Clinical trial NCT04394351
Conditions: Eosinophilic Esophagitis (EoE)
Sponsor: Regeneron Pharmaceuticals
Start date: 2020-09-01; Completion date: 2024-05-14
Enrollment: 102 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The Primary objective is to demonstrate the efficacy of dupilumab treatment compared with placebo in pediatric patients with active eosinophilic esophagitis (EoE) based on histologic improvement meeting validated histologic criteria.

The Secondary objectives are:

* To demonstrate the efficacy of dupilumab compared to placebo in pediatric patients with active EoE after 16 weeks of treatment as assessed by endoscopic visual measurements of disease activity using the Eosinophilic Esophagitis-Endoscopic Reference Score (EoE-EREFS) and histologic abnormalities as measured by the EoE Histology Scoring System (EoE-HSS)
* To evaluate the safety, tolerability, and immunogenicity of dupilumab treatment for up to 16 weeks in pediatric patients with active EoE
* To evaluate the effects of dupilumab on transcriptomic signatures associated with EoE and type 2 inflammation
* To study the effects of dupilumab on the type 2 inflammation gene expression signature
* To evaluate the concentration-time profile of functional dupilumab in serum in this population
* To assess efficacy of long-term (up to 160 weeks) dupilumab treatment
* To assess the impact of dupilumab treatment on changes in weight and growth during the extended active period and open-label extension period of the study
* To assess safety, tolerability, and immunogenicity of long-term (up to 160 weeks) dupilumab treatment
* To evaluate the impact of dupilumab treatment on EoE signs and symptoms

Detailed description:
This is a 3-part study:

* Part A: Double-blind 16-week treatment period
* Part B: 36-week extended active treatment period
* Part C: Up to108 weeks open-label extension period

Arms: arm 1: Part A consists of a 16-week double-blind treatment period. Patients will be randomized to receive dupilumab or placebo subcutaneous (SC) administration at tiered dosing regimens based on body weight arm 2: Part A consists of a 16-week double-blind treatment period. Patients will be randomized to receive dupilumab or placebo subcutaneous (SC) administration at tiered dosing regimens based on body weight arm 3: Part B consists of a 36-week extended active treatment period. All patients to receive subcutaneous (SC) administration at tiered dosing regimens based on body weight arm 4: Part B consists of a 36-week extended active treatment period. All patients to receive subcutaneous (SC) administration at tiered dosing regimens based on body weight arm 5: Part C consists of up to 108-week open-label extension period. All patients will receive higher exposure dupilumab subcutaneous (SC) administration at tiered dosing regimens based on body weight. No matching placebo administered in Part C.
Interventions: intervention 1: Dupilumab intervention 2: Matching Placebo
Intervention descriptions: intervention 1: Single-use, prefilled syringe intervention 2: Matching formulation and regimen (depending on the weight tier) as dupilumab without the active substance

Protocol documents:
Prot_000.pdf: 
EudraCT: 2019-003078-24 
IND Number: 136142 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY 
TO INVESTIGATE THE EFFICACY AND SAFETY OF DUPILUMAB IN 
PEDIATRIC PATIENTS WITH ACTIVE EOSINOPHILIC ESOPHAGITIS 
Compound: 
Dupilumab 
Study Name: 
EoE KIDS 
Clinical Phase: 
3 
Protocol Number: 
R668-EE-1877 
Protocol Version: 
R668-EE-1877 Amendment 4 
Amendment 4 Date of Issue 
See appended electronic signature page 
Amendment 3 Date of Issue 
13 June 2021 
Amendment 2 Date of Issue 
18 Nov 2020 
Amendment 1 Date of Issue: 
07 Apr 2020 
Original Date of Issue: 
18 Nov 2019 
Medical /Study Director: 
 
  
 
Clinical Scientist: 
 
 
  
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
  
 
 
 
 
 
 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Ab 
Antibody 
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 
BUN 
Blood urea nitrogen 
CCL 
Chemokine (C-C motif) ligand 
Cmax 
Maximal concentration 
CMH 
Cochran-Mantel-Haenszel (test) 
COA 
Clinical outcome assessment 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
CRSwNP 
Chronic rhinosinusitis with nasal polyps 
Ctrough 
Trough concentration 
DMC 
Data monitoring committee 
DSQ 
Dysphagia symptom questionnaire 
EC 
Ethics committee 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDP 
EoE diagnostic panel 
eGFR 
Estimated glomerular filtration rate 
EoE 
Eosinophilic esophagitis 
EoE-EREFS 
Eosinophilic Esophagitis-Endoscopic Reference Score 
EoE-HSS 
EoE Histology Scoring System 
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EOS 
End of study (visit) 
eos/hpf 
Eosinophils/high power field 
EOT 
End of treatment 
EPIT 
Epicutaneous immunotherapy 
ET 
Early termination 
EU 
European Union 
FAS 
Full analysis set 
FeNO 
Fractional exhaled nitric oxide 
FLG 
Filaggrin 
GCP 
Good Clinical Practice 
GIC 
Global Impression of Change 
GIS 
Global Impression of Severity 
HIV 
Human immunodeficiency virus 
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 
IVRS/IWRS 
Interactive voice/web response system 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAb 
Neutralizing antibody 
NES 
Normalized Enrichment Scores 
OIT 
Oral immunotherapy 
PCSV 
Potentially clinically significant value 
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PEESS 
Pediatric Eosinophilic Esophagitis Symptom Score 
PEIS 
Pediatric EoE Impact Scale 
PESQ 
Pediatric EoE Sign/Symptom Questionnaire 
PK 
Pharmacokinetic 
PPI 
Proton pump inhibitor 
PT 
Preferred term (MedDRA) 
QOL 
Quality of life 
Q2W 
Once every 2 weeks 
QW 
Once weekly 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SC 
Subcutaneous 
SCIT 
Subcutaneous immunotherapy 
SLIT 
Sublingual immunotherapy 
SOC 
System organ class 
SPRR3 
Small proline-rich protein 3 
SUSAR 
Suspected unexpected serious adverse reaction 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
Th2 
Type 2 helper T cell 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCF 
Worst observation carried forward 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................2 
AMENDMENT HISTORY ...........................................................................................................11 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................21 
1. 
INTRODUCTION ......................................................................................................32 
2. 
STUDY OBJECTIVES ..............................................................................................35 
2.1. 
Primary Objective .......................................................................................................35 
2.2. 
Secondary Objectives .................................................................................................35 
2.3. 
Exploratory Objectives ...............................................................................................35 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................36 
3.1. 
Hypotheses ..................................................................................................................36 
3.2. 
Rationale .....................................................................................................................36 
3.2.1. 
Rationale for Study Design .........................................................................................36 
3.2.2. 
Rationale for Dose Selection ......................................................................................38 
3.3. 
Benefit-Risk ................................................................................................................40 
3.3.1. 
Benefit-Risk for Participating in the Study ................................................................40 
3.3.1.1. 
Benefit .........................................................................................................................40 
3.3.1.2. 
Risk .............................................................................................................................41 
3.3.1.3. 
Benefit-Risk Conclusion .............................................................................................42 
3.3.2. 
Benefit-Risk for Background Treatment ....................................................................42 
4. 
ENDPOINTS ..............................................................................................................42 
4.1. 
Primary and Secondary Endpoints..............................................................................42 
4.1.1. 
Primary Endpoint ........................................................................................................42 
4.1.2. 
Secondary Endpoints ..................................................................................................43 
4.1.3. 
Exploratory Endpoints ................................................................................................45 
5. 
STUDY VARIABLES................................................................................................47 
5.1. 
Demographic and Baseline Characteristics ................................................................47 
5.2. 
Efficacy Variables ......................................................................................................47 
5.3. 
Safety Variables ..........................................................................................................47 
5.4. 
Pharmacokinetic Variables .........................................................................................47 
5.5. 
Immunogenicity Variables ..........................................................................................48 
5.6. 
Pharmacodynamic and Other Biomarker Variables ...................................................48 
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6. 
STUDY DESIGN .......................................................................................................49 
6.1. 
Study Description and Duration .................................................................................49 
6.1.1. 
End of Study Definition ..............................................................................................51 
6.2. 
Planned Interim Analysis ............................................................................................51 
6.3. 
Study Committees .......................................................................................................52 
6.3.1. 
Independent Data Monitoring Committee ..................................................................52 
7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............53 
7.1. 
Number of Patients Planned .......................................................................................53 
7.2. 
Study Population .........................................................................................................53 
7.2.1. 
Inclusion Criteria ........................................................................................................53 
7.2.2. 
Exclusion Criteria .......................................................................................................54 
7.2.2.1. 
Exclusion Criteria for Part A - Double-Blind Treatment ...........................................54 
7.2.2.2. 
Exclusion Criteria for Part B – Extended Active Treatment (and also for 
Entry into Part C for Patients with Uninterrupted Participation in the Study) ...........57 
7.2.2.3. 
Exclusion Criteria for Patients Re-Entering the Study (for Entry into Part C 
for Patients Who Have Completed Their EOS Visit Prior to Amendment 4) ............57 
7.3. 
Premature Withdrawal from the Study .......................................................................59 
7.4. 
Replacement of Patients .............................................................................................59 
8. 
STUDY TREATMENTS............................................................................................60 
8.1. 
Investigational and Reference Treatments ..................................................................60 
8.2. 
Background Treatments ..............................................................................................65 
8.3. 
Rescue Treatments and Procedures ............................................................................65 
8.4. 
Dose Modification and Study Treatment Discontinuation Rules ...............................66 
8.4.1. 
Dose Modification ......................................................................................................66 
8.4.2. 
Study Drug Discontinuation .......................................................................................66 
8.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................66 
8.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................67 
8.5. 
Management of Acute Reactions ................................................................................67 
8.5.1. 
Acute Injection Reactions ...........................................................................................67 
8.5.1.1. 
Systemic Injection Reactions ......................................................................................67 
8.5.1.2. 
Local Injection Site Reactions ....................................................................................68 
8.6. 
Method of Treatment Assignment ..............................................................................68 
8.7. 
Blinding ......................................................................................................................68 
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8.8. 
Emergency Unblinding (Applies to Part A and Part B only) .....................................69 
8.9. 
Treatment Logistics and Accountability .....................................................................69 
8.9.1. 
Packaging, Labeling, and Storage ..............................................................................69 
8.9.2. 
Supply and Disposition of Treatments .......................................................................69 
8.9.3. 
Treatment Accountability ...........................................................................................70 
8.9.4. 
Treatment Compliance ................................................................................................70 
8.10. 
Concomitant Medications and Procedures .................................................................70 
8.10.1. 
Prohibited Medications and Procedures .....................................................................70 
8.10.2. 
Permitted Medications and Procedures ......................................................................71 
8.10.3. 
Restricted Medications and Procedures during the Follow-Up Period ......................72 
8.11. 
Poststudy Treatments and Procedures ........................................................................72 
9. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................72 
9.1. 
Schedule of Events .....................................................................................................72 
9.1.1. 
Footnotes for the Schedule of Events Tables .............................................................84 
9.1.1.1. 
Footnotes for Table 1 ..................................................................................................84 
9.1.1.2. 
Footnotes for Table 2 ..................................................................................................86 
9.1.1.3. 
Footnotes for Table 3 ..................................................................................................87 
9.1.1.4. 
Footnotes for Table 4 ..................................................................................................88 
9.1.2. 
Early Termination Visit ..............................................................................................89 
9.1.3. 
Unscheduled Visits .....................................................................................................89 
9.1.4. 
Re-Entry Visit .............................................................................................................89 
9.2. 
Study Procedures ........................................................................................................90 
9.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................90 
9.2.2. 
Efficacy Procedures ....................................................................................................90 
9.2.2.1. 
Patient-, Caregiver-, or Clinician-Reported Outcome Measures ................................90 
9.2.2.2. 
Body Weight and Height ............................................................................................92 
9.2.2.3. 
Endoscopy with EoE-EREFS, Biopsies, and Imaging ...............................................92 
9.2.3. 
Safety Procedures .......................................................................................................94 
9.2.3.1. 
Vital Signs ..................................................................................................................94 
9.2.3.2. 
Physical Examination .................................................................................................94 
9.2.3.3. 
Laboratory Testing ......................................................................................................94 
9.2.4. 
Drug Concentration and Measurements .....................................................................96 
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9.2.5. 
Immunogenicity Measurements and Samples ............................................................96 
9.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................96 
9.2.6.1. 
Type 2 Inflammatory and Disease-Related Biomarkers .............................................96 
9.2.6.2. 
EoE Diagnostic Panel and Type 2 Inflammation Transcriptomics ............................97 
9.2.7. 
Biopsy Analyses .........................................................................................................97 
9.2.8. 
Future Biomedical Research (Optional) .....................................................................97 
9.2.8.1. 
Pharmacogenomic Analysis (Optional) ......................................................................98 
10. 
SAFETY EVALUATION AND REPORTING .........................................................99 
10.1. 
Recording and Reporting Adverse Events ..................................................................99 
10.1.1. 
General Guidelines .....................................................................................................99 
10.1.2. 
Reporting Procedure .................................................................................................100 
10.1.3. 
Events that Require Expedited Reporting to Sponsor ..............................................100 
10.2. 
Definitions ................................................................................................................101 
10.2.1. 
Adverse Event ...........................................................................................................101 
10.2.2. 
Serious Adverse Event ..............................................................................................101 
10.2.3. 
Adverse Events of Special Interest ...........................................................................101 
10.2.4. 
Severity .....................................................................................................................102 
10.2.5. 
Causality ...................................................................................................................102 
10.3. 
Safety Monitoring .....................................................................................................104 
10.4. 
Notifying Health Authorities, Institutional Review Board/Ethics Committee, 
and Investigators .......................................................................................................104 
11. 
STATISTICAL PLAN..............................................................................................105 
11.1. 
Statistical Hypothesis ................................................................................................105 
11.2. 
Justification of Sample Size......................................................................................105 
11.3. 
Analysis Sets .............................................................................................................106 
11.3.1. 
Efficacy Analysis Sets for Part A .............................................................................106 
11.3.2. 
Safety Analysis Set for Part A ..................................................................................106 
11.3.3. 
Analysis Set for Parts B and C .................................................................................106 
11.3.4. 
Pharmacokinetic Analysis Sets for All Parts ............................................................106 
11.3.5. 
Immunogenicity Analysis Sets for All Parts ............................................................106 
11.4. 
Statistical Methods ....................................................................................................106 
11.4.1. 
Patient Disposition ....................................................................................................107 
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11.4.2. 
Demography and Baseline Characteristics ...............................................................107 
11.4.3. 
Efficacy Analyses .....................................................................................................107 
11.4.3.1. 
Primary Efficacy Analysis ........................................................................................107 
11.4.3.2. 
Secondary Efficacy Analysis ....................................................................................108 
11.4.4. 
Control of Multiplicity ..............................................................................................109 
11.4.5. 
Safety Analysis .........................................................................................................109 
11.4.5.1. 
Adverse Events .........................................................................................................110 
11.4.5.2. 
Other Safety ..............................................................................................................110 
11.4.5.3. 
Treatment Exposure ..................................................................................................111 
11.4.5.4. 
Treatment Compliance ..............................................................................................111 
11.4.6. 
Pharmacokinetics ......................................................................................................111 
11.4.6.1. 
Analysis of Drug Concentration Data .......................................................................111 
11.4.7. 
Analysis of Immunogenicity Data ............................................................................111 
11.4.8. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ............................112 
11.4.9. 
Timing of Statistical Analysis ..................................................................................112 
11.5. 
Statistical Considerations Surrounding the Premature Termination of a Study .......113 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .......................................114 
12.1. 
Data Management and Electronic Systems ..............................................................114 
12.1.1. 
Data Management .....................................................................................................114 
12.1.2. 
Electronic Systems ....................................................................................................114 
12.2. 
Study Monitoring ......................................................................................................114 
12.2.1. 
Monitoring of Study Sites .........................................................................................114 
12.2.2. 
Source Document Requirements ..............................................................................115 
12.2.3. 
Case Report Form Requirements ..............................................................................115 
12.3. 
Audits and Inspections ..............................................................................................115 
12.4. 
Study Documentation ...............................................................................................116 
12.4.1. 
Certification of Accuracy of Data .............................................................................116 
12.4.2. 
Retention of Records ................................................................................................116 
13. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................117 
13.1. 
Good Clinical Practice Statement .............................................................................117 
13.2. 
Informed Consent .....................................................................................................117 
13.3. 
Patients Confidentiality and Data Protection ............................................................118 
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13.4. 
Institutional Review Board/Ethics Committee .........................................................118 
13.5. 
Clinical Study Data Transparency ............................................................................118 
14. 
PROTOCOL AMENDMENTS ................................................................................119 
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................119 
15.1. 
Premature Termination of the Study .........................................................................119 
15.2. 
Close-out of a Site ....................................................................................................119 
16. 
CONFIDENTIALITY ..............................................................................................120 
17. 
FINANCING AND INSURANCE ...........................................................................120 
18. 
PUBLICATION POLICY ........................................................................................120 
19. 
REFERENCES .........................................................................................................121 
20. 
INVESTIGATOR’S AGREEMENT ........................................................................126 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................127 
 
LIST OF TABLES 
Table 1: 
Schedule of Events - Screening and Double-Blind Treatment Period .......................73 
Table 2: 
Schedule of Events - Extended Active Treatment Period and Re-Entry Visit ...........75 
Table 3: 
Schedule of Events - Early Termination Visits and Unscheduled Visits ...................78 
Table 4: 
Schedule of Events Open-Label Extension Part C (OLE) and EOS Schedule 
of Events .....................................................................................................................80 
 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................49 
Figure 2: 
Endoscopy/Biopsy Procedure Flow Diagram .............................................................50 
Figure 3: 
Part A Weight-Tiered Dosing Regimens of Study Drug ............................................63 
Figure 4: 
Part B Weight-Tiered Dosing Regimens of Study Drug ............................................64 
Figure 5: 
Part C (OLE) Weight-Tiered Dosing Regimens of Study Drug .................................65 
 
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AMENDMENT HISTORY 
Amendment 4 
The primary purpose of this protocol amendment is 
 for the 
addition of a long-term extension period to evaluate the long-term safety of dupilumab in pediatric 
patients 1 to less than 12 years of age with active eosinophilic esophagitis. This long-term 
extension period will add up to 108 weeks of open-label treatment or until dupilumab becomes 
commercially available in the country of the participating patients (whichever comes first). 
Description of Change 
Rationale 
Section Changed 
Added an open-label 
extension (OLE) period 
(Part C) for patients 
completing Part B of this 
study.  Patients who have 
completed their end of study 
(EOS) visit prior to 
amendment 4 will be re-
evaluated for eligibility at a 
Re-Entry visit for 
participation in the open-
label extension period (Part 
C) and Safety Follow-up 
period. 
To assess the long-term safety of repeat doses 
of dupilumab in pediatric patients with 
eosinophilic esophagitis.  
 
 
Clinical Study Protocol 
Synopsis: Objectives, Study 
Design, Study Duration, 
Treatments, Endpoints, 
Statistical Plan 
Section 2.2  Secondary 
Objectives 
Section 3.2.1 Rationale for 
Study Design 
Section 3.2.2 Rationale for Dose 
Selection 
Section 4.1.2 Secondary 
Endpoints 
Section 4.1.3 Exploratory 
Endpoints 
Section 6.1 Study Description 
and Duration 
Figure 1 Study Flow Diagram 
Section 7.2.2.2 Exclusion 
Criteria for Part B – Extended 
Active Treatment (and also for 
Entry into Part C for Patients 
with Uninterrupted Participation 
in the Study) 
Section 8.1 Investigational and 
Reference Treatments 
Figure 5 Part C (OLE) Weight-
Tiered Dosing Regimens of 
Study Drug 
Section 8.7 Blinding 
Table 2 Schedule of Events - 
Extended Active Treatment 
Period and Re-Entry Visit 
Table 4 Schedule of Events 
Open-Label Extension Part C 
(OLE) and EOS Schedule of 
Events 
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Description of Change 
Rationale 
Section Changed 
Section 9.1.1.2 Footnotes for 
Table 2; Footnotes 12 and 13  
Section 9.1.1.4 Footnotes for 
Table 4 
Section 9.1.4 Re-Entry Visit 
Section 9.2.2.3 Endoscopy with 
EoE-EREFS, Biopsies, and 
Imaging 
Section 11.4.3.2 Secondary 
Efficacy Analysis 
Section 11.4.5 Safety Analysis 
Section 11.4.5.1 Adverse Events 
Section 11.4.9 Timing of 
Statistical Analysis 
Updated the Risk section 
The language has been updated with recently 
identified risks of dupilumab treatment 
Section 3.3.1.2 Risk 
Changed study drug dosing 
for OLE Part C 
• 
Changed the weight 
threshold from ≥60 
kg to ≥40 kg to 
receive 
 mg 
QW in Part C of the 
study 
• 
Changed the dosing 
regimen for the 
≥5kg to <15kg 
weight tier from 
mg Q2W to 
mg Q3W 
The pharmacokinetics of dupilumab are 
independent of age in children at least 6 years 
of age. The weight tier is being modified to 
align with the US-approved dose (
 mg 
QW) for adult and adolescent patients with 
EOE weighing at least 40 kg to ensure 
patients <12 years of age and ≥40 kg achieve 
exposures that were associated with clinically 
meaningful and significant symptomatic 
improvement in adults and adolescents.  
Similarly, the dose for patients ≥5 to <15 kg 
in Part C has been adjusted from 
 mg 
Q2W to 
 mg Q3W in order to provide 
exposures closer to that was observed in adult 
and adolescents with EOE receiving 
 mg 
QW. 
Clinical Study Protocol 
Synopsis: Treatment 
Section 3.2.2 Rationale for Dose 
Selection 
Section 8.1 Investigational and 
Reference Treatments 
Figure 5 Part C (OLE) Weight-
Tiered Dosing Regimens of 
Study Drug 
 
Updated the exploratory 
objective and endpoints 
assessing the impact of 
dupilumab treatment on 
changes in weight and 
growth to secondary 
objective and endpoints 
during the extended active 
period  
Growth rate and weight changes are 
important efficacy indicators of dupilumab 
treatment in pediatric EOE patients.  
Clinical Study Protocol 
Synopsis: Objectives and 
Endpoints 
Section 2.2 Secondary 
Objectives 
Section 4.1.2 Secondary 
Endpoints 
Section 4.1.3 Exploratory 
Endpoints 
Section 11.4.3.2 Secondary 
Efficacy Analysis 
 
Updated language in the 
confidentialy statement  
To align with Regeneron’s recent Clinical 
Study Protocol template  
Title Page 
Minor editorial corrections 
For clarification 
Throughout the protocol 
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Amendment 3 
The primary purpose of this protocol amendment is 
 for 
including an exit interview, to add symptom/sign-free days based on the PESQ-P or PESQ-C as a 
secondary endpoint, and to update the definition of primary estimand for patients treated with 
corticosteroids.  
Description of Change 
Rationale 
Section Changed 
Added a new procedure for an exit 
interview at Week 16/Visit 8 with 
caregivers. Patients aged ≥8 to <12 
years old (determined at the time of 
screening visit 1) may also join a 
portion of the exit interview. 
 
 
 
Clinical Study Protocol Synopsis: 
Procedures and Assessments 
Table 1 Schedule of Events - Screening 
and Double-Blind Treatment Period 
Section 9.1.1.1 Footnotes for Table 1, 
footnote number 16 
Section 9.2.2.1.6 Exit Interview 
Added secondary endpoints for 
assessing sign-free days as reported in 
the PESQ-C for all patients and 
symptom-free days as reported in the 
PESQ-P for patients aged ≥8 to <12 
years. 
 
 
 
Clinical Study Protocol Synopsis: 
Secondary Endpoints 
Section 4.1.2 Secondary Endpoints 
Section 9.2.2.1.1 Pediatric EoE 
Sign/Symptom Questionnaire (PESQ) 
Updated the primary estimand 
intercurrent event for initiation of 
treatment with systemic corticosteroids 
to include use of systemic and/or 
swallowed topical corticosteroids. 
 
 
 
Section 11.4.3.1 Primary Efficacy Analysis 
Added a physical examination at the 
baseline visit 
 
 
 
Table 1 Schedule of Events - Screening 
and Double-Blind Treatment Period 
Added tipping point analysis approach 
and WOCF-MI approach as sensitivity 
analyses for primary endpoint and 
removed the single imputation method 
for sensitivity analyses. 
 
 
 
Clinical Study Protocol Synopsis: Analysis 
Methods  
Section 11.4.3.1 Primary Efficacy Analysis 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
Added that the randomization 
stratification of baseline weight group 
may be pooled for CMH test adjusting 
for the randomization stratification 
factor (baseline weight group) 
The randomization 
stratification of baseline 
weight group may be 
pooled to ensure 
sufficient sample size of 
each stratum. 
Clinical Study Protocol Synopsis: 
Statistical Plan 
Section 11.4.3.1 Primary Efficacy Analysis 
Editorial changes to statistical analysis 
sections 
To improve clarity. 
Clinical Study Protocol Synopsis: 
Statistical Plan 
Section 11 Statistical Plan 
Section 11.1 Statistical Hypothesis 
Section 11.2 Justification of Sample Size 
Section 11.4.1 Patient Disposition 
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CONFIDENTIAL 
Description of Change 
Rationale 
Section Changed 
Section 11.4.5.1 Adverse Events 
Section 11.4.5.3 Treatment Exposure 
Section 11.4.7 Analysis of 
Immunogenicity Data 
 
 
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CONFIDENTIAL 
Amendment 2 
The purpose of this protocol amendment is to add an additional treatment arm to evaluate a lower 
exposure of dupilumab, 
. Additional updates were made for 
clarification of study conduct. The following table outlines the changes made to the protocol and 
the rationale.  
Description of Change 
Rationale 
Section Changed 
Added an additional treatment arm to 
evaluate lower exposure of 
investigational product.  
Accordingly, the number of study sites 
was increased, and the sample size was 
updated to reflect the new study 
design. There will be 90 patients 
randomized in a 1:1:1 ratio to receive 
either dupilumab in a higher (N=30) or 
lower (N=30) exposure dose arm, or 
matching placebo (N=30). There will 
be high exposure and low exposure 
placebo groups to match dupilumab 
regimens in the respective weight tiers 
and the details of randomization will 
be specified in the interactive 
voice/web response system 
(IVRS/IWRS) requirement document. 
High exposure and low exposure 
placebo groups will be pooled for 
analysis. 
Part A: 
Higher exposure regimens: 
• 
 mg once every 2 weeks (Q2W) 
in patients who weigh ≥5 kg to <15 
kg 
• 
 mg Q2W in patients who 
weigh ≥15 kg to <30 kg 
• 
 mg Q2W in patients who 
weigh ≥30 kg to <60 kg 
Lower exposure regimens: 
• 
 mg once every 4 weeks (Q4W) 
in patients who weigh ≥5 kg to <15 
kg 
• 
 mg Q4W in patients who 
weigh ≥15 kg to <30 kg  
• 
 mg Q2W in patients who 
weigh ≥30 kg to <60 kg 
Part B 
Higher exposure regimens: 
 
 
 
Clinical Study Protocol Synopsis: Site 
Locations, Study Design, Population, 
Treatments, Statistical Plan 
Section 3.2.1  Rationale for Study Design 
Section 3.2.2 Rationale for Dose Selection 
Section 6.1 Study Description and 
Duration 
Section 7.1  Number of Patients Planned 
Section 8 Study Treatments 
Section 8.1 Investigational and Reference 
Treatments 
Figure 3 Part A Weight-Tiered Dosing 
Regimens of Study Drug 
Figure 4 Part B Weight-Tiered Dosing 
Regimens of Study Drug  
Section 8.6 Method of Treatment 
Assignment 
Section 8.7 Blinding 
Section 9.1.1.1 Footnotes for Table 1, 
footnote #6  
Section 9.1.1.2 Footnotes for Table 2, 
footnote #4b  
Section 11.1 Statistical Hypothesis 
Section 11.2 Justification of Sample Size 
Section 11.4.4 Control of Multiplicity 
Section 11.4.5 Safety Analysis 
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Description of Change 
Rationale 
Section Changed 
• 
 mg Q2W in patients who 
weigh ≥5 kg to <15 kg 
• 
 mg Q2W in patients who 
weigh ≥15 kg to <30 kg 
• 
 mg Q2W in patients who 
weigh ≥30 kg to <60 kg 
• 
 mg QW in patients who weigh 
≥60 kg 
Lower exposure regimens: 
• 
 mg Q4W in patients who 
weigh ≥5 kg to <15 kg 
• 
 mg Q4W in patients who 
weigh ≥15 kg to <30 kg  
• 
 mg Q2W in patients who 
weigh ≥30 kg to <60 kg 
• 
 mg Q2W in patients who 
weigh ≥60 kg 
Added re-assignment of weight tiered 
extended active treatment during Part 
B if weight has increased to a larger 
weight tier at visit 12 / week 32. 
To maintain appropriate 
study drug exposure 
throughout the extended 
active treatment period. 
Clinical Study Protocol Synopsis: 
Treatments 
Section 3.2.2 Rationale for Dose Selection 
Section 8.1 Investigational and Reference 
Treatments 
Figure 4 Weight-Tiered Dosing Regimens 
of Study Drug – Part B 
Section 9.1.1.2 Footnotes for Table 2, 
footnote #4b 
Updated language referring to a “36-
week open-label treatment period” to 
be “36-week extended active treatment 
period”. 
For clarification that 
treatment will remain 
blinded for the extended 
active treatment period. 
Clinical Study Protocol Synopsis: Study 
Design, Statistical Plan 
Section 2.3 Exploratory Objectives 
Section 6.1 Study Description and 
Duration 
Section 11.3.1 Efficacy Analysis Sets 
Section 11.4.5.1 Adverse Events 
Section 11.4.9 Timing of Statistical 
Analysis  
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CONFIDENTIAL 
Description of Change 
Rationale 
Section Changed 
Updated text referring to an ongoing 
phase 3 trial evaluating the efficacy 
and safety of dupilumab in adult and 
adolescent patients with EoE (R668-
EE-1774) to clarify that Part A has 
now been completed. 
To align with the most 
recent data from R668-
EE-1774. 
Clinical Study Protocol Synopsis: 
Statistical Plan 
Section 1 Introduction 
Section 3.2.1  Rationale for Study Design 
Section 3.2.2 Rationale for Dose Selection 
Section 3.3.1.1 Benefit 
Section 3.3.1.3 Benefit-Risk Conclusion 
Section 11.2 Justification of Sample Size 
Added language to clarify general 
changes in study conduct in the 
context of the COVID-19 pandemic. 
To address guidance 
from the US and EU 
regarding the conduct of 
clinical trials during the 
COVID-19 pandemic. 
Section 3.3.1 Risk-Benefit for Participating 
in the Study 
Section 6.1 Study Description and 
Duration 
Section 9.1 Section 9.1 Schedule of Events 
Section 11 Statistical Plan 
Revised the adverse events of special 
interest (AESIs) definitions and 
adverse drug reactions (ADRs) for the 
dupilumab clinical development 
program. 
For program consistency 
 
 and to 
align with the most 
recent Investigator’s 
Brochure. 
Section 3.3.1.2  Risk 
Section 10.1.3 Events that Require 
Expedited Reporting to Sponsor 
Added a primary estimand for the 
primary endpoint. 
To implement a concept 
estimand in our primary 
analysis approaches for 
the primary endpoints 
based on ICH E9 (R1). 
Section 11.4.3.1 Primary Efficacy Analysis 
Minor editorial corrections. 
For clarification. 
Throughout the protocol. 
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CONFIDENTIAL 
Amendment 1 
The purpose of this amendment is to add the Pediatric Eosinophilic Esophagitis Symptom Score 
(PEESSv2.0- caregiver version) questionnaire as a secondary endpoint and to change the Pediatric 
EoE Sign/Symptom Questionnaire (PESQ-Caregiver and PESQ-Patient) questionnaires from 
exploratory to secondary endpoints. Additionally, the Eosinophilic Esophagitis-Endoscopic 
Reference Score (EoE-EREFS) procedure was revised to allow for centralized reading and scoring. 
Minor changes were made to clarify inclusion and exclusion criteria. Other minor changes were 
made 
 for general clarification. The following table 
outlines the changes made to the protocol and the rationale.  
Description of Change 
Brief Rationale 
Section # and Name 
Added the PEESS questionnaire at 
baseline and week 16 and added 
corresponding secondary objectives and 
endpoints. 
 
 
 
Clinical Study Protocol Synopsis: 
Objectives, Endpoints, Procedures and 
Assessments, Statistical Plan 
Section 2.2 Secondary Objectives 
Section 3.2.1 Rationale for Study Design 
Section 4.1.2 Secondary Endpoints 
Section 5.2 Efficacy Variables 
Table 1 Schedule of Events - Screening 
and Double-Blind Treatment Period 
Table 2: Schedule of Events - Extended 
Active Treatment Period and 12-Week 
Follow-Up Period 
Table 3: Schedule of Events - Early 
Termination Visits and Unscheduled Visits 
Section 9.1.1.1 Footnotes for Table 1, 
footnote #15  
Section 9.1.1.2 Footnotes for Table 2, 
footnote #11  
Section 11 Footnotes for Table 3, footnote 
#6  
Section 9.2.2.1.5 Pediatric Eosinophilic 
Esophagitis Symptom Score (PEESS) 
Section 19 References 
Updated the PESQ-Caregiver and PESQ-
Patient questionnaires from exploratory 
objectives and endpoints to secondary 
objectives and endpoints. 
 
 
 
 
Clinical Study Protocol Synopsis: 
Objectives, Endpoints, Statistical Plan 
Section 2.2 Secondary Objectives 
Section 2.3 Exploratory objectives 
Section 3.2.1 Rationale for Study Design 
Section 4.1.2 Secondary Endpoints 
Section 4.1.3 Exploratory Endpoints 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
Revised the EoE-EREFS procedure to 
allow for centralized reading and scoring 
To minimize inter-
rater variability for 
this endpoint. 
Clinical Study Protocol Synopsis: 
Procedures and Assessments 
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Description of Change 
Brief Rationale 
Section # and Name 
and specified that video is the preferred 
method of imaging. 
Section 9.1.1.1 Footnotes for Table 1, 
footnotes #2 and #9 
Section 9.1.1.2 Footnotes for Table 2, 
footnote #7 
Section 11 Footnotes for Table 3, footnote 
#4 
Section 9.2.2.3 Endoscopy with EoE-
EREFS and Biopsies, and Imaging 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
Clarified the endpoints and variables for 
transcriptome sequencing for analyzing 
RNA expression of EoE and type 2 
inflammation. 
For clarification. 
 
Clinical Study Protocol Synopsis: 
Objectives, Endpoints, Procedures and 
Assessments 
Section 2.2 Secondary Objectives 
Section 4.1.2 Secondary Endpoints 
Section 9.2.6.2 EoE Diagnostic Panel and 
Type 2 Inflammation Transcriptomics 
Section 11.4.3.2 Secondary Efficacy 
Analysis 
Section 19 References 
Added endpoints at week 52 
(corresponding to assessments already 
included in this study) for all secondary 
and exploratory endpoints (except for the 
PEESSv2.0 caregiver version). 
For clarification 
Clinical Study Protocol Synopsis: 
Endpoint(s) 
Section 4.1.2 Secondary Endpoints 
Section 4.1.3 Exploratory Endpoints 
Added laboratory collection and analysis 
of blood samples at visit 5/week 4 and 
visit 12/week 32 for chemistry and 
hematology. 
 
 
 
Table 1 Schedule of Events - Screening 
and Double-Blind Treatment Period 
Table 2: Schedule of Events - Extended 
Active Treatment Period and 12-Week 
Follow-Up Period 
Updated the permanent discontinuation of 
study drug for severe abnormal laboratory 
value requirements for neutrophil count, 
platelet count, alanine aminotransferase 
(ALT), and aspartate aminotransferase 
(AST) values to include all events of these 
severe laboratory values, regardless of 
assessment of relatedness to study drug. 
 
 
 
Section 8.4.2.1 Reasons for Permanent 
Discontinuation of Study Drug 
 
Updated inclusion criteria to add the 
requirement for completion of at least 8 
out of 14 days of eDiary for the PESQ-C 
prior to baseline/visit 3. 
 For clarification. 
Section 7.2.1 Inclusion Criteria, criterion 
#5 
Section 9.2.2.1 Patient-, Caregiver-, or 
Clinician-Reported Outcome Measures 
Clarified exclusion criterion #13 for the 
double-blind period and prohibited 
medications to allow for one-time steroid 
use with the anesthetic preparation (not 
For clarification. 
Section 7.2.2.1 Part A – Double-Blind 
Treatment, criterion #13 
Section 8.10.1 Prohibited Medications and 
Procedures 
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Description of Change 
Brief Rationale 
Section # and Name 
for EoE) used during the endoscopy 
procedures.  
Clarified the requirement that all pre-
dosing procedures (including endoscopy 
with biopsy) at the scheduled visit 8/week 
16 must occur prior to dosing with Part 
B/Extended Active Treatment study drug. 
For clarification. 
Section 9.1.1.2 Footnotes for Table 2, 
footnote #1 
Minor changes in language. 
For clarification and 
consistency 
throughout the 
protocol. 
Section 9.1.1.1 Footnotes for Table 1, 
footnote #14 
Section 11 Footnotes for Table 3, footnote 
#5 
Section 9.2.2.1.3 Global Impression of 
Change (GIC) 
Section 9.2.3.3 Laboratory Testing 
Section 9.2.8 Future Biomedical Research 
(Optional) 
Section 9.2.8.1 Pharmacogenomic Analysis 
(Optional) 
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CONFIDENTIAL 
CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the 
Efficacy and Safety of Dupilumab in Pediatric Patients with Active 
Eosinophilic Esophagitis 
Site Locations 
 
Principal Investigator 
Approximately 30 global study sites 
To be determined 
Objectives 
Primary: 
To demonstrate the efficacy of dupilumab treatment compared with placebo 
in pediatric patients with active eosinophilic esophagitis (EoE) based on 
histologic improvement meeting validated histologic criteria. 
Secondary: 
• 
To demonstrate the efficacy of dupilumab compared to placebo in 
pediatric patients with active EoE after 16 weeks of treatment as 
assessed by endoscopic visual measurements of disease activity using 
the Eosinophilic Esophagitis-Endoscopic Reference Score (EoE-
EREFS) and histologic abnormalities as measured by the EoE 
Histology Scoring System (EoE-HSS) 
• 
To evaluate the safety, tolerability, and immunogenicity of dupilumab 
treatment for up to 16 weeks in pediatric patients with active EoE 
• 
To evaluate the effects of dupilumab on transcriptomic signatures 
associated with EoE and type 2 inflammation  
• 
To study the effects of dupilumab on the type 2 inflammation gene 
expression signature 
• 
To evaluate the concentration-time profile of functional dupilumab in 
serum in this population 
• 
To assess efficacy of long-term (up to 160 weeks) dupilumab treatment 
• 
To assess the impact of dupilumab treatment on changes in weight and 
growth during the extended active period and open-label extension 
period of the study 
• 
To assess safety, tolerability, and immunogenicity of long-term (up to 
160 weeks) dupilumab treatment 
• 
To evaluate the impact of dupilumab treatment on EoE signs and 
symptoms 
• 
To assess the impact of dupilumab treatment on changes in weight and 
growth during the extended active and open-label extension period of 
the study 
Study Design 
This is a phase 3, multicenter, randomized, 3-part, double-blind, placebo-
controlled 
study 
investigating 
the 
efficacy, 
safety, 
tolerability, 
pharmacokinetics (PK), and immunogenicity of dupilumab in pediatric 
patients (ages ≥1 year to <12 years) with active EoE. This study consists of 
a screening period of up to 85 days, a double-blind 16-week treatment period 
(Part A), a 36-week extended active treatment period (Part B), a 108-week 
open-label extension period (Part C) and a 12-week follow-up period. 
After patients and their legal parents/legal guardians provide informed 
assent (as appropriate) and informed consent, patients will be assessed for 
study eligibility. 
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Patients are required to have a documented diagnosis of EoE that may be 
established either by a prior historical biopsy, as demonstrated by 
intraepithelial eosinophilic infiltration (peak eosinophils/high power field 
≥15 eos/hpf) (400×) from at least 1 esophageal region and performed after 
at least 8 weeks of treatment with an approved proton pump inhibitor (PPI) 
regimen, or by biopsies performed after approximately 8 weeks of PPI 
treatment initiated prior to screening or during the screening period, which 
demonstrates ≥15 eos/hpf) (400×) from at least 2 of the 3 esophageal regions 
(proximal, mid, and distal). 
Patients who are on PPIs during the screening period to rule out EoE disease 
management with this treatment, and are eligible to enroll in the study, have 
the choice either to remain on the PPI regimen during the entire study or 
stop the PPI regimen prior to baseline (visit 3); they then must remain off of 
PPIs during the entire study. 
Biopsies will be obtained by endoscopy at screening visit 2, the week 16 
visit, the week 52 visit, the week 100 visit, the week 160 visit, or 
immediately prior to start of rescue medication or procedures (only applies 
to rescue medication and/or procedures that occur before the week 52 visit). 
A total of at least 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 histology (needed for study 
inclusion criteria, as well as endpoint assessment) and the other for RNA 
extraction. 
Patients may receive concomitant medications (except for prohibited 
medications specified in the protocol body) as needed, at the discretion of 
the investigator, while continuing study treatment. Frequency of use and 
type of product will be documented.  
Efficacy, safety, laboratory assessments, and samples for assay of 
concentration of functional dupilumab in serum and potential anti-drug 
antibody (ADA) response to dupilumab, as well as research samples, will be 
performed or collected at specified time points throughout the study 
according to Schedule of Events specified in the protocol body. 
Study Duration 
The duration of the study for a patient is up to 172 weeks, excluding the 
screening period. 
End of Study Definition 
The end of study is defined as the date the last patient completes the last 
study visit, withdraws from the study, or is lost to follow-up (ie, the study 
patient can no longer be contacted by the investigator).  
Population 
 
 
Sample Size: 
Approximately 90 patients 
 
Target Population: 
Eligible patients for this study consist of patients with active EoE. 
Key inclusion criteria include the following: 
• 
Males and females aged ≥1 year to <12 years.  
• 
A documented diagnosis of EoE by endoscopic biopsy prior to 
screening, as demonstrated by intraepithelial eosinophilic infiltration 
(peak eosinophil count ≥15 eos/hpf) (400×) from at least 1 esophageal 
region and performed after at least 8 weeks of treatment with a PPI 
regimen. If the patient discontinued PPI therapy, the biopsy must have 
been performed within 2 weeks of the date of discontinuation.  
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CONFIDENTIAL 
If a prior (documented) 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 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 eosinophil count ≥15 
eos/hpf) in at least 2 of the 3 biopsied esophageal regions (proximal, 
mid, or distal). 
• 
History (by patient or caregiver report) of symptom(s) determined by 
the investigator to be the result of EoE (eg, abdominal pain, chest pain, 
acid reflux, food regurgitation, dysphagia, vomiting, or refusal to eat) 
in the month prior to screening. 
Treatments 
 
 
Study Drug 
 
Dose/Route/Schedule: 
Dupilumab 
Part A:  Part A is the double-blind, placebo-controlled portion of the study. 
Subcutaneous (SC) administration at tiered dosing regimens based on body 
weight at baseline. 
Higher exposure dupilumab regimens (Part A): 
• 
 mg once every 2 weeks (Q2W) in patients who weigh ≥5 kg to <15 
kg 
• 
 mg Q2W in patients who weigh ≥15 kg to <30 kg 
• 
 mg Q2W in patients who weigh ≥30 kg to <60 kg 
Lower exposure dupilumab regimens (Part A): 
• 
 mg once every 4 weeks (Q4W) in patients who weigh ≥5 kg to <15 
kg  
• 
 mg Q4W in patients who weigh ≥15 kg to <30 kg 
• 
 mg Q2W in patients who weigh ≥30 kg to <60 kg 
NOTE: In Part A, patients will receive dupilumab injections at the frequency 
of Q2W or Q4W with matching placebo alternating with dupilumab doses 
so the injection frequency will be Q2W for both groups for regimen-blinding 
purposes per treatment assignment. 
Part B:  Part B is the extended active treatment portion of the study. All 
patients (Part A active and placebo) will receive dupilumab based on body 
weight at visit 8 (week 16, end of double-blinded treatment period or start 
of extended treatment period) per the higher and lower exposure group to 
which they were assigned at randomization. If weight tier has increased at 
visit 12 / week 32, patients will be re-assigned to an extended active 
treatment regimen based on weight tiered dosing regimens below. 
Higher exposure dupilumab regimens (Part B): 
• 
 mg Q2W in patients who weigh ≥5 kg to <15 kg 
• 
 mg Q2W in patients who weigh ≥15 kg to <30 kg 
• 
 mg Q2W in patients who weigh ≥30 kg to <60 kg 
• 
 mg QW in patients who weigh ≥60 kg 
Lower exposure dupilumab regimens (Part B): 
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CONFIDENTIAL 
• 
 mg Q4W in patients who weigh ≥5 kg to <15 kg  
• 
 mg Q4W in patients who weigh ≥15 kg to <30 kg 
• 
 mg Q2W in patients who weigh ≥30 kg to <60 kg 
• 
 mg Q2W in patients who weigh ≥60 kg 
NOTE: In Part B, study drug or matching placebo will be administered Q2W 
for all patients in <60 kg weight-groups and QW for all patients in ≥60 kg 
weight-groups. Patients will receive alternating doses of dupilumab or 
placebo Q2W for patients <60 kg assigned to Q4W regimens or QW for 
patients ≥60 kg assigned to Q2W regimens for regimen-blinding purposes. 
Part C:  Part C is the open-label extension portion of the study. All patients 
(Part C) will receive higher exposure dupilumab regimens based on body 
weight at visit 17 (week 52, end of extended active treatment period) or start 
of open-label period (for re-entry patients). All patients who received lower 
exposure dupilumab during Part B will be re-assigned to higher exposure 
dupilumab regimens at the start of the open-label (Part C) period.  If weight 
increases place a patient into a higher weight tier at visit 17 / week 52 (or 
start of open-label period for re-entry patients) or at specified in-clinic visits 
in Part C, the patient will be re-assigned to an open-label treatment regimen 
based on the weight tiered dosing regimen specified below. 
Higher exposure dupilumab regimens (Part C): 
• 
 mg Q3W in patients who weigh ≥5 kg to <15 kg 
• 
 mg Q2W in patients who weigh ≥15 kg to <30 kg 
• 
 mg Q2W in patients who weigh ≥30 kg to <40 kg 
• 
 mg QW in patients who weigh ≥40 kg 
NOTE: In Part C, only active study drug (dupilumab) will be administered.  
No matching placebo will be administered in Part C. The weight-based 
dosing regimens will be as listed above. 
For Part C only: Patients located in a country where dupilumab is 
commercially available for treatment of EoE in patients ≥12 years old will 
be provided treatment with study drug until they are both (1) at least 12 years 
of age and (2) weigh at least 40 kg or the lowest weight for which the 
indication is approved for EoE. These patients will have an end of treatment 
visit at the next scheduled study visit upon meeting both criteria, followed 
by an end of study follow-up visit after 12 weeks. 
 
Placebo 
 
Route/Schedule: 
Matching dupilumab for the respective body-weight tier and exposure 
regimen (Part A and B only). 
Placebo for Part A: Dose matching placebo Q2W or alternating with 
dupilumab Q4W so the frequency will be Q2W for both groups for regimen-
blinding purposes in Part A.  
Placebo for Part B: Dose matching placebo alternating with dupilumab Q2W 
or Q4W so the frequency will be Q2W for the weight-based groups <60kg 
and QW for the weight-based group of ≥60 kg for regimen-blinding 
purposes in Part B.  
No matching placebo will be administered in Part C. 
 
Background Treatment 
Patients who are on PPIs during the screening period to rule out EoE disease 
management with this treatment, and are eligible to enroll in the study, have 
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Dose/Route/Schedule: 
the choice either to remain on the PPI regimen during the entire study or 
stop the PPI regimen prior to baseline; they then must remain off of PPIs 
during the entire study. 
Endpoints 
 
 
Primary: 
Proportion of patients achieving peak esophageal intraepithelial eosinophil 
count of ≤6 eos/hpf (400×) at week 16 
 
Secondary: 
Secondary Efficacy Endpoints for Part A and B: 
• 
Proportion of patients achieving peak esophageal intraepithelial 
eosinophil count of <15 eos/hpf at week 16 
• 
Percent change in peak esophageal intraepithelial eosinophil count 
(eos/hpf) from baseline to week 16 
• 
Absolute change in mean EoE grade score from the EoE-HSS from 
baseline to week 16 
• 
Absolute change in mean EoE stage score from the EoE-HSS from 
baseline to week 16 
• 
Absolute change in EoE-EREFS from baseline to week 16 
• 
Change from baseline in the type 2 inflammation transcriptional 
signature score at week 16  
• 
Change from baseline to week 16 in the proportion of days with 1 or 
more EoE signs as measured by the Pediatric EoE Sign/Symptom 
Questionnaire-caregiver version (PESQ-C) (for patients aged ≥1 to <12 
years) 
• 
Number of sign-free days during the 14-day period preceding week 16 
as measured by the PESQ-C (for patients aged ≥1 to <12 years) 
• 
Change from baseline to week 16 in the proportion of total segments 
within a day (night, morning, afternoon, evening) with 1 or more EoE 
signs as measured by PESQ-C (for patients aged ≥1 to <12 years) 
• 
Change from baseline to week 16 in the proportion of days with 1 or 
more EoE symptoms as measured by PESQ-P (patient version) (for 
patients aged ≥8 to <12 years) 
• 
Number of symptom-free days during the 14-day period preceding 
week 16 as measured by the PESQ-P (patient version) (for patients aged 
≥8 to <12 years) 
• 
Change from baseline to week 16 in the proportion of total segments 
within a day (night, morning, afternoon, evening) with 1 or more EoE 
symptoms as measured by PESQ-P (for patients aged ≥8 to <12 years)  
• 
Change in total score from baseline to week 16 as measured by the 
Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) v2.0- 
caregiver version questionnaire (for patients aged ≥1 to <12 years) 
• 
Normalized Enrichment Scores (NES) for the relative change from 
baseline to week 16 in the EoE diagnostic panel (EDP) transcriptome 
signature 
• 
NES for the relative change from baseline to week 16 in the type 2 
inflammation transcriptome signature 
NOTE:  
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o 
All the above primary and secondary endpoints (except for 
PEESSv2.0- caregiver version questionnaire) assessed at 
week 16 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. 
• 
Change from baseline in body weight for age percentile at week 52 
• 
Change in body mass index for age z-score from baseline to week 52 
for patients ≥2 years of age 
• 
Change in weight for age z-score from baseline to week 52 
• 
Change in weight for height z-score from baseline to week 52 
 
