute change in EoE Stage Score from the EoEHSS from baseline to 
week 24 
 
Other Secondary: 
Other secondary endpoints include the following: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil 
count of <15 eos/hpf at week 24 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil 
count of ≤1 eos/hpf at week 24 
• Percent change in DSQ from baseline to week 24 
• Normalized Enrichment Scores (NES) for the relative change from baseline 
to week 24 in the EoE diagnostic panel (EDP) transcriptome signature 
• NES for the relative change from baseline to week 24 in the type 2 
inflammation transcriptome signature 
• Absolute change from baseline to week 24 in health-related quality of life 
(QOL) as measured by EoE Impact Questionnaire (EoE-IQ) 
• Absolute change from baseline to week 24 in severity and/or frequency of 
EoE symptoms other than dysphagia  
• Proportion of patients who receive rescue medications or procedures during 
the 24-week placebo-controlled treatment period. 
• Absolute change from baseline in esophageal distensibility plateau 
measured by functional lumen imaging, if collected, at week 24. 
Note: All co-primary and secondary endpoints assessed at week 24 will be 
assessed at week 52 as secondary endpoints and summarized with 
descriptive statistics based on the treatment assignment in the double-blind 
treatment period as well as the extended active treatment assignment for 
patients previously in the placebo group. 
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Both co-primary and all secondary endpoints will be assessed at week 24 
and week 52 in in adult and adolescent patients with EoE who have 
previously received swallowed topical corticosteroids. 
Procedures and Assessments 
Efficacy assessments include the following: 
• Esophageal endoscopy with biopsies:  Biopsies will be obtained for 
histologic assessments including intraepithelial eosinophil count and 
EoEHSS (EoE Grade Score and EoE Stage Score). Biopsies will be 
evaluated by pathologists at a central pathology laboratory who will be 
blinded to treatment assignment. 
• For Part A enrolled patients, EoE-EREFS scoring will only be performed at 
the time of the endoscopies in Part A and Part C by the investigators who 
are performing the endoscopies (prior to biopsies). For Part B enrolled 
patients, EoE-EREFS scoring will be performed by both the investigators 
who perform the endoscopies in Part B and Part C as well as a centralized 
reading center. The centralized reading will be used for analysis, if available. 
If the centralized reading is not available, the EoE-EREFS performed by the 
investigator will be used for analysis. 
• For all endoscopies, the investigators will assess minor esophageal features 
including mucosal inflammatory and remodeling features. DSQ will be 
completed daily by patients in the eDiary to assess the frequency and 
severity of dysphagia. 
• The EoE-IQ, a disease-specific measure of health-related QOL in EoE 
patients, will be completed by patients at specified time points. 
• The EoE Symptom Questionnaire, a questionnaire measuring the frequency 
and severity of symptoms other than dysphagia and swallowing pain, will 
be completed by patients at specified time points. 
• The endolumenal functional lumen imaging probe (EndoFLIP) procedure 
to measure esophageal distensibility may be performed during the 
esophagogastroscopy procedures at selected North American sites in 
approximately 150 adult patients. 
Safety and tolerability will be assessed by physical examinations, vital signs, 
electrocardiograms (ECGs), clinical laboratory tests, and clinical evaluations. 
Patients will be asked to report all adverse events (AEs) experienced from the 
time of informed consent until their last study visit. 
Pharmacokinetics (PK):  Serum samples will be collected at specified time 
points for assay of dupilumab concentration. 
Anti-drug antibody (ADA):  Serum samples will be collected at specified time 
points for assay of ADA and exploratory analyses. 
Statistical Plan 
Sample Size  
Part A:  The planned sample size for Part A is approximately 40 patients in 
each treatment group. 
Part B:  Based on the Part A study results, the planned sample size for Part B 
is approximately 70 patients in each treatment group such that for the 
comparison of each dupilumab dose regimen to placebo: 
• 
This sample size will yield >99.9% power to detect a treatment difference 
of 55.4% in the proportion of patients achieving peak esophageal 
intraepithelial eosinophil count ≤6 eos/hpf at week 24 between placebo 
(5.1%) and the dupilumab treatment group (59.5%) at a 2-sided 
significance level of 5% using Fisher’s exact test. 
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• 
This sample size will provide >99.9% power to detect a treatment 
difference of -12.3 points in the mean change from baseline in the total 
DSQ score to week 24 at a 2-sided significance level of 5% using a two-
sample t-test, assuming a common standard deviation (SD) of 15.013.0. 
Therefore, the sample size of  70 patients/arm will provide an overall power 
of >99.9% (99.9% × 99.9%) for the co-primary endpoints, assuming no 
negative correlation between the two endpoints. In Part B, the same treatment 
effect for the two 300 mg dupilumab dose regimens (ie, QW and Q2W) is 
assumed. 
Efficacy Analysis Sets 
For Part A and Part B, the efficacy endpoints will be analyzed using the 
study-part-specific full analysis set (FAS) that includes all randomized patients 
in the corresponding study part. 
The efficacy endpoints in Part C (the extended active treatment period) will be 
summarized for all patients who received any extended active treatment study 
drug in that part. 
Safety Analysis Set 
For Part A and Part B, the study-part-specific safety analysis set (SAF) includes 
all randomized patients who received any study drug in the corresponding study 
part; it is based on the treatment received (as treated). Treatment 
compliance/administration and all clinical safety variables will be analyzed 
using the SAF. 
For safety analyses of the Part C extended treatment period, only a subset of 
SAF will be included, which is defined as those patients who received at least 
1 dose of Part C study drug. 
Statistical Analysis  
All statistical analyses will be conducted separately for Part A and Part B. 
Primary Efficacy Analysis (Part A and Part B): 
The co-primary endpoint of proportion of patients achieving a histologic 
response of peak esophageal intraepithelial eosinophil count ≤6 eos/hpf at 
week 24 will be analyzed using the Cochran-Mantel-Haenszel (CMH) test to 
assess the difference in the proportion of responders in the FAS, adjusting for 
the randomization stratification factors. 
The co-primary endpoint of absolute change from baseline in the DSQ total 
score at week 24 will be analyzed using an analysis of covariance (ANCOVA) 
model for the FAS with treatment group, randomization stratification factor, 
and relevant baseline measurement as covariates included in the model. 
To account for use of rescue treatment in the primary analysis, for peak 
esophageal intraepithelial eosinophil count of ≤6 eos/hpf, patients will be 
considered as non-responders after the use of rescue treatment. For absolute 
change from baseline in the DSQ total score, data will be imputed using 
multiple imputation (MI) for all time points subsequent to the use of rescue 
treatment.  
If a patient has missing value for the histological response (peak esophageal 
intraepithelial eosinophil count ≤6 eos/hpf) at week 24, the patient will be 
classified as a non-responder at week 24. 
If a patient has missing value for the DSQ total score at week 24, the missing 
data will be imputed by MI based on similar patients who remained in the trial 
with observed values relevant to analysis. Similarity is based on randomized 
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treatment group, baseline value, stratification factors, and available post-
baseline values. 
Sensitivity analyses will assess alternative methods to impute missing data. For 
the eosinophil responder analysis, sensitivity methods may include utilizing 
peak eosinophil values from imputations to determine responder status. 
Sensitivity analyses will also include an analysis without setting data 
post-rescue to missing. 
Secondary Efficacy Analysis (Part A and Part B):  
Secondary efficacy endpoints will be analyzed in the same fashion as the 
co-primary endpoints depending on the type of data, unless otherwise specified.  
For continuous efficacy data that are scheduled to be measured only once 
post-baseline at week 24, missing values at week 24 will be imputed with 
patient’s baseline value or the available post-baseline value, whichever is 
worse, ie, a worst observation carried forward (WOCF) approach. 
Subgroup analysis (eg, by age group) will also be performed. 
Secondary Efficacy Analysis (Part C):  
Efficacy endpoints in Part C will be summarized with descriptive statistics by 
treatment received in Part C. Inferential statistics will only be provided as 
needed. 
Multiplicity Considerations: 
Part A and Part B will have separate and independent 2-sided alpha level of 
0.05. 
Part A:  Statistical significance of the co-primary endpoints at the 2-sided 
Type I error rate of 5% will be required before drawing inferential conclusions 
about any secondary efficacy endpoints.  
Part B:  The co-primary endpoints will be tested for the comparison of 
dupilumab QW dose regimen to placebo first and if both endpoints are 
statistically significant, the testing will proceed to the co-primary endpoints of 
dupilumab Q2W, or the secondary endpoints of dupilumab QW, with the exact 
order to be specified in Part B statistical analysis plan (SAP). 
Safety Analysis: 
Safety analysis will be based on the SAF. This includes reported 
treatment-emergent AEs (TEAEs) and other safety data (ie, clinical laboratory 
evaluations, vital signs, and 12-lead ECG results). A descriptive summary of 
safety results will be presented by treatment group for each study part. 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Ab 
Antibody 
ACQ-5 
Asthma Control Questionnaire-5 
AD 
Atopic dermatitis 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BID 
Twice (two times) a day 
BUN 
Blood urea nitrogen 
CCL 
Chemokine (C-C motif) ligand 
CMH 
Cochran-Mantel-Haenszel (test) 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
Ctrough 
Trough concentration 
DMC 
Data monitoring committee 
DSQ 
Dysphagia Symptom Questionnaire 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDP 
EoE Diagnostic Panel  
eGFR 
Estimated glomerular filtration rate 
EndoFLIP 
Endolumenal functional lumen imaging probe 
EoE 
Eosinophilic esophagitis 
EoE-EREFS 
Eosinophilic Esophagitis-Endoscopic Reference Score 
EoEHSS 
EoE Histology Scoring System 
EoE-IQ 
EoE Impact Questionnaire 
EOS 
End of study (visit) 
eos/hpf 
Eosinophils/high power field 
EOT 
End of treatment 
EQ-5D-3L 
European Quality of Life 5-dimension (version 3L; 3-level) 
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ET 
Early termination 
 
 
EU 
European Union 
FAS 
Full analysis set 
FBR 
Future biomedical research 
FLG 
Filaggrin 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
IA 
Interim analysis 
IAF 
Informed assent form 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IFN-γ 
Interferon-gamma 
IgE 
Immunoglobulin E 
IgG4 
Immunoglobulin G4 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IL-4Rα 
Interleukin-4 receptor alpha 
IRB 
Institutional Review Board 
ISR 
Injection site reaction 
IVRS/IWRS 
Interactive voice/web response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation  
MMRM 
Mixed-effect model repeated measure 
NES 
Normalized Enrichment Scores  
OIT 
Oral immunotherapy 
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PCSV 
Potentially clinically significant value 
PGIC 
Patient Global Impression of Change of Dysphagia 
PGIS 
Patient Global Impression of Severity of Dysphagia 
PK 
Pharmacokinetic 
POEM 
Patient-Oriented Eczema Measure 
PPI 
Proton pump inhibitor 
PPS 
Per protocol set 
PRO 
Patient-reported outcome 
PT 
Preferred term (MedDRA) 
PVRM 
Pharmacovigilance and Risk Management 
QD 
Once a day 
QOL 
Quality of life 
Q2W 
Once every two weeks 
QW 
Once weekly 
RBC 
Red blood cell 
RQLQ(s)+12 
Rhinoconjunctivitis Quality of Life Questionnaires for 12 years and older 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SCIT 
Subcutaneous immunotherapy 
SD 
Standard deviation 
SLIT 
Sublingual immunotherapy 
SOC 
System organ class 
SPRR3 
Small proline-rich protein 3 
SUSAR 
Suspected unexpected serious adverse reaction 
TARC 
Thymus and activation-regulated chemokine 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
Th2 
Type 2 helper T cell 
TNSS 
Total Nasal Symptom Score 
TSLP 
Thymic stromal lymphopoietin 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCF 
Worst observation carried forward 
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TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................21 
1. 
INTRODUCTION ......................................................................................................31 
2. 
STUDY OBJECTIVES ..............................................................................................33 
2.1. 
Primary Objectives .....................................................................................................33 
2.2. 
Secondary Objectives .................................................................................................33 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................33 
3.1. 
Hypothesis ..................................................................................................................33 
3.2. 
Rationale .....................................................................................................................34 
3.2.1. 
Rationale for Study Design .........................................................................................34 
3.2.2. 
Rationale for Dose Selection ......................................................................................35 
3.2.3. 
Risk/Benefits of Participating in the Study ................................................................36 
3.2.3.1. 
Benefits .......................................................................................................................36 
3.2.3.2. 
Risks ...........................................................................................................................37 
3.2.3.3. 
Benefit/Risk Conclusion .............................................................................................37 
4. 
STUDY VARIABLES................................................................................................37 
4.1. 
Demographic and Baseline Characteristics ................................................................37 
4.2. 
Primary and Secondary Endpoints..............................................................................38 
4.2.1. 
Primary Endpoints ......................................................................................................38 
4.2.2. 
Secondary Endpoints ..................................................................................................38 
4.3. 
Pharmacokinetic Variables .........................................................................................39 
4.4. 
Anti-Drug Antibody Variables ...................................................................................39 
5. 
STUDY DESIGN .......................................................................................................39 
5.1. 
Study Description and Duration .................................................................................39 
5.1.1. 
Part A ..........................................................................................................................42 
5.1.1.1. 
Screening (Up to 12 Weeks) .......................................................................................42 
5.1.1.2. 
Randomization ............................................................................................................43 
5.1.1.3. 
Placebo-Controlled Double-Blind Treatment Period (24 Weeks) ..............................43 
5.1.2. 
Part B ..........................................................................................................................44 
5.1.2.1. 
Screening (Up to 12 Weeks) .......................................................................................44 
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5.1.2.2. 
Randomization ............................................................................................................44 
5.1.2.3. 
Placebo-Controlled Double-Blind Treatment Period (24 Weeks) ..............................44 
5.1.3. 
Part C (28-Week Extended Active Treatment Period) ...............................................45 
5.1.4. 
Follow-Up Period (12 Weeks) ....................................................................................45 
5.1.5. 
End of Study Definition ..............................................................................................45 
5.2. 
Planned Interim Analysis ............................................................................................45 
5.3. 
Study Committees .......................................................................................................45 
5.3.1. 
Independent Data Monitoring Committee ..................................................................45 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............46 
6.1. 
Number of Patients Planned .......................................................................................46 
6.2. 
Study Population .........................................................................................................46 
6.2.1. 
Inclusion Criteria for Parts A and B ...........................................................................46 
6.2.2. 
Exclusion Criteria for Parts A and B ..........................................................................47 
6.2.3. 
Exclusion Criteria for Part C (the Extended Active Treatment Period) .....................51 
6.3. 
Premature Withdrawal from the Study .......................................................................51 
6.4. 
Replacement of Patient ...............................................................................................51 
7. 
STUDY TREATMENTS............................................................................................52 
7.1. 
Investigational and Reference Treatments ..................................................................52 
7.2. 
Background Treatment ...............................................................................................52 
7.3. 
Rescue Treatments ......................................................................................................53 
7.4. 
Dose Modification and Study Treatment Discontinuation Rules ...............................53 
7.4.1. 
Dose Modification ......................................................................................................53 
7.4.2. 
Study Drug Discontinuation .......................................................................................53 
7.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................53 
7.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................54 
7.5. 
Method of Treatment Assignment ..............................................................................55 
7.5.1. 
Blinding ......................................................................................................................55 
7.5.2. 
Emergency Unblinding ...............................................................................................56 
7.5.3. 
Unblinding for Regulatory Reporting Purposes .........................................................56 
7.6. 
Treatment Logistics and Accountability .....................................................................56 
7.6.1. 
Packaging, Labeling, and Storage ..............................................................................56 
7.6.2. 
Supply and Disposition of Treatments .......................................................................56 
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7.6.3. 
Treatment Accountability ...........................................................................................57 
7.6.4. 
Treatment Compliance ................................................................................................57 
7.7. 
Concomitant Medications and Procedures .................................................................57 
7.7.1. 
Prohibited Medications and Procedures .....................................................................57 
7.7.2. 
Permitted Medications and Procedures ......................................................................58 
7.7.3. 
Restricted Medications and Procedures during the Follow-Up Period ......................58 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................59 
8.1. 
Schedule of Events .....................................................................................................59 
8.1.1. 
Footnotes for the Schedule of Events Tables .............................................................66 
8.1.1.1. 
Footnotes for Table 1 ..................................................................................................66 
8.1.1.2. 
Footnotes for Table 2 ..................................................................................................68 
8.1.1.3. 
Footnotes for Table 3 ..................................................................................................70 
8.1.2. 
Early Termination Visit ..............................................................................................71 
8.1.3. 
Unscheduled Visits before Rescue Treatment ............................................................71 
8.1.4. 
Unscheduled Visits for Other Reasons .......................................................................71 
8.2. 
Study Procedures ........................................................................................................72 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................72 
8.2.2. 
Efficacy Procedures ....................................................................................................72 
8.2.2.1. 
Endoscopy with EoE-EREFS and Biopsies, and Photographs ...................................72 
8.2.2.2. 
Dysphagia Symptom Questionnaire (DSQ) - Patient-reported Outcome 
(PRO) ..........................................................................................................................74 
8.2.2.3. 
EoE Impact Questionnaire (EoE-IQ) ..........................................................................75 
8.2.2.4. 
EoE Symptom Questionnaire .....................................................................................75 
8.2.2.5. 
Patient Global Impression of Change (PGIC) of Dysphagia ......................................75 
8.2.2.6. 
Patient Global Impression of Severity (PGIS) of Dysphagia .....................................76 
8.2.2.7. 
Total Nasal Symptom Score (TNSS) ..........................................................................76 
8.2.2.8. 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire for ages 12+ 
[RQLQ(S)+12] ............................................................................................................76 
8.2.2.9. 
Juniper Asthma Control Questionnaire (ACQ) ..........................................................77 
8.2.2.10. 
Patient-Oriented Eczema Measure (POEM) ...............................................................77 
8.2.2.11. 
European Quality of Life 5-Dimensional Scale (EQ-5D) ..........................................78 
8.2.3. 
Safety Procedures .......................................................................................................78 
8.2.3.1. 
Vital Signs ..................................................................................................................78 
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8.2.3.2. 
Physical Examination .................................................................................................78 
8.2.3.3. 
Body Weight and Height ............................................................................................78 
8.2.3.4. 
Electrocardiogram .......................................................................................................78 
8.2.3.5. 
Laboratory Testing ......................................................................................................78 
8.2.4. 
Drug Concentration and Measurements .....................................................................80 
8.2.5. 
Anti-Drug Antibody Measurements and Samples ......................................................80 
8.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................80 
8.2.6.1. 
EoE Diagnostic Panel and Type 2 Inflammation Transcriptomics ............................80 
8.2.6.2. 
Type 2 Inflammatory and Disease-Related Circulating Biomarkers ..........................81 
8.2.7. 
Future Biomedical Research (FBR) Serum/Plasma (Optional) ..................................82 
8.2.7.1. 
Genomics Substudy (Optional) ...................................................................................82 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................83 
9.1. 
Obligations of Investigator .........................................................................................83 
9.2. 
Obligations of Sponsor ...............................................................................................83 
9.3. 
Definitions ..................................................................................................................83 
9.3.1. 
Adverse Event .............................................................................................................83 
9.3.2. 
Serious Adverse Event ................................................................................................83 
9.3.3. 
Adverse Events of Special Interest .............................................................................84 
9.4. 
Recording and Reporting Adverse Events ..................................................................84 
9.4.1. 
Adverse Events ...........................................................................................................84 
9.4.2. 
Serious Adverse Events ..............................................................................................84 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................85 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................86 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................86 
9.4.6. 
Follow-up ....................................................................................................................86 
9.5. 
Evaluation of Severity and Causality .........................................................................86 
9.5.1. 
Evaluation of Severity ................................................................................................86 
9.5.2. 
Evaluation of Causality ...............................................................................................87 
9.6. 
Safety Monitoring .......................................................................................................88 
9.7. 
Investigator Alert Notification ....................................................................................89 
10. 
STATISTICAL PLAN................................................................................................89 
10.1. 
Statistical Hypothesis ..................................................................................................89 
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10.2. 
Justification of Sample Size........................................................................................89 
10.3. 
Analysis Sets ...............................................................................................................91 
10.3.1. 
Efficacy Analysis Sets ................................................................................................91 
10.3.2. 
Safety Analysis Set .....................................................................................................91 
10.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................91 
10.3.4. 
Anti-Drug Antibody Analysis Sets .............................................................................91 
10.4. 
Statistical Methods ......................................................................................................91 
10.4.1. 
Patient Disposition ......................................................................................................92 
10.4.2. 
Demography and Baseline Characteristics .................................................................92 
10.4.3. 
Efficacy Analyses .......................................................................................................92 
10.4.3.1. 
Primary Efficacy Analysis ..........................................................................................92 
10.4.3.2. 
Secondary Efficacy Analysis ......................................................................................94 
10.4.3.3. 
Multiplicity Considerations ........................................................................................96 
10.4.4. 
Safety Analysis ...........................................................................................................97 
10.4.4.1. 
Adverse Events ...........................................................................................................97 
10.4.4.2. 
Other Safety ................................................................................................................98 
10.4.4.3. 
Treatment Exposure ....................................................................................................98 
10.4.4.4. 
Treatment Compliance ................................................................................................99 
10.4.5. 
Pharmacokinetics ........................................................................................................99 
10.4.5.1. 
Analysis of Drug Concentration Data .........................................................................99 
10.4.6. 
Analysis of Anti-Drug Antibody Data ........................................................................99 
10.4.7. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ..............................99 
10.4.8. 
Analysis of Quality of Life Data ................................................................................99 
10.4.9. 
Timing of Statistical Analysis ....................................................................................99 
10.5. 
Additional Statistical Data Handling Conventions ...................................................100 
10.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .......100 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS ...................................100 
11.1. 
Data Management .....................................................................................................100 
11.2. 
Electronic Systems ....................................................................................................101 
12. 
STUDY MONITORING ..........................................................................................101 
12.1. 
Monitoring of Study Sites .........................................................................................101 
12.2. 
Source Document Requirements ..............................................................................101 
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12.3. 
Case Report Form Requirements ..............................................................................102 
13. 
AUDITS AND INSPECTIONS ...............................................................................102 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................102 
14.1. 
Good Clinical Practice Statement .............................................................................102 
14.2. 
Informed Consent .....................................................................................................103 
14.3. 
Patients Confidentiality and Data Protection ............................................................103 
14.4. 
Institutional Review Board/Ethics Committee .........................................................104 
15. 
PROTOCOL AMENDMENTS ................................................................................104 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................104 
16.1. 
Premature Termination of the Study .........................................................................104 
16.2. 
Close-out of a Site ....................................................................................................105 
17. 
STUDY DOCUMENTATION .................................................................................105 
17.1. 
Certification of Accuracy of Data .............................................................................105 
17.2. 
Retention of Records ................................................................................................105 
18. 
DATA QUALITY ASSURANCE ............................................................................106 
19. 
CONFIDENTIALITY ..............................................................................................106 
20. 
FINANCING AND INSURANCE ...........................................................................106 
21. 
PUBLICATION POLICY ........................................................................................107 
22. 
REFERENCES .........................................................................................................107 
23. 
INVESTIGATOR’S AGREEMENT ........................................................................112 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................113 
 
LIST OF TABLES 
Table 1: 
Parts A and B Schedule of Events – Screening Period and Double-Blind 
Treatment Period ........................................................................................................60 
Table 2: 
Part C Schedule of Events – Extended Active Treatment Period ...............................62 
Table 3: 
Follow-up Period, Early Termination Visit, and Unscheduled Visit ..........................64 
Table 4: 
Summary of Primary Estimand for Co-primary Endpoints ........................................93 
Table 5: 
Summary of Primary Estimand for Key Secondary Endpoints ..................................95 
 
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LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................40 
Figure 2: 
Study Design ...............................................................................................................41 
Figure 3: 
Endoscopy/Biopsy Procedure Flow Diagram .............................................................43 
 
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1. 
INTRODUCTION 
Eosinophilic esophagitis (EoE) is a chronic, inflammatory, allergic/immune-mediated disease of 
the esophagus. The disease is characterized by local eosinophilic inflammation leading to 
symptoms of esophageal dysfunction (Furuta, 2017) (Liacouras, 2011) (DeBrosse, 2011) 
(Falk, 2014). Although considered a rare disease, the current prevalence is estimated at 22.7 per 
100,000 worldwide (Arias, 2016) and appears to be on the increase (Dellon, 2014a). Eosinophilic 
esophagitis has been reported in all ages; however, most cases are in children and adults younger 
than 50 years (Dellon, 2014a) (Dellon, 2014b) (Dellon, 2007) (Kapel, 2008) (Liacouras, 2011) 
(Spergel, 2009). Gender differences in EoE have been consistently reported, with males affected 
3 to 4 times more often than females (Dellon, 2014a), but there are no gender-related differences 
in the clinical symptoms (Kapel, 2008) (Prasad, 2009) (Veerappan, 2009) (Hruz, 2011) 
(Ally, 2015). 
The primary clinical manifestations of EoE in both adults and children over 10 years of age are 
dysphagia and food impaction (Lucendo, 2017). These symptoms lead to substantially impaired 
quality of life (QOL) (DeBrosse, 2011) (Falk, 2014) (Straumann, 2008) (Straumann, 2003). 
Endoscopic findings are related to the inflammation in the esophagus and consist of fixed or 
transient concentric rings, longitudinal furrows, white plaques, reduced mucosal vascularity, 
fragile or crepe-like mucosa, and strictures. Rings and furrows are the most common, seen in nearly 
half of patients (Singla, 2016). 
Growing evidence suggests that a Type 2 cytokine-mediated immune response plays an important 
role in the development of EoE. This is thought to occur by provoking chronic eosinophil, mast 
cell, T cell, and lymphocyte-induced inflammation via cytokines known to regulate eosinophilic 
accumulation in the esophagus, such as interleukin (IL)-4, IL-5, IL-13, and eotaxin-1, -2, and -3 
(Abonia, 2010) (Abonia, 2012) (Blanchard, 2006) (Blanchard, 2008) (Blanchard, 2010) 
(Bullock, 2007) (Mishra, 2003) (Mishra, 2009`) (Straumann, 2001). Th2 cells are a subgroup of 
the T cells that regulate the activity of other immune cells by releasing Type 2 cytokines. IL-13 
has been found to be upregulated in the esophageal epithelium of EoE patients (Blanchard, 2007). 
The induction of eotaxin-3, an eosinophil chemoattractant, is thought to be an important factor in 
EoE pathogenesis (Blanchard, 2006) (Blanchard, 2007). The 2 most up-regulated genes in 
esophageal biopsies from EoE patients (compared to normal controls) encode eotaxin-3 and 
periostin, another protein induced by Type 2 cytokines and thought to promote inflammation and 
remodeling (Blanchard, 2006) (Blanchard, 2008). Furthermore, esophageal biopsies and blood 
samples of patients with active EoE have increased levels of cytokines and chemokines associated 
with Type 2 inflammation, including IL-4 and IL-13, thymic and stromal lymphopoeitin (TSLP), 
and eotaxin-3 secreted by the typical cells involved in allergic inflammation:  T cells, mast cells, 
basophils, invariant natural killer T cells (iNKTs), and esophageal epithelial cells. Mutations in 
the eotaxin-3 and TSLP genes, whose functions propagate Type 2 inflammation, have been 
associated with EoE risk (Cianferoni, 2016). 
Impaired barrier function of the esophageal epithelium is thought to play a role in EoE 
pathogenesis. Several genes in the epidermal differentiation complex, known to be down-regulated 
by Type 2 cytokines with resultant barrier dysfunction of the skin, are also down-regulated in 
primary esophageal epithelial cells in vitro. Furthermore, decreased mRNA expression of the 
epidermal differentiation complex gene filaggrin (FLG), and the esophagus-specific esophagin 
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(small proline-rich protein 3 [SPRR3]), was observed in esophageal biopsies from EoE patients 
compared to normal controls (Blanchard, 2010). The increased frequency at which FLG null alleles 
were found in EoE patients compared to controls provides further evidence of the barrier 
hypothesis in EoE (Blanchard, 2010). It is also known that FLG mRNA expression is directly 
suppressed by IL-4 and IL-13 in keratinocytes (Howell, 2007). The data suggest that Type 2 
cytokines may be driving not only an inflammatory response, but also epithelial barrier 
dysfunction in the esophagus. 
Consistent with the Type 2-mediated inflammation observed in esophageal tissue, patients with 
EoE have high rates of comorbid allergic diseases which are also associated with enhanced IL-4 
and IL-13 signaling, especially food allergies, atopic dermatitis (AD), asthma, and allergic rhinitis 
(Arora, 2012) (Assa’ad, 2008) (Liacouras, 2011) (Moawad, 2010) (Roy-Ghanta, 2008) 
(Weinbrand-Goichberg, 2013).  
The inflammatory damage to the esophageal epithelium results in symptoms of esophageal 
dysfunction, such as dysphagia. Chronic inflammation of the esophagus may also lead to 
remodeling, stricture formation, and fibrosis (Hirano, 2014). The fibrotic aspect of progressed 
disease is not well understood, and whether or not this can be reversed with treatment is unknown. 
Current therapeutic approaches include chronic dietary elimination, swallowed topical formulation 
corticosteroids (not approved for the treatment of EoE outside the European Union [EU]), and 
esophageal dilation. Emergency endoscopy for prolonged and/or painful food impaction is 
associated with a risk of severe esophageal injury and does not alter the underlying pathogenesis 
or progression of the disease. Although swallowed topical corticosteroids have been reported in 
clinical trials to induce partial clinical responses and histologic remission, they are not uniformly 
effective and can be associated with fungal infections as well as disease recurrence after 
discontinuation. 
Dupilumab is a human monoclonal immunoglobulin G4 (IgG4) antibody (Ab) that inhibits IL-4 
and IL-13 signaling by specifically binding to the IL-4 receptor alpha (IL-4Rα) subunit shared by 
the IL-4 and IL-13 receptor complexes. Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13 
Type 2 cytokine-induced responses, including the release of pro-inflammatory cytokines, 
chemokines, and IgE. Additionally, preclinical data demonstrate that treatment with dupilumab 
prevents infiltration of eosinophils into tissues. For these reasons, dupilumab was evaluated in 
adult patients with EoE in a phase 2, multicenter, double-blind, randomized, placebo-controlled 
study (R668-EE-1324), where it demonstrated substantial improvements in clinical, histologic, 
and endoscopic aspects of the disease. Dupilumab was well tolerated in the study, with safety data 
generally consistent with other dupilumab studies in AD patients and no particular safety signal 
associated with use in the EoE patient population. The results support the phase 3 evaluation of 
dupilumab in EoE. 
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
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2. 
STUDY OBJECTIVES  
2.1. 
Primary Objectives 
The primary objectives of the study by study part are: 
• Part A: To determine the treatment effect of dupilumab compared with placebo in 
adult and adolescent patients with EoE after 24 weeks of treatment as assessed by 
histological and clinical measures, and to inform/confirm the final sample size 
determination for Part B. 
• Part B: To demonstrate the efficacy of dupilumab treatment compared with placebo 
in adult and adolescent patients with EoE after 24 weeks of treatment as assessed by 
histological and clinical measures. 
• Part C: To assess the safety and efficacy of dupilumab treatment in adult and 
adolescent patients with EoE after up to 52 weeks of treatment as assessed by 
histological and clinical measures. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the safety, tolerability, and immunogenicity of dupilumab treatment for up 
to 52 weeks in adult and adolescent patients with EoE 
• To explore the relationship between dupilumab concentration and responses in adult 
and adolescent patients with EoE, using descriptive analyses 
• To evaluate the effects of dupilumab on transcriptomic signatures associated with 
EoE and type 2 inflammation  
• To demonstrate the efficacy of dupilumab treatment compared to placebo after 
24 weeks and 52 weeks of treatment in adult and adolescent patients with EoE who 
have previously received swallowed topical corticosteroids 
3. 
HYPOTHESIS AND RATIONALE  
3.1. 
Hypothesis 
In adult and adolescent patients ≥12 years of age with EoE, treatment with dupilumab will result 
in a statistically significant benefit compared to treatment with placebo, as measured by: 
• Relief of dysphagia, assessed by change in the Dysphagia Symptom Questionnaire 
(DSQ) score. 
• Reduction in eosinophilic esophageal infiltration, assessed by change in esophageal 
intraepithelial eosinophil count 
• Improvement in endoscopically identified esophageal mucosal inflammatory and 
remodeling features, assessed by change in the Eosinophilic Esophagitis-Endoscopic 
Reference Score (EoE-EREFS) 
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3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
The study is divided into 3 parts:   
• Part A consists of a screening period of up to 12 weeks, followed by a randomized, 
double-blind, placebo-controlled, 2-arm, parallel-group, 24-week treatment period. 
Patients who complete Part A will either enter Part C or continue to a 12-week follow-
up period (for patients who do not go on to Part C). 
• Part B consists of a screening period of up to 12 weeks, followed by a randomized, 
double-blind, placebo-controlled, 3-arm, parallel-group, 24-week treatment period. 
Patients who complete Part B will either enter Part C or continue to a 12-week follow-
up period (for patients who do not go on to Part C). Enrollment in Part B will begin 
immediately after the last patient has been randomized in Part A. 
• Part C is an extended active treatment period and consists of a 2-arm, 28-week 
treatment period. Patients who complete Part C will continue to a 12-week follow-up 
period. 
The co-primary endpoints selected for Parts A and B of the study (proportion of patients achieving 
peak esophageal intraepithelial eosinophil count of ≤6 eos/high power field [hpf] at week 24 and 
change in DSQ score from baseline to week 24) assess important clinical and histological measures 
of dysphagia symptoms and disease activity and progression. Eosinophilic infiltration of the 
esophageal mucosa is the hallmark of the disease and, in conjunction with characteristic clinical 
symptoms of esophageal dysfunction (solid food dysphagia, food impaction), is considered 
pathognomonic for EoE.  
Solid food dysphagia is the most common presenting symptom of EoE and food impaction 
necessitating endoscopic bolus removal occurs in 33% to 54% of adult EoE patients 
(Dellon, 2013). The DSQ is a daily patient-reported outcome (PRO) measure that has been 
validated for the measurement of dysphagia frequency and severity in patients with EoE 
(Dellon, 2013) (Hudgens, 2017). The questions ask whether solid food has been eaten; whether 
food has gone down slowly or become stuck; and what, if any, measures have been taken to achieve 
relief. 
Since the gross appearance of the esophageal mucosa assessed by endoscopy reflects both the 
inflammatory and fibrotic nature of the disease, EoE-EREFS is a key secondary endpoint. The 
EoE-EREFS is a validated classiﬁcation and grading system designed to standardize nomenclature 
for the major endoscopically identiﬁed esophageal features of EoE (edema, rings, exudates, 
furrows, and strictures) (Hirano, 2013). Recent studies have demonstrated the clinical relevance 
of endoscopic severity assessment in EoE. The severity of each of the EoE-EREFS subscores has 
been shown to be associated with patient-reported global symptom activity (Schoepfer, 2014). The 
use of a visual endoscopy score is consistent with the emphasis on endoscopic mucosal healing as 
a primary endpoint of therapeutics in inflammatory bowel disease, peptide ulcer disease and 
GERD (Hirano, 2017). 
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The study will include adolescents ≥12 years of age. The primary clinical manifestation of EoE in 
children and adolescents ≥10 years of age is dysphagia and food impaction, similar to adult patients 
(Lucendo, 2017). In addition, the disease appears to have the same underlying pathophysiology 
regardless of age; similar high rates of atopy as well as a genetic predisposition have been 
demonstrated in both the pediatric and adult populations. A unique genetic signature for EoE has 
been identified that is conserved in all patients with the disease, suggesting the biological 
manifestations of disease are the same across all age groups (Blanchard, 2006). Additional work 
demonstrated that a transcriptome of 96 genes in EoE patients was similar between both adults and 
children (Wen, 2013). 
Study treatment will be administered for approximately 24 weeks in the double-blind, placebo-
controlled phase to adequately assess the risk/benefit profile of a drug intended for chronic use. In 
the phase 2, multicenter, double-blind, randomized, placebo-controlled study in patients with EoE 
(R668-EE-1324), a plateau in clinical effect had not been observed by week 12 with a dose of 300 
mg once weekly (QW). An additional 28 weeks of extended active treatment in Part C for an 
overall exposure of approximately 52 weeks will provide data on the long-term efficacy and safety 
of dupilumab in patients with EoE. 
There are several justifications for the inclusion of a placebo control group in this study. Although 
there is an approved swallowed topical steroid treatment for EoE in the EU, it is only indicated for 
short-term use in adults, not for chronic treatment or treatment of pediatric patients (EMA Jorveza 
Assessment Report, 2017). Furthermore, it is only approved in this region and thus considered 
inappropriate for use in a global study. Studies show that patients with EoE frequently relapse, 
even while maintained on long-term topical steroid therapy (Eluri, 2017). Furthermore, although 
studies have shown that a prolonged delay in the diagnosis and treatment of EoE increases the risk 
of stricture formation in a time-dependent manner, the median delay in EoE diagnosis in these 
studies was 6 years, and duration of follow-up was over 20 years (Schoepfer, 2013). It is unlikely 
that a 24-week period of untreated disease will lead to irreversible stricture formation. Hence, 
while allocation to a placebo arm may result in temporary continuation of symptoms, it should not 
impact a patient’s long-term prognosis. In addition, rescue treatment (including swallowed steroids 
and dilation) is allowed for any patient who experiences intolerable symptoms during the study. 
Finally, study patients will be offered the opportunity to participate in the 28-week extended active 
treatment phase, thus offering some potential for direct benefit, even for patients initially enrolled 
in the placebo treatment arm. 
3.2.2. 
Rationale for Dose Selection  
Patients in Part A will receive either 300 mg dupilumab or placebo QW administered 
subcutaneously (SC). In the phase 2 study R668-EE-1324, dupilumab 300 mg QW was 
demonstrated to be efficacious with clinically significant improvements in histologic, endoscopic, 
and patient-reported symptoms after 12 weeks of treatment. Dupilumab was well tolerated with a 
favorable profile with no particular safety signal associated with use in the EoE patient population.  
Patients in Part B will receive 300 mg dupilumab SC once every two weeks (Q2W), 300 mg 
dupilumab SC QW or placebo SC QW. The 300 mg Q2W was chosen to provide dose-ranging 
information. Based on pharmacokinetic (PK) considerations, this dose is expected to achieve 
target-saturating concentrations over the dosing interval, and hence provide clinical benefit. The 
approved dose regimen for treatment of AD is 300 mg Q2W. In addition, this dose regimen 
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provided significant benefit in phase 3 studies of dupilumab for the treatment of adults and 
adolescents with moderate-to-severe asthma, and is currently being tested in adults with nasal 
polyposis. Dosing regimens with inter-dose intervals longer than Q2W have been suboptimal in 
AD and asthma and are not proposed for this trial, as the end of interval concentrations would be 
expected to be below those required for target saturation, and hence may not yield optimal benefit 
in patients with EoE. 
Both dupilumab 300 mg QW and Q2W have a well understood and favorable safety profile. 
Approximately 2500 AD patients were exposed to dupilumab; 645 AD 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. 
In both the AD and asthma programs, as is typical for monoclonal antibodies, body weight was 
found to be the most significant covariate affecting the PK of dupilumab, with patients of a lower 
body weight achieving higher concentrations of dupilumab. In the pivotal phase 3 studies in AD 
(R668-AD-1334, R668-AD-1416, and R668-AD-1224), adults with body weights of 41 kg or more 
received dupilumab doses of 300 mg Q2W and 300 mg QW, which were found to be well tolerated 
for 16 to 52 weeks. In Study EFC13579, 33 adolescent patients with asthma (median age of 
14 years with a range of 12 to 17 years; median weight 55 kg) received dupilumab 300 mg Q2W; 
a similar PK profile was observed between adolescent and adult patients with asthma. 
As dupilumab 300 mg QW has not been studied in lighter patients, subjects (adults or adolescents) 
with body weight <40 kg will be excluded from the study. 
3.2.3. 
Risk/Benefits of Participating in the Study 
Recognizing that the “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on 
the conduct of clinical trials, the sponsor does not intend to screen any new patients in this study 
unless the impact of the COVID-19 pandemic is deemed manageable and no longer interfering 
with the conduct of trials at individual sites, and patients can safely participate in this study. Until 
then, the sponsor plans to obtain approvals from health authorities/ethics committees to enable 
continuation of study sites for this study, as allowed by local laws and regulations. 
3.2.3.1. 
Benefits 
The efficacy and safety of dupilumab in adults with EoE were evaluated in a phase 2, randomized, 
double-blind, placebo-controlled study (R668-EE-1324). Treatment with weekly dupilumab 
300 mg SC for 12 weeks in patients with EoE reduced the frequency and intensity of dysphagia, 
the cardinal symptom of EoE. Improvement in clinical symptoms was accompanied by endoscopic 
and biopsy histologic evidence of reduced esophageal intraepithelial eosinophil infiltration, 
esophageal mucosal inflammation, and improved esophageal distensibility. Study patients could 
potentially benefit from dupilumab treatment, including patients randomized to receive placebo in 
Parts A and B, as all patients have the opportunity to receive dupilumab in the extended active 
treatment Part C of the study. 
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3.2.3.2. 
Risks 
As of 28 March 2020, over 8000 subjects have been enrolled into the dupilumab development 
program for the indications of AD, asthma, chromic rhinosinusitis with nasal polyps (CRSwNP), 
grass allergy, peanut allergy, bullous pemphigoid, and EoE (Investigator's Brochure Version 14). 
Based upon currently available data, 1 important identified risk, “Systemic Hypersensitivity 
(including those events associated with immunogenicity),” has been established. One serious case 
each of serum sickness and serum sickness-like reaction (both associated with high anti-drug 
antibody [ADA] titers) were reported in adult AD studies, however none were seen in the asthma 
development program. Additionally, there has been one report of anaphylaxis considered related 
to study drug by the Investigator in an asthma study. Based on the review of post-marketing data, 
signals of anaphylactic reaction and angioedema were confirmed and considered as adverse drug 
reactions (ADRs). 
A higher incidence of Injection Site reactions (ISRs) has been observed in the dupilumab-treated 
subjects, consistent with the SC injection of a protein biologic. Most ISRs were mild to moderate 
in intensity, and less than 2% were severe or led to treatment discontinuation. The proportion of 
patients experiencing ISRs diminished over time during the treatment period. 
Conjunctivitis, Conjunctivitis Allergic, Conjunctivitis Bacterial, Blepharitis, Dry Eye, Eye 
Pruritus, Herpes Simplex (primarily mucocutaneous in nature), and Oral Herpes have been 
identified as adverse drug reactions for the AD indication. There was no increase in incidence of 
these events observed in the completed asthma study. Conjunctivitis was also observed in the 
completed CRSwNP studies but with lower incidence than in the AD studies and without keratitis 
or increase in other ophthalmic events. Most events were mild in intensity and transient in nature, 
and did not necessitate treatment discontinuation. Based on the post-marketing safety data, events 
of angioedema, arthralgia, keratitis and ulcerative keratitis are now considered as ADRs. 
The purpose of protocol amendment 4 was to account for the COVID-19 pandemic and to 
minimize the risks to the patients in the trial as well as healthcare providers by allowing flexibility 
in the visit schedule while social distancing suggestions are in place. Allowing for this flexibility 
does not increase the risk of participating in this trial as there will be continued contact between 
the patients and study personnel despite postponement of in-person clinic visits. 
3.2.3.3. 
Benefit/Risk Conclusion 
The safety data available to date across multiple indications in conjunction with the clinical benefit 
of dupilumab demonstrated in the phase 2 EoE study support a favorable benefit-risk profile for 
dupilumab. 
4. 
STUDY VARIABLES  
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc.), 
disease characteristics including medical history, and medication history. 
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4.2. 
Primary and Secondary Endpoints 
4.2.1. 
Primary Endpoints 
The co-primary endpoints for both Parts A and B of the study are: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤6 eos/hpf at week 24 
• Absolute change in DSQ score from baseline to week 24  
4.2.2. 
Secondary Endpoints 
The key secondary endpoints for both Parts A and B of the study are: 
• Absolute change in EoE-EREFS from baseline to week 24 
• Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from 
baseline to week 24 
• Absolute change in EoE Grade Score from the EoE Histology Scoring System 
(EoEHSS) from baseline to week 24  
• Absolute change in EoE Stage Score from the EoEHSS from baseline to week 24 
The other secondary endpoints are: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
<15 eos/hpf at week 24 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤1 eos/hpf at week 24 
• Percent change in DSQ from baseline to week 24 
• Normalized Enrichment Scores (NES) for the relative change from baseline to week 
24 in the EoE diagnostic panel (EDP) transcriptome signature 
• NES for the relative change from baseline to week 24 in the type 2 inflammation 
transcriptome signature 
• Absolute change from baseline to week 24 in health-related QOL as measured by EoE 
Impact Questionnaire (EoE-IQ) 
• Absolute change from baseline to week 24 in severity and/or frequency of EoE 
symptoms other than dysphagia  
• Proportion of patients who receive rescue medications or procedures during the 
24-week placebo-controlled treatment period  
• Absolute change from baseline in esophageal distensibility plateau measured by 
functional lumen imaging, if collected, at week 24.  
Note:  All the above co-primary and secondary endpoints assessed at week 24 will be 
assessed at week 52 as secondary endpoints and summarized with descriptive statistics 
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based on the treatment assignment in the double-blind treatment period as well as the 
extended active treatment assignment for patients previously in the placebo group.  
Both co-primary and all secondary endpoints will be assessed at week 24 and week 52 in 
in adult and adolescent patients with EoE who have previously received swallowed 
topical corticosteroids. 
4.3. 
Pharmacokinetic Variables 
The pharmacokinetic variable is the trough concentration (Ctrough) of functional dupilumab in 
serum at each time point. Samples in this study will be collected using a sparse sampling schedule, 
eg, only 1 blood sample for drug concentration measurement is collected at any single clinic visit. 
These sampling time points (prior to dosing at each time point) are specified in Table 1, Table 2, 
and Table 3. 
4.4. 
Anti-Drug Antibody Variables 
The ADA variables are ADA status, titer, and time point/visit. Samples in this study will be 
collected at the clinic visits specified in Table 1, Table 2, and Table 3. 
5. 
STUDY DESIGN  
5.1. 
Study Description and Duration 
This study will investigate the efficacy and safety of dupilumab in adult and adolescent patients 
with EoE. The study will consist of 3 parts and a follow-up period:  Part A and Part B (each 
consisting of a 24-week double-blind treatment period), Part C (a 28-week extended active 
treatment period), and a 12-week follow-up period following the end of the extended active 
treatment period for patients who enter into Part C or following the end of Parts A and B of the 
double-blind treatment period for patients who do not enter Part C. 
Approximately 80 patients (40 per treatment group) are planned to be enrolled in Part A. 
Approximately 210 patients (70 per treatment group) are planned to be enrolled in Part B. At least 
10% of patients enrolled in Part B will be adolescents ≥12 years of age and at least 30% of patients 
enrolled in Part B must have a history of prior use of swallowed topical corticosteroids. At the end 
of the double-blind treatment visit (week 24) of Part A or Part B, eligible patients may enter Part C.  
The study flow diagram is provided in Figure 1. 
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Figure 1: 
Study Flow Diagram 
End of 
Study
Visit 1
D-85 to 
D-29
Baseline
Double-Blind Treatment Period
(24 weeks)
Screening Period
(up to 12 weeks)
Extended Treatment Period
(28 weeks)
Follow-Up Period
(12 weeks)
End of 
Extended 
Treatment
End of DB 
Treatment
Visit 2
D-21±7
(endoscopy 
with biopsies)
Visit 3
D1
Visit 11
D169
W24
(endoscopy 
with biopsies)
Visit 19
D365
W52
(endoscopy 
with 
biopsies)
Visit 20
D421
W64
Visit 7
D57
W8
Home e-Diary
 