Secondary Efficacy Endpoints for Part C (open-label extension period) 
only: 
• 
Proportion of patients achieving peak esophageal intraepithelial 
eosinophil count of ≤6 eos/hpf (400×) at week 100 and week 160 
• 
Proportion of patients achieving peak esophageal intraepithelial 
eosinophil count of <15 eos/hpf at week 100 and week 160 
• 
Percent change in peak esophageal intraepithelial eosinophil count 
(eos/hpf) from baseline to week 100 and week 160 
• 
Absolute change in mean EoE grade score from the EoE-HSS from 
baseline to week 100 and week 160  
• 
Absolute change in mean EoE stage score from the EoE-HSS from 
baseline to week 100 and week 160 
• 
Absolute change in EoE-EREFS from baseline to week 100 and week 
160 
• 
Normalized Enrichment Scores (NES) for the relative change from 
baseline to week 100 and 160 in the EoE diagnostic panel (EDP) 
transcriptome signature 
• 
NES for the relative change from baseline to week 100 and week 160 
in the type 2 inflammation transcriptome signature 
• 
Change in total score from baseline to week 160 as measured by the 
PEESSv2.0- caregiver version questionnaire  
• 
Proportion of patients (with food elimination diet regimens at baseline) 
that have a re-introduction of a previously eliminated food group by 
week 100 and by week 160 
• 
Change from baseline in body weight for age percentile up to week 160 
• 
Change in body mass index for age z-score for patients ≥2 years of age 
from baseline to up to week 160 
• 
Change in weight for age z-score from baseline to up to week 160 
• 
Change in weight for height z-score from baseline to up to week 160 
Safety Endpoints (Parts A, B, and C): 
• 
Incidence of treatment-emergent adverse events (TEAEs) during the 
16-week double-blind treatment period 
• 
Incidence of TEAEs during the 36-week extended treatment period 
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• 
Incidence of TEAEs during the 108-week open-label extension period 
• 
Incidence of treatment-emergent serious adverse events (SAEs) during 
the 16-week double-blind treatment period 
• 
Incidence of treatment-emergent SAEs during the 36-week extended 
treatment period 
• 
Incidence of treatment-emergent SAEs during the 108-week open-label 
extension period 
• 
Incidence of treatment-emergent adverse events of special interest 
(AESIs) during the 16-week double-blind treatment period 
• 
Incidence of treatment-emergent AESIs during the 36-week extended 
treatment period 
• 
Incidence of treatment-emergent AESIs during the 108-week open-
label extension period 
• 
Incidence of TEAEs leading to permanent discontinuation of study 
treatment during the 16-week double-blind treatment period 
• 
Incidence of TEAEs leading to permanent discontinuation of study 
treatment during the 36-week extended treatment period 
• 
Incidence of TEAEs leading to permanent discontinuation of study 
treatment during the 108-week open-label extension period 
• 
Incidence of treatment-emergent ADA responses and titer during the 
16-week double-blind, 36-week extended treatment periods, and 108-
week open-label extension period 
Clinical Pharmacology Endpoint:  
• 
Concentrations of functional dupilumab in serum by treatment regimen 
at each assessment time point from baseline to end of study 
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Procedures and Assessments 
Efficacy procedures and assessments include the following: 
• 
Endoscopy with EoE-EREFS and biopsies 
o 
EoE-EREFS imaging will be performed to assess the presence 
of exudates, edema, furrows, esophageal rings, and strictures. 
EoE-EREFS imaging will be read and scored by a qualified 
centralized reading center. For all endoscopies, the 
investigators will assess minor esophageal features including 
mucosal inflammatory and remodeling features. 
o 
Esophageal endoscopy with biopsies: After EoE-EREFS 
imaging has been completed, biopsies will be obtained for 
histologic assessments including intraepithelial eosinophil 
count and EoE-HSS (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. 
• 
Patient-, caregiver-, or clinician-reported outcome measures 
o 
Pediatric 
EoE 
Sign/Symptom 
Questionnaire 
(PESQ), 
including a patient version (PESQ-P) and caregiver version 
(PESQ-C) 
o 
Pediatric EoE Impact Scale (PEIS), including a patient version 
(PEIS-P) and a caregiver version (PEIS-C) 
o 
Global Impression of Change (GIC), including a patient 
version (GIC-P), a caregiver version (GIC-C), and a clinician 
version (GIC-Clin) 
o 
Global Impression of Severity (GIS), including a patient 
version (GIS-P), a caregiver version (GIS-C), and a clinician 
version (GIS-Clin) 
o 
The Pediatric Eosinophilic Esophagitis Symptom Score 
(PEESS) v2.0- caregiver version questionnaire 
o 
Telephone exit interview 
• 
Body weight and height (or length for patients <2 years of age); body 
mass index will be programmatically calculated based on the weight 
and height/length data 
Safety and tolerability procedures and assessments include vital signs, 
physical examination, clinical laboratory tests, ADA assessment, and 
clinical evaluations. Patients will be asked to report all adverse events (AEs) 
experienced from the time of informed assent/consent until their last study 
visit. 
Pharmacokinetics: Serum samples will be collected at specified time points 
for assay of functional dupilumab concentration. 
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Statistical Plan 
Sample Size: 
The planned sample size is a total of approximately 90 patients (1:1:1 ratio, 
30 patients in the higher dupliumab exposure group and 30 patients in the 
lower dupilumab exposure group and 30 patients in the placebo group). 
The assumptions used in sample size calculation were based on Part A of 
the R668-EE-1774 study (a phase 3 study for adults and adolescents with 
EoE) and R668-EE-1324 (a phase 2 study for adults with EoE). In Part A of 
the R668-EE-1774, the proportions of patients achieving peak esophageal 
intraepithelial eosinophil count of ≤6 eos/hpf at week 24 were 59.5% and 
5.1% for dupilumab and placebo, respectively. The proportions of 
adolescent patients achieving peak esophageal intraepithelial eosinophil 
count of ≤6 eos/hpf at week 24 were 36.4% and 0% for dupilumab and 
placebo, respectively. The treatment group difference observed in 
adolescents was approximately 36.5%. In the R668-EE-1324 study, the 
proportions of patients achieving histologic response at week 12 were 65% 
and 0% for dupilumab and placebo, respectively. The efficacy of dupilumab 
can be established as early as week 12. Based upon the similarity of 
pathophysiology and expected similarity of response between adults and 
pediatric patients, a similar proportion of responders at week 16 was 
assumed for sample size calculation. The lower exposure dupilumab group 
is assumed to have a similar treatment effect as the higher exposure 
dupilumab group. The treatment group difference observed in the R668-EE-
1774 Part A adolescents was assumed for the sample size calculation for this 
study in children aged ≥1 year to <12 years. It is estimated that with a total 
number of 90 patients (30 patients in the higher exposure dupilumab group, 
30 patients in the lower exposure dupilumab group, and 30 patients in the 
placebo group), at the 2-sided 5% significance level using Fisher’s exact 
test, the study can provide 95% power to detect a treatment difference of 
35.6% in the proportion of histologic responders (ie, patients achieving peak 
esophageal intraepithelial eosinophil count ≤6 eos/hpf) at week 16 between 
placebo (5.1%) and each dupilumab treatment group (40.7%).  
Efficacy Analysis Set for Part A: 
The full analysis set (FAS) includes all randomized patients in Part A; it is 
based on the treatment allocated (as randomized). Efficacy endpoints in 
Part A (double-blind treatment period) will be analyzed using the FAS. 
Safety Analysis Set for Part A: 
The safety analysis set (SAF) includes all randomized patients who received 
any Part A 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. 
Analysis Set for Part B and Part C 
For efficacy and safety analyses of Parts B and C, only a subset of SAF for 
Part A will be included, which is defined as those patients who received at 
least 1 dose of corresponding Part B or/and C study drug.  
Analysis Methods: 
Primary Efficacy Analysis in Part A 
The primary analysis of proportion of patients achieving a histologic 
response of peak esophageal intraepithelial eosinophil count ≤6 eos/hpf at 
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week 16 will be analyzed using the Cochran-Mantel-Haenszel (CMH) test 
to assess the difference in the proportion of responders in the full analysis 
set (FAS), adjusting for the randomization stratification factor (baseline 
weight group). The randomization stratification of baseline weight group 
may be pooled to ensure the sufficient sample size of each stratum. 
To account for use of rescue treatment, patients will be considered as non-
responder after rescue treatment. 
If a patient has missing value for the histological response (peak esophageal 
intraepithelial eosinophil count ≤6 eos/hpf) at week 16, the patient will be 
classified as a non-responder at week 16.  
Sensitivity analyses will assess alternative methods to impute missing data. 
The sensitivity analyses will include a tipping point analysis approach and a 
worst observation carried forward -Multiple Imputation (WOCF-MI) 
approach. 
Subgroup analyses (eg, by weight) may be performed. Details will be 
specified in the SAP. 
Secondary Efficacy Analysis 
Analysis of secondary endpoints in Part A 
Secondary efficacy endpoints that measure binary responses (eg, peak 
esophageal intraepithelial eosinophil count <15 eos/hpf) will be analyzed in 
the same fashion as the primary endpoint. 
Continuous secondary efficacy endpoints will be analyzed using an analysis 
of covariance (ANCOVA) model for the FAS with treatment group, 
randomization stratification factor, and relevant baseline measurement as a 
covariate included in the model. 
For continuous efficacy data that are scheduled to be measured repeatedly 
post-baseline up to week 16, missing data will be imputed by the pattern-
mixture approach. Specifically, the WOCF-Multiple Imputation (WOCF-
MI) approach. 
Analysis of secondary endpoints in Part B 
Efficacy data in Part B will be summarized with descriptive statistics for 
treatment received in Part B as well as by treatment group as in Part A 
(double-blind treatment period). No missing values will be imputed. 
Analysis of secondary endpoints in Part C 
Efficacy data in Part C will be summarized with descriptive statistics for 
treatment received in Part C as well as by treatment group in Part A (double-
blind treatment period) and Part B (extended active treatment period). No 
missing values will be imputed. 
Multiplicity Consideration 
For multiplicity adjustment, a hierarchical procedure will be used to control 
the overall Type-1 error rate at 0.05 for the primary endpoint and the 
selected secondary efficacy endpoints for each dupilumab dose regimen 
versus placebo in Part A only. Each hypothesis will be formally tested only 
if the preceding one is significant at the 2-sided 0.05 significance level. The 
primary endpoint will be tested for the higher exposure dupilumab group 
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first and then for the lower exposure dupilumab group. The hierarchical 
order of the selected secondary endpoints will be specified in the SAP. 
Part B and Part C data will be summarized using descriptive statistics, there 
is no multiplicity issue. 
Safety Analysis 
Safety analysis will be based on the safety analysis set (SAF) in the 
respective study part. This includes reported TEAEs and other safety data 
(ie, clinical laboratory evaluations and vital signs). A descriptive summary 
of safety results will be presented by treatment group for each study part. 
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1. 
INTRODUCTION 
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by esophageal 
dysfunction and eosinophilic inflammation in the esophagus; it is thought to be triggered by an 
abnormal type 2 immune response to food allergens (Furuta, 2017) (Liacouras, 2011). Chronic 
esophageal inflammation leads to progressive remodeling, stricture formation, and fibrosis 
(Hirano, 2014) (Schoepfer, 2014) (Dellon, 2018). Although considered a rare disease, the current 
prevalence is estimated at 22.7 people per 100,000 worldwide (Arias, 2016) and appears to be on 
the increase (Dellon, 2014). There is a low rate of spontaneous remission. Eosinophilic esophagitis 
has been reported in all ages; however, most cases are in children and adults younger than 50 years 
(Dellon, 2014) (Dellon, 2007) (Kapel, 2008) (Liacouras, 2011) (Spergel, 2009). Children under 
the age of 18 represent approximately 30% of the EoE patient population (Dellon, 2014) 
(Prasad, 2009). In the United Sates, based on data from insurance claims within the Truven 
MarketScan database, the estimated number of patients between newborn and 11 years of age with 
EoE is approximately 35,000. Gender differences in EoE have been consistently reported, with 
males affected 3 to 4 times more often than females (Dellon, 2014), 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). Clinical features in younger children 
are non-specific in nature and vary significantly depending on the patient’s age and ability of the 
patient to describe salient symptoms. Infants and toddlers are more likely to present with feeding 
difficulties, vomiting, or regurgitation with the potential for failure to thrive, whereas school-age 
children present with complaints of abdominal pain and heartburn (Iuliano, 2018). Older children 
with symptomatic EoE may also modify their dietary and eating behavior by taking small bites, 
chewing thoroughly, eating slowly, drinking copious fluids, and avoiding food consistencies that 
stick, which is highly suggestive of dysphagia, as this is a feeding behavior reported in adults as 
an attempt to prevent esophageal food impactions (Iuliano, 2018). These symptoms lead to 
substantially impaired quality of life (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. Furrows and white plaques are likely the 
most common finding in children. Rings are not common in children, although rings and furrows 
are the most commonly seen in nearly half of adult patients (Singla, 2016). Some patients 
(particularly pediatric) may present with a normal-appearing esophagus, but still have 
histologically active EoE (Wechsler, 2018).  
Current standard of care for EoE consists of food-elimination diets, off-label proton pump 
inhibitors (PPIs), off-label use of swallowed topical corticosteroids, and esophageal dilation. 
Esophageal dilation is frequently utilized to relieve dysphagia symptoms caused by esophageal 
strictures. Since strictures do not occur as commonly in children, esophageal dilation is not as 
commonly performed in children with EoE as compared to in adults with EoE (Chehade, 2018) 
(Furuta, 2017). The standard therapies for EoE are limited by variable response rates, relapse after 
therapy cessation, and adverse effects on quality of life. These limitations lead to a significant 
unmet need for new treatments targeting key pathways driving EoE inflammation (Spergel, 2012) 
(Greuter, 2017). Dietary modification is a standard treatment for patients with EoE. Diets 
eliminating specific foods can be effective in a significant percentage of patients; however, 30% 
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to 40% of patients do not have resolution of disease with dietary modification (Nhu, 2019). Proton 
pump inhibitors can result in histologic remission in approximately 50% of patients with EoE 
(Lucendo, 2017) with the remaining patients unresponsive. Swallowed topical corticosteroids have 
been reported in clinical trials to induce partial clinical responses and histologic remission; 
however, they are not uniformly effective and may be associated with local fungal infections, as 
well as a risk of growth suppression and hypothalamic–pituitary–adrenal axis suppression 
following systemic absorption (Golekoh, 2016), limiting their use to short term. Emergency 
endoscopy for prolonged and/or painful food impaction, and esophageal dilation to provide relief 
from strictures, are associated with a risk of severe esophageal injury and do not alter the 
underlying pathogenesis or progression of the disease. To date, the United States (US) Food and 
Drug Administration (FDA) has not approved pharmacologic therapies for EoE for children less 
than 12 years; the European Commission has approved budesonide oral dispersible tablets for the 
treatment of EoE in adults, but no approved medicinal product is available for the treatment of 
EoE in children in the European Union (EU).  
Growing evidence suggests that a type 2 immune response plays an important pathogenic role in 
the development of EoE in genetically susceptible individuals. Food allergens permeate an 
impaired esophageal epithelial barrier and initiate an inflammatory reaction where activated type 2 
helper T cells (Th2) increase tissue levels of type 2 cytokines, such as interleukin (IL)-5, IL-13, 
and IL-4. These cytokines are responsible for driving eosinophil recruitment and activation. 
Several genes in the epidermal differentiation complex such as filaggrin (FLG), desmogelin 1 
(DSG1), and the esophagus-specific esophagin (small proline-rich protein 3 [SPRR3]), are down-
regulated by type 2 cytokines with resultant epithelial barrier dysfunction (Blanchard, 2007) 
(Blanchard, 2010) (Wen, 2013). Eotaxin-3 (chemokine [C-C motif] ligand 26 gene [CCL26]) is a 
potent eosinophil chemoattractant which is highly regulated by IL-13 and IL-4, and variants in the 
gene are associated with increased EoE risk; it is 1 of the top upregulated genes in esophageal 
pinch biopsies in EoE patients compared to controls (Blanchard, 2006) (Sherrill, 2014). Upon 
activation, eosinophils can secrete a variety of pro-inflammatory cytokines and chemokines or 
degranulate, releasing preformed granules containing cationic and cytotoxic proteins that are 
injurious to the tissues. While EoE involves an eosinophil-predominant inflammation, there is 
evidence to suggest that other immune cells, such as mast cells, basophils, and invariant natural 
killer T cells also mediate the inflammation (Straumann, 2012) (O'Shea, 2018).  
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 immunoglobulin E (IgE) (Hamilton, 2014). Additionally, preclinical data 
demonstrate that treatment with dupilumab prevents infiltration of eosinophils into tissues. 
Dupilumab (brand name DUPIXENT®) is approved in the US and EU for the treatment of adult 
and adolescent patients aged 12 years and older with atopic dermatitis (AD). Dupilumab has also 
been approved in the US as an add-on maintenance treatment for adults and adolescents (age 12 
and older) with moderate-to-severe asthma with an eosinophilic phenotype or with oral 
corticosteroid-dependent asthma; it is approved in the EU for severe asthma with type 2 
inflammation characterized by raised blood eosinophils and/or raised fractional exhaled nitric 
oxide (FeNO) in patients who are inadequately controlled with a high-dose inhaled corticosteroid 
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plus another medicinal product for maintenance treatment. Dupilumab has also been approved in 
the US and EU for chronic rhinosinusitis with nasal polyps (CRSwNP).    Dupilumab is currently 
approved in the United States for the treatment of adult and pediatric patients aged 12 years and 
older, weighing at least 40 kg, with eosinophilic esophagitis (EoE). 
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 (Hirano, 2019a). In the 
dupilumab group, Straumann Dysphagia Index Patient-Reported Outcome scores were reduced by 
a mean value of 3.0 at week 10, compared with a mean reduction of 1.3 in the placebo group 
(P=.0304). At week 12, dupilumab reduced peak esophageal intraepithelial eosinophil count by a 
mean 86.8 eos/high power field (hpf) (reduction of 107.1 %, P <.0001 vs placebo), and the 
endoscopic reference score was reduced by 1.6 (P=.0006 vs placebo). Dupilumab was well 
tolerated by the study patients, with safety data generally consistent with other dupilumab studies 
and with no new safety signals associated with use in the EoE patient population (Hirano, 2019b). 
These results support pursuing further development of dupilumab for the treatment of EoE in adult, 
adolescent, and pediatric patients. As such, a phase 3 trial evaluating the efficacy and safety of 
dupilumab in adult and adolescent patients with EoE (R668-EE-1774) was initiated. The co-
primary endpoint for the adult and adolescent trial includes both a validated symptom 
measurement utilizing the dysphagia symptom questionnaire (DSQ) and histologic evaluation.  
R668-EE-1774 Part A met both of its co-primary endpoints in symptomatic (dysphagia) and 
histological response, as well as all key secondary endpoints in histologic, endoscopic, and 
molecular (transcriptomic) domains for patients treated with dupilumab 
 mg QW. 
R668-EE-1774 Part B of the study was considered positive for treatment with dupilumab 
 mg 
QW, as this dose regimen showed statistically significant improvement in both co-primary 
endpoints. In contrast, treatment with dupilumab 
 mg Q2W did not meet the co-primary 
endpoint of symptomatic improvement but demonstrated statistically significant improvement in 
the co-primary endpoint for histological response. Further, dupilumab 
 mg Q2W demonstrated 
a similar magnitude in response as 
 mg QW for other secondary histologic, endoscopic, and 
molecular (transcriptomic) endpoints. 
Histological and molecular evidence suggest that the disease has the same underlying pathogenesis 
in different age groups and responds similarly to swallowed topical corticosteroid treatment 
regardless of age (Straumann, 2012). Therefore, for the pediatric trial, where symptoms are more 
heterogeneous, success of the trial will be determined by histologic measures; however, symptom 
assessments will be evaluated through exploratory endpoints. 
The R668-EE-1877 phase 3 Part A study met its primary endpoint (proportion of patients with 
peak eosinophil count ≤6/high power field [hpf] in esophageal biopsy tissue) for both higher and 
lower exposure dupilumab regimens at week 16 (p-values < 0.0001). Additionally, as part of a 
prespecified exploratory analysis, the dupilumab treatment groups experienced increases in body 
weight for age percentile from baseline as compared to placebo at week 16.  Safety results from 
R668-EE-1877 Part A were generally consistent with the known safety profile of dupilumab in its 
approved EoE indication for children and adults aged 12 years and older who weigh at least 40 kg.  
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 Objective 
To demonstrate the efficacy of dupilumab treatment compared with placebo in pediatric patients 
with active EoE based on histologic improvement meeting validated histologic criteria. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To demonstrate the efficacy of dupilumab compared to placebo in pediatric patients 
with active EoE after 16 weeks of treatment as assessed by endoscopic visual 
measurements of disease activity using the Eosinophilic Esophagitis-Endoscopic 
Reference Score (EoE-EREFS) and histologic abnormalities as measured by the EoE 
Histology Scoring System (EoE-HSS) 
• To evaluate the safety, tolerability, and immunogenicity of dupilumab treatment for up 
to 16 weeks in pediatric patients with active EoE 
• To evaluate the effects of dupilumab on transcriptomic signatures associated with EoE 
and type 2 inflammation  
• To study the effects of dupilumab on the type 2 inflammation gene expression signature 
• To evaluate the concentration-time profile of functional dupilumab in serum in this 
population 
• To assess efficacy of long-term (up to 160 weeks) dupilumab treatment 
• To assess the impact of dupilumab treatment on changes in weight and growth during 
the extended active period and open-label extension period of the study  
• To assess safety, tolerability, and immunogenicity of long-term (up to 160 weeks) 
dupilumab treatment 
• To evaluate the impact of dupilumab treatment on EoE signs and symptoms 
• To assess the impact of dupilumab treatment on changes in weight and growth during 
the extended active and open-label extension period of the study  
2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To explore impact of dupilumab treatment on health-related quality of life 
• To explore impact of dupilumab on global impression of change and severity of disease 
• To explore impact of dupilumab treatment on changes in weight and growth during the 
double-blind phase. 
• To conduct exploratory research to study EoE and dupilumab mechanism of action in 
pediatric patients, including predictive biomarker discovery and/or validation 
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3. 
HYPOTHESIS AND RATIONALE 
3.1. 
Hypotheses 
In pediatric patients (ages ≥1 year to <12 years) with active EoE, dupilumab will significantly 
reduce eosinophilic inflammation compared to placebo, as measured by reduction in eosinophilic 
esophageal infiltration (assessed by change in esophageal peak intraepithelial eosinophil count and 
EoE-HSS score). 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
This is a randomized, 3-part, double-blind, placebo-controlled study to evaluate the efficacy and 
safety of dupilumab in pediatric EoE. Children with active EoE, ages ≥1 year to <12 years, who 
are PPI histologically non-responsive, will be randomized 1:1:1 to receive either higher exposure 
dupilumab (N=30) or lower exposure dupilumab (N=30) (in a tiered, weight-based dosing schema) 
or placebo (N=30) over 16 weeks. In the absence of valid and reliable clinical outcomes assessment 
(COA) tools for symptom assessment, primary efficacy will be assessed by a histological endpoint:  
proportion of patients with histologic remission (≤6 eos/hpf). A total sample size of 90 patients is 
based on the number of patients to inform the primary clinical efficacy histological endpoint and 
to characterize the safety profile of dupilumab in pediatric patients with EoE.  
Rationale for Endpoints 
In 2017, guidelines on EoE were published to optimize diagnosis and treatment of the condition. 
An extensive literature search was completed with systematic evidence-based reviews. A task 
force of 21 physicians and researchers addressed questions related to EoE. There was agreement 
among members of the task force that clinical symptoms and signs are variable across age groups; 
however, objectively, the histologic criterion of EoE is at least 15 eos/hpf in esophageal mucosa 
(Lucendo, 2017). 
Given the key disease feature of EoE is esophageal dysfunction, and esophageal health is the only 
consistent way to observe treatment difference in children, the proposed primary endpoint in this 
study is the proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤6 eos/hpf (400×). It is also a responder endpoint that was significantly improved by dupilumab 
in the adult phase 2 study R668-EE-1324 (65.2% responders at week 12) and is a co-primary 
endpoint in the adult/adolescent phase 3 study R668-EE-1774. In Part A of this phase 3 study, the 
proportions of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf at 
week 24 were 59.5% and 5.1% for dupilumab and placebo, respectively. The consensus 
recommendation for diagnosis of EoE is peak esophageal intraepithelial eosinophil cell count 
≥15 eos/hpf. Reduction to ≤6 eos/hpf may be an optimal response threshold for clinical trials, as it 
identified most patients who had a combined symptomatic and endoscopic response 
(Dellon, 2007). 
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The EoE-HSS is a recently validated histologic scoring system that measures other histological 
abnormalities in addition to the density of eosinophilic infiltration, including eosinophil surface 
layering, eosinophil abscesses, basal zone hyperplasia, dilated intercellular spaces, surface 
epithelial alteration, and dyskeratotic epithelial cells. It has been confirmed in adults to have 
external reliability and this scoring system is highly responsive to treatment (Collins, 2017) 
(Warners, 2018). 
The visual EoE esophageal anatomical 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 EoE-EREFS utilizes a 
composite score using standardized methodology to assess clinical signs of EoE disease. 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); and Stricture (absent, present). Endoscopic findings in EoE have 
been well described and are observed in the vast majority of EoE patients, though the type and 
frequency vary by age. The EoE-EREFS scoring system has been externally validated to identify 
disease in EoE children and adults, to reflect changes in disease severity after treatment, and it has 
been used in multiple clinical trials (Hirano, 2017) (Wechsler, 2018). 
Other efficacy endpoints, endoscopic analysis of severity by EoE-EREFS, and EoE-HSS histologic 
response will be collected as secondary efficacy endpoints. In a phase 2 study of RPC4046, a 
monoclonal antibody against IL-13, the EoE-HSS instrument was used and assessed by a 
centralized, blinded pathologist with expertise in eosinophilic disorders. This study showed that 
reductions in mean adjusted EoE-HSS grade scores of 31 points and stage scores of 27 points 
between RPC4046 and placebo were statistically significant after 16 weeks of anti-IL-13 treatment 
in adults with active EoE (Hirano, 2019a). In R668-EE-1877 Part A, as part of a prespecified 
exploratory analysis, the dupilumab treatment groups experienced increases in body weight for 
age percentile from baseline as compared to placebo at week 16. Given that growth rate and weight 
changes are important efficacy indicators of dupilumab treatment in pediatric EOE patients, weight 
and growth changes will be assessed as secondary endpoints for the extended active and open label 
extension treatment periods. 
In terms of clinical outcomes, the caregiver-reported versions of the Pediatric EoE Sign/Symptom 
Questionnaire (PESQ-C) and the Pediatric Eosinophilic Esophagitis Symptom Score (PEESSv2.0) 
questionnaire will be used as secondary endpoints. Since patient-reported symptoms are expected 
to be reliable for pediatric patients >8 years of age (Matza, 2013), the patient-reported version of 
the PESQ (PESQ-P) will also be used as a secondary endpoint. Finally, health-related quality of 
life (HRQoL) and EoE disease status will be measured as exploratory endpoints using the Pediatric 
EoE Impact Scale (PEIS) and the Global Impression of Severity (GIS) and Global Impression of 
Change (GIC) questionnaires.  
Safety of dupilumab in this pediatric patient population is a key question, and therefore safety 
endpoints will also be included as secondary endpoints in this study. In addition, pharmacokinetics 
(PK) will also be analyzed as a secondary endpoint. 
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3.2.2. 
Rationale for Dose Selection  
Based on the known safety, efficacy, and PK of dupilumab, which has been studied in adults, 
adolescents, and children as young as 6 months of age, the dose regimen to be investigated in this 
study in children with EoE aged ≥1 year to <12 years is weight-based dosing as follows:  
Higher exposure dupilumab regimens for Parts A, B, and C (approximates Ctrough of 
 mg QW 
regimen in adults): 
• 
 
 
• 
 
• 
 
• 
 
 
• 
 
Lower exposure dupilumab regimens for Part A and B (approximates Ctrough of 
 mg Q2W 
regimen in adults): 
• 
 mg once every 4 weeks (Q4W) in patients who weigh ≥5 kg to <15 kg 
• 
 mg Q4W in patients who weigh ≥15 kg to <30 kg 
• 
 mg Q2W in patients who weigh ≥30 kg to <60 kg 
• 
 mg Q2W in patients who weigh ≥60 kg (Part B Only) 
NOTE: Patients ≥ 60 kg are excluded from enrollment into Part A, but patients may reach this 
weight tier during the extended active period (Part B) or open label extension period  (Part C). All 
patients will be reassigned a weight-tiered dose for the higher exposure dupilumab regimen in 
Part C at visit 17 / week 52 (or start of open label period for re-entry patients).  At specified in-
clinic visits in Part C, patients that have increased in body weight to a higher weight tier will be 
re-assigned to an appropriate open-label treatment regimen for their corresponding weight. 
During Part A and Part B, patients will receive dupilumab injections at the frequency of QW, 
Q2W, or Q4W with matching placebo alternating with dupilumab doses so the injection frequency 
will be identical within weight tiers for regimen-blinding purposes. Patients will remain within the 
originally assigned higher or lower dosing exposure arm throughout Part A and Part B.   
For Part C, patients will receive the higher exposure dupilumab weight tiered dosing regimen.  No 
matching placebo will be administered in Part C. The doses and regimens of dupilumab are 
intended to approximate the steady-state trough concentrations (Ctrough) observed in adult patients 
receiving 
 mg QW for the higher exposure regimen. In order to achieve similar exposures 
across this broad age range, the doses will be assigned by weight tiers.   
In adults, dupilumab regimens of 
 mg Q2W were shown to be well tolerated and efficacious in 
patients with asthma, AD and CRSwNP. The 
 mg QW dose in adult patients has shown 
significant clinical and histological efficacy in a previous proof-of-concept study (R668-EE-1324) 
as well as in an on-going study in adolescent and adult patients with EoE (R668-EE-1774). The 
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 mg QW dose has been shown to be well tolerated in patients with EoE, consistent with its 
evaluation in other type 2 inflammatory diseases. No clinically significant differences in the 
pharmacokinetics of dupilumab have been observed between healthy subjects or patients with 
asthma, AD, CRSwNP, or EoE. 
The dupilumab 
 mg Q2W dose is an approved dosing regimen in adult patients with atopic 
dermatitis, chronic rhinosinusitis with nasal polyposis, or asthma (in the US), as well as in 
adolescent patients 12 years of age or older with asthma (in the US) and adolescents and children 
(≥6 years of age) with atopic dermatitis who weigh ≥60 kg. The weight-tiered pediatric regimen 
of dupilumab 
 mg Q4W in ≥15 to <30 kg or 
 mg Q2W in ≥30 to <60 kg was also approved 
in the US in patients ≥6 to <12 years of age with AD and was selected to produce exposures in 
pediatric patients similar to those in adults receiving 
 mg Q2W. The safety profile also has 
been comparable between adult and pediatric (≥6 to <18 years) patients in AD as well as in asthma 
populations receiving dupilumab 
 mg Q2W regimen.  
In adults and adolescents with EoE receiving dupilumab 
 mg QW or Q2W (R668-EE-1774 
Part B), both regimens significantly improved histologic endpoints relative to placebo, but only 
 mg QW also improved dysphagia symptoms. Dupilumab 
mg QW is approved in the US 
for use in adults and adolescents with EoE weighing at least 40 kg.  Given the higher exposure and 
lower exposure dupilumab regimen approximate the steady-state (Ctrough) observed in adult 
patients receiving 
 mg QW and Q2W, respectively, the higher exposure regimen will be 
administered in Part C of this study to provide the maximum potential benefit to pediatric patients 
with EoE. Within the higher exposure dupilumab regimen, the body weight threshold at which 
patients switch from 
 mg Q2W to 
 mg QW will be changed from 60 kg in Part B to 40 kg 
in Part C to align with the approved regimen for adults and adolescents with EoE.  The 
pharmacokinetics of dupilumab are independent of age in children at least 6 years of age and by 
modifying this weight tier, pediatric patients ≥40 kg will receive the same dupilumab dose in 
Part C as approved in the US for adult and adolescent patients with EoE of similar body weight. It 
is expected that pediatric patients who weigh  ≥40 kg will be at least 6 years of age 
(CDC Growth Charts: United States, 2000). The dose for patients ≥5 to <15 kg in Part C will also 
be adjusted from 
 mg Q2W to 
 mg Q3W for the higher exposure dupilumab regimen to 
provide a closer approximation of the trough concentrations in adults and adolescents with EOE 
receiving 
 mg QW.  
From trials in the dupilumab program across indications evaluating both the 
 mg QW and the 
 mg Q2W doses in adult patients with AD or in adult and adolescent patients with EoE, the 
 mg Q2W regimen has a similar safety profile to that of 
 mg QW regimen, with the 
exception of a higher incidence of injection site reactions in the 
 mg QW regimen, which is 
likely associated with more frequent injections with drug substance. No loading dose is proposed 
in this study, consistent with the dosing regimens being evaluated in the phase 3 study of adult and 
adolescent patients (≥12 years of age) with EoE (R668-EE-1774). 
Due to the rarity of EoE in children ≥1 year to <12 years, larger studies evaluating multiple dose 
regimens are not feasible. Dupilumab exposures in pediatric patients were simulated using a 
population PK model developed including data collected across multiple studies in pediatric 
patients with AD ≥6 months to <18 years of age. Both the higher and lower exposure regimens 
were selected to provide steady-state exposures that did not exceed the 95th percentile of maximal 
concentrations (Cmax) for the 
 mg QW adult dose, and did not fall below the 5th percentile of 
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Ctrough for the 
 mg Q2W adult dose. The subset of patients ≥5 to <15 kg receiving 
 mg Q3W 
or ≥40 to <60 kg receiving 
 mg QW in Part C may exhibit  Cmax values higher than the overall 
adult 
 mg QW population, but are expected to be within the range of exposures observed for 
adolescents ≥40 receiving 
 mg QW.  Dupilumab has a wide safety margin and no exposure-
related adverse events have been identified, hence the higher Cmax in these groups is not considered 
to be clinically relevant. 
Enrollment in Part A is limited to patients weighing <60 kg, but it is possible that patient weight 
may increase above this threshold during the study. Patients weighing ≥60 kg at the time of dose 
assignment at visit 8 / week 16 and/or visit 12 / week 32 or ≥40 kg at visit 17 / week 52 of Part B 
(or at start of open label period for re-entry patients) and/or during specified in-clinic visits for 
Part C of the study will receive regimens equivalent to the reference adult dose(s).  Patients located 
in a country where dupilumab is commercially available for treatment of EoE in patients ≥12 years 
old will be provided treatment with study drug until they are both (1) at least 12 years of age and 
(2) weigh at least 40 kg or the lowest weight for which the indication is approved. These patients 
will have an end of treatment visit at the next scheduled study visit upon meeting both criteria, 
followed by an end of study follow-up visit after 12 weeks. 
The proposed regimens provide similar exposures that have been effective and well tolerated in 
multiple indications in adults and adolescents. For the higher exposure regimens, these predicted 
Ctrough values are similar to what has been demonstrated to be effective in adult patients with EoE. 
For the lower exposure regimens, the predicted Ctrough values are similar to what has been 
demonstrated to be effective in other type 2 inflammatory indications. 
3.3. 
Benefit-Risk 
3.3.1. 
Benefit-Risk for 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 patients in this study until 
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. For further 
information regarding COVID-19 pandemic study impact, see Section 9. 
3.3.1.1. 
Benefit 
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). In the initial phase 2 study, treatment 
with weekly dupilumab 
 mg subcutaneously (SC) for 12 weeks in patients with EoE reduced 
the frequency and intensity of dysphagia. 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.  
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Additionally, data from the ongoing phase 3 randomized, double-blind, placebo-controlled study 
(R668-EE-1774-Part A) showed a substantial and statistically significant improvements in clinical, 
endoscopic, and histologic measures of the disease in adult and adolescent patients treated with 
dupilumab 
mg SC (N=42) versus placebo (N=39) at week 24. R668-EE-1774 Part B of the 
study was considered positive for treatment with dupilumab 
 mg QW, as this dose regimen 
showed statistically significant improvement in both co-primary endpoints. In contrast, treatment 
with dupilumab 
 mg Q2W did not meet the co-primary endpoint of symptomatic improvement 
but demonstrated statistically significant improvement in the co-primary endpoint for histological 
response. Further, dupilumab 
 mg Q2W demonstrated a similar magnitude in response as 
 
mg QW for other secondary histologic, endoscopic, and molecular (transcriptomic) endpoints. 
Dupilumab is currently approved in the United States for the treatment of adult and pediatric 
patients aged 12 years and older, weighing at least 40 kg, with eosinophilic esophagitis (EoE).  
This is the first time a phase 3 trial with a biologic treatment has reported improvement in patients’ 
ability to swallow food, as reported by a daily questionnaire.  
The R668-EE-1877 phase 3 Part A study met its primary endpoint (proportion of patients with 
peak eosinophil count ≤6/high power field [hpf] in esophageal biopsy tissue) for both higher and 
lower exposure dupilumab regimens at week 16 (p-values < 0.0001). Additionally, as part of a 
prespecified exploratory analysis, the dupilumab treatment groups experienced increases in body 
weight for age percentile from baseline as compared to placebo at week 16. 
Although presenting symptoms of EoE may vary when comparing children to adolescents and 
adults, the underlying disease is thought to be the same. Therefore, the efficacy demonstrated in 
adults and adolescents with EoE who were treated with dupilumab is expected to be replicated in 
the pediatric population. Study patients could potentially benefit from dupilumab treatment, 
including patients randomized to receive placebo in Part A, as all patients have the opportunity to 
receive dupilumab in the extended active treatment Part B and open-label extension Part C of the 
study. 
3.3.1.2. 
Risk 
Dupilumab has demonstrated a favorable safety profile in clinical studies across all approved 
indications. Dupilumab was well tolerated by the study patients in trial R668-EE-1774 and safety 
results from R668-EE-1877 Part A were generally consistent with the known safety profile of 
dupilumab in its approved EoE indication for children and adults aged 12 years and older who 
weigh at least 40 kg.  
The identified adverse drug reactions (ADR) across all indications are Injection Site Reactions 
(ISRs), Sickness-like Reaction/Serum Sickness and Anaphylactic Reaction. Though serious serum 
sickness and serum sickness-like reactions were observed rarely and only in atopic dermatitis (AD) 
clinical trials; and dupilumab-related anaphylactic reaction was observed rarely and only in an 
asthma clinical trial, they are considered ADRs across all indications as hypersensitivity is not 
expected to be indication specific. As protein therapeutics, all mAbs are potentially immunogenic. 
Systemic hypersensitivity is considered an important identified risk for dupilumab.  
Eosinophilia associated with clinical symptoms in asthma patients is an important potential risk, 
based on cases of eosinophilic granulomatosis with polyangiitis and eosinophilic pneumonia 
reported in asthma clinical trials (as well as in adult patients with co-morbid asthma in the 
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CRSwNP development program). These events usually, but not always, may be associated with 
the reduction of oral corticosteroid therapy. A causal association between dupilumab and these 
conditions has not been established. The DUPIXENT® US Prescribing Information lists upper 
respiratory tract infections (composed of several terms including, but not limited to, COVID-19, 
sinusitis, and upper respiratory tract infection) in the 'Adverse Reactions' section for the adult and 
adolescent EoE indication. In the AD clinical studies, Conjunctivitis, Conjunctivitis Allergic, 
Conjunctivitis Bacterial, Blepharitis, Dry Eye, Eye Pruritus, Herpes Simplex (primarily 
mucocutaneous in nature), Eosinophilia and Oral Herpes were identified ADRs. The eye and 
herpes related ADRs appear to be predominantly AD indication specific. Conjunctivitis is also 
considered an ADR for the CRSwNP indication, although it occurred at a lower incidence in these 
studies than in AD studies. Most events were mild in intensity, transient in nature, and did not 
necessitate treatment discontinuation. In the completed AD studies in children aged 6 to 17 years, 
the safety profile was consistent with that reported in adults and there was no new safety concerns 
identified. In a study in patients aged 6 to 11 years with asthma, Enterobiasis and Eosinophilia 
were identified as additional ADRs. Angioedema, arthralgia, keratitis, ulcerative keratitis and 
facial rash have been identified as ADRs in the post-marketing setting.  
3.3.1.3. 
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 and Part A and B of the phase 3 EoE study, 
support a favorable benefit-risk profile for dupilumab. 
A risk-benefit statement with respect to the overall clinical development program is provided in 
the Investigator’s Brochure. 
3.3.2. 
Benefit-Risk for Background Treatment 
Proton pump inhibitors are FDA-approved for the short-term treatment in children for healing of 
EoE (CMS, 2013). A trial of PPIs prior to endoscopy with biopsy will ensure that pediatric patients 
with EoE who show improvement/resolution in their signs and symptoms of EoE with this 
treatment are appropriately excluded from this trial. Proton pump inhibitors are generally well 
tolerated, and risks associated with short-term use are minimal. The most common adverse 
reactions seen in pediatric patients are headache, diarrhea, constipation, and nausea. Chronic acid 
suppression can minimize the effectiveness of any medication requiring an acidic environment for 
absorption. Commonly prescribed medications affected by acid suppression are ampicillin esters, 
digoxin, atazanavir, ketoconazole, and iron salts. 
4. 
ENDPOINTS 
4.1. 
Primary and Secondary Endpoints 
4.1.1. 
Primary Endpoint 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤6 eos/hpf (400×) at week 16 
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4.1.2. 
Secondary Endpoints 
Secondary Efficacy Endpoints for Part A and B: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
<15 eos/hpf at week 16 
• Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from 
baseline to week 16 
• Absolute change in mean EoE grade score from the EoE-HSS from baseline to week 16 
• Absolute change in mean EoE stage score from the EoE-HSS from baseline to week 16 
• Absolute change in EoE EREFS from baseline to week 16 
• Change from baseline in the type 2 inflammation transcriptional signature score at 
week 16  
• Change from baseline to week 16 in the proportion of days with 1 or more EoE signs 
as measured by the Pediatric EoE Sign/Symptom Questionnaire-caregiver version 
(PESQ-C) (for patients aged ≥1 to <12 years) 
• Number of sign-free days during the 14-day period preceding week 16 as measured 
by the PESQ-C (for patients aged ≥1 to <12 years) 
• Change from baseline to week 16 in the proportion of total segments within a day 
(night, morning, afternoon, evening) with 1 or more EoE signs as measured by PESQ-
C (for patients aged ≥1 to <12 years) 
• Change from baseline to week 16 in the proportion of days with 1 or more EoE 
symptoms as measured by PESQ-P (patient version) (for patients aged ≥8 to <12 years) 
• Number of symptom-free days during the 14-day period preceding week 16 as 
measured by the PESQ-P (patient version) (for patients aged ≥8 to <12 years) 
• Change from baseline to week 16 in the proportion of total segments within a day 
(night, morning, afternoon, evening) with 1 or more EoE symptoms as measured by 
PESQ-P (for patients aged ≥8 to <12 years)  
• Change in total score from baseline to week 16 as measured by the PEESSv2.0- 
caregiver version questionnaire (for patients aged ≥1 to <12 years) 
• Normalized Enrichment Scores (NES) for the relative change from baseline to week 
16 in the EoE diagnostic panel (EDP) transcriptome signature 
• NES for the relative change from baseline to week 16 in the type 2 inflammation 
transcriptome signature 
• NOTE: 
− All the above primary and secondary endpoints (except for PEESSv2.0- caregiver 
version questionnaire) assessed at week 16 will be assessed at week 52 as 
secondary endpoints and summarized with descriptive statistics based on the 
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treatment assignment in the double-blind treatment period as well as the extended 
active treatment assignment for patients previously in the placebo group. 
• Change from baseline in body weight for age percentile at week 52 
• Change in body mass index for age z-score from baseline to week 52 for patients  ≥2 
years of age 
• Change in weight for age z-score from baseline to week 52 
•  Change in weight for height z-score from baseline to week 52 
 
Secondary Efficacy Endpoints for Part C (open-label extension period) only: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 
eos/hpf (400×) at week 100 and week 160 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
<15 eos/hpf at week 100 and week 160 
• Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from 
baseline to week 100 and week 160 
• Absolute change in mean EoE grade score from the EoE-HSS from baseline to week 
100 and week 160  
• Absolute change in mean EoE stage score from the EoE-HSS from baseline to week 
100 and week 160 
• Absolute change in EoE-EREFS from baseline to week 100 and week 160 
• Normalized Enrichment Scores (NES) for the relative change from baseline to week 
100 and 160 in the EoE diagnostic panel (EDP) transcriptome signature 
• NES for the relative change from baseline to week 100 and week 160 in the type 2 
inflammation transcriptome signature 
• Change in total score from baseline to week 160 as measured by the PEESSv2.0- 
caregiver version questionnaire  
• Proportion of patients (with food elimination diet regimens at baseline) that have a re-
introduction of a previously eliminated food group by week 100 and by week 160 
• Change from baseline in body weight for age percentile up to week 160 
• Change in body mass index for age z-score for patients ≥2 years of age from baseline 
to up to week 160 
• Change in weight for age z-score from baseline to up to week 160 
• Change in weight for height z-score from baseline to up to week 160 
 
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Safety Endpoints (Part A, B, and C): 
• Incidence of treatment-emergent adverse events (TEAEs) during the 16-week double-
blind treatment period 
• Incidence of TEAEs during the 36-week extended treatment period 
• Incidence of TEAEs during the 108-week open-label extension period 
• Incidence of treatment-emergent serious adverse events (SAEs) during the 16-week 
double-blind treatment period 
• Incidence of treatment-emergent SAEs during the 36-week extended treatment period 
• Incidence of treatment-emergent SAEs during the 108-week open-label extension 
period 
• Incidence of treatment-emergent adverse events of special interest (AESIs) during the 
16-week double-blind treatment period 
• Incidence of treatment-emergent AESIs during the 36-week extended treatment 
period 
• Incidence of treatment-emergent AESIs during the 108-week open-label extension 
period 
• Incidence of TEAEs leading to permanent discontinuation of study treatment during 
the 16-week double-blind treatment period 
• Incidence of TEAEs leading to permanent discontinuation of study treatment during 
the 36-week extended treatment period 
• Incidence of TEAEs leading to permanent discontinuation of study treatment during 
the 108-week open-label extension period 
• Incidence of treatment-emergent ADA responses and titer during the 16-week double-
blind, 36-week extended treatment periods, and 108-week open-label extension 
period 
Clinical Pharmacology Endpoint: 
Concentrations of functional dupilumab in serum by treatment regimen at each assessment 
time point from baseline to end of study 
4.1.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤1 eos/hpf at week 16 
• Percent change in total score of Pediatric EoE Impact Scale-caregiver version (PEIS-
C) from baseline to week 16 (for caregivers of patients aged ≥1 to <12 years) 
• Percent change in total PEIS-P (patient version) score from baseline to week 16 (for 
patients aged ≥8 to <12 years) 
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• Change in GIC-patient, caregiver, and clinician version score at up to week 52 
• Change in GIS-patient, caregiver, and clinician version score from baseline to up to 
week 160/EOT 
• Change from baseline in body weight for age percentile at week 16 
• Change in body mass index for age z-score from baseline to week 16 for patients ≥2 
years of age 
• Change in weight for age z-score from baseline to week 16 
• Change in weight for height z-score from baseline to week 16 
 
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5. 
STUDY VARIABLES 
5.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, sex, race, weight, height, etc.), 
EoE disease characteristics, medical history, and medication history for each patient. 
5.2. 
Efficacy Variables 
The efficacy variables include measurements or scores for individual patients of the following:   
• From the endoscopy with EoE-EREFS and biopsies procedure: peak esophageal 
intraepithelial eosinophil counts, score of EoE-HSS (including EoE grade and stage 
scores), and score of EoE-EREFS 
• Patient-, caregiver-, or clinician-reported outcomes:   
− score of the PESQ-P (for patients aged ≥8 to <12 years) and the PESQ-C (for 
patients aged ≥1 to <12 years) 
− score of the PEIS-P (for patients aged ≥8 to <12 years) and the PEIS-C (for 
caregivers of patients aged ≥1 to <12 years) 
− score of the GIC-P (for patients aged ≥8 to <12 years), GIC-C (for caregivers of 
patients aged ≥1 to <12 years), and GIC-Clin (for patients aged ≥1 to <12 years) 
− score of the GIS-P (for patients aged ≥8 to <12 years), GIS-C (for caregivers of 
patients aged ≥1 to <12 years), and GIS-Clin (for patients aged ≥1 to <12 years) 
− score of the PEESSv2.0- caregiver version (for patients aged ≥1 to <12 years)  
• Measurement of body weight and height or length for patients <2 years of age; body 
mass index will be programmatically calculated based on weight and height/length 
data 
5.3. 
Safety Variables 
Safety variables include recording, measurements, or laboratory test results for individual patients 
of the following: adverse events (AEs); vital signs including heart rate, blood pressure, respiration 
rate, and body temperature; physical examination findings; results of laboratory tests including 
hematology, blood chemistry, urinalysis, and pregnancy test.  
5.4. 
Pharmacokinetic Variables 
The PK variable is the concentration of functional dupilumab in serum and time point for 
individual patients. These sampling timepoints are specified in Table 1, Table 2, Table 3, and 
Table 4.  
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5.5. 
Immunogenicity Variables 
The immunogenicity variables are ADA status, titer, neutralizing antibody (NAb) status, and 
time point/visit. Samples in this study will be collected at the clinic visits specified in Table 1, 
Table 2, Table 3, and Table 4.  
5.6. 
Pharmacodynamic and Other Biomarker Variables 
Pharmacodynamic and biomarker variables include laboratory test results for individual patients 
of the following: serum total IgE and eotaxin-3. 
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6. 
STUDY DESIGN 
6.1. 
Study Description and Duration 
This is a phase 3, multicenter, randomized, 3-part, double-blind, placebo-controlled study 
investigating the efficacy, safety, tolerability, PK, and immunogenicity of dupilumab in pediatric 
patients (ages ≥1 to <12 years) with active EoE. 
Approximately 90 patients will be randomized (1:1:1 ratio for higher exposure dupilumab group: 
lower exposure dupilumab group: placebo) at approximately 30 study sites globally. The dosing 
of the placebo group will be matched with higher exposure and lower exposure dupilumab 
regimens in the respective weight tiers and placebo with different dosing will be combined. The 
details on the randomization will be specified in an interactive voice/web response system 
(IVRS/IWRS) requirement document.  
This study consists of a screening period of up to 85 days, a double-blind 16-week treatment period 
(Part A), a 36-week extended active treatment period (Part B), a 108-week open-label extension 
period (Part C) and a 12-week follow-up period. The open-label extension period (Part C) will add 
up to 108 weeks of open-label treatment or until dupilumab becomes commercially available in 
the country of the participating patients (whichever comes first).      
The study flow diagram is provided in Figure 1. 
Figure 1: 
Study Flow Diagram 
 
After patients and their legal parents/legal guardians provide informed assent (as appropriate) and 
informed consent, patients will be assessed for study eligibility.  
Patients who have completed their end of study (EOS) visit prior to amendment 4 will be re-
evaluated for eligibility at a Re-Entry visit for participation in the open-label extension period (Part 
C) and Safety Follow-up period (see Section 7.2.2.3). Patients who have entered the safety follow-
up period after completing Part B at the time of amendment 4 approval may immediately enter the 
open-label extension (Part C) without being required to complete an EOS visit prior to entering 
Part C. 
Patients are required to have a documented diagnosis of EoE which may be established either by 
a prior historical biopsy, as demonstrated by intraepithelial eosinophilic infiltration (peak 
eosinophils/high power field ≥15 eos/hpf) (400×) from at least 1 esophageal region and performed 
after at least 8 weeks of treatment with an approved PPI regimen, or by biopsies performed after 
approximately 8 weeks of PPI treatment initiated prior to screening or during the screening period, 
which demonstrates ≥15 eos/hpf) (400×) from at least 2 of the 3 esophageal regions (proximal, 
mid, and distal); if the PPI regimen is stopped, biopsies must occur within 2 weeks of stopping the 
PPI. See Figure 2 for endoscopy/biopsy procedure flow chart. 
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Figure 2: 
Endoscopy/Biopsy Procedure Flow Diagram 
Historical esophageal biopsy showing at least 15 (eos/hpf) after 8-weeks of 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)
If other clinical and laboratory eligibility criteria are met
8-week trial of PPIs
Note:  the PPI trial can be initiated prior to screening
 
* Biopsy specimens from the antrum and duodenum will be obtained in all patients to rule out 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 16, week 52, week 100, and week 160. 
Patients who are on PPIs during the screening period to rule out EoE disease management with 
this treatment, and are eligible to enroll in the study, have the choice either to remain on the PPI 
regimen during the entire study or stop the PPI regimen prior to baseline; they then must remain 
off of PPIs during the entire study. 
Biopsies will be obtained by endoscopy at the screening visit 2, week 16 visit, week 52, week 100 
and week 160 visits, or immediately prior to start of rescue medication or procedures (only applies 
to rescue medication and/or procedures that occur before the week 52 visit). A total of at least 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 histology (needed for study 
inclusion criteria, as well as endpoint assessment) and the others for RNA extraction. Biopsies will 
be used for exploratory research to study EoE, dupilumab mechanism of action, and to identify or 
validate predictive biomarkers (efficacy and/or safety). Exploratory analyses of the biopsies may 
include but are not limited to immunohistochemistry [IHC] and RNA sequencing (or other 
methods for assessing RNA expression and RNAscope). 
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Patients may be re-screened if they fail the Part A baseline screening evaluation, unless the reason 
for screen failure is related to histologic inclusion criteria. The baseline endoscopy with biopsies 
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. 
Patients may receive concomitant medications (except for prohibited medications specified in 
Section 8.10.1) as needed, at the discretion of the investigator, while continuing study treatment. 
Frequency of use and type of product will be documented.  
Efficacy, safety, laboratory assessments, and samples for assay of concentration of functional 
dupilumab in serum and potential ADA response to dupilumab, as well as research samples, will 
be performed or collected at specified time points throughout the study according to the Schedule 
of Events in Table 1, Table 2, Table 3, and Table 4. 
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 (visit 3), the first visit of Part B and the first visit of Part C occur in the clinic. 
Endoscopies with biopsies are required at the visit 2 screening biopsy and at approximately week 
16, week 52, week 100, and week 160. 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 in response to COVID-19 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. 
6.1.1. 
End of Study Definition 
The end of study is defined as the date the last patient completes the last study visit, withdraws 
from the study, or is lost to follow-up (ie, the study patient can no longer be contacted by the 
investigator). 
6.2. 
Planned Interim Analysis 
No interim analysis is planned for this study.  
The primary analysis may be performed once all patients in the study have completed the 16-week 
double-blind treatment period in Part A as specified in the protocol (week 16 visit or earlier for 
those patients who are withdrawn prematurely from the study). If performed, this primary analysis 
will be considered the final analysis for the primary and week 16 secondary efficacy endpoints. A 
description of the statistical methods to be employed and blinding implications are in Section 11. 
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6.3. 
Study Committees 
6.3.1. 
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. 
All activities and responsibilities of the DMC are described in the DMC charter. 
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7. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
7.1. 
Number of Patients Planned 
Approximately 90 pediatric patients are planned to be enrolled.  
7.2. 
Study Population 
Eligible patients for this study consist of patients with active EoE, ages ≥1 to <12 years. 
7.2.1. 
Inclusion Criteria 
A patient must meet the following criteria to be eligible for inclusion in the study: 
1. Male or female, ages ≥1 year to <12 years 
2. A documented diagnosis of EoE by endoscopic biopsy prior to screening, as demonstrated 
by intraepithelial eosinophilic infiltration (peak eosinophil count ≥15 eos/hpf) (400×) from 
at least 1 esophageal region and performed after at least 8 weeks of treatment with a 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 (documented) 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 PPI regimen for at least 8 weeks during the screening period 
before their baseline endoscopy/biopsies. 
3. Baseline endoscopic biopsies with a demonstration on central reading of intraepithelial 
eosinophilic infiltration (peak eosinophil count ≥15 eos/hpf) in at least 2 of the 3 biopsied 
esophageal regions (proximal, mid, or distal) 
4. History (by patient or caregiver report) of symptom(s) determined by the investigator to be 
the result of EoE (eg, abdominal pain, chest pain, acid reflux, food regurgitation, 
dysphagia, vomiting, or refusal to eat) in the month prior to screening 
5. Patients ≥8 to <12 years of age and caregiver or legal guardians of all patients must be able 
to understand and complete the study requirements and study-related questionnaires. At 
least 8 out of 14 days of eDiary for the PESQ-C should be completed prior to 
baseline/visit 3. 
6. Parents or legal guardians must provide signed informed consent. Assent should be 
collected from patient, if applicable, as per local regulatory (competent authority/ethics) 
guidelines, based upon the age and level of maturity of the patient. 
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7.2.2. 
Exclusion Criteria 
7.2.2.1. 
Exclusion Criteria for Part A - Double-Blind Treatment 
A patient who meets any of the following criteria will be excluded from the study: 
1. Body weight <5 kg or ≥60 kg at screening 
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: eosinophilic 
gastroenteritis, hypereosinophilic syndrome, and eosinophilic granulomatosis with 
polyangiitis (Churg-Strauss syndrome)  
5. Active Helicobacter pylori 
6. Helminthic infection 
7. History of Crohn’s disease, ulcerative colitis, celiac disease, or prior esophageal 
surgery 
8. Any esophageal stricture unable to be passed with a standard, diagnostic, upper 
endoscope or any critical esophageal stricture that requires dilation at screening 
9. Treatment with swallowed topical corticosteroids within 8 weeks prior to baseline 
standard of care endoscopy 
10. Treatment with subcutaneous immunotherapy (SCIT) unless on a stable maintenance 
dose for at least 1 year 
11. Prior treatment with sublingual immunotherapy (SLIT), epicutaneous immunotherapy 
(EPIT), or oral immunotherapy (OIT) 
12. Initiation, discontinuation, or change in the dosage regimen of the following 
medications within 8 weeks prior to the baseline endoscopy: PPIs, leukotriene 
inhibitors, and nasal and/or inhaled corticosteroids 
13. Treatment with systemic immunosuppressant/immunomodulating drugs, including but 
not limited to systemic corticosteroids, mepolizumab, omalizumab, cyclosporine, 
mycophenolate-mofetil, 
interferon-gamma 
(IFN-γ), 
Janus 
kinase 
inhibitors, 
azathioprine, and methotrexate within 3 months prior to screening 
a. NOTE: One-time use of a corticosteroid as a part of the anesthetic preparation 
used during each endoscopy procedure is allowed. 
14. Treatment with an investigational drug within 2 months or within 5 half-lives (if 
known), whichever is longer, prior to baseline visit 
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15. 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 
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 before the baseline visit 
NOTE: For patients who have vaccination with live, attenuated vaccines planned 
during the course of the study (based on national vaccination schedule/local 
guidelines), it will be determined, after consultation with a pediatrician, whether the 
administration of vaccine can be postponed until after the end of study, or preponed to 
before the start of the study, without compromising the health of the patient: 
− Patients for whom administration of live (attenuated) vaccine can be safely 
postponed would be eligible to enroll into the study 
− Patients who have their vaccination preponed can enroll in the study only after at 
least 4 weeks following administration of the vaccine 
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:  Patients 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  
NOTE:  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 or positivity for 
Hepatitis B or Hepatitis C antigens 
23. 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) 
24. Any of the following abnormal laboratory values at screening: 
− Platelets <100 × 103/μL 
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− Neutrophils ≤1.5 × 103/μL  
− Estimated glomerular filtration rate (eGFR) (Totri, 2017) <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. Estimated glomerular filtration rate will be 
calculated using the Bedside Schwartz formula.  
25. 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 
active malignancy, short life expectancy, uncontrolled diabetes, cardiovascular 
conditions (eg, New York Heart Association Class III or IV cardiac failure), severe 
renal conditions (eg, patients on dialysis), 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.), and 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.). 
26. History of malignancy within 5 years prior to screening 
27. History of alcohol or drug dependence within 6 months prior to screening, in the 
opinion of the investigator 
28. 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. 
29. Patient’s immediate family is a member of the investigational team. 
30. Patient is female who is pregnant, breastfeeding, or planning to become pregnant or 
breastfeed during the study.  
31. Patient is of childbearing potential* who is 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 (IUS)  
c. and/or sexual abstinence†, ‡. 
*Women of childbearing potential (WOCBP) are defined as women who are fertile 
following menarche until becoming postmenopausal, unless permanently sterile. 
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Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and 
bilateral oophorectomy.  
† 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 drugs. 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 amenorrhea method (LAM) are 
not acceptable methods of contraception. Female condom and male condom should not 
be used together. 
32. Female patients who experience menarche and who are unwilling to follow the precautions 
for WOCBP 
33. Known systemic hypersensitivity to dupilumab or the excipients of the drug product 
7.2.2.2. 
Exclusion Criteria for Part B – Extended Active Treatment (and also for Entry 
into Part C for Patients with Uninterrupted Participation in the Study)  
1. Patients who, during the double-blind treatment period (for entry into the extended active 
period) or during the extended active treatment period (for entry into the open-label 
extension period), developed an SAE and/or AE deemed related to study drug and which 
led to discontinuation of investigational product (patients who are prematurely 
discontinued from study drug due to lack of efficacy are eligible to enter Part B and/or Part 
C) 
2. Patients who, during the double-blind treatment period (for entry into the extended active 
period), or extended active treatment period (for entry into the open-label extension period) 
were prematurely withdrawn because of a protocol violation, poor compliance, or inability 
to complete required study assessments 
3. Patients who did not undergo endoscopy with biopsies at week 16 and/or week 52 or prior 
to receiving rescue treatment 
Note: If the endoscopy with biopsies could not occur due to COVID-19 restrictions 
and rescue treatment was needed to be initiated without delay, these patients will 
be eligible to participate in Part C.  
4. Female patients who experience menarche and who are unwilling to follow the precautions 
for WOCBP 
7.2.2.3. 
Exclusion Criteria for Patients Re-Entering the Study (for Entry into Part C for 
Patients Who Have Completed Their EOS Visit Prior to Amendment 4) 
A patient who meets any of the following criteria will not be permitted to re-enter the study: 
1. Patients who are ≥12 years old, weigh ≥40 kg (or minimum weight for which dupilumab 
is approved for EoE), and dupilumab is commercially available for the treatment of EoE in 
their country. 
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2. Patients who, during their previous participation in this clinical trial, developed an SAE 
and/or AE deemed related to dupilumab, which in the opinion of the investigator or of the 
medical monitor could indicate that continued treatment with dupilumab may present an 
unreasonable risk for the patient.  
3. Patients who did not undergo endoscopy with biopsies at week 16 and/or week 52 or prior 
to receiving rescue treatment. 
Note: If the endoscopy with biopsies could not occur due to COVID-19 
restrictions and rescue treatment was needed to be initiated without delay, these 
patients will be eligible to participate in Part C.  
4. Patients who became pregnant during their previous participation in this dupilumab clinical 
trial. 
5. Patients who, during their previous participation in this trial, were prematurely withdrawn 
because of a protocol violation, poor compliance, or inability to complete required study 
assessments. 
6. Known history of HIV infection or HIV seropositivity. 
7. Known history of positive HBsAg, HBcAb, or hepatitis C antibody.  
NOTE: Patients who are HBsAg negative and HBsAb positive are considered immune after 
a natural infection has cleared or they have been vaccinated against hepatitis B. Therefore, 
they are acceptable for the study.  
8. Treatment with an investigational drug (other than dupilumab) within 2 months or within 
5 half-lives (if known), whichever is longer, prior to the re-entry visit 
9. Treatment with systemic immunosuppressant/immunomodulating drugs, including but not 
limited to mepolizumab, omalizumab, cyclosporine, mycophenolate-mofetil, interferon-
gamma (IFN-γ), Janus kinase inhibitors, azathioprine, and methotrexate within 3 months 
prior to re-entry visit 
10. Treatment with a live (attenuated) vaccine within 4 weeks before the re-entry visit. 
11. Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or 
antifungals within 2 weeks before re-entry visit  
12. Pregnant or breastfeeding females 
13. Females unwilling to use adequate birth control, if of reproductive potential and sexually 
active (see Exclusion Criterion 31  above for applicable definitions). 
14. Any other medical or psychological condition that, in the opinion of the investigator, may 
suggest a new and/or insufficiently understood disease, may present an unreasonable risk 
to the patient as a result of his/her participation in the trial, may make the patient’s 
participation unreliable, or may interfere with study assessments. The specific justification 
for patients excluded under this criterion will be noted in the source documents. 
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7.3. 
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. 
Patients who are withdrawn prematurely from the study will be asked to complete the early 
termination visit, as described in Section 9.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 8.4.2. 
7.4. 
Replacement of Patients 
Patients prematurely discontinued from study or study drug will not be replaced. 
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8. 
STUDY TREATMENTS 
The following drug product will be provided. Instructions on dose preparation are provided in the 
pharmacy manual. 
Patients will receive dupilumab injections at the frequency of QW, Q2W, or Q4W with matching 
placebo alternating with dupilumab doses so the injection frequency will be identical within weight 
tiers for regimen-blinding purposes (Parts A and B). Patients will remain within the originally 
assigned higher or lower dosing exposure arm throughout the study (Part A and Part B).  For 
Part C, all patients will receive the higher exposure dupilumab weight tiered dosing regimen (QW, 
Q2W, or Q3W).  No matching placebo will be administered in Part C. 
Study drug administration at the study sites will be performed only by injection personnel who 
will not perform any clinical assessment/procedures (this restriction is not required during Part C) 
(Table 1, Table 2, Table 3, and Table 4). 
Dupilumab: 
• Dupilumab 
 mg/mL: Each 2.25 mL single-use, prefilled syringe with cap delivers 
 mg of study drug (2.0 mL of a 
 mg/mL solution) 
• Dupilumab 
 mg/mL: Each 1.14 mL single-use, prefilled syringe with cap delivers 
 mg of study drug (1.14 mL of a 
 mg/mL solution) 
• Dupilumab 
 mg/mL: Each 0.67 mL single-use, prefilled syringe with cap delivers 
 mg study drug (0.67 mL of a 
 mg/mL solution). 
Placebo-matching dupilumab (for Parts A and B): 
• 2 mL placebo matching 
 mg dupilumab formulation 
• 1.14 mL placebo matching 
 mg dupilumab formulation 
• 0.67 mL placebo matching 
 mg dupilumab formulation 
8.1. 
Investigational and Reference Treatments 
The weight-tiered dosing regimens of the study drug are described below. 
• Part A:  16-Week Double-Blind Treatment Period: Part A is the double-blind, 
placebo-controlled portion of the study. Subcutaneous (SC) administration at tiered 
dosing regimens based on body weight at baseline. 
Higher exposure dupilumab regimens (Part A): 
• 
 mg Q2W in patients who weigh ≥5 kg to <15 kg 
• 
 mg Q2W in patients who weigh ≥15 kg to <30 kg 
• 
 mg Q2W in patients who weigh ≥30 kg to <60 kg 
Lower exposure dupilumab regimens (Part A):  
• 
 mg Q4W in patients who weigh ≥5 kg to <15 kg  
• 
 mg Q4W in patients who weigh ≥15 kg to <30 kg 
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• 
 mg Q2W in patients who weigh ≥30 kg to <60 kg 
NOTE: In Part A, patients will receive dupilumab injections at the frequency of Q2W or 
Q4W with matching placebo alternating with dupilumab doses so the injection frequency 
will be Q2W for both groups for regimen-blinding purposes per treatment assignment in 
Part A. 
− Placebo for Part A: Dose matching placebo Q2W or alternating with dupilumab Q4W 
so the frequency will be Q2W for both groups for regimen-blinding purposes in Part 
A.  
− See Figure 3: Weight-Tiered Dosing Regimens of Study Drug – Part A. 
• Part B:  36-Week Extended Active Treatment Period:  Part B is the extended active 
treatment portion of the study. All patients (Part A active and placebo) will receive 
dupilumab based on body weight at visit 8 (week 16, end of double-blinded treatment 
period or start of extended treatment period) per the higher and lower exposure group 
to which they were assigned at randomization. If weight tier has increased at visit 12 / 
week 32, patients will be re-assigned to an extended active treatment regimen based on 
weight tiered dosing regimens below. 
Higher exposure dupilumab regimens (Part B): 
• 
 mg Q2W in patients who weigh ≥5 kg to <15 kg 
• 
 mg Q2W in patients who weigh ≥15 kg to <30 kg 
• 
 mg Q2W in patients who weigh ≥30 kg to <60 kg 
• 
 mg QW in patients who weigh ≥60 kg 
Lower exposure dupilumab regimens (Part B): 
• 
 mg Q4W in patients who weigh ≥5 kg to <15 kg  
• 
 mg Q4W in patients who weigh ≥15 kg to <30 kg 
• 
 mg Q2W in patients who weigh ≥30 kg to <60 kg 
• 
 mg Q2W in patients who weigh ≥60 kg 
NOTE: In Part B, study drug or matching placebo will be administered Q2W for all patients 
in <60 kg weight-groups and QW for all patients in ≥60 kg weight-groups. Patients will 
receive alternating doses of dupilumab or placebo Q2W for patients <60 kg assigned to 
Q4W regimens or QW for patients ≥60 kg assigned to Q2W regimens for regimen-blinding 
purposes 
− Placebo for Part B: Dose matching placebo alternating with dupilumab Q2W or Q4W 
so the frequency will be Q2W for the weight-based groups <60kg and QW for the 
weight-based group of ≥60 kg for regimen-blinding purposes in Part B. 
See Figure 4: Part B Weight-Tiered Dosing Regimens of Study Drug. 
 
 
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• Part C:  Up to 108-Week Open-Label Extension Period:  Part C is the open-label 
extension period of the study. All patients (Part C) will receive higher exposure 
dupilumab regimens based on body weight at visit 17 (week 52, end of extended active 
treatment period) or start of open-label period (for re-entry patients). All patients who 
received lower exposure dupilumab during Part B will be re-assigned to higher 
exposure dupilumab regimens at the start of the open-label (Part C) period.  If weight 
increases place a patient into a higher weight tier at visit 17 / week 52 (or start of open-
label period for re-entry patients) or at specified in-clinic visits in Part C, the patient 
will be re-assigned to an open-label treatment regimen based on the weight tiered 
dosing regimen specified below. 
Higher exposure dupilumab regimens (Part C): 
• 
 mg Q3W in patients who weigh ≥5 kg to <15 kg 
• 
 mg Q2W in patients who weigh ≥15 kg to <30 kg 
• 
 mg Q2W in patients who weigh ≥30 kg to <40 kg 
• 
 mg QW in patients who weigh ≥40 kg 
NOTE: In Part C, only active study drug (dupilumab) will be administered.  No 
matching placebo will be administered in Part C. The weight-based dosing regimens 
will be as listed above (see Figure 5).  
For Part C only: Patients located in a country where dupilumab is commercially 
available for treatment of EoE in patients ≥12 years old will be provided treatment with 
study drug until they are both (1) at least 12 years of age and (2) weigh at least 40 kg 
or the lowest weight for which the indication is approved for EoE. These patients will 
have an end of treatment visit at the next scheduled study visit upon meeting both 
criteria, followed by an end of study follow-up visit after 12 weeks. 
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Figure 3: 
Part A Weight-Tiered Dosing Regimens of Study Drug  
 
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Figure 4: 
Part B Weight-Tiered Dosing Regimens of Study Drug  
 
 
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Figure 5: 
Part C (OLE) Weight-Tiered Dosing Regimens of Study Drug  
 
8.2. 
Background Treatments 
Patients who undergo a trial of PPI therapy prior to screening or during the screening period of 
Part A have the choice either to remain on the PPI regimen during Parts A and B or stop the PPI 
regimen prior to baseline; they then must remain off of PPIs during Parts A and B. Patients may 
adjust their PPI therapy use during Part C.  Refer to the study binder for specific PPI dosing 
recommendations. 
8.3. 
Rescue Treatments and Procedures 
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. For Parts A and B, 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 during Parts A or B will not undergo the subsequent scheduled endoscopy/biopsy 
at week 16 and/or week 52, respectively. 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.  For Part C (OLE), 
rescue treatment is also allowed. If rescue therapy is initiated during Part C (OLE), an 
endoscopy/biopsy before initiating rescue treatment is at discretion of the investigator discretion; 
future endoscopies/biopsies (week 100 and week 160) would still be required.  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. 
 