DB = double-blind. 
Note:  For patients who do not have at least 11 daily entries during the 14 days immediately preceding the planned 
randomization date (baseline), randomization should be postponed until this requirement is met, but without 
exceeding the 85-day maximum duration for screening. 
This study consists of 3 parts:  Part A and Part B are 24-week treatment, randomized, double-blind, 
placebo-controlled study phases, and Part C is a 28-week, extended active treatment phase that 
will enroll patients from Part A and Part B. A depiction of the randomization scheme for this study 
is below in Figure 2 . 
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Figure 2: 
Study Design 
 
Note: If there are restrictions to the clinical study as a result of the COVID-19 pandemic, it may 
be necessary to adjust the visit schedule, convert in-person visits to telephone contacts, and 
postpone study procedures until the next available in clinic study visit. It is necessary that the 
randomization visit (V3) and the first visit of Part C (V11) occur in the clinic. Endoscopies with 
biopsies are required at approximately week 24 and week 52. If it is not possible to complete the 
endoscopies with biopsies due to COVID-19 restrictions and provided there are no specific safety 
concerns for the patient, patients may continue their current study medication regimen until the 
endoscopies with biopsies can be performed. All temporary mechanisms utilized, and deviations 
from planned study procedures are to be documented as being related to COVID-19 and will 
remain in effect only for the duration of the public health emergency. Once COVID-19 conditions 
resolve, all study visits and procedures should follow the schedule of events as specified in Table 1, 
Table 2, and Table 3. 
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5.1.1. 
Part A 
5.1.1.1. 
Screening (Up to 12 Weeks) 
After adult patients provide informed consent and adolescent patients and/or their legal 
parents/legal guardians provide informed consent and informed assent (as appropriate), patients 
will be assessed for study eligibility at visit 1.  
Study participants are required to have a conﬁrmed diagnosis of EoE which may be established 
either by a prior historical biopsy showing ≥15 intraepithelial eosinophils per high-power ﬁeld 
(eos/hpf) from at least one esophageal region after at least 8 weeks of treatment with a high-dose 
proton pump inhibitor (PPI) using any approved PPI or by biopsies performed after approximately 
8 weeks of high-dose PPI treatment initiated prior to screening or during the screening period, 
which demonstrate ≥15 intraepithelial eos/hpf in at least 2 out of 3 esophageal regions (proximal, 
mid, and distal); see Figure 3 for endoscopy/biopsy procedure flow chart. Patients who are on PPIs 
during the screening period and are eligible to enroll in the study must continue a high-dose PPI 
regimen during the study (see details in Section 7.2). Patients are allowed to switch among the 
approved background therapy options for high-dose PPI use during the study.  
All patients who meet the other clinical and laboratory eligibility criteria will undergo endoscopy 
with biopsies at visit 2 (day -21±7) to establish a baseline reference measure. For patients without 
a historical biopsy, the visit 2 biopsy will serve as both confirmation of EoE diagnosis and the 
baseline reference measure. 
All biopsies performed during this study will be evaluated by pathologists at a central pathology 
laboratory who will be blinded to treatment assignment. 
Note:  Biopsy specimens from the stomach and/or duodenum will be obtained in all patients 
<18 years of age to rule out alternate etiologies of esophageal eosinophilia. Targeted, stomach, 
and/or duodenal biopsies will be obtained in adults only in the event of abnormal endoscopic 
findings (other than typical EoE findings) or clinical suspicion of alternate etiologies. All 
randomized patients found to have stomach and/or duodenal abnormalities at baseline will have 
follow-up stomach and/or duodenal biopsies at week 24 and week 52. 
After confirmation of EoE diagnosis, patients will be given an electronic diary (eDiary) to record 
dysphagia symptoms on a daily basis during the 2 weeks prior to the baseline visit (visit 3). 
Patients may be re-screened once if they fail the screening evaluation, unless the reason for screen 
failure is related to histologic or clinical disease severity inclusion criteria. The baseline endoscopy 
with biopsy and EoE-EREFS scoring will not be repeated for re-screened patients. These results 
will continue to be valid baseline data. Re-screening must occur within 6 months of the screen 
failure. 
For patients whose DSQ diary compliance does not meet eligibility requirements within the 21-day 
interval between Visit 2 and Visit 3 (at least 11 daily entries during the 14 days immediately 
preceding the planned randomization date), randomization may be postponed as long as the total 
duration of the screening period does not exceed the 85-day maximum. 
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Figure 3: 
Endoscopy/Biopsy Procedure Flow Diagram 
Historical esophageal biopsy showing at least 15 (eos/hpf) after 8-weeks of high-dose PPI
Proceed to Screening Endoscopy/Biopsies* at visit 2
If other clinical and laboratory eligibility criteria are met
Yes
No
Proceed to Screening Endoscopy/Biopsies* at visit 2
Endoscopy/Biopsies must be performed while on PPI
Histology results of the biopsies evaluated by a qualified 
central histology laboratory*
Peak intraepithelial eosinophil count sent to study site for 
eligibility assessment at baseline (visit 3)
*Biopsy specimens from the antrum and/or duodenum will be obtained in all patients <18 years of age to rule out alternate etiologies. 
Antral and/or duodenal biopsies will be obtained in adults only in the event of abnormal endoscopic findings (other than typical EoE 
findings) or clinical suspicion of alternate etiologies.  All randomized patients found to have stomach and/or duodenal abnormalities 
at baseline will have follow-up stomach and/or duodenal biopsies at week 24 and week 52.
If other clinical and laboratory eligibility criteria are met
8-week trial of high dose PPIs
Note:  the PPI trial can be initiated prior to screening
 