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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, Table 3, and Table 4 except for 
endoscopy/biopsy, as noted above. For the purpose of efficacy analyses for Part A, patients who 
receive rescue treatment during the study will be considered treatment failures. 
8.4. 
Dose Modification and Study Treatment Discontinuation Rules 
8.4.1. 
Dose Modification 
Dose Modification, beyond what is specified by the protocol on dose regimen changes based on 
weight changes (see below), is not allowed. 
Since dose is weight-tiered, weight at baseline will be used to determine dose for the 16-week 
double-blinded treatment period, weight at visit 8 (week 16) will be used to determine dose for 
start of the 36-week extended active treatment period and weight at Visit 17 / week 52 (or start of 
open-label period) will be used to determine the dose for the open-label extension period. All 
patients (Part C) will receive higher exposure dupilumab regimens based on body weight at visit 17 
(week 52, end of extended active treatment period) or start of open-label period (for re-entry 
patients). Dose adjustments (based on increased weight) will be made during Part C at specified 
in-clinic visits as indicated in Table 4.  
8.4.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug should be encouraged to remain in the 
study. Those who agree and do not withdraw from the study 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 study assessments, per Section 9.1.2 . 
8.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
• Evidence of pregnancy 
• Serious or severe allergic reactions considered related to study drug 
• Specific types of liver dysfunction [eg, Hy’s law is met (Malmberg, 2009)] 
• Patient or legal parent/legal guardian withdraws assent or consent 
• Anaphylactic reaction or other severe systemic reaction deemed related to study drug  
• Diagnosis of a malignancy during study  
• Any infection that is opportunistic, such as TB and other infections whose nature or 
course may suggest an immunocompromised status 
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• Severe laboratory abnormalities: 
o Neutrophil count ≤0.5 × 103/µL 
o Platelet count ≤50 × 103/µL 
o ALT and/or AST values >3 × ULN with total bilirubin >2 × ULN, excluding 
confirmed Gilbert’s Syndrome 
o Confirmed AST and/or ALT >5 × ULN (for more than 2 weeks) 
8.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug dosing will be temporarily discontinued in the event of: 
• 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 that may or may not require treatment with some prohibited 
medications (eg, systemic immunosuppressive/immunomodulating drugs) 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 and receiving 
study drug 
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. 
After the condition leading to temporary discontinuation of study drug resolves, study drug dosing 
may resume. A decision to temporarily discontinue study drug and/or resume study drug dosing 
should be discussed with the Regeneron Pharmaceuticals, Inc. medical monitor. 
If a patient requires a prohibited medication at any time during the study, the principal investigator 
should contact the Regeneron medical monitor (except for illness requiring prompt treatment). 
Based on the discussions, study drug may be continued or temporarily or permanently 
discontinued.  
8.5. 
Management of Acute Reactions  
8.5.1. 
Acute Injection Reactions 
8.5.1.1. 
Systemic Injection Reactions 
Emergency equipment and medication for the treatment of systemic reactions must be available 
for immediate use. All injection reactions must be reported as AEs (as defined in Section 10.2.1) 
and graded using the grading scales as instructed in Section 10.2.4. 
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Acute systemic reactions following injection of study drug (SC) should be treated using clinical 
judgment to determine the appropriate response according to typical clinical practice.  
8.5.1.2. 
Local Injection Site Reactions 
Local injection site reactions must be reported as AEs and graded according to Section 10.2.4. 
8.6. 
Method of Treatment Assignment 
In Part A, approximately 90 patients will be randomized in a 1:1:1 ratio to receive higher or lower 
exposure dose arms of dupilumab  (dose regimen according to the weight tier described in 
Section 8.1) or placebo according to a central randomization scheme provided by an IVRS/IWRS 
to the designated study pharmacist (or qualified designee). Randomization will be stratified 
according to weight at baseline (≥5 kg to <15 kg, ≥15 kg to <30 kg, or ≥30 kg to <60 kg).  
8.7. 
Blinding 
Study patients, the principal investigators, and study site personnel will remain blinded to all 
randomization assignments. For Parts A and B, study drug administration at the study sites will be 
performed only by injection personnel who will not perform any clinical assessment/procedures. 
During the conduct of Parts A and B, 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. 
If the primary analysis is performed on Part A data (see Section 6.2), Part A will be unblinded for 
selected sponsor study personnel while Part B is ongoing. The team performing the primary 
analysis will be separate from the ongoing study team. No study personnel involved in the day-to-
day conduct of the study will have access to any unblinded data before the database is locked for 
Part B of this study.  All participants will receive open-label dupilumab during Part C. 
Blinded study drug kits coded with a medication numbering system will be used for the double-
blind (Part A) and extended active (Part B) treatment periods. In order to maintain the blind (until 
the database is locked for Part B), lists linking these codes with product lot numbers will not be 
accessible to individuals involved in study conduct. Part C study drug will be labeled with 
dupilumab. 
During the double-blind (Part A) and extended active (Part B) treatment periods, anti-drug 
antibody, drug concentration results, any post-treatment tissue eosinophil counts and histologic 
results, and biomarker results (eotaxin-3 and total IgE) will not be communicated to the sites, and 
the sponsor’s blinded study 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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8.8. 
Emergency Unblinding (Applies to Part A and Part B only) 
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event (eg, pregnancy) and when a treatment decision is contingent 
on knowing the patient’s treatment assignment. Study drug will be discontinued for patients whose 
treatment has been unblinded (Section 8.4.2): 
• 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. Unblinding is performed using the 
IVRS/IWRS which will notify Regeneron.  
− 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 and when a treatment decision is contingent on knowing the patient’s treatment 
assignment. 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. 
8.9. 
Treatment Logistics and Accountability 
8.9.1. 
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. Part C study drug will be labeled with 
dupilumab. 
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
8.9.2. 
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 destroyed on site after sponsor 
approval or returned to the sponsor or designee.  
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8.9.3. 
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 medication 
• dispensed to each patient 
• returned from each patient (if applicable), and 
• 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. 
8.9.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
8.10. 
Concomitant Medications and Procedures 
Any treatment administered from the time of informed consent/assent to 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 treatment. This includes medications that were started before 
the study and are ongoing during the study. 
8.10.1. 
Prohibited Medications and Procedures 
Treatment with the following concomitant medications is prohibited through week 52 and may 
result in temporary or permanent discontinuation of study drug (see Section 8.4.2). While the 
investigator may suspend study treatment at any time, any change to study drug administration 
should be discussed with the medical monitor.  
• Swallowed topical corticosteroids (may be used as rescue treatment for EoE) (Parts A 
and B only) 
• Systemic corticosteroids (may be used as rescue treatment for EoE) (Parts A and B 
only) 
− NOTE: One-time use of a corticosteroid as a part of the anesthetic preparation 
used during each endoscopy procedure is also allowed. 
• Systemic immunosuppressive/immunomodulating drugs (including, but not limited 
to, mepolizumab, omalizumab, cyclosporine, mycophenolate-mofetil, azathioprine, 
methotrexate, IFN-γ, or other immunomodulatory biologics) 
• Treatment with an investigational drug (other than dupilumab) 
• For Parts A and B: Initiation, discontinuation, or change in dosage regimen after 
baseline of the following medications (stable doses of these medications are allowed): 
− Proton pump inhibitors 
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− Systemic leukotriene inhibitors 
• For Parts A and B: Initiation, discontinuation, or change in dosage regimen of nasal 
and/or inhaled corticosteroids within 8 weeks prior to visit 2, visit 8, or visit 17 
endoscopies with biopsies 
• Initiation of SCIT, or change in dose for those patients on a stable dose of SCIT, 
within 1 year prior to screening (For Parts A and B only) 
• SLIT, OIT, or EPIT (For Parts A and B only) 
 
• Treatment with a live (attenuated) vaccine, eg:  
− 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 (for Parts A and B): 
• Major elective surgical procedures 
• Esophageal dilation (may be used as rescue procedure) 
• Initiation or change of food-elimination diet regimen  
8.10.2. 
Permitted Medications and Procedures 
Other than the prohibited medications listed in Section 8.10.1, treatment with concomitant 
medications is permitted during the study. If there is any question regarding whether a concomitant 
medication may be used during the study, the study site should contact the medical monitor. 
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8.10.3. 
Restricted Medications and Procedures during the Follow-Up Period 
Patients may receive the prohibited medications/procedures listed in Section 8.10.1 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.  
8.11. 
Poststudy Treatments and Procedures 
No poststudy treatments are required or planned. 
9.
STUDY SCHEDULE OF EVENTS AND PROCEDURES
9.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1. 
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: 
Schedule of Events - Screening and Double-Blind Treatment Period 
 
Screening Period 
Part A:  16-Week Double-Blind Treatment Period 
Study Procedure 
Screening1, 3 
V1 
Screening2 
V2 
Baseline 
V3 
V4 
V5 
V6 
V7 
DB EOT4 
V8 
Week (W) 
 
 
 
W2 
W4 
W8 
W12 
W16 
Day (D) 
D-85 to D-1 
D1 
D15 
D29 
D57 
D85 
D113 
Visit Window (Days [d]) 
 
 
 
±7 d 
±3 d 
±3 d 
±3 d 
+7 d 
Screening/Baseline: 
Inclusion/Exclusion 
X 
 
X 
 
 
 
 
 
Informed Consent/Assent 
X 
 
 
 
 
 
 
 
Informed consent/assent for optional genomic sub-study 
X 
 
 
 
 
 
 
 
Informed consent/assent for optional future biomedical 
research sub-study 
X 
 
 
 
 
 
 
 
Med History/Demographics 
X 
 
 
 
 
 
 
 
Age in months 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
Treatment: 
Training for SC Injection5 
 
 
X 
X 
 
 
 
 
Administer Study Drug6 
 
 
X 
X 
X 
X 
X 
 
Con Medications/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
Weight, Height (or length for patients <2 years of age) 
X 
 
X 
X 
X 
X 
X 
X 
Pediatric EoE Sign/Symptom Questionnaire:7  
Patient version (PESQ-P) 
Caregiver version (PESQ-C) 
 
(Daily Diary) 
Pediatric EoE Impact Scale:7  
Patient version (PEIS-P) 
Caregiver version (PEIS-C) 
 
 
X 
 
 
 
 
X 
Global Impression of Change:8  
Patient version (GIC-P) 
Caregiver version (GIC-C) 
Clinician version (GIC-Clin) 
 
 
 
 
 
 
X 
X 
Global Impression of Severity:8 
Patient version (GIS-P) 
Caregiver version (GIS-C) 
Clinician version (GIS-Clin) 
 
 
X 
 
 
 
X 
X 
Pediatric Eosinophilic Esophagitis Symptom Score: 15 
Caregiver version (PEESSv2.0) 
 
 
X 
 
 
 
 
X 
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Screening Period 
Part A:  16-Week Double-Blind Treatment Period 
Study Procedure 
Screening1, 3 
V1 
Screening2 
V2 
Baseline 
V3 
V4 
V5 
V6 
V7 
DB EOT4 
V8 
Week (W) 
 
 
 
W2 
W4 
W8 
W12 
W16 
Day (D) 
D-85 to D-1 
D1 
D15 
D29 
D57 
D85 
D113 
Visit Window (Days [d]) 
 
 
 
±7 d 
±3 d 
±3 d 
±3 d 
+7 d 
Endoscopy with Biopsies and EoE-EREFS2, 9 
 
X2a 
 
 
 
 
 
X2,2b 
Exit Interview 16 
 
 
 
 
 
 
 
X 
Safety10: 
Vital Signs11 
X 
 
X11 
X11 
X 
X 
X 
X 
Physical Examination 
X 
 
X 
 
 
 
 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing10, 12: 
Hematology 
X 
 
X 
 
X 
 
 
X 
Chemistry 
X 
 
X 
 
X 
 
 
X 
Pregnancy test (WOCBP)13 
Serum 
 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urinalysis14 
X 
 
 
 
 
 
 
 
PK and ADA Samples10: 
Functional dupilumab PK sample 
 
 
X 
 
X 
 
 
X 
Anti-dupilumab antibody sample 
 
 
X 
 
 
 
 
X 
Biomarkers and Genomics: 
 
 
 
 
 
 
 
 
Serum Total IgE 
 
 
X 
 
X 
 
 
 
Eotaxin-3 
 
 
X 
 
X 
 
 
X 
Optional pharmacogenetics DNA samples (cheek swab) 
 
 
X 
 
 
 
 
 
ADA = anti-drug antibody; EoE-EREFS = Eosinophilic Esophagitis-Endoscopic Reference Score; EOS = end of study; EOT = end of treatment; PRO = patient-
reported outcome; ET = early termination; PEESS = Pediatric Eosinophilic Esophagitis Symptom Score; PESQ-P = Pediatric EoE Sign/Symptom Questionnaire 
(patient version); PESQ-C = Pediatric EoE Sign/Symptom Questionnaire (caregiver version); PEIS-P = Pediatric EoE Impact Scale (patient version); PEIS-C = 
Pediatric EoE Impact Scale (caregiver version);  GIC-P = Global Impression of Change (patient version); GIC-C = Global Impression of Change (caregiver 
version); GIC-Clin = Global Impression of Change (clinician version); GIS-P = Global Impression of Severity (patient version); GIS-C = Global Impression of 
Severity (caregiver version); GIS-Clin = Global Impression of Severity (clinician version) 
 
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Table 2: 
Schedule of Events - Extended Active Treatment Period and Re-Entry Visit 
Part B:  36-Week Extended Active Treatment Period 
Re-Entry Visit (for patients who 
re-enter the study for Part C)13 
Study Procedure 
V81 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V1712 
Week (W) 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
Day (D) 
D113 
D141 
D169 
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 
+7 d
Screening for Part 
B/C: 
Inclusion/Exclusion 
X 
X 
Informed Consent 
X 
Medical History 
X 
Treatment: 
Administer Study 
Drug4a, 4b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Con Meds/Procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy: 
Age in months 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight, Height (or 
length for patients 
<2 years of age)2 
X4b 
X 
X 
X 
X4b 
X 
X 
X 
X 
X 
Pediatric EoE 
Sign/Symptom 
Questionnaire:5 
Patient version 
(PESQ-P) 
Caregiver version 
(PESQ-C) 
(Daily Diary) 
Pediatric EoE Impact 
Scale:5  
Patient version 
(PEIS-P) 
Caregiver version 
(PEIS-C) 
X 
X 
X 
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Part B:  36-Week Extended Active Treatment Period 
Re-Entry Visit (for patients who 
re-enter the study for Part C)13 
Study Procedure 
V81 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V1712 
 
Week (W) 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
 
Day (D) 
D113 
D141 
D169 
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 
+7 d 
 
Global Impression of 
Change:6 
Patient version 
(GIC-P) 
Caregiver version 
(GIC-C) 
Clinician version 
(GIC-Clin) 
X 
 
 
 
X 
 
 
 
 
X 
 
Global Impression of 
Severity:6 
Patient version (GIS-
P) 
Caregiver version 
(GIS-C) 
Clinician version 
(GIS-Clin) 
X 
 
 
 
X 
 
 
 
 
X 
 
Pediatric Eosinophilic 
Esophagitis Symptom 
Score:11 
Caregiver version 
(PEESSv2.0) 
X 
 
 
 
 
 
 
 
 
 
 
Endoscopy with 
Biopsies and EoE-
EREFS7,7a 
X7,7a 
 
 
 
 
 
 
 
 
X7,7a 
 
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Part B:  36-Week Extended Active Treatment Period 
Re-Entry Visit (for patients who 
re-enter the study for Part C)13 
Study Procedure 
V81 
V9 
V10 
V11 
V12 
V13 
V14 
V15 
V16 
V1712 
Week (W) 
W16 
W20 
W24 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
Day (D) 
D113 
D141 
D169 
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 
+7 d
Safety: 
Vital Signs2,3,8 
X8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examination2 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology2 
X 
X 
X 
X 
Chemistry2 
X 
X 
X 
X 
Pregnancy test 
(WOCBP)2,9 
urine 
urine 
urine 
urine 
urine 
urine 
urine 
urine 
urine 
urine 
urine 
Urinalysis2,10 
X 
X 
X 
PK and ADA 
Samples: 
Functional dupilumab 
PK sample2 
X 
X 
X 
Anti-dupilumab 
antibody sample2 
X 
X 
X 
Biomarkers: 
Serum total IgE2 
X 
X 
Eotaxin-32
X 
X 
ADA = anti-drug antibody; EoE-EREFS = Eosinophilic Esophagitis-Endoscopic Reference Score; EOS = end of study; EOT = end of treatment; PEESS = 
Pediatric Eosinophilic Esophagitis Symptom Score;  PRO = patient-reported outcome; PESQ-P = Pediatric EoE Sign/Symptom Questionnaire (patient version); 
PESQ-C = Pediatric EoE Sign/Symptom Questionnaire (caregiver version); PEIS-P = Pediatric EoE Impact Scale (patient version); PEIS-C = Pediatric EoE 
Impact Scale (caregiver version); GIC-P = Global Impression of Change (patient version); GIC-C = Global Impression of Change (caregiver version); GIC-Clin 
= Global Impression of Change (clinician version); GIS-P = Global Impression of Severity (patient version); GIS-C = Global Impression of Severity (caregiver 
version); GIS-Clin = Global Impression of Severity (clinician version)  
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Table 3: 
Schedule of Events - Early Termination Visits and Unscheduled Visits 
Study Procedure 
ET1
(Before Part C) 
ET1
(During Follow-up) 
ET1
(During Part 
C) 
Unscheduled Visit 
(before Rescue 
Treatment) 
Unscheduled Visit 
(For Other Reasons) 
Treatment: 
Con Meds/Procedures 
X 
X 
X 
X 
X 
Efficacy: 
Age in months 
X 
X 
X 
X 
X 
Weight, Height (or length for 
patients <2 years of age) 
X 
X 
X 
X 
Pediatric EoE Sign/Symptom 
Questionnaire:2 
Patient version (PESQ-P)  
Caregiver version (PESQ-C) 
(Daily Diary) 
X 
X 
Pediatric EoE Impact Scale:2 
Patient version (PEIS-P) 
Caregiver version (PEIS-C) 
X 
X 
X 
X 
Global Impression of 
Change:3 
Patient version (GIC-P) 
Caregiver version (GIC-C) 
Clinician version (GIC-
Clin) 
X 
X 
X 
Global Impression of 
Severity:3
Patient version (GIS-P) 
Caregiver version (GIS-C) 
Clinician version (GIS-Clin) 
X 
X 
X 
X 
Pediatric Eosinophilic 
Esophagitis Symptom Score:6
Caregiver version 
(PEESSv2.0) 
X 
X 
X 
Endoscopy with Biopsies with 
EoE-EREFS4 
X4, 4a 
X4, 4a 
X4b 
Safety: 
Vital Signs 
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
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CONFIDENTIAL 
Study Procedure 
ET1
(Before Part C) 
ET1
(During Follow-up) 
ET1
(During Part 
C) 
Unscheduled Visit 
(before Rescue 
Treatment) 
Unscheduled Visit 
(For Other Reasons) 
Laboratory Testing: 
Hematology 
X 
X 
X 
Chemistry 
X 
X 
X 
Pregnancy test (WOCBP) 
urine 
urine 
urine 
Urinalysis5 
X 
X 
X 
PK and ADA Samples: 
Functional dupilumab PK 
sample 
X 
X 
X 
Anti-dupilumab antibody 
sample 
X 
X 
Biomarkers: 
Serum total IgE 
X 
Eotaxin-3 
X 
ADA = anti-drug antibody; EoE-EREFS = Eosinophilic Esophagitis-Endoscopic Reference Score; EOS = end of study; EOT = end of treatment; PEESS = 
Pediatric Eosinophilic Esophagitis Symptom Score; PRO = patient reported outcome; PESQ-P = Pediatric EoE Sign/Symptom Questionnaire (patient version); 
PESQ-C = Pediatric EoE Sign/Symptom Questionnaire (caregiver version); PEIS-P = Pediatric EoE Impact Scale (patient version); PEIS-C = Pediatric EoE 
Impact Scale (caregiver version);  GIC-P = Global Impression of Change (patient version); GIC-C = Global Impression of Change (caregiver version); GIC-Clin 
= Global Impression of Change (clinician version); GIS-P = Global Impression of Severity (patient version); GIS-C = Global Impression of Severity (caregiver 
version); GIS-Clin = Global Impression of Severity (clinician version); WOCBP = Women of childbearing potential 
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Table 4: 
Schedule of Events Open-Label Extension Part C (OLE) and EOS Schedule of Events 
Open-Label Extension Period 
12-Week 
Follow-
Up 
Study 
Procedure 
V 
171,7 
PV 
1911 
PV 
2011 
V 
21 
PV 
2211 
V 
23 
PV 
2411 
V 
25 
PV 
2611 
V 
27 
PV 
2811 
V 
29 
PV 
3011 
V 
31 
PV 
3211 
 
V 
33 
PV 
3411 
V 
35 
PV 
3611 
EOT 
V37 
EOS13 
V38 
Week (W) 
W 
52 
W 
56 
W 
60 
W 
64 
W 
72 
W 
76 
W 
84 
W 
88 
W 
96 
W 
100 
W 
108 
W 
112 
W 
120 
W 
124 
W 
132 
W 
136 
W 
144 
W 
148 
W 
152 
W 
160 
Last 
Visit     
+12 Wk 
Day (D) 
D 
365 
D 
393 
D 
420 
D 
449 
D 
505 
D 
533 
D 
589 
D 
617 
D 
673 
D 
701 
D 
757 
D 
785 
D 
841 
D 
869 
D 
925 
D 
953 
D 
1009 
D 
1037 
D 
1065 
D 
1121 
Last 
Dose 
+84D 
Visit Window 
(Days [d]) 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
+7d 
Inclusion/ 
Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment: 
 
Administer 
study drug 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
dispensation  
for 
 
 
Study drug 
dispensation  
for 
 
Study drug 
accountability 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Concomitant 
medications/ 
procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Efficacy: 
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CONFIDENTIAL 
Open-Label Extension Period 
12-Week
Follow-
Up 
Study 
Procedure 
V 
171,7 
PV 
1911 
PV 
2011 
V 
21 
PV 
2211 
V 
23 
PV 
2411 
V 
25 
PV 
2611 
V 
27 
PV 
2811 
V 
29 
PV 
3011 
V 
31 
PV 
3211 
V 
33 
PV 
3411 
V 
35 
PV 
3611 
EOT 
V37 
EOS13 
V38 
Week (W) 
W 
52 
W 
56 
W 
60 
W 
64 
W 
72 
W 
76 
W 
84 
W 
88 
W 
96 
W 
100 
W 
108 
W 
112 
W 
120 
W 
124 
W 
132 
W 
136 
W 
144 
W 
148 
W 
152 
W 
160 
Last 
Visit 
+12 Wk
Day (D) 
D 
365 
D 
393 
D 
420 
D 
449 
D 
505 
D 
533 
D 
589 
D 
617 
D 
673 
D 
701 
D 
757 
D 
785 
D 
841 
D 
869 
D 
925 
D 
953 
D 
1009 
D 
1037 
D 
1065 
D 
1121 
Last 
Dose 
+84D
Visit Window 
(Days [d]) 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
+7d
Age in 
Months 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight, 
Height (or 
length for 
patients <2 
years of 
age)14 
X9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EoE-
EREFS10
X 
X 
Endoscopy 
with biopsies
X 
X
Pediatric 
Eosinophilic 
Esophagitis 
Symptom 
Score:
Caregiver 
version 
(PEESSv2.0)8 
X 
X 
X 
X 
X 
Pediatric EoE 
Impact 
Scale:3 
X9 
X 
X 
X 
X 
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CONFIDENTIAL 
Open-Label Extension Period 
12-Week 
Follow-
Up 
Study 
Procedure 
V 
171,7 
PV 
1911 
PV 
2011 
V 
21 
PV 
2211 
V 
23 
PV 
2411 
V 
25 
PV 
2611 
V 
27 
PV 
2811 
V 
29 
PV 
3011 
V 
31 
PV 
3211 
 
V 
33 
PV 
3411 
V 
35 
PV 
3611 
EOT 
V37 
EOS13 
V38 
Week (W) 
W 
52 
W 
56 
W 
60 
W 
64 
W 
72 
W 
76 
W 
84 
W 
88 
W 
96 
W 
100 
W 
108 
W 
112 
W 
120 
W 
124 
W 
132 
W 
136 
W 
144 
W 
148 
W 
152 
W 
160 
Last 
Visit     
+12 Wk 
Day (D) 
D 
365 
D 
393 
D 
420 
D 
449 
D 
505 
D 
533 
D 
589 
D 
617 
D 
673 
D 
701 
D 
757 
D 
785 
D 
841 
D 
869 
D 
925 
D 
953 
D 
1009 
D 
1037 
D 
1065 
D 
1121 
Last 
Dose 
+84D 
Visit Window 
(Days [d]) 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
+7d 
Patient 
version 
(PEIS-P) 
Caregiver 
version 
(PEIS-C) 
Global 
Impression of 
Severity:4 
Patient 
version 
(GIS-P) 
Caregiver 
version 
(GIS-C) 
Clinician 
version (GIS-
Clin) 
X9 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
Safety: 
Vital signs 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Physical 
examination 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Adverse 
events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Regeneron Pharmaceuticals, Inc. 
Page 83 
 
CONFIDENTIAL 
Open-Label Extension Period 
12-Week 
Follow-
Up 
Study 
Procedure 
V 
171,7 
PV 
1911 
PV 
2011 
V 
21 
PV 
2211 
V 
23 
PV 
2411 
V 
25 
PV 
2611 
V 
27 
PV 
2811 
V 
29 
PV 
3011 
V 
31 
PV 
3211 
 
V 
33 
PV 
3411 
V 
35 
PV 
3611 
EOT 
V37 
EOS13 
V38 
Week (W) 
W 
52 
W 
56 
W 
60 
W 
64 
W 
72 
W 
76 
W 
84 
W 
88 
W 
96 
W 
100 
W 
108 
W 
112 
W 
120 
W 
124 
W 
132 
W 
136 
W 
144 
W 
148 
W 
152 
W 
160 
Last 
Visit     
+12 Wk 
Day (D) 
D 
365 
D 
393 
D 
420 
D 
449 
D 
505 
D 
533 
D 
589 
D 
617 
D 
673 
D 
701 
D 
757 
D 
785 
D 
841 
D 
869 
D 
925 
D 
953 
D 
1009 
D 
1037 
D 
1065 
D 
1121 
Last 
Dose 
+84D 
Visit Window 
(Days [d]) 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
±7d 
+7d 
Laboratory Testing  
Hematology, 
Chemistry 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Pregnancy 
test5 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urinalysis6 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
PK and ADA Samples:   
PK Sample12 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
Anti-
dupilumab 
antibody 
sample 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
Biomarkers: 
Collection of 
plasma and 
serum sample 
for 
exploratory 
research 
X9 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
X 
ADA = anti-drug antibody; EoE-EREFS = Eosinophilic Esophagitis-Endoscopic Reference Score; EOS = end of study; EOT = end of treatment; PEESS = 
Pediatric Eosinophilic Esophagitis Symptom Score; PRO = patient-reported outcome; PEIS-P = Pediatric EoE Impact Scale (patient version); PEIS-C = Pediatric 
EoE Impact Scale (caregiver version); GIS-P = Global Impression of Severity (patient version); GIS-C = Global Impression of Severity (caregiver version); GIS-
Clin = Global Impression of Severity (clinician version); PV = Phone Visit; V = Clinic Visit 
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Page 84 
 
CONFIDENTIAL 
9.1.1. 
Footnotes for the Schedule of Events Tables 
9.1.1.1. 
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 PPI 
treatment), the screening period will be extended for up to 12 weeks (day -85) to allow for 
at least 8 weeks of 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/imaging for EoE-EREFS/biopsy procedures should be performed after all 
other efficacy and safety assessments. 
2a. The baseline esophageal endoscopy with biopsies and the stomach and/or 
duodenum endoscopies with biopsies should be performed with sufficient time 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 PPI. Patients may be randomized as soon as their endoscopy/biopsy results 
are confirmed, and all other eligibility criteria are met.  
2b. 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 subsequent scheduled endoscopy/biopsy at week 16 and/or week 52. 
3. Patients may be re-screened 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. 
4. Assessments indicated for this week 16 (end of treatment) visit should be performed for all 
patients. For patients who will enter extended treatment, there are additional events listed 
for the week 16 visit in Table 2. 
5. Patients and/or caregivers will be trained on administration of study drug. 
6. On scheduled in-clinic study visit days, study drug will be administered in the clinic (by 
the patient, site staff, or caregiver) after all assessments are completed. Study drug 
administered at the study sites by site staff will be performed only by injection personnel 
who will not perform any clinical assessment/procedures. Study drug will be 
provided/dispensed for those doses scheduled to be administered at home before the next 
in-clinic visit. Study drug administration that occurs in clinic should occur per the Schedule 
of Events in Tables 1 and 2. Parents (or caregivers) will return the study kit box (for 
prefilled syringes) at each subsequent in-clinic visit. Parents (or caregivers) who prefer to 
have the clinic staff administer study drug may choose to have injections administered in 
the clinic. 
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Page 85 
 
CONFIDENTIAL 
7. The PESQ-P will be completed daily by patients >8 to <12 years of age (determined at the 
time of screening visit 1) just before going to bed for the night. The PESQ-C will be 
completed daily by caregivers of patients >1 to <12 years of age (determined at the time of 
screening visit 1) after the patients go to bed for the night. The PESQ-P and PESQ-C will 
be completed via an electronic diary (diary) and site personnel should conduct regular 
checks of patient and caregiver diary compliance. The PEIS-P and PEIS-C will be 
completed during site visits as indicated in the Schedule of Events table by the patients and 
caregivers, respectively. 
8. The GIS-P, GIS-C, GIS-Clin and the GIC-P, GIC-C, and GIC-Clin will be completed by 
patients during site visits (>8 to <12 years of age determined at the time of screening 
visit 1), caregivers (of patients >1 to <12 years of age determined at the time of screening 
visit 1), and study investigator/clinician, respectively. 
9. EoE-EREFS imaging will be analyzed and scored by a central reading center. Minor 
esophageal features will be assessed by the investigator. 
10. Assessments will be performed and blood samples will be collected before the 
administration of study drug. In the event of suspected SAEs, such as anaphylaxis or 
hypersensitivity, functional dupilumab PK sample and anti-dupilumab antibody sample 
may be collected at or near the event. 
11. Patients will be closely monitored at the study site at visits 3 and 4 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. Vital signs should be taken predose at 
all other indicated visits. 
12. Tuberculosis testing will be performed on a country-by-country basis according to local 
guidelines if required by regulatory authorities or ECs. 
13. A negative result must be obtained prior to the randomization visit for all females post-
menarche. 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. 
14. Urinalysis is only required for patients aged ≥6 years. 
15. The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) version 2.0 will be 
completed by caregivers of patients >1 to <12 years of age (determined at the time of 
screening visit 1). 
16. Exit interviews will be conducted by a trained interviewer by telephone within 14 days of 
completing week 16/visit 8.  These interviews will be completed with caregivers. Patients 
aged ≥8 to <12 years old (determined at the time of screening visit 1)  may also join a 
portion of the exit interview.   
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9.1.1.2. 
Footnotes for Table 2 
1. This visit is the same as the week 16 visit for the double-blind study portion (Table 1), and 
all other assessments indicated for week 16 (Table 1) should be performed. Endoscopy 
with biopsies at visit 8/week 16 must be completed prior to administration of study drug 
for Part B Extended Active Treatment. 
2. Study assessments will be performed, and blood samples will be collected prior to 
administration of study drug. In the event of suspected SAEs, such as anaphylaxis or 
hypersensitivity, functional dupilumab PK sample and anti-dupilumab antibody sample 
may be collected at or near the event. 
3. 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. 4a. Study drug administration will continue through week 50.  
4b. Weight assessed at visit 8 / week 16 and visit 12 / week 32 will be used to determine 
weight-tiered dose for the 36-week extended active treatment period. If weight has 
increased at visit 12 such that the patient meets a larger weight tier, weight-tiered dosing 
will be re-assigned according to the patient’s weight at this visit. If weight is the same or 
decreased at visit 12, then weight-tiered dosing will remain as originally assigned at visit 
8 / week 16. The patient will remain within the original exposure dosing assignment (higher 
exposure group or lower exposure group). On scheduled in-clinic study visit days, study 
drug will be administered in the clinic (by the patient, site staff, or caregiver). Study drug 
administered at the study sites by site staff will be performed only by injection personnel 
who will not perform any clinical assessment/procedures. Study drug will be provided for 
those scheduled doses to be administered at home before the next in-clinic visit. Parents 
(or caregivers) will return the study kit box (for prefilled syringes) at each subsequent in-
clinic visit. Study drug administration that occurs in clinic should occur per the Schedule 
of Events table. Parents (or caregivers) who prefer to have the clinic staff administer study 
drug may choose to have injections administered in the clinic.  
5. The PESQ-P will be completed daily by patients >8 to <12 years of age (determined at the 
time of screening visit 1) just before going to bed for the night. The PESQ-C will be 
completed daily by caregivers of patients >1 to <12 years of age (determined at the time of 
screening visit 1) after the patients go to bed for the night. The PESQ-P and PESQ-C will 
be completed via an electronic diary (diary) and site personnel should conduct regular 
checks of patient and caregiver diary compliance. The PEIS-P and PEIS-C will be 
completed during site visits as indicated in the Schedule of Events table by the patients and 
caregivers, respectively. 
6. The GIS-P, GIS-C, GIS-Clin and the GIC-P, GIC-C, and GIC-Clin will be completed 
during site visits by patients (>8 to <12 years of age determined at the time of screening 
visit 1), caregivers (of patients >1 to <12 years of age determined at the time of screening 
visit 1), and study investigator/clinician, respectively. 
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CONFIDENTIAL 
7. Endoscopy/imaging for EoE-EREFS/biopsy procedures should be performed after all other 
efficacy and safety assessments. Minor esophageal features will be assessed by the 
investigator. 
7a. 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 16 and 52. 
8. 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 at visit 8. 
9. 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. 
10. Urinalysis is only required for patients aged ≥6 years. 
11. The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) version 2.0 will be 
completed by caregivers of patients >1 to <12 years of age (determined at the time of 
screening visit 1). 
12. Assessments indicated for this week 52 (end of extended active treatment) visit should be 
performed for all patients. For patients who will enter the open-label extension period, 
there are additional events listed for the week 52 visit in Table 4. 
13. For a complete list of procedures to be performed for Re-Entry patients, please see Table 4. 
9.1.1.3. 
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. The PESQ-P will be completed daily by patients >8 to <12 years of age (determined at the 
time of screening visit 1) just before going to bed for the night. The PESQ-C will be 
completed daily by caregivers of patients >1 to <12 years of age (determined at the time of 
screening visit 1) after the patients go to bed for the night. The PESQ-P and PESQ-C will 
be completed via an electronic diary (diary) and site personnel should conduct regular 
checks of patient and caregiver diary compliance. The PEIS-P and PEIS-C will be 
completed during site visits as indicated in the Schedule of Events table by the patients and 
caregivers, respectively. 
3. The GIS-P, GIS-C, GIS-Clin and the GIC-P, GIC-C, and GIC-Clin will be completed 
during site visits as indicated by patients (>8 to <12 years of age determined at the time of 
screening visit 1), caregivers (of patients >1 to <12 years of age determined at the time of 
screening visit 1), and study investigator/clinician, respectively. 
4. EoE-EREFS imaging will be analyzed and scored by a central reading center. Minor 
esophageal features will be assessed by the investigator.  
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4a. For patients who receive rescue treatment, endoscopy/imaging for EoE-EREFS/biopsy 
procedures will be performed prior to initiation of rescue treatment. Patients undergoing 
endoscopy/biopsy prior to rescue will not undergo the any future scheduled 
endoscopy/biopsy (weeks 16, 52, 100 and/or 160). 
4b. Endoscopy/imaging for EoE-EREFS/biopsy will be performed only if the unscheduled 
visit is for the purpose of administering rescue therapy. 
5. Urinalysis is only required for patients aged ≥6 years 
6. The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) version 2.0 will only be 
completed by caregivers of patients >1 to <12 years of age (determined at the time of 
screening visit 1) at an early termination and/or unscheduled visit before rescue visit(s).  
9.1.1.4. 
Footnotes for Table 4 
1. This visit is the same as the week 52 visit for the extended active treatment period for those 
patients entering Part C immediately after Part B (Table 2) or during the Safety follow-up 
period, and all other assessments indicated for week 52 (Table 2) should be performed prior 
to this portion of the visit. 
2. Endoscopy with biopsies at visit 17/week 52 must be completed prior to administration of 
study drug for Part C - Open-Label Extension Period. Study drug administration is based 
on weight-tier (Section 8.1 Investigational and Reference Treatments) Weight must be 
collected at all in-clinic visits. Dose is assigned to match weight group for baseline for Part 
C (Week 52) and re-assigned after week 52 only if weight increases. 
3. The PEIS-P and PEIS-C will be completed during site visits as indicated in the Schedule 
of Events table by the patients and caregivers, respectively. 
4. The GIS-P, GIS-C, and GIS-Clin will be completed by patients during site visits (>8 to 
<12 years of age determined at the time of screening visit 1), caregivers (of patients ≥1 to 
<12 years of age determined at the time of screening visit 1), and study 
investigator/clinician, respectively. 
5. All females post-menarche must have monthly pregnancy testing during Part C (Table 4). 
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. 
6. Urinalysis is only required for patients aged ≥6 years. 
7. Patients who have completed their end of study visit (Visit 18 in previous protocol 
versions) prior to entering the open-label extension period must complete the procedures 
indicated for the Re-Entry Visit (Table 2) and are eligible for re-entry to the study for the 
open-label extension period and safety follow-up periods only.  The Re-Entry Visit for 
eligible re-entry patients may be combined with the week 52 Visit procedures for Part C 
(Table 4). 
8. The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) version 2.0 will be 
completed by caregivers of patients ≥1 to <12 years of age (determined at the time of 
screening visit 1). 
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9. These procedures are required for re-entry patients only. 
10. EoE-EREFS imaging will be analyzed and scored by a central reading center. Minor 
esophageal features will be assessed by the investigator. 
11. For the phone visits, patients are not required to come to the clinic.  Patients may have 
study drug shipped to them and administered at home by their parents and/or caregivers; 
however, patients and their parents/caregiver have the option to come to the clinic and have 
study drug administered by site personnel if they prefer to do so. Phone contacts at any 
time during Part C are encouraged to ensure compliance and safety of study drug dosing.  
12. Blood samples for dupilumab concentration measurement will be collected before the 
administration of study drug. The PK sample collected may be used for dupilumab ADA 
analysis based on the overall clinical presentation at that time. In the event of suspected 
SAEs, such as anaphylaxis or hypersensitivity, additional blood samples may be collected 
at or near the event for PK and ADA assessments. 
13. The End of Study (EOS) visit may occur twice for Re-Entry patients. 
14. Weight-based dosing should be adjusted based on the patient’s weight at specified in-clinic 
visits.  
9.1.2. 
Early Termination Visit 
Patients who are withdrawn from the study will be asked to return to the clinic for an early 
termination visit consisting of the assessments described in Table 3. 
9.1.3. 
Unscheduled Visits 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. 
9.1.4. 
Re-Entry Visit 
Patients who have completed their end of study visit prior to entering the open-label extension 
period are eligible for re-entry to the study for the open-label extension period. The following 
study procedures are required at a Re-Entry Visit: 
• Part C re-entry criteria (Section 7.2.2.2) 
• Informed consent 
• Updates for all relevant medical history and prior and concomitant 
medications/procedures 
• Physical Examination 
• Age, weight, height (length for patients <2 years of age) 
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9.2. 
Study Procedures 
9.2.1. 
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: demographics and medical history. Tuberculosis testing 
will be performed on a country-by-country basis according to local guidelines if required by 
regulatory authorities or ECs.  
9.2.2. 
Efficacy Procedures 
9.2.2.1. 
Patient-, Caregiver-, or Clinician-Reported Outcome Measures 
NOTE: The patient-, caregiver-, or clinician-reported outcome measures will be completed per 
appropriate age range (at screening visit 1) for the respective outcome measures specified in the 
subsections below. For outcome measures to be completed on visit days with assessments and 
study drug administration at the clinic, these outcome measures should be completed prior to 
receiving study drug. Patients ≥8 to <12 years of age and caregiver or legal guardians of all patients 
must be able to understand and complete the study requirements and study-related questionnaires. 
At least 8 out of 14 days of eDiary for the PESQ-C should be completed prior to baseline / visit 3. 
9.2.2.1.1. Pediatric EoE Sign/Symptom Questionnaire (PESQ) 
The PESQ has a patient version (PESQ-P) and caregiver version (PESQ-C). 
• The PESQ-P is a patient-reported outcome measure intended to be completed 
independently by EoE patients >8 to <12 years of age. The PESQ-P will measure 
occurrence and severity of EoE symptoms and will be completed once daily via an 
electronic diary. 
 
 
 
 
 
• The PESQ-C is an observer-reported outcome measure intended to be completed 
independently by caregivers of all pediatric EoE patients in the study. The PESQ-C 
will measure occurrence of signs of EoE and will be completed once daily via an 
electronic diary. 
 
 
 
 
 
9.2.2.1.2. Pediatric EoE Impact Scale (PEIS) 
The Pediatric EoE Impact Scale (PEIS) has a patient version (PEIS-P) and a caregiver version 
(PEIS-C). The PEIS-P and PEIS-C will be completed per the Schedule of Events in Table 1, 
Table 2, Table 3, and Table 4. 
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• The PEIS-P is a patient-reported outcome measure intended to be completed 
independently by pediatric EoE patients >8 to <12 years of age. The PEIS-P will 
assess the impact of EoE on patients’ health-related during the past 1 week. 
• The PEIS-C is intended to be completed independently by caregivers of pediatric EoE 
patients >1 to <12 years of age. The PEIS-C will assess the impact of the pediatric 
patient’s EoE on caregiver anxiety, social and professional activities, activities of 
daily living, and relationships during the past 1 week. 
9.2.2.1.3.  Global Impression of Change (GIC) 
The GIC has a patient version (GIC-P), a caregiver version (GIC-C), and a clinician version (GIC-
Clin). The GIC-P, GIC-C, and GIC-Clin will be completed per the Schedule of Events in Table 1, 
Table 2, and Table 3 . 
• The GIC-P is a single-item patient-reported outcome measure intended to be 
completed independently by pediatric EoE patients >8 to <12 years of age. The GIC-
P will assess the patient’s impression about the overall change (improvement or 
worsening) in his/her EoE condition since study treatment initiation. 
• The GIC-C is a single-item observer-reported outcome measure intended to be 
completed independently by caregivers of pediatric EoE patients >1 to <12 years of 
age. The GIC-C will assess the caregiver’s impression about the overall change 
(improvement or worsening) in the pediatric patient’s EoE condition since study 
treatment initiation. 
• The GIC-Clin is a single-item observer-reported outcome measure intended to be 
completed independently by study investigator-physician of all pediatric EoE patients 
in the study. The GIC-Clin will assess the study investigator’s/clinician’s impression 
about the overall change (improvement or worsening) in the pediatric patient’s EoE 
condition since study treatment initiation. 
9.2.2.1.4. Global Impression of Severity (GIS) 
The GIS has a patient version (GIS-P), a caregiver version (GIS-C), and a clinician version (GIS-
Clin). The GIS-P, GIS-C, and GIS-Clin will be completed per the Schedule of Events in Table 1, 
Table 2, Table 3, and Table 4. 
• The GIS-P is a single-item patient-reported outcome measure intended to be 
completed independently by pediatric EoE patients >8 to <12 years of age. The GIS-P 
will assess the patient’s impression about the overall severity of his/her EoE condition 
during the past 1 week. 
• The GIS-C is a single-item observer-reported outcomes measure intended to be 
completed independently by caregivers of pediatric EoE patients >1 to <12 years of 
age. The GIS-C will assess the caregiver’s impression about the overall severity of 
the pediatric patient’s EoE condition during the past 1 week. 
• The GIS-Clin is a single-item observer-reported outcomes measure intended to be 
completed independently by study investigator-physician of all pediatric EoE patients 
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in the study. The GIS-Clin will assess the study investigator’s/clinician’s impression 
about the overall severity of the pediatric patient’s EoE condition during the past 1 
week. 
9.2.2.1.5. Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) 
• The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) version 2.0- 
caregiver version is a caregiver reported outcomes measure which assesses the 
frequency and severity of EoE symptoms among pediatric patients (Franciosi, 2011). 
The PEESSv2.0 caregiver version consists of 20 items and has a one-month recall 
period. The total PEESSv2.0 score ranges from 0 to 100; higher scores indicate 
greater symptom burden of among pediatric EoE patients. This questionnaire will be 
collected on paper per the Schedule of Events (Table 1, Table 2, Table 3 and 
Table 4). 
9.2.2.1.6. Exit Interview 
• Exit interviews will be conducted by a trained interviewer by telephone within 
14 days of completing week 16/visit 8.  These interviews will be completed with 
caregivers. Patients aged ≥8 to <12 years old (determined at the time of screening 
visit 1) may also join a portion of the exit interview.  This exit interview will support 
interpretation of clinically meaningful change in signs/symptoms during the study. 
Detailed instructions related to these interviews will be available at the clinical site. 
Patient caregiver contact details will be provided by the clinical site to a trained 
interviewer to schedule and complete the exit interview. 
9.2.2.2. 
Body Weight and Height 
Body weight in kg and height in cm (or length for patients <2 years of age) will be measured at 
time points according to Table 1, Table 2, Table 3 and Table 4. Body mass index will be 
programmatically calculated based on the weight and height data. 
9.2.2.3. 
Endoscopy with EoE-EREFS, Biopsies, and Imaging 
Imaging for EoE-EREFS and biopsies will be assessed. Video is the preferred method of imaging, 
but photographs may be used in special circumstances (eg, technical difficulty). Training will be 
provided to study sites on performing these procedures and will be conducted prior to biopsies. 
All biopsies performed during this study will be evaluated by a qualified central histology 
laboratory.  
The endoscopy/EoE-EREFS/biopsy procedure will be performed per the Schedule of Events in 
Table 1, Table 2, Table 3 and Table 4.  
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). Imaging should be collected for EoE-EREFS 
analysis and scoring by a centralized reading center. Video is the preferred method of imaging, but 
photographs may be used in special circumstances (eg, technical difficulty). 
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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) 
In addition to the major features above, data for the following minor features will be assessed by 
the investigator: 
• 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), week 16, week 52, 
week 100, and week 160 visits, and immediately prior to start of rescue medication or procedures 
(only applies to rescue medication/or procedures that occur before Week 52 visit). 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 at least 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 histology (needed for study inclusion criteria, as 
well as endpoint assessment) and the others for RNA extraction. 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. Residual biopsy samples processed for histopathological analyses 
may also be used for exploratory research; samples may be used for immunohistochemical or 
RNAscope analyses (Section 9.2.7). 
In addition, biopsy specimens from the stomach and duodenum will be obtained at visit 2 in all 
patients to rule out alternate etiologies of esophageal eosinophilia. 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 16, week 52, week 100 and week 160. 
Biopsy samples for histopathological analyses 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 
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central pathology laboratory for central reading. These samples will be assessed for peak 
eosinophil count per hpf, and EoE grade scores and stage scores will be assigned. Eosinophilic 
esophagitis grade and stage scores evaluate 8 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).  
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 it will not be included in 
the overall EoE grade and stage scores. Severity (grade) and extent (stage) of abnormalities will 
be 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. 
Video and/or Photographs 
Video and/or photographs should be taken by the site as part of the endoscopic procedure and 
biopsy collection. A copy of these video and/or photographs will be requested from the study sites. 
Details for collecting and sending these video and/or photographs will be provided in the study 
regulatory binders. Video is the preferred method of imaging, but photographs may be used in 
special circumstances (eg, technical difficulty). 
9.2.3. 
Safety Procedures 
9.2.3.1. 
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, Table 3, and 
Table 4. 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. 
9.2.3.2. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 1, Table 2, Table 3, and Table 4. Care should be taken to examine and assess any 
abnormalities that may be present, as indicated by the patient’s medical history. 
9.2.3.3. 
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, Table 3, 
Table 4. Detailed instructions for blood sample collection are in the laboratory manual provided 
to study sites. Tests will include: 
Blood Chemistry 
Sodium 
Creatinine 
 
Potassium 
Blood urea nitrogen (BUN) 
 
Chloride 
Aspartate aminotransferase (AST) 
 
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Carbon dioxide 
Alanine aminotransferase (ALT) 
 
Calcium 
Alkaline phosphatase 
 
Glucose 
Lactate dehydrogenase (LDH) 
 
Albumin 
Estimated glomerular filtration rate (eGFR) 
 
Total protein, serum 
Total and indirect bilirubin 
 
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 WOCBP. Serum or urine pregnancy testing 
will be performed at time points listed in Table 1, Table 2, and Table 3, and Table 4. 
• Tuberculosis testing will be performed on a country-by-country basis according to local 
guidelines if required by regulatory authorities or ethics boards. 
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 10.1.1. 
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9.2.4. 
Drug Concentration and Measurements 
Samples for drug concentration measurement will be collected at visits listed in Table 1, Table 2, 
and Table 3, and Table 4 . 
9.2.5. 
Immunogenicity Measurements and Samples 
Samples for ADA and NAb assessment will be collected at time points listed in Table 1, Table 2, 
and Table 3, and Table 4. Samples positive in the ADA assay will be analyzed for the presence of 
neutralizing antibody in the NAb assay. 
9.2.6. 
 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 may also be used to evaluate markers related to toxicity, if needed. 
Samples for total IgE, serum, and eotaxin-3 (heparinized plasma) will be collected at time points 
according to Table 1, Table 2, and Table 3,. The biomarkers studied are relevant to the 
pathophysiology of EoE, response to treatment (ie, assessment of type 2 inflammation), and 
dupilumab mechanism of action, and will be assessed for predictive utility. 
Any residual samples left over from the main study may be used for exploratory research. 
9.2.6.1. 
Type 2 Inflammatory and Disease-Related Biomarkers 
Eotaxin-3 and total IgE are measures of type 2 inflammation, and are known pharmacodynamic 
markers for dupilumab in AD, asthma, and nasal polyposis. 
9.2.6.1.1. Total IgE 
IL-4 and IL-13 regulate B cell class switching to IgE. Dupilumab has been shown to suppress IgE 
(total and allergen-specific) in AD, asthma, and CRSwNP patients. Serum concentrations of total 
IgE will be measured at time points indicated in Table 1, Table 2, and Table 3 . Modulation of IgE 
is a pharmacodynamic measure. Data analysis will be described in the statistical analysis plan 
(SAP) and the results will be provided in the clinical study report (CSR). 
9.2.6.1.2. 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, Table 2, and Table 3. Modulation of 
eotaxin-3 is a pharmacodynamic measure. Data analysis will be described in the SAP and the 
results will be provided in the CSR.  
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9.2.6.2. 
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, pre-clinical 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 SAP. 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 
(Barbie, 2009) (Subramanian, 2005). NES scores will be calculated for each transcriptome 
signature for each sample for statistical analyses in Table 1, Table 2, Table 3 and Table 4 . 
9.2.7. 
Biopsy Analyses 
Biopsy samples will be used for exploratory research related to EoE, dupilumab efficacy and 
safety, and inflammation.  
Residual biopsy samples processed for histopathological analyses may also be used for exploratory 
research described above. Samples may be used for immunohistochemical or RNAscope analyses. 
Biopsies processed for RNA extraction will be used for RNA expression profiling. RNA 
sequencing, qRT-PCR, and other methods may be used to evaluate expression profiles before and 
after treatment. 
9.2.8. 
 Future Biomedical Research (Optional) 
Patients/legal parents or legal guardians who agree for their child to participate in the future 
biomedical research sub-study will be required to assent/consent to this optional sub-study before 
samples are 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 unused samples may be utilized for future biomedical research that 
may or may not be directly related to the study, including being used as reference samples and 
assay development or validation. After 15 years, any residual samples will be destroyed. The 
results of these future biomedical research analyses will not be presented in the CSR. 
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9.2.8.1. 
Pharmacogenomic Analysis (Optional) 
Patients/legal parents or legal guardians who agree for their child to participate in the genomics 
sub-study will be required to assent/consent to this optional sub-study before collection of the 
samples. Cheek swab samples for DNA extraction should be collected on day 1/baseline (predose), 
but can be collected at a later study visit. DNA samples will be collected for 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. The samples will be 
single-coded as defined by the International Council for Harmonisation (ICH) guideline E15. 
Samples will be stored for up to 15 years after the final date of the database lock. If there are 
specific site or country requirements involving the pharmacogenomic analyses which the sponsor 
is unable to comply with, samples will not be collected at those sites. 
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, target pathway, 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, and DNA copy number variation 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.  
Research findings from the optional genomic sub-study will not be disclosed to the patient or 
principal investigator, even if they have implications for a patient’s health and management. 
Genetic results from this sub-study are for research purposes only and not for medical diagnosis 
or for reproductive decision-making 
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10. 
SAFETY EVALUATION AND REPORTING 
10.1. 
Recording and Reporting Adverse Events 
10.1.1. 
General Guidelines 
The investigator must promptly record all clinical events occurring during the study data collection 
period, from the time of signing the informed consent form (ICF) to the end of study. Medical 
conditions that existed or were diagnosed prior to the signing of the ICF will be recorded as part 
of medical history. Abnormal laboratory values and vital signs observed at the time of informed 
consent should also be recorded as medical history. Any subsequent 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 should also be recorded as an AE.  
At each visit, the investigator will determine whether any AEs have occurred by evaluating the 
patient. Adverse events may be directly observed, reported spontaneously by the patient or by 
questioning the patient at each study visit. Patients should be questioned in a general way, without 
asking about the occurrence of any specific symptoms. The Investigator must assess all AEs to 
determine seriousness, severity, and causality, in accordance with the definitions in Section 10.2. 
The investigator’s assessment must be clearly documented in the site’s source documentation with 
the investigator’s signature. The investigator should follow up on SAEs (and AESIs) until they 
have resolved or are considered clinically stable; AEs should be followed until they are resolved 
or last study visit, whichever comes first. 
Always report the diagnosis as the AE or SAE term. When a diagnosis is unavailable, report the 
primary sign or symptom as the AE or SAE term with additional details included in the narrative 
until the diagnosis becomes available. If the signs and symptoms are distinct and do not suggest a 
common diagnosis, report them as individual entries of AE or SAE.  
Laboratory results, vital signs, and other diagnostic results or findings should be appraised by the 
Investigator to determine their clinical significance. Isolated abnormal laboratory results, vital sign 
findings, or other diagnostic findings (ie, not part of a reported diagnosis) should be reported as 
AEs if they are symptomatic, lead to study drug discontinuation or dose reduction, require 
corrective treatment, or constitute an AE in the investigator’s clinical judgment. 
For events that are serious due to hospitalization, the reason for hospitalization must be reported 
as the SAE (diagnosis or symptom requiring hospitalization). A procedure is not an AE or SAE, 
but the reason for the procedure may be an AE or SAE. Pre-planned (prior to signing the Informed 
Consent Form) procedures, treatments requiring hospitalization for pre-existing conditions that do 
not worsen in severity, and admission for palliative or social care should not be reported as SAEs 
(see Section 10.2 for Definitions).  
For deaths, the underlying or immediate cause of death should always be reported as an SAE.  
Any SAE that may occur subsequent to the reporting period (end of the follow-up period) that the 
investigator assesses as related to study drug should also be reported. 
All AEs, SAEs, AESIs, and pregnancy reports are to be reported according to the procedures in 
Section 10.1.3.  
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10.1.2. 
Reporting Procedure  
All events (serious and non-serious) must be reported with the investigator’s assessment of the 
event’s seriousness, severity, and causality to the (when applicable: blinded) study drug. For SAEs 
and AESIs, a detailed narrative summarizing the course of the event, including its evaluation, 
treatment, and outcome should be provided on the AE CRF. Specific or estimated dates of event 
onset, treatment, and resolution should be included, when available. Medical history, concomitant 
medications, and laboratory data that are relevant to the event should also be summarized in the 
narrative. For fatal events, the narrative should state whether an autopsy was or will be performed, 
and include the results if available. Information not available at the time of the initial report must 
be documented in a follow-up report. Source documents (including hospital or medical records, 
diagnostic reports, etc.) will be summarized in the narrative on the AE CRF, and retained at the 
study center and available upon request.  
Urgent safety queries must be followed up and addressed promptly. Follow-up information and 
response to non-urgent safety queries should be combined for reporting to provide the most 
complete data possible within each follow-up.  
10.1.3. 
Events that Require Expedited Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
• SAEs. 
• Adverse Events of Special Interest (AESI; serious and nonserious):  Adverse events 
of special interest for this study include the following:   
− Anaphylactic reactions  
− Systemic hypersensitivity reactions  
− Helminthic infections  
− Clinically symptomatic eosinophilia (or eosinophilia associated with clinical 
symptoms) 
− Any severe type of conjunctivitis or blepharitis 
− Keratitis 
− Severe injection site reactions 
− Herpes simplex infection 
− Arthralgia 
• 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. 
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10.2. 
Definitions 
10.2.1. 
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 (ICH 
E2A Guideline. Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting, Oct 1994).  
10.2.2. 
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, 
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.  
10.2.3. 
Adverse Events of Special Interest 
An AESI, serious or non-serious, is one of scientific and medical interest 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. 
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10.2.4. 
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 symptoms may be needed. 
Severe:  Produces significant impairment of functioning or incapacitation and is a definite hazard 
to the patient’s health. Treatment for symptom may be given and/or patient hospitalized. 
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 injection site reactions will be graded according to the following scale (semi-colon 
indicates “or” within description of grade: 
Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of erythema or 
induration that does not interfere with activity 
Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or interferes 
with activity; discomfort with movement; 5.1 cm to 10 cm erythema or induration or induration 
that interferes with activity 
Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; >10 cm erythema or induration; prevents daily activity; requires 
emergency room visit or hospitalization; necrosis or exfoliative dermatitis 
10.2.5. 
Causality 
The investigator must provide causality assessment as to whether or not there is a reasonable 
possibility that the drug caused the AE, based on evidence or facts, his/her clinical judgment, and 
the following definitions. The causality assessment must be made based on the available 
information and can be updated as new information becomes available. 
For double-blinded studies using an active comparator, the investigator should consider all study 
drugs in determining event causality.  
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The following factors should be considered when assessing causality: 
• Temporal relationship: time to onset versus time drug was administered 
• Nature of the reactions: immediate versus long term 
• Clinical and pathological features of the events  
• Existing information about the drug and same class of drugs  
• Concomitant medications  
• Underlying and concurrent illnesses  
• Response to dechallenge (drug discontinuation) or dose reduction  
• Response to rechallenge (re-introduction of the drug) or dose increase, when applicable  
• Patient’s medical and social history  
Causality to the study drug (including study drug administration): 
• Related: 
− The AE follows a reasonable temporal sequence from study drug administration, 
and cannot be reasonably explained by the nature of the reaction, patient’s clinical 
state (eg, disease under study, concurrent diseases, concomitant medications), or 
other external factors. 
or 
− The AE follows a reasonable temporal sequence from study drug administration, 
and is a known reaction to the drug under study or its class of drugs, or is predicted 
by known pharmacology. 
• Not Related: 
− The AE does not follow a reasonable sequence from study drug administration, or 
can be reasonably explained by the nature of the reaction, patient’s clinical state 
(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
Causality to the study conduct (protocol-specified procedure): 
• Related: 
− The AE follows a reasonable temporal sequence from a protocol-specified 
procedure, and cannot be reasonably explained by the nature of the reaction, 
patient’s clinical state (eg, disease under study, concurrent diseases, concomitant 
medications), or other external factors. 
• Not Related: 
− The AE does not follow a reasonable sequence from a protocol-specified procedure, 
or can be reasonably explained by the nature of the reaction, patient’s clinical state 
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(eg, disease under study, concurrent diseases, and concomitant medications) or 
other external factors. 
10.3. 
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; Risk Management; 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. 
10.4. 
Notifying Health Authorities, Institutional Review Board/Ethics 
Committee, and Investigators 
During the study, the sponsor and/or the CRO will inform health authorities, ECs/institutional 
review boards (IRBs), and the participating investigators of any SUSARs (suspected unexpected 
serious adverse reactions) occurring in other study centers or other studies of the active study drug 
dupilumab, as appropriate per local reporting requirements. In addition, the sponsor and/or CRO 
will comply with any additional local safety reporting requirements. All notifications to 
investigators will contain only blinded information.  
Upon receipt of the sponsor’s notification of a SUSAR that occurred with the study drug, the 
investigator will inform the IRB/EC unless delegated to the sponsor. 
Event expectedness for study drug (dupilumab) is assessed against the Reference Safety 
Information section of the Investigator’s Brochure that is effective for expedited safety reporting. 
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/IRB as appropriate. 
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11. 
STATISTICAL PLAN 
This section provides the basis for the SAP for the study.  
Endpoints are listed in Section 4. Analysis variables are listed in Section 5.  
Data collected through the implementation of new CRFs regarding the impact of the COVID-19 
pandemic on patients will be summarized (eg, discontinuation due to COVID-19). Any additional 
analyses and methods required to investigate the impact of COVID-19 on the efficacy (eg, missing 
data due to COVID-19) and safety evaluation will be specified in the SAP.  
11.1. 
Statistical Hypothesis 
The following null hypothesis and alternative of the primary endpoint will be tested for the 
comparison of each dupilumab treatment group to placebo for Part A: 
• Null hypothesis (H0): The success rate (where success is achieving peak esophageal 
intraepithelial eosinophil count of ≤6 eos/hpf at week 16) is equal between dupilumab 
groups (higher exposure group or lower exposure group) and placebo. 
• Alternative hypothesis (H1): The success rate differs at week 16 between dupilumab 
and placebo. 
No formal hypothesis and adjustment for multiplicity will be undertaken for Parts B and C. 
11.2. 
Justification of Sample Size 
The planned sample size is a total of approximately 90 patients (1:1:1 ratio, 30 patients in the 
higher dupilumab exposure group, 30 patients in the lower dupilumab exposure group, and 30 
patients in the placebo group). See Section 3.2.2 for dose selection rationale. 
The assumptions used in sample size calculation were based on Part A of the R668-EE-1774 study 
(a phase 3 study for adults and adolescents with EoE) and R668-EE-1324 (a phase 2 study for 
adults with EoE). In Part A of the R668-EE-1774, the proportions of patients achieving a peak 
esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 24 were 59.5% and 5.1% for 
dupilumab and placebo, respectively. In Part A of the R668-EE-1774, the proportions of 
adolescent patients achieving peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf at 
week 24 were 36.4% and 0% for dupilumab and placebo, respectively. The treatment group 
difference observed in adolescents was approximately 36.5%. In the R668-EE-1324 study, the 
proportions of patients achieving histologic response at week 12 were 65% and 0% for dupilumab 
and placebo, respectively. The efficacy of dupilumab can be established as early as week 12. Based 
upon the similarity of pathophysiology and expected similarity of response between adults and 
pediatric patients, a similar proportion of responders at week 16 was assumed for sample size 
calculation. The lower exposure dupilumab group is assumed to have a similar treatment effect to 
the higher exposure dupilumab group. The treatment group difference observed in the R668-EE-
1774 Part A adolescents was assumed for the sample size calculation for this study in children 
aged ≥1 year to <12 years. It is estimated that with a total number of 90 patients (30 patients in the 
higher exposure dupilumab group, 30 patients in the lower exposure dupilumab group, and 
30 patients in the placebo group), at the 2-sided 5% significance level using Fisher’s exact test, the 
study can provide 95% power to detect a treatment difference of 35.6% in the proportion of 
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histologic responders (ie, patients achieving peak esophageal intraepithelial eosinophil count 
≤6 eos/hpf) at week 16 between placebo (5.1%) and each dupilumab treatment group (40.7%).  
Sample size calculations were made using nQuery Advisor 7.0.  
11.3. 
Analysis Sets 
11.3.1. 
Efficacy Analysis Sets for Part A 
For Part A, the full analysis set (FAS) includes all randomized patients in Part A; it is based on the 
treatment allocated (as randomized). Efficacy endpoints in Part A (double-blind treatment period) 
will be analyzed using the FAS. 
11.3.2. 
Safety Analysis Set for Part A 
For Part A, the safety analysis set (SAF) includes all randomized patients who received any Part A 
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. 
11.3.3. 
Analysis Set for Parts B and C 
For efficacy and safety analyses of Parts B and C, only a subset of SAF for Part A will be 
included, which is defined as those patients who received at least 1 dose of Part B or/and Part C 
study drug.  
11.3.4. 
Pharmacokinetic Analysis Sets for All Parts 
The PK analysis population includes all patients who received any study drug and who had at least 
1 non-missing result following the first dose of study drug. 
11.3.5. 
Immunogenicity Analysis Sets for All Parts 
The ADA analysis set includes all patients who received any study drug and had at least 1 non-
missing ADA result following the first study dose.  
The NAb analysis set includes all patients who received any study drug and who are negative in 
the ADA assay or with at least 1 non-missing result in the NAb assay (patients who are ADA-
negative are set to negative in the NAb analysis set). 
11.4. 
Statistical Methods 
For continuous variables, descriptive statistics will include the following information: the number 
of patients reflected in the calculation (n), mean, standard deviation, Q1, median, Q3, minimum, 
and maximum.  
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
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11.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients who have signed the ICF 
• The total number of randomized patients:  received a randomization number 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued from study treatment, and the reasons 
for discontinuation 
11.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.  
11.4.3. 
Efficacy Analyses 
11.4.3.1. Primary Efficacy Analysis 
The primary analysis of proportion of patients achieving a histologic response of peak esophageal 
intraepithelial eosinophil count ≤6 eos/hpf at week 16 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 factor (baseline weight group). The randomization 
stratification of baseline weight group may be pooled to ensure the sufficient sample size of each 
stratum. 
For the primary estimands of interest for the primary endpoint, the intercurrent events, strategies, 
and the corresponding missing data handling approaches are provided as below: 
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Endpoint 
Category 
Estimands 
Endpoint(s) 
Population 
Intercurrent event(s) 
strategy and missing data 
handling 
Population-level 
summary/Analysis 
 
Primary 
Endpoint 
Proportion of 
patients achieving 
peak esophageal 
intraepithelial 
eosinophil count of 
≤6 eos/hpf (400×) at 
week 16 
FAS 
The intercurrent events will 
be handled as follows: 
• 
Treatment 
discontinuation: data 
collected after the 
patient discontinued 
treatment will be 
included in the analysis 
(Treatment policy 
strategy) 
• 
Initiation of treatment 
with systemic and/or 
swallowed topical 
corticosteroids drugs: 
patients will be 
considered as non-
responders after such 
event (composite 
variable strategy) 
Note: the composite strategy 
will be considered if a 
patient receives rescue 
medication any time during 
the study. 
 