5.1.1.2. 
Randomization 
At the baseline visit (visit 3), patients who continue to meet eligibility criteria will enter the 
24-week treatment period and be randomized in a 1:1 ratio to dupilumab 300 mg SC QW or 
placebo SC. Patients may be randomized as soon as their baseline endoscopy/biopsy results are 
available and DSQ eDiary entries are completed. 
Randomization will be stratified by age (≥18 vs. ≥12 to <18 years of age) and use of PPI at 
randomization (yes vs. no). 
5.1.1.3. 
Placebo-Controlled Double-Blind Treatment Period (24 Weeks) 
During the approximately 24-week, placebo-controlled, double-blind treatment period, clinic visits 
are scheduled per the schedule of events (Table 1). Patients and parents/caregivers will be trained 
on injecting study drug at the first 3 visits during the double-blind treatment period. Patients will 
be closely monitored at the study site at visits 3 to 6 (baseline visit, study weeks 1, 2, and 4) for a 
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minimum of 30 minutes after the administration of study drug. During weeks when no clinic visit 
is scheduled or if a scheduled visit cannot occur due to COVID-19 restrictions, the patient or 
parent/caregiver will administer study drug. Doses of study drug administered at home should be 
administered one week after the prior dose of study drug. Study drug administration that occurs in 
clinic should occur per the Schedule of Events in Tables 1 and 2. Patients and parents/caregivers 
who prefer to have clinic staff administer study drug may choose to have injections administered 
in the clinic. Study drug may be shipped from the clinical site to the patient's home if necessary.  
The planned end of treatment visit for the double-blind treatment period is at approximately week 
24. The co-primary endpoints will be assessed at week 24, one week after the last dose of study 
drug during the double-blind treatment period.  
Patients who prematurely discontinue study treatment will be encouraged to remain in the study 
and attend all subsequent scheduled visits. 
At the end of double-blind treatment visit (week 24), eligible patients in Part A may enter Part C, 
which consists of an approximately 28-week extended active treatment period. Eligibility 
requirements for the extended active treatment period are provided in Section 6.2.3. Patients who 
do not enter Part C may enter a 12-week follow-up period (Section 5.1.4). 
Patients who participate in Part A are not eligible to participate in Part B. 
5.1.2. 
Part B 
Enrollment for Part B will begin immediately after the last patient is enrolled in Part A. 
5.1.2.1. 
Screening (Up to 12 Weeks) 
The screening procedures for Part B are identical to those described above for Part A. 
5.1.2.2. 
Randomization 
At the baseline visit (visit 3), patients who continue to meet eligibility criteria will enter the 
24-week double-blind treatment period and will be randomized in a 1:1:1 ratio to dupilumab 
300 mg SC QW, dupilumab 300 mg SC Q2W, or placebo SC. Eligible patients may be randomized 
as soon as their baseline endoscopy/biopsy results are available and DSQ eDiary entries are 
completed. 
Randomization will be stratified by age (≥18 vs ≥12 to <18 years of age) and use of PPI at 
randomization (yes vs. no).  
5.1.2.3. 
Placebo-Controlled Double-Blind Treatment Period (24 Weeks) 
Procedures for Part B are identical to those described above for Part A. 
Patients who prematurely discontinue study treatment will be encouraged to remain in the study 
and attend all subsequent scheduled visits. 
At the end of double-blind treatment visit (week 24), eligible patients in Part B may enter Part C, 
which consists of an approximately 28-week extended active treatment period. Eligibility 
requirements for the extended active treatment period are provided in Section 6.2.3. Patients who 
do not enter Part C will enter a 12-week follow-up period (Section 5.1.4). 
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5.1.3. 
Part C (28-Week Extended Active Treatment Period) 
At the end of the double-blind treatment visit (week 24), eligible patients in Parts A and B may 
enter an approximately 28-week extended active treatment period where all patients will receive 
active treatment with dupilumab but only patients in Part B will be blinded to treatment regimen 
in Part C. The eligibility criteria for Part C are provided in Section 6.2.3. 
Patients from Part A who are randomized to placebo during the double-blind treatment period will 
receive dupilumab 300 mg QW during Part C. Patients from Part A who are randomized to 
dupilumab 300 mg QW during the double-blind treatment period will continue to receive 
dupilumab 300 mg QW during Part C.  
Patients from Part B who are randomized to placebo during the double-blind treatment period will 
be re-randomized in a 1:1 ratio to dupilumab 300 mg QW or dupilumab 300 mg Q2W. Patients 
randomized to dupilumab 300 mg Q2W will also receive matching placebo alternating with 
dupilumab doses so the injection frequency will be identical for both groups for regimen-blinding 
purposes. All other patients will remain on the same dupilumab dose regimen to which they are 
randomized during the double-blind treatment period. Treatment assignment in Part C will be 
managed by an interactive voice/web response system (IVRS/IWRS) to maintain blinding of 
treatment assignment in Part B. 
5.1.4. 
Follow-Up Period (12 Weeks) 
All patients will be followed up for an additional 12 weeks after completing Part C. Patients in 
Parts A and B who choose not to participate in or are ineligible for Part C will be followed for an 
additional 12 weeks immediately after their respective trial part.  
5.1.5. 
End of Study Definition 
The end of study is defined as the last visit of the last patient in the study. 
5.2. 
Planned Interim Analysis  
No interim analysis (IA) is planned.  
Timing of the double-blind treatment period and extended active treatment period analyses are 
described in Section 10.4.9. 
5.3. 
Study Committees  
5.3.1. 
Independent Data Monitoring Committee 
An independent Data Monitoring Committee (DMC), composed of members who are independent 
from the sponsor and the study investigators, will monitor patient safety by conducting formal 
reviews of accumulated safety data that will be blinded by treatment group; if requested, the DMC 
may have access to the treatment allocation code or any other requested data for the purposes of a 
risk-benefit assessment. 
The DMC will provide the sponsor with appropriate recommendations on the conduct of the 
clinical study to ensure the protection and safety of the patients enrolled in the study. 
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All activities and responsibilities of the DMC are described in the DMC charter. 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
Approximately 80 patients (40 per treatment group) are planned to be enrolled in Part A. 
Approximately 210 patients (70 per treatment group) are planned to be enrolled in Part B at 
multiple global sites.  
6.2. 
Study Population  
Eligible patients for this study consist of adult males and females ≥18 years of age and adolescent 
males and females ≥12 to <18 years of age at the time of study entry with EoE. At least 10% of 
patients enrolled in Part B will be adolescents ≥12 to <18 years of age. At least 30% of patients 
enrolled in Part B must have a history of prior use of swallowed topical corticosteroids for the 
treatment of EoE. 
6.2.1. 
Inclusion Criteria for Parts A and B 
A patient must meet the following criteria to be eligible for inclusion in Part A and Part B of the 
study: 
1. 
Male or female, ≥12 years of age 
2. 
A documented diagnosis of EoE by endoscopic biopsy prior to screening, as demonstrated 
by intraepithelial eosinophilic infiltration (peak cell count ≥15 eos/hpf) from at least one 
esophageal region and performed after at least 8 weeks of treatment with a high-dose PPI 
regimen. If the patient discontinued PPI therapy, the biopsy must have been performed 
within 2 weeks of the date of discontinuation. 
If a prior (historical) endoscopic biopsy meeting these criteria is not available (or no prior 
biopsy is available), patients who meet other clinical and laboratory eligibility criteria will 
undergo treatment with a high-dose PPI regimen for at least 8 weeks before their baseline 
endoscopy/biopsies. (See Section 7.2 for acceptable high-dose PPI regimens). 
Note: If the patient is already using an acceptable high dose PPI regimen at the time of the 
screening visit, the baseline endoscopy may be scheduled at any point during the screening 
period after 8 weeks of treatment have been documented.  
3. 
Baseline endoscopic biopsies with a demonstration on central reading of intraepithelial 
eosinophilic infiltration (peak cell count ≥15 eos/hpf) in at least 2 of the 3 biopsied 
esophageal regions (proximal, mid, or distal) 
4. 
History (by patient report) of an average of at least 2 episodes of dysphagia (with intake of 
solids) per week in the 4 weeks prior to screening 
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5. 
At least 4 episodes of dysphagia in the 2 weeks prior to baseline, documented via eDiary, 
at least 2 of which require liquids, coughing or gagging, vomiting, or medical attention to 
obtain relief 
6. 
Completed at least 11 of 14 days of DSQ eDiary data entry in the 2 weeks prior to the 
baseline visit (visit 3) 
7. 
Baseline DSQ score ≥10. 
8. 
Able to understand and complete study-related questionnaires 
9. 
Willing and able to comply with clinic visits and study-related procedures 
10. Provide informed consent signed by study patient or legally acceptable representative. For 
adolescents, parent or legal guardian must provide signed informed consent (patients must 
also provide separate informed assent to enroll in the study, and the assent documented 
either in a separate informed assent form [IAF] or in the informed consent form [ICF] 
signed by the parent(s)/legal guardian [as appropriate based on local regulations and 
requirements]). 
6.2.2. 
Exclusion Criteria for Parts A and B 
A patient who meets any of the following criteria will be excluded from Part A and Part B of the 
study: 
1. 
Body weight ≤40 kg 
2. 
Prior participation in a dupilumab clinical trial, or past or current treatment with dupilumab 
3. 
Initiation or change of a food-elimination diet regimen or re-introduction of a previously 
eliminated food group in the 6 weeks prior to screening. Patients on a food-elimination diet 
must remain on the same diet throughout the study. 
4. 
Other causes of esophageal eosinophilia or the following conditions:  hypereosinophilic 
syndrome and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) 
Note:  Patients with eosinophilic gastroenteritis are eligible, provided they meet other 
eligibility criteria. 
5. 
Active Helicobacter pylori infection 
6. 
History of achalasia, Crohn’s disease, ulcerative colitis, celiac disease, and prior 
esophageal surgery 
7. 
Any esophageal stricture unable to be passed with a standard, diagnostic, 9 to10 mm upper 
endoscope or any critical esophageal stricture that requires dilation at screening 
8. History of bleeding disorders or esophageal varices that, in the opinion of the investigator, 
would put the patient at undue risk for significant complications from an endoscopy 
procedure  
9. 
Treatment with swallowed topical corticosteroids within 8 weeks prior to baseline 
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10. Initiation, discontinuation, or change in the dosage regimen of the following medications 
within 8 weeks prior to the baseline endoscopy: 
• Proton pump inhibitors (except for patients who require a PPI trial prior to baseline 
endoscopy) 
• Leukotriene inhibitors 
• Nasal and/or inhaled corticosteroids 
• Patients on a stable dose of these medications for at least 8 weeks prior to the baseline 
endoscopy may be included in the study, but must not change the dose during the 
study. 
11. Initiation, discontinuation, or change in the dosage regimen of SC immunotherapy (SCIT) 
• Patients on a stable dose of these medications for at least 1 year prior to visit 1 may 
be included in the study, but must not change the dose during the study. 
12. Treatment with sublingual immunotherapy (SLIT) 
13. Treatment with oral immunotherapy (OIT) within 6 months prior to visit 1 
14. The following treatments within 3 months prior to screening, or any condition that, in the 
opinion of the investigator, is likely to require such treatment(s) during the study: 
• Systemic immunosuppressant/immunomodulating drugs, including but not limited to 
systemic 
corticosteroids, 
omalizumab, 
cyclosporine, 
mycophenolate-mofetil, 
interferon-gamma [IFN-γ], Janus kinase inhibitors, azathioprine, and methotrexate  
− Note: One-time use of a corticosteroid as a part of the anesthetic preparation used 
during each endoscopy procedure is allowed. 
15. Treatment with an investigational drug within 2 months or within 5 half-lives (if known), 
whichever is longer, prior to visit 1 
16. Planned or anticipated use of any prohibited medications and procedures during the study 
17. Planned or anticipated major surgical procedure during the study 
18. Treatment with a live (attenuated) vaccine within 4 weeks prior to the baseline visit 
19. Active parasitic infection or suspected parasitic infection, unless clinical and (if necessary) 
laboratory assessments have ruled out active infection before randomization 
20. Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or 
antifungals within 2 weeks before baseline visit. 
Note:  A patient may be re-screened after the infection resolves. 
21. Known or suspected immunodeficiency disorder, including history of invasive 
opportunistic infections (eg, tuberculosis [TB], non-tuberculous mycobacterial infections, 
histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite 
infection resolution, or otherwise recurrent infections of abnormal frequency, or prolonged 
infections suggesting an immune-compromised status, as judged by the investigator. 
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Tuberculosis testing will be performed on a country-by-country basis according to local 
guidelines if required by regulatory authorities or ethics committees (ECs). 
22. Known history of human immunodeficiency virus (HIV) infection 
23. Established diagnosis of hepatitis B viral infection at the time of screening or positive for 
hepatitis B surface antigen (HBsAg) at the time of screening 
• Patients who have gained immunity for hepatitis B virus infection after vaccination 
(patients who are HBsAg negative, hepatitis B surface antibody [HBsAb] positive, and 
hepatitis B core antibody [HBcAb] negative are eligible for the study). 
• Patients with positive HBcAb are eligible for the study only if hepatitis B virus DNA 
level is undetectable.  
24. Established diagnosis of hepatitis C viral (HCV) infection at the time of screening Patients 
positive for hepatitis C Ab are eligible for the study only if HCV RNA is negative. 
25. On current treatment for hepatic disease including but not limited to acute or chronic 
hepatitis, cirrhosis, or hepatic failure, or has evidence of liver disease as indicated by 
persistent (confirmed by repeated tests ≥2 weeks apart) elevated transaminases (alanine 
aminotransferase [ALT] and/or aspartate aminotransferase [AST]) more than 3 times the 
upper limit of normal [ULN] during the screening period) 
26. Any of the following abnormal lab values at screening: 
• Platelets <100 ×103/μL 
• Neutrophils <1.5 × 103/μL 
• Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 
Note:  If an abnormal value is detected at screening, a repeat test should be performed to 
confirm the abnormality. Only if the repeat test confirms the abnormality would the 
patient be categorized as a screen failure. eGFR will be calculated using the Modification 
of Diet in Renal Disease (MDRD) equation in adult patients and using the Bedside 
Schwartz formula in patients <18 years of age. 
27. Severe concomitant illness(es) that, in the investigator’s judgment, would adversely affect 
the patient’s participation in the study. Examples include but are not limited to short life 
expectancy, uncontrolled diabetes, cardiovascular conditions (eg, NYHA Class III or IV 
cardiac failure), severe renal conditions (eg, severe nephrotic syndrome), hepatobiliary 
conditions (eg, Child-Pugh class B or C), neurological conditions (eg, demyelinating 
diseases), active major autoimmune diseases (eg, lupus, inflammatory bowel disease, 
rheumatoid arthritis, etc.), other severe endocrinologic, gastrointestinal, metabolic, 
pulmonary, or lymphatic diseases. The specific justification for patients excluded under 
this criterion will be noted in study documents (chart notes, case report forms [CRF], etc).  
28. History of malignancy within 5 years prior to screening, except completely treated in situ 
carcinoma of the cervix and completely treated non-metastatic squamous or basal cell 
carcinoma of the skin 
29. History of alcohol or drug abuse within 6 months prior to screening 
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30. Any other medical or psychological condition including relevant laboratory abnormalities 
at screening that, in the opinion of the investigator, suggest a new and/or insufficiently 
understood disease, may present an unreasonable risk to the study patient as a result of 
his/her participation in this clinical trial, may make patient’s participation unreliable, or 
may interfere with study assessments. The specific justification for patients excluded under 
this criterion will be noted in study documents. 
31. Patient or his/her immediate family is a member of the investigational team 
32. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed 
during the study 
33. Women of childbearing potential* 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. Highly effective contraceptive measures include:  
a. Stable use of combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, 
injectable, implantable) associated with inhibition of ovulation initiated 2 or more 
menstrual cycles prior to screening 
b. Intrauterine device; intrauterine hormone-releasing system 
c. Bilateral tubal ligation 
d. Vasectomized partner 
e. And/or sexual abstinence†, ‡. 
*Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential. Pregnancy testing and contraception are not 
required for women with documented hysterectomy or tubal ligation. 
†Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
‡Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method are not 
acceptable methods of contraception. Female condom and male condom should not be 
used together.  
34. Known systemic hypersensitivity to dupilumab or the excipients of the drug product 
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6.2.3. 
Exclusion Criteria for Part C (the Extended Active Treatment Period) 
A patient who meets any of the following criteria will not be permitted to enter Part C (the extended 
active treatment period): 
1. 
Patients who, during the double-blind treatment period, developed a serious adverse event 
(SAE) and/or adverse event (AE) deemed related to study drug, which in the opinion of the 
investigator could indicate that continued treatment with study drug may present an 
unreasonable risk for the patient 
2. 
Patients who, during the double-blind treatment period, were prematurely withdrawn 
because of a protocol violation, poor compliance, or inability to complete required study 
assessments 
3. 
Patients who became pregnant during the double-blind treatment period 
4. 
Patients who are prematurely discontinued from study drug due to an AE (patients who are 
prematurely discontinued from study drug due to lack of efficacy are eligible to enter 
Part C) 
5. 
Patients who did not undergo endoscopy with biopsies prior to receiving rescue treatment 
Note: If the endoscopy with biopsies cannot occur due to COVID-19 restrictions, 
rescue treatment should be initiated without delay and these patients will be 
eligible to participate in Part C when the patient can next return to the clinic.  
6. 
Systemic hypersensitivity to dupilumab or the excipients of the drug product based on 
participation in Part A or Part B 
6.3. 
Premature Withdrawal from the Study  
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures). An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patient who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 8.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.4.2. 
6.4. 
Replacement of Patient 
Patient prematurely discontinued from study/study drug will not be replaced. 
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7. 
STUDY TREATMENTS  
7.1. 
Investigational and Reference Treatments 
Dupilumab drug product is supplied for this study in the following concentration:   
• Dupilumab 150 mg/mL:  Each 2.0 mL single-use prefilled glass syringe with snap-off 
cap delivers 300 mg of study drug (2.0 mL of a 150 mg/mL solution) 
Placebo matching dupilumab is prepared in the same formulation without the addition of protein 
(ie, active substance, anti-IL-4Rα monoclonal Ab). 
In the double-blind placebo-controlled Parts A and B, as well as Part C, all patients will receive 
QW SC injections. For the dupilumab 300 mg SC Q2W group, in order to maintain the blind, there 
will be an SC injection of placebo in between dupilumab doses so the injection frequency will 
match the other 2 groups (dupilumab QW and placebo) (see randomization/treatment assignment 
in Section 5.1.1.2 for Part A, Section 5.1.2.2 for Part B, Section 5.1.3 for Part C, and Section 7.5). 
In the extended active treatment Part C, patients will receive dupilumab injections at the frequency 
(QW or Q2W with matching placebo alternating with  dupilumab doses so the injection frequency 
will be identical for both groups for regimen-blinding purposes) per their treatment assignment 
(see Section 5.1.3 and Section 7.5). 
Study drug will be administered by SC injections. Subcutaneous injection sites of study drug 
should be alternated among the different quadrants of the abdomen (avoiding navel and waist 
areas), upper thighs, and upper arms so that the same site is not injected for 2 consecutive 
administrations. 
Instructions on dose preparation are provided in the pharmacy manual. 
7.2. 
Background Treatment 
Patients who undergo a trial of high-dose PPI therapy initiated prior to screening or during the 
screening period of Part A or Part B must remain on a dosage regimen listed below for the duration 
of the 52-week treatment period. A high-dose PPI regimen is defined as follows: 
• omeprazole 40 mg once a day (QD) or 20 mg twice a day (BID) 
• esomeprazole 40 mg QD or 20 mg BID 
• lansoprazole 60 mg QD or 30 mg BID 
• dexlansoprazole 60 mg QD  
• rabeprazole 40 mg QD or 20 mg BID  
• pantoprazole 80 mg QD or 40 mg BID 
Patients who present at the initial screening visit with current use of PPIs must also remain on the 
same or similar approved dosage regimen for the duration of the 52-week treatment period. 
Patients may change to a different approved PPI medication during the study. PPI therapy is 
prohibited for all other patients. 
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7.3. 
Rescue Treatments 
If medically necessary (eg, for treatment of intolerable EoE symptoms), rescue medications 
(systemic and/or swallowed topical corticosteroids) or emergency esophageal dilation are allowed 
for study patients in Parts A, B, and C. An endoscopy with biopsy will be performed prior to the 
initiation of rescue therapy. Patients who undergo an endoscopy with biopsy due to the initiation 
of rescue therapy will not undergo the scheduled end of treatment visit endoscopy/biopsy at weeks 
24 and 52. Patients who receive rescue treatment during the double-blind period of the study will 
not be eligible for the extended active treatment period unless an endoscopy with biopsy is 
performed prior to the initiation of rescue treatment. However, if the endoscopy with biopsies 
cannot occur due to COVID-19 restrictions, rescue treatment should not be delayed, and these 
patients will be eligible for Part C. Part C treatment will be initiated per the schedule of events and 
only at an in-clinic visit.  
Patients receiving rescue therapy may continue to receive study drug. They will remain blinded 
and will be asked to return to the clinic for all remaining study visits for the double-blind treatment 
period and the follow-up period, and participate in all assessments for these visits according to the 
schedule of events specified in Table 1, Table 2, and Table 3, except for endoscopy/biopsy, as 
noted above. For the purpose of efficacy analyses, patients who receive rescue treatment during 
the study will be considered treatment failures. 
7.4. 
Dose Modification and Study Treatment Discontinuation Rules 
7.4.1. 
Dose Modification 
Dose modification for an individual patient is not allowed.  
7.4.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug during the double-blind treatment period 
will be asked to return to the clinic for all remaining study visits for the double-blind treatment 
period and follow-up period per the visit schedule. 
Patients who permanently discontinue from study drug during the extended active treatment period 
will be asked to return to the clinic for all remaining study visits per the visit schedule. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete an early termination (ET) visit, per Section 8.1.2. 
7.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
• Evidence of pregnancy 
• Anaphylactic reaction or other severe systemic reaction deemed related to study drug  
• Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix or 
squamous or basal cell carcinoma of the skin. Patient must be withdrawn for these latter 
malignancies if they cannot be adequately treated by local resection. 
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• Any infection that is opportunistic, such as TB and other infections whose nature or 
course may suggest an immunocompromised status 
• Severe laboratory abnormalities assessed as related to study drug: 
− Neutrophil count ≤0.5 × 103/µL 
− Platelet count ≤50 × 103/µL 
− ALT and/or AST values >3 × ULN with total bilirubin >2 × ULN, excluding 
confirmed Gilbert’s Syndrome 
− Confirmed AST and/or ALT >5 × ULN (for more than 2 weeks) 
7.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug dosing may be temporarily discontinued in the event of: 
• Severe laboratory abnormalities (as noted in Section 7.4.2.1) where a causal 
relationship to study drug can be reasonably excluded, (ie, an alternative cause is 
evident):  study drug will be discontinued but may be resumed when the laboratory 
abnormality is sufficiently normalized. At minimum, the laboratory value(s) must 
return to a level that no longer meets the specified criteria for discontinuation, as 
defined in Section 7.4.2.1. A decision to resume study treatment will be made jointly 
by the investigator and medical monitor (medical monitor’s written approval is 
required). 
• An infection that requires parenteral treatment with antibiotic, antifungal, antiviral, 
antiparasitic, or antiprotozoal agents, or requires oral treatment with such agents for 
longer than 2 weeks 
• Other intercurrent illnesses or major surgery which could, in the opinion of the 
investigator, present an unreasonable risk to the patient as a result of his/her continued 
participation in the study 
After the condition leading to suspension of dosing normalizes sufficiently, study treatment may 
resume at the discretion of the principal investigator in consultation with the medical monitor. 
A decision to temporarily discontinue study drug and/or to reinstitute study treatment should be 
discussed with the medical monitor. The investigator may suspend study treatment at any time, 
even without consultation with the medical monitor if the urgency of the situation requires 
immediate action and if this is determined to be in the patient’s best interest. However, the medical 
monitor should be contacted as soon as possible in any case of study drug discontinuation. 
Resumption of study treatment after temporary discontinuation requires consultation and 
agreement between the investigator and the medical monitor. 
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7.5. 
Method of Treatment Assignment  
In Part A, approximately 80 patients (40 per group) will be randomized in a 1:1 ratio to receive 
dupilumab 300 mg QW or placebo according to a central randomization scheme provided by an 
IVRS/IWRS to the designated study pharmacist (or qualified designee). 
In Part B, approximately 210 patients will be randomized in a 1:1:1 ratio to receive dupilumab 
300 mg QW, dupilumab 300 mg Q2W, or placebo (approximately 70 patients per group) according 
to a central randomization scheme provided by IVRS/IWRS to the designated study pharmacist 
(or qualified designee). 
Randomization for both Part A and Part B will be stratified according to age at the time of the 
screening visit (≥12 to <18 years of age vs. ≥18 years of age) and use of PPI at randomization (yes 
vs. no).  
For patients entering Part C from Part B, those who are randomized to placebo during Part B will 
be re-randomized in a 1:1 ratio to receive dupilumab 300 mg QW or dupilumab 300 mg Q2W 
(with matching placebo alternating with dupilumab doses so the injection frequency will be 
identical for both groups for regimen-blinding purposes) in Part C, and those who are randomized 
to one of the dupilumab dose regimens in Part B will remain on the same dupilumab dose regimen 
in Part C. Patients who received 300 mg Q2W in Part B will also continue with matching placebo 
alternating with dupilumab doses so the injection frequency will be identical for both groups for 
regimen-blinding purposes. Treatment assignment in Part C for all patients from Part B, regardless 
of their previously assigned treatment in Part B, will be managed by IVRS/IWRS to maintain 
blinding. 
7.5.1. 
Blinding  
Study patients, the principal investigators, and study site personnel will remain blinded to all 
randomization assignments throughout the study. The blinded Regeneron Medical/Study Director, 
Study Monitor, and any other Regeneron and contract research organization (CRO) personnel who 
are in regular contact with the study site will remain blinded to all patient randomization 
assignments. 
All study personnel will be blinded to data during each study part until the respective database 
lock. Part A will be unblinded while Part B is ongoing. 
Blinded study drug kits coded with a medication numbering system will be used. In order to 
maintain the blind, lists linking these codes with product lot numbers will not be accessible to 
individuals involved in study conduct. 
Anti-drug antibody, drug concentration results, and any post-treatment tissue eosinophil counts 
and histologic results, and biomarker results (eotaxin-3, thymus and activation-regulated 
chemokine [TARC], total IgE and allergen-specific IgEs) will not be communicated to the sites, 
and the sponsor’s blinded operational team will not have access to results associated with patient 
identification until after the database is locked for the respective study part. 
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7.5.2. 
Emergency Unblinding 
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event (eg, pregnancy). 
• If unblinding is required: 
− Only the investigator will make the decision to unblind the treatment assignment. 
− Only the affected patients will be unblinded. 
− The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator. If there is no study pharmacist, the 
investigator for the site will unblind the patient. 
− The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the patient. 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency. In the event that there is no study pharmacist, the individual at the site fulfilling 
that role will be the only unblinded member of the site personnel. 
7.5.3. 
Unblinding for Regulatory Reporting Purposes 
Treatment assignments for certain patients may be unblinded to Pharmacovigilance personnel for 
the purpose of regulatory reporting of suspected unexpected serious adverse reactions (SUSARs) 
to health authorities in accordance with local regulations. 
7.6. 
Treatment Logistics and Accountability 
7.6.1. 
Packaging, Labeling, and Storage 
A medication numbering system will be used to label blinded investigational study drug. Lists 
linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging. In order to maintain the blind, these lists will 
not be accessible to individuals involved in study conduct.  
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
7.6.2. 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study. At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be returned to the sponsor or designee 
for destruction, unless it’s specified that the site may perform their own destruction. 
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7.6.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study drug that is: 
• dispensed to each patient, 
• returned from each patient (if applicable), or 
• disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
7.6.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
7.7. 
Concomitant Medications and Procedures  
Any treatment administered from the time of informed consent to the final study visit will be 
recorded. Any treatment administered from the time of first dose of study drug to the final study 
visit will be considered concomitant medication; this includes medications that were started before 
the study and are ongoing during the study. 
7.7.1. 
Prohibited Medications and Procedures  
Treatment with the following concomitant medications is prohibited through week 52:   
• Swallowed topical corticosteroids (may be used as rescue treatment for EoE) 
• Systemic corticosteroids (may be used as rescue treatment for EoE)  
− Note: One-time use of a corticosteroid as a part of the anesthetic preparation used 
during each endoscopy procedure is allowed. 
• Systemic immunosuppressive/immunomodulating drugs (including, but not limited to, 
omalizumab, cyclosporine, mycophenolate-mofetil, azathioprine, methotrexate, IFN-γ, 
or other biologics)  
• Treatment with an investigational drug (other than dupilumab) 
• Initiation, discontinuation, or change in dosage regimen of the following medications 
within 8 weeks prior to the baseline endoscopy (stable doses of these medications are 
allowed) 
− Proton pump inhibitors, unless used for a required PPI trial during the screening 
period or in patients who present at the initial screening visit with current use of 
PPIs 
− Systemic leukotriene inhibitors 
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− Nasal and/or inhaled corticosteroids 
• Initiation of SCIT, or change in dose for those patients on a stable dose of SCIT within 
1 year prior to screening  
• SLIT 
• OIT 
• Treatment with an investigational drug (other than dupilumab) 
• Treatment with a live (attenuated) vaccine 
Chickenpox (varicella) 
FluMist-Influenza 
Intranasal influenza 
Measles (rubeola) 
Measles-mumps-rubella combination 
Measles-mumps-rubella-varicella combination 
Mumps 
Oral polio (Sabin) 
Oral typhoid 
Rubella 
Smallpox (vaccinia) 
Yellow fever 
Bacille Calmette-Guerin 
Rotavirus 
Varicella zoster (shingles) 
The following concomitant procedures are prohibited during study treatment (through week 52): 
• Major elective surgical procedures 
• Esophageal dilation (may be used as rescue procedure) 
• Initiation or change of food-elimination diet regimen 
7.7.2. 
Permitted Medications and Procedures  
Other than the prohibited medications listed in Section 7.7.1, treatment with concomitant 
medications are permitted during the study. Medications used to treat chronic disease such as 
diabetes and hypertension are also permitted. If there is any question regarding whether a 
concomitant medication may be used during the study, the study site should contact the medical 
monitor. 
7.7.3. 
Restricted Medications and Procedures during the Follow-Up Period 
Patients may receive the prohibited medications/procedures listed in Section 7.7.1 as needed 
during the follow-up period, with the exception of live (attenuated) vaccine, which should not be 
used within 3 months after the last dose of study drug. Investigators are advised to prescribe 
prohibited medications/procedures judiciously, only when they are absolutely required for the 
appropriate management of study patients. 
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8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1 for the 
screening period and double-blind treatment period in Parts A and B, in Table 2 for the extended 
active treatment period in Part C, and in Table 3 for the follow-up period, ET visit, and 
unscheduled visit. 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms. 
Examples of such mechanisms may include, but are not limited to, any of the following:  phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff. Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All 
temporary mechanisms utilized, and deviations from planned study procedures are to be 
documented as being related to COVID-19 and will remain in effect only for the duration of the 
public health emergency. 
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Table 1: 
Parts A and B Schedule of Events – Screening Period and Double-Blind Treatment Period 
 
Screening Period 
24-Week Double-Blind Treatment Period18 
Study Procedure 
Screening1 
V1 
Screening 
Endoscopy/ 
Biopsy2 
V2 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
DB 
EOT 
V113 
Week (W) 
 
 
 
W1 
W2 
W4 
W8 
W12 
W16 
W20 
W243 
Day (D) 
D-85 to  
D-291 
D-212 
D1 
D8 
D15 
D29 
D57 
D85 
D113 
D141 
D169 
Visit Window (Days [d]) 
 
±7 d 
 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
+7 d 
Screening4/Baseline: 
Informed consent and assent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
Med. history, Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Randomization2a 
 
 
X2a 
 
 
 
 
 
 
 
 
Treatment: 
Training for self-injection5 
 
 
X 
X6a 
X6a 
 
 
 
 
 
 
Administer study drug6, 6a 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug dispensation6, 6a 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Study drug accountability 
 
 
 
X6a 
X6a 
X 
X 
X 
X 
X 
X 
Concomitant medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy:7 
DSQ PRO (daily)8 
assessed by patient daily using eDiary  
PGIC9 
 
 
 
 
 
 
 
X  
 
X  
X 
PGIS9 
 
 
X 
 
 
 
 
X  
 
X  
X 
EoE Impact Questionnaire 10 
 
 
X 
 
 
 
 
X 
 
 
X 
EoE Symptom Questionnaire10 
 
 
X 
 
 
 
 
X 
 
 
X 
TNSS11 
 
 
X 
 
 
 
 
X 
 
 
X 
RQLQ(S)+1211 
 
 
X 
 
 
 
 
X 
 
 
X 
ACQ-511 
 
 
X 
 
 
 
 
X 
 
 
X 
POEM11 
 
 
X 
 
 
 
 
X 
 
 
X 
EQ-5D-3L 
X17 
 
X17 
 
 
 
 
 
 
 
  
EoE-EREFS2,12 
 
X2, 2a, 4 
 
 
 
 
 
 
 
 
X2, 2b 
Endoscopy with biopsies (histology, IHC, 
RNA, EndoFLIP)2 
 
X2, 2a, 4 
 
 
 
 
 
 
 
 
X2, 2b 
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Screening Period 
24-Week Double-Blind Treatment Period18 
Study Procedure 
Screening1 
V1 
Screening 
Endoscopy/ 
Biopsy2 
V2 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
DB 
EOT 
V113 
Week (W) 
 
 
 
W1 
W2 
W4 
W8 
W12 
W16 
W20 
W243 
Day (D) 
D-85 to  
D-291 
D-212 
D1 
D8 
D15 
D29 
D57 
D85 
D113 
D141 
D169 
Visit Window (Days [d]) 
 
±7 d 
 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
+7 d 
Safety: 7, 7a, 18 
Vital signs13 
X 
X 
X13 
X13, 13a 
X13, 13a 
X13, 13a 
X13a 
X13a 
X13a 
X13a 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
X14 
Weight 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
x 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing:7, 7a 
Hematology, Chemistry 
X 
 
X 
 
 
 
 
X 
 
 
X 
Serology tests 15  
X 
 
 
 
 
 
 
 
 
 
 
Serum FSH 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test16 
Serum 
Urine 
Urine 
 
 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urinalysis 
X 
 
X 
 
 
 
 
X 
 
 
X 
PK and ADA:7, 7a 
PK sample 
 
 
X 
 
  
  
 
X 
 
 
X 
ADA sample 
 
 
X 
 
 
  
 
X 
 
 
X 
Biomarkers and Genomics:7, 7a 
Whole blood DNA (optional) 
 
 
X 
 
 
 
 
 
 
 
 
Whole blood RNA (optional) 
X 
 
X 
 
 
 
 
 
 
 
X 
Plasma Eotaxin-3 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Serum TARC 
X 
 
X 
 
 
X 
 
 
 
 
X 
Serum Total IgE 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Allergen-specific IgE, IgG4  
X 
 
X 
 
 
X 
 
X 
 
 
X 
Future Biomarker Serum/Plasma 
X 
 
X 
 
 
X 
 
X 
 
 
X 
ADA = anti-drug antibody; DB EOT = end of double-blind treatment period; DSQ = Dysphagia Symptom Questionnaire; ECG = electrocardiogram; 
EoE-EREFS = Eosinophilic Esophagitis-Endoscopic Reference Score; EQ-5D-3L = European Quality of Life 5-dimension (version 3L; 3-level); IHC = 
immunohistochemistry; PGIC = Patient Global Impression of Change of Dysphagia; PGIS = Patient Global Impression of Severity of Dysphagia; POEM = 
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Patient-Oriented Eczema Measure; PRO = patient-reported outcome; PK = pharmacokinetic; RQLQ(S)+12 = Rhinoconjunctivitis Quality of Life Questionnaire 
for patients aged 12+ years; TNSS = Total Nasal Symptom Score; V = visit 
Table 2: 
Part C Schedule of Events – Extended Active Treatment Period 
 
28-Week Extended Active Treatment Period 14 
Study Procedure 
V111 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
EOT 
V19 
Week (W) 
W241 
W26 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
Day (D) 
D169 
D183 
D197 
D225 
D253 
D281 
D309 
D337 
D365 
Visit Window (Days [d]) 
+7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
+7 d 
Treatment:2 
Administer study drug 3, 4, 4a 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug dispensation 4, 4a 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/procedures 
 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy:2 
DSQ eDiary5 
--------------------------- completed daily by patient --------------------------------→ 
PGIC6 
 
 
 
 
X 
 
 
 
X 
PGIS6 
 
 
 
 
X 
 
 
 
X 
EoE Impact Questionnaire7 
 
 
 
 
X 
 
 
 
X 
EoE Symptom Questionnaire 7 
 
 
 
 
X 
 
 
 
X 
TNSS 8 
 
 
 
 
X 
 
 
 
X 
RQLQ(S)+12 8 
 
 
 
 
X 
 
 
 
X 
POEM 8 
 
 
 
 
X 
 
 
 
X 
ACQ-5 8 
 
 
 
 
X 
 
 
 
X 
EoE-EREFS 9, 10 
 
 
 
 
 
 
 
 
X10, 10a 
Endoscopy with biopsies (histology, 
IHC, RNA, EndoFLIP)10 
 
 
 
 
 
 
 
 
X10, 10a 
Safety: 2, 2a, 14 
Vital signs 11 
X11 
X11 
X 
X 
X 
X 
X 
X 
X 
Height 12 
 
 
 
 
 
 
 
 
X 
Weight 
 
X 
X 
X 
X 
 
 
 
X 
Physical examination 
 
 
 
 
 
 
 
 
X 
ECG 
 
 
 
 
 
 
 
 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
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28-Week Extended Active Treatment Period 14 
Study Procedure 
V111 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
EOT 
V19 
Week (W) 
W241 
W26 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
Day (D) 
D169 
D183 
D197 
D225 
D253 
D281 
D309 
D337 
D365 
Visit Window (Days [d]) 
+7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
+7 d 
Laboratory Testing:2, 2a 
Hematology, Chemistry 
 
 
 
 
X 
 
 
 
X 
Pregnancy test 13 
 
Urine 
 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urinalysis 
 
  
 
  
X 
 
 
 
X 
PK and ADA:2, 2a   
PK Sample 
 
 
 
X 
 
 
 
 
X 
ADA sample 
 
 
 
X 
 
 
 
 
X 
Biomarkers:2, 2a 
Whole blood RNA (optional) 
 
 
 
 
 
 
 
 
X 
Plasma Eotaxin-3 
 
X 
 
X 
 
 
 
 
X 
Serum TARC 
 
 
 
 
 
 
 
 
X 
Serum Total IgE 
 
X 
 
X 
 
 
 
 
X 
Allergen-specific IgE, IgG4  
 
X 
 
X 
 
 
 
 
X 
Future Biomarker Serum/Plasma 
 
X 
 
X 
 
 
 
 
X 
ADA = anti-drug antibody; DSQ = Dysphagia Symptom Questionnaire; ECG = electrocardiogram; EoE-EREFS = Eosinophilic Esophagitis-Endoscopic 
Reference Score; EOT = end of extended active treatment period; IHC = immunohistochemistry; POEM = Patient-Oriented Eczema Measure; PRO = patient 
reported outcome; PGA = physician global assessment; PGIC = Patient Global Impression of Change of Dysphagia; PGIS = Patient Global Impression of 
Severity of Dysphagia; PK = pharmacokinetic; RQLQ(S)+12 = Rhinoconjunctivitis Quality of Life Questionnaire for patients aged 12+ years; TNSS = Total 
Nasal Symptom Score; V = visit 
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Table 3: 
Follow-up Period, Early Termination Visit, and Unscheduled Visit 
Study Procedure 
12-Week Follow-Up 
EOS Visit 
Early 
Termination 
during 12-
Week Follow-
Up1 
Early 
Termination 
during Parts 
A, B, or C1 
Unscheduled Visit before 
Rescue Treatment 
Unscheduled 
Visit for Other 
Reasons 
Week (W) 
12 weeks after EOT visit 
 
 
 
 
Day (D) 
84 days after EOT visit 
 
 
 
 
Visit Window (Days [d]) 
±7 d 
 
 
 
 
Concomitant 
medications/procedures10 
X 
X 
X 
X 
X 
Efficacy: 
DSQ eDiary2 
completed daily by 
patient→ 
 
X 
X 
 
PGIC3 
 
 
X 
X 
 
PGIS3 
 
 
X 
X 
 
EoE Impact Questionnaire 4 
 
 
X 
X 
 
EoE Symptom Questionnaire 4 
 
 
X 
X 
 
TNSS 5 
 
 
X 
X 
 
RQLQ(S)+12 5 
 
 
X 
X 
 
ACQ-5 5 
 
 
X 
X 
 
POEM 5 
 
 
X 
X 
 
EoE-EREFS 6, 7 
 
 
X 7, 7a 
X 8 
 
Endoscopy with biopsies (histology, 
IHC, RNA)7 
 
 
X 7, 7a 
X 8 
 
Safety10:  
Vital signs  
X 
X 
X 
X 
 
Height 9 
 
 
X 
 
 
Weight 
X 
X 
X 
 
 
Physical examination 
 
 
X 
 
 
ECG 
 
 
X 
 
 
Adverse events 
X 
X 
X 
X 
X 
Laboratory Testing10: 
Hematology, Chemistry 
X 
X 
X 
 
 
Pregnancy test 
Urine 
Urine 
Urine 
 
 
Urinalysis 
X 
X 
X 
 
 
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Study Procedure 
12-Week Follow-Up 
EOS Visit 
Early 
Termination 
during 12-
Week Follow-
Up1 
Early 
Termination 
during Parts 
A, B, or C1 
Unscheduled Visit before 
Rescue Treatment 
Unscheduled 
Visit for Other 
Reasons 
Week (W) 
12 weeks after EOT visit 
 
 
 
 
Day (D) 
84 days after EOT visit 
 
 
 
 
Visit Window (Days [d]) 
±7 d 
 
 
 
 
PK and ADA10: 
PK Sample 
X 
X 
X 
X 
 
ADA sample 
X 
X 
X 
X 
X 
Biomarkers: 
Future Biomarker Serum/Plasma 
(optional) 
 
 
X 
 
 
ADA = anti-drug antibody; DSQ = Dysphagia Symptom Questionnaire; ECG = electrocardiogram; EoE-EREFS = Eosinophilic Esophagitis-Endoscopic 
Reference Score; EOS = end of study (visit); EOT = end of treatment period; POEM = Patient-Oriented Eczema Measure; PRO = patient-reported outcome; 
PGA = physician global assessment; PGIC = Patient Global Impression of Change of Dysphagia; PGIS = Patient Global Impression of Severity of Dysphagia; 
PK = pharmacokinetic; RQLQ(S)+12 = Rhinoconjunctivitis Quality of Life Questionnaire for patients aged 12+ years; TNSS = Total Nasal Symptom Score 
 