Missing data handling: 
patients with a missing value 
for the primary endpoint at 
week 16 due to study 
discontinuation or other 
reasons will be considered to 
be non-responders 
Cochran-Mantel-Haenszel 
(CMH) test adjusting for 
the randomization 
stratification factor 
(baseline weight group) will 
be utilized.  
The estimated proportion of 
the treatment difference 
between dupilumab groups 
and placebo, and its 2-sided 
95% confidence intervals 
will be provided based on 
the CMH test. 
Sensitivity analyses will assess alternative methods to impute missing data. The sensitivity 
analyses will include tipping point analysis approach and worst observation carried forward – 
multiple imputation (WOCF-MI) approach.  
Subgroup analyses (eg, by weight) may be performed. Details will be specified in the SAP. 
11.4.3.2. Secondary Efficacy Analysis 
Efficacy Endpoints at Week 16 (Part A) 
Secondary efficacy endpoints that measure binary responses (eg, peak esophageal intraepithelial 
eosinophil count <15 eos/hpf) will be analyzed in the same fashion as the primary endpoint. 
Continuous secondary efficacy endpoints will be analyzed using an analysis of covariance 
(ANCOVA) model for the FAS with treatment group, randomization stratification factor, and 
relevant baseline measurement as a covariate included in the model. 
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To account for use of rescue treatment, data will be set to missing for all time points subsequent 
to the use of rescue treatment. 
For continuous efficacy data that are scheduled to be measured repeatedly post-baseline up to 
week 16 (eg, change in the proportion of days with 1 or more EoE signs from baseline to week 16 
as measured by PESQ-C), missing data will be imputed by the pattern-mixture approach. 
Specifically, the WOCF-Multiple Imputation (WOCF-MI) approach, where the WOCF approach 
will be used for the missing data due to rescue treatment/AE/lack of efficacy and the MI approach 
will be used for the missing due to other reasons.  
For continuous efficacy data that are scheduled to be measured only once post-baseline up to 
week 16, missing values at week 16 will be imputed with patient’s baseline value or the available 
post-baseline value, whichever is worse, ie, a WOCF approach.   
The primary analysis of EoE-EREFS will be based on centralized readings.  
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 16 between the dupilumab and placebo 
groups is statistically significant. P-values will be reported. 
Efficacy Endpoints at Week 52 (Part B)  
Efficacy endpoints at week 52 (Part B) will be analyzed descriptively at given visits for treatment 
received in Part B as well as by treatment group as in Part A (double-blind treatment period). No 
missing values will be imputed. These descriptive analyses may include statistical tests depending 
on the type of data in the same way as described above.  
Efficacy Endpoints (Part C)  
Efficacy data in Part C will be summarized with descriptive statistics for treatment received in 
Part C as well as by treatment group as in Part A (double-blind treatment period) and Part B 
(extended active treatment period). No missing values will be imputed. 
11.4.4. 
Control of Multiplicity 
For multiplicity adjustment, a hierarchical procedure will be used to control the overall Type-1 
error rate at 0.05 for the primary endpoint and the selected secondary efficacy endpoints for each 
dupilumab dose regimen versus placebo in Part A only. Each hypothesis will be formally tested 
only if the preceding one is significant at the 2-sided 0.05 significance level. The primary endpoint 
will be tested for the higher exposure dupilumab group first and then for the lower exposure 
dupilumab group. The hierarchical order of the secondary endpoints will be specified in the SAP. 
As Part B and C data will be summarized using descriptive statistics, there is no multiplicity issue. 
11.4.5. 
Safety Analysis 
Safety analysis will be based on the SAF in the respective study part. This includes reported 
TEAEs and other safety data (ie, clinical laboratory evaluations and vital signs). A descriptive 
summary of safety results will be presented for each study part by treatment that patients receive 
in respective part as below: 
• Part A: placebo, lower dupilumab exposure group, higher dupilumab exposure group 
and combine dupilumab group    
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• Part B: lower dupilumab exposure group, higher dupilumab exposure group and total 
Pooled Part A and Part B may be presented and details will be specified in SAP. 
• Part C: higher dupilumab exposure group 
11.4.5.1.  Adverse Events 
Definitions 
For safety variables, 2 observation periods are defined: 
• The pretreatment 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 first dose of study drug to 
end of study. The treatment-emergent period includes the double-blind treatment 
period, extended active treatment period, and open-label extension period (up to 160 
weeks in total) and the 12-week follow-up period. 
− Treatment period: date of the first dose of study drug to week 160 visit date for 
those patients who completed the week 160 visit with available visit date; or date 
of the first dose of study drug to study day 1121 (study day 1 being the first dose 
date) or the date of patient last contact, whichever is earlier, for those patients who 
did not complete week 160 visit or had missing week 160 visit date 
− Follow-up period: date after the end of treatment period to end of study 
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a pre-existing condition during the treatment-emergent period. 
Analysis 
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA®). 
Summaries of all TEAEs by treatment group will include: 
• 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 10.2.4), 
presented by SOC and PT 
• Treatment-related TEAEs, presented by HLT, SOC and PT 
• TEAEs leading to permanent treatment discontinuation, presented by SOC and PT 
• Treatment-emergent AESIs (defined with a PT or a prespecified grouping) 
Serious adverse events leading to death and other SAEs will be summarized by treatment group. 
11.4.5.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiration rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics. 
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The 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 PCSVs 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. 
11.4.5.3. Treatment Exposure 
The duration of exposure during part A, part B and part C of the study will be presented by 
treatment group and calculated as: 
(Date of last study drug injection in the specific study part – date of first study drug injection in 
the specific study part) + 14 days  
Number (%) of patients exposed to study drug during each study part and cumulatively across 
study parts will be presented by specific time periods for each treatment group. The time periods 
of interest will be specified in the SAP. 
In addition, duration of exposure during the study will be summarized for each treatment group 
using number of patients, means, standard deviation, minimums, medians, and maximums. 
A summary of the number of doses by treatment group will be provided.  
11.4.5.4. Treatment Compliance 
The compliance with study treatment will be calculated for each study part as follows: 
Treatment Compliance = (Number of study drug injections during exposure period)/(Number 
of planned study drug injections during exposure period) × 100% 
The treatment compliance will be presented by specific ranges for each treatment group. The 
ranges of interest will be specified in the SAP. 
11.4.6. 
Pharmacokinetics 
11.4.6.1. Analysis of Drug Concentration Data 
The concentrations of functional dupilumab in serum will be summarized by descriptive statistics 
at each time point. No formal statistical hypothesis testing will be performed.  
11.4.7. 
Analysis of Immunogenicity Data 
Immunogenicity will be characterized by the ADA and NAb response observed:  
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• Pre-existing immunoreactivity, defined as a positive ADA assay response at baseline, with 
all post-dose ADA results negative, or a positive assay response at baseline, with all post-
dose ADA assay responses less than 4-fold over baseline titer levels 
• Treatment-emergent ADA response, defined as any post-dose positive ADA assay 
response when the baseline results are negative or missing 
• Treatment-boosted ADA response, defined as any post-dose positive ADA assay response 
that is 4-fold over baseline titer levels when baseline is positive in the ADA assay  
• Maximum ADA titer values 
− Low (titer <1,000) 
− Moderate (1,000≤ titer ≤10,000) 
− High (titer >10,000)  
• NAb status for samples that are positive in the ADA assay  
Incidence of treatment-emergent ADA and NAb will be assessed as absolute occurrence (N) and 
percent of patients (%), grouped by dose group and ADA titer level. 
Plots of drug concentrations will be examined and the influence of ADAs and NAbs on individual 
PK profiles evaluated. Assessment of impact of ADA and NAbs on safety and efficacy may be 
provided. 
11.4.8. 
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. 
Exploratory analyses performed on biopsies will not be reported in the CSR. Other exploratory 
analyses may be performed but will not be described in the SAP or CSR. 
11.4.9. 
 Timing of Statistical Analysis 
The primary analysis may be performed when the last patient completes 16 weeks of treatment 
duration in Part A. No changes in the conduct of the study will be made based on this primary 
analysis. The assessment of primary and secondary endpoints specified in Section 4.1.1 and 
Section 4.1.2 will be analyzed descriptively in Part B as the final analysis. Part C will be described 
descriptively. Hence, there will be no need for alpha adjustment due to the primary analysis. 
In order to maintain study integrity (with respect to the extended active treatment and post-
treatment follow-up safety visits) in the event a decision is made to perform the primary analysis, 
a dissemination plan will be written. This plan will clearly identify the team (including the 
statistician) that will perform the primary analysis and all related activities, restrict other clinical 
team members and other sponsor personnel from access to individual patient treatment allocation 
and site level analysis results, and ensure that the dedicated team will not participate in the data 
review or data decisions for the following extended active treatment safety analyses.  
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11.5. 
Statistical Considerations Surrounding the Premature Termination 
of a Study 
If the study is terminated prematurely, 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 15.1. 
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12. 
QUALITY CONTROL AND 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 described in this section.  
12.1. 
Data Management and Electronic Systems 
12.1.1. 
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). 
A medical coding plan will specify the processes and the dictionary used for coding. All data 
coding (eg, AEs, baseline findings, medication, medical history/surgical history) will be done 
using internationally recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC)/paper CRF.  
12.1.2. 
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, study drug supply 
• EDC system – data capture – Medidata Rave 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance safety database 
• nQuery Advisor – sample size calculations 
• Digital archive system for endoscopic photographic and video images 
12.2. 
Study Monitoring 
12.2.1. 
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. This study will use the principles of risk-based 
monitoring (ICH). This means that the number of visits for any given site may vary based on site 
risk indicators. 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. 
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12.2.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). The site is responsible to ensure quality within their records and systems and are 
accountable for ensuring that all source data and CRF data are timely, accurate, and complete. 
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. 
12.2.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on electronic case report 
forms (eCRFs) within the EDC system by trained site personnel. All required CRFs must be 
completed for each and every patient enrolled in the study. The investigator must ensure the 
accuracy, completeness, and timeliness of the data reported to the sponsor in the CRFs. 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. 
12.3. 
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. 
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12.4. 
Study Documentation 
12.4.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the CRF/eCRF must be 
signed electronically by the investigator. This signed declaration accompanies each set of patient 
final CRF/eCRF that will be provided to the sponsor. 
12.4.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs, 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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13. 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigator(s) 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. 
13.2. 
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/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 patient and his/her parent(s) or legal guardian(s) prior to the 
patient’s participation in the study and after the aims, methods, objectives, and potential hazards 
of the study have been explained to the fullest possible extent in language that the patient and the 
parent(s) or legal guardian(s) can understand. The ICF should be signed and dated by the patient’s 
parent(s) or legal guardian(s) and the same investigator or designee who explained the ICF. 
Local law must be observed in deciding whether 1 or both parents’/guardians’ consent 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/EC and in accordance with the local regulations and requirements. 
• Patients who can write but cannot read will have the assent form read to them before 
writing their name on the form. 
• Patients who can understand but who can neither write nor read will have the 
ICF/assent read to them in the presence of an impartial witness, who will sign and date 
the ICF to confirm that informed consent was given. 
The original ICF 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 patient’s parent(s) or legal guardian(s). 
If new safety information results in significant changes in the risk/benefit assessment, or if there 
are significant changes to the study procedures, the ICF must be reviewed and updated 
appropriately. All study patients and their parent(s) or legal guardian(s) must be informed of the 
new information and provide their written consent if they wish for the patient to continue in the 
study. The original, signed revised ICF must be maintained in the patient’s study record and a copy 
must be given to the patient’s parent(s) or legal guardian(s). 
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13.3. 
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) must be kept in strict confidence. 
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. 
13.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB/EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF, 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/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/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/EC approval letter with a current list of the IRB/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/EC review and approval of all study documents (including approval of ongoing 
studies) must be kept on file by the investigator. 
13.5. 
Clinical Study Data Transparency 
Final study results will be published on a public clinical trial website according to applicable local 
guidelines and regulations. Treatment codes will be disseminated to each investigation site 
thereafter. 
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14. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB/EC-
approved amendment. Where required per local legislation, regulatory authority approval will also 
be sought.  
15. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-
OUT OF A SITE 
15.1. 
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. 
15.2. 
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/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. 
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16. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
17. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
18. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
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enrichment analysis: a knowledge-based approach for interpreting genome-wide expression 
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Totri CR, Eichenfield LF, Logan K, Proudfoot L, Schmitt J, Lara-Corrales I, et al. Prescribing 
practices for systemic agents in the treatment of severe pediatric atopic dermatitis in the US and 
Canada: The PeDRA TREAT survey. J Am Acad Dermatol 2017; 76(2):281-285. 
 
Veerappan GR, Perry JL, Duncan TJ, Baker TP, Maydonovitch C, Lake JM, et al. Prevalence of 
eosinophilic esophagitis in an adult population undergoing upper endoscopy: a prospective study. 
Clin Gastroenterol Hepatol 2009; 7(4):420-426, 426.e421-422. 
 
Warners MJ, Ambarus CA, Bredenoord AJ, Verheij J, Lauwers GY, Walsh JC, et al. Reliability 
of histologic assessment in patients with eosinophilic oesophagitis. Aliment Pharmacol Ther 2018; 
47(7):940-950. 
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CONFIDENTIAL 
 
Wechsler JB, Bolton SM, Amsden K, Wershil BK, Hirano I,Kagalwalla AF. Eosinophilic 
Esophagitis Reference Score Accurately Identifies Disease Activity and Treatment Effects in 
Children. Clin Gastroenterol Hepatol 2018; 16(7):1056-1063. 
 
Wen T, Stucke EM, Grotjan TM, Kemme KA, Abonia JP, Putnam PE, et al. Molecular diagnosis 
of eosinophilic esophagitis by gene expression profiling. Gastroenterology 2013; 145(6):1289-
1299. 
 
 
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CONFIDENTIAL 
20. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol: A Randomized, Double-Blind, Placebo-Controlled Study to 
Investigate the Efficacy and Safety of Dupilumab in Pediatric Patients with Active 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 IRB/EC. 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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CONFIDENTIAL 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Lead, and 
Biostatistician) 
To the best of my knowledge, this report accurately describes the planned conduct of the study. 
Study Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the 
Efficacy and Safety of Dupilumab in Pediatric Patients with Active 
Eosinophilic Esophagitis   
Protocol Number: 
R668-EE-1877 
Protocol Version: 
R668-EE-1877 Amendment 4 
 
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 Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
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SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 98 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: FINAL 
Clinical Study Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and 
Safety of Dupilumab in Pediatric Patients with Active Eosinophilic Esophagitis 
Compound: 
Dupilumab (REGN668) 
Protocol Number: 
R668-EE-1877 Amendment 3 
Clinical Phase:  
Phase 3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
Clinical Trial Manager: 
Study Medical Director: 
Version/Date: 
Original Statistical Analysis Plan / January 27, 2022 
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NCT04394351


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Statistical Analysis Plan 
 
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The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
See appended electronic signature page 
  
 
See appended electronic signature page 
 
 
See appended electronic signature page 
  
 
See appended electronic signature page 
 
 
See appended electronic signature page 
  
 
See appended electronic signature page 
 
 
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TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................6 
LIST OF FIGURES .........................................................................................................................6 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
OVERVIEW ...............................................................................................................10 
1.1. 
Background/Rationale ................................................................................................10 
1.2. 
Study Objectives .........................................................................................................12 
1.2.1. 
Primary Objectives .....................................................................................................12 
1.2.2. 
Secondary Objectives .................................................................................................12 
1.2.3. 
Exploratory Objectives ...............................................................................................13 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................13 
1.2.5. 
Revision History for SAP Amendments .....................................................................13 
2. 
INVESTIGATION PLAN ..........................................................................................14 
2.1. 
Study Design and Randomization ..............................................................................14 
2.2. 
Statistical Hypothesis ..................................................................................................16 
2.3. 
Sample Size and Power Considerations .....................................................................17 
2.4. 
Study Plan ...................................................................................................................17 
3. 
ANALYSIS POPULATIONS ....................................................................................19 
3.1. 
The Full Analysis Set (FAS) .......................................................................................19 
3.2. 
The Safety Analysis Set (SAF) ...................................................................................19 
3.3. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................21 
3.4. 
The Immunogenicity Analysis Set..............................................................................21 
3.5. 
Subgroups ...................................................................................................................21 
4. 
ANALYSIS VARIABLES .........................................................................................23 
4.1. 
Demographic and Baseline Characteristics ................................................................23 
4.2. 
Medical History ..........................................................................................................24 
4.3. 
Pre-Treatment/Concomitant Medication/Procedures .................................................25 
4.4. 
Efficacy Variable ........................................................................................................27 
4.4.1. 
Primary Efficacy Variable ..........................................................................................27 
4.4.2. 
Secondary Efficacy Variable(s) ..................................................................................28 
4.4.3. 
Exploratory Variable(s) ..............................................................................................35 
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4.5. 
Safety Variables ..........................................................................................................41 
4.5.1. 
Adverse Events and Serious Adverse Events .............................................................41 
4.5.2. 
Adverse Events of Special Interest .............................................................................41 
4.5.3. 
Laboratory Safety Variables .......................................................................................42 
4.5.4. 
Vital Signs ..................................................................................................................43 
4.5.5. 
Physical Examination Variables .................................................................................43 
4.6. 
Pharmacokinetic Variables .........................................................................................43 
4.7. 
Immunogenicity Variables ..........................................................................................43 
4.8. 
Biomarker Variables ...................................................................................................43 
4.9. 
Clinical Outcome Assessments for Psychometric Validity Assessment ....................43 
5. 
STATISTICAL METHODS .......................................................................................44 
5.1. 
Demographics and Baseline Characteristics ...............................................................44 
5.2. 
Medical History ..........................................................................................................44 
5.3. 
Prior/Concomitant Medications/Procedures ...............................................................45 
5.4. 
Subject Disposition .....................................................................................................45 
5.5. 
Extent of Study Treatment Exposure ..........................................................................46 
5.5.1. 
Exposure to Investigational Product ...........................................................................46 
5.6. 
Analyses of Efficacy Variables ..................................................................................47 
5.6.1. 
Analysis of Primary Efficacy Variable .......................................................................51 
5.6.2. 
Analysis of Secondary Efficacy Variables .................................................................53 
5.6.3. 
Adjustment for Multiple Comparison .........................................................................55 
5.6.4. 
Subgroup Analysis ......................................................................................................55 
5.6.5. 
Analysis of Exploratory Efficacy Variables ...............................................................56 
5.7. 
Analysis of Safety Data ..............................................................................................56 
5.7.1. 
Adverse Events ...........................................................................................................56 
5.7.2. 
Clinical Laboratory Measurements.............................................................................57 
5.7.3. 
Analysis of Vital Signs ...............................................................................................58 
5.7.4. 
Physical Exams ...........................................................................................................58 
5.8. 
Analysis of Pharmacokinetic Data ..............................................................................58 
5.9. 
Analysis of Immunogenicity Data ..............................................................................59 
5.9.1. 
Analysis of ADA ........................................................................................................59 
5.9.2. 
Analysis of Neutralizing Antibody (NAb) Data .........................................................60 
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5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................60 
5.10.1. 
Association of immunogenicity with exposure ..........................................................60 
5.10.2. 
Immunogenicity and Safety/Efficacy .........................................................................61 
5.11. 
Analysis of Biomarker Data .......................................................................................61 
5.12. 
Analysis of Psychometric Validity of Clinical Outcome Assessment 
Measures .....................................................................................................................62 
6. 
DATA CONVENTIONS ............................................................................................63 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................63 
6.2. 
General Data Handling Convention ............................................................................63 
6.3. 
Data Handling Convention for Missing Data .............................................................63 
6.4. 
Visit Windows ............................................................................................................66 
6.5. 
Statistical Technical Issues .........................................................................................69 
7. 
INTERIM ANALYSIS ...............................................................................................70 
8. 
TIMING OF STATISTICAL ANALYSIS .................................................................71 
9. 
SOFTWARE ...............................................................................................................72 
10. 
REFERENCES ...........................................................................................................73 
11. 
APPENDIX.................................................................................................................77 
11.1. 
Summary of Statistical Analyses ................................................................................77 
11.1.1. 
Summary of Efficacy Analyses ..................................................................................77 
11.1.2. 
Summary of Safety Analyses ......................................................................................78 
11.2. 
Schedule of Time and Events .....................................................................................79 
11.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................89 
11.4. 
Search Criteria for TEAEs of Special Interest ............................................................94 
11.5. 
EoE Histology Scoring System (EoE-HSS) Feature Evaluation Per Collins et 
al. 2017 .......................................................................................................................95 
11.6. 
Gene Lists Comparising Each Transcriptome Endpoint ............................................97 
 
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LIST OF TABLES 
Table 1: 
Summary of Primary Estimand for Primary Endpoint and Secondary 
Endpoints in Part A .....................................................................................................48 
Table 2 
Analysis Visit Window for Efficacy Endpoints in Part A ..........................................66 
Table 3 
Analysis Visit Window for Safety and Biomarkers in Part A ....................................67 
Table 4 
Analysis Visit Window for Efficacy Endpoints in Part B ..........................................67 
Table 5 
Analysis Visit Window for Safety and Biomarker Endpoints in Part B .....................68 
Table 6 
Analysis Visit Window for 12-week Follow-up Period after Part A/Part B 
End of Treatment ........................................................................................................68 
Table 7: 
Schedule of Events – Screening and Double-Blind Treatment Period .......................79 
Table 8: 
Schedule of Events – Extended Active Treatment Period and 12-Week 
Follow-Up Period .......................................................................................................81 
Table 9: 
Schedule of Events - Early Termination Visits and Unscheduled Visits ...................83 
 
LIST OF FIGURES 
Figure 1: 
Part A Weight-Tiered Dosing Regimens of Study Drug ............................................15 
Figure 2: 
Part B Weight-Tiered Dosing Regimens of Study Drug ............................................16 
Figure 3 
Study Flow Diagram ...................................................................................................17 
 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Ab 
Antibody 
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 
BUN 
Blood urea nitrogen 
CCL 
Chemokine (C-C motif) ligand 
CMH 
Cochran-Mantel-Haenszel (test) 
COA 
Clinical outcome assessment 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
DSQ 
Dysphagia symptom questionnaire 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDP 
EoE diagnostic panel 
eGFR 
Estimated glomerular filtration rate 
EoE 
Eosinophilic esophagitis 
EoE-EREFS 
Eosinophilic Esophagitis-Endoscopic Reference Score 
EoE-HSS 
EoE Histology Scoring System 
EOS 
End of study (visit) 
eos/hpf 
Eosinophils/high power field 
EOT 
End of treatment 
EPIT 
Epicutaneous immunotherapy 
ET 
Early termination 
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EU 
European Union 
FAS 
Full analysis set 
FLG 
Filaggrin 
GIC 
Global Impression of Change 
GIS 
Global Impression of Severity 
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 
IVRS/IWRS 
Interactive voice/web response system 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAb 
Neutralizing antibody 
NES 
Normalized Enrichment Scores 
OIT 
Oral immunotherapy 
PCSV 
Potentially clinically significant value 
PEESS 
Pediatric Eosinophilic Esophagitis Symptom Score 
PEIS 
Pediatric EoE Impact Scale 
PESQ 
Pediatric EoE Sign/Symptom Questionnaire 
PK 
Pharmacokinetic 
PPI 
Proton pump inhibitor 
PT 
Preferred term (MedDRA) 
QOL 
Quality of life 
Q2W 
Once every 2 weeks 
QW 
Once weekly 
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RBC 
Red blood cell 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SC 
Subcutaneous 
SCIT 
Subcutaneous immunotherapy 
SLIT 
Sublingual immunotherapy 
SOC 
System organ class 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
Th2 
Type 2 helper T cell 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCF 
Worst observation carried forward 
 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to database lock. 
The SAP is intended to be a comprehensive and detailed description of the strategy and statistical 
methods to be used in the data analysis of R668-EE-1877. 
This plan will be finalized prior to the data lock for the end of Part A of study R668-EE-1877, i.e., 
the last patient reaching the week 16 visit in Part A. 
1.1. 
Background/Rationale 
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by esophageal 
dysfunction and eosinophilic inflammation in the esophagus; it is thought to be triggered by an 
abnormal type 2 immune response to food allergens (Furuta, 2017) (Liacouras, 2011). Chronic 
esophageal inflammation leads to progressive remodeling, stricture formation, and fibrosis 
(Hirano, 2014) (Schoepfer, 2014) (Dellon, 2018). Although considered a rare disease, the current 
prevalence is estimated at 22.7 people per 100,000 worldwide (Arias, 2016) and appears to be on 
the increase (Dellon, 2014). Eosinophilic esophagitis has been reported in all ages; however, most 
cases are in children and adults younger than 50 years (Dellon, 2014) (Dellon, 2007) (Kapel, 2008) 
(Liacouras, 2011) (Spergel, 2009). Children under the age of 18 represent approximately 30% of 
the EoE patient population (Dellon, 2014) (Prasad, 2009). The primary clinical manifestations of 
EoE in both adults and children over 10 years of age are dysphagia and food impaction 
(Lucendo, 2017). Clinical features in younger children are non-specific in nature and vary 
significantly depending on the patient’s age and ability of the patient to describe salient symptoms. 
Infants and toddlers are more likely to present with feeding difficulties, vomiting, or regurgitation 
with the potential for failure to thrive, whereas school-age children present with complaints of 
abdominal pain and heartburn (Iuliano, 2018). Older children with symptomatic EoE may also 
modify their dietary and eating behavior by taking small bites, chewing thoroughly, eating slowly, 
drinking copious fluids, and avoiding food consistencies that stick, which is highly suggestive of 
dysphagia, as this is a feeding behavior reported in adults as an attempt to prevent esophageal food 
impactions (Iuliano, 2018). These symptoms lead to substantially impaired quality of life 
(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. Furrows and white plaques are likely the most common finding in children. Rings 
are not common in children, although rings and furrows are the most commonly seen in nearly 
half of adult patients (Singla, 2016). Some patients (particularly pediatric) may present with a 
normal-appearing esophagus, but still have histologically active EoE (Wechsler, 2018). 
Current standard of care for children with EoE consists of food-elimination diets, off-label proton 
pump inhibitors (PPIs), off-label use of swallowed topical corticosteroids, and esophageal dilation. 
Esophageal dilation is frequently utilized to relieve dysphagia symptoms caused by esophageal 
strictures. Since strictures do not occur as commonly in children, esophageal dilation is not as 
commonly performed in children with EoE as compared to adults with EoE (Chehade, 2018) 
(Furuta, 2017). The standard therapies for EoE are limited by variable response rates, relapse after 
therapy cessation, and adverse effects on quality of life. These limitations lead to a significant 
unmet need for new treatments targeting key pathways driving EoE inflammation (Spergel, 2012) 
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(Greuter, 2017). Proton pump inhibitors can result in histologic remission in approximately 50% 
of patients with EoE (Lucendo, 2017) with the remaining patients unresponsive. Swallowed topical 
corticosteroids have been reported in clinical trials to induce partial clinical responses and 
histologic remission; however, they are not uniformly effective and may be associated with local 
fungal infections, as well as a risk of growth suppression and hypothalamic–pituitary–adrenal axis 
suppression following systemic absorption (Golekoh, 2016), limiting their use to short term.  
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 immunoglobulin E (IgE) (Hamilton, 2014). Additionally, preclinical data 
demonstrate that treatment with dupilumab prevents infiltration of eosinophils into tissues. 
Dupilumab was evaluated in adult patients with EoE in a phase 2, multicenter, double-blind, 
randomized, placebo-controlled study (R668-EE-1324), where substantial improvements in 
clinical, histologic, and endoscopic aspects of the disease were demonstrated (Hirano, 2019a). 
Dupilumab was well tolerated by the study patients, with safety data generally consistent with 
other dupilumab studies and with no new safety signals associated with use in the EoE patient 
population (Hirano, 2019b). These results support pursuing further development of dupilumab for 
the treatment of EoE in adult, adolescent, and pediatric patients. As such, a multi-part phase 3 trial 
evaluating the efficacy and safety of dupilumab in adult and adolescent patients with EoE (R668-
EE-1774) was initiated. 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 enrolls patients from Part A and Part B.  The co-primary endpoints for 
the adult and adolescent study include both a validated symptom measurement utilizing the 
dysphagia symptom questionnaire (DSQ) and histologic evaluation. Part A of study R668-EE-
1774 evaluating the once weekly (QW) regimen revealed a significant effect on both of the co-
primary endpoints. In Part B of study R668-EE-1774, the dupilumab 
mg weekly demonstrated 
a significant effect on both of the co-primary endpoints and clinically meaningful improvements 
in other secondary histological, endoscopic, molecular and other patient reported outcomes. 
Although dupilumab 
 mg Q2W dosing regimen showed significant improvement in the 
histologic primary endpoint over a 24-week treatment period, dupilumab 
 mg Q2W did not 
show improvement in EoE disease symptoms compared with placebo even though, the magnitude 
of improvements in all other secondary histologic, endoscopic, and molecular endpoints of EoE 
were similar to the ones observed with the dupilumab 
 mg QW dosing regimen. Histological 
and molecular evidence suggest that the disease has the same underlying pathogenesis across age 
groups and responds similarly to swallowed topical corticosteroid treatment regardless of age 
(Straumann, 2012). Therefore, for the pediatric trial, where symptoms are heterogeneous, success 
of the trial will be determined by histologic measures; however, symptom assessments will be 
evaluated through secondary and exploratory endpoints. 
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Study R668-EE-1877 is a randomized, 2-part, double-blind, placebo-controlled study to evaluate 
the efficacy and safety of dupilumab in pediatric EoE patients aged ≥ 1 year to <12 years. Children 
with active EoE, aged ≥1 year to <12 years, who are PPI non-responsive as determined by 
esophageal histology, will be randomized 2:2:1:1 to receive either a higher exposure dupilumab 
dose regimen (n=30) or a lower exposure dupilumab dose regimen (n=30) (in a weight-tiered 
dosing schema) or a higher exposure-matched placebo (n=15) or a lower exposure-matched 
placebo (n=15) over 16 weeks (Figure 1). Primary efficacy will be assessed by a histological 
endpoint: proportion of patients with histologic remission (≤6 eos/hpf). A total sample size of 90 
patients is based on the number of patients to inform the primary efficacy histological endpoint 
and to characterize the safety profile of dupilumab in pediatric patients with EoE.  
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
To demonstrate the efficacy of dupilumab treatment compared with placebo in pediatric patients 
aged ≥ 1 year to <12 years with active EoE based on histologic improvement meeting validated 
histologic criteria. 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To demonstrate the efficacy of dupilumab compared to placebo in pediatric patients with 
active EoE after 16 weeks of treatment as assessed by endoscopic visual measurements of 
disease activity using the Eosinophilic Esophagitis-Endoscopic Reference Score (EoE-
EREFS) and histologic abnormalities as measured by the EoE Histology Scoring System 
(EoE-HSS) 
• To evaluate the safety, tolerability, and immunogenicity of dupilumab treatment for up to 
16 weeks in pediatric patients with active EoE 
• To evaluate the effects of dupilumab on transcriptomic signatures associated with EoE and 
type 2 inflammation  
• To study the effects of dupilumab on the type 2 inflammation gene expression signature 
• To evaluate the concentration-time profile of functional dupilumab in serum in this 
population 
• To assess efficacy of long-term (52 weeks) dupilumab treatment 
• To assess safety, tolerability, and immunogenicity of long-term (52 weeks) dupilumab 
treatment 
• To evaluate the impact of dupilumab treatment on EoE signs and symptoms  
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1.2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To explore impact of dupilumab treatment on health-related quality of life 
• To explore impact of dupilumab on global impression of change and severity of disease 
• To explore impact of dupilumab treatment on changes in weight and growth during the 
double-blind and extended active phases 
• To conduct exploratory research to study EoE and dupilumab mechanism of action in 
pediatric patients, including predictive biomarker discovery and/or validation 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
NA 
1.2.5. 
Revision History for SAP Amendments 
NA 
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Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
CONFIDENTIAL 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a phase 3, multicenter, randomized, 2-part, double-blind, placebo-controlled study 
investigating the efficacy, safety, tolerability, PK, and immunogenicity of dupilumab in pediatric 
patients (aged ≥1 to <12 years) with active EoE.  
In Part A, approximately 90 patients aged ≥ 1 year to <12 years will be randomized in a 2:2:1:1 
ratio to receive a higher exposure dosing regimen, a lower exposure dosing regimen of dupilumab, 
a higher exposure-matched placebo or a lower exposure-matched placebo for a 16-week treatment 
period according to a central randomization scheme provided by an IWRS to the designated study 
pharmacist (or qualified designee). Randomization will be stratified according to weight at 
baseline (≥5 kg to <15 kg, ≥15 kg to <30 kg, or ≥30 kg to <60 kg). The dosing of the placebo 
group will be matched with high exposure and low exposure dupilumab regimens in the respective 
weight tiers. Patients will remain within the originally assigned higher or lower dosing exposure 
arm throughout the study. At the end of Part A, eligible patients will be provided an option to enter 
into Part B, which is a 36-week extended active treatment period with dupilumab. All patients 
(Part A active and placebo) will receive dupilumab based on body weight at visit 8/week 16 per 
the higher- and lower-exposure dosing group to which they were assigned at randomization. 
Treatment assignment in Part B is managed by an IWRS to maintain blinding of treatment 
assignment. Since the objective of using the tiered body weight dose level approach is to maintain 
a uniform drug exposure, as patients grow over the course of the study if a patient’s weight tier 
has increased at visit 12/week 32, the patient will be re-assigned to the corresponding extended 
active treatment regimen based on weight tier at visit 12/week 32. All patients will be followed up 
for an additional 12 weeks after completing Part B. Patients in Part A who are not entering Part B 
would enter a 12-week follow-up period immediately after Part A. 
See Figure 1 and Figure 2 for Part A/Part B weight-tiered dosing regimens of study drug. 
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Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
CONFIDENTIAL 
Page 17 of 98 
2.3. 
Sample Size and Power Considerations 
The planned sample size is a total of approximately 90 patients (2:2:1:1 ratio, 30 patients in the 
higher exposure dupilumab group, 30 patients in the lower exposure dupilumab group, 15 patients 
in the higher exposure-matched placebo group, and 15 patients in the lower exposure-matched 
placebo group). 
The assumptions used in the sample size calculation were based on Part A of the R668-EE-1774 
study in adults and adolescents with EoE. Based upon the similarity of pathophysiology and 
expected similarity of histologic response between adults and pediatric patients, a similar 
proportion of responders at week 16 was assumed for sample size calculation. The lower exposure 
dupilumab group was assumed to have a similar treatment effect to the higher exposure dupilumab 
group. The treatment group difference observed in the R668-EE-1774 Part A adolescents was 
assumed for the sample size calculation for this study in children aged ≥1 year to <12 years. In 
Part A of R668-EE-1774, the proportions of patients achieving a peak esophageal intraepithelial 
eosinophil count of ≤6 eos/hpf at week 24 were 59.5% and 5.1% for dupilumab and placebo, 
respectively. In Part A of R668-EE-1774, the proportions of adolescent patients achieving peak 
esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 24 were 36.4% and 0% for 
dupilumab and placebo, respectively. The treatment group difference observed in adolescents was 
approximately 36.5%. It is estimated that with a total number of 90 patients (30 patients in the 
higher exposure dupilumab group, 30 patients in the lower exposure dupilumab group, and 30 
patients in the combined placebo group), at the 2-sided 5% significance level using Fisher’s exact 
test, the study can provide 95% power to detect a treatment difference of 35.6% in the proportion 
of histologic responders (i.e., patients achieving peak esophageal intraepithelial eosinophil count 
≤6 eos/hpf) at week 16 between placebo (5.1%) and each dupilumab treatment group (40.7%). 
Sample size calculations were performed using nQuery Advisor 7.0. 
2.4. 
Study Plan 
Patients will undergo a screening period of up to 85 days, a double-blind 16-week treatment period 
(Part A), a 36-week extended active treatment period (Part B), and a 12-week follow-up period. 
The study flow diagram is provided in Figure 3 
Study Flow Diagram. 
Figure 3 
Study Flow Diagram 
 
After patients and their legal parents/legal guardians provide informed assent (as appropriate) and 
informed consent, patients will be assessed for study eligibility.  
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Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
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Patients are required to have a documented diagnosis of EoE which may be established either by 
a prior historical biopsy, as demonstrated by intraepithelial eosinophilic infiltration (peak 
eosinophils/high power field ≥15 eos/hpf) (400×) from at least 1 esophageal region and performed 
after at least 8 weeks of treatment with an approved PPI regimen, or by biopsies performed after 
approximately 8 weeks of PPI treatment initiated prior to screening or during the screening period, 
which demonstrates ≥15 eos/hpf) (400×) from at least 2 of the 3 esophageal regions (proximal, 
mid, and distal); if the PPI regimen is stopped, biopsies must occur within 2 weeks of stopping the 
PPI. Patients who are on PPIs during the screening period and are eligible to enroll in the study, 
have the choice either to remain on the PPI regimen during the entire study or stop the PPI regimen 
prior to baseline and then must remain off PPIs during the entire study. 
Biopsies will be obtained during endoscopy at screening visit 2, at the week 16 visit, and at the 
week 52 visit, or immediately prior to start of rescue medication or procedures. A total of at least 
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 histology (needed 
for study inclusion criteria, as well as endpoint assessment) and the others for RNA extraction. 
Biopsies will be used for exploratory research to study EoE, dupilumab mechanism of action, and 
to identify or validate predictive biomarkers (efficacy and/or safety). Exploratory analyses of the 
biopsies may include but are not limited to immunohistochemistry [IHC] and RNA sequencing (or 
other methods for assessing RNA expression and RNAscope). 
Patients may be re-screened if they fail the screening evaluation, unless the reason for screen 
failure is related to histologic inclusion criteria. The baseline endoscopy with biopsies 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. 
Patients who permanently discontinue from study drug will be encouraged to remain in the study. 
Those who agree and do not withdraw from the study will be asked to return to the clinic for all 
remaining study visits per the visit schedule.  
At the end of the double-blind treatment period (week 16), eligible patients in Part A may enter 
Part B, which consists of 36-week extended active treatment. Patients who do not enter Part B will 
enter a 12-week follow-up period. 
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 (visit 3) and the first visit of Part B occur in the clinic. Endoscopies with 
biopsies are required at approximately week 16 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 be allowed to continue their current study medication 
regimen until the endoscopies with biopsies can be performed. All temporary mechanisms utilized, 
and deviations from planned study procedures in response to COVID-19 will 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. 
The study event table is presented in Section 11.2. 
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Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
CONFIDENTIAL 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following population of analysis will be 
used for all statistical analysis. 
The full analysis set (FAS) is the primary analysis population for Part A efficacy analyses. The 
Part A safety analysis set (SAF) is the basis for Part A safety analyses.  
The Part B SAF is the basis for both efficacy and safety analyses of Part B. 
3.1. 
The Full Analysis Set (FAS) 
For Part A, the FAS includes all randomized patients in Part A; it is based on the treatment 
allocated (as randomized). Efficacy endpoints in Part A (double-blind treatment period) will be 
analyzed using the FAS. 
For Part B, the efficacy endpoints in Part B (extended active treatment period) will be summarized 
for all patients who received any study drug in Part B. 
3.2. 
The Safety Analysis Set (SAF) 
Part A: 
The Part A SAF includes all randomized patients who received any Part A study drug; it is based 
on the treatment received (as treated). Treatment administration and all clinical safety variables 
will be analyzed using the SAF. 
Part B: 
For safety analyses of Part B (extended active treatment period), only a subset of SAF (Part B 
SAF) will be included, which is defined as those patients who received at least 1 dose of Part B 
study drug. 
The actual treatment group as treated for Part A is defined by the following rules: 
• For a patient randomized to higher exposure dupilumab or lower exposure dupilumab, 
if the patient received all placebo injections in Part A, the actual treatment will be 
assigned as placebo. 
• For a patient randomized to higher exposure dupilumab or lower exposure dupilumab, 
if the patient received at least one dupilumab injections in Part A, the actual treatment 
will be assigned as the planned treatment. 
• For a patient randomized to placebo, if the patient received at least one dupilumab 
injections in Part A, the actual treatment will be assigned as lower exposure 
dupilumab. 
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Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
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For safety summaries, the following analysis periods are defined: 
• Part A 16-week treatment period is defined as: 
− For patients who entered Part B: Day 1 to the date of first dose of study drug for 
Part B Extended Active Treatment period (or week 16 visit if patient entered Part 
B but never received any Part B study drug) 
− For patients who did not enter Part B 
▪ Day 1 to week 16 visit if patients completed week 16 visit with a known 
visit date 
▪ Day 1 to study day 113 (+7 days) if patients had missing week 16 visit 
date, or to patients’ last study participation date if patients did not 
complete week 16, whichever is earlier. For patients who received 
extended dosing in the double-blind treatment period due to the COVID-
19 pandemic, and week 16 visit date is not available, 16-week treatment 
period will end on their last study participation date. 
• Part B extended treatment period for patients who entered Part B is defined as: 
− The day after the first dose of study drug in Part B to the date of week 52 visit if 
patients completed week 52 with known visit date 
− The day after the first dose of study drug in Part B to study day 365 (+7 days) if 
patients had missing week 52 visit date, or to the last study participation date if 
patients did not complete week 52 visit, whichever is earlier. For patients who 
received extended dosing in the extended treatment period due to the COVID-19 
pandemic, and week 52 visit date is not available, 36-week extended treatment 
period will end on their last study participation date 
• Follow-up period is defined as: 
− For patients who entered Part B: the day after the end of Part B extended 
treatment period to the patient last study participation date 
− For patients who did not enter Part B: the day after the end of Part A 16-week 
treatment period to the last study participation date 
The Part A and Part B SAFs will be the basis for the safety analyses for the Part A treatment period 
and Part B treatment period, respectively; however, for the analyses during the follow-up period, 
only a subset of the corresponding SAFs will be included, which is defined as the patients who 
entered the follow-up period and had at least one visit after week 16 visit (for Part A SAF) or week 
52 visit (for Part B SAF). 
Due to COVID-19 pandemic, patients are allowed to extend their current assigned dose regimen 
of study drug (Part A and/or Part B) until endoscopy with biopsy can be performed at week 16 
visit and/or week 52 visit. The safety data during the extended dosing period will also be presented 
in the corresponding analysis period. 
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Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
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3.3. 
The Pharmacokinetic Analysis Set (PKAS) 
The PK analysis population includes all patients who received any study drug and who had at least 
1 non-missing result following the first dose of study drug. The PK analysis set is based on the 
actual treatment received (as treated) rather than as randomized. 
3.4. 
The Immunogenicity Analysis Set 
The ADA analysis set (AAS) includes all patients who received any amount of study drug (active 
or placebo [safety analysis set]) and had at least one non-missing anti-drug antibody result 
following the first dose of study drug or placebo. The ADA analysis set is based on the actual 
treatment received (as treated) rather than as randomized. 
The NAb analysis set includes all treated patients who received any study drug (active or placebo), 
have at least one non-missing anti-drug antibody result following the first dose of study drug 
(active or placebo), and either tested negative at all ADA sampling times or tested positive for 
ADA with at least one non-missing NAb result after first dose of the study drug (active or placebo). 
Patients who are ADA negative are set to negative and included as such in the NAb analysis set. 
3.5. 
Subgroups 
Subgroups are defined by key baseline factors recorded on the eCRF (unless otherwise specified) 
and listed as follows. 
Subgroups to be considered for both primary efficacy and safety analyses: 
• Age group (years; ≥1- <6, ≥6 -<12; ≥1- <8, ≥8 -<12) 
• Sex (Male, Female) 
• Duration of EoE (years from start date of EoE to randomization date; <5, ≥5) 
• Baseline weight group (≥5 - <15 kg, ≥15- <30 kg, ≥30- <60 kg) 
• Prior use of swallowed topical steroids (STC) for the treatment of EoE (Yes, No) 
• Inadequate response, intolerant and/or contraindicated to swallowed topical 
corticosteroids (STC) (Yes, No) * 
• History of atopic dermatitis (Yes, No) 
• History of asthma (Yes, No) 
• History of allergic rhinitis (Yes, No) 
• History of food allergy (Yes, No) 
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Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
CONFIDENTIAL 
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Subgroups to be considered for primary efficacy endpoint only: 
• Baseline BMI group (kg/m2; overweight: ≥85 percentile of BMI for ≥2 years based 
on age and gender, ≥95 percentile of weight based on length (height), age and gender 
for <2 years, not overweight: not meeting the criteria of overweight) [based on CDC 
(Center for Disease Control and Prevention) chart] 
• Use of PPI at randomization (Yes, No) 
• Prior esophageal dilations (Yes, No) 
• Subject on a food elimination diet at the time of screening (Yes, No) 
• Subject on a food elimination diet in the past (Yes, No) 
Subgroup to be considered for selected secondary efficacy endpoints only (details are in 
Section 5.6.4): 
• Prior use of swallowed topical steroids (STC) for the treatment of EoE (Yes, No) 
NOTE: The subgroup analysis may not be performed if the number of patients within the subgroup 
is <10% of overall sample size. The stratification factor is not included in the subgroup analysis 
of primary efficacy endpoint. 
* The inadequate response, intolerant and/or contraindicated to STC subgroup is defined as  
• Contraindicated to STC: patients never used STC for the treatment of EoE, and the 
reasons for never using STC were concomitant medical concern or contraindication 
(e.g., diabetes, immunomodulating treatment) or potential side-effect(s) from STC 
• Inadequate response: patients had used STC for the treatment of EoE but the 
treatment with STC was not effective in relieving EoE symptoms 
• Intolerant to STC: patients had used STC for the treatment of EoE and the treatment 
with STC was effective in relieving EoE symptoms, with the reasons for stopping 
STC for EoE being concomitant medical concern or contraindication or side effect(s) 
 
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Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics variables will be summarized: 
• Demographic variables: Age at screening as a continuous variable and with grouping 
(years; 1-<6 years, 6-<12 years; 1-<8 years, ≥8-<12 years), Sex (Male, Female), 
Ethnicity with grouping (Hispanic or Latino, Not-Hispanic or Latino), Race with 
grouping (White, Black or African American, Asian, Other), Country, Baseline 
weight as a continuous variable and with grouping (kg; ≥5-<15 kg, ≥15- <30 kg, ≥30- 
<60 kg), Height/length (cm), and calculated BMI (kg/m2; overweight, not 
overweight) [see the BMI grouping definition in Section 3.5]. 
• Baseline disease characteristics 
− Pediatric EoE Sign Questionnaire (PESQ-C [caregiver version]) (details of PESQ-
C are in Section 4.4.2) 
▪ Proportion of days with 1 or more EoE signs for PESQ-C 
▪ Proportion of total segments within a day (night, morning, afternoon, 
evening) with 1 or more EoE signs for PESQ-C 
▪ Number of sign-free days during the 14-day period preceding baseline 
visit for PESQ-C 
− Pediatric EoE Symptom Questionnaire (PESQ-P [patient version]) (details of 
PESQ-P are in Section 4.4.2) 
▪ Proportion of days with 1 or more EoE symptoms for PESQ-P 
▪ Proportion of total segments within a day (night, morning, afternoon, 
evening) with 1 or more EoE symptoms for PESQ-P 
▪ Number of symptom-free days during the 14-day period preceding 
baseline visit for PESQ-P 
− Pediatric Eosinophilic Esophagitis Symptom Score (PEESSv2.0 [caregiver 
version]) 
− Global Impression of Severity (GIS-P [patient version], GIS-C [caregiver 
version], GIS-Clin [clinician version]) (details of GIS-P, GIS-C and GIS-Clin are 
in Section 4.4.3) 
‒ Pediatric EoE Impact Scale (PEIS-C [caregiver version] and PEIS-P [patient 
version]) (details of PEIS-C and PEIS-P are in Section 4.4.3) 
− Duration of EoE as a continuous variable and with grouping (years; <5, ≥5) 
− Age at EoE onset as a continuous variable and with grouping (years; <5, ≥5)  
‒ Peak esophageal intraepithelial eosinophil count (eos/hpf) of three regions 
(proximal, mid, and distal) 
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Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
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‒ Mean stage score from the EoE-HSS summed over three regions (proximal, mid, 
and distal) 
‒ Mean grade score from the EoE-HSS summed over three regions (proximal, mid, 
and distal) 
‒ Prior use of STC for EoE (Yes, No) 
− Effectiveness of prior use of STC for EoE (Yes, No) 
− Inadequate response, intolerant and/or contraindicated to STC (Yes or No) 
− Prior esophageal dilations (Yes, No) 
‒ Number of prior esophageal dilations 
− Patients treated with PPI at randomization (Yes, No) 
‒ Patient on food elimination diet in past (Yes, No) 
‒ Patient on food elimination diet at screening (Yes, No) 
‒ Historical esophageal biopsy showing ≥15 (eso/hpf [400 ×]) after 8 weeks of high-
dose PPI (Yes, No) 
‒ Prior use of STC for EoE and prior esophageal dilation (Yes, No) 
‒ EREFS total score 
‒ Baseline serum total immunoglobulin E (IgE) as a continuous variable and with 
grouping (IU/mL; <100, ≥100) 
‒ Baseline blood peripheral EOS as a continuous variable and with grouping (Giga/L; 
<0.15, ≥0.15; <0.30, ≥0.30; <0.50, ≥0.50) 
4.2. 
Medical History 
Medical history will be coded using MedDRA. The same MedDRA version will be used for Part 
A and Part A patients’ data in Part B within the scope of DBL. Information related to EoE medical 
history and comorbid atopic conditions include diagnosis of EoE, atopic dermatitis, asthma, 
allergic rhinitis, allergic conjunctivitis, chronic rhinosinusitis, nasal polyps, food allergy, hives, 
contact dermatitis, other allergies (medications, animals, plants, mold, dust mites, etc.). Patient 
dietary status at the time of screening is also collected with information on whether patient has 
ever been on a food elimination diet in the past, type of food elimination, and reason for elimination 
of specific food. 
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Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
CONFIDENTIAL 
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4.3. 
Pre-Treatment/Concomitant Medication/Procedures 
Medications/Procedures will be recorded from the day of informed consent until the end-of-study 
(EOS) visit. Medications will be coded using WHO Drug Dictionary (WHODRUG). Medications 
of interest include PPIs and swallowed topical/systemic corticosteroids for the treatment of EoE. 
Pre-treatment medications/procedures: medications taken or procedures performed prior to 
administration of the first dose of study drug. 
Concomitant medications/procedures (CM/CP): medications taken or procedures performed 
following the first dose of study drug through the EOS visit. This includes medications or 
procedures that were started before the study and are ongoing during the study. Furthermore, 
CM/CP will be categorized according to analysis periods (as defined in Section 3.2): 
• CMs/CPs taken during the Part A 16-week double-blind treatment period 
• CMs/CPs taken during the Part B 36-week extended active treatment period 
• CMs/CPs taken during the 12-week follow-up period 
Prohibited concomitant medications/procedures during the study: 
Treatment with the following concomitant medications is prohibited through week 52 and may 
result in temporary or permanent discontinuation of study drug: 
• Swallowed topical corticosteroids (may be used as rescue treatment of EoE) 
• Systemic corticosteroids (may be used as rescue treatment of 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, mepolizumab, omalizumab, cyclosporine, mycophenolate-mofetil, azathioprine, 
methotrexate, IFN-γ, or other immunomodulatory biologics) 
• Treatment with an investigational drug (other than dupilumab) 
• Initiation, discontinuation, or change in dosage regimen after baseline of the 
following medications (stable doses of these medications are allowed): 
‒ Proton pump inhibitors 
‒ Systemic leukotriene inhibitors 
• Initiation, discontinuation, or change in dosage regimen of nasal and/or inhaled 
corticosteroids within 8 weeks prior to visit 2, visit 8, or visit 17 endoscopies with 
biopsies 
• Initiation of SCIT, or change in dose for those patients on a stable dose of SCIT, 
within 1 year prior to screening  
• Sublingual immunotherapy (SLIT) 
• OIT 
• Epicutaneous immunotherapy (EPIT) 
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Statistical Analysis Plan 
 
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• Treatment with a live (attenuated) vaccine, e.g.:  
− 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 
Patients may receive the prohibited medications/procedures listed above 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. 
Blinded adjudication of prohibited medications and procedures will be performed by the medical 
director (or medical monitor) before database locks with documented procedures. 
Rescue treatments (including both medications and procedures): If medically necessary (e.g., for 
treatment of intolerable EoE symptoms), rescue medications (systemic and/or swallowed topical 
corticosteroids) or emergency esophageal dilations are allowed for study patients. An endoscopy 
with biopsy will be performed prior to the initiation of rescue therapy. Patients who undergo an 
endoscopy with biopsy due to initiation of rescue therapy will not undergo the subsequent 
scheduled endoscopy/biopsy at week 16 and/or week 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. 
Patients receiving rescue therapy may continue to receive study drug. They will remain blinded 
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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 except for 
endoscopy/biopsy, as noted above. For the purpose of primary endpoint efficacy analyses, patients 
who receive rescue treatment during the study will be considered treatment failures. 
Blinded adjudication of rescue treatments will be implemented before database locks by 
considering the type of medication or procedure, indication, timing, frequency, and the potential 
impact of the use of the medication or procedure. The rescue treatments will be adjudicated by the 
medical director (or medical monitor) with documented procedures. 
Gastric/Duodenum and Targeted Biopsy 
Biopsy specimens from the stomach and duodenum will be obtained at visit 2 in all patients to rule 
out alternate etiologies of esophageal eosinophilia. 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 16 and week 52. 
4.4. 
Efficacy Variable 
4.4.1. 
Primary Efficacy Variable 
The primary endpoint is: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤6 eos/hpf (400×) at week 16 
Peak esophageal intraepithelial eosinophil count 
Peak esophageal intraepithelial eosinophil count will be measured from esophageal biopsies. 
Biopsies will be obtained by endoscopy at the second screening visit (visit 2), at week 16, and at 
week 52 visits, and immediately prior to start of rescue medication or rescue procedure and during 
the early termination visits. A total of at least 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 histology (needed for study inclusion criteria, as well as endpoint 
assessment) and the others for RNA extraction. 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. Biopsy samples for histopathological analyses 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. The peak esophageal intraepithelial eosinophil 
count at each visit is the maximum of the quantities of eosinophils in the most inflamed high power 
fields (hpfs) across the 3 regions. For example, if the quantity of eosinophils in the most inflamed 
hpf is 2/hpf, 3/hpf, and 4/hpf from the proximal, mid, and distal regions, respectively, the peak 
eosinophil count will be considered as 4/hpf for week 16. If the quantity of eosinophils is missing 
for 1 or 2 esophageal regions, the peak eosinophil count will be the maximum of the quantities of 
eosinophils from the region(s) where eosinophil quantities are available.  
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4.4.2. 
Secondary Efficacy Variable(s) 
The secondary endpoints are: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
<15 eos/hpf at week 16 
• Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from baseline 
to week 16 
• Absolute change in mean EoE grade score from the EoE-HSS from baseline to week 16 
• Absolute change in mean EoE stage score from the EoE-HSS from baseline to week 16 
• Absolute change in EoE-EREFS from baseline to week 16 
• Change from baseline to week 16 in the proportion of days with 1 or more EoE signs as 
measured by the PESQ-C (for patients aged ≥1 to <12 years) 
• Number of sign-free days during the 14-day period preceding week 16 as measured by the 
PESQ-C (for patients aged ≥1 to <12 years) 
• Change from baseline to week 16 in the proportion of total segments within a day (night, 
morning, afternoon, evening) with 1 or more EoE signs as measured by the PESQ-C (for 
patients aged ≥1 to <12 years) 
• Change from baseline to week 16 in the proportion of days with 1 or more EoE symptoms 
as measured by the PESQ-P (for patients aged ≥8 to <12 years) 
• Number of symptom-free days during the 14-day period preceding week 16 as measured 
by the PESQ-P (for patients aged ≥8 to <12 years) 
• Change from baseline to week 16 in the proportion of total segments within a day (night, 
morning, afternoon, evening) with 1 or more EoE symptoms as measured by the PESQ-P 
(for patients aged ≥8 to <12 years)  
• Change in total score from baseline to week 16 as measured by the PEESSv2.0 (caregiver 
version) (for patients aged ≥1 to <12 years) 
• Normalized Enrichment Scores (NES) for the relative change from baseline to week 16 in 
the EoE diagnostic panel (EDP) transcriptome signature 
• NES for the relative change from baseline to week 16 in the type 2 inflammation 
transcriptome signature 
NOTE: All the above primary and secondary endpoints assessed at week 16 for Part A will be 
assessed at week 52 for Part B (except for PEESSv2.0 [caregiver version]) 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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Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) 
The EoE-HSS is a recently validated histologic scoring system that measures other histological 
abnormalities in addition to the density of eosinophilic infiltration. It has been confirmed in adults 
to have external reliability and this scoring system is highly responsive to treatment (Collins, 2017) 
(Warners, 2018). Eosinophilic esophagitis grade and stage scores evaluate 8 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). Assessment of lamina propria fibrosis may not be possible if the 
esophageal biopsy specimens do not contain adequate amounts of subepithelium lamina propria; 
in this case it will not be included in the overall EoE grade and stage scores. 
Histology results will be interpreted by a pathologist at a central pathology reading center who will 
be blinded to the treatment assignment. Severity (grade) and extent (stage) of abnormalities will 
be scored using a 4-point scale (0 normal; 3 maximum change). The detailed scoring scheme for 
each feature is provided in Section 11.5. The mean grade or mean stage score from EoE-HSS is 
the ratio of the sum of the assigned score for each evaluated feature divided by the maximum 
possible score (maximum value is 24). For example, if each of 8 features has maximum grade of 
3 for a biopsy, the mean grade score is 1 (24/24). If one feature is not evaluated, the maximum 
possible score is reduced by 3. Maximum possible score reduction may occur when lamina propria 
fibrosis is not present. If all other features are evaluable, the maximum possible score for a biopsy 
lacking lamina propria fibrosis is reduced from 24 to 21 because of 7 evaluated features. Both 
mean grade and mean stage scores will be determined for biopsies from 3 esophageal regions 
(proximal, mid, and distal). The algorithm of the calculation of mean grade and mean stage scores 
is as follows. 
• The mean grade and mean stage scores summed over the 3 regions is the final score used 
in the primary analysis of the associated endpoints. An example table is provided below to 
illustrate the calculation of mean grade and mean stage scores. For example, the mean 
grade is 0.33, 0.33, and 0.42 from the proximal, mid, and distal regions, respectively, and 
the final mean grade score is 1.08 (0.33+0.33+0.42).  
• If a mean score is available from at least 1 of the 3 regions, the sum of available mean 
scores will be used as final mean score. For example, if the mean grade score is 0.33 and 
0.33 from the proximal and mid regions but missing from distal region, the final mean 
grade score will be 0.66 (0.33+0.33). 
 
Feature 
Esophageal region 
Proximal 
Mid 
Distal 
Eosinophilic inflammation 
3 
3 
3 
Basal zone hyperplasia 
2 
3 
3 
Eosinophil abscess 
2 
2 
3 
Surface layering 
0 
0 
0 
Dilated intercellular spaces 
0 
0 
0 
Surface epithelial alteration 
0 
0 
0 
Dyskeratotic epithelial cells 
0 
0 
0 
Lamina propria fibrosis 
Missing due to absence 
0 
1 
8-feature Mean Grade Score 
(3+2+2)/21=0.33 
(3+3+2)/24=0.33 
(3+3+3+1)/24=0.42 
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Eosinophilic Esophagitis-Endoscopic Reference Score (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 EoE-EREFS utilizes a composite score using 
standardized methodology to assess clinical signs of EoE disease. Imaging should be collected for 
EoE-EREFS analysis and scoring by a centralized reading center. 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 [0], present [1]) 
• Rings (absent [0], mild [1], moderate [2], severe [3]) 
• Exudates (absent [0], mild [1], severe [2]) 
• Furrows (absent [0], mild [1], severe [2]) 
• Stricture (absent [0], present [1]) 
The score for each region is the sum of assigned scores for each of the above 5 major features and 
ranges from 0 to 9. The total score (summing scores for the proximal and distal regions) ranges 
from 0 to 18 and is the final score used for the analysis. If the score is available only from 1 of the 
2 regions, that available score is used as total score. For example, if score is 8 from the proximal 
region and missing from the distal region, the total score is 8. 
In addition to the major features above, data for the following minor features will be assessed by 
the investigator: 
• 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). 
EoE-EREFS will be assessed by endoscopy at screening visit 2, week 16, and week 52 or ET visits 
by centralized reading center. For patients who receive rescue treatment, endoscopy/imaging for 
EoE-EREFS/biopsy procedures will be performed prior to initiation of rescue treatment. 
Transcriptome Endpoints 
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, pre-clinical 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 Section 11.6. 
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4.4.3. 
Exploratory Variable(s) 
The exploratory endpoints are: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤1 
eos/hpf at week 16 
• Percent change in total score of Pediatric EoE Impact Scale (caregiver version) (PEIS-C) 
from baseline to week 16 (for patients aged ≥1 to <12 years) 
• Percent change in total Pediatric EoE Impact Scale (patient version) (PEIS-P) score from 
baseline to week 16 (for patients aged ≥8 to <12 years) 
NOTE: Total score of PEIS-C or PEIS-P refers to averaging the scores of each of the individual 
questions, not totaling the scores from each of the individual questions.  
• Change in GIC-patient, caregiver, and clinician version score 
NOTE: Change in GIC for different questionnaires refers to the question itself asking the overall 
change of patient’s/caregiver’s EoE condition, not the change from baseline (the GIC is not 
administered at baseline).  
• Change in GIS-patient, caregiver, and clinician version score 
• Change from baseline in body weight for age percentile at week 16 
• Change in body mass index for age z-score from baseline to week 16 for patients ≥2 years 
of age 
• Change in weight for age z-score from baseline to week 16 
• Change in weight for height z-score from baseline to week 16 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 
eos/hpf at week 16 and achieving absolute change from baseline to week 16 in the 
proportion of days with 1 or more EoE signs as measured by PESQ-C  
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 
eos/hpf at week 16 and achieving percent change from baseline to week 16 in the 
proportion of days with 1 or more EoE signs as measured by PESQ-C  
• Absolute change from baseline to week 16 in EREFS (excluding stricture) 
• Absolute change from baseline to week 16 in EREFS inflammation sub-score 
• Absolute change from baseline to week 16 in EREFS remodeling sub-score 
NOTE: All the above exploratory endpoints assessed at week 16 will be assessed at week 52 as 
exploratory 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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Pediatric EoE Impact Scale (PEIS) 
The Pediatric EoE Impact Scale (PEIS) has a patient version (PEIS-P) and a caregiver version 
(PEIS-C). 
PEIS-P is a patient-reported outcome measure intended to be completed independently by pediatric 
EoE patients ≥8 to <12 years of age. The PEIS-P will assess the impact of EoE on the patient 
during the past 1 week. Response to each item below (except item 5) is on a 5-point scale (0 = 
“Never”, 1 = “Almost never”, 2 = “Sometimes”, 3 = “Almost always”, 4 = “Always”). Response 
to item 5 is on a 6-point scale (0 = “Never”, 1 = “Almost never”, 2 = “Sometimes”, 3 = “Almost 
always”, 4 = “Always”, 5 = “Not applicable - I did not go to school during the past 7 days”). The 
PEIS-P average score is the sum of non-missing responses divided by the number of items with 
non-missing responses (note: response of “Not Applicable - I did not go to school during the past 
7 days” is considered as missing response and not be counted in the average score). The average 
score could range from 0 to 4. 
Item No. 
Question 
1 
During the past 7 days, how often were you worried because of your EoE?  
2 
During the past 7 days, how often did you feel sad because of your EoE? 
3 
During the past 7 days, how often were you embarrassed in front of other people because of your 
EoE? 
4 
During the past 7 days, how often did you have difficulty sleeping at night because of your EoE? 
5 
During the past 7 days, how often did you have difficulty concentrating at school because of your 
EoE? 
6 
During the past 7 days, how often did you have difficulty playing with your friends because of your 
EoE? 
PEIS-C is intended to be completed independently by caregivers of pediatric EoE patients ≥1 to 
<12 years of age. The PEIS-C will assess the impact of the pediatric patient’s EoE on caregiver 
anxiety, social and professional activities, activities of daily living, and relationships during the 
past 1 week. Response to each item (except item 4 and 4a) is on a 5-point scale (0 = “Not at all”, 
1 = “Very little”, 2 = “A little”, 3 = “Very much”, 4 = “Extremely”). If response to item 4 is “No”, 
items 4a and 4b will be skipped and considered as missing response. The PEIS-C average score is 
the sum of non-missing responses divided by the number of items with non-missing responses 
(note: response to item 4a is not included in the score calculation). The average score could range 
from 0 to 4. 
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Item No. 
Question 
1 
During the past 7 days, how worried were you because of your child’s EoE? 
2 
During the past 7 days, how sad were you because of your child’s EoE? 
3 
During the past 7 days, how much did your child’s EoE limit your social activities? 
4 
Are you currently employed (working for pay)? (If “Yes”, go to question 4a and then 4b. If “No”, go 
to Question 5) 
4a 
During the past 7 days, how many days did you miss work because of your child’s EoE 
4b 
During the past 7 days, how much did your child’s EoE limit your productivity while you were 
working? 
5 
During the past 7 days, how much did your child’s EoE limit your everyday activities (for example: 
house chores, going shopping)? 
6 
During the past 7 days, how much did your child’s EoE cause problems with your personal 
relationships? 
Global Impression of Change (GIC) 
The GIC has a patient version (GIC-P), a caregiver version (GIC-C), and a clinician version (GIC-
Clin). 
• The GIC-P is a single-item patient-reported outcome measure intended to be completed 
independently by pediatric EoE patients ≥8 to <12 years of age. The GIC-P will assess the 
patient’s impression about the overall change (improvement or worsening) in his/her EoE 
condition since study treatment initiation. 
• The GIC-C is a single-item observer-reported outcome measure intended to be completed 
independently by caregivers of pediatric EoE patients ≥1 to <12 years of age. The GIC-C 
will assess the caregiver’s impression about the overall change (improvement or 
worsening) in the pediatric patient’s EoE condition since study treatment initiation. 
• The GIC-Clin is a single-item observer-reported outcome measure intended to be 
completed independently by study investigator-physician of all pediatric EoE patients in 
the study. The GIC-Clin will assess the study investigator’s/clinician’s impression about 
the overall change (improvement or worsening) in the pediatric patient’s EoE condition 
since study treatment initiation. 
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The GIC-P, GIC-C, GIC-Clin score could range from 1 to 7. 
Questionnaire 
Question 
Response (score) 
GIC-P 
Since you started getting the study injection, how would you 
describe the overall change in your eosinophilic esophagitis 
(EoE)? 
A lot better (1) 
Somewhat better (2) 
A little better (3) 
No change (4) 
A little worse (5) 
Somewhat worse (6) 
A lot worse (7) 
GIC-C 
Since your child started getting the study injection, how 
would you describe the overall change in your child’s 
eosinophilic esophagitis (EoE)? 
Very much improved (1) 
Much improved (2) 
Minimally improved (3) 
No change (4) 
Minimally worse (5) 
Much worse (6) 
Very much worse (7) 
GIC-Clin 
Since your patient started getting the study injection, how 
would you describe the overall change in your patient’s 
eosinophilic esophagitis (EoE)? 
Very much improved (1) 
Much improved (2) 
Minimally improved (3) 
No change (4) 
Minimally worse (5) 
Much worse (6) 
Very much worse (7) 
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Global Impression of Severity (GIS) 
The GIS has a patient version (GIS-P), a caregiver version (GIS-C), and a clinician version (GIS-
Clin). 
• The GIS-P is a single-item patient-reported outcome measure intended to be completed 
independently by pediatric EoE patients ≥8 to <12 years of age. The GIS-P will assess the 
patient’s impression about the overall severity of his/her EoE condition during the past 1 
week. 
• The GIS-C is a single-item observer-reported outcome measure intended to be completed 
independently by caregivers of pediatric EoE patients ≥1 to <12 years of age. The GIS-C 
will assess the caregiver’s impression about the overall severity of the pediatric patient’s 
EoE condition during the past 1 week. 
• The GIS-Clin is a single-item observer-reported outcome measure intended to be 
completed independently by study investigator-physician of all pediatric EoE patients in 
the study. The GIS-Clin will assess the study investigator’s/clinician’s impression about 
the overall severity of the pediatric patient’s EoE condition during the past 1 week. 
The GIS-P, GIS-C, and GIS-Clin score could range from 1 to 4. 
Questionnaire 
Question 
Response (score) 
GIS-P 
During the past 7 days, how bad was your eosinophilic 
esophagitis (EoE)? 
 