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8.1.1. 
Footnotes for the Schedule of Events Tables 
8.1.1.1. 
Footnotes for Table 1 
1. For patients without a satisfactory prior endoscopy/biopsy (eg, histological criteria were 
not met, or the biopsy was not performed while patient was on at least 8 weeks of high-dose 
PPI treatment), the screening period will be extended for up to 12 weeks (day -85) to allow 
for at least 8 weeks of high-dose PPI treatment prior to the screening endoscopy/biopsies. 
For all other patients, the screening period will be shorter, with sufficient time to allow 
screening assessments and laboratory test results to be available prior to the baseline 
endoscopy/biopsies. 
2. The endoscopy/EoE-EREFS/biopsy procedures should be performed after all other 
efficacy and safety assessments. 
a. The baseline endoscopy with biopsies should be performed at approximately 
day -21±7 days to allow for availability of the intraepithelial eosinophil count result 
from the central pathology laboratory prior to day 1. For patients without a 
satisfactory prior historical endoscopy/biopsy, the baseline endoscopy/biopsies must 
be performed after at least 8 weeks of high-dose PPI. Patients may be randomized as 
soon as their endoscopy/biopsy results are available and DSQ eDiary entries are 
completed. 
Note:  Biopsy specimens from the stomach and/or duodenum will be obtained in all 
patients <18 years of age to rule out alternate etiologies. Stomach and/or duodenal 
biopsies will be obtained in adults only in the event of abnormal endoscopic findings 
(other than typical EoE findings) or clinical suspicion of alternate etiologies. 
b. For patients who receive rescue treatment during the double-blind treatment period, 
the endoscopy/EoE-EREFS/biopsy procedures will be performed prior to the 
initiation of rescue treatment. Patients undergoing endoscopy/biopsy prior to rescue 
will not undergo the scheduled endoscopy/biopsy at week 24 
Note:  All randomized patients found to have stomach and/or duodenal abnormalities 
at baseline will have follow-up stomach and/or duodenal biopsies at week 24 and 
week 52. 
c. The EndoFLIP procedure to measure esophageal distensibility may be performed 
during the esophagogastroscopy procedures at selected North American sites in 
approximately 150 adult patients. 
3. Assessments indicated for this week 24 (end of treatment) visit should be performed for all 
patients in Parts A and B. For patients who will enter Part C, there are additional events 
listed in week 24 visit in Table 2 for Part C. 
4. Patients may be re-screened once if they fail the screening evaluation, unless the reason for 
screen failure is related to histologic or clinical disease severity inclusion criteria. The 
baseline endoscopy with biopsy and EoE-EREFS scoring will not be repeated for re-
screened patients. These results will continue to be valid baseline data. Re-screening must 
occur within 6 months of the screen failure. 
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5. Patients and/or caregivers will be trained on administration of study drug at a minimum at 
visit 3/day 1 
6. On scheduled in-clinic study visit days, study drug will be administered in the clinic (by 
the patient, site staff, or caregiver). Study drug will be provided for those doses scheduled 
to be administered at home before the next in-clinic visit. Doses of study drug administered 
at home should be administered 1 week after the prior dose of study drug. Study drug 
administration that occurs in clinic should occur per the Schedule of Events in Table 1 and 
Table 2. Patients will be closely monitored at the study site at visits 3 to 6 for a minimum 
of 30 minutes after the administration of study drug. In addition to the predose assessments, 
AEs and vital signs (body temperature, blood pressure, respiratory rate and heart rate) will 
be assessed at 30 minutes (±10 minutes) post-dose. 
a. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic 
visits, after visit 3/day 1 patients/caregivers may be dispensed study drug for at-home 
dosing. Additionally, if the visit 11/week 24 endoscopy with biopsies is delayed due 
to COVID-19 restrictions, extended blinded dosing of study drug is allowed until this 
visit can occur. If extended dosing of the study drug occurs beyond week 23, the 
clinic staff must contact the patient every 4 weeks (at a minimum) to collect any AE 
(including ISRs), any change in concomitant medications and/or procedures, and 
monthly pregnancy test results, if required. 
7. Assessments will be performed and blood samples will be collected before the 
administration of study drug. 
a. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic 
visits, procedures/sample collection should occur at the next available in-clinic visit. 
Pregnancy testing must be performed as indicated (in-clinic or at-home) monthly (at a 
minimum) and results reported in a timely manner. 
8. DSQ eDiary will be completed once daily by the patients after their last meal of the day 
but before they go to bed. Site personnel should conduct regular checks of patient eDiary 
compliance.  
9. Patient Global Impression of Change (PGIC) of Dysphagia and Patient Global Impression 
of Severity (PGIS) of Dysphagia will be completed by the patient via electronic 
questionnaire at the indicated site visits. See Section 8.2.2.5 and Section 8.2.2.6.  
10. EoE Impact Questionnaire and EoE Symptom Questionnaire will be completed by the 
patient via electronic questionnaire at the indicated site visits. See Section 8.2.2.3 and 
Section 8.2.2.4.  
11. Total Nasal Symptom Score (TNSS) and Rhinoconjunctivitis Quality of Life Questionnaire 
for patients aged 12+ years [RQLQ(S)+12] will be administered only to patients with a 
documented history of allergic rhinitis; Asthma Control Questionnaire-5 (ACQ-5) will be 
administered only to patients with a documented history of asthma; Patient-Oriented 
Eczema Measure (POEM) will be administered only to patients with a documented history 
of AD. TNSS, POEM, ACQ-5 and RQLQ(S)+12 will be completed via electronic 
questionnaire and at the indicated site visits. The questionnaires will be administered only 
to the subset of patients who fluently speak the language in which the questionnaire is 
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presented (based on the availability of validated translations in participating countries). See 
Section 8.2.2.7, Section 8.2.2.8, Section 8.2.2.9, and Section 8.2.2.10. 
12. EoE-EREFS should be completed by the investigator before biopsies for all patients are 
performed. For Part B enrolled patients, EoE-EREFS will be performed by both the 
investigators who perform the endoscopies as well as a centralized reading center, that will 
provide EoE-EREFS analysis and scoring from endoscopy imaging. For all endoscopies, 
the investigators will assess minor esophageal features including mucosal inflammatory 
and remodeling features.  
13.  At visits 3 through 6, vital signs (body temperature, blood pressure, respiratory rate, heart 
rate) should be taken predose and 30 minutes (±10 minutes) post-dose. Vital signs should 
be taken predose at all other indicated visits.  
a. If study drug administration is not possible in-clinic due to staff or patient availability 
due to COVID-19 restrictions, vital signs pre- and post-dose may not be performed. 
14. For adolescent patients only. 
15. Includes HIV Ab, HBsAg, HBsAb, HBcAb, HCV Ab, and TB. Tuberculosis testing will 
be performed on a country-by-country basis according to local guidelines if required by 
regulatory authorities or ECs. 
16. Not required if post-menopausal status confirmed at screening. A negative result must be 
obtained prior to the randomization visit. In case of a positive urine test, the study treatment 
will be withheld and a serum pregnancy test to confirm the pregnancy should be performed 
as soon as possible. A confirmed pregnancy will lead to study drug discontinuation in all 
cases. 
17. The EQ-5D-3L should be administered one time at either visit 1 or visit 3 for newly 
screened patients. 
18. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, 
the clinic staff should make every effort to contact the patient at the timepoint of the 
expected in-clinic visit to collect any AEs (including ISRs), any change in concomitant 
medications and/or procedures, and monthly pregnancy test results, if required. 
8.1.1.2. 
Footnotes for Table 2 
1. This visit is the same as the week 24 visit for Parts A and B (Table 1), and all other 
assessments indicated for week 24 of Parts A and B (Table 1) should be performed. All 
pre-dosing procedures (including endoscopy with biopsy) at visit 11/week 24 must be 
completed prior to administration of study drug for Part C extended active treatment. 
2. Study assessments will be performed and blood samples will be collected prior to 
administration of study drug. 
a. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic 
visits, procedures/sample collection should occur at the next available in-clinic visit. 
Pregnancy testing must be performed as indicated (in-clinic or at-home) monthly (at a 
minimum) and results reported in a timely manner. 
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3. Patients will be closely monitored at the study site at visits 11 (at a minimum) and 12, if 
possible, for a minimum of 30 minutes after the administration of study drug. In addition 
to predose assessments, AEs and vital signs (body temperature, blood pressure, respiratory 
rate, and heart rate) will be assessed at 30 minutes (±10 minutes) post-dose.  
4. All pre-dosing procedures (including endoscopy with biopsy) at the scheduled visit 
11/week 24 must occur prior to dosing with Part C / extended active treatment study drug. 
On scheduled in-clinic study visit days, study drug will be administered in the clinic (by 
the patient, site staff, or caregiver). Study drug will be provided for those scheduled doses 
to be administered at home before the next in-clinic visit. Doses of study drug administered 
at home should be administered 1 week after the prior dose of study drug. Study drug 
administration that occurs in clinic should occur per the Schedule of Events in Table 1 and 
Table 2. 
a. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic 
visits, after visit 11/week 24 patients/caregivers may be dispensed study drug for at-
home dosing. Additionally, if the visit 19/ week 52 endoscopy with biopsies is 
delayed due to COVID-19 restrictions, extended dosing of study drug is allowed until 
this visit can occur. If extended dosing of the study drug occurs beyond week 51, the 
clinic staff must contact the patient every 4 weeks (at a minimum) to collect any AEs 
(including ISRs any change in concomitant medications and/or procedures, and 
monthly pregnancy test results, if required. 
5. DSQ eDiary will be completed once daily by the patients after their last meal of the day 
but before they go to bed. Site personnel should conduct regular checks of patient eDiary 
compliance.  
6. PGIC and PGIS will be completed by the patient via electronic questionnaire at the 
indicated site visits. See Section 8.2.2.5 and Section 8.2.2.6. 
7. EoE Impact Questionnaire and EoE Symptom Questionnaire will be completed by the 
patient via electronic questionnaire at the indicated site visits. See Section 8.2.2.3 and 
Section 8.2.2.4. 
8. TNSS and RQLQ(S)+12 will be administered only to patients with a documented history 
of allergic rhinitis; ACQ-5 will be administered only to patients with a documented history 
of asthma, and POEM will be administered only to patients with a documented history of 
AD. TNSS, POEM, ACQ-5 and RQLQ(S)+12 will be completed via electronic 
questionnaire and at the indicated site visits. The questionnaires will be administered only 
to the subset of patients who fluently speak the language in which the questionnaire is 
presented (based on the availability of validated translations in participating countries). See 
Section 8.2.2.7, Section 8.2.2.8, Section 8.2.2.9, and Section 8.2.2.10. 
9. EoE-EREFS should be completed by the investigator before biopsies for all patients are 
performed. For Part B enrolled patients, EoE-EREFS will be performed by both the 
investigators who perform the endoscopies as well as a centralized reading center who will 
provide EoE-EREFS analysis and scoring from endoscopy imaging. For all endoscopies, 
the investigators will assess minor esophageal features including mucosal inflammatory 
and remodeling features.  
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10. Endoscopy/EoE-EREFS/biopsy procedures should be performed after all other efficacy 
and safety assessments. The EndoFLIP procedure to measure esophageal distensibility may 
be performed during the esophagogastroscopy procedures at selected North American sites 
in approximately 150 adult patients. 
Note:  All randomized patients found to have stomach and/or duodenal abnormalities at 
baseline will have follow-up stomach and/or duodenal biopsies at weeks 24 and 52. 
a. For patients who receive rescue treatment, endoscopy/EoE-EREFS/biopsy procedures 
will be performed prior to initiation of rescue treatment. Patients undergoing 
endoscopy/biopsy prior to rescue will not undergo the scheduled endoscopy/biopsy at 
weeks 24 and 52. 
11. At visits 11 and 12, vital signs (body temperature, blood pressure, respiratory rate, heart 
rate) should be taken predose and 30 minutes (±10 minutes) post-dose. Only predose vital 
signs are required at subsequent visits. 
12. For adolescents only 
13. In case of a positive urine pregnancy test, the study treatment will be withheld and a serum 
pregnancy test to confirm the pregnancy should be performed as soon as possible. A 
confirmed pregnancy will lead to study drug discontinuation in all cases. 
14. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, 
the clinic staff should make every effort to contact the patient at the timepoint of the 
expected in-clinic visit to collect any AEs (including ISRs), any change in concomitant 
medications and/or procedures, and monthly pregnancy test results, if required. 
8.1.1.3. 
Footnotes for Table 3 
1. Patients who are withdrawn from study drug will be asked to complete the 12-week follow-
up period and the end of study visit. 
2. DSQ eDiary will be completed once daily by the patients after their last meal of the day 
but before they go to bed. Site personnel should conduct regular checks of patient eDiary 
compliance.  
3. PGIC and PGIS will be completed by the patient via electronic questionnaire at the 
indicated site visits. See Section 8.2.2.5 and Section 8.2.2.6. 
4. EoE Impact Questionnaire and EoE Symptom Questionnaire will be completed by the 
patient via electronic questionnaire at the indicated site visits. See Section 8.2.2.3 and 
Section 8.2.2.4. 
5. TNSS and RQLQ(S)+12 will be administered only to patients with a documented history 
of allergic rhinitis; ACQ-5 will be administered only to patients with a documented history 
of asthma, and only in countries in which a valid translation is available; POEM will be 
administered only to patients with a documented history of AD. TNSS, POEM, ACQ-5 
and RQLQ(S)+12 will be completed via electronic questionnaire and at the indicated site 
visits. See Section 8.2.2.7, Section 8.2.2.8, Section 8.2.2.9, and Section 8.2.2.10. 
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6. EoE-EREFS should be completed by the investigator before biopsies for all patients are 
performed. For Part B enrolled patients, EoE-EREFS will be performed by both the 
investigators who perform the endoscopies as well as a centralized reading center who 
will provide EoE-EREFS analysis and scoring from endoscopy imaging. For all 
endoscopies, the investigators will assess minor esophageal features including mucosal 
inflammatory and remodeling features.  
7. Endoscopy/EoE-EREFS/biopsy procedures should be performed after all other efficacy 
and safety assessments. The EndoFLIP procedure to measure esophageal distensibility may 
be performed during the esophagogastroscopy procedures at selected North American sites 
in approximately 150 adult patients. 
Note:  All randomized patients found to have stomach and/or duodenal abnormalities at 
baseline will have follow-up stomach and/or duodenal biopsies at weeks 24 and 52 or ET 
visit. 
a. For patients who receive rescue treatment during the double-blind treatment period, 
endoscopy/EoE-EREFS/biopsy procedures will be performed prior to initiation of 
rescue treatment. Rescue treatment should not be delayed if an endoscopy with 
biopsies cannot occur due to COVID-19 restrictions. Patients undergoing 
endoscopy/biopsy prior to rescue will not undergo the scheduled endoscopy/biopsy at 
weeks 24 and 52. 
8. Endoscopy/EoE-EREFS/biopsy will be performed only if the Unscheduled Visit is for the 
purpose of administering rescue therapy. 
9. For adolescents only. 
10. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, 
the clinic staff should make every effort to contact the patient at the timepoint of the 
expected in-clinic visit to collect any AEs (including ISRs), any change in concomitant 
medications and/or procedures, and monthly pregnancy test results, if required. 
8.1.2. 
Early Termination Visit 
Patients who are withdrawn from the study will be asked to return to the clinic for an ET visit 
consisting of the assessments described in Table 3. 
8.1.3. 
Unscheduled Visits before Rescue Treatment 
Before patients receive rescue treatment, efficacy assessments, PK and ADA sampling specified 
in Table 3 should be performed. 
8.1.4. 
Unscheduled Visits for Other Reasons 
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 reason, as warranted. 
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8.2. 
Study Procedures 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population:  serum follicle stimulating hormone (FSH) (for 
confirmation of menopausal status) and serology tests (HIV Ab, HBsAg, HBcAb, HCV Ab, and 
TB). Tuberculosis testing will be performed on a country-by-country basis according to local 
guidelines if required by regulatory authorities or ECs. 
8.2.2. 
Efficacy Procedures  
8.2.2.1. 
Endoscopy with EoE-EREFS and Biopsies, and Photographs 
During the endoscopy procedure, EoE-EREFS and biopsies will be performed in the listed order. 
Training will be provided to study sites on performing this procedure. All biopsies performed 
during this study will be evaluated by a qualified central histology laboratory. Photographs and/or 
video may be taken as part of the endoscopic procedure and biopsy collection. For Part B enrolled 
patients, video imaging should be collected for EoE-EREFS analysis and scoring by a centralized 
reading center. 
The endoscopy/EoE-EREFS/biopsy procedure will be performed per the Schedule of Events in 
Table 1, Table 2, and Table 3. 
EoE-EREFS 
The EoE esophageal characteristics will be analyzed based on the EoE-EREFS, a validated scoring 
system for inflammatory and remodeling features of disease using both overall scores and scores 
for each individual characteristic (Hirano, 2013). The proximal and distal esophageal regions will 
be scored separately; the score for each region ranges from 0 to 9 and the overall score ranges from 
0 to 18. The major esophageal features include:   
• Edema (absent, present) 
• Rings (absent, mild, moderate, severe) 
• Exudates (absent, mild, severe) 
• Furrows (absent, mild, severe) 
• Stricture (absent, present) 
EoE-EREFS should be completed by the investigator before biopsies for all patients are performed. 
For Part B enrolled patients, EoE-EREFS will be performed by both the investigators who perform 
the endoscopies as well as a centralized reading center who will provide EoE-EREFS analysis and 
scoring from endoscopy imaging. The centralized reading will be used for analysis, if available. If 
the centralized reading is not available, the EoE-EREFS performed by the investigator will be used 
for analysis. A copy of the EoE-EREFS is provided in the study regulatory binders. 
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In addition to the major features above, data for the following minor features will also be captured 
by the physician performing the endoscopy procedure: 
• Crepe paper esophagus (mucosal fragility or laceration upon passage of diagnostic 
endoscope): absent, present 
• Narrow caliber esophagus (reduced luminal diameter of the majority of the tubular 
esophagus): absent, present 
• Stricture diameter 
Mucosal changes associated with gastroesophageal reflux disease will also be recorded using the 
Los Angeles classification system for erosions (No Erosions or Grade A, B, C, or D). 
Biopsies 
Biopsies will be obtained by endoscopy at the second screening visit (visit 2, day -21 ± 7), week 24 
and week 52 visits, and immediately prior to start of rescue medication or procedures during the 
double-blind treatment period. The screening endoscopy should be performed at a time during the 
screening period that will allow results to be available prior to day -1 for assessment of eligibility. 
A total of 9 mucosal pinch biopsies will be collected at each time point from 3 esophageal regions:  
3 proximal, 3 mid, and 3 distal. Two samples from each region will be used for the histology 
(needed for study inclusion criteria, as well as endpoint assessment) and other tissue analyses (may 
include but not limited, to immunohistochemistry [IHC], RNA scope (in situ hybridization), and 
RNA sequencing). To participate in the study, patients must have a peak intraepithelial eosinophil 
count ≥15 eos/hpf (400×) in at least 2 of the 3 esophageal regions sampled. Any remaining tissue 
blocks will be banked for exploratory research. The third sample from each region will be 
processed for RNA analyses.  
In addition, biopsy specimens from the stomach and/or duodenum will be obtained at visit 2 in all 
patients <18 years of age to rule out alternate etiologies of esophageal eosinophilia. Targeted, 
stomach and/or duodenal biopsies will be obtained in adults only in the event of abnormal 
endoscopic findings (other than typical EoE findings) or clinical suspicion of alternate etiologies. 
Gastric biopsy samples should include 2 samples from the antrum and 2 samples from the body. 
Duodenal biopsy samples should include 2 bulb samples and 2 from another portion of the 
duodenum. All randomized patients found to have stomach and/or duodenal abnormalities at 
baseline will have follow-up stomach and/or duodenal biopsies at week 24 and week 52. 
Biopsy samples will be sent to a central pathology laboratory for processing and analysis. If 
required by the investigator institution, biopsy samples will be processed and analyzed by the local 
laboratory, and the processed specimen will be sent to the central pathology laboratory for central 
reading. These samples will be assessed for peak eos per hpf and EoE Grade Scores and Stage 
Scores will be assigned. EoE Grade and Stage Scores evaluate eight features: eosinophil density, 
basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular 
spaces, surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis 
(absent/present). Additional analyses on these data may also be performed. 
Assessment of lamina propria fibrosis may not be possible if the esophageal biopsy specimens do 
not contain adequate amounts of subepithelium lamina propria and then will not be included in the 
overall EoE Grade and Stage Scores. Severity (grade) and extent (stage) of abnormalities will be 
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scored using a 4-point scale (0 normal; 3 maximum change). The endoscopy with biopsies 
procedure will be performed the same way at all scheduled visits. 
Histology results will be interpreted by a pathologist at a central pathology reading center who will 
be blinded to the treatment assignment. Detailed instructions for biopsy sample collection and 
handling will be provided in the study regulatory binders. 
EndoFLIP 
A substudy of esopohageal distensibility utilizing the endolumenal functional lumen imaging 
probe (EndoFLIP, Medtronic, USA) may also be performed at selected North American sites in 
approximately 150 adult patients, with measurements taken as part of the esophagogastroscopy 
procedure performed at screening, week 24 and week 52. 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 controls (Kwiatek, 2011). Moreover, the 
esophageal distensibility has been associated with outcomes of both food impaction and need for 
esophageal dilation (Nicodème, 2013). Details of the EndoFLIP procedure will be provided in the 
study regulatory binders. 
Photographs and/or Video 
Photographs and/or video may be taken by the site as part of the endoscopic procedure and biopsy 
collection. A copy of these photographs and/or video will be requested from the study sites. Details 
for collecting and sending these photographs and/or video will be provided in the study regulatory 
binders. For Part B enrolled patients, video imaging should be collected for EoE-EREFS analysis 
and scoring by a centralized reading center. 
8.2.2.2. 
Dysphagia Symptom Questionnaire (DSQ) - Patient-reported Outcome (PRO) 
The DSQ is a validated PRO that has been used in clinical studies to measure the frequency and 
intensity of dysphagia (Hudgens, 2017). For patients who respond “No” to Question 1 (“Since you 
woke up this morning, did you eat solid food?”), a modification was made to the DSQ by asking 
a follow-up question to probe if patients avoided solid food due to their problems with swallowing 
solid food. This modified DSQ will be completed by the patient daily using an eDiary from 
screening through end of study or ET visit. A copy of the DSQ is provided in the study regulatory 
binders. 
The DSQ uses a daily recall period and comprises 3 questions on the presence and severity of EoE 
dysphagia. All patients respond to questions 1 and 2 and are required to have eaten solid foods 
(‘Yes’ to question 1: “Since you woke up this morning, did you eat solid food?”) in order to 
proceed with the questionnaire. If a patient answers “No” to question 1, the remaining items on 
the DSQ are not scored. Patients who respond “No” to question 2 (“Since you woke up this 
morning, has food gone down slowly or been stuck in your throat?”) are given a score of zero, and 
do not go on to answer question 3 (the diary is recorded as completed for that day). Those who 
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respond ‘Yes’ to questions 1 and 2 move on to question 3, which is scored on a 5-point scale that 
infers severity of dysphagia based on the patient’s action to alleviate symptoms, ranging from no 
action to seeking medical attention. The DSQ scoring algorithm is therefore constructed from the 
responses to questions 2 and 3, to ensure that the final score is driven by the frequency and severity 
of dysphagia. To calculate the DSQ score, a minimum of 8 diary entries is required for each 14-day 
period to derive a standardized total score based on the cumulative scores through 14 days. DSQ 
scores can theoretically range from 0 to 84, with a lower score indicating less-frequent or less-
severe dysphagia.  
Although Question 4 related to pain was included in the DSQ, it is considered as a standalone item 
for exploratory analysis.  
8.2.2.3. 
EoE Impact Questionnaire (EoE-IQ) 
The EoE-IQ is a disease-specific measure of health-related QOL in EoE patients developed by the 
sponsor. The EoE-IQ measures EoE impact on emotional, social, work and school, and sleep 
aspect of a patient. 
This assessment will be recorded by the patient using electronic questionnaire per the Schedule of 
Events in Table 1, Table 2, and Table 3. A copy of the EoE-IQ is provided in the study regulatory 
binders. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, 
after visit 3/day 1, site staff should make every effort to conduct telephone interviews to complete 
these questionnaires. Site staff should conduct the telephone interviews on the date of scheduled 
site visit by following an interview guide provided by the sponsor. Patient responses from the 
interviewer administered questionnaires will be captured by the site staff on a paper-copy print-
out of the questionnaire screenshots.  
8.2.2.4. 
EoE Symptom Questionnaire 
The EOE Symptom Questionnaire is a questionnaire measuring the frequency and severity of 
symptoms other than dysphagia and pain with swallowing. It is developed by the sponsor. The 
EoE Symptom Questionnaire will be completed by patients using electronic questionnaire per the 
Schedule of Events in Table 1, Table 2, and Table 3. 
If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, after 
visit 3/day 1, site staff should make every effort to conduct telephone interviews to complete these 
questionnaires. Site staff should conduct the telephone interviews on the date of scheduled site 
visit by following an interview guide provided by the sponsor. Patient responses from the 
interviewer administered questionnaires will be captured by the site staff on a paper-copy print-
out of the questionnaire screenshots.  
8.2.2.5. 
Patient Global Impression of Change (PGIC) of Dysphagia 
The PGIC is a one-item questionnaire that asks patients to provide the overall self-assessment of 
change of difficulty swallowing food. The PGIC will be completed by patients using electronic 
questionnaire per the Schedule of Events in Table 1, Table 2, and Table 3. 
If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, after 
visit 3/day 1, site staff should make every effort to conduct telephone interviews to complete these 
questionnaires. Site staff should conduct the telephone interviews on the date of scheduled site 
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visit by following an interview guide provided by the sponsor. Patient responses from the 
interviewer administered questionnaires will be captured by the site staff on a paper-copy print-
out of the questionnaire screenshots.  
8.2.2.6. 
Patient Global Impression of Severity (PGIS) of Dysphagia 
The PGIS is a one-item questionnaire that asks patients to provide the overall self-assessment of 
difficulty of swallowing food. The PGIS will be completed by patients using electronic 
questionnaire per the Schedule of Events in Table 1, Table 2, and Table 3. 
If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, after 
visit 3/day 1, site staff should make every effort to conduct telephone interviews to complete these 
questionnaires. Site staff should conduct the telephone interviews on the date of scheduled site 
visit by following an interview guide provided by the sponsor. Patient responses from the 
interviewer administered questionnaires will be captured by the site staff on a paper-copy print-
out of the questionnaire screenshots.  
8.2.2.7. 
Total Nasal Symptom Score (TNSS) 
The Total Nasal Symptom Score (TNSS), measured on a 0-9 scale, is a composite symptom 
assessment of congestion, itching/sneezing, and rhinorrhea (each graded on a 0-3 scale, 3 being 
severe). The TNSS will be administered only to patients with a documented history of allergic 
rhinitis and who fluently speak a language in which the questionnaire is presented (based on 
availability of translations in participating countries). The TNSS will be completed by patients per 
the Schedule of Events in Table 1, Table 2, and Table 3. 
If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, after 
visit 3/day 1, site staff should make every effort to conduct telephone interviews to complete these 
questionnaires. Site staff should conduct the telephone interviews on the date of scheduled site 
visit by following an interview guide provided by the sponsor. Patient responses from the 
interviewer administered questionnaires will be captured by the site staff on a paper-copy print-
out of the questionnaire screenshots.  
8.2.2.8. 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire for ages 12+ 
[RQLQ(S)+12] 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire for ages 12+ [RQLQ(S)+12] is a 
self-administered questionnaire to measure health-related QOL in those 12 years of age and above, 
as a result of perennial or seasonal allergic rhinitis. There are 28 items on the RQLQ(S) in 
7 domains:  activity limitation, sleep problems, nasal symptoms, eye symptoms, non-nasal/eye 
symptoms, practical problems, and emotional function. The RQLQ(S)+12 responses are based on 
a 7-point Likert scale with responses ranging from 0 (not troubled) to 6 (extremely troubled). The 
overall RQLQ(S)+12 score is the mean of all 28 responses and the individual domain scores are 
the means of the items in those domains. Higher scores indicated more health-related QOL 
impairment (lower scores were better). A change of 0.5 point or more in total score is considered 
to be clinically meaningful. 
The RQLQ(S)+12 will be performed per the Schedule of Events in Table 1, Table 2, and Table 3. 
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If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, after 
visit 3/day 1, site staff should make every effort to conduct telephone interviews to complete these 
questionnaires. Site staff should conduct the telephone interviews on the date of scheduled site 
visit by following an interview guide provided by the sponsor. Patient responses from the 
interviewer administered questionnaires will be captured by the site staff on a paper-copy print-
out of the questionnaire screenshots.  
8.2.2.9. 
Juniper Asthma Control Questionnaire (ACQ) 
The 5-question version of the Juniper ACQ (ACQ-5) is a validated questionnaire to evaluate 
asthma control. The ACQ-5 score is the mean of the scores of the 5 items and ranges from 0 (totally 
controlled) to 6 (severely uncontrolled). Scores less than 1.0 reflect adequately controlled asthma, 
and scores 1.0 or greater reflect inadequately controlled asthma. Higher score indicates lower 
asthma control. The recommended change of 0.50 is a reasonable threshold to define a meaningful 
individual-level change. The ACQ-5 will be administered only to patients with a documented 
history of asthma and who fluently speak a language in which the questionnaire is presented (based 
on availability of validated translations in participating countries). The ACQ-5 will be completed 
by patients using electronic questionnaire per the Schedule of Events in Table 1, Table 2, and 
Table 3. 
If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, after 
visit 3/day 1, site staff should make every effort to conduct telephone interviews to complete these 
questionnaires. Site staff should conduct the telephone interviews on the date of scheduled site 
visit by following an interview guide provided by the sponsor. Patient responses from the 
interviewer administered questionnaires will be captured by the site staff on a paper-copy print-
out of the questionnaire screenshots.  
8.2.2.10. Patient-Oriented Eczema Measure (POEM) 
The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess 
disease symptoms in children and adults with AD (Charman, 2004). The format is a response to 
7 items (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) using a 5-point 
scale, based on frequency of occurrence during the past week. The possible scores for each 
question were:  0 (no days), 1 (1 to 2 days), 2 (3 to 4 days), 3 (5 to 6 days), and 4 (every day), with 
a composite scoring system of 0 to 28; a higher score is indicative of more severe AD. 
The following POEM banding scores have been established (Charman, 2004):  0 to 2=clear or 
almost clear; 3 to 7=mild eczema; 8 to 16=moderate eczema; 17 to 24=severe eczema; and 25 to 
28=very severe eczema. 
The POEM will be administered only to patients with a documented history of AD and who 
fluently speak a language in which the questionnaire is presented (based on availability of 
validated translations in participating countries). The POEM will be completed by patients per the 
Schedule of Events in Table 1, Table 2, and Table 3. 
If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, after 
visit 3/day 1, site staff should make every effort to conduct telephone interviews to complete these 
questionnaires. Site staff should conduct the telephone interviews on the date of scheduled site 
visit by following an interview guide provided by the sponsor. Patient responses from the 
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interviewer administered questionnaires will be captured by the site staff on a paper-copy print-
out of the questionnaire screenshots.  
8.2.2.11. European Quality of Life 5-Dimensional Scale (EQ-5D) 
The European Quality of Life 5-dimension (EQ-5D) scale is a standardized questionnaire used to 
assess health status (Rabin, 2014) (Brooks, 1996). It consists of a descriptive system and the EQ 
visual analogue scale (EQ VAS). The EQ-5D-3L (3-level) descriptive system comprises of the 
following 
5 
dimensions: 
mobility, 
self-care, 
usual 
activities, pain/discomfort, 
and 
anxiety/depression. For each dimension, patients select one of 3 levels: no problems, some 
problems, and extreme problems. The EQ VAS records the patient’s self-rated health on a vertical 
visual analogue scale where the endpoints are labelled ‘Best imaginable health state’ and ‘Worst 
imaginable health state’. The EQ-5D-3L will be completed by patients per the Schedule of Events 
in Table 1. 
8.2.3. 
Safety Procedures  
8.2.3.1. 
Vital Signs 
Vital signs, including heart rate, blood pressure, respiratory rate, and body temperature will be 
collected predose and 30 minutes post-dose at time points listed in Table 1, Table 2, and Table 3. 
Heart rate and blood pressure will be measured with the patient in a sitting position, after the 
patient has rested comfortably for at least 5 minutes. 
8.2.3.2. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 1, Table 2, and Table 3. Care should be taken to examine and assess any abnormalities that 
may be present, as indicated by the patient’s medical history. 
8.2.3.3. 
Body Weight and Height 
Body weight and height will be measured at time points according to Table 1, Table 2, and Table 3. 
8.2.3.4. 
Electrocardiogram 
Electrocardiograms (ECG) will be performed before blood is drawn during visits requiring blood 
draws. A standard 12-lead ECG will be performed predose at time points listed in Table 1, Table 2, 
and Table 3. Heart rate will be recorded from the ventricular rate and the PR, QRS, and QT 
(identify QTcB or QTcF) intervals will be recorded. The ECG strips or reports will be retained 
with the source documentation, and the results will be documented in the electronic case report 
form (eCRF). 
Electrocardiogram results will be interpreted by a central reading center. Instructions for 
performing the assessment and transmitting ECG data are provided in the study regulatory binders. 
8.2.3.5. 
Laboratory Testing 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory. Samples will be collected predose at time points listed in Table 1, Table 2, and Table 3. 
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Detailed instructions for blood sample collection are in the laboratory manual provided to study 
sites. Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total and indirect bilirubin 
Potassium 
Creatinine 
Total cholesterol 
Chloride 
Blood urea nitrogen (BUN) 
Low-density lipoprotein (LDL) 
Carbon dioxide 
AST 
High-density lipoprotein (HDL) 
Calcium 
ALT 
Triglycerides 
Glucose 
Alkaline phosphatase 
Uric acid 
Albumin 
Lactate dehydrogenase (LDH) 
Estimated glomerular filtration rate (eGFR) 
Creatine phosphokinase (CPK)1 
 