Not bad (1) 
A little bad (2) 
Bad (3) 
Very bad (4) 
GIS-C 
During the past 7 days, how severe was your child’s 
eosinophilic esophagitis (EoE)? 
 
Mild (1) 
Moderate (2) 
Severe (3) 
Very severe (4) 
GIS-Clin 
Overall, how severe is your patient’s eosinophilic 
esophagitis (EoE)? 
 
Mild (1) 
Moderate (2) 
Severe (3) 
Very severe (4) 
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Body Weight and Body Mass Index (BMI) Z-scores and Percentiles 
Body weight for age z-score, body weight for age percentile, body weight for height/length z-
score, and BMI for age z-score at each visit will be calculated based on the growth charts from 
Centers for Disease Control and Prevention (CDC) for ages 0 to 20 years (for ages 2 to <12 years) 
and World Health Organization (WHO) growth charts for ages 0 to <2 years (for ages 1 to <2 
years). These charts included a set of smoothed percentiles along with CDC LMS (Lambda-Mu-
Sigma) parameters to allow the calculation of other percentiles or z-scores (Flegal, 2013). To 
obtain the z-score for body weight or BMI, the following equation will be used Z = [(X/M)L-
1]/(L×S) for L≠0; Z = ln(X/M)/S for L = 0, where X is the measured body weight or BMI at each 
visit and L, M, and S values are from CDC table. The corresponding percentile can be obtained 
from standard normal distribution. The following CDC growth charts will be used. The growth 
chart is provided in half month intervals for age. 
• Weight-for-age chart (weight in kilograms) for birth to 36 months population by sex and 
age 
• Weight-for-age chart for 2 to 20 years population in kilograms by sex and age 
• Weight-for-stature chart (weight in kilograms) by sex and stature (stature in centimeters) 
• BMI for age charts for 2 to 20 years population by sex and age 
For example, to obtain the weight for age z-score of a 24-month-old male who weighs 14.5 kg, the 
corresponding L, M, and S values in weight-for-age charts for 2 to 20 years population are -
0.20615245, 12.6707633, 0.108125811, respectively. By applying the above LMS method 
equation z-score is 1.23 and the corresponding percentile is 89%. 
EREFS (excluding stricture), Inflammation, and Remodeling Sub-scores 
The EREFS (excluding stricture), inflammation sub-score, and remodeling sub-score for each 
region is the sum of assigned scores for each of the included major features as listed below. The 
sub-scores summed for the proximal and distal regions will be used for analysis. 
Sub-score 
Major features included 
Range 
(per region) 
Range 
(proximal + distal) 
EREFS (excluding 
stricture) total score 
Edema + Rings + Exudates + 
Furrows 
0 - 8 
0 - 16 
Inflammation sub-score 
Edema + Exudates + Furrows 
0 - 5 
0 -10 
Remodeling sub-score 
Rings + Stricture 
0 - 4 
0 - 8 
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4.5. 
Safety Variables 
4.5.1. 
Adverse Events and Serious Adverse Events 
Adverse events and serious adverse events will be collected from the time of informed consent 
signature and then at each visit until the end of the study. All adverse events are to be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). 
The definition of adverse events and serious adverse events are provided in protocol Section 10.2.1 
and Section 10.2.2. Pre-treatment AE and treatment-emergent AE (TEAE) are defined as follows: 
• Pre-treatment signs and symptoms (pre-treatment AEs) are AEs that developed or 
worsened in severity during the pre-treatment period. 
• TEAEs are defined as those that are not present at baseline or represent the exacerbation 
of a pre-existing condition during the treatment-emergent period. 
‒ TEAEs for part A treatment period are defined as TEAEs with onset date during 
the Part A treatment period.  
‒ TEAEs for part B extended active treatment period are defined as TEAEs with onset 
during the Part B extended treatment period.  
‒ TEAEs for follow-up period are defined as TEAEs with onset during the follow-up 
period. 
4.5.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) 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 
• Arthralgia 
For detailed definition of these AESIs, please see Section 11.4. 
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4.5.3. 
Laboratory Safety Variables 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory. Samples will be collected predose at time points according to visit schedule 
(Section 11.2). Tests will include: 
Blood Chemistry 
Sodium 
Creatinine 
 
Potassium 
Blood urea nitrogen (BUN) 
 
Chloride 
Aspartate aminotransferase (AST) 
 
Carbon dioxide 
Alanine aminotransferase (ALT) 
 
Calcium 
Alkaline phosphatase 
 
Glucose 
Lactate dehydrogenase (LDH) 
 
Albumin 
Estimated glomerular filtration rate (eGFR) 
 
Total protein, serum 
Total and indirect bilirubin 
 
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 WOCBP. Serum or urine pregnancy testing 
will be performed at time points listed in visit schedule (Section 11.2). 
• Tuberculosis testing will be performed on a country-by-country basis according to local 
guidelines if required by regulatory authorities or ethics boards. 
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4.5.4. 
Vital Signs 
Vital signs, including heart rate, blood pressure, respiration rate, and body temperature will be 
collected predose and 30 minutes post-dose at time points listed in the schedule of events in 
Section 11.2. 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. Body weight in kg and height in cm 
(or length for patients <2 years of age) will be measured at the time points listed in the schedule 
of events table in Section 11.2. Body mass index will be programmatically calculated based on the 
weight and height data. 
4.5.5. 
Physical Examination Variables 
The physical examination variable values are dichotomized as normal and abnormal. 
A thorough and complete physical examination will be performed at the screening visit 1, baseline 
visit 3, week 16, week 52, ET visit before follow-up or unscheduled visit before rescue treatment. 
4.6. 
Pharmacokinetic Variables  
The PK variable is the concentration of functional dupilumab in serum and time for individual 
patients. Serum samples for measuring functional dupilumab concentrations will be collected at 
time points according to Section 11.2. 
4.7. 
Immunogenicity Variables 
The immunogenicity variables include ADA status, NAb status, and titer at nominal sampling 
time/visit. Serum samples for ADA will be collected at the clinic visits specified in Section 11.2. 
Samples positive in the dupilumab ADA assay will be further characterized for ADA titers and for 
the presence of NAb against dupilumab. 
4.8. 
Biomarker Variables 
Biomarkers to be analyzed in this study are:  
• Serum total IgE 
• Eotaxin-3 
Serum/plasma samples for measurements of biomarkers to study the pharmacodynamic activity of 
dupilumab in EoE patients will be collected at time points according to Section 11.2. 
4.9. 
Clinical Outcome Assessments for Psychometric Validity Assessment 
The measurement properties of the PESQ-C and PESQ-P (as described in Section 4.4.2) will be 
evaluated using anchor-based methods and qualitative insights from the week 16 exit interviews. 
The details of the analyses are specified in the R668-EE-1877 psychometric analysis plan. 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, Q1, Q3, standard deviation, minimum, and 
maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
Missing values at baseline will not be imputed unless otherwise specified. 
All data will be summarized by the following treatment groups in each study period: 
• Part A 
− Higher exposure dupilumab dose regimen 
− Lower exposure dupilumab dose regimen 
− Combined dupilumab group (for safety analysis only) 
− Placebo 
• Part B 
− Higher exposure dupilumab dose regimen/Higher exposure dupilumab dose 
regimen 
− Lower exposure dupilumab dose regimen/Lower exposure dupilumab dose regimen 
− Combined dupilumab group (for safety analysis only) 
− Placebo/Higher exposure dupilumab dose regimen 
− Placebo/Lower exposure dupilumab dose regimen 
− Placebo/Combined dupilumab group (for safety analysis only) 
− Total (for safety analysis only) 
5.1. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment groups and for study 
total based on the FAS. A separate summary will be provided for Part B SAF patients. 
5.2. 
Medical History 
Medical history will be summarized by primary System Organ Class (SOC) and Preferred Term 
(PT) for each treatment group and for study total based on the FAS. The table will be sorted by 
decreasing frequency of SOC followed by PT based on the overall incidence across treatment 
groups. 
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5.3. 
Prior/Concomitant Medications/Procedures  
Number and proportion of patients taking prior/concomitant medications, prohibited 
medications/procedures, and rescue medications/procedures will be summarized for each 
treatment group and study total, based on study period specific FAS, by ATC Level 2 and ATC 
Level 4, sorted by decreasing frequency of ATC Level 2 and ATC Level 4 in the combined 
dupilumab treatment group. Patients will be counted once in each medication class linked to the 
medication. 
Number and proportion of patients taking PPIs for the treatment of EoE will be summarized by 
PPI therapy name. In addition, number and proportion of patients taking swallowed 
topical/systemic corticosteroids for the treatment of EoE will be summarized for swallowed topical 
corticosteroids and systemic corticosteroids by ATC Level 2 and ATC Level 4, respectively. 
Number and proportion of patients undergoing prior/concomitant procedures will be summarized 
for each treatment group and study total, based on the study period specific FAS, by SOC and PT, 
and sorted by decreasing frequency of SOC and PT in the combined dupilumab treatment group. 
Separate summaries will be provided for Part A and Part B concomitant medications/procedures. 
5.4. 
Subject Disposition 
The following summaries will be provided for each treatment group and study total (unless 
otherwise specified): 
• The total number of screened patients (for study total only) 
• The total number of randomized patients: received a randomization number from IWRS 
• The total number of patients in each analysis set 
• The total number of patients who discontinued the study treatment in Part A, and the 
reasons for discontinuation (including COVID-19 related reasons) 
• The total number of patients who discontinued the study in Part A, and the reasons for 
discontinuation (including COVID-19 related reasons) 
• Number of patients who entered into Part B 
• The total number of patients who discontinued the study treatment in Part B, and the 
reasons for discontinuation (including COVID-19 related reasons) 
• The total number of patients who discontinued the study in Part B, and the reasons for 
discontinuation (including COVID-19 related reasons) 
• Number of patients who entered 12-week follow-up period from Part A and Part B, 
respectively 
Summary table of important protocol deviations in each study treatment period will be provided. 
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5.5. 
Extent of Study Treatment Exposure  
5.5.1. 
Exposure to Investigational Product 
The duration of exposure to study drug is calculated separately for Part A, Part B, and the overall 
study as follows: 
(Date of last study drug injection in the respective study period – date of first study drug 
injection in the respective study part) + 14 
NOTE: exposure will be calculated based on the last study drug injection date and first study drug 
injection date regardless of temporary dosing interruption or dosing extension due to COVID-19. 
For patients with extended dosing due to COVID-19, the duration of exposure may exceed 16 
weeks for Part A or 36 weeks for Part B as study design. 
Summary of exposure to study drug will include the number of study drug doses administered and 
the duration of exposure. Duration of exposure will be summarized for each treatment group using 
the number of patients, mean, standard deviation, median, Q1, Q3, minimum, and maximum. 
These summaries will be provided for Part A and Part B separately. 
In addition, the duration of exposure will be summarized categorically by counts (n) and 
percentages (%) for each of the following categories and cumulatively by these categories as well: 
• Part A: ≥ 7 days, ≥ 14 days, ≥ 21 days, ≥ 28 days, ≥ 35 days, ≥ 42 days, ≥ 49 days, ≥ 
56 days, ≥ 63 days, ≥ 70 days, ≥ 77 days, ≥ 84 days, ≥ 91 days, ≥ 98 days, ≥ 105 days, 
≥112 days, with an increment of 1 week for each subsequent category. 
• Part B: ≥ 7 days, ≥ 14 days, ≥ 21 days , ≥ 28 days, ≥ 35 days, ≥ 42 days, ≥ 49 days, ≥ 
56 days, ≥ 63 days, ≥ 70 days, ≥ 77 days, ≥ 84 days, ≥ 91 days, ≥ 98 days, ≥ 105 days, 
≥112 days, ≥119 days, ≥126 days, ≥133 days , ≥140 days, ≥147 days, ≥154 days, ≥161 
days, ≥168 days, ≥175 days, ≥182 days, ≥189 days, ≥196 days, ≥203 days, ≥210 days, 
≥217 days, ≥224 days, ≥231 days, ≥238 days, ≥245 days, ≥252 days, with an increment 
of 1 week for each subsequent category. 
For patients who received at least 1 dose of study drug, the total duration of exposure to study drug 
during the study (throughout Part A and Part B) is calculated as: 
(Date of last study drug injection in the study – date of first study drug injection) + 14 
The duration of observation period during the study is calculated as: 
(Date of last study visit – date of first study injection) + 1 
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The duration of observation period will be summarized descriptively using number of patients, 
mean, standard deviation, median, Q1, Q3, minimum, and maximum. In addition, the number (n) 
and proportion (%) of patients with observation periods will be presented by specific time periods. 
The time periods of interest are specified as follows:  
• Part A: ≥ 8 days, ≥ 15 days, ≥ 22 days, ≥ 29 days, ≥ 36 days, ≥ 43 days, ≥ 50 days, ≥ 
57 days, ≥ 64 days, ≥ 71 days, ≥ 78 days, ≥ 85 days, ≥ 92 days, ≥ 99 days, ≥ 106 days, 
≥113 days, with an increment of 1 week for each subsequent category. 
• Part B: ≥ 8 days, ≥ 15 days, ≥ 22 days, ≥ 29 days, ≥ 36 days, ≥ 43 days, ≥ 50 days,  ≥ 
57 days, ≥ 64 days, ≥ 71 days, ≥ 78 days, ≥ 85 days, ≥ 92 days, ≥ 99 days, ≥ 106 days, 
≥113 days, ≥120 days, ≥127 days, ≥134 days , ≥141 days, ≥148 days, ≥155 days, ≥162 
days, ≥169 days, ≥176 days, ≥183 days, ≥190 days, ≥197 days, ≥204 days, ≥211 days, 
≥218 days, ≥225 days, ≥232 days, ≥239 days, ≥246 days, ≥253 days, with an increment 
of 1 week for each subsequent category. 
5.6. 
Analyses of Efficacy Variables 
The analyses of efficacy variables are described in the subsections below and summarized in 
Section 11.1. The intercurrent events, strategies, and the corresponding missing data handling 
approaches for the primary estimand of interest for the primary endpoint are provided in Table 1 . 
 
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Table 1: 
Summary of Primary Estimand for Primary Endpoint and Secondary Endpoints in Part A 
Endpoint 
Category 
Estimands 
Endpoint(s) 
Population 
Intercurrent event(s) strategy and 
missing data handling 
Population-level summary/Analysis 
 
Primary 
Endpoint 
Proportion of patients 
achieving peak esophageal 
intraepithelial eosinophil 
count of ≤6 eos/hpf (400×) at 
week 16 
FAS 
The intercurrent events will be handled 
as follows: 
• 
Treatment discontinuation: data 
collected after the patient 
discontinued treatment will be 
included in the analysis (treatment 
policy strategy) 
• 
Initiation of treatment with systemic 
and/or swallowed topical 
corticosteroids drugs and dilation: 
patients will be considered as non-
responders after such event 
(composite variable strategy) 
Note: the composite strategy will be 
considered if a patient receives rescue 
medication any time during the study. 
 
Missing data handling: patients with a 
missing value for the primary endpoint at 
week 16 due to study discontinuation or 
other reasons will be considered non-
responders. Missing data due to COVID-
19 will be imputed by multiple 
imputation (MI). 
Cochran-Mantel-Haenszel (CMH) test 
adjusting for the randomization 
stratification factor (baseline weight 
group) will be utilized.  
The estimated proportion of the 
treatment difference between 
dupilumab groups and placebo, and its 
2-sided 95% confidence intervals will 
be provided based on the CMH test. 
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Endpoint 
Category 
Estimands 
Endpoint(s) 
Population 
Intercurrent event(s) strategy and 
missing data handling 
Population-level summary/Analysis 
 
Secondary 
Endpoints 
Binary endpoints (e.g., 
proportion of patients 
achieving peak esophageal 
intraepithelial eosinophil 
count of <15 eos/hpf at week 
16) 
FAS 
The intercurrent events strategy and 
missing data handling methods will be 
the same with the primary endpoint. 
The primary analysis method will be 
the same as for the primary endpoint. 
Continuous endpoints that 
are scheduled to be measured 
repeatedly post-baseline up 
to week 16 (e.g., change in 
the proportion of days with 1 
or more EoE signs from 
baseline to week 16 as 
measured by the PESQ-C) 
FAS 
The intercurrent events will be handled 
as follows: 
• 
Treatment discontinuation: data 
collected after the patient 
discontinued treatment will be 
included in the analysis (treatment 
policy strategy) 
• 
Initiation of treatment with systemic 
and/or swallowed topical 
corticosteroids drugs and dilation: 
data after such events will be 
assigned by the worst observed 
value (composite variable strategy) 
 
Missing data handling: patients with a 
missing value at week 16 due to AE/lack 
of efficacy will be imputed using WOCF 
method, and MI approach will be used 
for the missing data due to other reasons. 
Continuous secondary efficacy 
endpoints at week 16 will be analyzed 
using an analysis of covariance 
(ANCOVA) model with treatment 
groups, randomization stratification 
factor, and relevant baseline 
measurement as a covariate included in 
the model. 
The least square (LS) means and 
difference in LS means between 
dupilumab groups and placebo will be 
presented. 
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Endpoint 
Category 
Estimands 
Endpoint(s) 
Population 
Intercurrent event(s) strategy and 
missing data handling 
Population-level summary/Analysis 
 
Continuous endpoints that 
are scheduled to be measured 
only once post-baseline up to 
week 16 (e.g., absolute 
change in EoE-EREFS from 
baseline to week 16) 
FAS 
The intercurrent events will be handled 
as follows: 
• 
Treatment discontinuation: data 
collected after the patient 
discontinued treatment will be 
included in the analysis (treatment 
policy strategy) 
• 
Initiation of treatment with systemic 
and/or swallowed topical 
corticosteroids drugs and dilation: 
data after such events will be 
assigned by the worst observed 
value (composite variable strategy) 
 
Missing data handling: patients with a 
missing value due to COVID-19 will be 
imputed using MI approach, and WOCF 
method will be used for missing not due 
to COVID-19. WOCF method refers to 
missing values at week 16 will be 
imputed with patient’s baseline value or 
the available post-baseline value, 
whichever is worse. 
 
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5.6.1. 
Analysis of Primary Efficacy Variable 
The primary analysis of proportion of patients achieving a histologic response of peak esophageal 
intraepithelial eosinophil count ≤6 eos/hpf at week 16 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 factor (baseline weight group [≥5 - <15 kg, ≥15- <30 kg, ≥30- 
<60 kg]). The randomization stratification of baseline weight group may be pooled to ensure the 
sufficient sample size of each stratum. Estimates of treatment difference and its 95% confidence 
interval will be presented along with the p-values. 
Data may be collected after the patient discontinued treatment and will be included in the analyses. 
To account for the use of rescue treatment, patients will be considered as non-responder for all 
time points subsequent to the use of rescue treatment in the primary analysis. 
If week 16 biopsy is performed after the date when the first dose of Part B study drug is 
administered, patients will be considered as non-responder in the analysis. 
Due to COVID-19 restrictions, patients may postpone the week 16 visit until an in-clinic visit can 
be done for biopsy. Before the biopsy procedure could be performed, study drug would be shipped 
to patients directly to enable them to extend their current assigned dose regimen of study drug. The 
data from those delayed week 16 visits will be used in the primary analysis as long as the patients 
keep the extended dosing before biopsy. 
Missing data at week 16 will be handled according to the reasons for missingness as follows: 
• If the peak esophageal intraepithelial eosinophil count at week 16 is missing due to 
COVID-19 pandemic, the data will be imputed by multiple imputation (MI) using a 
seed number of 6681877 for 10 times based on patients who have non-missing 
eosinophil counts at week 16. The MI will utilize the regression method with treatment 
group, randomization stratification factor, baseline eosinophil count as covariates and 
week 16 eosinophil count as response variable in the regression model. The imputed 
week 16 eosinophil counts will determine whether that patient will be classified as a 
responder or non-responder.  
• If a patient has missing value for the histological response (peak esophageal 
intraepithelial eosinophil count) at week 16 due to reasons not related to the COVID-
19 pandemic (e.g., discontinuation from study), the patient will be classified as a non-
responder at week 16. 
Each of the imputed complete datasets will be analyzed by the CMH test. Statistical inference 
obtained from all imputed data will be combined using Rubin’s formula (Ratitch, 2013). 
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Sensitivity analyses 
Sensitivity analyses will assess alternative methods to impute missing data and include the 
following for the primary endpoint. 
1. Tipping point analysis approach: To assess the robustness of analysis results under 
MNAR (missing not at random) assumption, a delta-adjusting pattern-mixture approach 
for tipping point analysis (Ratitch, 2013) will be conducted for the primary endpoint. The 
impact from missing data due to study discontinuation or other reasons on the comparisons 
in proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 
eos/hpf at week 16 between each dupilumab group and placebo control group will be 
examined, by adjusting for stratification factor: 
• A series of analyses will be performed by applying a specified sequence of 
different values of shift parameter to the 3 treatment groups for the data 
imputation: in the placebo group, different values (>0) of shift parameter will 
be subtracted from the imputed peak eosinophil count; in each of dupilumab 
group, different values (<0) of shift parameter will be added to the imputed peak 
eosinophil count. The imputed peak eosinophil count which is negative will be 
replaced by 0. Patients who achieve peak eosinophil count of ≤6 eos/hpf will 
be derived based on the imputed peak eosinophil count after shifting. 
• For each combination of different values of shift parameter applied to the 3 
treatment groups, 10 multiple imputed datasets will be generated using a seed 
number of 6681877. Proportion of patients achieving peak esophageal 
intraepithelial eosinophil count of ≤6 eos/hpf will be analyzed using CMH test. 
The results obtained from 10 multiple imputed datasets will be combined using 
Rubin’s formula (Ratitch, 2013) for statistical inference, i.e., p-value and 
treatment difference between active treatment groups and placebo group. 
• A “tipping point” will be identified when the result is no longer statistically 
significant (i.e., p-value >0.05). 
2. Worst observation carried forward - multiple imputation (WOCF-MI) approach: 
Data after rescue treatment or the missing peak esophageal intraepithelial eosinophil count 
at week 16 due to AE/lack of efficacy will be imputed with patient’s baseline value or the 
available post-baseline value up to week 16, whichever is worse, i.e., WOCF. The missing 
data due to other reasons will be imputed by MI using a seed number of 6681877 for 10 
times based on patients who have non-missing eosinophil counts at week 16. The imputed 
week 16 eosinophil counts will determine whether that patient will be classified as a 
responder or non-responder. The 10 complete datasets after the imputations will be 
analyzed using CMH test. The results from the 10 analyses will be combined using the 
SAS MIANALYZE procedure (Ratitch, 2013). 
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5.6.2. 
Analysis of Secondary Efficacy Variables 
Binary endpoints at week 16 
Secondary efficacy endpoints that measure binary responses at week 16 will be analyzed in the 
same fashion as the primary endpoint, including the method to handle missing data. 
Continuous endpoints at week 16 
Continuous secondary efficacy endpoints at week 16 will be analyzed using an analysis of 
covariance (ANCOVA) model for the FAS with treatment groups, randomization stratification 
factor, and relevant baseline measurement as a covariate included in the model. For 
endoscopy/biopsy-based endpoints (i.e., esophageal intraepithelial eos count, EoE-EREFS, EoE-
HSS), if week 16 endoscopy/biopsy is performed after the date when the first dose of Part B study 
drug is administered, data from that endoscopy/biopsy will be set to missing in the analysis. 
To account for the use of rescue treatment, data will be set to missing for all time points subsequent 
to the use of rescue treatment. 
For continuous efficacy data that are scheduled to be measured repeatedly post-baseline up to week 
16 (e.g., change in the proportion of days with 1 or more EoE signs from baseline to week 16 as 
measured by the PESQ-C), missing data will be imputed by the pattern-mixture approach. 
Specifically, the WOCF-MI approach, where the WOCF approach will be used for imputing the 
missing data due to rescue treatment/AE/lack of efficacy, and the MI approach will be used for the 
missing data due to other reasons (e.g., missing PESQ-C data due to less than 8 diary entries for 
the 14-day period). MI will follow the steps below using a seed number of 6681877 in both steps: 
• Step 1: Use the Markov Chain Monte Carlo (MCMC) method to fill in the intermittent 
missing values so that a monotone missing pattern will be formed. 
• Step 2: For each of the imputed datasets with monotone missing pattern in Step 1, the 
remaining missing data will be imputed using regression method with treatment group, 
randomization stratification factor, relevant baseline measurement as a covariate, and 
the post-baseline measurements up to week 16 as response variable. 
• Step 3: Each of the 40 imputed datasets will be combined with the dataset imputed by 
WOCF approach, and then analyzed using the ANCOVA.  
• Step 4: The results from the 40 analyses on the complete datasets will be combined to 
generate a valid overall statistical inference using Rubin’s formula (Ratitch, 2013). The 
least square (LS) means and difference in LS means between dupilumab groups and 
placebo will be presented. 
The cumulative distribution function (CDF) of the absolute change from baseline in the proportion 
of days (or total segments within a day) with 1 or more EoE signs as measured by the PESQ-C at 
week 16 and from baseline in the proportion of days (or total segments within a day) with 1 or 
more EoE symptoms as measured by the PESQ-P at week 16 will be graphed to present the 
between-treatment-group differences at each level of the change. 
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For continuous efficacy data that are scheduled to be measured only once post-baseline up to week 
16 (e.g., absolute change in EoE-EREFS from baseline to week 16), a hybrid approach WOCF-MI 
will be used to handle missing data. That is, missing values at week 16 due to reasons not related 
to COVID-19 pandemic will be imputed with patient’s baseline value or the available post-baseline 
value, whichever is worse, i.e., a WOCF approach, and missing values at week 16 due to COVID-
19 pandemic will be imputed using MI as described in the primary analysis of the primary endpoint 
of histologic response in Section 5.6.1. The 10 complete datasets after the imputations will be 
analyzed using ANCOVA. The results from the 10 analyses will be combined using the SAS 
MIANALYZE procedure. 
The primary analysis of EoE-EREFS will be based on centralized readings.  
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 16 between the dupilumab and placebo 
groups is statistically significant. Missing NES data will be imputed by Last Observation Carried 
Forward (LOCF) approach. P-values will be reported. 
Secondary endpoints in Part B 
Secondary endpoints at week 52 (Part B) will be analyzed descriptively at given visits for treatment 
received in Part B as well as by treatment group as in Part A (double-blind treatment period). No 
missing values will be imputed.  
All observed values, regardless of whether rescue treatment is used, or data are collected after 
withdrawal from study treatment, will be used for analysis. No missing values will be imputed. 
For categorical efficacy variables, the proportion of patients meeting response criteria at each visit 
will be calculated using the number of patients with non-missing value at the visit as the 
denominator. 
For efficacy variables whose calculations involve baseline values, e.g., absolute (or percent) 
change from baseline, separate summaries will be provided for analyses using the study baseline 
and Part B baseline values. The study baseline is the latest available valid measurement taken prior 
to or on the date of the first dose of study drug administration (scheduled to be administered at the 
baseline visit 3). Part B baseline is the last available valid measurement taken prior to or on the 
date of the first dose of extended active treatment period (scheduled to be administered at week 16 
visit).  
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5.6.3. 
Adjustment for Multiple Comparison 
The following multiplicity adjustment approach, a hierarchical procedure, will be used to control 
the overall Type-1 error rate at 0.05 for the primary endpoint and the secondary endpoints across 
the 2 dupilumab dose regimens versus placebo in Part A only. Each hypothesis will be formally 
tested only if the preceding one is significant at the 2-sided 0.05 significance level. The hierarchical 
testing order is shown in the below table (all comparisons are with the placebo). 
 
Endpoints 
Dupilumab 
Higher 
Exposure 
Dupilumab 
Lower 
Exposure 
Dupilumab 
Primary 
endpoint 
Proportion of patients achieving peak esophageal 
intraepithelial eosinophil count of ≤6 eos/hpf at week 16 
1 
10 
Secondary 
endpoints 
Proportion of patients achieving peak esophageal 
intraepithelial eosinophil count of <15 eos/hpf at week 16 
2 
11 
Percent change in peak esophageal intraepithelial 
eosinophil count (eos/hpf) from baseline to week 16 
3 
12 
Absolute change in mean EoEHSS grade score from the 
EoE-HSS from baseline to week 16 
4 
13 
Absolute change in mean EoEHSS stage score from the 
EoE-HSS from baseline to week 16 
5 
14 
NES for the relative change from baseline to week 16 in 
the type 2 inflammation transcriptome signature 
6 
15 
 
NES for the relative change from baseline to week 16 in 
the EoE diagnostic panel (EDP) transcriptome signature 
7 
16 
Absolute change in EoE EREFS from baseline to week 16 
8 
17 
Change from baseline to week 16 in the proportion of days 
with 1 or more EoE signs as measured by the PESQ-C (for 
patients aged ≥1 to <12 years) 
9 
18 
5.6.4. 
Subgroup Analysis 
Subgroups described in Section 3.5 will be summarized for the primary efficacy endpoint (as listed 
in Section 4.4.1) and the below selected secondary endpoints. Treatment difference and its 95% 
confidence interval in subgroups of patients will be presented in forest plots. The stratification 
factor (baseline weight group) will not be included in the subgroup analysis when applying the 
CMH test and ANCOVA. 
• Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from 
baseline to week 16 
• Absolute change in mean EoEHSS grade score from the EoE-HSS from baseline to 
week 16 
• Absolute change in mean EoEHSS stage score from the EoE-HSS from baseline to 
week 16 
• Absolute change in EoE EREFS from baseline to week 16 
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5.6.5. 
Analysis of Exploratory Efficacy Variables 
The exploratory efficacy endpoints at week 16 or week 52 will be analyzed descriptively. 
All observed values, regardless of whether rescue treatment is used, or data are collected after 
withdrawal from study treatment, will be used for analysis. No missing values will be imputed. 
The CDF of the proportion of patients achieving peak esophageal intraepithelial eosinophil count 
of ≤6 eos/hpf at week 16 and achieving absolute/percent change from baseline to week 16 in the 
proportion of days with 1 or more EoE signs as measured by PESQ-C will be graphed to present 
the between-treatment-group differences at each level of the change. 
5.7. 
Analysis of Safety Data 
The analysis of safety and tolerance will be performed on the SAF, as defined in Section 3.2. 
The safety analysis will be based on the reported AEs and other safety information (clinical 
laboratory evaluations and vital signs).  
Thresholds for Potential Clinically Significant Values (PCSV) in laboratory variables and vital 
signs are defined in Section 11.3. Treatment-emergent PCSV is any PCSV developed or worsened 
in severity compared to the baseline during the treatment and follow-up period. When identifying 
treatment-emergent PCSVs in Part B, baseline for Part B PCSVs is the last available valid 
measurement taken prior to the first dose of extended active treatment in Part B (scheduled to be 
administered at week 16 visit). 
The time interval to detect any event or abnormality is between the first injection of study 
medication and EOS. 
The summary of safety results will be presented for each treatment group for each study period. 
For safety variables/summaries involving baseline values, e.g., absolute change from baseline or 
shift table, study period specific baseline will be utilized. Summaries for Part A will use the study 
baseline (i.e., the latest available valid measurement prior to the first dose of study drug in the 
study). Summaries for Part B and follow-up period will use Part B baseline (i.e., the last available 
valid measurement prior to the first dose of extended active treatment in Part B). 
5.7.1. 
Adverse Events  
The number and proportion of patients reporting TEAEs will be summarized for Part A 16-week 
double-blind treatment period, Part B 36-week extended active treatment period, and 12-week 
follow-up period, as described in Section 3.2. 
AE incidence tables will be presented by treatment group for the SAF as well as subgroups defined 
for safety analysis (Section 3.5). TEAE summaries will present the number (n) and percentage (%) 
of patients experiencing an TEAE by SOC and PT, sorted by decreasing frequency of SOC and 
PT for the combined dupilumab treatment group. Multiple occurrences of AEs of the same PT (or 
SOC) in the same patient will be counted only once for that PT (or SOC). For tables presenting 
severity of events, the worst severity will be chosen for patients with multiple instances of the 
same event. The denominator for computation of percentage is the number of patients in each 
treatment group for the corresponding analysis period as specified in Section 3.2. 
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An overall summary of TEAEs will be provided with number (n) and percentages (%) of patients 
with any: 
• TEAE 
• Serious TEAE 
• TEAE of special interest (AESI) 
• TEAE with fatal outcome 
• TEAE leading to permanent treatment discontinuation 
Detailed summaries of all TEAEs in each treatment group will include: 
• TEAEs 
− TEAEs by primary SOC/PT 
− TEAEs by primary SOC/PT with incidence of PT ≥5% in any treatment group 
− TEAEs by severity and by primary SOC/PT 
− TEAEs related to study medication as assessed by the investigator by primary 
SOC/PT 
− TEAEs of special interest by AESI category (see Section 11.4) and primary 
SOC/PT 
• Serious TEAEs by SOC/PT 
• TEAEs leading to permanent discontinuation of study treatment by primary SOC/PT 
• TEAEs with fatal outcome by primary SOC/PT 
The number and proportion of patients with injection site reaction by PT will be summarized. 
5.7.2. 
Clinical Laboratory Measurements  
Laboratory measurements include clinical chemistry, hematology, and urinalysis results, and will 
be converted to values in standard international (SI) units. Summaries of laboratory variables will 
include: 
• Descriptive statistics of laboratory result and change from baseline by visit 
• The number (n) and percentage (%) of patients with treatment-emergent PCSVs. This 
summary will be provided on the subgroup of SAF patients who did not meet the PCSV 
criterion at the baseline 
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
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5.7.3. 
Analysis of Vital Signs 
Summaries of vital sign variables will include: 
• Descriptive statistics of vital sign variable and change from baseline by visit 
• The number (n) and percentage (%) of subjects with treatment-emergent PCSV. This 
summary will be provided on the subgroup of SAF patients who did not meet the PCSV 
criterion at the baseline 
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
5.7.4. 
Physical Exams 
Abnormal status will be tabulated for assessments of each physical exam category and presented 
by visit. 
5.8. 
Analysis of Pharmacokinetic Data 
The following analyses will be conducted: 
• Descriptive statistics of functional dupilumab concentrations in serum at each sampling 
time by dose 
• Graphical presentations of median and mean (+/- SD) functional dupilumab 
concentration in serum vs nominal time profiles. Plots of concentration vs time will be 
provided as both non-log and semi-log. When plotted as non-log, concentrations less 
than LLOQ will be set to zero (0). When plotted as semi-log, for concentrations less 
than LLOQ, LLOQ/2 will be imputed. 
• Graphical presentations of individual functional dupilumab concentration in serum vs 
actual sampling time profiles. When plotted as non-log, concentrations less than LLOQ 
will be set to zero (0). When plotted as semi-log, for concentrations less than LLOQ, 
LLOQ/2 will be imputed. 
• Assessment of the impact of anti-drug antibodies on functional dupilumab 
concentrations in serum 
No formal statistical analysis will be performed. 
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5.9. 
Analysis of Immunogenicity Data 
5.9.1. 
Analysis of ADA  
The immunogenicity variables mentioned in Section 4.7 will be summarized using descriptive 
statistics. Immunogenicity will be characterized by ADA status, ADA category, and maximum 
titer observed in patients in the ADA analysis set.  
The ADA status of each patient may be classified as one of the following:  
• Positive 
• Pre-existing - If the baseline sample is positive and all post baseline ADA titers are 
reported as less than 4-fold the baseline titer value 
• Negative - If all samples are found to be negative in the ADA assay 
The ADA category of each positive patient is classified as: 
• Treatment-boosted - A positive result at baseline in the ADA assay with at least one 
post baseline titer result ≥ 4-fold the baseline titer value  
• Treatment-emergent - A negative result or missing result at baseline with at least one 
positive post baseline result in the ADA assay. Patients that are treatment-emergent 
will be further categorized as follows: 
− Persistent - A positive result in the ADA assay detected in at least 2 consecutive 
post baseline samples separated by at least a 12-week post baseline period (based 
on nominal sampling time), with no ADA-negative results in-between, regardless 
of any missing samples 
− Indeterminate - A positive result in the ADA assay at the last collection time point 
only, regardless of any missing samples 
− Transient - Not persistent or indeterminate, regardless of any missing samples 
The maximum titer category of each patient is classified as: 
• Low (titer <1,000) 
• Moderate (1,000 ≤ titer ≤ 10,000) 
• High (titer >10,000) 
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The following listings will be provided by treatment group and ADA titer level: 
• Number (n) and percent (%) of ADA-negative patients 
• Number (n) and percent (%) of patients with pre-existing immunoreactivity  
• Number (n) and percent (%) of treatment-emergent ADA positive patients  
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of transient treatment-emergent ADA positive patients 
• Number (n) and percent (%) of treatment-boosted ADA positive patients  
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent, 
and treatment-boosted ADA response. 
5.9.2. 
Analysis of Neutralizing Antibody (NAb) Data 
Samples positive in the dupilumab ADA assay will be further characterized for the presence of 
NAb to dupilumab. The absolute occurrence (n) and percent of patients (%) with NAb status will 
be provided for patients in the NAb analysis set by treatment groups. 
• Negative: Samples tested negative in the ADA assay, or samples positive in the ADA 
assay but tested negative in the NAb assay. 
• Positive: Samples tested positive in the NAb assay.  
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy 
The analyses in this section will only be performed if the incidence of treatment emergent ADA 
positive is sufficient to make meaningful conclusions (i.e., more than 5% in any treatment group). 
5.10.1. 
Association of immunogenicity with exposure 
Potential association between immunogenicity and systemic exposure to dupilumab will be 
explored by treatment groups. Plots of dupilumab concentration may be provided for analyzing 
the potential impact of ADA category, maximum titer category, and NAb status on individual 
patient drug concentration profile. 
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5.10.2. 
Immunogenicity and Safety/Efficacy 
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period:  
• TEAE 
• Serious TEAE 
• TEAE leading to permanent treatment discontinuation 
• Injection site reaction (HLT= “Injection site reaction”) 
• Hypersensitivity (AESI category “Hypersensitivity”) 
• Anaphylaxis (SMQ: Anaphylactic Reaction [Narrow]) 
Potential association between immunogenicity variables and efficacy endpoint profiles may be 
explored (e.g., scatter plot or spaghetti plot).  
The safety and efficacy analyses mentioned above will be conducted using the following ADA 
response categories: 
• ADA Positive 
− Treatment-emergent 
− Treatment-boosted 
• Maximum post-baseline titer category 
• NAb positive  
5.11. 
Analysis of Biomarker Data 
Descriptive statistics for the observed values, change from baseline, and percent change from 
baseline values by treatment and visit will be provided for the biomarker variables as described in 
Section 4.8. Biomarker values after the first rescue treatment used are set to missing (censoring), 
then LOCF approach will be used to impute the missing data at each visit for Part A analysis, and 
all observed values will be used for Part B analysis. 
The Wilcoxon signed-rank test will be used to test if the change or percentage change from baseline 
value is significantly different from zero. Nominal p-value will be reported. 
Correlation of baseline Eotaxin-3 and total IgE (measured value) with the histologic responder 
(histologic response of peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 16) 
will be explored using the logistic model. The model will include the histologic responder/non-
responder as the dependent variable, with randomization stratification factor, the log10 
transformed baseline biomarker data, treatment group, and treatment by baseline biomarker 
interaction as the predictor variables. Model coefficients and P-value will be provided to indicate 
significance of the correlation/association. Patients are considered non-responders after the rescue 
treatment is used. In addition, patients with missing peak eosinophil count at week 16 are 
considered as non-responders. 
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5.12. 
Analysis of Psychometric Validity of Clinical Outcome Assessment 
Measures 
Results of psychometric analysis of the PESQ-C and PESQ-P will be summarized in a clinical 
outcome assessment (COA) dossier. Evidence of content validity and measurement properties of 
relevant COAs will be submitted to the Agency. 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the Baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of investigational product. If any 
randomized patients are not treated, the baseline will be the last value on or prior to the 
randomization. Part B baseline is defined as the last available valid measurement taken prior to the 
first dose of extended treatment in Part B.  
The following rules specify the determination by both date/time information: 
1. The date and time of first injection will be used to determine the baseline for the AE, vital 
sign, lab (including biomarker), PK, and ADA data. 
2. Only the date of first injection will be used to determine the baseline for other data except 
AE, vital sign, lab (including biomarker), PK, or ADA. 
For re-screened patients, all data from the same patient will be used to derive baseline regardless 
of whether the data are from the screen failure patient ID or enrolled patient ID. 
6.2. 
General Data Handling Convention 
For the laboratory safety variables and biomarker data, if the data are below the lower limit of 
quantification (LLOQ) / limit of linearity, half of the lower limit value (i.e., LLOQ/2) will be used 
for quantitative analyses. For data above the upper limit of quantification (ULOQ) / limit of 
linearity, the upper limit value (i.e., ULOQ) will be used for quantitative analyses. 
6.3. 
Data Handling Convention for Missing Data 
Missing data will not be imputed in listings. This section includes the methods for missing data 
imputation for some summary analyses, if necessary. 
Adverse event 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAEs. If the assessment of relationship of a TEAE to the study drug is missing, it 
will be classified as “related” in the frequency tables by relation to the study drug. 
Adverse event start date 
AE start date will be used for AE classification and analysis of AESIs. If AE start date is not 
complete, then the character variable will keep the original incomplete date, the numerical date 
variable will be imputed, and an imputation flag will indicate which date component is missing. 
If AE start day is missing, and AE start month and year are not missing: If AE start year is the 
same as first dose year and the AE start month is the same as the first dose month, then impute AE 
start day using the day of first dose. If this leads to a date after the AE end date, use AE end date 
instead. Otherwise impute the AE start day using the first day of the month. If this leads to a date 
before informed consent, the informed consent date will be used. Imputation flag is ‘D’. 
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If AE start month is missing, and AE start year is not missing: If AE start year is less than the first 
dose year, use the informed consent day and month. If AE start year is equal to the first dose year, 
use the first dose day and month. If this leads to a date after the AE end date, use AE end date 
instead. If AE start year is after the first dose year, use 01 January. Imputation flag is ‘M’. 
If AE start year is missing: Impute AE start date using the day of first dose. If this leads to a date 
after the AE end date, use AE end date instead. Imputation flag is ‘Y’. 
Adverse event end date 
The general recommendation is not to impute AE end date. However, since AE end date will be 
used for the imputation of AE start date, in order to carry through the logic for programming, the 
following intermediate step will be used. Afterwards, only the original character/numeric date 
recorded in CRF will be kept in the final analysis dataset. 
If AE end day is missing, and AE end month and year are not missing: Impute AE end date using 
the last day of the month. If this leads to a date after end of study follow up date, use the end of 
study date instead. 
If AE end month is missing, and AE end year is not missing: Impute AE end date using 31 
December as the day and month. If this leads to a date after end of study follow up date, use the 
end of study date instead. 
If AE end year is missing: Impute AE end date using the end of study date. 
Medication start and end date missing 
To determine whether a medication is pre-treatment medication or concomitant medication or 
both, the missing medication start date is estimated as early as possible, and the missing medication 
end date is estimated as late as possible. If the medication start date is missing, the onset day will 
not be calculated in medication listings. 
Prior medication start date 
If start day is missing, and start month and year are not missing: Impute the start day using the first 
day of the month. Imputation flag is ‘D’; 
If start month is missing, and start year is not missing: Impute the day and month using 01January. 
Imputation flag is ‘M’. 
If start year is missing: Impute start date using 2 years before informed consent date. Imputation 
flag is ‘Y’. 
A special note: for start date with year missing, the general principle is not to impute. However, 
in order to simplify the programming flow, the imputation is proposed to align with the protocol 
which specifies to collect up to 2 years prior medication. Since the start date of prior medication 
will not be used in any analysis, the rule will not impact the analysis result. 
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Prior medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date on or after first dose intake date, use first dose intake date -1 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date on or after first dose intake date, use first dose intake date 1 
instead. Imputation flag is ‘M’ 
If end year is missing: Impute end date using the first dose intake date -1. Imputation flag is ‘Y’. 
Concomitant medication start date 
The imputation rule for concomitant medication start date is the same as AE start date. 
Concomitant medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date after end of study follow up date, use the last visit study date 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date after end of study follow up date, use the last study visit date 
instead. Imputation flag is ‘M’. 
If end year is missing: Impute date using the end of last study visit date. Imputation flag is ‘Y’. 
Medication coding 
Medications whose ATC level 4 cannot be coded will be summarized by setting ATC4=ATC2 in 
the table programs. However, these uncoded ATC level 4 records still need to be confirmed with 
study data management and study medical director. 
PCSV 
Patients who had post-baseline PCSV but missing baseline value will be regarded as having 
treatment emergent PCSV. 
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6.4. 
Visit Windows 
Data analyzed by-visit-analysis (efficacy [excluding daily diary data], laboratory data, vital sign, 
ADA) will be summarized by the study scheduled visits described in study protocol and SAP 
Section 11.2, “Schedule of Time and Events”. 
The analysis visit windows will be created per study Schedule of Events table for each parameter 
and will be applied if the data from the study scheduled visits are unavailable. The following 
general rules will be applied to unscheduled visit and/or early termination (ET) visit mapping for 
each parameter: 
1. If ET visit falls in an analysis window which has no missing value of this parameter, ET 
visit will be mapped to the next scheduled visit. 
2. If both ET visit and unscheduled visit of the same parameter are available in the same 
analysis visit window, only ET visit will be mapped.  
3. If multiple unscheduled visits of the same parameter are available in the same analysis visit 
window, the unscheduled visits will be mapped using the following rules: 
a. The closest unscheduled visit from the target day will be selected. 
b. If multiple unscheduled visits occur on the same day, the first unscheduled visit will be 
utilized.  
4. If unscheduled visit is greater than 4 weeks apart from the target day of the scheduled visit, 
the unscheduled visit will not be mapped.  
Unscheduled visit and early termination (ET) visit will be mapped per the analysis visit windows 
for Part A and Part B (Table 2-6) based on the study day and visit of each parameter, respectively. 
The analysis visit windows may be applied to the scheduled assessments for PEIS, GIC and GIS. 
Part A (data collected after the first injection in Part B will not be used for Part A analysis) 
Table 2 
Analysis Visit Window for Efficacy Endpoints in Part A 
Visit from SOE 
Target 
Study Day 
in Part A 
Analysis Visit Window based on Study Daya in Part A 
Histology endpoints, 
Transcriptome 
endpoints, EOE-EREFS, 
PEIS-P, PEIS-C, PEESS 
GIC-P, GIC-C, 
GIC-Clin 
GIS-P, GIS-C 
Baseline 
1 
≤1 
 
≤1 
Week 12 
85 
 
[2, 99] 
[2, 99] 
Week 16 
(Part A end of treatment) 
113 
≥2 b 
≥100 b 
≥100 b 
a. 
Study days are calculated from the day of 1st injection of Part A. Study day = (date of assessment – 1st injection 
date + 1) when date of assessment is on or after the 1st injection date; otherwise, study day = date of assessment – 
1st injection date. If patient never received any dose of study drug, randomization date will be used in place of 1st 
injection date.  
b. If unscheduled visit or ET visit occurs in this window, and it is after the first dose of Part B, it will be considered 
as part of Part B visits. 
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Table 3 
Analysis Visit Window for Safety and Biomarkers in Part A 
Visit from SOE 
Target 
Study Day 
in Part A 
Analysis Visit Window based on Study Daya in Part A 
Vital Signs 
Physical 
Examination 
Laboratory, 
PK, Eotaxin-3 
ADA 
Serum 
total IgE 
Baseline 
1 
≤1 
≤1 
≤1 
≤1 
≤1 
Week 2 
15 
[2, 22] 
 
 
 
 
Week 4 
29 
[23, 43] 
 
[2, 71] 
 
≥2b 
Week 8 
57 
[44, 71] 
 
 
 
 
Week 12 
85 
[72, 99] 
 
 
 
 
Week 16 
(Part A end of 
treatment) 
113 
≥100b 
≥2b 
≥72b 
≥2b 
 
a. 
Study days are calculated from the day of 1st injection of Part A. Study day = (date of assessment – 1st injection 
date + 1) when date of assessment is on or after the 1st injection date; otherwise, study day = date of assessment – 
1st injection date. If patient never received any dose of study drug, randomization date will be used in place of 1st 
injection date.  
b. If unscheduled visit or ET visit occurs in this window, and it is after the first dose of Part B, it will be considered 
as part of Part B visits. 
Part B (only applies to patients who received at least 1 dose of Part B study drug) 
Table 4 
Analysis Visit Window for Efficacy Endpoints in Part B 
Visit from SOE 
Target Study 
Day in Part B 
Analysis Visit Window based on Study Daya in Part B 
Histology endpoints, 
Transcriptome endpoints, 
EOE-EREFS 
PEIS-P, PEIS-C, GIC-P, GIC-C, 
GIC-Clin, GIS-P, GIS-C, GIS-
Clin 
Baseline of Part B 
1 
≤1 
≤1 
Week 32 
113 
 
[2, 183] 
Week 52 
(Part B end of treatment) 
253 
≥2 
≥184 
a. 
Study days are calculated from the day of 1st injection of Part B. Study day = (date of assessment – 1st injection 
date + 1) when date of assessment is on or after the 1st injection date; otherwise, study day = date of assessment – 
1st injection date. If patient never received any dose of study drug, randomization date will be used in place of 1st 
injection date.  
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Table 5 
Analysis Visit Window for Safety and Biomarker Endpoints in Part B 
Visit from SOE 
Target 
Study 
Day in 
Part B 
Analysis Visit Window based on Study Daya in Part B 
Vital Signs 
Physical Examination, 
Urinalysis, Serum total 
IgE, Eotaxin-3 
Hematology, 
Chemistry, PK, ADA 
Baseline of Part B 
1 
≤1 
≤1 
≤1 
Week 20 
29 
[2, 43] 
 
 
Week 24 
57 
[44, 71] 
 
 
Week 28 
85 
[72, 99] 
 
 
Week 32 
113 
[100, 127] 
 
[2, 183] 
Week 36 
141 
[128, 155] 
 
 
Week 40 
169 
[156, 183] 
 
 
Week 44 
197 
[184, 211] 
 
 
Week 48 
225 
[212, 239] 
 
 
Week 52 
(Part B end of 
treatment) 
253 
≥240 
≥2 
≥184 
a. 
Study days are calculated from the day of 1st injection of Part B. Study day = (date of assessment – 1st injection 
date + 1) when date of assessment is on or after the 1st injection date; otherwise, study day = date of assessment – 
1st injection date. If patient never received any dose of study drug, randomization date will be used in place of 1st 
injection date.  
12-week follow-up period after Part A/Part B end of treatment 
Table 6 
Analysis Visit Window for 12-week Follow-up Period after Part A/Part B End 
of Treatment 
Visit from SOE 
Target Study Day after 
EOT Visita 
Analysis Window based on Study 
Daya after EOT 
Week 64 EOS Visit  
(Patient not entering Part B) 
85  
(relative to week 16 visit) 
≥2b 
Week 64 EOS Visit  
(Patient entering Part B) 
85  
(relative to week 52 visit) 
≥2b 
a. 
Study days are calculated from the day of week 16 visit for patients not entering Part B or the day of week 52 visit 
for patients entering Part B. Study day = (date of assessment – week 16/week 52 visit +1) when date of assessment 
is on or after week 16/week 52 visit. If patient does not complete week 16/week 52 visit, week 64 visit will be not 
applicable for this patient.  
b. If unscheduled visit occurs after Part A/Part B EOT visit, and patient enters follow-up period, 1) the study day is 
≤42 (6 weeks after Part A/Part B EOT visit), it will be considered for week 16/week 52 visit; 2) the study day is 
>42, it will be considered for EOS visit. 
 
For PESQ-P and PESQ-C data (collected daily by eDiary), the analysis visit windows will be 
implemented following the procedures below: 
Part A (diaries collected after the first injection in Part B will not be used for Part A analysis) 
Step 1: Diary study day derivation 
• If diary date ≥ 1st injection date of study Part A and < 1st injection date of study Part B, 
Part A diary study day= diary date – 1st injection date in the study + 1; 
• If diary date < 1st injection date of study Part A, Part A diary study day= diary date – 
1st injection date in the study. 
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Step 2: Analysis visit windows are defined as Day -14 to Day -1 = BL, Day 1 to Day 14 = week 2, 
Day 15 to Day 28 = week 4, etc., with 14-day intervals between visit windows, through Day 99 to 
Day 112 = week 16. For patients who never entered Part B, analysis windows in the 12-week follow-
up period will continue with 14-day intervals as Day 113 to Day 126 = week 18, Day 127 to Day 
140 = week 20, etc. 
Part B (only applies to patients who received at least 1 dose of Part B study drug) 
Step 1: Diary study day derivation 
• For diary date ≥ 1st injection date of study Part B, Part B diary study day = diary date 
– 1st injection date in Part B + 1; 
• For diary date < 1st injection date of study Part B, Part B diary study day = diary date 
– 1st injection date in Part B. 
Step 2: Analysis visit windows are defined as Day -14 to Day -1 = Part B BL, Day 1 to Day 14 = 
week 18, Day 15 to Day 28 = week 20, etc., with 14-day intervals between visit windows, through 
Day 239 to Day 253 = week 52. For patients who entered 12-week follow-up period after Part B, 
analysis windows will continue with 14-day intervals as Day 254 to Day 267 = week 54, Day 268 
to Day 281 = week 56, etc. 
6.5. 
Statistical Technical Issues 
None. 
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7. 
INTERIM ANALYSIS 
No interim analysis is planned. 
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8. 
TIMING OF STATISTICAL ANALYSIS 
The primary analysis will be performed when the last patient has completed the last Part A visit 
including patients who have terminated early in Part A. The assessments of primary, secondary, 
and exploratory efficacy endpoints through the end of Part A during the primary analysis will be 
the final (and only) analyses of these endpoints. Hence, there will be no need for alpha adjustment 
due to this primary analysis. Available Part B data will also be analyzed and evaluated, including 
assessment of secondary endpoints at week 52. The final analysis will occur when all patients who 
enter the 12-week follow-up period immediately from Part A or Part B completed the follow-up 
period. 
To maintain study integrity with respect to the post Part A visits and analyses, a dissemination 
plan will be written. This plan will clearly identify the Part A unblinded team (including the 
statistician) that will perform the Part A analysis and all related activities, restrict other clinical 
team members and other Sponsor personnel from access to individual patient treatment allocation 
and site level analysis results, and ensure that the dedicated Part A unblinded team will not 
participate in the data review or data decisions for the following post treatment analyses. However, 
the dedicated team can participate in the analysis following the final database lock. 
 
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9. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher. 
 
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10. 
REFERENCES 
1. 
Arias A, Perez-Martinez I, Tenias JM, Lucendo AJ. Systematic review with meta-analysis: 
the incidence and prevalence of eosinophilic oesophagitis in children and adults in 
population-based studies. Aliment Pharmacol Ther 2016; 43(1):3-15. 
2. 
Barbie DA, Tamayo P, Boehm JS, Kim SY, Moody SE, Dunn IF, et al. Systematic RNA 
interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 2009; 
462(7269):108-12. 
3. 
Chehade M, Jones SM, Pesek RD, Burks AW, Vickery BP, Wood RA, et al. Phenotypic 
Characterization of Eosinophilic Esophagitis in a Large Multicenter Patient Population from 
the Consortium for Food Allergy Research. J Allergy Clin Immunol Pract 2018; 6(5):1534-
44.e5. 
4. 
Collins MH, Martin LJ, Alexander ES, Boyd JT, Sheridan R, He H, et al. Newly developed 
and validated eosinophilic esophagitis histology scoring system and evidence that it 
outperforms peak eosinophil count for disease diagnosis and monitoring. Dis Esophagus 
2017; 30(3):1-8. 
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DeBrosse CW, Franciosi JP, King EC, Butz BK, Greenberg AB, Collins MH, et al. Long-
term outcomes in pediatric-onset esophageal eosinophilia. J Allergy Clin Immunol 2011; 
128(1):132-8. 
6. 
Dellon ES. Epidemiology of eosinophilic esophagitis. Gastroenterol Clin North Am 2014; 
43(2):201-18. 
7. 
Dellon ES, Aderoju A, Woosley JT, Sandler RS, Shaheen NJ. Variability in diagnostic criteria 
for eosinophilic esophagitis: a systematic review. Am J Gastroenterol 2007; 102(10):2300-
13. 
8. 
Dellon ES, Hirano I. Epidemiology and Natural History of Eosinophilic Esophagitis. 
Gastroenterology 2018; 154(2):319-32.e3. 
9. 
Dellon, ES, Veerappan R, Selitsky SR, Parker JS, Higgins LL, Beitia RM,, Robert M. Genta 
RM , and Lash RH. A Gene Expression Panel is Accurate for Diagnosis and Monitoring 
Treatment of Eosinophilic Esophagitis in Adults. Clin Transl Gastroenterol. 2017 Feb 
9;8(2):e74. doi: 10.1038/ctg.2017.2. 
10. Falk GW. Clinical presentation of eosinophilic esophagitis in adults. Gastroenterol Clin North 
Am 2014; 43(2):231-42. 
11. Flegal KM, Cole TJ. Construction of LMS parameters for the Centers for Disease Control and 
Prevention 2000 growth charts. Natl Health Stat Report. 2013 Feb 11;(63):1-3. 
12. Food and Drug Administration (FDA). Eosinophilic Esophagitis: Developing Drugs for 
Treatment Guidance for industry. September 2020. 
13. Franciosi JP, Hommel KA, DeBrosse CW, Greenberg AB, Greenler AJ, Abonia JP, et al. 
Development of a validated patient-reported symptom metric for pediatric eosinophilic 
esophagitis: qualitative methods. BMC Gastroenterol 2011; 11(126). 
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Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
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14. Furuta GT, Aceves SS. The National Biome Initiative: An allergy perspective. J Allergy Clin 
Immunol 2017; 139(4):1131-4. 
15. Golekoh MC, Hornung LN, Mukkada VA, Khoury JC, Putnam PE, Backeljauw PF. Adrenal 
Insufficiency after Chronic Swallowed Glucocorticoid Therapy for Eosinophilic Esophagitis. 
J Pediatr 2016; 170(240-5. 
16. Greuter T, Bussmann C, Safroneeva E, Schoepfer AM, Biedermann L, Vavricka SR, et al. 
Long-Term Treatment of Eosinophilic Esophagitis With Swallowed Topical Corticosteroids: 
Development and Evaluation of a Therapeutic Concept. Am J Gastroenterol 2017; 
112(10):1527-35. 
17. Hamilton JD, Suarez-Farinas M, Dhingra N, Cardinale I, Li X, Kostic A, et al. Dupilumab 
improves the molecular signature in skin of patients with moderate-to-severe atopic 
dermatitis. J Allergy Clin Immunol 2014; 134(6):1293-300. 
18. Hirano I, Aceves SS. Clinical implications and pathogenesis of esophageal remodeling in 
eosinophilic esophagitis. Gastroenterol Clin North Am 2014; 43(2):297-316. 
19. Hirano I, Collins MH, Assouline-Dayan Y, Evans L, Gupta S, Schoepfer AM, et al. RPC4046, 
a Monoclonal Antibody Against IL13, Reduces Histologic and Endoscopic Activity in 
Patients With Eosinophilic Esophagitis. Gastroenterology 2019a; 156(3):592-603.e10. 
20. Hirano I, Dellon ES, Hamilton JD, Collins MH, Peterson K, Chehade M, et al. Efficacy of 
Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis. 
Gastroenterology 2019b. 
21. Hirano I, Moy N, Heckman MG, Thomas CS, Gonsalves N, Achem SR. Endoscopic 
assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel 
classification and grading system. Gut. 2013 Apr;62(4):489-95. PubMed PMID: 22619364. 
22. ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and content of clinical 
study reports (E3). International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. 
23. ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for clinical 
trials (E8). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
24. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. 
25. Iuliano S, Minelli R, Vincenzi F, Gaiani F, Ruberto C, Leandro G, et al. Eosinophilic 
esophagitis in pediatric age, state of the art and review of the literature. Acta Biomed 2018; 
89(8-s):20-6. 
26. Kapel RC, Miller JK, Torres C, Aksoy S, Lash R, Katzka DA. Eosinophilic esophagitis: a 
prevalent disease in the United States that affects all age groups. Gastroenterology 2008; 
134(5):1316-21. 
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Statistical Analysis Plan 
 
Date: January 27, 2022 
 
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27. Liacouras CA, Furuta GT, Hirano I, Atkins D, Attwood SE, Bonis PA, et al. Eosinophilic 
esophagitis: updated consensus recommendations for children and adults. J Allergy Clin 
Immunol 2011; 128(1):3-20.e6; quiz 1-2. 
28. Lucendo AJ, Molina-Infante J, Arias A, von Arnim U, Bredenoord AJ, Bussmann C, et al. 
Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for 
diagnosis and management in children and adults. United European Gastroenterol J 2017; 
5(3):335-58. 
29. Prasad GA, Alexander JA, Schleck CD, Zinsmeister AR, Smyrk TC, Elias RM, et al. 
Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota. 
Clin Gastroenterol Hepatol 2009; 7(10):1055-61. 
30. Ratitch B. Lipkovich I, O’Kelly. Combining Analysis Results from Multiply Imputed 
Categorical Data. PharmaSUG 2013. 
31. Ratitch, Bohdana, Michael O'Kelly, and Robert Tosiello. Missing data in clinical trials: from 
clinical assumptions to statistical analysis using pattern mixture models. Pharmaceutical 
Statistics 12.6 (2013): 337-347. 
32. Schoepfer AM, Straumann A, Panczak R, Coslovsky M, Kuehni CE, Maurer E, et al. 
Development and validation of a symptom-based activity index for adults with eosinophilic 
esophagitis. Gastroenterology 2014; 147(6):1255-66.e21. 
33. Sherrill JD, Kiran KC, Blanchard C, Stucke EM, Kemme KA, Collins MH, et al. Analysis 
and expansion of the eosinophilic esophagitis transcriptome by RNA sequencing. Genes 
Immun 2014; 15(6):361-9. 
34. Singla MB, Moawad FJ. An Overview of the Diagnosis and Management of Eosinophilic 
Esophagitis. Clin Transl Gastroenterol 2016; 7(e155). 
35. Spergel JM, Brown-Whitehorn TF, Beausoleil JL, Franciosi J, Shuker M, Verma R, et al. 14 
years of eosinophilic esophagitis: clinical features and prognosis. J Pediatr Gastroenterol Nutr 
2009; 48(1):30-6. 
36. Spergel JM, Rothenberg ME, Collins MH, Furuta GT, Markowitz JE, Fuchs G, 3rd, et al. 
Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-
blind, randomized, placebo-controlled trial. J Allergy Clin Immunol 2012; 129(2):456-63, 
63.e1-3. 
37. Straumann A. The natural history and complications of eosinophilic esophagitis. Gastrointest 
Endosc Clin N Am 2008; 18(1):99-118; ix. 
38. Straumann A, Aceves SS, Blanchard C, Collins MH, Furuta GT, Hirano I, et al. Pediatric and 
adult eosinophilic esophagitis: similarities and differences. Allergy 2012; 67(4):477-90. 
39. Straumann A, Spichtin HP, Grize L, Bucher KA, Beglinger C, Simon HU. Natural history of 
primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years. 
Gastroenterology 2003; 125(6):1660-9. 
40. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set 
enrichment analysis: a knowledge-based approach for interpreting genome-wide expression 
profiles. Proc Natl Acad Sci U S A 2005; 102(43):15545-15550. 
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Statistical Analysis Plan 
 
Date: January 27, 2022 
 
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41. Warners MJ, Ambarus CA, Bredenoord AJ, Verheij J, Lauwers GY, Walsh JC, et al. 
Reliability of histologic assessment in patients with eosinophilic oesophagitis. Aliment 
Pharmacol Ther 2018; 47(7):940-50. 
42. Wechsler JB, Bolton SM, Amsden K, Wershil BK, Hirano I, Kagalwalla AF. Eosinophilic 
Esophagitis Reference Score Accurately Identifies Disease Activity and Treatment Effects in 
Children. Clin Gastroenterol Hepatol 2018; 16(7):1056-63. 
 
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Statistical Analysis Plan 
 
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11. 
APPENDIX 
11.1. 
Summary of Statistical Analyses 
11.1.1. 
Summary of Efficacy Analyses 
Endpoint 
Analysis 
Populations 
Primary Statistical Method 
Supportive/Sensitive  
Statistical Method 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoint 
Proportion of patients achieving peak 
esophageal intraepithelial eosinophil count 
of ≤6 eos/hpf (400×) at week 16 
 
FAS 
Cochran-Mantel-Haenszel 
test/Missing as non-responder 
Cochran-Mantel-
Haenszel test with tipping 
point analysis approach 
and WOCF-MI approach, 
respectively 
Yes [1] 
Histogram 
Secondary Endpoints 
Secondary continuous variable 
FAS 
ANCOVA with WOCF-MI 
approach for endpoints measured 
repeatedly (e.g., change from 
baseline in the proportion of days 
with 1 or more EoE signs as 
measured by the PESQ-C); 
ANCOVA with WOCF-MI 
approach for endpoints measured 
only once post-baseline up to 
week 16 (e.g., percent change in 
peak eosinophil count from 
baseline to week 16) 
NA 
No 
Line plot 
except EoE-
EREFS 
endpoint; 
Bar chart for 
EoE-EREFS 
endpoint 
Secondary binary variable 
FAS 
Cochran-Mantel-Haenszel 
test/Missing as non-responder 
NA 
No 
Histogram 
[1] Note: The subgroup analysis may not be performed if the number of patients within the subgroup is <10% of overall sample size. The stratification factor is not 
included in the subgroup analysis of primary efficacy endpoint. 
 
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11.1.2. 
Summary of Safety Analyses 
Endpoint 
Analysis 
Populations 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Adverse Events 
SAF 
Descriptive statistics 
No 
TEAEs by Primary 
SOC/PT only [1] 
No 
Laboratory Measures 
SAF 
Descriptive statistics 
No 
No 
No 
Vital sign 
SAF 
Descriptive statistics 
No 
No 
No 
[1] Note: The subgroup analysis may not be performed if the number of patients within the subgroup is <10% of overall sample size.  
 
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Footnotes for the Schedule of Events Tables 
Footnotes for Table 7 
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 PPI 
treatment), the screening period will be extended for up to 12 weeks (day -85) to allow for 
at least 8 weeks of 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/imaging for EoE-EREFS/biopsy procedures should be performed after all 
other efficacy and safety assessments. 
2a. The baseline esophageal endoscopy with biopsies and the stomach and/or 
duodenum endoscopies with biopsies should be performed with sufficient time 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 PPI. Patients may be randomized as soon as their endoscopy/biopsy results 
are confirmed, and all other eligibility criteria are met.  
2b. 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 subsequent scheduled endoscopy/biopsy at week 16 and/or week 52. 
3. Patients may be re-screened 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. 
4. Assessments indicated for this week 16 (end of treatment) visit should be performed for all 
patients. For patients who will enter extended treatment, there are additional events listed 
for the week 16 visit in Table 8. 
5. Patients and/or caregivers will be trained on administration of study drug. 
6. On scheduled in-clinic study visit days, study drug will be administered in the clinic (by 
the patient, site staff, or caregiver) after all assessments are completed. Study drug 
administered at the study sites by site staff will be performed only by injection personnel 
who will not perform any clinical assessment/procedures. Study drug will be 
provided/dispensed for those doses scheduled to be administered at home before the next 
in-clinic visit. Study drug administration that occurs in clinic should occur per the Schedule 
of Events in Table 7 and Table 8. Parents (or caregivers) will return the study kit box (for 
prefilled syringes) at each subsequent in-clinic visit. Parents (or caregivers) who prefer to 
have the clinic staff administer study drug may choose to have injections administered in 
the clinic. 
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7. The PESQ-P will be completed daily by patients >8 to <12 years of age (determined at the 
time of screening visit 1) just before going to bed for the night. The PESQ-C will be 
completed daily by caregivers of patients >1 to <12 years of age (determined at the time of 
screening visit 1) after the patients go to bed for the night. The PESQ-P and PESQ-C will 
be completed via an electronic diary (diary) and site personnel should conduct regular 
checks of patient and caregiver diary compliance. The PEIS-P and PEIS-C will be 
completed during site visits as indicated in the Schedule of Events table by the patients and 
caregivers, respectively. 
8. The GIS-P, GIS-C, GIS-Clin and the GIC-P, GIC-C, and GIC-Clin will be completed by 
patients during site visits (>8 to <12 years of age determined at the time of screening 
visit 1), caregivers (of patients >1 to <12 years of age determined at the time of screening 
visit 1), and study investigator/clinician, respectively. 
9. EoE-EREFS imaging will be analyzed and scored by a central reading center. Minor 
esophageal features will be assessed by the investigator. 
10. Assessments will be performed, and blood samples will be collected before the 
administration of study drug. In the event of suspected SAEs, such as anaphylaxis or 
hypersensitivity, functional dupilumab PK sample and anti-dupilumab antibody sample 
may be collected at or near the event. 
11. Patients will be closely monitored at the study site at visits 3 and 4 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. Vital signs should be taken predose at 
all other indicated visits. 
12. Tuberculosis testing will be performed on a country-by-country basis according to local 
guidelines if required by regulatory authorities or ECs. 
13. A negative result must be obtained prior to the randomization visit for all females post-
menarche. 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. 
14. Urinalysis is only required for patients aged ≥6 to <12 years. 
15. The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) version 2.0 will be 
completed by caregivers of patients >1 to <12 years of age (determined at the time of 
screening visit 1). 
16. Exit interviews will be conducted by a trained interviewer via telephone within 14 days of 
completing Week 16/Visit 8. These interviews will be completed with caregivers. Patients 
aged ≥8 to <12 years old (determined at the time of screening visit 1] may also join a 
portion of the exit interview). 
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CONFIDENTIAL 
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Footnotes for Table 8 
1. This visit is the same as the week 16 visit for the double-blind study portion (Table 7), and 
all other assessments indicated for week 16 (Table 7) should be performed. Endoscopy 
with biopsies at visit 8/week 16 must be completed prior to administration of study drug 
for Part B Extended Active Treatment. 
2. Study assessments will be performed, and blood samples will be collected prior to 
administration of study drug. In the event of suspected SAEs, such as anaphylaxis or 
hypersensitivity, functional dupilumab PK sample and anti-dupilumab antibody sample 
may be collected at or near the event. 
3. 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. 4a. Study drug administration will continue through week 50.  
4b. Weight assessed at visit 8 / week 16 and visit 12 / week 32 will be used to determine 
weight-tiered dose for the 36-week extended active treatment period. If weight has 
increased at visit 12 such that the patient meets a larger weight tier, weight-tiered dosing 
will be re-assigned according to the patient’s weight at this visit. If weight is the same or 
decreased at visit 12, then weight-tiered dosing will remain as originally assigned at visit 
8 / week 16. The patient will remain within the original exposure dosing assignment (higher 
exposure group or lower exposure group). On scheduled in-clinic study visit days, study 
drug will be administered in the clinic (by the patient, site staff, or caregiver). Study drug 
administered at the study sites by site staff will be performed only by injection personnel 
who will not perform any clinical assessment/procedures. Study drug will be provided for 
those scheduled doses to be administered at home before the next in-clinic visit. Parents 
(or caregivers) will return the study kit box (for prefilled syringes) at each subsequent in-
clinic visit. Study drug administration that occurs in clinic should occur per the Schedule 
of Events table. Parents (or caregivers) who prefer to have the clinic staff administer study 
drug may choose to have injections administered in the clinic.  
5. The PESQ-P will be completed daily by patients >8 to <12 years of age (determined at the 
time of screening visit 1) just before going to bed for the night. The PESQ-C will be 
completed daily by caregivers of patients >1 to <12 years of age (determined at the time of 
screening visit 1) after the patients go to bed for the night. The PESQ-P and PESQ-C will 
be completed via an electronic diary (diary) and site personnel should conduct regular 
checks of patient and caregiver diary compliance. The PEIS-P and PEIS-C will be 
completed during site visits as indicated in the Schedule of Events table by the patients and 
caregivers, respectively. 
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Statistical Analysis Plan 
 
Date: January 27, 2022 
 
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6. The GIS-P, GIS-C, GIS-Clin and the GIC-P, GIC-C, and GIC-Clin will be completed 
during site visits by patients (>8 to <12 years of age determined at the time of screening 
visit 1), caregivers (of patients >1 to <12 years of age determined at the time of screening 
visit 1), and study investigator/clinician, respectively. 
7. Endoscopy/imaging for EoE-EREFS/biopsy procedures should be performed after all other 
efficacy and safety assessments. Minor esophageal features will be assessed by the 
investigator. 
7a. 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 16 and 52. 
8. 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 at visit 8. 
9. 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. 
10. Urinalysis is only required for patients aged ≥6 to <12 years. 
11. The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) version 2.0 will be 
completed by caregivers of patients >1 to <12 years of age (determined at the time of screening 
visit 1). 
Footnotes for Table 9 
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. The PESQ-P will be completed daily by patients >8 to <12 years of age (determined at the 
time of screening visit 1) just before going to bed for the night. The PESQ-C will be 
completed daily by caregivers of patients >1 to <12 years of age (determined at the time of 
screening visit 1) after the patients go to bed for the night. The PESQ-P and PESQ-C will 
be completed via an electronic diary (diary) and site personnel should conduct regular 
checks of patient and caregiver diary compliance. The PEIS-P and PEIS-C will be 
completed during site visits as indicated in the Schedule of Events table by the patients and 
caregivers, respectively. 
3. The GIS-P, GIS-C, GIS-Clin and the GIC-P, GIC-C, and GIC-Clin will be completed 
during site visits as indicated by patients (>8 to <12 years of age determined at the time of 
screening visit 1), caregivers (of patients >1 to <12 years of age determined at the time of 
screening visit 1), and study investigator/clinician, respectively. 
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Statistical Analysis Plan 
 
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4. EoE-EREFS imaging will be analyzed and scored by a central reading center. Minor 
esophageal features will be assessed by the investigator.  
4a. For patients who receive rescue treatment, endoscopy/imaging for 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 16 and 52. 
4b. Endoscopy/imaging for EoE-EREFS/biopsy will be performed only if the unscheduled 
visit is for the purpose of administering rescue therapy. 
5. Urinalysis is only required for patients aged ≥6 to <12 years 
The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) version 2.0 will only be 
completed by caregivers of patients >1 to <12 years of age (determined at the time of screening 
visit 1) an early termination and/or unscheduled visit before rescue visit(s) performed prior to visit 
8 / week 16. There is no requirement to perform PEESS after visit 8 / week 16. 
11.3. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Where criteria for ≥6 to <12 years are different from criteria for ≥1 to <6 years, the children criteria 
are provided in the [brackets] in the combined column. The criteria inside the “Combined” column 
will be used for display purpose in the reporting outputs. Applicable criteria will be applied to 
parameters collected in the study to identify treatment-emergent PCSV cases. 
Parameter 
≥6 to <12 years 
≥1 to <6 years 
Combined 
Clinical chemistry 
ALT/SGPT 
≥3 and <5 ULN and baseline 
<3 ULN 
≥5 and <10 ULN and 
baseline <5 ULN 
≥10 and <20 ULN and 
baseline <10 ULN 
≥20 ULN and baseline <20 
ULN 
≥3 and <5 ULN and baseline 
<3 ULN 
≥5 and <10 ULN and 
baseline <5 ULN 
≥10 and <20 ULN and 
baseline <10 ULN 
≥20 ULN and baseline <20 
ULN 
≥3 and <5 ULN and baseline <3 
ULN 
≥5 and <10 ULN and baseline 
<5 ULN 
≥10 and <20 ULN and baseline 
<10 ULN 
≥20 ULN and baseline <20 
ULN 
AST/SGOT 
≥3 and <5 ULN and baseline 
<3 ULN 
≥5 and <10 ULN and 
baseline <5 ULN 
≥10 and <20 ULN and 
baseline <10 ULN 
≥20 ULN and baseline <20 
ULN 
≥3 and <5 ULN and baseline 
<3 ULN 
≥5 and <10 ULN and 
baseline <5 ULN 
≥10 and <20 ULN and 
baseline <10 ULN 
≥20 ULN and baseline <20 
ULN 
≥3 and <5 ULN and baseline <3 
ULN 
≥5 and <10 ULN and baseline 
<5 ULN 
≥10 and <20 ULN and baseline 
<10 ULN 
≥20 ULN and baseline <20 
ULN 
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Parameter 
≥6 to <12 years 
≥1 to <6 years 
Combined 
Alkaline 
Phosphatase 
(ALP) 
≥1.5 ULN and baseline < 1.5 
ULN 
≥1.5 ULN and baseline < 1.5 
ULN 
 
≥1.5 ULN and baseline < 1.5 
ULN 
Total 
Bilirubin 
≥1.3 ULN and baseline < 1.3 
ULN 
≥1.3 ULN and baseline < 1.3 
ULN 
≥1.3 ULN and baseline < 1.3 
ULN 
Conjugated 
Bilirubin 
(Direct Bilirubin >35% Total 
Bilirubin and Total Bilirubin 
≥1.3 ULN) and (Direct 
Bilirubin ≤35% Total 
Bilirubin or Total Bilirubin 
<1.3 ULN) at baseline 
(Direct Bilirubin >35% Total 
Bilirubin and Total Bilirubin 
≥1.3 ULN) and (Direct 
Bilirubin ≤35% Total 
Bilirubin or Total Bilirubin 
<1.3 ULN) at baseline 
(Direct Bilirubin >35% Total 
Bilirubin and Total Bilirubin 
≥1.3 ULN) and (Direct Bilirubin 
≤35% Total Bilirubin or Total 
Bilirubin <1.3 ULN) at baseline 
(ALT or 
AST) and 
Total 
Bilirubin 
(TBILI) 
((ALT >3 ULN or AST>3 
ULN) and TBILI>2 ULN) 
and ((ALT ≤3 ULN and 
AST ≤3 ULN) or TBILI ≤2 
ULN) at baseline 
((ALT >3 ULN or AST>3 
ULN) and TBILI>2 ULN) 
and ((ALT ≤3 ULN and AST 
≤3 ULN) or TBILI ≤2 ULN) 
at baseline 
((ALT >3 ULN or AST>3 
ULN) and TBILI>2 ULN) and 
((ALT ≤3 ULN and AST ≤3 
ULN) or TBILI ≤2 ULN) at 
baseline 
Creatinine 
≥90 µmol/L and baseline < 
90 µmol/L 
≥30% change from baseline 
≥1 to <4 years: >62 µmol/L 
and ≤ 62 µmol/L at baseline 
≥4 to <6 years: >71 µmol/L 
and ≤ 71 µmol/L at baseline 
≥90 [≥1 to <4 years: >62; ≥4 to 
<6 years: >71] µmol/L and 
baseline < 90 [≥1 to <4 years: ≤ 
62; ≥4 to <6 years: ≤ 71] 
µmol/L  
≥30% change from baseline (≥6 
to <12 years only) 
Albumin 
≤25 g/L and >25 g/L at 
baseline 
NA 
≤25 g/L and >25 g/L at baseline 
(≥6 to <12 years only) 
Blood Urea 
Nitrogen 
(BUN) 
≥7.14 mmol/L and <7.14 
mmol/L at baseline 
≥6.4 mmol/L and <6.4 
mmol/L at baseline 
≥7.14 [≥6.4] mmol/L and <7.14 
[<6.4] mmol/L at baseline 
Chloride 
<80 mmol/L and ≥ 80 
mmol/L at baseline 
≥115 mmol/L and <115 
mmol/L at baseline 
≤80 mmol/L and >80 mmol/L 
at baseline 
≥115 mmol/L and <115 
mmol/L at baseline 
<80 [≤80] mmol/L and baseline 
≥ 80 [>80] mmol/L 
≥115 mmol/L and baseline <115 
mmol/L  
Sodium 
<129 mmol/L and ≥ 129 
mmol/L at baseline 
≥150 mmol/L and < 150 
mmol/L at baseline 
≤129 mmol/L and >129 
mmol/L at baseline 
≥150 mmol/L and <150 
mmol/L at baseline 
<129 [≤129] mmol/L and 
baseline ≥ 129 [>129] mmol/L 
≥150 mmol/L and baseline < 
150 mmol/L  
                                        VV-RIM-00185218-1.0 Approved - 01 Feb 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
CONFIDENTIAL 
Page 91 of 98 
Parameter 
≥6 to <12 years 
≥1 to <6 years 
Combined 
Potassium 
≤3.5 mmol/L and > 3.5 
mmol/L at baseline 
≥5.5 mmol/L and < 5.5 
mmol/L at baseline 
≤3.5 mmol/L and >3.5 
mmol/L at baseline 
≥5.5 mmol/L and <5.5 
mmol/L at baseline 
≤3.5 mmol/L and baseline > 3.5 
mmol/L 
≥5.5 mmol/L and baseline < 5.5 
mmol/L  
Calcium total 
<2.0 mmol/L and ≥2.0 
mmol/L at baseline 
≥2.9 mmol/L and <2.9 
mmol/L at baseline 
≤2.0 mmol/L and >2.0 
mmol/L at baseline 
≥2.9 mmol/L and <2.9 
mmol/L at baseline 
<2.0 [≤2.0] mmol/L and ≥2.0 
[>2.0] mmol/L at baseline 
≥2.9 mmol/L and <2.9 mmol/L 
at baseline 
Glucose 
Hypoglycaemia: <2.7 
mmol/L and ≥2.7 mmol/L at 
baseline  
Hyperglycaemia: ≥10.0 
mmol/L (unfasted) and < 
10.0 mmol/L (unfasted) at 
baseline; 
≥7.0 mmol/L (fasted) and 
<7.0 mmol/L (fasted) at 
baseline  
Hypoglycaemia: <2.7 
mmol/L and ≥2.7 mmol/L at 
baseline 
Hyperglycaemia: ≥10.0 
mmol/L (unfasted) and < 10.0 
mmol/L (unfasted) at 
baseline;  
≥7.0 mmol/L (fasted) and 
<7.0 mmol/L (fasted) at 
baseline  
Hypoglycaemia: <2.7 mmol/L 
and ≥2.7 mmol/L at baseline  
Hyperglycaemia: ≥10.0 mmol/L 
(unfasted) and < 10.0 mmol/L 
(unfasted) at baseline; 
≥7.0 mmol/L (fasted) and <7.0 
mmol/L (fasted) at baseline  
Hematology 
WBC 
<5.0 Giga/L and ≥5.0 Giga/L 
at baseline 
>17.0 Giga/L and ≤17.0 
Giga/L at baseline  
≥1 to <2 years:  
<4.0 Giga/L and ≥ 4.0 Giga/L 
at baseline 
>20.0 Giga/L and ≤20.0 
Giga/L at baseline 
≥2 to <6 years:  
<3.0 Giga/L and ≥ 3.0 Giga/L 
at baseline 
>16.0 Giga/L and ≤ 16.0 
Giga/L at baseline 
<5.0 [≥1 to <2 years: <4.0; ≥2 to 
<6 years: <3.0] Giga/L and ≥5.0 
[≥1 to <2 years: ≥ 4.0; ≥2 to <6 
years: ≥ 3.0] Giga/L at baseline 
 
>17.0 [≥1 to <2 years: >20.0; ≥2 
to <6 years: >16.0] Giga/L and 
≤17.0 [≥1 to <2 years: ≤20.0; ≥2 
to <6 years: ≤ 16.0] Giga/L at 
baseline 
Lymphocytes 
(ALC) 
<1.0 Giga/L and ≥1.0 Giga/L 
at baseline 
>8.0 Giga/L and ≤8.0 Giga/L 
at baseline  
<1.0 Giga/L and ≥ 1.0 Giga/L 
at baseline 
>10.5 Giga/L and ≤10.5 
Giga/L at baseline 
<1.0 Giga/L and ≥1.0 Giga/L at 
baseline 
>8.0 [>10.5] Giga/L and ≤8.0 
[≤10.5] Giga/L at baseline 
Neutrophils 
<1.2 Giga/L and ≥1.2 Giga/L 
at baseline 
>ULN and baseline ≤ ULN 
<1.2 Giga/L and ≥ 1.2 Giga/L 
at baseline 
<1.2 Giga/L and ≥1.2 Giga/L at 
baseline 
>ULN and baseline ≤ ULN (≥6 
to <12 years only) 
Eosinophils 
(>0.5 Giga/L and >ULN) 
and (≤0.5 Giga/L or ≤ ULN 
at baseline) 
(>0.5 Giga/L and >ULN) and 
(≤0.5 Giga/L or ≤ ULN at 
baseline) 
(>0.5 Giga/L and >ULN) and 
(≤0.5 Giga/L or ≤ ULN at 
baseline) 
                                        VV-RIM-00185218-1.0 Approved - 01 Feb 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
CONFIDENTIAL 
Page 92 of 98 
Parameter 
≥6 to <12 years 
≥1 to <6 years 
Combined 
Monocytes  
>0.7 Giga/L and ≤ 0.7 
Giga/L at baseline 
NA 
>0.7 Giga/L and ≤ 0.7 Giga/L at 
baseline (≥6 to <12 years only) 
Hemoglobin 
<100 g/L and ≥100 g/L at 
baseline or any decrease ≥ 
20 g/L 
≥200 g/L and <200 g/L at 
baseline 
≥1 to <2 years:  
<90 g/L and ≥ 90 g/L at 
baseline or any decrease ≥ 20 
g/L  
≥2 to <6 years:  
<100 g/L and ≥ 100 g/L at 
baseline or any decrease ≥ 20 
g/L 
<100 [≥1 to <2 years: < 90] g/L 
and ≥100 [≥1 to <2 years: ≥ 90] 
g/L at baseline or any decrease 
≥ 20 g/L 
≥200 g/L and <200 g/L at 
baseline (≥6 to <12 years only) 
Hematocrit 
< 32% and ≥ 32% at baseline 
>47% and ≤ 47% at baseline 
≥1 to <2 years:  
< 29% and ≥ 29% at baseline 
> 42% and ≤ 42% at baseline  
≥2 to <6 years:  
< 32% and ≥ 32% at baseline 
> 47% and ≤ 47% at baseline 
< 32% [≥1 to <2 years: < 29%] 
and ≥ 32% [≥1 to <2 years: ≥ 
29%] at baseline 
>47% [≥1 to <2 years: > 42%] 
and ≤ 47% [≥1 to <2 years: ≤ 
42%] at baseline 
Platelets 
<100 Giga/L and ≥100 
Giga/L at baseline 
>700 Giga/L and ≤700 
Giga/L at baseline 
<100 Giga/L and ≥100 
Giga/L at baseline 
> 700 Giga/L and ≤700 
Giga/L at baseline 
<100 Giga/L and ≥100 Giga/L 
at baseline 
> 700 Giga/L and ≤700 Giga/L 
at baseline 
Urinalysis 
Ketonuria 
Presence and absence at 
baseline 
NA 
Presence and absence at 
baseline (≥6 to <12 years only) 
Glycosuria 
Presence and absence at 
baseline 
NA 
Presence and absence at 
baseline (≥6 to <12 years only) 
Microscopic 
Hematuria 
>5 RBCs/hpf and ≤5 
RBCs/hpf at baseline 
NA 
>5 RBCs/ hpf and ≤5 RBCs/ hpf 
at baseline (≥6 to <12 years 
only) 
Proteinuria 
≥ 1+ and <1+ at baseline 
NA 
≥ 1+ and <1+ at baseline (≥6 to 
<12 years only) 
Vital Signs 
HR 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline ≥20 bpm 
≥1 to <3 years: 
≤63 bpm and decrease from 
baseline ≥20 bpm 
≥140 bpm and increase from 
baseline ≥20 bpm 
≥3 to <6 years: 
≤59 bpm and decrease from 
baseline ≥20 bpm 
≥140 bpm and increase from 
baseline ≥20 bpm 
≤50 [≥1 to 3 years: ≤63; ≥3 to 
<6 years: ≤59] bpm and 
decrease from baseline ≥20 bpm 
≥120 [≥140] bpm and increase 
from baseline ≥20 bpm 
                                        VV-RIM-00185218-1.0 Approved - 01 Feb 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
CONFIDENTIAL 
Page 93 of 98 
Parameter 
≥6 to <12 years 
≥1 to <6 years 
Combined 
SBP 
≤80 mmHg and decrease 
from baseline ≥20 mmHg 
≥120 mmHg and increase 
from baseline ≥ 20 mmHg 
≥1 to <3 years: 
≤70 mmHg and decrease 
from baseline ≥20 mmHg 
≥116 mmHg and increase 
from baseline ≥20 mmHg 
≥3 to <6 years: 
≤70 mmHg and decrease 
from baseline ≥20 mmHg 
≥121 mmHg and increase 
from baseline ≥20 mmHg 
≤80 [≤70] mmHg and decrease 
from baseline ≥20 mmHg 
≥120 [≥1 to 3 years: ≥116; ≥3 to 
<6 years: ≥121] mmHg and 
increase from baseline ≥ 20 
mmHg 
DBP 
≤48 mmHg and decrease 
from baseline ≥10 mmHg  
≥72 mmHg and increase 
from baseline ≥ 20mmHg 
≥1 to <3 years: 
≤34 mmHg and decrease 
from baseline ≥10 mmHg 
≥77 mmHg and increase from 
baseline ≥10 mmHg 
≥3 to <6 years: 
≤34 mmHg and decrease 
from baseline ≥10 mmHg  
≥83 mmHg and increase from 
baseline ≥10 mmHg  
≤48 [≤34] mmHg and decrease 
from baseline ≥10 mmHg  
≥72 [≥1 to 3 years: ≥77; ≥3 to 
<6 years: ≥83] mmHg and 
increase from baseline ≥ 20 
mmHg [≥ 10 mmHg] 
Temperature 
Rectal, ear (Tympanic): 
>100.4 °F/38.0 °C 
Oral: >99.5 °F/37.5 °C  
Axillary or skin infrared 
(temporal): >99 °F/37.2 °C 
Rectal, ear (Tympanic): 
>102.2 °F/39.0 °C 
Oral or pacifier: 
>102.2°F/39.0°C 
Axillary or skin infrared 
(temporal): >102.2°F/39.0°C 
Rectal, ear (Tympanic): >100.4 
°F/38.0 °C [>102.2 °F/39.0 °C] 
Oral: >99.5 °F/37.5 °C 
[>102.2°F/39.0°C] 
Axillary or skin infrared 
(temporal): >99 °F/37.2 °C 
[>102.2°F/39.0°C] 
Respiratory 
rate 
<16 per minutes and ≥16 per 
minute at baseline 
>30 per minute and ≤30 per 
minute at baseline 
<20 per minute and ≥20 per 
minute at baseline 
>34 per minute and ≤34 per 
minute at baseline 
<16 [<20] per minute and ≥16 
[≥ 20] per minute at baseline 
>30 [> 34] per minute and ≤30 
[≤ 34] per minute at baseline 
Weight 
≥5 % weight loss from 
baseline 
≥5 % weight loss from 
baseline 
≥5 % weight loss from baseline 
                                        VV-RIM-00185218-1.0 Approved - 01 Feb 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
CONFIDENTIAL 
Page 94 of 98 
11.4. 
Search Criteria for TEAEs of Special Interest 
AESI Category 
Search Criteria 
Anaphylactic reactions  
Narrow SMQ for anaphylactic reaction 
Systemic hypersensitivity 
reactions  
 
Narrow SMQ for hypersensitivity  
Note:  manual adjudication of relevant PTs will be required by the study 
medical monitor, before database lock 
Helminthic infections 
HLT = Cestode infections 
HLT = Helminthic infections NEC 
HLT = Nematode infections 
HLT = Trematode infections 
Clinically symptomatic 
eosinophilia (or eosinophilia 
associated with clinical 
symptoms)  
HLT = Eosinophilic disorders  
PT = Eosinophil count increased 
Note: manual adjudication of relevant PTs will be required by the study 
medical monitor, before database lock. 
Any severe type of conjunctivitis 
or blepharitis 
Broad CMQ conjunctivitis PTs 
1. Conjunctivitis   2. Conjunctivitis allergic   3. Conjunctivitis bacterial   4. 
Conjunctivitis viral   5. Atopic keratoconjunctivitis   6. Blepharitis   7. Dry eye   
8. Eye irritation   9. Eye pruritus   10. Lacrimation increased   11. Eye discharge   
12. Foreign body sensation in eyes   13. Photophobia   14. Ocular hyperaemia   
15. Conjunctival hyperaemia   16. Xerophthalmia 
Blepharitis PTs  
1. Blepharitis allergic    2. Bacterial blepharitis 
AND 
Serious AE= “Yes” OR Severity= “severe” 
Keratitis 
Narrow SMQ for corneal disorders 
Severe injection site reactions 
HLT=Injection Site Reactions 
AND 
Serious AE= “Yes” OR Severity= “severe” 
Herpes simplex infection 
HLT=Herpes viral infections  
Arthralgia 
PT=Arthralgia  
Note: The search criteria are meant to assist the process of identification of TEAE of Special Interest/TEAE Syndrome. 
However, since these criteria might not be exhaustive in some cases or may not be specific in other cases, an additional 
blinded review of all PTs in the database may be performed by the medical monitor, based on medical judgement, to 
identify any TEAE of Special Interest/TEAE Syndrome that might have been missed by the criteria or to identify any 
TEAE may been inaccurately assigned as AESI by the algorithmic search.  
                                        VV-RIM-00185218-1.0 Approved - 01 Feb 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
CONFIDENTIAL 
Page 95 of 98 
11.5. 
EoE Histology Scoring System (EoE-HSS) Feature Evaluation Per 
Collins et al. 2017 
Feature 
Grade Score 
Stage Score 
Eosinophilic inflammation (EI) 
0 = intraepithelial eosinophils not 
present 
1 = PEC <15/HPF 
2 = PEC 15-59/HPF 
3 = PEC >60/HPF  
0 = intraepithelial eosinophils 0-
14/HPF, 
1 = PEC ≥15/HPF in <33% of 
HPFs 
2 = PEC ≥15/HPF in 33-66% of 
HPFs 
3 = PEC ≥15/HPF in >66% of 
HPFs 
Basal zone hyperplasia (BZH) 
0 = BZH not present  
1 = basal zone occupies >15% but 
<33% of total epithelial thickness  
2 = basal zone occupies 33-66% of 
total epithelial thickness  
3 = basal zone occupies >66% of 
total epithelial thickness  
0 = BZH not present 
1 = BZH (any grade >0) in <33% of 
epithelium 
2 = BZH (any grade >0) in 33-66% 
of epithelium 
3 = BZH (any grade >0) in >66% of 
epithelium 
Eosinophil abscess (EA) 
0 = groups or aggregates of 
eosinophils not present 
1 = group of 4-9 eosinophils 
2 = group of 10-20 eosinophils 
3 = group of >20 eosinophils 
0 = groups or aggregates of 
eosinophils not present 
1 = EA (any grade >0) in <33% of 
epithelium 
2 = EA (any grade >0) in 33-66% 
of epithelium 
3 = EA (any grade >0) in > 66% of 
epithelium 
Surface layering (SL) 
0 = absent SL (fewer than 3 aligned 
eosinophils) 
1 = SL of 3-4 eosinophils 
2 = SL of 5-10 eosinophils 
3 = SL of >10 eosinophils 
0 = absent SL 
1 = SL (any grade >0) in <33% of 
epithelium 
2 = SL (any grade >0) in 33-66% of 
epithelium 
3 = SL (any grade >0) in >66% of 
epithelium. 
Dilated intercellular spaces (DIS) 
0 = DIS not seen at any 
magnification 
1 = intercellular bridges in DIS 
visible at 400X magnification only 
2 = intercellular bridges in DIS 
visible at 200X magnification 
3 = intercellular bridges in DIS 
visible at 100X magnification or 
lower 
0 = DIS not seen at any 
magnification 
1 = DIS (any grade >0) in <33% of 
epithelium 
2 = DIS (any grade >0) in 33-66% 
of epithelium 
3 = DIS (any grade >0) in >66% of 
epithelium 
                                        VV-RIM-00185218-1.0 Approved - 01 Feb 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
CONFIDENTIAL 
Page 96 of 98 
Feature 
Grade Score 
Stage Score 
Surface epithelial alteration (SEA) 
0 = SEA not present 
1= SEA without eosinophils 
2 = SEA with any eosinophils 
3 = shed altered surface epithelium 
admixed with numerous eosinophils 
consistent with exudate 
0 = SEA not present 
1 = SEA (any grade >0) in <33% of 
epithelium 
2 = SEA (any grade >0) in 33-66% 
of epithelium 
3 = SEA (any grade >0) in >66% of 
epithelium 
Dyskeratotic epithelial cells (DEC) 
0 = DEC not present 
1 = 1 DEC/HPF 
2 = 2-5 DEC/HPF 
3 = >5 DEC/HPF 
0 = DEC not present 
1 = DEC (any grade >0) in <33% of 
epithelium 
2 = DEC (any grade >0) in 33-66% 
of epithelium 
3 = DEC (any grade >0) in >66% of 
epithelium 
Lamina propria fibrosis (LPF) 
0 = LPF not present 
1 = fibers are cohesive and 
interfiber spaces cannot be 
demarcated 
2 = fiber diameter equals the 
diameter of a basal cell nucleus 
3 = fiber diameter exceeds the 
diameter of a basal cell nucleus 
0 = LPF not present 
1 = LPF (any grade >0) in <33% of 
lamina propria 
2 = LPF (any grade >0) in 33-66% 
of lamina propria 
3 = LPF (any grade >0) in >66% of 
lamina propria 
PEC = peak eosinophil count (quantity of eosinophils in the most inflamed high power field) 
                                        VV-RIM-00185218-1.0 Approved - 01 Feb 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
CONFIDENTIAL 
Page 97 of 98 
11.6. 
Gene Lists Comparising Each Transcriptome Endpoint 
EoE diagnostic panel 
Type 2 inflammation signature 
CDH26 
CDH20 
CLDN10 
CTNNAL1 
DSG1 
CHL1 
CXCL6 
CCL26 
CXCL1 
IL8 
IL5 
IL13 
CCR3 
CLC 
IL5RA 
CRISP2 
FLG 
UPK1A 
SPINK7 
CRISP3 
ACPP 
UPK1B 
CA2 
PHLDB2 
MUC4 
GCNT3 
EPPK1 
ZNF365 
CITED2 
ARG1 
ALOX12 
IGJ 
TNFAIP6 
CFB 
HRH1 
CFI 
APOBEC3A 
MMP12 
CD200R1 
HPGDS 
FCGR3A 
FCGR3B 
RUNX2 
ALOX15 
GRK5 
SAMSN1 
PMCH  
SLC16A6 
IL4 
IL13 
IL13RA1 
IL4R 
IL5 
IL33 
TSLP 
IL25 
CCL11 
CCL13 
CCL17 
CCL18 
CCL24 
CCL26 
IL1RL1 
FCER1A 
FCER2 
CCR3 
CCR4 
SIGLEC8 
HDC 
PTGDS 
PTGDR2 
CLC 
ALOX15 
MUC5B 
MUC5AC 
POSTN 
DPP4 
CMA1 
TPSAB1 
HRH1 
GATA1 
GATA3 
ARG1 
STAT6 
                                        VV-RIM-00185218-1.0 Approved - 01 Feb 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan 
 
Date: January 27, 2022 
 
CONFIDENTIAL 
Page 98 of 98 
EoE diagnostic panel 
Type 2 inflammation signature 
KCNJ2 
ANO1 
SLC26A4 
TPSAB1 
TPSB2 
CPA3 
CMA1 
NEFM 
NEFL 
PNLIPRP3 
ENDOU 
CDA  
EML1 
SUSD2 
GPR160 
TSPAN12 
LRRC31 
GLDC  
GYS2 
IGFL1 
MT1M    
CRYM 
UBD 
GRPEL2 
RTP4 
ACTG2 
CTSC   
POSTN 
KRT23 
COL8A2 
IL32 
IL4 
MSRB3 
CCL8 
EPX  
EPB41L3 
SYNPO2 
COL1A2 
TRIM2 
SYNPO2L 
NCAM1 
F3 
TSLP  
H19 
FKBP5 
SLAMF7 
PTGFRN  
 
                                        VV-RIM-00185218-1.0 Approved - 01 Feb 2022 GMT-5:00


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                                        VV-RIM-00185218-1.0 Approved - 01 Feb 2022 GMT-5:00


Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 100 
Document’s type 
Document Reference 
Effective Date 
Standard 
BDM-STD-STA4-2.2 
March 1, 2015 
STATISTICAL ANALYSIS PLAN 
VERSION: AMENDMENT 1 
Clinical Study Protocol Title: 
A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and 
Safety of Dupilumab in Pediatric Patients with Active Eosinophilic Esophagitis 
Compound: 
Dupilumab (REGN668) 
Protocol Number: 
R668-EE-1877 Amendment 3 
Clinical Phase:  
Phase 3 
Sponsor: 
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
Clinical Trial Manager: 
Study Medical Director: 
Version/Date: 
Amendment 1/ June 2, 2022 
VV-RIM-00199013-1.0 Approved - 03 Jun 2022 GMT-5:00
NCT04394351


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan Amendment 1 
 
Date: June 2, 2022 
 
CONFIDENTIAL 
Page 2 of 100 
The approval signatures below indicate that these individuals have reviewed the Statistical 
Analysis Plan (SAP) and agreed on the planned analysis defined in this document for 
reporting. 
See appended electronic signature page 
  
 
See appended electronic signature page 
 
 
See appended electronic signature page 
 
 
See appended electronic signature page 
 
 
See appended electronic signature page 
 
 
See appended electronic signature page 
 
 
                                        VV-RIM-00199013-1.0 Approved - 03 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan Amendment 1 
 
Date: June 2, 2022 
 
CONFIDENTIAL 
Page 3 of 100 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
OVERVIEW ...............................................................................................................10 
1.1. 
Background/Rationale ................................................................................................10 
1.2. 
Study Objectives .........................................................................................................12 
1.2.1. 
Primary Objectives .....................................................................................................12 
1.2.2. 
Secondary Objectives .................................................................................................12 
1.2.3. 
Exploratory Objectives ...............................................................................................13 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol ................................13 
1.2.5. 
Revision History for SAP Amendments .....................................................................13 
2. 
INVESTIGATION PLAN ..........................................................................................14 
2.1. 
Study Design and Randomization ..............................................................................14 
2.2. 
Statistical Hypothesis ..................................................................................................16 
2.3. 
Sample Size and Power Considerations .....................................................................17 
2.4. 
Study Plan ...................................................................................................................17 
3. 
ANALYSIS POPULATIONS ....................................................................................19 
3.1. 
The Full Analysis Set (FAS) .......................................................................................19 
3.2. 
The Safety Analysis Set (SAF) ...................................................................................19 
3.3. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................21 
3.4. 
The Immunogenicity Analysis Set..............................................................................21 
3.5. 
Subgroups ...................................................................................................................21 
4. 
ANALYSIS VARIABLES .........................................................................................23 
4.1. 
Demographic and Baseline Characteristics ................................................................23 
4.2. 
Medical History ..........................................................................................................24 
4.3. 
Pre-Treatment/Concomitant Medication/Procedures .................................................25 
4.4. 
Efficacy Variable ........................................................................................................27 
4.4.1. 
Primary Efficacy Variable ..........................................................................................27 
4.4.2. 
Secondary Efficacy Variable(s) ..................................................................................28 
4.4.3. 
Exploratory Variable(s) ..............................................................................................35 
4.5. 
Safety Variables ..........................................................................................................41 
4.5.1. 
Adverse Events and Serious Adverse Events .............................................................41 
4.5.2. 
Adverse Events of Special Interest .............................................................................41 
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4.5.3. 
Laboratory Safety Variables .......................................................................................42 
4.5.4. 
Vital Signs ..................................................................................................................43 
4.5.5. 
Physical Examination Variables .................................................................................43 
4.6. 
Pharmacokinetic Variables .........................................................................................43 
4.7. 
Immunogenicity Variables ..........................................................................................43 
4.8. 
Biomarker Variables ...................................................................................................43 
4.9. 
Clinical Outcome Assessments for Psychometric Validity Assessment ....................43 
5. 
STATISTICAL METHODS .......................................................................................44 
5.1. 
Demographics and Baseline Characteristics ...............................................................44 
5.2. 
Medical History ..........................................................................................................44 
5.3. 
Prior/Concomitant Medications/Procedures ...............................................................45 
5.4. 
Subject Disposition .....................................................................................................45 
5.5. 
Extent of Study Treatment Exposure ..........................................................................46 
5.5.1. 
Exposure to Investigational Product ...........................................................................46 
5.6. 
Analyses of Efficacy Variables ..................................................................................47 
5.6.1. 
Analysis of Primary Efficacy Variable .......................................................................51 
5.6.2. 
Analysis of Secondary Efficacy Variables .................................................................53 
5.6.3. 
Adjustment for Multiple Comparison .........................................................................55 
5.6.4. 
Subgroup Analysis ......................................................................................................56 
5.6.5. 
Analysis of Exploratory Efficacy Variables ...............................................................56 
5.7. 
Analysis of Safety Data ..............................................................................................56 
5.7.1. 
Adverse Events ...........................................................................................................57 
5.7.2. 
Clinical Laboratory Measurements.............................................................................58 
5.7.3. 
Analysis of Vital Signs ...............................................................................................58 
5.7.4. 
Physical Exams ...........................................................................................................58 
5.8. 
Analysis of Pharmacokinetic Data ..............................................................................58 
5.9. 
Analysis of Immunogenicity Data ..............................................................................59 
5.9.1. 
Analysis of ADA ........................................................................................................59 
5.9.2. 
Analysis of Neutralizing Antibody (NAb) Data .........................................................60 
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................60 
5.10.1. 
Association of immunogenicity with exposure ..........................................................60 
5.10.2. 
Immunogenicity and Safety/Efficacy .........................................................................61 
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5.11. 
Analysis of Biomarker Data .......................................................................................61 
5.12. 
Analysis of Psychometric Validity of Clinical Outcome Assessment 
Measures .....................................................................................................................62 
6. 
DATA CONVENTIONS ............................................................................................63 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................63 
6.2. 
General Data Handling Convention ............................................................................63 
6.3. 
Data Handling Convention for Missing Data .............................................................63 
6.4. 
Visit Windows ............................................................................................................66 
6.5. 
Statistical Technical Issues .........................................................................................69 
7. 
INTERIM ANALYSIS ...............................................................................................70 
8. 
TIMING OF STATISTICAL ANALYSIS .................................................................71 
9. 
SOFTWARE ...............................................................................................................72 
10. 
REFERENCES ...........................................................................................................73 
11. 
APPENDIX.................................................................................................................77 
11.1. 
Summary of Statistical Analyses ................................................................................77 
11.1.1. 
Summary of Efficacy Analyses ..................................................................................77 
11.1.2. 
Summary of Safety Analyses ......................................................................................78 
11.2. 
Schedule of Time and Events .....................................................................................79 
11.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................89 
11.4. 
Search Criteria for TEAEs of Special Interest ............................................................94 
11.5. 
EoE Histology Scoring System (EoE-HSS) Feature Evaluation Per Collins et 
al. 2017 .......................................................................................................................95 
11.6. 
Gene Lists Comprising Each Transcriptome Endpoint ..............................................97 
11.7. 
SAS Syntax Code for Multiple Imputation with CMH Test ......................................99 
 
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LIST OF TABLES 
Table 1: 
Summary of Primary Estimand for Primary Endpoint and Secondary 
Endpoints in Part A .....................................................................................................48 
Table 2 
Analysis Visit Window for Efficacy Endpoints in Part A ..........................................66 
Table 3 
Analysis Visit Window for Safety and Biomarkers in Part A ....................................67 
Table 4 
Analysis Visit Window for Efficacy Endpoints in Part B ..........................................67 
Table 5 
Analysis Visit Window for Safety and Biomarker Endpoints in Part B .....................68 
Table 6 
Analysis Visit Window for 12-week Follow-up Period after Part A/Part B 
End of Treatment ........................................................................................................68 
Table 7: 
Schedule of Events – Screening and Double-Blind Treatment Period .......................79 
Table 8: 
Schedule of Events – Extended Active Treatment Period and 12-Week 
Follow-Up Period .......................................................................................................81 
Table 9: 
Schedule of Events - Early Termination Visits and Unscheduled Visits ...................83 
 
LIST OF FIGURES 
Figure 1: 
Part A Weight-Tiered Dosing Regimens of Study Drug ............................................15 
Figure 2: 
Part B Weight-Tiered Dosing Regimens of Study Drug ............................................16 
Figure 3 
Study Flow Diagram ...................................................................................................17 
 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Ab 
Antibody 
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 
BUN 
Blood urea nitrogen 
CCL 
Chemokine (C-C motif) ligand 
CMH 
Cochran-Mantel-Haenszel (test) 
COA 
Clinical outcome assessment 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
DSQ 
Dysphagia symptom questionnaire 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDP 
EoE diagnostic panel 
eGFR 
Estimated glomerular filtration rate 
EoE 
Eosinophilic esophagitis 
EoE-EREFS 
Eosinophilic Esophagitis-Endoscopic Reference Score 
EoE-HSS 
EoE Histology Scoring System 
EOS 
End of study (visit) 
eos/hpf 
Eosinophils/high power field 
EOT 
End of treatment 
EPIT 
Epicutaneous immunotherapy 
ET 
Early termination 
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EU 
European Union 
FAS 
Full analysis set 
FLG 
Filaggrin 
GIC 
Global Impression of Change 
GIS 
Global Impression of Severity 
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 
IVRS/IWRS 
Interactive voice/web response system 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MH 
Mantel-Haenszel 
NAb 
Neutralizing antibody 
NES 
Normalized Enrichment Scores 
OIT 
Oral immunotherapy 
PCSV 
Potentially clinically significant value 
PEESS 
Pediatric Eosinophilic Esophagitis Symptom Score 
PEIS 
Pediatric EoE Impact Scale 
PESQ 
Pediatric EoE Sign/Symptom Questionnaire 
PK 
Pharmacokinetic 
PPI 
Proton pump inhibitor 
PT 
Preferred term (MedDRA) 
QOL 
Quality of life 
Q2W 
Once every 2 weeks 
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QW 
Once weekly 
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SC 
Subcutaneous 
SCIT 
Subcutaneous immunotherapy 
SLIT 
Sublingual immunotherapy 
SOC 
System organ class 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
Th2 
Type 2 helper T cell 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WH 
Wilson-Hilferty 
WOCF 
Worst observation carried forward 
 
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1. 
OVERVIEW 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying the statistical approaches for the analysis of study data prior to database lock. 
The SAP is intended to be a comprehensive and detailed description of the strategy and statistical 
methods to be used in the data analysis of R668-EE-1877. 
This plan will be finalized prior to the data lock for the end of Part A of study R668-EE-1877, i.e., 
the last patient reaching the week 16 visit in Part A. 
1.1. 
Background/Rationale 
Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized by esophageal 
dysfunction and eosinophilic inflammation in the esophagus; it is thought to be triggered by an 
abnormal type 2 immune response to food allergens (Furuta, 2017) (Liacouras, 2011). Chronic 
esophageal inflammation leads to progressive remodeling, stricture formation, and fibrosis 
(Hirano, 2014) (Schoepfer, 2014) (Dellon, 2018). Although considered a rare disease, the current 
prevalence is estimated at 22.7 people per 100,000 worldwide (Arias, 2016) and appears to be on 
the increase (Dellon, 2014). Eosinophilic esophagitis has been reported in all ages; however, most 
cases are in children and adults younger than 50 years (Dellon, 2014) (Dellon, 2007) (Kapel, 2008) 
(Liacouras, 2011) (Spergel, 2009). Children under the age of 18 represent approximately 30% of 
the EoE patient population (Dellon, 2014) (Prasad, 2009). The primary clinical manifestations of 
EoE in both adults and children over 10 years of age are dysphagia and food impaction 
(Lucendo, 2017). Clinical features in younger children are non-specific in nature and vary 
significantly depending on the patient’s age and ability of the patient to describe salient symptoms. 
Infants and toddlers are more likely to present with feeding difficulties, vomiting, or regurgitation 
with the potential for failure to thrive, whereas school-age children present with complaints of 
abdominal pain and heartburn (Iuliano, 2018). Older children with symptomatic EoE may also 
modify their dietary and eating behavior by taking small bites, chewing thoroughly, eating slowly, 
drinking copious fluids, and avoiding food consistencies that stick, which is highly suggestive of 
dysphagia, as this is a feeding behavior reported in adults as an attempt to prevent esophageal food 
impactions (Iuliano, 2018). These symptoms lead to substantially impaired quality of life 
(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. Furrows and white plaques are likely the most common finding in children. Rings 
are not common in children, although rings and furrows are the most commonly seen in nearly 
half of adult patients (Singla, 2016). Some patients (particularly pediatric) may present with a 
normal-appearing esophagus, but still have histologically active EoE (Wechsler, 2018). 
Current standard of care for children with EoE consists of food-elimination diets, off-label proton 
pump inhibitors (PPIs), off-label use of swallowed topical corticosteroids, and esophageal dilation. 
Esophageal dilation is frequently utilized to relieve dysphagia symptoms caused by esophageal 
strictures. Since strictures do not occur as commonly in children, esophageal dilation is not as 
commonly performed in children with EoE as compared to adults with EoE (Chehade, 2018) 
(Furuta, 2017). The standard therapies for EoE are limited by variable response rates, relapse after 
therapy cessation, and adverse effects on quality of life. These limitations lead to a significant 
unmet need for new treatments targeting key pathways driving EoE inflammation (Spergel, 2012) 
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(Greuter, 2017). Proton pump inhibitors can result in histologic remission in approximately 50% 
of patients with EoE (Lucendo, 2017) with the remaining patients unresponsive. Swallowed topical 
corticosteroids have been reported in clinical trials to induce partial clinical responses and 
histologic remission; however, they are not uniformly effective and may be associated with local 
fungal infections, as well as a risk of growth suppression and hypothalamic–pituitary–adrenal axis 
suppression following systemic absorption (Golekoh, 2016), limiting their use to short term.  
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 immunoglobulin E (IgE) (Hamilton, 2014). Additionally, preclinical data 
demonstrate that treatment with dupilumab prevents infiltration of eosinophils into tissues. 
Dupilumab was evaluated in adult patients with EoE in a phase 2, multicenter, double-blind, 
randomized, placebo-controlled study (R668-EE-1324), where substantial improvements in 
clinical, histologic, and endoscopic aspects of the disease were demonstrated (Hirano, 2019a). 
Dupilumab was well tolerated by the study patients, with safety data generally consistent with 
other dupilumab studies and with no new safety signals associated with use in the EoE patient 
population (Hirano, 2019b). These results support pursuing further development of dupilumab for 
the treatment of EoE in adult, adolescent, and pediatric patients. As such, a multi-part phase 3 trial 
evaluating the efficacy and safety of dupilumab in adult and adolescent patients with EoE (R668-
EE-1774) was initiated. 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 enrolls patients from Part A and Part B.  The co-primary endpoints for 
the adult and adolescent study include both a validated symptom measurement utilizing the 
dysphagia symptom questionnaire (DSQ) and histologic evaluation. Part A of study R668-EE-
1774 evaluating the once weekly (QW) regimen revealed a significant effect on both of the co-
primary endpoints. In Part B of study R668-EE-1774, the dupilumab 
 mg weekly demonstrated 
a significant effect on both of the co-primary endpoints and clinically meaningful improvements 
in other secondary histological, endoscopic, molecular and other patient reported outcomes. 
Although dupilumab 
 mg Q2W dosing regimen showed significant improvement in the 
histologic primary endpoint over a 24-week treatment period, dupilumab 
 mg Q2W did not 
show improvement in EoE disease symptoms compared with placebo even though, the magnitude 
of improvements in all other secondary histologic, endoscopic, and molecular endpoints of EoE 
were similar to the ones observed with the dupilumab 
 mg QW dosing regimen. Histological 
and molecular evidence suggest that the disease has the same underlying pathogenesis across age 
groups and responds similarly to swallowed topical corticosteroid treatment regardless of age 
(Straumann, 2012). Therefore, for the pediatric trial, where symptoms are heterogeneous, success 
of the trial will be determined by histologic measures; however, symptom assessments will be 
evaluated through secondary and exploratory endpoints. 
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Study R668-EE-1877 is a randomized, 2-part, double-blind, placebo-controlled study to evaluate 
the efficacy and safety of dupilumab in pediatric EoE patients aged ≥ 1 year to <12 years. Children 
with active EoE, aged ≥1 year to <12 years, who are PPI non-responsive as determined by 
esophageal histology, will be randomized 2:2:1:1 to receive either a higher exposure dupilumab 
dose regimen (n=30) or a lower exposure dupilumab dose regimen (n=30) (in a weight-tiered 
dosing schema) or a higher exposure-matched placebo (n=15) or a lower exposure-matched 
placebo (n=15) over 16 weeks (Figure 1). Primary efficacy will be assessed by a histological 
endpoint: proportion of patients with histologic remission (≤6 eos/hpf). A total sample size of 90 
patients is based on the number of patients to inform the primary efficacy histological endpoint 
and to characterize the safety profile of dupilumab in pediatric patients with EoE.  
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
To demonstrate the efficacy of dupilumab treatment compared with placebo in pediatric patients 
aged ≥ 1 year to <12 years with active EoE based on histologic improvement meeting validated 
histologic criteria. 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To demonstrate the efficacy of dupilumab compared to placebo in pediatric patients with 
active EoE after 16 weeks of treatment as assessed by endoscopic visual measurements of 
disease activity using the Eosinophilic Esophagitis-Endoscopic Reference Score (EoE-
EREFS) and histologic abnormalities as measured by the EoE Histology Scoring System 
(EoE-HSS) 
• To evaluate the safety, tolerability, and immunogenicity of dupilumab treatment for up to 
16 weeks in pediatric patients with active EoE 
• To evaluate the effects of dupilumab on transcriptomic signatures associated with EoE and 
type 2 inflammation  
• To study the effects of dupilumab on the type 2 inflammation gene expression signature 
• To evaluate the concentration-time profile of functional dupilumab in serum in this 
population 
• To assess efficacy of long-term (52 weeks) dupilumab treatment 
• To assess safety, tolerability, and immunogenicity of long-term (52 weeks) dupilumab 
treatment 
• To evaluate the impact of dupilumab treatment on EoE signs and symptoms  
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1.2.3. 
Exploratory Objectives 
The exploratory objectives of the study are: 
• To explore impact of dupilumab treatment on health-related quality of life 
• To explore impact of dupilumab on global impression of change and severity of disease 
• To explore impact of dupilumab treatment on changes in weight and growth during the 
double-blind and extended active phases 
• To conduct exploratory research to study EoE and dupilumab mechanism of action in 
pediatric patients, including predictive biomarker discovery and/or validation 
1.2.4. 
Modifications from the Statistical Section in the Final Protocol 
NA 
1.2.5. 
Revision History for SAP Amendments 
The purpose of this SAP amendment is to make the following revisions before the Part A 
database lock 
: 
(1) Clarification of primary analysis for primary efficacy variable  
(2) Modification of hierarchical testing order 
(3) Specification of supplementary analyses  
Description of Change 
Section Changed 
To clarify the intercurrent events strategy and 
missing data handling, and to clarify that the 
CMH test will be performed on binary efficacy 
variables with the Mantel-Haenszel estimates 
provided 
1. Section 5.6 Analyses of Efficacy 
Variables, “Table 1 Summary of Primary 
Estimand for Primary Endpoint and 
Secondary Endpoints in Part A” 
2. Section 5.6.1 Analysis of Primary 
Efficacy Variable 
3. Section 5.6.2 Analysis of Secondary 
Efficacy Variables 
To add a supplementary analysis for the 
primary endpoint with patients discontinuing 
treatment considered as non-responders  
Section 5.6.1 Analysis of Primary Efficacy 
Variable 
To add a supplementary analysis for the 
secondary endpoint of change from baseline to 
week 16 in the proportion of days with 1 or 
more EoE signs, as measured by the PESQ-C 
Section 5.6.2 Analysis of Secondary 
Efficacy Variables 
To update the hierarchical testing order 
Section 5.6.3 Adjustment for Multiple 
Comparison 
To add subgroup analyses for the secondary 
endpoint of change from baseline to week 16 in 
the proportion of days with 1 or more EoE 
signs, as measured by the PESQ-C 
Section 5.6.4 Subgroup Analysis 
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2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
This is a phase 3, multicenter, randomized, 2-part, double-blind, placebo-controlled study 
investigating the efficacy, safety, tolerability, PK, and immunogenicity of dupilumab in pediatric 
patients (aged ≥1 to <12 years) with active EoE.  
In Part A, approximately 90 patients aged ≥ 1 year to <12 years will be randomized in a 2:2:1:1 
ratio to receive a higher exposure dosing regimen, a lower exposure dosing regimen of dupilumab, 
a higher exposure-matched placebo or a lower exposure-matched placebo for a 16-week treatment 
period according to a central randomization scheme provided by an IWRS to the designated study 
pharmacist (or qualified designee). Randomization will be stratified according to weight at 
baseline (≥5 kg to <15 kg, ≥15 kg to <30 kg, or ≥30 kg to <60 kg). The dosing of the placebo 
group will be matched with high exposure and low exposure dupilumab regimens in the respective 
weight tiers. Patients will remain within the originally assigned higher or lower dosing exposure 
arm throughout the study. At the end of Part A, eligible patients will be provided an option to enter 
into Part B, which is a 36-week extended active treatment period with dupilumab. All patients 
(Part A active and placebo) will receive dupilumab based on body weight at visit 8/week 16 per 
the higher- and lower-exposure dosing group to which they were assigned at randomization. 
Treatment assignment in Part B is managed by an IWRS to maintain blinding of treatment 
assignment. Since the objective of using the tiered body weight dose level approach is to maintain 
a uniform drug exposure, as patients grow over the course of the study if a patient’s weight tier 
has increased at visit 12/week 32, the patient will be re-assigned to the corresponding extended 
active treatment regimen based on weight tier at visit 12/week 32. All patients will be followed up 
for an additional 12 weeks after completing Part B. Patients in Part A who are not entering Part B 
would enter a 12-week follow-up period immediately after Part A. 
See Figure 1 and Figure 2 for Part A/Part B weight-tiered dosing regimens of study drug. 
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2.3. 
Sample Size and Power Considerations 
The planned sample size is a total of approximately 90 patients (2:2:1:1 ratio, 30 patients in the 
higher exposure dupilumab group, 30 patients in the lower exposure dupilumab group, 15 patients 
in the higher exposure-matched placebo group, and 15 patients in the lower exposure-matched 
placebo group). 
The assumptions used in the sample size calculation were based on Part A of the R668-EE-1774 
study in adults and adolescents with EoE. Based upon the similarity of pathophysiology and 
expected similarity of histologic response between adults and pediatric patients, a similar 
proportion of responders at week 16 was assumed for sample size calculation. The lower exposure 
dupilumab group was assumed to have a similar treatment effect to the higher exposure dupilumab 
group. The treatment group difference observed in the R668-EE-1774 Part A adolescents was 
assumed for the sample size calculation for this study in children aged ≥1 year to <12 years. In 
Part A of R668-EE-1774, the proportions of patients achieving a peak esophageal intraepithelial 
eosinophil count of ≤6 eos/hpf at week 24 were 59.5% and 5.1% for dupilumab and placebo, 
respectively. In Part A of R668-EE-1774, the proportions of adolescent patients achieving peak 
esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 24 were 36.4% and 0% for 
dupilumab and placebo, respectively. The treatment group difference observed in adolescents was 
approximately 36.5%. It is estimated that with a total number of 90 patients (30 patients in the 
higher exposure dupilumab group, 30 patients in the lower exposure dupilumab group, and 30 
patients in the combined placebo group), at the 2-sided 5% significance level using Fisher’s exact 
test, the study can provide 95% power to detect a treatment difference of 35.6% in the proportion 
of histologic responders (i.e., patients achieving peak esophageal intraepithelial eosinophil count 
≤6 eos/hpf) at week 16 between placebo (5.1%) and each dupilumab treatment group (40.7%). 
Sample size calculations were performed using nQuery Advisor 7.0. 
2.4. 
Study Plan 
Patients will undergo a screening period of up to 85 days, a double-blind 16-week treatment period 
(Part A), a 36-week extended active treatment period (Part B), and a 12-week follow-up period. 
The study flow diagram is provided in Figure 3  
Figure 3 
Study Flow Diagram 
 