1 CPK isoenzymes will be measured when CPK >5 × ULN  
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Microscopic analysis will only be done in the event of abnormal dipstick results. 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Other Laboratory Tests 
• Pregnancy testing will be performed for all women of childbearing potential. Serum or 
urine pregnancy testing will be performed at time points listed in Table 1, Table 2, and 
Table 3. A serum FSH test will be performed if menopausal status is in question. 
• The following tests will be performed at screening:  HIV, HBsAg, HBsAb, HBcAb, 
hepatitis C Ab, TB (will be performed on a country-by-country basis according to local 
guidelines if required by regulatory authorities or ethics boards), and alcohol and drug 
screen test. 
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Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality. When necessary, appropriate ancillary investigations 
should be initiated. If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the Medical/Study Director must 
be consulted.  
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 9.4.5. 
8.2.4. 
Drug Concentration and Measurements 
Samples for functional dupilumab concentration in serum will be collected predose at visits listed 
in Table 1, Table 2, and Table 3. Detailed instructions for blood sample collection are included in 
the laboratory manual provided to study sites 
Any unused samples may be used for exploratory biomarker research. 
8.2.5. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA assessment will be collected predose at time points listed in Table 1, Table 2, 
and Table 3. Detailed instructions for blood sample collection are included in the laboratory 
manual provided to study sites. 
Any unused samples may be used for exploratory biomarker research. 
8.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures 
In this study, research assessments will be performed to explore EoE, how dupilumab may modify 
the underlying disease process in EoE, type 2 inflammation, and predictors of dupilumab safety 
and efficacy.  
Samples for eotaxin-3 (heparinized plasma); serum TARC, total IgE, and allergen-specific IgE and 
IgG4s will be collected at time points according to Table 1 and Table 2. The biomarkers studied 
are believed to be relevant to the pathophysiology of EoE, response to treatment (ie, assessment 
of type 2 inflammation) and baseline predictors of response and dupilumab mechanism of action. 
8.2.6.1. 
EoE Diagnostic Panel and Type 2 Inflammation Transcriptomics 
The differential gene expression profiles of esophageal biopsies of EoE patients compared to 
healthy controls is the EoE disease transcriptome (Sherrill, 2014). This disease gene expression 
signature was further refined to a smaller gene set to be used as an EoE diagnostic panel (EDP) 
(Dellon, 2017). 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 study of EoE (Regeneron unpublished data). The gene lists 
comprising the EDP and type 2 transcriptomes can be found in the statistical analysis plan (SAP). 
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In a phase 2 study of EoE (R668-EE-1324), dupilumab significantly decreased the disease, EDP, 
and type 2 transcriptome signatures (Regeneron unpublished data).  
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 set 
(Subramanian, 2005) (Barbie, 2009). NES scores will be calculated for each transcriptome 
signature for each sample for statistical analyses, collected as part of procedures in Table 1, 
Table 2, and Table 3. 
8.2.6.2. 
Type 2 Inflammatory and Disease-Related Circulating Biomarkers 
Eotaxin-3, Thymus and Activation Regulated Chemokine (TARC), and IgE (total and specific) are 
measures of type 2 inflammation, and are known pharmacodynamic markers for dupilumab in AD, 
asthma, and nasal polyposis. 
8.2.6.2.1. Eotaxin-3 
Eotaxin-3 (also known as CCL26), an eosinophil chemokine, is up-regulated in esophageal mucosa 
of EoE patients relative to controls (Blanchard, 2006), and variants in the gene have been 
associated with disease risk. Eotaxin-3 mRNA expression in skin is down-regulated by dupilumab 
in AD (Hamilton, 2014). Circulating concentrations have been shown to decrease in asthma and 
nasal polyposis patients treated with dupilumab. Eotaxin-3 will be measured in heparinized plasma 
from samples collected at time points indicated in Table 1 and Table 2. Modulation of eotaxin-3 
is an exploratory measure. Data analysis will be described in the SAP and the results will be 
provided in the clinical study report (CSR).  
8.2.6.2.2. Thymus and Activation Regulated Chemokine (TARC) 
TARC is a type 2 chemokine for Th2 cells and other inflammatory cells expressing the CCR4 
receptor. TARC expression is regulated by IL4 and IL13, and rapidly decreases upon dupilumab 
treatment in AD, asthma, and nasal polyps. Serum TARC will be measured at time points indicated 
in Table 1 and Table 2. Modulation of TARC is an exploratory measure. Data analysis will be 
described in the SAP and the results will be provided in the CSR. 
8.2.6.2.3. Total and Allergen-Specific IgEs 
IL4 and IL13 regulate B cell class switching to, as well as production of, IgE. Dupilumab has been 
shown to suppress IgE (total and allergen-specific) in AD, asthma, and nasal polyposis patients. 
Serum concentrations of IgE (total and a panel of allergen-specific) will be measured at time points 
indicated in Table 1. Modulation of IgE is an exploratory measure. Data analysis will be described 
in the SAP and the results will be provided in the CSR. 
8.2.6.2.4. Allergen-Specific IgG4s 
Allergen-specific IgG4s have been found to be elevated in esophageal tissue and in circulation of 
EoE patients. Because the factors driving histological abnormalities and symptoms are unclear, 
IgG4 has been proposed as a pathological driver in the disease (Clayton, 2014) (Wright, 2016). To 
evaluate the potential role of IgG4 in EoE pathogenesis, as well as whether or not dupilumab 
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modulates these markers, a panel of serum allergen-specific IgG4s will be measured in samples 
collected at times indicated in Table 1 and Table 2. Modulation of allergen-specific IgG4s is an 
exploratory measure. Data analysis will be described in the SAP and results will be provided in 
the CSR. 
8.2.7. 
Future Biomedical Research (FBR) Serum/Plasma (Optional) 
Patients/parents or legal guardians who agree to participate in the future biomedical research 
(FBR) substudy will be required to consent to this optional substudy before FBR samples are 
collected and banked in long-term storage. The unused biomarker samples for study-related 
research, as well as unused PK and ADA samples, will be stored for up to 15 years after the final 
date of the database lock. The FBR samples may be utilized for future biomedical research of EoE 
and related diseases, and the effects of dupilumab on target pathway modulation. Additional 
samples will be collected for future biomedical research according to Schedule of Events in 
Table 1, Table 2, and Table 3. After 15 years, any residual samples will be destroyed. The results 
of these future biomedical research analyses will not be presented in the CSR. Patients are not 
required to participate in the FBR substudy in order to enroll in the primary study. 
8.2.7.1. 
Genomics Substudy (Optional) 
Patients/parent or legal guardians who agree to participate in the genomics substudy will be 
required to consent to this optional substudy before collection of the samples. Patients are not 
required to participate in the genomics substudy in order to enroll in the primary study. 
Whole blood samples for DNA extraction should be collected on day 1/baseline (predose), but can 
be collected at a later study visit. Whole blood samples for RNA extraction will be collected at 
time points according to Table 1. 
DNA and blood RNA samples will be collected for the pharmacogenomics analyses to understand 
the genetic determinants of efficacy and safety associated with the treatments in this study, and the 
molecular basis of EoE and related diseases. These samples will be single-coded as defined by the 
International Council on Harmonisation (ICH) guideline E15. Samples will be stored for up to 
15 years after the final date of the database lock.  
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or 
biomarker response to dupilumab, other EoE clinical outcome measures, and possible AEs. In 
addition, associations between genomic variants and prognosis or progression of EoE as well as 
related allergic/atopic diseases may also be studied. These data may be used or combined with data 
collected from other studies to identify and validate genomic markers related to the study drug or 
EoE and related diseases.  
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions. Other methods, including whole-exome 
sequencing, whole-genome sequencing, DNA copy number variation, and transcriptome 
sequencing (or other methods for quantitating RNA expression) may also be performed. The list 
of methods may be expanded to include novel methodology that may be developed during the 
course of this study or sample storage period. Results from the genomic analyses will not be 
reported in the CSR. 
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9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/EC all 
unanticipated problems involving risks to patients/subjects, according to local regulations. This 
may include death from any cause and all SAEs related to the use of the study drug. It is 
recommended that all SAEs be reported to the IRB/EC, according to local regulations. 
9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (SUSAR), to the health 
authorities, ECs/IRBs as appropriate, and to the investigators (in a blinded manner).  
Any AE not listed as an expected event in the Reference Safety Information section of the 
Investigator’s Brochure will be considered as unexpected. Any worsening of or new onset of 
symptoms related to EoE during the screening period prior to study drug administration will be 
considered expected. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the CSR to health authorities and ECs/IRBs as appropriate.  
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
In-patient hospitalization is defined as admission to a hospital (any duration) or an 
emergency room visit for longer than 24 hours. Prolongation of existing hospitalization 
is defined as a hospital stay that is longer than was originally anticipated for the event, 
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or is prolonged due to the development of a new AE as determined by the investigator 
or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect 
• Is an important medical event – Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events. See Section 9.4 for more 
information on recording and reporting SAEs. 
9.3.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and medical 
concern specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate. Such an event might warrant 
further investigation in order to characterize and understand it. Depending on the nature of the 
event, rapid communication by the trial sponsor to other parties (eg, regulators) might also be 
warranted (Section 9.4.3). 
9.4. 
Recording and Reporting Adverse Events  
9.4.1. 
Adverse Events 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of study. Refer to the study regulatory binders for the procedures to be 
followed. 
Information on follow-up for AEs is provided in Section 9.4.6. Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours. Refer to the study regulatory binders for the procedure to 
be followed. 
Information not available at the time of the initial report must be documented in a follow-up report. 
Substantiating data such as relevant hospital or medical records and diagnostic test reports may 
also be requested. 
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In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
• SAE with an onset within 30 days of the end of study or within 84 days (12 weeks) of 
last study drug administration if the patient early terminated from the study – the SAE 
will be reported to the sponsor. The investigator should make every effort to obtain 
follow-up information on the outcome until the event is considered chronic and/or 
stable. 
• SAE with an onset day greater than 30 days from the end of study or ET visit – only 
fatal SAEs and those deemed by the investigator to be drug-related SAEs will be 
reported to the sponsor. The investigator should make every effort to obtain follow-up 
information on the outcome of a drug-related SAE until the event is considered chronic 
and/or stable. 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
Symptomatic Overdose of Study Drug: 
Accidental or intentional overdose of at least 2 times 
the intended dose of study drug within the intended therapeutic window, if 
associated with an AE. 
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female study patient, during the study or within 
12 weeks of the last dose of study drug. Any complication of pregnancy affecting 
a female study patient and/or fetus and/or newborn that meets the SAE criteria must 
be reported as an SAE. Outcome for all pregnancies should be reported to the 
sponsor. 
Adverse Events of Special Interest: All AESI, serious and non-serious, must be reported within 
24 hours of identification using the same reporting process as for SAE reporting, 
per Section 9.4.2. Adverse events of special interest for this study include the 
following:   
• Anaphylactic reactions  
• Systemic hypersensitivity reactions  
• Helminthic infections 
• Any severe type of conjunctivitis or blepharitis 
• Keratitis 
• Clinically symptomatic eosinophilia (or eosinophilia associated with clinical 
symptoms)  
• Severe injection site reactions 
• Herpes simplex infection 
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• Arthralgia 
Refer to the study manual for the procedures to be followed. 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
Medical/Study Director within 30 days. 
Refer to the study regulatory binders for the procedures to be followed. 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
• The test result is associated with accompanying symptoms, and/or 
• The test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
• The test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the Medical/Study Director in the event the investigator feels that an abnormal test finding 
should be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE. Any abnormal test result that is determined to be an error does not require reporting as an AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale outlined 
in Section 9.5.1. 
9.4.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious adverse event information will be followed up until the event is resolved or considered 
chronic and/or stable. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
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 symptom may be needed. 
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Severe:  Produces significant impairment of functioning or incapacitation and is a definite hazard 
to the subject’s health. Treatment for symptom may be given and/or patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Injection Site Reactions 
The severity of ISRs 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 
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 ER 
visit or hospitalization; necrosis or exfoliative dermatitis 
9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the blinded investigator, and will be a 
clinical decision based on all available information. The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
Not Related: 
There is no reasonable possibility that the event may have been caused by 
the study drug. 
Related: There is a reasonable possibility that the event may have been caused by the study 
drug. 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided below. 
Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by the study drug? 
No: 
• Due to external causes such as environmental factors or other treatment(s) being 
administered 
• Due to the patient’s disease state or clinical condition 
• Do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug 
• Do not reappear or worsen when dosing with study drug is resumed 
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• Are not a suspected response to the study drug based upon preclinical data or prior 
clinical data 
Yes: 
• Could not be explained by environmental factors or other treatment(s) being 
administered 
• Could not be explained by the patient’s disease state or clinical condition 
• Follow a reasonable temporal sequence following the time of administration of the dose 
of study drug  
• Resolve or improve after discontinuation of study drug  
• Reappear or worsen when dosing with study drug  
• Are known or suspected to be a response to the study drug based upon preclinical data 
or prior clinical data 
Relationship of Adverse Events to Study Procedure:  
The relationship of AEs to study procedure (eg, endoscopy or biopsy) will be assessed by the 
investigator, and will be a clinical decision based on all available information. The following 
question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the procedure? 
The possible answers are: 
Not Related: 
There is no reasonable possibility that the event may have been caused by 
the procedure. 
Related: 
There is a reasonable possibility that the event may have been caused by the 
procedure. 
The sponsor will request information to justify the causality assessment of SAEs, as needed. 
9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion. The sponsor will monitor the 
safety data from across all study sites. The Medical/Study Director will have primary responsibility 
for the emerging safety profile of the compound, but will be supported by other departments (eg, 
Pharmacovigilance and Risk Management (PVRM); Biostatistics and Data Management). Safety 
monitoring will be performed on an ongoing basis (eg, individual review of SAEs) and on a 
periodic cumulative aggregate basis. 
In addition, the DMC will conduct safety reviews for all dupilumab studies (see details in 
Section 5.3.1). 
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9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the reference 
safety information in the Investigator’s Brochure, and has a reasonable suspected causal 
relationship to the study drug). 
10. 
STATISTICAL PLAN 
This section provides the basis for the SAPs for the study. The part-specific SAP(s) may be revised 
during the study to accommodate amendments to the clinical study protocol and to make changes 
to adapt to unexpected issues in study execution and data that may affect the planned analyses. 
The final SAP(s) will be issued before the database is locked for respective part. 
Analysis variables are listed in Section 4. 
Results from different parts of this study will be summarized and/or analyzed separately unless 
otherwise specified. 
10.1. 
Statistical Hypothesis  
For comparisons of each of the 2 dupilumab treatment groups to placebo, the following hypotheses 
of the co-primary endpoints will be tested, where pd is the true proportion of patients achieving 
peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 24 and μd is the true mean 
change from baseline in the DSQ total score at week 24 in each of the dupilumab group; and pp 
and μp are the corresponding true values in the placebo group. 
• Null hypothesis (H0):  pp = pd or μp = μd, ie, the proportion of patients achieving peak 
esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 24 OR the mean 
change from baseline in the DSQ total score at week 24 is the same between the 
dupilumab group and the placebo group. 
• Alternative hypothesis (H1):  pp ≠ pd and μp ≠ μd, ie, the proportion of patients 
achieving peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 24 
AND the mean change from baseline in the DSQ total score at week 24 is different 
between the dupilumab group and the placebo group. 
10.2. 
Justification of Sample Size 
The assumptions used in sample size calculations for Part A are based on results from a phase 2 
study of dupilumab (R668-EE-1324) and reported data of a phase 2 study of budesonide 
(Dellon, 2017) in patients with EoE as follows: 
• In the study of dupilumab, a treatment difference of 65.2% was observed in the 
proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤6 eos/hpf after 12 weeks of treatment (placebo 0% vs. dupilumab 65.2%). DSQ was 
not assessed in this study. The overall dropout rate was 8.5% during the 12-week 
treatment period. 
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• In the study of budesonide oral suspension, a treatment difference of 36% was observed 
in the proportion of patients achieving peak esophageal intraepithelial eosinophil count 
of ≤6 eos/hpf after 12 weeks of treatment (placebo 3% vs. budesonide 39%). The mean 
(standard deviation [SD]) of change from baseline in DSQ total score at week 12 
was -7.5 (10.7) in placebo and -14.3 (13.0) in the budesonide group, corresponding to 
a treatment group difference of -6.8. The overall dropout rate was 6.5% during the 
12-week treatment period. 
With the consideration that a higher dropout rate may be observed for a longer treatment period, a 
dropout rate of 15% is assumed for all sample size calculations provided below. 
Part A 
The planned sample size for Part A is approximately 40 patients in each treatment group such that 
for the comparison of each dupilumab dose regimen to placebo: 
• This sample size will yield >99% power to detect a treatment difference of 62% in the 
proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤6 eos/hpf at week 24 (placebo 3% vs. dupilumab 65%) at a 2-sided significance level 
of 5% using Fisher’s exact test.  
• With respect to the treatment group difference in the mean change from baseline in 
DSQ total score, assuming a common SD of 13.0, this sample size is expected to 
generate a 95% confidence interval whose half-width is 5.7. If the true treatment 
difference is -9.0 points, the statistical power for the co-primary endpoint of DSQ will 
be 80% using a two-sample t-test. 
Part B 
The study includes two double-blind placebo-controlled randomized parts: Part A and Part B. An 
objective of Part A was to evaluate the Part B sample size. Part A database lock occurred on 
20 May 2020 and the study results for the co-primary endpoints from Part A are below: 
• The proportion of patients achieving peak esophageal intraepithelial eosinophil count 
of ≤6 eos/hpf at 24 weeks was 5.1% in placebo group and 59.5% in dupilumab 300mg 
QW group with a treatment difference of 55.4% 
• The mean (standard deviation [SD]) of change from baseline in DSQ total score at week 
24 was -9.6 (15.2) in placebo and -21.9 (14.6) in the dupilumab 300mg QW group with 
a treatment group difference of -12.3.  
Based on the Part A study results, the planned sample size for Part B is approximately 70 patients 
in each treatment group such that for the comparison of each dupilumab dose regimen to placebo: 
• This sample size will yield >99.9% power to detect a treatment difference of 55.4% in 
the proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤6 eos/hpf at week 24 between placebo (5.1% ) and each dupilumab treatment group 
(59.5%) at a 2-sided significance level of 5% using Fisher’s exact test.  
• This sample size will provide >99.9% power to detect a treatment difference of -12.3 
points in the mean change from baseline in the total DSQ score to week 24 at a 2-sided 
significance level of 5% using a two-sample t-test, assuming a common SD of 15.0.  
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Therefore, the sample size of 70 patients/arm will provide an overall power of >99.9% (99.9% × 
99.9%) for the co-primary endpoints, assuming no negative correlation between the two endpoints. 
In Part B, the same treatment effect for the two 300 mg dupilumab dose regimens (ie, QW and 
Q2W) is assumed. 
Sample size calculations were made using nQuery Advisor 7.0. 
10.3. 
Analysis Sets  
10.3.1. 
Efficacy Analysis Sets 
Part A and Part B 
For Part A and Part B, the efficacy endpoints will be analyzed using the study part-specific full 
analysis set (FAS) that includes all randomized patients in the corresponding study part. Efficacy 
analyses for these 2 parts will be based on the treatment allocated by the randomization and carried 
out separately for each part. Analysis on the FAS will be considered to be primary. 
The study-part specific per protocol set (PPS) will include all patients in the corresponding FAS 
except for those who are excluded due to important protocol violations.  
All efficacy endpoints will be evaluated on the FAS; the co-primary endpoints will also be 
evaluated on the PPS.  
Part C 
The efficacy endpoints in Part C (the extended active treatment period) will be summarized for all 
patients who received any extended active treatment study drug in that part. 
10.3.2. 
Safety Analysis Set 
For Part A and Part B, the study part-specific safety analysis set (SAF) includes all randomized 
patients who received any study drug; it is based on the treatment received (as treated). Treatment 
compliance/administration and all clinical safety variables will be analyzed using the SAF. 
For safety analyses of the Part C extended active treatment period, only a subset of SAF will be 
included, which is defined as those patients who received at least 1 dose of Part C study drug. 
10.3.3. 
Pharmacokinetic Analysis Sets 
The PK analysis set includes all treated patients who received any study drug and who had at 
least 1 non-missing result following the first dose of study drug.  
10.3.4. 
Anti-Drug Antibody Analysis Sets 
The ADA analysis set includes all treated patients who received any study drug and who had at 
least 1 non-missing ADA result following the first dose of study drug.  
10.4. 
Statistical Methods  
For continuous variables, descriptive statistics will include the following information:  the number 
of patients reflected in the calculation (n), mean, median, SD, minimum, first and third quartiles, 
and maximum.  
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For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
10.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients: met the inclusion criteria regarding the target 
indication and signed the ICF 
• The total number of randomized patients:  received a randomization number 
• The total number of patients in each analysis set (eg, FAS, provided in Section 10.3) 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued study treatment, and the reasons for 
discontinuation 
• The total number of patients who took rescue medications/procedures  
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patients prematurely discontinued from study treatment, along with reasons 
for discontinuation 
10.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.  
10.4.3. 
Efficacy Analyses 
10.4.3.1. Primary Efficacy Analysis 
The co-primary endpoint of proportion of patients achieving a histologic response of esophageal 
intraepithelial eosinophil count of ≤6 eos/hpf at week 24 visit will be analyzed using the Cochran-
Mantel-Haenszel (CMH) test to assess the difference in the proportion of responders in the FAS 
adjusting for the randomization stratification factors. In anticipation of sparse responders in the 
placebo group, the Fisher’s exact test will be performed as a supportive analysis to confirm the 
results from the CMH test. 
The co-primary endpoint of absolute change from baseline in the DSQ total score at week 24 will 
be analyzed using an analysis of covariance (ANCOVA) model for the FAS with treatment group, 
randomization stratification factor, and relevant baseline measurement as covariates included in 
the model. The cumulative proportion of responders over the entire range of possible cut-off points 
will be graphed to present the between-treatment-group differences at any responder level. 
The intercurrent events, strategies, and the corresponding missing data handling approaches for 
the primary estimands of interest for the co-primary endpoints are provided in Table 4. 
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Table 4: 
Summary of Primary Estimand for Co-primary Endpoints 
Co-Primary Endpoint Intercurrent event(s) 
Strategy 
Missing data handling 
method 
Proportion of patients 
achieving a histologic 
response of esophageal 
intraepithelial 
eosinophil count of ≤6 
eos/hpf at week 24 visit 
Initiation of treatment 
with systemic and/or 
swallowed topical 
corticosteroids drugs 
for EoE (rescue 
treatment) 
Composite strategy: Patients 
will be considered as non-
responders after such events. 
(1) Missing data due to 
COVID-19 will be imputed 
by multiple imputation 
(MI). 
(2) Missing data due to reasons 
not related to COVID-19 
will be imputed as non-
responder. 
Initiation or change of 
treatment with 
systemic 
corticosteroid drugs 
for conditions other 
than EoE (prohibited 
medications)  
Treatment policy strategy: 
Data collected after the 
patient received treatment 
with systemic corticosteroid 
drugs for conditions other 
than EoE will be included in 
the analyses. 
Treatment 
discontinuation 
Treatment policy strategy: 
Data collected after the 
patient discontinued treatment 
will be included in the 
analyses. 
Absolute change from 
baseline in the DSQ 
total score at week 24 
Initiation of treatment 
with systemic and/or 
swallowed topical 
corticosteroids drugs 
for EoE (rescue 
treatment) 
Hypothetical strategy: Data 
will be assigned using MI 
after such events.  
Missing data will be imputed by 
multiple imputation (MI). 
 