After patients and their legal parents/legal guardians provide informed assent (as appropriate) and 
informed consent, patients will be assessed for study eligibility.  
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Patients are required to have a documented diagnosis of EoE which may be established either by 
a prior historical biopsy, as demonstrated by intraepithelial eosinophilic infiltration (peak 
eosinophils/high power field ≥15 eos/hpf) (400×) from at least 1 esophageal region and performed 
after at least 8 weeks of treatment with an approved PPI regimen, or by biopsies performed after 
approximately 8 weeks of PPI treatment initiated prior to screening or during the screening period, 
which demonstrates ≥15 eos/hpf) (400×) from at least 2 of the 3 esophageal regions (proximal, 
mid, and distal); if the PPI regimen is stopped, biopsies must occur within 2 weeks of stopping the 
PPI. Patients who are on PPIs during the screening period and are eligible to enroll in the study, 
have the choice either to remain on the PPI regimen during the entire study or stop the PPI regimen 
prior to baseline and then must remain off PPIs during the entire study. 
Biopsies will be obtained during endoscopy at screening visit 2, at the week 16 visit, and at the 
week 52 visit, or immediately prior to start of rescue medication or procedures. A total of at least 
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 histology (needed 
for study inclusion criteria, as well as endpoint assessment) and the others for RNA extraction. 
Biopsies will be used for exploratory research to study EoE, dupilumab mechanism of action, and 
to identify or validate predictive biomarkers (efficacy and/or safety). Exploratory analyses of the 
biopsies may include but are not limited to immunohistochemistry [IHC] and RNA sequencing (or 
other methods for assessing RNA expression and RNAscope). 
Patients may be re-screened if they fail the screening evaluation, unless the reason for screen 
failure is related to histologic inclusion criteria. The baseline endoscopy with biopsies 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. 
Patients who permanently discontinue from study drug will be encouraged to remain in the study. 
Those who agree and do not withdraw from the study will be asked to return to the clinic for all 
remaining study visits per the visit schedule.  
At the end of the double-blind treatment period (week 16), eligible patients in Part A may enter 
Part B, which consists of 36-week extended active treatment. Patients who do not enter Part B will 
enter a 12-week follow-up period. 
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 (visit 3) and the first visit of Part B occur in the clinic. Endoscopies with 
biopsies are required at approximately week 16 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 be allowed to continue their current study medication 
regimen until the endoscopies with biopsies can be performed. All temporary mechanisms utilized, 
and deviations from planned study procedures in response to COVID-19 will 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. 
The study event table is presented in Section 11.2. 
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3. 
ANALYSIS POPULATIONS 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline ICH E9 
Statistical Principles for Clinical Trials (ICH, 1998), the following population of analysis will be 
used for all statistical analysis. 
The full analysis set (FAS) is the primary analysis population for Part A efficacy analyses. The 
Part A safety analysis set (SAF) is the basis for Part A safety analyses.  
The Part B SAF is the basis for both efficacy and safety analyses of Part B. 
3.1. 
The Full Analysis Set (FAS) 
For Part A, the FAS includes all randomized patients in Part A; it is based on the treatment 
allocated (as randomized). Efficacy endpoints in Part A (double-blind treatment period) will be 
analyzed using the FAS. 
For Part B, the efficacy endpoints in Part B (extended active treatment period) will be summarized 
for all patients who received any study drug in Part B. 
3.2. 
The Safety Analysis Set (SAF) 
Part A: 
The Part A SAF includes all randomized patients who received any Part A study drug; it is based 
on the treatment received (as treated). Treatment administration and all clinical safety variables 
will be analyzed using the SAF. 
Part B: 
For safety analyses of Part B (extended active treatment period), only a subset of SAF (Part B 
SAF) will be included, which is defined as those patients who received at least 1 dose of Part B 
study drug. 
The actual treatment group as treated for Part A is defined by the following rules: 
• For a patient randomized to higher exposure dupilumab or lower exposure dupilumab, 
if the patient received all placebo injections in Part A, the actual treatment will be 
assigned as placebo. 
• For a patient randomized to higher exposure dupilumab or lower exposure dupilumab, 
if the patient received at least one dupilumab injections in Part A, the actual treatment 
will be assigned as the planned treatment. 
• For a patient randomized to placebo, if the patient received at least one dupilumab 
injections in Part A, the actual treatment will be assigned as lower exposure 
dupilumab. 
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For safety summaries, the following analysis periods are defined: 
• Part A 16-week treatment period is defined as: 
− For patients who entered Part B: Day 1 to the date of first dose of study drug for 
Part B Extended Active Treatment period (or week 16 visit if patient entered Part 
B but never received any Part B study drug) 
− For patients who did not enter Part B 
▪ Day 1 to week 16 visit if patients completed week 16 visit with a known 
visit date 
▪ Day 1 to study day 113 (+7 days) if patients had missing week 16 visit 
date, or to patients’ last study participation date if patients did not 
complete week 16, whichever is earlier. For patients who received 
extended dosing in the double-blind treatment period due to the COVID-
19 pandemic, and week 16 visit date is not available, 16-week treatment 
period will end on their last study participation date. 
• Part B extended treatment period for patients who entered Part B is defined as: 
− The day after the first dose of study drug in Part B to the date of week 52 visit if 
patients completed week 52 with known visit date 
− The day after the first dose of study drug in Part B to study day 365 (+7 days) if 
patients had missing week 52 visit date, or to the last study participation date if 
patients did not complete week 52 visit, whichever is earlier. For patients who 
received extended dosing in the extended treatment period due to the COVID-19 
pandemic, and week 52 visit date is not available, 36-week extended treatment 
period will end on their last study participation date 
• Follow-up period is defined as: 
− For patients who entered Part B: the day after the end of Part B extended 
treatment period to the patient last study participation date 
− For patients who did not enter Part B: the day after the end of Part A 16-week 
treatment period to the last study participation date 
The Part A and Part B SAFs will be the basis for the safety analyses for the Part A treatment period 
and Part B treatment period, respectively; however, for the analyses during the follow-up period, 
only a subset of the corresponding SAFs will be included, which is defined as the patients who 
entered the follow-up period and had at least one visit after week 16 visit (for Part A SAF) or week 
52 visit (for Part B SAF). 
Due to COVID-19 pandemic, patients are allowed to extend their current assigned dose regimen 
of study drug (Part A and/or Part B) until endoscopy with biopsy can be performed at week 16 
visit and/or week 52 visit. The safety data during the extended dosing period will also be presented 
in the corresponding analysis period. 
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3.3. 
The Pharmacokinetic Analysis Set (PKAS) 
The PK analysis population includes all patients who received any study drug and who had at least 
1 non-missing result following the first dose of study drug. The PK analysis set is based on the 
actual treatment received (as treated) rather than as randomized. 
3.4. 
The Immunogenicity Analysis Set 
The ADA analysis set (AAS) includes all patients who received any amount of study drug (active 
or placebo [safety analysis set]) and had at least one non-missing anti-drug antibody result 
following the first dose of study drug or placebo. The ADA analysis set is based on the actual 
treatment received (as treated) rather than as randomized. 
The NAb analysis set includes all treated patients who received any study drug (active or placebo), 
have at least one non-missing anti-drug antibody result following the first dose of study drug 
(active or placebo), and either tested negative at all ADA sampling times or tested positive for 
ADA with at least one non-missing NAb result after first dose of the study drug (active or placebo). 
Patients who are ADA negative are set to negative and included as such in the NAb analysis set. 
3.5. 
Subgroups 
Subgroups are defined by key baseline factors recorded on the eCRF (unless otherwise specified) 
and listed as follows. 
Subgroups to be considered for both primary efficacy and safety analyses: 
• Age group (years; ≥1- <6, ≥6 -<12; ≥1- <8, ≥8 -<12) 
• Sex (Male, Female) 
• Duration of EoE (years from start date of EoE to randomization date; <5, ≥5) 
• Baseline weight group (≥5 - <15 kg, ≥15- <30 kg, ≥30- <60 kg) 
• Prior use of swallowed topical steroids (STC) for the treatment of EoE (Yes, No) 
• Inadequate response, intolerant and/or contraindicated to swallowed topical 
corticosteroids (STC) (Yes, No) * 
• History of atopic dermatitis (Yes, No) 
• History of asthma (Yes, No) 
• History of allergic rhinitis (Yes, No) 
• History of food allergy (Yes, No) 
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Subgroups to be considered for primary efficacy endpoint only: 
• Baseline BMI group (kg/m2; overweight: ≥85 percentile of BMI for ≥2 years based 
on age and gender, ≥95 percentile of weight based on length (height), age and gender 
for <2 years, not overweight: not meeting the criteria of overweight) [based on CDC 
(Center for Disease Control and Prevention) chart] 
• Use of PPI at randomization (Yes, No) 
• Prior esophageal dilations (Yes, No) 
• Subject on a food elimination diet at the time of screening (Yes, No) 
• Subject on a food elimination diet in the past (Yes, No) 
Subgroup to be considered for selected secondary efficacy endpoints only (details are in 
Section 5.6.4): 
• Prior use of swallowed topical steroids (STC) for the treatment of EoE (Yes, No) 
NOTE: The subgroup analysis may not be performed if the number of patients within the subgroup 
is <10% of overall sample size. The stratification factor is not included in the subgroup analysis 
of primary efficacy endpoint. 
* The inadequate response, intolerant and/or contraindicated to STC subgroup is defined as  
• Contraindicated to STC: patients never used STC for the treatment of EoE, and the 
reasons for never using STC were concomitant medical concern or contraindication 
(e.g., diabetes, immunomodulating treatment) or potential side-effect(s) from STC 
• Inadequate response: patients had used STC for the treatment of EoE but the 
treatment with STC was not effective in relieving EoE symptoms 
• Intolerant to STC: patients had used STC for the treatment of EoE and the treatment 
with STC was effective in relieving EoE symptoms, with the reasons for stopping 
STC for EoE being concomitant medical concern or contraindication or side effect(s) 
 
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4. 
ANALYSIS VARIABLES 
4.1. 
Demographic and Baseline Characteristics 
The following demographic and baseline characteristics variables will be summarized: 
• Demographic variables: Age at screening as a continuous variable and with grouping 
(years; 1-<6 years, 6-<12 years; 1-<8 years, ≥8-<12 years), Sex (Male, Female), 
Ethnicity with grouping (Hispanic or Latino, Not-Hispanic or Latino), Race with 
grouping (White, Black or African American, Asian, Other), Country, Baseline 
weight as a continuous variable and with grouping (kg; ≥5-<15 kg, ≥15- <30 kg, ≥30- 
<60 kg), Height/length (cm), and calculated BMI (kg/m2; overweight, not 
overweight) [see the BMI grouping definition in Section 3.5]. 
• Baseline disease characteristics 
− Pediatric EoE Sign Questionnaire (PESQ-C [caregiver version]) (details of PESQ-
C are in Section 4.4.2) 
▪ Proportion of days with 1 or more EoE signs for PESQ-C 
▪ Proportion of total segments within a day (night, morning, afternoon, 
evening) with 1 or more EoE signs for PESQ-C 
▪ Number of sign-free days during the 14-day period preceding baseline 
visit for PESQ-C 
− Pediatric EoE Symptom Questionnaire (PESQ-P [patient version]) (details of 
PESQ-P are in Section 4.4.2) 
▪ Proportion of days with 1 or more EoE symptoms for PESQ-P 
▪ Proportion of total segments within a day (night, morning, afternoon, 
evening) with 1 or more EoE symptoms for PESQ-P 
▪ Number of symptom-free days during the 14-day period preceding 
baseline visit for PESQ-P 
− Pediatric Eosinophilic Esophagitis Symptom Score (PEESSv2.0 [caregiver 
version]) 
− Global Impression of Severity (GIS-P [patient version], GIS-C [caregiver 
version], GIS-Clin [clinician version]) (details of GIS-P, GIS-C and GIS-Clin are 
in Section 4.4.3) 
‒ Pediatric EoE Impact Scale (PEIS-C [caregiver version] and PEIS-P [patient 
version]) (details of PEIS-C and PEIS-P are in Section 4.4.3) 
− Duration of EoE as a continuous variable and with grouping (years; <5, ≥5) 
− Age at EoE onset as a continuous variable and with grouping (years; <5, ≥5)  
‒ Peak esophageal intraepithelial eosinophil count (eos/hpf) of three regions 
(proximal, mid, and distal) 
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‒ Mean stage score from the EoE-HSS summed over three regions (proximal, mid, 
and distal) 
‒ Mean grade score from the EoE-HSS summed over three regions (proximal, mid, 
and distal) 
‒ Prior use of STC for EoE (Yes, No) 
− Effectiveness of prior use of STC for EoE (Yes, No) 
− Inadequate response, intolerant and/or contraindicated to STC (Yes or No) 
− Prior esophageal dilations (Yes, No) 
‒ Number of prior esophageal dilations 
− Patients treated with PPI at randomization (Yes, No) 
‒ Patient on food elimination diet in past (Yes, No) 
‒ Patient on food elimination diet at screening (Yes, No) 
‒ Historical esophageal biopsy showing ≥15 (eso/hpf [400 ×]) after 8 weeks of high-
dose PPI (Yes, No) 
‒ Prior use of STC for EoE and prior esophageal dilation (Yes, No) 
‒ EREFS total score 
‒ Baseline serum total immunoglobulin E (IgE) as a continuous variable and with 
grouping (IU/mL; <100, ≥100) 
‒ Baseline blood peripheral EOS as a continuous variable and with grouping (Giga/L; 
<0.15, ≥0.15; <0.30, ≥0.30; <0.50, ≥0.50) 
4.2. 
Medical History 
Medical history will be coded using MedDRA. The same MedDRA version will be used for Part 
A and Part A patients’ data in Part B within the scope of DBL. Information related to EoE medical 
history and comorbid atopic conditions include diagnosis of EoE, atopic dermatitis, asthma, 
allergic rhinitis, allergic conjunctivitis, chronic rhinosinusitis, nasal polyps, food allergy, hives, 
contact dermatitis, other allergies (medications, animals, plants, mold, dust mites, etc.). Patient 
dietary status at the time of screening is also collected with information on whether patient has 
ever been on a food elimination diet in the past, type of food elimination, and reason for elimination 
of specific food. 
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4.3. 
Pre-Treatment/Concomitant Medication/Procedures 
Medications/Procedures will be recorded from the day of informed consent until the end-of-study 
(EOS) visit. Medications will be coded using WHO Drug Dictionary (WHODRUG). Medications 
of interest include PPIs and swallowed topical/systemic corticosteroids for the treatment of EoE. 
Pre-treatment medications/procedures: medications taken or procedures performed prior to 
administration of the first dose of study drug. 
Concomitant medications/procedures (CM/CP): medications taken or procedures performed 
following the first dose of study drug through the EOS visit. This includes medications or 
procedures that were started before the study and are ongoing during the study. Furthermore, 
CM/CP will be categorized according to analysis periods (as defined in Section 3.2): 
• CMs/CPs taken during the Part A 16-week double-blind treatment period 
• CMs/CPs taken during the Part B 36-week extended active treatment period 
• CMs/CPs taken during the 12-week follow-up period 
Prohibited concomitant medications/procedures during the study: 
Treatment with the following concomitant medications is prohibited through week 52 and may 
result in temporary or permanent discontinuation of study drug: 
• Swallowed topical corticosteroids (may be used as rescue treatment of EoE) 
• Systemic corticosteroids (may be used as rescue treatment of 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, mepolizumab, omalizumab, cyclosporine, mycophenolate-mofetil, azathioprine, 
methotrexate, IFN-γ, or other immunomodulatory biologics) 
• Treatment with an investigational drug (other than dupilumab) 
• Initiation, discontinuation, or change in dosage regimen after baseline of the 
following medications (stable doses of these medications are allowed): 
‒ Proton pump inhibitors 
‒ Systemic leukotriene inhibitors 
• Initiation, discontinuation, or change in dosage regimen of nasal and/or inhaled 
corticosteroids within 8 weeks prior to visit 2, visit 8, or visit 17 endoscopies with 
biopsies 
• Initiation of SCIT, or change in dose for those patients on a stable dose of SCIT, 
within 1 year prior to screening  
• Sublingual immunotherapy (SLIT) 
• OIT 
• Epicutaneous immunotherapy (EPIT) 
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• Treatment with a live (attenuated) vaccine, e.g.:  
− 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 
Patients may receive the prohibited medications/procedures listed above 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. 
Blinded adjudication of prohibited medications and procedures will be performed by the medical 
director (or medical monitor) before database locks with documented procedures. 
Rescue treatments (including both medications and procedures): If medically necessary (e.g., for 
treatment of intolerable EoE symptoms), rescue medications (systemic and/or swallowed topical 
corticosteroids) or emergency esophageal dilations are allowed for study patients. An endoscopy 
with biopsy will be performed prior to the initiation of rescue therapy. Patients who undergo an 
endoscopy with biopsy due to initiation of rescue therapy will not undergo the subsequent 
scheduled endoscopy/biopsy at week 16 and/or week 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. 
Patients receiving rescue therapy may continue to receive study drug. They will remain blinded 
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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 except for 
endoscopy/biopsy, as noted above. For the purpose of primary endpoint efficacy analyses, patients 
who receive rescue treatment during the study will be considered treatment failures. 
Blinded adjudication of rescue treatments will be implemented before database locks by 
considering the type of medication or procedure, indication, timing, frequency, and the potential 
impact of the use of the medication or procedure. The rescue treatments will be adjudicated by the 
medical director (or medical monitor) with documented procedures. 
Gastric/Duodenum and Targeted Biopsy 
Biopsy specimens from the stomach and duodenum will be obtained at visit 2 in all patients to rule 
out alternate etiologies of esophageal eosinophilia. 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 16 and week 52. 
4.4. 
Efficacy Variable 
4.4.1. 
Primary Efficacy Variable 
The primary endpoint is: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤6 eos/hpf (400×) at week 16 
Peak esophageal intraepithelial eosinophil count 
Peak esophageal intraepithelial eosinophil count will be measured from esophageal biopsies. 
Biopsies will be obtained by endoscopy at the second screening visit (visit 2), at week 16, and at 
week 52 visits, and immediately prior to start of rescue medication or rescue procedure and during 
the early termination visits. A total of at least 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 histology (needed for study inclusion criteria, as well as endpoint 
assessment) and the others for RNA extraction. 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. Biopsy samples for histopathological analyses 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. The peak esophageal intraepithelial eosinophil 
count at each visit is the maximum of the quantities of eosinophils in the most inflamed high power 
fields (hpfs) across the 3 regions. For example, if the quantity of eosinophils in the most inflamed 
hpf is 2/hpf, 3/hpf, and 4/hpf from the proximal, mid, and distal regions, respectively, the peak 
eosinophil count will be considered as 4/hpf for week 16. If the quantity of eosinophils is missing 
for 1 or 2 esophageal regions, the peak eosinophil count will be the maximum of the quantities of 
eosinophils from the region(s) where eosinophil quantities are available.  
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4.4.2. 
Secondary Efficacy Variable(s) 
The secondary endpoints are: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
<15 eos/hpf at week 16 
• Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from baseline 
to week 16 
• Absolute change in mean EoE grade score from the EoE-HSS from baseline to week 16 
• Absolute change in mean EoE stage score from the EoE-HSS from baseline to week 16 
• Absolute change in EoE-EREFS from baseline to week 16 
• Change from baseline to week 16 in the proportion of days with 1 or more EoE signs as 
measured by the PESQ-C (for patients aged ≥1 to <12 years) 
• Number of sign-free days during the 14-day period preceding week 16 as measured by the 
PESQ-C (for patients aged ≥1 to <12 years) 
• Change from baseline to week 16 in the proportion of total segments within a day (night, 
morning, afternoon, evening) with 1 or more EoE signs as measured by the PESQ-C (for 
patients aged ≥1 to <12 years) 
• Change from baseline to week 16 in the proportion of days with 1 or more EoE symptoms 
as measured by the PESQ-P (for patients aged ≥8 to <12 years) 
• Number of symptom-free days during the 14-day period preceding week 16 as measured 
by the PESQ-P (for patients aged ≥8 to <12 years) 
• Change from baseline to week 16 in the proportion of total segments within a day (night, 
morning, afternoon, evening) with 1 or more EoE symptoms as measured by the PESQ-P 
(for patients aged ≥8 to <12 years)  
• Change in total score from baseline to week 16 as measured by the PEESSv2.0 (caregiver 
version) (for patients aged ≥1 to <12 years) 
• Normalized Enrichment Scores (NES) for the relative change from baseline to week 16 in 
the EoE diagnostic panel (EDP) transcriptome signature 
• NES for the relative change from baseline to week 16 in the type 2 inflammation 
transcriptome signature 
NOTE: All the above primary and secondary endpoints assessed at week 16 for Part A will be 
assessed at week 52 for Part B (except for PEESSv2.0 [caregiver version]) 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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Eosinophilic Esophagitis Histology Scoring System (EoE-HSS) 
The EoE-HSS is a recently validated histologic scoring system that measures other histological 
abnormalities in addition to the density of eosinophilic infiltration. It has been confirmed in adults 
to have external reliability and this scoring system is highly responsive to treatment (Collins, 2017) 
(Warners, 2018). Eosinophilic esophagitis grade and stage scores evaluate 8 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). Assessment of lamina propria fibrosis may not be possible if the 
esophageal biopsy specimens do not contain adequate amounts of subepithelium lamina propria; 
in this case it will not be included in the overall EoE grade and stage scores. 
Histology results will be interpreted by a pathologist at a central pathology reading center who will 
be blinded to the treatment assignment. Severity (grade) and extent (stage) of abnormalities will 
be scored using a 4-point scale (0 normal; 3 maximum change). The detailed scoring scheme for 
each feature is provided in Section 11.5. The mean grade or mean stage score from EoE-HSS is 
the ratio of the sum of the assigned score for each evaluated feature divided by the maximum 
possible score (maximum value is 24). For example, if each of 8 features has maximum grade of 
3 for a biopsy, the mean grade score is 1 (24/24). If one feature is not evaluated, the maximum 
possible score is reduced by 3. Maximum possible score reduction may occur when lamina propria 
fibrosis is not present. If all other features are evaluable, the maximum possible score for a biopsy 
lacking lamina propria fibrosis is reduced from 24 to 21 because of 7 evaluated features. Both 
mean grade and mean stage scores will be determined for biopsies from 3 esophageal regions 
(proximal, mid, and distal). The algorithm of the calculation of mean grade and mean stage scores 
is as follows. 
• The mean grade and mean stage scores summed over the 3 regions is the final score 
used in the primary analysis of the associated endpoints. An example table is provided 
below to illustrate the calculation of mean grade and mean stage scores. For example, 
the mean grade is 0.33, 0.33, and 0.42 from the proximal, mid, and distal regions, 
respectively, and the final mean grade score is 1.08 (0.33+0.33+0.42).  
• If a mean score is available from at least 1 of the 3 regions, the sum of available mean 
scores will be used as final mean score. For example, if the mean grade score is 0.33 
and 0.33 from the proximal and mid regions but missing from distal region, the final 
mean grade score will be 0.66 (0.33+0.33). 
 
Feature 
Esophageal region 
Proximal 
Mid 
Distal 
Eosinophilic inflammation 
3 
3 
3 
Basal zone hyperplasia 
2 
3 
3 
Eosinophil abscess 
2 
2 
3 
Surface layering 
0 
0 
0 
Dilated intercellular spaces 
0 
0 
0 
Surface epithelial alteration 
0 
0 
0 
Dyskeratotic epithelial cells 
0 
0 
0 
Lamina propria fibrosis 
Missing due to absence 
0 
1 
8-feature Mean Grade Score 
(3+2+2)/21=0.33 
(3+3+2)/24=0.33 
(3+3+3+1)/24=0.42 
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Eosinophilic Esophagitis-Endoscopic Reference Score (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 EoE-EREFS utilizes a composite score using 
standardized methodology to assess clinical signs of EoE disease. Imaging should be collected for 
EoE-EREFS analysis and scoring by a centralized reading center. 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 [0], present [1]) 
• Rings (absent [0], mild [1], moderate [2], severe [3]) 
• Exudates (absent [0], mild [1], severe [2]) 
• Furrows (absent [0], mild [1], severe [2]) 
• Stricture (absent [0], present [1]) 
The score for each region is the sum of assigned scores for each of the above 5 major features and 
ranges from 0 to 9. The total score (summing scores for the proximal and distal regions) ranges 
from 0 to 18 and is the final score used for the analysis. If the score is available only from 1 of the 
2 regions, that available score is used as total score. For example, if score is 8 from the proximal 
region and missing from the distal region, the total score is 8. 
In addition to the major features above, data for the following minor features will be assessed by 
the investigator: 
• 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). 
EoE-EREFS will be assessed by endoscopy at screening visit 2, week 16, and week 52 or ET visits 
by centralized reading center. For patients who receive rescue treatment, endoscopy/imaging for 
EoE-EREFS/biopsy procedures will be performed prior to initiation of rescue treatment. 
Transcriptome Endpoints 
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, pre-clinical 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 Section 11.6. 
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4.4.3. 
Exploratory Variable(s) 
The exploratory endpoints are: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤1 
eos/hpf at week 16 
• Percent change in total score of Pediatric EoE Impact Scale (caregiver version) (PEIS-C) 
from baseline to week 16 (for patients aged ≥1 to <12 years) 
• Percent change in total Pediatric EoE Impact Scale (patient version) (PEIS-P) score from 
baseline to week 16 (for patients aged ≥8 to <12 years) 
NOTE: Total score of PEIS-C or PEIS-P refers to averaging the scores of each of the individual 
questions, not totaling the scores from each of the individual questions.  
• Change in GIC-patient, caregiver, and clinician version score 
NOTE: Change in GIC for different questionnaires refers to the question itself asking the overall 
change of patient’s/caregiver’s EoE condition, not the change from baseline (the GIC is not 
administered at baseline).  
• Change in GIS-patient, caregiver, and clinician version score 
• Change from baseline in body weight for age percentile at week 16 
• Change in body mass index for age z-score from baseline to week 16 for patients ≥2 years 
of age 
• Change in weight for age z-score from baseline to week 16 
• Change in weight for height z-score from baseline to week 16 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 
eos/hpf at week 16 and achieving absolute change from baseline to week 16 in the 
proportion of days with 1 or more EoE signs as measured by PESQ-C  
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 
eos/hpf at week 16 and achieving percent change from baseline to week 16 in the 
proportion of days with 1 or more EoE signs as measured by PESQ-C  
• Absolute change from baseline to week 16 in EREFS (excluding stricture) 
• Absolute change from baseline to week 16 in EREFS inflammation sub-score 
• Absolute change from baseline to week 16 in EREFS remodeling sub-score 
NOTE: All the above exploratory endpoints assessed at week 16 will be assessed at week 52 as 
exploratory 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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Pediatric EoE Impact Scale (PEIS) 
The Pediatric EoE Impact Scale (PEIS) has a patient version (PEIS-P) and a caregiver version 
(PEIS-C). 
PEIS-P is a patient-reported outcome measure intended to be completed independently by pediatric 
EoE patients ≥8 to <12 years of age. The PEIS-P will assess the impact of EoE on the patient 
during the past 1 week. Response to each item below (except item 5) is on a 5-point scale (0 = 
“Never”, 1 = “Almost never”, 2 = “Sometimes”, 3 = “Almost always”, 4 = “Always”). Response 
to item 5 is on a 6-point scale (0 = “Never”, 1 = “Almost never”, 2 = “Sometimes”, 3 = “Almost 
always”, 4 = “Always”, 5 = “Not applicable - I did not go to school during the past 7 days”). The 
PEIS-P average score is the sum of non-missing responses divided by the number of items with 
non-missing responses (note: response of “Not Applicable - I did not go to school during the past 
7 days” is considered as missing response and not be counted in the average score). The average 
score could range from 0 to 4. 
Item No. 
Question 
1 
During the past 7 days, how often were you worried because of your EoE?  
2 
During the past 7 days, how often did you feel sad because of your EoE? 
3 
During the past 7 days, how often were you embarrassed in front of other people because of your 
EoE? 
4 
During the past 7 days, how often did you have difficulty sleeping at night because of your EoE? 
5 
During the past 7 days, how often did you have difficulty concentrating at school because of your 
EoE? 
6 
During the past 7 days, how often did you have difficulty playing with your friends because of your 
EoE? 
PEIS-C is intended to be completed independently by caregivers of pediatric EoE patients ≥1 to 
<12 years of age. The PEIS-C will assess the impact of the pediatric patient’s EoE on caregiver 
anxiety, social and professional activities, activities of daily living, and relationships during the 
past 1 week. Response to each item (except item 4 and 4a) is on a 5-point scale (0 = “Not at all”, 
1 = “Very little”, 2 = “A little”, 3 = “Very much”, 4 = “Extremely”). If response to item 4 is “No”, 
items 4a and 4b will be skipped and considered as missing response. The PEIS-C average score is 
the sum of non-missing responses divided by the number of items with non-missing responses 
(note: response to item 4a is not included in the score calculation). The average score could range 
from 0 to 4. 
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Item No. 
Question 
1 
During the past 7 days, how worried were you because of your child’s EoE? 
2 
During the past 7 days, how sad were you because of your child’s EoE? 
3 
During the past 7 days, how much did your child’s EoE limit your social activities? 
4 
Are you currently employed (working for pay)? (If “Yes”, go to question 4a and then 4b. If “No”, go 
to Question 5) 
4a 
During the past 7 days, how many days did you miss work because of your child’s EoE 
4b 
During the past 7 days, how much did your child’s EoE limit your productivity while you were 
working? 
5 
During the past 7 days, how much did your child’s EoE limit your everyday activities (for example: 
house chores, going shopping)? 
6 
During the past 7 days, how much did your child’s EoE cause problems with your personal 
relationships? 
Global Impression of Change (GIC) 
The GIC has a patient version (GIC-P), a caregiver version (GIC-C), and a clinician version (GIC-
Clin). 
• The GIC-P is a single-item patient-reported outcome measure intended to be completed 
independently by pediatric EoE patients ≥8 to <12 years of age. The GIC-P will assess the 
patient’s impression about the overall change (improvement or worsening) in his/her EoE 
condition since study treatment initiation. 
• The GIC-C is a single-item observer-reported outcome measure intended to be completed 
independently by caregivers of pediatric EoE patients ≥1 to <12 years of age. The GIC-C 
will assess the caregiver’s impression about the overall change (improvement or 
worsening) in the pediatric patient’s EoE condition since study treatment initiation. 
• The GIC-Clin is a single-item observer-reported outcome measure intended to be 
completed independently by study investigator-physician of all pediatric EoE patients in 
the study. The GIC-Clin will assess the study investigator’s/clinician’s impression about 
the overall change (improvement or worsening) in the pediatric patient’s EoE condition 
since study treatment initiation. 
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The GIC-P, GIC-C, GIC-Clin score could range from 1 to 7. 
Questionnaire 
Question 
Response (score) 
GIC-P 
Since you started getting the study injection, how would you 
describe the overall change in your eosinophilic esophagitis 
(EoE)? 
A lot better (1) 
Somewhat better (2) 
A little better (3) 
No change (4) 
A little worse (5) 
Somewhat worse (6) 
A lot worse (7) 
GIC-C 
Since your child started getting the study injection, how 
would you describe the overall change in your child’s 
eosinophilic esophagitis (EoE)? 
Very much improved (1) 
Much improved (2) 
Minimally improved (3) 
No change (4) 
Minimally worse (5) 
Much worse (6) 
Very much worse (7) 
GIC-Clin 
Since your patient started getting the study injection, how 
would you describe the overall change in your patient’s 
eosinophilic esophagitis (EoE)? 
Very much improved (1) 
Much improved (2) 
Minimally improved (3) 
No change (4) 
Minimally worse (5) 
Much worse (6) 
Very much worse (7) 
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Global Impression of Severity (GIS) 
The GIS has a patient version (GIS-P), a caregiver version (GIS-C), and a clinician version (GIS-
Clin). 
• The GIS-P is a single-item patient-reported outcome measure intended to be completed 
independently by pediatric EoE patients ≥8 to <12 years of age. The GIS-P will assess the 
patient’s impression about the overall severity of his/her EoE condition during the past 1 
week. 
• The GIS-C is a single-item observer-reported outcome measure intended to be completed 
independently by caregivers of pediatric EoE patients ≥1 to <12 years of age. The GIS-C 
will assess the caregiver’s impression about the overall severity of the pediatric patient’s 
EoE condition during the past 1 week. 
• The GIS-Clin is a single-item observer-reported outcome measure intended to be 
completed independently by study investigator-physician of all pediatric EoE patients in 
the study. The GIS-Clin will assess the study investigator’s/clinician’s impression about 
the overall severity of the pediatric patient’s EoE condition during the past 1 week. 
The GIS-P, GIS-C, and GIS-Clin score could range from 1 to 4. 
Questionnaire 
Question 
Response (score) 
GIS-P 
During the past 7 days, how bad was your eosinophilic 
esophagitis (EoE)? 
Not bad (1) 
A little bad (2) 
Bad (3) 
Very bad (4) 
GIS-C 
During the past 7 days, how severe was your child’s 
eosinophilic esophagitis (EoE)? 
Mild (1) 
Moderate (2) 
Severe (3) 
Very severe (4) 
GIS-Clin 
Overall, how severe is your patient’s eosinophilic 
esophagitis (EoE)? 
Mild (1) 
Moderate (2) 
Severe (3) 
Very severe (4) 
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Body Weight and Body Mass Index (BMI) Z-scores and Percentiles 
Body weight for age z-score, body weight for age percentile, body weight for height/length z-
score, and BMI for age z-score at each visit will be calculated based on the growth charts from 
Centers for Disease Control and Prevention (CDC) for ages 0 to 20 years (for ages 2 to <12 years) 
and World Health Organization (WHO) growth charts for ages 0 to <2 years (for ages 1 to <2 
years). These charts included a set of smoothed percentiles along with CDC LMS (Lambda-Mu-
Sigma) parameters to allow the calculation of other percentiles or z-scores (Flegal, 2013). To 
obtain the z-score for body weight or BMI, the following equation will be used Z = [(X/M)L-
1]/(L×S) for L≠0; Z = ln(X/M)/S for L = 0, where X is the measured body weight or BMI at each 
visit and L, M, and S values are from CDC table. The corresponding percentile can be obtained 
from standard normal distribution. The following CDC growth charts will be used. The growth 
chart is provided in half month intervals for age. 
• Weight-for-age chart (weight in kilograms) for birth to 36 months population by sex and 
age 
• Weight-for-age chart for 2 to 20 years population in kilograms by sex and age 
• Weight-for-stature chart (weight in kilograms) by sex and stature (stature in centimeters) 
• BMI for age charts for 2 to 20 years population by sex and age 
For example, to obtain the weight for age z-score of a 24-month-old male who weighs 14.5 kg, the 
corresponding L, M, and S values in weight-for-age charts for 2 to 20 years population are -
0.20615245, 12.6707633, 0.108125811, respectively. By applying the above LMS method 
equation z-score is 1.23 and the corresponding percentile is 89%. 
EREFS (excluding stricture), Inflammation, and Remodeling Sub-scores 
The EREFS (excluding stricture), inflammation sub-score, and remodeling sub-score for each 
region is the sum of assigned scores for each of the included major features as listed below. The 
sub-scores summed for the proximal and distal regions will be used for analysis. 
Sub-score 
Major features included 
Range 
(per region) 
Range 
(proximal + distal) 
EREFS (excluding 
stricture) total score 
Edema + Rings + Exudates + 
Furrows 
0 - 8 
0 - 16 
Inflammation sub-score 
Edema + Exudates + Furrows 
0 - 5 
0 -10 
Remodeling sub-score 
Rings + Stricture 
0 - 4 
0 - 8 
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4.5. 
Safety Variables 
4.5.1. 
Adverse Events and Serious Adverse Events 
Adverse events and serious adverse events will be collected from the time of informed consent 
signature and then at each visit until the end of the study. All adverse events are to be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). 
The definition of adverse events and serious adverse events are provided in protocol Section 10.2.1 
and Section 10.2.2. Pre-treatment AE and treatment-emergent AE (TEAE) are defined as follows: 
• Pre-treatment signs and symptoms (pre-treatment AEs) are AEs that developed or 
worsened in severity during the pre-treatment period. 
• TEAEs are defined as those that are not present at baseline or represent the exacerbation 
of a pre-existing condition during the treatment-emergent period. 
‒ TEAEs for part A treatment period are defined as TEAEs with onset date during 
the Part A treatment period.  
‒ TEAEs for part B extended active treatment period are defined as TEAEs with onset 
during the Part B extended treatment period.  
‒ TEAEs for follow-up period are defined as TEAEs with onset during the follow-up 
period. 
4.5.2. 
Adverse Events of Special Interest 
Adverse events of special interest (AESI) 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 
• Arthralgia 
For detailed definition of these AESIs, please see Section 11.4. 
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4.5.3. 
Laboratory Safety Variables 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory. Samples will be collected predose at time points according to visit schedule 
(Section 11.2). Tests will include: 
Blood Chemistry 
Sodium 
Creatinine 
 
Potassium 
Blood urea nitrogen (BUN) 
 
Chloride 
Aspartate aminotransferase (AST) 
 
Carbon dioxide 
Alanine aminotransferase (ALT) 
 
Calcium 
Alkaline phosphatase 
 
Glucose 
Lactate dehydrogenase (LDH) 
 
Albumin 
Estimated glomerular filtration rate (eGFR) 
 
Total protein, serum 
Total and indirect bilirubin 
 
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 WOCBP. Serum or urine pregnancy testing 
will be performed at time points listed in visit schedule (Section 11.2). 
• Tuberculosis testing will be performed on a country-by-country basis according to local 
guidelines if required by regulatory authorities or ethics boards. 
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4.5.4. 
Vital Signs 
Vital signs, including heart rate, blood pressure, respiration rate, and body temperature will be 
collected predose and 30 minutes post-dose at time points listed in the schedule of events in 
Section 11.2. 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. Body weight in kg and height in cm 
(or length for patients <2 years of age) will be measured at the time points listed in the schedule 
of events table in Section 11.2. Body mass index will be programmatically calculated based on the 
weight and height data. 
4.5.5. 
Physical Examination Variables 
The physical examination variable values are dichotomized as normal and abnormal. 
A thorough and complete physical examination will be performed at the screening visit 1, baseline 
visit 3, week 16, week 52, ET visit before follow-up or unscheduled visit before rescue treatment. 
4.6. 
Pharmacokinetic Variables  
The PK variable is the concentration of functional dupilumab in serum and time for individual 
patients. Serum samples for measuring functional dupilumab concentrations will be collected at 
time points according to Section 11.2. 
4.7. 
Immunogenicity Variables 
The immunogenicity variables include ADA status, NAb status, and titer at nominal sampling 
time/visit. Serum samples for ADA will be collected at the clinic visits specified in Section 11.2. 
Samples positive in the dupilumab ADA assay will be further characterized for ADA titers and for 
the presence of NAb against dupilumab. 
4.8. 
Biomarker Variables 
Biomarkers to be analyzed in this study are:  
• Serum total IgE 
• Eotaxin-3 
Serum/plasma samples for measurements of biomarkers to study the pharmacodynamic activity of 
dupilumab in EoE patients will be collected at time points according to Section 11.2. 
4.9. 
Clinical Outcome Assessments for Psychometric Validity Assessment 
The measurement properties of the PESQ-C and PESQ-P (as described in Section 4.4.2) will be 
evaluated using anchor-based methods and qualitative insights from the week 16 exit interviews. 
The details of the analyses are specified in the R668-EE-1877 psychometric analysis plan. 
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5. 
STATISTICAL METHODS 
For continuous variables, descriptive statistics will include the following: the number of patients 
reflected in the calculation (n), mean, median, Q1, Q3, standard deviation, minimum, and 
maximum. 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
Missing values at baseline will not be imputed unless otherwise specified. 
All data will be summarized by the following treatment groups in each study period: 
• Part A 
− Higher exposure dupilumab dose regimen 
− Lower exposure dupilumab dose regimen 
− Combined dupilumab group (for safety analysis only) 
− Placebo 
• Part B 
− Higher exposure dupilumab dose regimen/Higher exposure dupilumab dose 
regimen 
− Lower exposure dupilumab dose regimen/Lower exposure dupilumab dose regimen 
− Combined dupilumab group (for safety analysis only) 
− Placebo/Higher exposure dupilumab dose regimen 
− Placebo/Lower exposure dupilumab dose regimen 
− Placebo/Combined dupilumab group (for safety analysis only) 
− Total (for safety analysis only) 
5.1. 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics will be summarized by treatment groups and for study 
total based on the FAS. A separate summary will be provided for Part B SAF patients. 
5.2. 
Medical History 
Medical history will be summarized by primary System Organ Class (SOC) and Preferred Term 
(PT) for each treatment group and for study total based on the FAS. The table will be sorted by 
decreasing frequency of SOC followed by PT based on the overall incidence across treatment 
groups. 
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5.3. 
Prior/Concomitant Medications/Procedures  
Number and proportion of patients taking prior/concomitant medications, prohibited 
medications/procedures, and rescue medications/procedures will be summarized for each 
treatment group and study total, based on study period specific FAS, by ATC Level 2 and ATC 
Level 4, sorted by decreasing frequency of ATC Level 2 and ATC Level 4 in the combined 
dupilumab treatment group. Patients will be counted once in each medication class linked to the 
medication. 
Number and proportion of patients taking PPIs for the treatment of EoE will be summarized by 
PPI therapy name. In addition, number and proportion of patients taking swallowed 
topical/systemic corticosteroids for the treatment of EoE will be summarized for swallowed topical 
corticosteroids and systemic corticosteroids by ATC Level 2 and ATC Level 4, respectively. 
Number and proportion of patients undergoing prior/concomitant procedures will be summarized 
for each treatment group and study total, based on the study period specific FAS, by SOC and PT, 
and sorted by decreasing frequency of SOC and PT in the combined dupilumab treatment group. 
Separate summaries will be provided for Part A and Part B concomitant medications/procedures. 
5.4. 
Subject Disposition 
The following summaries will be provided for each treatment group and study total (unless 
otherwise specified): 
• The total number of screened patients (for study total only) 
• The total number of randomized patients: received a randomization number from IWRS 
• The total number of patients in each analysis set 
• The total number of patients who discontinued the study treatment in Part A, and the 
reasons for discontinuation (including COVID-19 related reasons) 
• The total number of patients who discontinued the study in Part A, and the reasons for 
discontinuation (including COVID-19 related reasons) 
• Number of patients who entered into Part B 
• The total number of patients who discontinued the study treatment in Part B, and the 
reasons for discontinuation (including COVID-19 related reasons) 
• The total number of patients who discontinued the study in Part B, and the reasons for 
discontinuation (including COVID-19 related reasons) 
• Number of patients who entered 12-week follow-up period from Part A and Part B, 
respectively 
Summary table of important protocol deviations in each study treatment period will be provided. 
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5.5. 
Extent of Study Treatment Exposure  
5.5.1. 
Exposure to Investigational Product 
The duration of exposure to study drug is calculated separately for Part A, Part B, and the overall 
study as follows: 
(Date of last study drug injection in the respective study period – date of first study drug 
injection in the respective study part) + 14 
NOTE: exposure will be calculated based on the last study drug injection date and first study drug 
injection date regardless of temporary dosing interruption or dosing extension due to COVID-19. 
For patients with extended dosing due to COVID-19, the duration of exposure may exceed 16 
weeks for Part A or 36 weeks for Part B as study design. 
Summary of exposure to study drug will include the number of study drug doses administered and 
the duration of exposure. Duration of exposure will be summarized for each treatment group using 
the number of patients, mean, standard deviation, median, Q1, Q3, minimum, and maximum. 
These summaries will be provided for Part A and Part B separately. 
In addition, the duration of exposure will be summarized categorically by counts (n) and 
percentages (%) for each of the following categories and cumulatively by these categories as well: 
• Part A: ≥ 7 days, ≥ 14 days, ≥ 21 days, ≥ 28 days, ≥ 35 days, ≥ 42 days, ≥ 49 days, ≥ 
56 days, ≥ 63 days, ≥ 70 days, ≥ 77 days, ≥ 84 days, ≥ 91 days, ≥ 98 days, ≥ 105 days, 
≥112 days, with an increment of 1 week for each subsequent category. 
• Part B: ≥ 7 days, ≥ 14 days, ≥ 21 days , ≥ 28 days, ≥ 35 days, ≥ 42 days, ≥ 49 days, ≥ 
56 days, ≥ 63 days, ≥ 70 days, ≥ 77 days, ≥ 84 days, ≥ 91 days, ≥ 98 days, ≥ 105 days, 
≥112 days, ≥119 days, ≥126 days, ≥133 days , ≥140 days, ≥147 days, ≥154 days, ≥161 
days, ≥168 days, ≥175 days, ≥182 days, ≥189 days, ≥196 days, ≥203 days, ≥210 days, 
≥217 days, ≥224 days, ≥231 days, ≥238 days, ≥245 days, ≥252 days, with an increment 
of 1 week for each subsequent category. 
For patients who received at least 1 dose of study drug, the total duration of exposure to study drug 
during the study (throughout Part A and Part B) is calculated as: 
(Date of last study drug injection in the study – date of first study drug injection) + 14 
The duration of observation period during the study is calculated as: 
(Date of last study visit – date of first study injection) + 1 
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The duration of observation period will be summarized descriptively using number of patients, 
mean, standard deviation, median, Q1, Q3, minimum, and maximum. In addition, the number (n) 
and proportion (%) of patients with observation periods will be presented by specific time periods. 
The time periods of interest are specified as follows:  
• Part A: ≥ 8 days, ≥ 15 days, ≥ 22 days, ≥ 29 days, ≥ 36 days, ≥ 43 days, ≥ 50 days, ≥ 
57 days, ≥ 64 days, ≥ 71 days, ≥ 78 days, ≥ 85 days, ≥ 92 days, ≥ 99 days, ≥ 106 days, 
≥113 days, with an increment of 1 week for each subsequent category. 
• Part B: ≥ 8 days, ≥ 15 days, ≥ 22 days, ≥ 29 days, ≥ 36 days, ≥ 43 days, ≥ 50 days,  ≥ 
57 days, ≥ 64 days, ≥ 71 days, ≥ 78 days, ≥ 85 days, ≥ 92 days, ≥ 99 days, ≥ 106 days, 
≥113 days, ≥120 days, ≥127 days, ≥134 days , ≥141 days, ≥148 days, ≥155 days, ≥162 
days, ≥169 days, ≥176 days, ≥183 days, ≥190 days, ≥197 days, ≥204 days, ≥211 days, 
≥218 days, ≥225 days, ≥232 days, ≥239 days, ≥246 days, ≥253 days, with an increment 
of 1 week for each subsequent category. 
5.6. 
Analyses of Efficacy Variables 
The analyses of efficacy variables are described in the subsections below and summarized in 
Section 11.1. The intercurrent events, strategies, and the corresponding missing data handling 
approaches for the primary estimand of interest for the primary endpoint are provided in Table 1 . 
 
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Table 1: 
Summary of Primary Estimand for Primary Endpoint and Secondary Endpoints in Part A 
Endpoint 
Category 
Estimands 
Endpoint(s) 
Population 
Intercurrent event(s) strategy and 
missing data handling 
Population-level summary/Analysis 
 
Primary 
Endpoint 
Proportion of patients 
achieving peak esophageal 
intraepithelial eosinophil 
count of ≤6 eos/hpf (400×) at 
week 16 
FAS 
The intercurrent events will be handled as 
follows: 
• 
Treatment discontinuation: data 
collected after the patient 
discontinued treatment will be 
included in the analysis (treatment 
policy strategy) 
• 
Initiation of treatment with systemic 
and/or swallowed topical 
corticosteroids drugs and dilation: 
patients will be considered as non-
responders after such event 
(composite variable strategy) 
Note: the composite strategy will be 
considered if a patient receives rescue 
treatment a any time during the study. 
 
Missing data handling: patients with a 
missing value for the primary endpoint at 
week 16 due to study discontinuation or 
other reasons will be considered non-
responders. Missing data due to COVID-
19 will be imputed by multiple imputation 
(MI). 
Cochran-Mantel-Haenszel (CMH) test 
adjusting for the randomization 
stratification factor (baseline weight 
group) will be utilized.  
The Mantel-Haenszel estimate of 
odds ratios between each of 
dupilumab groups and placebo, 
and its 2-sided 95% confidence 
intervals will be provided. 
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Endpoint 
Category 
Estimands 
Endpoint(s) 
Population 
Intercurrent event(s) strategy and 
missing data handling 
Population-level summary/Analysis 
 
Secondary 
Endpoints 
Binary endpoints (e.g., 
proportion of patients 
achieving peak esophageal 
intraepithelial eosinophil 
count of <15 eos/hpf at week 
16) 
FAS 
The intercurrent events strategy and 
missing data handling methods will be the 
same with the primary endpoint. 
The primary analysis method will be 
the same as for the primary endpoint. 
Continuous endpoints that 
are scheduled to be measured 
repeatedly post-baseline up 
to week 16 (e.g., change in 
the proportion of days with 1 
or more EoE signs from 
baseline to week 16 as 
measured by the PESQ-C) 
FAS 
The intercurrent events will be handled as 
follows: 
• 
Treatment discontinuation: data 
collected after the patient 
discontinued treatment will be 
included in the analysis (treatment 
policy strategy) 
• 
Initiation of treatment with systemic 
and/or swallowed topical 
corticosteroids drugs and dilation: 
data after such events will be assigned 
by the worst observed value 
(composite variable strategy) 
 
Missing data handling: after 
discontinuation of the study due to 
AE/lack of efficacy b prior to week 16, 
patients with a missing value at week 16 
will be imputed using WOCF method, and 
MI approach will be used for the missing 
data due to other reasons. 
Continuous secondary efficacy 
endpoints at week 16 will be analyzed 
using an analysis of covariance 
(ANCOVA) model with treatment 
groups, randomization stratification 
factor, and relevant baseline 
measurement as a covariate included 
in the model. 
The least square (LS) means and 
difference in LS means between 
dupilumab groups and placebo will be 
presented. 
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Endpoint 
Category 
Estimands 
Endpoint(s) 
Population 
Intercurrent event(s) strategy and 
missing data handling 
Population-level summary/Analysis 
 
Continuous endpoints that 
are scheduled to be measured 
only once post-baseline up to 
week 16 (e.g., absolute 
change in EoE-EREFS from 
baseline to week 16) 
FAS 
The intercurrent events will be handled as 
follows: 
• 
Treatment discontinuation: data 
collected after the patient 
discontinued treatment will be 
included in the analysis (treatment 
policy strategy) 
• 
Initiation of treatment with systemic 
and/or swallowed topical 
corticosteroids drugs and dilation: 
data after such events will be assigned 
by the worst observed value 
(composite variable strategy) 
 
Missing data handling: patients with a 
missing value due to COVID-19 will be 
imputed using MI approach, and WOCF 
method will be used for missing not due to 
COVID-19. WOCF method refers to 
missing values at week 16 will be imputed 
with patient’s baseline value or the 
available post-baseline value, whichever is 
worse. 
a: The rescue treatment(s) include systemic and/or swallowed topical corticosteroid drugs and esophageal dilation. Blinded adjudication (blinded to the treatment assignment) of 
rescue treatment(s) will be performed by medical director (or medical monitor) prior to the Part A database lock.  
b: Patients who are discontinued from the study due to AE or lack of efficacy are captured in the case report form “Study Completion”. 
 
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5.6.1. 
Analysis of Primary Efficacy Variable 
The primary analysis of proportion of patients achieving a histologic response of peak esophageal 
intraepithelial eosinophil count ≤6 eos/hpf at week 16 will be analyzed using the Cochran-Mantel-
Haenszel (CMH) test (chi-squared test based on the odds ratio), adjusting for the randomization 
stratification factor (baseline weight group [≥5 - <15 kg, ≥15- <30 kg, ≥30- <60 kg]). The 
randomization stratification of baseline weight group may be pooled to ensure the sufficient 
sample size of each stratum. The pooling algorithm of the baseline weight group will be applied if 
the number of patients in one of the treatment arms in a baseline weight group is ≤ 4.  In this case 
the weight group will be pooled with an adjacent tiered weight group that has the least number of 
patients in that weight group (e.g. if the number of patients in >=15-<30kg weight group is ≤ 4 in 
one of the treatment arms, the weight group will be pooled with the smaller of either the >=5-
<15kg weight group or the <=30 kg weight group). Estimates of odd ratios and its 95% confidence 
intervals (CI) will be presented along with the p-values between each dupilumab group and 
placebo. In addition, the estimates of treatment difference and its 95% CI will be provided based 
on the Mantel-Haenszel (MH) method.   
Data may be collected after the patient discontinued treatment and will be included in the analyses. 
To account for the use of rescue treatment, patients will be considered as non-responder for all 
time points subsequent to the use of rescue treatment in the primary analysis. 
If week 16 biopsy is performed after the date when the first dose of Part B study drug is 
administered, patients will be considered as non-responder in the analysis. 
Due to COVID-19 restrictions, patients may postpone the week 16 visit until an in-clinic visit can 
be done for biopsy. Before the biopsy procedure could be performed, study drug would be shipped 
to patients directly to enable them to extend their current assigned dose regimen of study drug. The 
data from those delayed week 16 visits will be used in the primary analysis as long as the patients 
keep the extended dosing before biopsy. If patients whose extended dosing due to COVID-19 is 
interrupted (ie. investigational product not administered for 4 consecutive weeks or missing >=3 
total injections for non-safety reasons), their week 16 biopsy data will be set to missing and 
imputed using multiple imputation (MI). 
Missing data at week 16 will be handled according to the reasons for missingness as follows: 
• If the peak esophageal intraepithelial eosinophil count at week 16 is missing due to 
COVID-19 pandemic, the data will be imputed by multiple imputation (MI) using a 
seed number of 6681877 for 10 times based on patients who have non-missing 
eosinophil counts at week 16. The MI will utilize the regression method with treatment 
group, randomization stratification factor, baseline eosinophil count as covariates and 
week 16 eosinophil count as response variable in the regression model. The imputed 
week 16 eosinophil counts will determine whether that patient will be classified as a 
responder or non-responder.  
• If a patient has missing value for the histological response (peak esophageal 
intraepithelial eosinophil count) at week 16 due to reasons not related to the COVID-
19 pandemic (e.g., discontinuation from study), the patient will be classified as a non-
responder at week 16. 
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Each of the imputed complete datasets will be analyzed by the CMH test. The estimates of odds 
ratios will be log-transformed to normalize these estimates before applying Rubin’s formula. The 
Wilson-Hilferty (WH) (Wilson & Hilferty, 1931) transformation will be used to normalize test 
statistics before combining result of the CMH test. Statistical inference obtained from the Wilson-
Hilferty transformed statistics of all imputed data will be combined using Rubin’s formula 
(Ratitch, 2013). See Appendix 11.7 for the Statistical Analysis Software (SAS) syntax code for 
the multiple imputation and the analysis. 
Sensitivity analyses 
Sensitivity analyses will assess alternative methods to impute missing data and include the 
following for the primary endpoint. 
1. Tipping point analysis approach: To assess the robustness of analysis results under 
MNAR (missing not at random) assumption, a delta-adjusting pattern-mixture approach 
for tipping point analysis (Ratitch, 2013) will be conducted for the primary endpoint. The 
impact from missing data due to study discontinuation or other reasons on the comparisons 
in proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 
eos/hpf at week 16 between each dupilumab group and placebo control group will be 
examined, by adjusting for stratification factor: 
• A series of analyses will be performed by applying a specified sequence of 
different values of shift parameter to the 3 treatment groups for the data 
imputation: in the placebo group, different values (>0) of shift parameter will 
be subtracted from the imputed peak eosinophil count; in each of dupilumab 
group, different values (<0) of shift parameter will be added to the imputed peak 
eosinophil count. The imputed peak eosinophil count which is negative will be 
replaced by 0. Patients who achieve peak eosinophil count of ≤6 eos/hpf will 
be derived based on the imputed peak eosinophil count after shifting. 
• For each combination of different values of shift parameter applied to the 3 
treatment groups, 10 multiple imputed datasets will be generated using a seed 
number of 6681877. Proportion of patients achieving peak esophageal 
intraepithelial eosinophil count of ≤6 eos/hpf will be analyzed using CMH test. 
The results obtained from 10 multiple imputed datasets will be combined using 
Rubin’s formula (Ratitch, 2013) for statistical inference, i.e., p-value and 
treatment difference between active treatment groups and placebo group. 
• A “tipping point” will be identified when the result is no longer statistically 
significant (i.e., p-value >0.05). 
2. Worst observation carried forward - multiple imputation (WOCF-MI) approach: 
Data after rescue treatment or the missing peak esophageal intraepithelial eosinophil count 
at week 16 due to AE/lack of efficacy will be imputed with patient’s baseline value or the 
available post-baseline value up to week 16, whichever is worse, i.e., WOCF. The missing 
data due to other reasons will be imputed by MI using a seed number of 6681877 for 10 
times based on patients who have non-missing eosinophil counts at week 16. The imputed 
week 16 eosinophil counts will determine whether that patient will be classified as a 
responder or non-responder. The 10 complete datasets after the imputations will be 
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analyzed using CMH test. The results from the 10 analyses will be combined using the 
SAS MIANALYZE procedure (Ratitch, 2013). 
Supplementary analysis 
A supplementary analysis will be performed to consider the composite strategy for treatment 
discontinuation, in which the patient will be considered as a non-responder after treatment 
discontinuation regardless of the reason for discontinuation. 
5.6.2. 
Analysis of Secondary Efficacy Variables 
Binary endpoints at week 16 
Secondary efficacy endpoints that measure binary responses at week 16 will be analyzed in the 
same fashion as the primary endpoint, including the method to handle missing data. 
Continuous endpoints at week 16 
Continuous secondary efficacy endpoints at week 16 will be analyzed using an analysis of 
covariance (ANCOVA) model for the FAS with treatment groups, randomization stratification 
factor, and relevant baseline measurement as a covariate included in the model. For 
endoscopy/biopsy-based endpoints (i.e., esophageal intraepithelial eos count, EoE-EREFS, EoE-
HSS), if week 16 endoscopy/biopsy is performed after the date when the first dose of Part B study 
drug is administered, data from that endoscopy/biopsy will be set to missing in the analysis. 
To account for the use of rescue treatment, data will be set to missing for all time points subsequent 
to the use of rescue treatment. 
For continuous efficacy data that are scheduled to be measured repeatedly post-baseline up to week 
16 (e.g., change in the proportion of days with 1 or more EoE signs from baseline to week 16 as 
measured by the PESQ-C), missing data will be imputed by the pattern-mixture approach. 
Specifically, the WOCF-MI approach, where the WOCF approach will be used for imputing the 
missing data if data are missing subsequent to rescue treatment or discontinuation of study due to 
AE/lack of efficacy as captured in CRF “Study Completion”; the MI approach will be used for the 
missing data due to other reasons (e.g., missing PESQ-C data due to less than 8 diary entries for 
the 14-day period). The rescue treatment(s) include systemic and/or swallowed topical 
corticosteroids drugs and esophageal dilation. Blinded adjudication (blinded to the treatment 
assignment) of rescue treatment(s) will be performed by medical director (or medical monitor) 
prior to the Part A database lock. 
MI will follow the steps below using a seed number of 6681877 in both steps: 
• Step 1: Use the Markov Chain Monte Carlo (MCMC) method to fill in the intermittent 
missing values so that a monotone missing pattern will be formed. 
• Step 2: For each of the imputed datasets with monotone missing pattern in Step 1, the 
remaining missing data will be imputed using regression method with treatment group, 
randomization stratification factor, relevant baseline measurement as a covariate, and 
the post-baseline measurements up to week 16 as response variable. 
• Step 3: Each of the 40 imputed datasets will be combined with the dataset imputed by 
WOCF approach, and then analyzed using the ANCOVA.  
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• Step 4: The results from the 40 analyses on the complete datasets will be combined to 
generate a valid overall statistical inference using Rubin’s formula (Ratitch, 2013). The 
least square (LS) means and difference in LS means between dupilumab groups and 
placebo will be presented. 
The cumulative distribution function (CDF) of the absolute change from baseline in the proportion 
of days (or total segments within a day) with 1 or more EoE signs as measured by the PESQ-C at 
week 16 and from baseline in the proportion of days (or total segments within a day) with 1 or 
more EoE symptoms as measured by the PESQ-P at week 16 will be graphed to present the 
between-treatment-group differences at each level of the change. 
For continuous efficacy data that are scheduled to be measured only once post-baseline up to week 
16 (e.g., absolute change in EoE-EREFS from baseline to week 16), a hybrid approach WOCF-MI 
will be used to handle missing data. That is, missing values at week 16 due to reasons not related 
to COVID-19 pandemic will be imputed with patient’s baseline value or the available post-baseline 
value, whichever is worse, i.e., a WOCF approach, and missing values at week 16 due to COVID-
19 pandemic will be imputed using MI as described in the primary analysis of the primary endpoint 
of histologic response in Section 5.6.1. The 10 complete datasets after the imputations will be 
analyzed using ANCOVA. The results from the 10 analyses will be combined using the SAS 
MIANALYZE procedure. 
The primary analysis of EoE-EREFS will be based on centralized readings.  
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 16 between the dupilumab and placebo 
groups is statistically significant. Missing NES data will be imputed by Last Observation Carried 
Forward (LOCF) approach. P-values will be reported. 
For the change from baseline to week 16 in the proportion of days with 1 or more EoE signs as 
measured by the PESQ-C, a supplementary analysis will be performed to require a minimum of 4 
eDiary entries (including days when caregivers did not observe any EoE signs) per week to derive 
the proportion during a 14-day period. 
Secondary endpoints in Part B 
Secondary endpoints at week 52 (Part B) will be analyzed descriptively at given visits for treatment 
received in Part B as well as by treatment group as in Part A (double-blind treatment period). No 
missing values will be imputed.  
All observed values, regardless of whether rescue treatment is used, or data are collected after 
withdrawal from study treatment, will be used for analysis. No missing values will be imputed. 
For categorical efficacy variables, the proportion of patients meeting response criteria at each visit 
will be calculated using the number of patients with non-missing value at the visit as the 
denominator. 
For efficacy variables whose calculations involve baseline values, e.g., absolute (or percent) 
change from baseline, separate summaries will be provided for analyses using the study baseline 
and Part B baseline values. The study baseline is the latest available valid measurement taken prior 
to or on the date of the first dose of study drug administration (scheduled to be administered at the 
baseline visit 3). Part B baseline is the last available valid measurement taken prior to or on the 
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date of the first dose of extended active treatment period (scheduled to be administered at week 16 
visit).  
5.6.3. 
Adjustment for Multiple Comparison 
The following multiplicity adjustment approach, a hierarchical procedure, will be used to control 
the overall Type-1 error rate at 0.05 for the primary endpoint and the secondary endpoints across 
the 2 dupilumab dose regimens versus placebo in Part A only. Each hypothesis will be formally 
tested only if the preceding one is significant at the 2-sided 0.05 significance level. The hierarchical 
testing order is shown in the below table (all comparisons are with the placebo). 
 