Initiation or change of 
treatment with 
systemic 
corticosteroid drugs 
for conditions other 
than EoE (prohibited 
medications) 
Treatment policy strategy: 
Data collected after the 
patient received treatment 
with systemic corticosteroid 
drugs for conditions other 
than EoE conditions will be 
included in the analyses. 
Treatment 
discontinuation 
Treatment policy strategy: 
Data collected after the 
patient discontinued treatment 
will be included in the 
analyses. 
To account for use of rescue treatment in the primary analysis, for peak esophageal intraepithelial 
eosinophil count of ≤6 eos/hpf, patients will be considered as non-responders after the use of rescue 
treatment. For absolute change from baseline in the DSQ total score, data will be imputed using 
multiple imputation (MI) for all time points subsequent to the use of rescue treatment.  
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If a patient has missing value for the histological response (peak esophageal intraepithelial 
eosinophil count of ≤6 eos/hpf) at week 24 visit due to reasons not related to COVID-19, the 
patient will be classified as a non-responder at week 24. Multiple imputation (MI) will be used for 
missing histological response due to COVID-19. 
If a patient has missing value for the DSQ total score at week 24, their missing data will be imputed 
by multiple imputation (MI) based on similar patients who remained in the trial with observed 
values relevant to analysis. Similarity is based on randomized treatment group, baseline value, 
stratification factors, and available post-baseline values. To account for the uncertainty in the 
imputation, missing data at week 24 will be imputed 50 times to generate 50 complete datasets by 
using the MI procedure in Statistical Analysis Software (SAS).  
MI will follow the 2 steps below using a random seed number of 6681774 in both steps: 
• Step 1:  Use the Markov Chain Monte Carlo (MCMC) method to fill in intermittent 
missing values (ie, those missing values followed by observed values at subsequent 
visits) so that a monotone missing pattern will be formed. 
• Step 2:  Using the datasets from step 1, missing data through week 24 will be imputed 
using the regression method with treatment group, randomization stratification, 
relevant baseline measurement, and post-baseline measurement up to week 24 included 
in the regression model.  
Once imputations are made, the week 24 data of each of the complete datasets will be analyzed 
using ANCOVA. The results from the 50 analyses on the complete datasets will be combined to 
generate a valid overall statistical inference according to Rubin’s formula (Rubin, 1987) using the 
SAS MIANALYZE procedure. 
Sensitivity analyses will assess alternative methods to impute missing data under the assumption 
of missing at random or missing not at random. For the esophageal-intraepithelial-eosinophil 
responder analysis, alternative methods may include utilizing peak esophageal intraepithelial 
eosinophil count values from imputations to determine responder status. For the analysis of change 
from baseline in the DSQ total score, alternative methods may include mixed-effect model for 
repeated measures (MMRM), last observation carried forward (LOCF), and tipping point analysis. 
Sensitivity analyses will also include an analysis without setting data post-rescue to missing. 
Sensitivity analyses may include but are not limited to the methods specified above. Details will 
be specified in the SAP. 
Handling of missing data or delayed procedures due to COVID-19 and any additional analyses 
required to investigate the impact of COVID-19 to understand estimated treatment effect will be 
detailed in the SAP. 
10.4.3.2. Secondary Efficacy Analysis 
10.4.3.2.1. Analysis of Secondary Efficacy Endpoints in Part A and Part B 
Binary endpoints: 
Secondary efficacy endpoints that measure binary responses at week 24 will be analyzed in the 
same fashion as the co-primary endpoint of histologic response of peak esophageal intraepithelial 
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eosinophil count of ≤6 eos/hpf, including the method to handle missing data and planned 
sensitivity analyses.  
Continuous endpoints: 
For Part A enrolled patients, EoE-EREFS assessed by investigators will be used in the analysis (no 
centralized readings available). For Part B enrolled patients, the primary analysis of EoE-EREFS 
will be based on centralized readings, if available. If the centralized reading is not available, the 
EoE-EREFS performed by the investigator will be used for analysis. 
Continuous secondary efficacy endpoints at week 24 will be analyzed using ANCOVA in a similar 
fashion to the co-primary endpoint of change from baseline in the DSQ total score.  
For continuous efficacy data that are scheduled to be measured repeatedly post-baseline up to week 
24 (eg, percent change in DSQ score from baseline to week 24), missing data will be imputed by 
MI as described in the primary efficacy analysis of the DSQ co-primary endpoint. Sensitivity 
analyses similar to those specified for the DSQ co-primary endpoint will be conducted. 
For continuous efficacy data that are to be measured only once post-baseline up to week 24 
(eg, percent change in peak eos/hpf from baseline to week 24), missing values at week 24 will be 
imputed with patient’s baseline value or the available post-baseline value, whichever is worse, 
ie, a worst observation carried forward (WOCF) approach. MI approach is not suitable for 
handling missing data in this case due to the fact that the complete case patients will not have 
measurements available at the time points when measurements are obtained for ET patients 
(designed to be at their ET visits) to enable the imputation of week 24 missing values for early 
terminated patients. A sensitivity analysis, using the LOCF approach to impute missing values at 
week 24, will be performed. 
To account for use of rescue treatment, data will be imputed by MI for continuous endpoints 
repeatedly measured or by WOCF for continuous endpoints measured only once up to week 24 
visit after the use of rescue treatment.  
For the four key secondary endpoints, the primary estimand and details about the intercurrent 
events strategy and missing data handling are presented in Table 5. 
Table 5: 
Summary of Primary Estimand for Key Secondary Endpoints 
Key Secondary Endpoint 
Intercurrent event(s) 
Strategy 
Missing data handling 
method 
• 
Absolute change in EoE-
EREFS from baseline to 
week 24 
• 
Percent change in peak 
esophageal intraepithelial 
eosinophil count 
(eos/hpf) from baseline 
to week 24 
• 
Absolute change in EoE 
Grade Score from the 
EoEHSS from baseline 
to week 24  
Initiation of treatment with 
systemic and/or swallowed 
topical corticosteroids 
drugs for EoE (rescue 
treatment) 
Composite strategy: data 
after rescue treatment 
will be assigned by the 
worst possible value 
Missing values at week 24 
will be imputed with 
WOCF approach 
including baseline. 
Initiation or change of 
treatment with systemic 
corticosteroid drugs for 
conditions other than EoE 
(prohibited medications) 
Treatment policy 
strategy: Data collected 
after the patient received 
treatment with systemic 
corticosteroid drugs for 
conditions other than 
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Key Secondary Endpoint 
Intercurrent event(s) 
Strategy 
Missing data handling 
method 
• 
Absolute change in EoE 
Stage Score from the 
EoEHSS from baseline 
to week 24 
EoE will be included in 
the analyses. 
Treatment discontinuation 
Treatment policy 
strategy: Data collected 
after the patient 
discontinued treatment 
will be included in the 
analyses. 
Sensitivity analyses will also include an analysis without setting data post-rescue to missing. 
Subgroup analysis (eg, by age group) will also be performed and details will be specified in SAP. 
For transcriptome endpoints, the Wilcoxon rank-sum test will be used to test if the difference in 
median NES of the relative change from baseline to week 24 between the dupilumab and placebo 
groups is statistically significant. P-values will be reported. 
10.4.3.2.2. Analysis of Secondary Efficacy Endpoints in Part C  
Efficacy variables measured in Part C will use the last non-missing value prior to the first dose of 
extended active treatment study drug as their baseline assessments. These efficacy variables will 
be summarized with descriptive statistics by received treatment in Part C. Inferential statistics will 
only be conducted as needed. 
10.4.3.3. Multiplicity Considerations 
Part A and Part B will be carried out as 2 separate sub-studies with no overlap in patients. 
Therefore, each study part will have separate and independent 2-sided alpha level of 0.05. In the 
event that sample size of Part B is changed based on observed data from Part A, there will be no 
alpha adjustment as data from Part A are considered external information to Part B. 
To demonstrate efficacy for a dupilumab dose regimen, both of the individual co-primary 
endpoints need to be statistically significant at the 2-sided 0.05 level for that dose regimen.  
Part A: Statistical significance of both co-primary efficacy endpoints will be required before 
drawing inferential conclusions about any secondary efficacy endpoints. The hierarchical order of 
secondary endpoints will be specified in Part A SAP. 
Part B: Type I error rate will be controlled using a hierarchical testing procedure. The co-primary 
endpoints will be tested for the comparison of dupilumab QW dose regimen to placebo first and if 
both endpoints are statistically significant, the testing will proceed to the co-primary endpoints of 
dupilumab Q2W, or the secondary endpoints of dupilumab QW, with the exact order to be 
specified in Part B SAP. 
As Part C data will be summarized using descriptive statistics, there is no multiplicity issue. 
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10.4.4. 
Safety Analysis 
Safety analysis will be based on the SAF. This includes reported treatment-emergent adverse 
events (TEAEs) and other safety data (ie, clinical laboratory evaluations, vital signs, and 12-lead 
ECG results). A descriptive summary of safety results will be presented by treatment group for 
each study part. The use of rescue treatment will be summarized. 
Any additional analyses and methods required to investigate the impact of COVID-19, including 
extended dosing, on the safety evaluation will be specified in the SAP. 
10.4.4.1. Adverse Events 
Definitions 
For AEs, 2 observation periods are defined: 
• The pre-treatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The treatment-emergent period is defined as the day from the first dose of study 
treatment through the end of study including the follow-up period. The treatment-
emergent period includes the placebo-controlled treatment period plus the extended 
active treatment period (52 weeks in total) and the 12-week follow-up period. 
− Treatment period: date of the first dose of study drug to the end of the 52-week 
treatment period (placebo-controlled plus extended-active treatment) 
− Follow-up period: day after the end of the treatment period to the end of study. 
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a preexisting condition during the treatment-emergent period. 
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®). Coding will be to lowest level terms. The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries of the TEAEs will include the following for each study part: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 9.5.1), presented 
by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
• Treatment-emergent AESIs (defined with a PT or a pre-specified grouping) 
Deaths and other SAEs will be listed and summarized. The summary will include the number (n) 
and percentage (%) of patients with at least 1 SAE as well as the number of SAEs. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized. 
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TEAEs that occurred in Part A or Part B will be summarized by the treatment patient received in 
the respective part, and also for combined dupilumab QW and Q2W treatment groups. 
TEAEs that occurred in Part C will be summarized by treatment received in Part C.  
10.4.4.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiratory rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics.  
Number and percentage of patients with a treatment-emergent potentially clinically significant 
value (PCSV) will be summarized for each vital sign variable. The criteria for treatment-emergent 
PCSV will be defined in the SAP. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a treatment-emergent PCSV will be summarized for each 
clinical laboratory test. The criteria for treatment-emergent PCSV will be defined in the SAP. 
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out-of-range laboratory values. 
10.4.4.3. Treatment Exposure 
The duration of exposure during each study part will be calculated as follows: 
• (date of last dose of study drug in the specific study part – date of first dose of study 
drug in the specific study part) + 7 days 
In addition, duration of cumulative exposure to dupilumab across study parts will be calculated for 
patients who participate in both the double-blind treatment period (Part A or Part B) and the 
extended active treatment period as follows: 
• (date of last dose of study drug – date of first dose of dupilumab in the study) + 7 days. 
Number and percentage of patients exposed to study drug within a study part and across study 
parts will be summarized by time periods of specific lengths for each treatment group. The lengths 
of interest will be specified in the SAP.  
In addition, duration of exposure within a study part and across study parts will be summarized as 
a continuous variable for each treatment group with the number of patients reflected in the 
calculation (n), mean, median, SD, minimum, the first and third quartiles, and maximum. 
A summary of the number of study-part-specific doses for each treatment group will be provided. 
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10.4.4.4. Treatment Compliance 
The compliance with protocol-defined study treatment will be calculated for each of the 3 study 
parts separately as follows: 
Treatment compliance = 
number of administered doses of study drug   
number of planned doses of study drug 
×100% 
The treatment compliance will be summarized descriptively by specific ranges for each treatment 
group. The ranges of interest will be specified in the SAP. 
10.4.5. 
Pharmacokinetics 
10.4.5.1. Analysis of Drug Concentration Data 
For this study, sampling will be sparse and the types of analyses will be descriptive statistics at 
each sampling time. No formal statistical analysis will be performed. 
10.4.6. 
Analysis of Anti-Drug Antibody Data 
ADA data will be summarized using descriptive statistics by treatment group. Samples that are 
positive in the ADA assay will be further characterized for the presence of neutralizing antibody.  
Plots of drug concentrations will be examined and the influence of ADAs on individual PK profiles 
may be evaluated. Where appropriate, assessment of impact of ADA on safety and efficacy will 
be provided. 
10.4.7. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
Biomarker results will be summarized by baseline, measured values, change from baseline, and 
percent change from baseline to each scheduled assessment time point with descriptive statistics. 
10.4.8. 
Analysis of Quality of Life Data 
Quality of life data will be analyzed using the same method as specified for the continuous 
secondary efficacy variables.  
10.4.9. 
Timing of Statistical Analysis 
Multiple steps of analyses are planned for this study.  
• The first database lock will occur after the last Part A patient has completed their end 
of Part A visit including patients who have terminated early in Part A.  
• The second database lock will occur after the last Part A patient has completed their 
week 52 visit of Part C including Part A patients who have terminated early in Part A 
or Part C.  
• The third database lock will occur after the last Part B patient has completed their end 
of Part B visit including patients who have terminated early in Part B.  
• After the last patient completes the last visit in Part C, analysis of all week 52 efficacy 
and safety endpoints may be performed. 
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• The last database lock will occur after the last patient completes their last end of study 
visit. The end-of-study analysis will include data through the end of the 12-week 
follow-up period. 
10.5. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline:  
• The baseline assessment for each study part will be the latest, valid predose assessment 
available for the corresponding study part, respectively 
General rules for handling missing data:  
• If the start date of an AE or concomitant medication is incomplete or missing, it will 
be assumed to have occurred on or after the intake of study medication, except if an 
incomplete date (eg, month and year) clearly indicates that the event started prior to 
treatment. If the partial date indicates the same month or year of the intake of study 
medication date, then the start date by the study medication intake date will be imputed; 
otherwise, the missing day or month by the first day or the first month will be imputed.  
• No imputations for missing laboratory data, ECG data, vital sign data, or physical 
examination data will be made. 
Unscheduled assessments: 
• Extra assessments (laboratory data or vital signs associated with non-protocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in 
listings and summaries. If more than 1 laboratory value is available for a given visit, 
the first observation will be used in summaries and all observations will be presented 
in listings.  
10.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study  
If the study is terminated prematurely for other reasons, only those parameters required for the 
development program and/or reporting to regulatory authorities will be summarized. Investigator 
and sponsor responsibilities surrounding the premature termination of a study are presented in 
Section 16.1. 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (Sponsor). 
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A medical coding plan (included in the data management plan) will specify the processes and the 
dictionary used for coding. All data coding (eg, AEs, baseline findings, medication, medical 
history/surgical history/EoE comorbidity history, etc.) will be done using internationally 
recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC) system 
Medidata Rave. 
11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IVRS/IWRS system – randomization and study drug supply 
• EDC system – data capture/uploading  
• Electronic patient diary – data capture/uploading 
• Central ECG reading center-digital images 
• nQuery Advisor – sample size calculations 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance and Risk Management (PVRM) safety system 
• Digital archive system for endoscopic photographic and video images 
12. 
STUDY MONITORING 
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, CRO monitor) will visit each site prior to enrollment of 
the first patient, and periodically during the study.  
The investigator must allow study-related monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
12.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
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12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on eCRFs within the EDC 
system by trained site personnel. All required CRFs must be completed for each and every patient 
enrolled in the study. After review of the clinical data for each patient, the investigator must 
provide an electronic signature. A copy of each patient CRF casebook is to be retained by the 
investigator as part of the study record and must be available at all times for inspection by 
authorized representatives of the sponsor and regulatory authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee. 
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system. For corrections made via data queries, a reason for any alteration 
must be provided. 
13. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities. Should this occur, the investigator is responsible for: 
• Informing the sponsor of a planned inspection by the authorities as soon as notification 
is received, and authorizing the sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
• Taking all appropriate measures requested by the sponsor to resolve the problems found 
during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities. Conditions of study material storage are also subject to inspection. In addition, 
representatives of the sponsor may observe the conduct of any aspect of the clinical study or its 
supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS  
14.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigators to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
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14.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB- or EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each adult patient, and written informed consent or assent from 
each adolescent patient and written informed consent from his/her parent(s) or legal guardian(s), 
prior to patient’s participation in the study and after the aims, methods, objectives, and potential 
hazards of the study have been explained to the patient and adolescent patient’s parent(s) or legal 
guardian(s) in language that he/she can understand. The ICF should be signed and dated by the 
adult patient, and the ICF/IAF by adolescent patient and his/her parent(s) or legal guardian(s), and 
by the investigator or authorized designee who reviewed the ICF/IAF with the patient/patient’s 
parent(s) or legal guardian(s).  
For adolescent patients, local law must be observed in deciding whether the consent of 1 or both 
parents/guardians is required. If only 1 parent or guardian signs the consent form, the investigator 
must document the reason the other parent or guardian did not sign. The patient may also be 
required to sign and date the ICF, as determined by the IRB or EC and in accordance with the local 
regulations and requirements. 
• Patients/parents/guardians who can write but cannot read will have the ICF/IAF read 
to them before signing and dating the ICF/IAF. 
• Patients who can understand but who can neither write nor read will have the ICF/IAF 
read to them in presence of an impartial witness, who will sign and date the ICF/IAF 
to confirm that informed consent/assent was given. 
The original ICF/IAF must be retained by the investigator as part of the patient’s study record, and 
a copy of the signed ICF must be given to the adult patient, or to the adolescent patient and his/her 
parent(s) or legal guardian(s). 
If new safety information results in significant changes in the risk/benefit assessment, the ICF/IAF 
must be reviewed and updated appropriately. All study patients (and adolescent patients’ parent[s] 
or legal guardian[s]) must be informed of the new information and provide their written 
consent/assent if they wish to continue in the study. The original signed revised ICF/IAF must be 
maintained in the patient’s study record and a copy must be given to the adult patient, and the 
adolescent patient and his/her parent(s) or legal guardian(s). 
14.3. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by a patient identification number only, 
on CRFs or other documents submitted to the sponsor. Documents that will not be submitted to 
the sponsor (eg, signed ICF/IAF) must be kept in strict confidence. 
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The patient’s and investigator’s personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations. The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
14.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB or EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF/IAF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in which 
case the IRB or EC should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB or EC should be informed of any event likely to affect the safety of patients 
or the continued conduct of the clinical study. 
A copy of the IRB or EC approval letter with a current list of the IRB or EC members and their 
functions must be received by the sponsor prior to shipment of drug supplies to the investigator. 
The approval letter should include the study number and title, the documents reviewed, and the 
date of the review. 
Records of the IRB or EC review and approval of all study documents (including approval of 
ongoing studies) must be kept on file by the investigator. 
15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB- or 
EC-approved amendment. All substantial protocol amendments will be approved by the competent 
authorities before changes are implemented according to national regulations. 
16. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
16.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely. Reasons may include efficacy, safety, 
or futility, among others. Should the sponsor decide to terminate the study, the investigator(s) will 
be notified in writing. 
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16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice. The final decision should be made through mutual agreement with the sponsor. 
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing. Reasons 
may include the following, among others:  
• The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB or EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of patient final 
eCRF that will be provided to the sponsor. 
17.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs/IAFs, source 
documents, investigator copies of CRFs, and drug accountability records for at least 15 years 
following the completion or discontinuation of the study, or longer, if a longer period is required 
by relevant regulatory authorities. The investigator must obtain written approval from the sponsor 
before discarding or destroying any essential study documents during the retention period 
following study completion or discontinuation. Records must be destroyed in a manner that 
ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
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18. 
DATA QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s). The planned quality assurance and quality 
control procedures for the study are summarized.  
Data Management 
The sponsor is responsible for the data management of this study including quality checking of the 
data (Section 11.1). 
Study Monitoring 
The investigator must allow study-related monitoring, IRB/EC review, audits, and inspections 
from relevant health regulatory authorities, and provide direct access to source data documents 
(Section 12.1, Section 12.2, and Section 13)   
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements (Section 12.1).  
All subject/patient data collected during the study will be recorded on paper or electronic CRF 
unless the data are transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for affirming that data entries in the CRF are accurate and correct by 
electronically signing a declaration that accompanies each set of patient/subject final CRF 
(Section 12.3 and Section 17.1).  
Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the information 
entered in the CRF (Section 12.2).  
The investigator will retain all records and documents, including signed ICFs, pertaining to the 
conduct of this study for at least 15 years after study completion, unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor (Section 17.2).  
19. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
20. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
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21. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
22. 
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Falk GW. Clinical presentation of eosinophilic esophagitis in adults. Gastroenterology Clinics of 
North America. 2014 Jun;43(2):231-42. PubMed PMID: 24813512. 
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Krueger JG, Graham N, Yancopoulos GD, Pirozzi G, Guttman-Yassky E. Dupilumab improves 
the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy 
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of the oesophageal features of eosinophilic oesophagitis: validation of a novel classification and 
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population-based study in Olten County, Switzerland. J Allergy Clin Immunol. 2011 
Dec;128(6):1349-1350.e5. PubMed PMID: 22019091 
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Patient Rep Outcomes. 2017;1(1):3. doi: 10.1186/s41687-017-0006-5. Epub 2017 Sep 12. 
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Kwiatek MA, Hirano I, Kahrilas PJ, Rothe J, Luger D, Pandolfino JE. Mechanical properties of 
the esophagus in eosinophilic esophagitis. Gastroenterology. 2011 Jan;140(1):82-90. doi: 
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Lucendo AJ,2, Molina-Infante J, Arias Á, et al, Guidelines on eosinophilic esophagitis: evidence-
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23. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol:  A PHASE 3, RANDOMIZED, 3-PART STUDY TO 
INVESTIGATE THE EFFICACY AND SAFETY OF DUPILUMAB IN ADULT AND 
ADOLESCENT PATIENTS WITH EOSINOPHILIC ESOPHAGITIS, and agree to abide by all 
provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved. I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the Institutional Review Board or Ethics 
Committee. I agree to ensure that this information will not be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
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SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this protocol accurately describes the conduct of the study. 
Study Title: 
A Phase 3, Randomized, 3-Part Study to Investigate the Efficacy and Safety 
of Dupilumab in Adult and Adolescent Patients with Eosinophilic Esophagitis 
Protocol Number: 
R668-EE-1774 
Protocol Version: 
R668-EE-1774 Amendment 5 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00

Signature Page for VV-RIM-00127522 v1.0
Signature Page for VV-RIM-00127522 v1.0 Approved
ESig Approval
-2020 13:11:18 GMT+0000
ESig Approval
20 13:59:08 GMT+0000
ESig Approval
000
ESig Approval
-2020 18:35:37 GMT+0000
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00