Endpoints 
Dupilumab 
Higher 
Exposure 
Dupilumab 
Lower 
Exposure 
Dupilumab 
Primary 
endpoint 
Proportion of patients achieving peak esophageal 
intraepithelial eosinophil count of ≤6 eos/hpf at week 16 
1 
2 
Secondary 
endpoints 
Proportion of patients achieving peak esophageal 
intraepithelial eosinophil count of <15 eos/hpf at week 16 
3 
11 
Percent change in peak esophageal intraepithelial 
eosinophil count (eos/hpf) from baseline to week 16 
4 
12 
Absolute change in mean EoEHSS grade score from the 
EoE-HSS from baseline to week 16 
5 
13 
Absolute change in mean EoEHSS stage score from the 
EoE-HSS from baseline to week 16 
6 
14 
NES for the relative change from baseline to week 16 in 
the type 2 inflammation transcriptome signature 
7 
15 
 
NES for the relative change from baseline to week 16 in 
the EoE diagnostic panel (EDP) transcriptome signature 
8 
16 
Absolute change in EoE EREFS from baseline to week 16 
9 
17 
Change from baseline to week 16 in the proportion of days 
with 1 or more EoE signs as measured by the PESQ-C (for 
patients aged ≥1 to <12 years) 
10 
18 
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5.6.4. 
Subgroup Analysis 
Subgroups described in Section 3.5 will be summarized for the primary efficacy endpoint (as listed 
in Section 4.4.1) and the below selected secondary endpoints. Treatment difference and its 95% 
confidence interval in subgroups of patients will be presented in forest plots. The stratification 
factor (baseline weight group) will not be included in the subgroup analysis when applying the 
CMH test and ANCOVA. 
• Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from 
baseline to week 16 
• Absolute change in mean EoEHSS grade score from the EoE-HSS from baseline to 
week 16 
• Absolute change in mean EoEHSS stage score from the EoE-HSS from baseline to 
week 16 
• Absolute change in EoE EREFS from baseline to week 16 
• Change from baseline to week 16 in the proportion of days with 1 or more EoE signs 
as measured by the PESQ-C (for patients aged ≥1 to <12 years) 
5.6.5. 
Analysis of Exploratory Efficacy Variables 
The exploratory efficacy endpoints at week 16 or week 52 will be analyzed descriptively. 
All observed values, regardless of whether rescue treatment is used, or data are collected after 
withdrawal from study treatment, will be used for analysis. No missing values will be imputed. 
The CDF of the proportion of patients achieving peak esophageal intraepithelial eosinophil count 
of ≤6 eos/hpf at week 16 and achieving absolute/percent change from baseline to week 16 in the 
proportion of days with 1 or more EoE signs as measured by PESQ-C will be graphed to present 
the between-treatment-group differences at each level of the change. 
5.7. 
Analysis of Safety Data 
The analysis of safety and tolerance will be performed on the SAF, as defined in Section 3.2. 
The safety analysis will be based on the reported AEs and other safety information (clinical 
laboratory evaluations and vital signs).  
Thresholds for Potential Clinically Significant Values (PCSV) in laboratory variables and vital 
signs are defined in Section 11.3. Treatment-emergent PCSV is any PCSV developed or worsened 
in severity compared to the baseline during the treatment and follow-up period. When identifying 
treatment-emergent PCSVs in Part B, baseline for Part B PCSVs is the last available valid 
measurement taken prior to the first dose of extended active treatment in Part B (scheduled to be 
administered at week 16 visit). 
The time interval to detect any event or abnormality is between the first injection of study 
medication and EOS. 
The summary of safety results will be presented for each treatment group for each study period. 
For safety variables/summaries involving baseline values, e.g., absolute change from baseline or 
shift table, study period specific baseline will be utilized. Summaries for Part A will use the study 
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baseline (i.e., the latest available valid measurement prior to the first dose of study drug in the 
study). Summaries for Part B and follow-up period will use Part B baseline (i.e., the last available 
valid measurement prior to the first dose of extended active treatment in Part B). 
5.7.1. 
Adverse Events  
The number and proportion of patients reporting TEAEs will be summarized for Part A 16-week 
double-blind treatment period, Part B 36-week extended active treatment period, and 12-week 
follow-up period, as described in Section 3.2. 
AE incidence tables will be presented by treatment group for the SAF as well as subgroups defined 
for safety analysis (Section 3.5). TEAE summaries will present the number (n) and percentage (%) 
of patients experiencing an TEAE by SOC and PT, sorted by decreasing frequency of SOC and 
PT for the combined dupilumab treatment group. Multiple occurrences of AEs of the same PT (or 
SOC) in the same patient will be counted only once for that PT (or SOC). For tables presenting 
severity of events, the worst severity will be chosen for patients with multiple instances of the 
same event. The denominator for computation of percentage is the number of patients in each 
treatment group for the corresponding analysis period as specified in Section 3.2. 
An overall summary of TEAEs will be provided with number (n) and percentages (%) of patients 
with any: 
• TEAE 
• Serious TEAE 
• TEAE of special interest (AESI) 
• TEAE with fatal outcome 
• TEAE leading to permanent treatment discontinuation 
Detailed summaries of all TEAEs in each treatment group will include: 
• TEAEs 
− TEAEs by primary SOC/PT 
− TEAEs by primary SOC/PT with incidence of PT ≥5% in any treatment group 
− TEAEs by severity and by primary SOC/PT 
− TEAEs related to study medication as assessed by the investigator by primary 
SOC/PT 
− TEAEs of special interest by AESI category (see Section 11.4) and primary 
SOC/PT 
• Serious TEAEs by SOC/PT 
• TEAEs leading to permanent discontinuation of study treatment by primary SOC/PT 
• TEAEs with fatal outcome by primary SOC/PT 
The number and proportion of patients with injection site reaction by PT will be summarized. 
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5.7.2. 
Clinical Laboratory Measurements  
Laboratory measurements include clinical chemistry, hematology, and urinalysis results, and will 
be converted to values in standard international (SI) units. Summaries of laboratory variables will 
include: 
• Descriptive statistics of laboratory result and change from baseline by visit 
• The number (n) and percentage (%) of patients with treatment-emergent PCSVs. This 
summary will be provided on the subgroup of SAF patients who did not meet the PCSV 
criterion at the baseline 
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
5.7.3. 
Analysis of Vital Signs 
Summaries of vital sign variables will include: 
• Descriptive statistics of vital sign variable and change from baseline by visit 
• The number (n) and percentage (%) of subjects with treatment-emergent PCSV. This 
summary will be provided on the subgroup of SAF patients who did not meet the PCSV 
criterion at the baseline 
• Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
5.7.4. 
Physical Exams 
Abnormal status will be tabulated for assessments of each physical exam category and presented 
by visit. 
5.8. 
Analysis of Pharmacokinetic Data 
The following analyses will be conducted: 
• Descriptive statistics of functional dupilumab concentrations in serum at each sampling 
time by dose 
• Graphical presentations of median and mean (+/- SD) functional dupilumab 
concentration in serum vs nominal time profiles. Plots of concentration vs time will be 
provided as both non-log and semi-log. When plotted as non-log, concentrations less 
than LLOQ will be set to zero (0). When plotted as semi-log, for concentrations less 
than LLOQ, LLOQ/2 will be imputed. 
• Graphical presentations of individual functional dupilumab concentration in serum vs 
actual sampling time profiles. When plotted as non-log, concentrations less than LLOQ 
will be set to zero (0). When plotted as semi-log, for concentrations less than LLOQ, 
LLOQ/2 will be imputed. 
• Assessment of the impact of anti-drug antibodies on functional dupilumab 
concentrations in serum 
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No formal statistical analysis will be performed. 
5.9. 
Analysis of Immunogenicity Data 
5.9.1. 
Analysis of ADA  
The immunogenicity variables mentioned in Section 4.7 will be summarized using descriptive 
statistics. Immunogenicity will be characterized by ADA status, ADA category, and maximum 
titer observed in patients in the ADA analysis set.  
The ADA status of each patient may be classified as one of the following:  
• Positive 
• Pre-existing - If the baseline sample is positive and all post baseline ADA titers are 
reported as less than 4-fold the baseline titer value 
• Negative - If all samples are found to be negative in the ADA assay 
The ADA category of each positive patient is classified as: 
• Treatment-boosted - A positive result at baseline in the ADA assay with at least one 
post baseline titer result ≥ 4-fold the baseline titer value  
• Treatment-emergent - A negative result or missing result at baseline with at least one 
positive post baseline result in the ADA assay. Patients that are treatment-emergent 
will be further categorized as follows: 
− Persistent - A positive result in the ADA assay detected in at least 2 consecutive 
post baseline samples separated by at least a 12-week post baseline period (based 
on nominal sampling time), with no ADA-negative results in-between, regardless 
of any missing samples 
− Indeterminate - A positive result in the ADA assay at the last collection time point 
only, regardless of any missing samples 
− Transient - Not persistent or indeterminate, regardless of any missing samples 
The maximum titer category of each patient is classified as: 
• Low (titer <1,000) 
• Moderate (1,000 ≤ titer ≤ 10,000) 
• High (titer >10,000) 
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The following listings will be provided by treatment group and ADA titer level: 
• Number (n) and percent (%) of ADA-negative patients 
• Number (n) and percent (%) of patients with pre-existing immunoreactivity  
• Number (n) and percent (%) of treatment-emergent ADA positive patients  
− Number (n) and percent (%) of persistent treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of indeterminate treatment-emergent ADA positive 
patients 
− Number (n) and percent (%) of transient treatment-emergent ADA positive patients 
• Number (n) and percent (%) of treatment-boosted ADA positive patients  
Listing of all ADA titer levels will be provided for patients with pre-existing, treatment-emergent, 
and treatment-boosted ADA response. 
5.9.2. 
Analysis of Neutralizing Antibody (NAb) Data 
Samples positive in the dupilumab ADA assay will be further characterized for the presence of 
NAb to dupilumab. The absolute occurrence (n) and percent of patients (%) with NAb status will 
be provided for patients in the NAb analysis set by treatment groups. 
• Negative: Samples tested negative in the ADA assay, or samples positive in the ADA 
assay but tested negative in the NAb assay. 
• Positive: Samples tested positive in the NAb assay.  
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy 
The analyses in this section will only be performed if the incidence of treatment emergent ADA 
positive is sufficient to make meaningful conclusions (i.e., more than 5% in any treatment group). 
5.10.1. 
Association of immunogenicity with exposure 
Potential association between immunogenicity and systemic exposure to dupilumab will be 
explored by treatment groups. Plots of dupilumab concentration may be provided for analyzing 
the potential impact of ADA category, maximum titer category, and NAb status on individual 
patient drug concentration profile. 
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5.10.2. 
Immunogenicity and Safety/Efficacy 
Potential association between immunogenicity variables and safety may be explored with a 
primary focus on the following safety events during the TEAE period:  
• TEAE 
• Serious TEAE 
• TEAE leading to permanent treatment discontinuation 
• Injection site reaction (HLT= “Injection site reaction”) 
• Hypersensitivity (AESI category “Hypersensitivity”) 
• Anaphylaxis (SMQ: Anaphylactic Reaction [Narrow]) 
Potential association between immunogenicity variables and efficacy endpoint profiles may be 
explored (e.g., scatter plot or spaghetti plot).  
The safety and efficacy analyses mentioned above will be conducted using the following ADA 
response categories: 
• ADA Positive 
− Treatment-emergent 
− Treatment-boosted 
• Maximum post-baseline titer category 
• NAb positive  
5.11. 
Analysis of Biomarker Data 
Descriptive statistics for the observed values, change from baseline, and percent change from 
baseline values by treatment and visit will be provided for the biomarker variables as described in 
Section 4.8. Biomarker values after the first rescue treatment used are set to missing (censoring), 
then LOCF approach will be used to impute the missing data at each visit for Part A analysis, and 
all observed values will be used for Part B analysis. 
The Wilcoxon signed-rank test will be used to test if the change or percentage change from baseline 
value is significantly different from zero. Nominal p-value will be reported. 
Correlation of baseline Eotaxin-3 and total IgE (measured value) with the histologic responder 
(histologic response of peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 16) 
will be explored using the logistic model. The model will include the histologic responder/non-
responder as the dependent variable, with randomization stratification factor, the log10 
transformed baseline biomarker data, treatment group, and treatment by baseline biomarker 
interaction as the predictor variables. Model coefficients and P-value will be provided to indicate 
significance of the correlation/association. Patients are considered non-responders after the rescue 
treatment is used. In addition, patients with missing peak eosinophil count at week 16 are 
considered as non-responders. 
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5.12. 
Analysis of Psychometric Validity of Clinical Outcome Assessment 
Measures 
Results of psychometric analysis of the PESQ-C and PESQ-P will be summarized in a clinical 
outcome assessment (COA) dossier. Evidence of content validity and measurement properties of 
relevant COAs will be submitted to the Agency. 
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6. 
DATA CONVENTIONS 
The following analysis conventions will be used in the statistical analysis.  
6.1. 
Definition of Baseline for Efficacy/Safety Variables 
Unless otherwise specified, the Baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of investigational product. If any 
randomized patients are not treated, the baseline will be the last value on or prior to the 
randomization. Part B baseline is defined as the last available valid measurement taken prior to the 
first dose of extended treatment in Part B.  
The following rules specify the determination by both date/time information: 
1. The date and time of first injection will be used to determine the baseline for the AE, vital 
sign, lab (including biomarker), PK, and ADA data. 
2. Only the date of first injection will be used to determine the baseline for other data except 
AE, vital sign, lab (including biomarker), PK, or ADA. 
For re-screened patients, all data from the same patient will be used to derive baseline regardless 
of whether the data are from the screen failure patient ID or enrolled patient ID. 
6.2. 
General Data Handling Convention 
For the laboratory safety variables and biomarker data, if the data are below the lower limit of 
quantification (LLOQ) / limit of linearity, half of the lower limit value (i.e., LLOQ/2) will be used 
for quantitative analyses. For data above the upper limit of quantification (ULOQ) / limit of 
linearity, the upper limit value (i.e., ULOQ) will be used for quantitative analyses. 
6.3. 
Data Handling Convention for Missing Data 
Missing data will not be imputed in listings. This section includes the methods for missing data 
imputation for some summary analyses, if necessary. 
Adverse event 
If the intensity of a TEAE is missing, it will be classified as “severe” in the frequency tables by 
intensity of TEAEs. If the assessment of relationship of a TEAE to the study drug is missing, it 
will be classified as “related” in the frequency tables by relation to the study drug. 
Adverse event start date 
AE start date will be used for AE classification and analysis of AESIs. If AE start date is not 
complete, then the character variable will keep the original incomplete date, the numerical date 
variable will be imputed, and an imputation flag will indicate which date component is missing. 
If AE start day is missing, and AE start month and year are not missing: If AE start year is the 
same as first dose year and the AE start month is the same as the first dose month, then impute AE 
start day using the day of first dose. If this leads to a date after the AE end date, use AE end date 
instead. Otherwise impute the AE start day using the first day of the month. If this leads to a date 
before informed consent, the informed consent date will be used. Imputation flag is ‘D’. 
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If AE start month is missing, and AE start year is not missing: If AE start year is less than the first 
dose year, use the informed consent day and month. If AE start year is equal to the first dose year, 
use the first dose day and month. If this leads to a date after the AE end date, use AE end date 
instead. If AE start year is after the first dose year, use 01 January. Imputation flag is ‘M’. 
If AE start year is missing: Impute AE start date using the day of first dose. If this leads to a date 
after the AE end date, use AE end date instead. Imputation flag is ‘Y’. 
Adverse event end date 
The general recommendation is not to impute AE end date. However, since AE end date will be 
used for the imputation of AE start date, in order to carry through the logic for programming, the 
following intermediate step will be used. Afterwards, only the original character/numeric date 
recorded in CRF will be kept in the final analysis dataset. 
If AE end day is missing, and AE end month and year are not missing: Impute AE end date using 
the last day of the month. If this leads to a date after end of study follow up date, use the end of 
study date instead. 
If AE end month is missing, and AE end year is not missing: Impute AE end date using 31 
December as the day and month. If this leads to a date after end of study follow up date, use the 
end of study date instead. 
If AE end year is missing: Impute AE end date using the end of study date. 
Medication start and end date missing 
To determine whether a medication is pre-treatment medication or concomitant medication or 
both, the missing medication start date is estimated as early as possible, and the missing medication 
end date is estimated as late as possible. If the medication start date is missing, the onset day will 
not be calculated in medication listings. 
Prior medication start date 
If start day is missing, and start month and year are not missing: Impute the start day using the first 
day of the month. Imputation flag is ‘D’; 
If start month is missing, and start year is not missing: Impute the day and month using 01January. 
Imputation flag is ‘M’. 
If start year is missing: Impute start date using 2 years before informed consent date. Imputation 
flag is ‘Y’. 
A special note: for start date with year missing, the general principle is not to impute. However, 
in order to simplify the programming flow, the imputation is proposed to align with the protocol 
which specifies to collect up to 2 years prior medication. Since the start date of prior medication 
will not be used in any analysis, the rule will not impact the analysis result. 
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Prior medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date on or after first dose intake date, use first dose intake date -1 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date on or after first dose intake date, use first dose intake date 1 
instead. Imputation flag is ‘M’ 
If end year is missing: Impute end date using the first dose intake date -1. Imputation flag is ‘Y’. 
Concomitant medication start date 
The imputation rule for concomitant medication start date is the same as AE start date. 
Concomitant medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date after end of study follow up date, use the last visit study date 
instead. Imputation flag is ‘D’. 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date after end of study follow up date, use the last study visit date 
instead. Imputation flag is ‘M’. 
If end year is missing: Impute date using the end of last study visit date. Imputation flag is ‘Y’. 
Medication coding 
Medications whose ATC level 4 cannot be coded will be summarized by setting ATC4=ATC2 in 
the table programs. However, these uncoded ATC level 4 records still need to be confirmed with 
study data management and study medical director. 
PCSV 
Patients who had post-baseline PCSV but missing baseline value will be regarded as having 
treatment emergent PCSV. 
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6.4. 
Visit Windows 
Data analyzed by-visit-analysis (efficacy [excluding daily diary data], laboratory data, vital sign, 
ADA) will be summarized by the study scheduled visits described in study protocol and SAP 
Section 11.2, “Schedule of Time and Events”. 
The analysis visit windows will be created per study Schedule of Events table for each parameter 
and will be applied if the data from the study scheduled visits are unavailable. The following 
general rules will be applied to unscheduled visit and/or early termination (ET) visit mapping for 
each parameter: 
1. If ET visit falls in an analysis window which has no missing value of this parameter, ET 
visit will be mapped to the next scheduled visit. 
2. If both ET visit and unscheduled visit of the same parameter are available in the same 
analysis visit window, only ET visit will be mapped.  
3. If multiple unscheduled visits of the same parameter are available in the same analysis visit 
window, the unscheduled visits will be mapped using the following rules: 
a. The closest unscheduled visit from the target day will be selected. 
b. If multiple unscheduled visits occur on the same day, the first unscheduled visit will be 
utilized.  
4. If unscheduled visit is greater than 4 weeks apart from the target day of the scheduled visit, 
the unscheduled visit will not be mapped.  
Unscheduled visit and early termination (ET) visit will be mapped per the analysis visit windows 
for Part A and Part B (Table 2-6) based on the study day and visit of each parameter, respectively. 
The analysis visit windows may be applied to the scheduled assessments for PEIS, GIC and GIS. 
Part A (data collected after the first injection in Part B will not be used for Part A analysis) 
Table 2 
Analysis Visit Window for Efficacy Endpoints in Part A 
Visit from SOE 
Target 
Study Day 
in Part A 
Analysis Visit Window based on Study Daya in Part A 
Histology endpoints, 
Transcriptome 
endpoints, EOE-EREFS, 
PEIS-P, PEIS-C, PEESS 
GIC-P, GIC-C, 
GIC-Clin 
GIS-P, GIS-C 
Baseline 
1 
≤1 
 
≤1 
Week 12 
85 
 
[2, 99] 
[2, 99] 
Week 16 
(Part A end of treatment) 
113 
≥2 b 
≥100 b 
≥100 b 
a. 
Study days are calculated from the day of 1st injection of Part A. Study day = (date of assessment – 1st injection 
date + 1) when date of assessment is on or after the 1st injection date; otherwise, study day = date of assessment – 
1st injection date. If patient never received any dose of study drug, randomization date will be used in place of 1st 
injection date.  
b. If unscheduled visit or ET visit occurs in this window, and it is after the first dose of Part B, it will be considered 
as part of Part B visits. 
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Table 3 
Analysis Visit Window for Safety and Biomarkers in Part A 
Visit from SOE 
Target 
Study Day 
in Part A 
Analysis Visit Window based on Study Daya in Part A 
Vital Signs 
Physical 
Examination 
Laboratory, 
PK, Eotaxin-3 
ADA 
Serum 
total IgE 
Baseline 
1 
≤1 
≤1 
≤1 
≤1 
≤1 
Week 2 
15 
[2, 22] 
 
 
 
 
Week 4 
29 
[23, 43] 
 
[2, 71] 
 
≥2b 
Week 8 
57 
[44, 71] 
 
 
 
 
Week 12 
85 
[72, 99] 
 
 
 
 
Week 16 
(Part A end of 
treatment) 
113 
≥100b 
≥2b 
≥72b 
≥2b 
 
a. 
Study days are calculated from the day of 1st injection of Part A. Study day = (date of assessment – 1st injection 
date + 1) when date of assessment is on or after the 1st injection date; otherwise, study day = date of assessment – 
1st injection date. If patient never received any dose of study drug, randomization date will be used in place of 1st 
injection date.  
b. If unscheduled visit or ET visit occurs in this window, and it is after the first dose of Part B, it will be considered 
as part of Part B visits. 
Part B (only applies to patients who received at least 1 dose of Part B study drug) 
Table 4 
Analysis Visit Window for Efficacy Endpoints in Part B 
Visit from SOE 
Target Study 
Day in Part B 
Analysis Visit Window based on Study Daya in Part B 
Histology endpoints, 
Transcriptome endpoints, 
EOE-EREFS 
PEIS-P, PEIS-C, GIC-P, GIC-C, 
GIC-Clin, GIS-P, GIS-C, GIS-
Clin 
Baseline of Part B 
1 
≤1 
≤1 
Week 32 
113 
 
[2, 183] 
Week 52 
(Part B end of treatment) 
253 
≥2 
≥184 
a. 
Study days are calculated from the day of 1st injection of Part B. Study day = (date of assessment – 1st injection 
date + 1) when date of assessment is on or after the 1st injection date; otherwise, study day = date of assessment – 
1st injection date. If patient never received any dose of study drug, randomization date will be used in place of 1st 
injection date.  
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Table 5 
Analysis Visit Window for Safety and Biomarker Endpoints in Part B 
Visit from SOE 
Target 
Study 
Day in 
Part B 
Analysis Visit Window based on Study Daya in Part B 
Vital Signs 
Physical Examination, 
Urinalysis, Serum total 
IgE, Eotaxin-3 
Hematology, 
Chemistry, PK, ADA 
Baseline of Part B 
1 
≤1 
≤1 
≤1 
Week 20 
29 
[2, 43] 
 
 
Week 24 
57 
[44, 71] 
 
 
Week 28 
85 
[72, 99] 
 
 
Week 32 
113 
[100, 127] 
 
[2, 183] 
Week 36 
141 
[128, 155] 
 
 
Week 40 
169 
[156, 183] 
 
 
Week 44 
197 
[184, 211] 
 
 
Week 48 
225 
[212, 239] 
 
 
Week 52 
(Part B end of 
treatment) 
253 
≥240 
≥2 
≥184 
a. 
Study days are calculated from the day of 1st injection of Part B. Study day = (date of assessment – 1st injection 
date + 1) when date of assessment is on or after the 1st injection date; otherwise, study day = date of assessment – 
1st injection date. If patient never received any dose of study drug, randomization date will be used in place of 1st 
injection date.  
12-week follow-up period after Part A/Part B end of treatment 
Table 6 
Analysis Visit Window for 12-week Follow-up Period after Part A/Part B End 
of Treatment 
Visit from SOE 
Target Study Day after 
EOT Visita 
Analysis Window based on Study 
Daya after EOT 
Week 64 EOS Visit  
(Patient not entering Part B) 
85  
(relative to week 16 visit) 
≥2b 
Week 64 EOS Visit  
(Patient entering Part B) 
85  
(relative to week 52 visit) 
≥2b 
a. 
Study days are calculated from the day of week 16 visit for patients not entering Part B or the day of week 52 visit 
for patients entering Part B. Study day = (date of assessment – week 16/week 52 visit +1) when date of assessment 
is on or after week 16/week 52 visit. If patient does not complete week 16/week 52 visit, week 64 visit will be not 
applicable for this patient.  
b. If unscheduled visit occurs after Part A/Part B EOT visit, and patient enters follow-up period, 1) the study day is 
≤42 (6 weeks after Part A/Part B EOT visit), it will be considered for week 16/week 52 visit; 2) the study day is 
>42, it will be considered for EOS visit. 
 
For PESQ-P and PESQ-C data (collected daily by eDiary), the analysis visit windows will be 
implemented following the procedures below: 
Part A (diaries collected after the first injection in Part B will not be used for Part A analysis) 
Step 1: Diary study day derivation 
• If diary date ≥ 1st injection date of study Part A and < 1st injection date of study Part B, 
Part A diary study day= diary date – 1st injection date in the study + 1; 
• If diary date < 1st injection date of study Part A, Part A diary study day= diary date – 
1st injection date in the study. 
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Step 2: Analysis visit windows are defined as Day -14 to Day -1 = BL, Day 1 to Day 14 = week 2, 
Day 15 to Day 28 = week 4, etc., with 14-day intervals between visit windows, through Day 99 to 
Day 112 = week 16. For patients who never entered Part B, analysis windows in the 12-week follow-
up period will continue with 14-day intervals as Day 113 to Day 126 = week 18, Day 127 to Day 
140 = week 20, etc. 
Part B (only applies to patients who received at least 1 dose of Part B study drug) 
Step 1: Diary study day derivation 
• For diary date ≥ 1st injection date of study Part B, Part B diary study day = diary date 
– 1st injection date in Part B + 1; 
• For diary date < 1st injection date of study Part B, Part B diary study day = diary date 
– 1st injection date in Part B. 
Step 2: Analysis visit windows are defined as Day -14 to Day -1 = Part B BL, Day 1 to Day 14 = 
week 18, Day 15 to Day 28 = week 20, etc., with 14-day intervals between visit windows, through 
Day 239 to Day 253 = week 52. For patients who entered 12-week follow-up period after Part B, 
analysis windows will continue with 14-day intervals as Day 254 to Day 267 = week 54, Day 268 
to Day 281 = week 56, etc. 
6.5. 
Statistical Technical Issues 
None. 
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7. 
INTERIM ANALYSIS 
No interim analysis is planned. 
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8. 
TIMING OF STATISTICAL ANALYSIS 
The primary analysis will be performed when the last patient has completed the last Part A visit 
including patients who have terminated early in Part A. The assessments of primary, secondary, 
and exploratory efficacy endpoints through the end of Part A during the primary analysis will be 
the final (and only) analyses of these endpoints. Hence, there will be no need for alpha adjustment 
due to this primary analysis. Available Part B data will also be analyzed and evaluated, including 
assessment of secondary endpoints at week 52. The final analysis will occur when all patients who 
enter the 12-week follow-up period immediately from Part A or Part B completed the follow-up 
period. 
To maintain study integrity with respect to the post Part A visits and analyses, a dissemination 
plan will be written. This plan will clearly identify the Part A unblinded team (including the 
statistician) that will perform the Part A analysis and all related activities, restrict other clinical 
team members and other Sponsor personnel from access to individual patient treatment allocation 
and site level analysis results, and ensure that the dedicated Part A unblinded team will not 
participate in the data review or data decisions for the following post treatment analyses. However, 
the dedicated team can participate in the analysis following the final database lock. 
 
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9. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher. 
 
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10. 
REFERENCES 
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Chehade M, Jones SM, Pesek RD, Burks AW, Vickery BP, Wood RA, et al. Phenotypic 
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Collins MH, Martin LJ, Alexander ES, Boyd JT, Sheridan R, He H, et al. Newly developed 
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DeBrosse CW, Franciosi JP, King EC, Butz BK, Greenberg AB, Collins MH, et al. Long-
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Dellon ES. Epidemiology of eosinophilic esophagitis. Gastroenterol Clin North Am 2014; 
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Dellon ES, Aderoju A, Woosley JT, Sandler RS, Shaheen NJ. Variability in diagnostic criteria 
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Dellon ES, Hirano I. Epidemiology and Natural History of Eosinophilic Esophagitis. 
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14. Furuta GT, Aceves SS. The National Biome Initiative: An allergy perspective. J Allergy Clin 
Immunol 2017; 139(4):1131-4. 
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112(10):1527-35. 
17. Hamilton JD, Suarez-Farinas M, Dhingra N, Cardinale I, Li X, Kostic A, et al. Dupilumab 
improves the molecular signature in skin of patients with moderate-to-severe atopic 
dermatitis. J Allergy Clin Immunol 2014; 134(6):1293-300. 
18. Hirano I, Aceves SS. Clinical implications and pathogenesis of esophageal remodeling in 
eosinophilic esophagitis. Gastroenterol Clin North Am 2014; 43(2):297-316. 
19. Hirano I, Collins MH, Assouline-Dayan Y, Evans L, Gupta S, Schoepfer AM, et al. RPC4046, 
a Monoclonal Antibody Against IL13, Reduces Histologic and Endoscopic Activity in 
Patients With Eosinophilic Esophagitis. Gastroenterology 2019a; 156(3):592-603.e10. 
20. Hirano I, Dellon ES, Hamilton JD, Collins MH, Peterson K, Chehade M, et al. Efficacy of 
Dupilumab in a Phase 2 Randomized Trial of Adults With Active Eosinophilic Esophagitis. 
Gastroenterology 2019b. 
21. Hirano I, Moy N, Heckman MG, Thomas CS, Gonsalves N, Achem SR. Endoscopic 
assessment of the oesophageal features of eosinophilic oesophagitis: validation of a novel 
classification and grading system. Gut. 2013 Apr;62(4):489-95. PubMed PMID: 22619364. 
22. ICH. (1996, July 30). ICH Harmonized tripartite guideline: Structure and content of clinical 
study reports (E3). International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. 
23. ICH. (1997, July 17). ICH Harmonized tripartite guideline: General considerations for clinical 
trials (E8). International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use. 
24. ICH. (1998, February 5). ICH Harmonized tripartite guideline: Statistical principles for 
clinical trials (E9). International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use. 
25. Iuliano S, Minelli R, Vincenzi F, Gaiani F, Ruberto C, Leandro G, et al. Eosinophilic 
esophagitis in pediatric age, state of the art and review of the literature. Acta Biomed 2018; 
89(8-s):20-6. 
26. Kapel RC, Miller JK, Torres C, Aksoy S, Lash R, Katzka DA. Eosinophilic esophagitis: a 
prevalent disease in the United States that affects all age groups. Gastroenterology 2008; 
134(5):1316-21. 
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Statistical Analysis Plan Amendment 1 
 
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27. Liacouras CA, Furuta GT, Hirano I, Atkins D, Attwood SE, Bonis PA, et al. Eosinophilic 
esophagitis: updated consensus recommendations for children and adults. J Allergy Clin 
Immunol 2011; 128(1):3-20.e6; quiz 1-2. 
28. Lucendo AJ, Molina-Infante J, Arias A, von Arnim U, Bredenoord AJ, Bussmann C, et al. 
Guidelines on eosinophilic esophagitis: evidence-based statements and recommendations for 
diagnosis and management in children and adults. United European Gastroenterol J 2017; 
5(3):335-58. 
29. Prasad GA, Alexander JA, Schleck CD, Zinsmeister AR, Smyrk TC, Elias RM, et al. 
Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, Minnesota. 
Clin Gastroenterol Hepatol 2009; 7(10):1055-61. 
30. Ratitch B. Lipkovich I, O’Kelly. Combining Analysis Results from Multiply Imputed 
Categorical Data. PharmaSUG 2013. 
31. Ratitch, Bohdana, Michael O'Kelly, and Robert Tosiello. Missing data in clinical trials: from 
clinical assumptions to statistical analysis using pattern mixture models. Pharmaceutical 
Statistics 12.6 (2013): 337-347. 
32. Schoepfer AM, Straumann A, Panczak R, Coslovsky M, Kuehni CE, Maurer E, et al. 
Development and validation of a symptom-based activity index for adults with eosinophilic 
esophagitis. Gastroenterology 2014; 147(6):1255-66.e21. 
33. Sherrill JD, Kiran KC, Blanchard C, Stucke EM, Kemme KA, Collins MH, et al. Analysis 
and expansion of the eosinophilic esophagitis transcriptome by RNA sequencing. Genes 
Immun 2014; 15(6):361-9. 
34. Singla MB, Moawad FJ. An Overview of the Diagnosis and Management of Eosinophilic 
Esophagitis. Clin Transl Gastroenterol 2016; 7(e155). 
35. Spergel JM, Brown-Whitehorn TF, Beausoleil JL, Franciosi J, Shuker M, Verma R, et al. 14 
years of eosinophilic esophagitis: clinical features and prognosis. J Pediatr Gastroenterol Nutr 
2009; 48(1):30-6. 
36. Spergel JM, Rothenberg ME, Collins MH, Furuta GT, Markowitz JE, Fuchs G, 3rd, et al. 
Reslizumab in children and adolescents with eosinophilic esophagitis: results of a double-
blind, randomized, placebo-controlled trial. J Allergy Clin Immunol 2012; 129(2):456-63, 
63.e1-3. 
37. Straumann A. The natural history and complications of eosinophilic esophagitis. Gastrointest 
Endosc Clin N Am 2008; 18(1):99-118; ix. 
38. Straumann A, Aceves SS, Blanchard C, Collins MH, Furuta GT, Hirano I, et al. Pediatric and 
adult eosinophilic esophagitis: similarities and differences. Allergy 2012; 67(4):477-90. 
39. Straumann A, Spichtin HP, Grize L, Bucher KA, Beglinger C, Simon HU. Natural history of 
primary eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5 years. 
Gastroenterology 2003; 125(6):1660-9. 
40. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set 
enrichment analysis: a knowledge-based approach for interpreting genome-wide expression 
profiles. Proc Natl Acad Sci U S A 2005; 102(43):15545-15550. 
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41. Warners MJ, Ambarus CA, Bredenoord AJ, Verheij J, Lauwers GY, Walsh JC, et al. 
Reliability of histologic assessment in patients with eosinophilic oesophagitis. Aliment 
Pharmacol Ther 2018; 47(7):940-50. 
42. Wechsler JB, Bolton SM, Amsden K, Wershil BK, Hirano I, Kagalwalla AF. Eosinophilic 
Esophagitis Reference Score Accurately Identifies Disease Activity and Treatment Effects in 
Children. Clin Gastroenterol Hepatol 2018; 16(7):1056-63. 
43. Wilson, E.B., Hilferty, M.M. The Distribution of Chi-squared. Proceedings of the National 
Academy of Sciences 1931, Washington, 17, 684–688. 
 
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11. 
APPENDIX 
11.1. 
Summary of Statistical Analyses 
11.1.1. 
Summary of Efficacy Analyses 
Endpoint 
Analysis 
Populations 
Primary Statistical Method 
Supportive/Sensitive  
Statistical Method 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoint 
Proportion of patients achieving peak 
esophageal intraepithelial eosinophil count 
of ≤6 eos/hpf (400×) at week 16 
 
FAS 
Cochran-Mantel-Haenszel 
test/Missing as non-responder 
Cochran-Mantel-
Haenszel test with tipping 
point analysis approach 
and WOCF-MI approach, 
respectively 
Yes [1] 
Histogram 
Secondary Endpoints 
Secondary continuous variable 
FAS 
ANCOVA with WOCF-MI 
approach for endpoints measured 
repeatedly (e.g., change from 
baseline in the proportion of days 
with 1 or more EoE signs as 
measured by the PESQ-C); 
ANCOVA with WOCF-MI 
approach for endpoints measured 
only once post-baseline up to 
week 16 (e.g., percent change in 
peak eosinophil count from 
baseline to week 16) 
NA 
Yes [2] 
Line plot 
except EoE-
EREFS 
endpoint; 
Bar chart for 
EoE-EREFS 
endpoint 
Secondary binary variable 
FAS 
Cochran-Mantel-Haenszel 
test/Missing as non-responder 
NA 
No 
Histogram 
[1] Note: The subgroup analysis may not be performed if the number of patients within the subgroup is <10% of overall sample size. The stratification factor is 
not included in the subgroup analysis of primary efficacy endpoint. 
[2] Note: The subgroup analysis will be performed on selected secondary endpoints only, see Section 5.6.4.  
 
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11.1.2. 
Summary of Safety Analyses 
Endpoint 
Analysis 
Populations 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Adverse Events 
SAF 
Descriptive statistics 
No 
TEAEs by Primary 
SOC/PT only [1] 
No 
Laboratory Measures 
SAF 
Descriptive statistics 
No 
No 
No 
Vital sign 
SAF 
Descriptive statistics 
No 
No 
No 
[1] Note: The subgroup analysis may not be performed if the number of patients within the subgroup is <10% of overall sample size.  
 
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Footnotes for the Schedule of Events Tables 
Footnotes for Table 7 
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 PPI 
treatment), the screening period will be extended for up to 12 weeks (day -85) to allow for 
at least 8 weeks of 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/imaging for EoE-EREFS/biopsy procedures should be performed after all 
other efficacy and safety assessments. 
2a. The baseline esophageal endoscopy with biopsies and the stomach and/or 
duodenum endoscopies with biopsies should be performed with sufficient time 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 PPI. Patients may be randomized as soon as their endoscopy/biopsy results 
are confirmed, and all other eligibility criteria are met.  
2b. 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 subsequent scheduled endoscopy/biopsy at week 16 and/or week 52. 
3. Patients may be re-screened 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. 
4. Assessments indicated for this week 16 (end of treatment) visit should be performed for all 
patients. For patients who will enter extended treatment, there are additional events listed 
for the week 16 visit in Table 8. 
5. Patients and/or caregivers will be trained on administration of study drug. 
6. On scheduled in-clinic study visit days, study drug will be administered in the clinic (by 
the patient, site staff, or caregiver) after all assessments are completed. Study drug 
administered at the study sites by site staff will be performed only by injection personnel 
who will not perform any clinical assessment/procedures. Study drug will be 
provided/dispensed for those doses scheduled to be administered at home before the next 
in-clinic visit. Study drug administration that occurs in clinic should occur per the Schedule 
of Events in Table 7 and Table 8. Parents (or caregivers) will return the study kit box (for 
prefilled syringes) at each subsequent in-clinic visit. Parents (or caregivers) who prefer to 
have the clinic staff administer study drug may choose to have injections administered in 
the clinic. 
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7. The PESQ-P will be completed daily by patients >8 to <12 years of age (determined at the 
time of screening visit 1) just before going to bed for the night. The PESQ-C will be 
completed daily by caregivers of patients >1 to <12 years of age (determined at the time of 
screening visit 1) after the patients go to bed for the night. The PESQ-P and PESQ-C will 
be completed via an electronic diary (diary) and site personnel should conduct regular 
checks of patient and caregiver diary compliance. The PEIS-P and PEIS-C will be 
completed during site visits as indicated in the Schedule of Events table by the patients and 
caregivers, respectively. 
8. The GIS-P, GIS-C, GIS-Clin and the GIC-P, GIC-C, and GIC-Clin will be completed by 
patients during site visits (>8 to <12 years of age determined at the time of screening 
visit 1), caregivers (of patients >1 to <12 years of age determined at the time of screening 
visit 1), and study investigator/clinician, respectively. 
9. EoE-EREFS imaging will be analyzed and scored by a central reading center. Minor 
esophageal features will be assessed by the investigator. 
10. Assessments will be performed, and blood samples will be collected before the 
administration of study drug. In the event of suspected SAEs, such as anaphylaxis or 
hypersensitivity, functional dupilumab PK sample and anti-dupilumab antibody sample 
may be collected at or near the event. 
11. Patients will be closely monitored at the study site at visits 3 and 4 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. Vital signs should be taken predose at 
all other indicated visits. 
12. Tuberculosis testing will be performed on a country-by-country basis according to local 
guidelines if required by regulatory authorities or ECs. 
13. A negative result must be obtained prior to the randomization visit for all females post-
menarche. 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. 
14. Urinalysis is only required for patients aged ≥6 to <12 years. 
15. The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) version 2.0 will be 
completed by caregivers of patients >1 to <12 years of age (determined at the time of 
screening visit 1). 
16. Exit interviews will be conducted by a trained interviewer via telephone within 14 days of 
completing Week 16/Visit 8. These interviews will be completed with caregivers. Patients 
aged ≥8 to <12 years old (determined at the time of screening visit 1] may also join a 
portion of the exit interview). 
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Footnotes for Table 8 
1. This visit is the same as the week 16 visit for the double-blind study portion (Table 7), and 
all other assessments indicated for week 16 (Table 7) should be performed. Endoscopy 
with biopsies at visit 8/week 16 must be completed prior to administration of study drug 
for Part B Extended Active Treatment. 
2. Study assessments will be performed, and blood samples will be collected prior to 
administration of study drug. In the event of suspected SAEs, such as anaphylaxis or 
hypersensitivity, functional dupilumab PK sample and anti-dupilumab antibody sample 
may be collected at or near the event. 
3. 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. 4a. Study drug administration will continue through week 50.  
4b. Weight assessed at visit 8 / week 16 and visit 12 / week 32 will be used to determine 
weight-tiered dose for the 36-week extended active treatment period. If weight has 
increased at visit 12 such that the patient meets a larger weight tier, weight-tiered dosing 
will be re-assigned according to the patient’s weight at this visit. If weight is the same or 
decreased at visit 12, then weight-tiered dosing will remain as originally assigned at visit 
8 / week 16. The patient will remain within the original exposure dosing assignment (higher 
exposure group or lower exposure group). On scheduled in-clinic study visit days, study 
drug will be administered in the clinic (by the patient, site staff, or caregiver). Study drug 
administered at the study sites by site staff will be performed only by injection personnel 
who will not perform any clinical assessment/procedures. Study drug will be provided for 
those scheduled doses to be administered at home before the next in-clinic visit. Parents 
(or caregivers) will return the study kit box (for prefilled syringes) at each subsequent in-
clinic visit. Study drug administration that occurs in clinic should occur per the Schedule 
of Events table. Parents (or caregivers) who prefer to have the clinic staff administer study 
drug may choose to have injections administered in the clinic.  
5. The PESQ-P will be completed daily by patients >8 to <12 years of age (determined at the 
time of screening visit 1) just before going to bed for the night. The PESQ-C will be 
completed daily by caregivers of patients >1 to <12 years of age (determined at the time of 
screening visit 1) after the patients go to bed for the night. The PESQ-P and PESQ-C will 
be completed via an electronic diary (diary) and site personnel should conduct regular 
checks of patient and caregiver diary compliance. The PEIS-P and PEIS-C will be 
completed during site visits as indicated in the Schedule of Events table by the patients and 
caregivers, respectively. 
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Date: June 2, 2022 
 
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6. The GIS-P, GIS-C, GIS-Clin and the GIC-P, GIC-C, and GIC-Clin will be completed 
during site visits by patients (>8 to <12 years of age determined at the time of screening 
visit 1), caregivers (of patients >1 to <12 years of age determined at the time of screening 
visit 1), and study investigator/clinician, respectively. 
7. Endoscopy/imaging for EoE-EREFS/biopsy procedures should be performed after all other 
efficacy and safety assessments. Minor esophageal features will be assessed by the 
investigator. 
7a. 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 16 and 52. 
8. 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 at visit 8. 
9. 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. 
10. Urinalysis is only required for patients aged ≥6 to <12 years. 
11. The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) version 2.0 will be 
completed by caregivers of patients >1 to <12 years of age (determined at the time of screening 
visit 1). 
Footnotes for Table 9 
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. The PESQ-P will be completed daily by patients >8 to <12 years of age (determined at the 
time of screening visit 1) just before going to bed for the night. The PESQ-C will be 
completed daily by caregivers of patients >1 to <12 years of age (determined at the time of 
screening visit 1) after the patients go to bed for the night. The PESQ-P and PESQ-C will 
be completed via an electronic diary (diary) and site personnel should conduct regular 
checks of patient and caregiver diary compliance. The PEIS-P and PEIS-C will be 
completed during site visits as indicated in the Schedule of Events table by the patients and 
caregivers, respectively. 
3. The GIS-P, GIS-C, GIS-Clin and the GIC-P, GIC-C, and GIC-Clin will be completed 
during site visits as indicated by patients (>8 to <12 years of age determined at the time of 
screening visit 1), caregivers (of patients >1 to <12 years of age determined at the time of 
screening visit 1), and study investigator/clinician, respectively. 
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4. EoE-EREFS imaging will be analyzed and scored by a central reading center. Minor 
esophageal features will be assessed by the investigator.  
4a. For patients who receive rescue treatment, endoscopy/imaging for 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 16 and 52. 
4b. Endoscopy/imaging for EoE-EREFS/biopsy will be performed only if the unscheduled 
visit is for the purpose of administering rescue therapy. 
5. Urinalysis is only required for patients aged ≥6 to <12 years 
The Pediatric Eosinophilic Esophagitis Symptom Score (PEESS) version 2.0 will only be 
completed by caregivers of patients >1 to <12 years of age (determined at the time of screening 
visit 1) an early termination and/or unscheduled visit before rescue visit(s) performed prior to visit 
8 / week 16. There is no requirement to perform PEESS after visit 8 / week 16. 
11.3. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Where criteria for ≥6 to <12 years are different from criteria for ≥1 to <6 years, the children criteria 
are provided in the [brackets] in the combined column. The criteria inside the “Combined” column 
will be used for display purpose in the reporting outputs. Applicable criteria will be applied to 
parameters collected in the study to identify treatment-emergent PCSV cases. 
Parameter 
≥6 to <12 years 
≥1 to <6 years 
Combined 
Clinical chemistry 
ALT/SGPT 
≥3 and <5 ULN and baseline 
<3 ULN 
≥5 and <10 ULN and 
baseline <5 ULN 
≥10 and <20 ULN and 
baseline <10 ULN 
≥20 ULN and baseline <20 
ULN 
≥3 and <5 ULN and baseline 
<3 ULN 
≥5 and <10 ULN and 
baseline <5 ULN 
≥10 and <20 ULN and 
baseline <10 ULN 
≥20 ULN and baseline <20 
ULN 
≥3 and <5 ULN and baseline <3 
ULN 
≥5 and <10 ULN and baseline 
<5 ULN 
≥10 and <20 ULN and baseline 
<10 ULN 
≥20 ULN and baseline <20 
ULN 
AST/SGOT 
≥3 and <5 ULN and baseline 
<3 ULN 
≥5 and <10 ULN and 
baseline <5 ULN 
≥10 and <20 ULN and 
baseline <10 ULN 
≥20 ULN and baseline <20 
ULN 
≥3 and <5 ULN and baseline 
<3 ULN 
≥5 and <10 ULN and 
baseline <5 ULN 
≥10 and <20 ULN and 
baseline <10 ULN 
≥20 ULN and baseline <20 
ULN 
≥3 and <5 ULN and baseline <3 
ULN 
≥5 and <10 ULN and baseline 
<5 ULN 
≥10 and <20 ULN and baseline 
<10 ULN 
≥20 ULN and baseline <20 
ULN 
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Parameter 
≥6 to <12 years 
≥1 to <6 years 
Combined 
Alkaline 
Phosphatase 
(ALP) 
≥1.5 ULN and baseline < 1.5 
ULN 
≥1.5 ULN and baseline < 1.5 
ULN 
 
≥1.5 ULN and baseline < 1.5 
ULN 
Total 
Bilirubin 
≥1.3 ULN and baseline < 1.3 
ULN 
≥1.3 ULN and baseline < 1.3 
ULN 
≥1.3 ULN and baseline < 1.3 
ULN 
Conjugated 
Bilirubin 
(Direct Bilirubin >35% Total 
Bilirubin and Total Bilirubin 
≥1.3 ULN) and (Direct 
Bilirubin ≤35% Total 
Bilirubin or Total Bilirubin 
<1.3 ULN) at baseline 
(Direct Bilirubin >35% Total 
Bilirubin and Total Bilirubin 
≥1.3 ULN) and (Direct 
Bilirubin ≤35% Total 
Bilirubin or Total Bilirubin 
<1.3 ULN) at baseline 
(Direct Bilirubin >35% Total 
Bilirubin and Total Bilirubin 
≥1.3 ULN) and (Direct Bilirubin 
≤35% Total Bilirubin or Total 
Bilirubin <1.3 ULN) at baseline 
(ALT or 
AST) and 
Total 
Bilirubin 
(TBILI) 
((ALT >3 ULN or AST>3 
ULN) and TBILI>2 ULN) 
and ((ALT ≤3 ULN and 
AST ≤3 ULN) or TBILI ≤2 
ULN) at baseline 
((ALT >3 ULN or AST>3 
ULN) and TBILI>2 ULN) 
and ((ALT ≤3 ULN and AST 
≤3 ULN) or TBILI ≤2 ULN) 
at baseline 
((ALT >3 ULN or AST>3 
ULN) and TBILI>2 ULN) and 
((ALT ≤3 ULN and AST ≤3 
ULN) or TBILI ≤2 ULN) at 
baseline 
Creatinine 
≥90 µmol/L and baseline < 
90 µmol/L 
≥30% change from baseline 
≥1 to <4 years: >62 µmol/L 
and ≤ 62 µmol/L at baseline 
≥4 to <6 years: >71 µmol/L 
and ≤ 71 µmol/L at baseline 
≥90 [≥1 to <4 years: >62; ≥4 to 
<6 years: >71] µmol/L and 
baseline < 90 [≥1 to <4 years: ≤ 
62; ≥4 to <6 years: ≤ 71] 
µmol/L  
≥30% change from baseline (≥6 
to <12 years only) 
Albumin 
≤25 g/L and >25 g/L at 
baseline 
NA 
≤25 g/L and >25 g/L at baseline 
(≥6 to <12 years only) 
Blood Urea 
Nitrogen 
(BUN) 
≥7.14 mmol/L and <7.14 
mmol/L at baseline 
≥6.4 mmol/L and <6.4 
mmol/L at baseline 
≥7.14 [≥6.4] mmol/L and <7.14 
[<6.4] mmol/L at baseline 
Chloride 
<80 mmol/L and ≥ 80 
mmol/L at baseline 
≥115 mmol/L and <115 
mmol/L at baseline 
≤80 mmol/L and >80 mmol/L 
at baseline 
≥115 mmol/L and <115 
mmol/L at baseline 
<80 [≤80] mmol/L and baseline 
≥ 80 [>80] mmol/L 
≥115 mmol/L and baseline <115 
mmol/L  
Sodium 
<129 mmol/L and ≥ 129 
mmol/L at baseline 
≥150 mmol/L and < 150 
mmol/L at baseline 
≤129 mmol/L and >129 
mmol/L at baseline 
≥150 mmol/L and <150 
mmol/L at baseline 
<129 [≤129] mmol/L and 
baseline ≥ 129 [>129] mmol/L 
≥150 mmol/L and baseline < 
150 mmol/L  
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Parameter 
≥6 to <12 years 
≥1 to <6 years 
Combined 
Potassium 
≤3.5 mmol/L and > 3.5 
mmol/L at baseline 
≥5.5 mmol/L and < 5.5 
mmol/L at baseline 
≤3.5 mmol/L and >3.5 
mmol/L at baseline 
≥5.5 mmol/L and <5.5 
mmol/L at baseline 
≤3.5 mmol/L and baseline > 3.5 
mmol/L 
≥5.5 mmol/L and baseline < 5.5 
mmol/L  
Calcium total 
<2.0 mmol/L and ≥2.0 
mmol/L at baseline 
≥2.9 mmol/L and <2.9 
mmol/L at baseline 
≤2.0 mmol/L and >2.0 
mmol/L at baseline 
≥2.9 mmol/L and <2.9 
mmol/L at baseline 
<2.0 [≤2.0] mmol/L and ≥2.0 
[>2.0] mmol/L at baseline 
≥2.9 mmol/L and <2.9 mmol/L 
at baseline 
Glucose 
Hypoglycaemia: <2.7 
mmol/L and ≥2.7 mmol/L at 
baseline  
Hyperglycaemia: ≥10.0 
mmol/L (unfasted) and < 
10.0 mmol/L (unfasted) at 
baseline; 
≥7.0 mmol/L (fasted) and 
<7.0 mmol/L (fasted) at 
baseline  
Hypoglycaemia: <2.7 
mmol/L and ≥2.7 mmol/L at 
baseline 
Hyperglycaemia: ≥10.0 
mmol/L (unfasted) and < 10.0 
mmol/L (unfasted) at 
baseline;  
≥7.0 mmol/L (fasted) and 
<7.0 mmol/L (fasted) at 
baseline  
Hypoglycaemia: <2.7 mmol/L 
and ≥2.7 mmol/L at baseline  
Hyperglycaemia: ≥10.0 mmol/L 
(unfasted) and < 10.0 mmol/L 
(unfasted) at baseline; 
≥7.0 mmol/L (fasted) and <7.0 
mmol/L (fasted) at baseline  
Hematology 
WBC 
<5.0 Giga/L and ≥5.0 Giga/L 
at baseline 
>17.0 Giga/L and ≤17.0 
Giga/L at baseline  
≥1 to <2 years:  
<4.0 Giga/L and ≥ 4.0 Giga/L 
at baseline 
>20.0 Giga/L and ≤20.0 
Giga/L at baseline 
≥2 to <6 years:  
<3.0 Giga/L and ≥ 3.0 Giga/L 
at baseline 
>16.0 Giga/L and ≤ 16.0 
Giga/L at baseline 
<5.0 [≥1 to <2 years: <4.0; ≥2 to 
<6 years: <3.0] Giga/L and ≥5.0 
[≥1 to <2 years: ≥ 4.0; ≥2 to <6 
years: ≥ 3.0] Giga/L at baseline 
 
>17.0 [≥1 to <2 years: >20.0; ≥2 
to <6 years: >16.0] Giga/L and 
≤17.0 [≥1 to <2 years: ≤20.0; ≥2 
to <6 years: ≤ 16.0] Giga/L at 
baseline 
Lymphocytes 
(ALC) 
<1.0 Giga/L and ≥1.0 Giga/L 
at baseline 
>8.0 Giga/L and ≤8.0 Giga/L 
at baseline  
<1.0 Giga/L and ≥ 1.0 Giga/L 
at baseline 
>10.5 Giga/L and ≤10.5 
Giga/L at baseline 
<1.0 Giga/L and ≥1.0 Giga/L at 
baseline 
>8.0 [>10.5] Giga/L and ≤8.0 
[≤10.5] Giga/L at baseline 
Neutrophils 
<1.2 Giga/L and ≥1.2 Giga/L 
at baseline 
>ULN and baseline ≤ ULN 
<1.2 Giga/L and ≥ 1.2 Giga/L 
at baseline 
<1.2 Giga/L and ≥1.2 Giga/L at 
baseline 
>ULN and baseline ≤ ULN (≥6 
to <12 years only) 
Eosinophils 
(>0.5 Giga/L and >ULN) 
and (≤0.5 Giga/L or ≤ ULN 
at baseline) 
(>0.5 Giga/L and >ULN) and 
(≤0.5 Giga/L or ≤ ULN at 
baseline) 
(>0.5 Giga/L and >ULN) and 
(≤0.5 Giga/L or ≤ ULN at 
baseline) 
                                        VV-RIM-00199013-1.0 Approved - 03 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan Amendment 1 
 
Date: June 2, 2022 
 
CONFIDENTIAL 
Page 92 of 100 
Parameter 
≥6 to <12 years 
≥1 to <6 years 
Combined 
Monocytes  
>0.7 Giga/L and ≤ 0.7 
Giga/L at baseline 
NA 
>0.7 Giga/L and ≤ 0.7 Giga/L at 
baseline (≥6 to <12 years only) 
Hemoglobin 
<100 g/L and ≥100 g/L at 
baseline or any decrease ≥ 
20 g/L 
≥200 g/L and <200 g/L at 
baseline 
≥1 to <2 years:  
<90 g/L and ≥ 90 g/L at 
baseline or any decrease ≥ 20 
g/L  
≥2 to <6 years:  
<100 g/L and ≥ 100 g/L at 
baseline or any decrease ≥ 20 
g/L 
<100 [≥1 to <2 years: < 90] g/L 
and ≥100 [≥1 to <2 years: ≥ 90] 
g/L at baseline or any decrease 
≥ 20 g/L 
≥200 g/L and <200 g/L at 
baseline (≥6 to <12 years only) 
Hematocrit 
< 32% and ≥ 32% at baseline 
>47% and ≤ 47% at baseline 
≥1 to <2 years:  
< 29% and ≥ 29% at baseline 
> 42% and ≤ 42% at baseline  
≥2 to <6 years:  
< 32% and ≥ 32% at baseline 
> 47% and ≤ 47% at baseline 
< 32% [≥1 to <2 years: < 29%] 
and ≥ 32% [≥1 to <2 years: ≥ 
29%] at baseline 
>47% [≥1 to <2 years: > 42%] 
and ≤ 47% [≥1 to <2 years: ≤ 
42%] at baseline 
Platelets 
<100 Giga/L and ≥100 
Giga/L at baseline 
>700 Giga/L and ≤700 
Giga/L at baseline 
<100 Giga/L and ≥100 
Giga/L at baseline 
> 700 Giga/L and ≤700 
Giga/L at baseline 
<100 Giga/L and ≥100 Giga/L 
at baseline 
> 700 Giga/L and ≤700 Giga/L 
at baseline 
Urinalysis 
Ketonuria 
Presence and absence at 
baseline 
NA 
Presence and absence at 
baseline (≥6 to <12 years only) 
Glycosuria 
Presence and absence at 
baseline 
NA 
Presence and absence at 
baseline (≥6 to <12 years only) 
Microscopic 
Hematuria 
>5 RBCs/hpf and ≤5 
RBCs/hpf at baseline 
NA 
>5 RBCs/ hpf and ≤5 RBCs/ hpf 
at baseline (≥6 to <12 years 
only) 
Proteinuria 
≥ 1+ and <1+ at baseline 
NA 
≥ 1+ and <1+ at baseline (≥6 to 
<12 years only) 
Vital Signs 
HR 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline ≥20 bpm 
≥1 to <3 years: 
≤63 bpm and decrease from 
baseline ≥20 bpm 
≥140 bpm and increase from 
baseline ≥20 bpm 
≥3 to <6 years: 
≤59 bpm and decrease from 
baseline ≥20 bpm 
≥140 bpm and increase from 
baseline ≥20 bpm 
≤50 [≥1 to 3 years: ≤63; ≥3 to 
<6 years: ≤59] bpm and 
decrease from baseline ≥20 bpm 
≥120 [≥140] bpm and increase 
from baseline ≥20 bpm 
                                        VV-RIM-00199013-1.0 Approved - 03 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan Amendment 1 
 
Date: June 2, 2022 
 
CONFIDENTIAL 
Page 93 of 100 
Parameter 
≥6 to <12 years 
≥1 to <6 years 
Combined 
SBP 
≤80 mmHg and decrease 
from baseline ≥20 mmHg 
≥120 mmHg and increase 
from baseline ≥ 20 mmHg 
≥1 to <3 years: 
≤70 mmHg and decrease 
from baseline ≥20 mmHg 
≥116 mmHg and increase 
from baseline ≥20 mmHg 
≥3 to <6 years: 
≤70 mmHg and decrease 
from baseline ≥20 mmHg 
≥121 mmHg and increase 
from baseline ≥20 mmHg 
≤80 [≤70] mmHg and decrease 
from baseline ≥20 mmHg 
≥120 [≥1 to 3 years: ≥116; ≥3 to 
<6 years: ≥121] mmHg and 
increase from baseline ≥ 20 
mmHg 
DBP 
≤48 mmHg and decrease 
from baseline ≥10 mmHg  
≥72 mmHg and increase 
from baseline ≥ 20mmHg 
≥1 to <3 years: 
≤34 mmHg and decrease 
from baseline ≥10 mmHg 
≥77 mmHg and increase from 
baseline ≥10 mmHg 
≥3 to <6 years: 
≤34 mmHg and decrease 
from baseline ≥10 mmHg  
≥83 mmHg and increase from 
baseline ≥10 mmHg  
≤48 [≤34] mmHg and decrease 
from baseline ≥10 mmHg  
≥72 [≥1 to 3 years: ≥77; ≥3 to 
<6 years: ≥83] mmHg and 
increase from baseline ≥ 20 
mmHg [≥ 10 mmHg] 
Temperature 
Rectal, ear (Tympanic): 
>100.4 °F/38.0 °C 
Oral: >99.5 °F/37.5 °C  
Axillary or skin infrared 
(temporal): >99 °F/37.2 °C 
Rectal, ear (Tympanic): 
>102.2 °F/39.0 °C 
Oral or pacifier: 
>102.2°F/39.0°C 
Axillary or skin infrared 
(temporal): >102.2°F/39.0°C 
Rectal, ear (Tympanic): >100.4 
°F/38.0 °C [>102.2 °F/39.0 °C] 
Oral: >99.5 °F/37.5 °C 
[>102.2°F/39.0°C] 
Axillary or skin infrared 
(temporal): >99 °F/37.2 °C 
[>102.2°F/39.0°C] 
Respiratory 
rate 
<16 per minutes and ≥16 per 
minute at baseline 
>30 per minute and ≤30 per 
minute at baseline 
<20 per minute and ≥20 per 
minute at baseline 
>34 per minute and ≤34 per 
minute at baseline 
<16 [<20] per minute and ≥16 
[≥ 20] per minute at baseline 
>30 [> 34] per minute and ≤30 
[≤ 34] per minute at baseline 
Weight 
≥5 % weight loss from 
baseline 
≥5 % weight loss from 
baseline 
≥5 % weight loss from baseline 
                                        VV-RIM-00199013-1.0 Approved - 03 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan Amendment 1 
 
Date: June 2, 2022 
 
CONFIDENTIAL 
Page 94 of 100 
11.4. 
Search Criteria for TEAEs of Special Interest 
AESI Category 
Search Criteria 
Anaphylactic reactions  
Narrow SMQ for anaphylactic reaction 
Systemic hypersensitivity 
reactions  
 
Narrow SMQ for hypersensitivity  
Note:  manual adjudication of relevant PTs will be required by the study 
medical monitor, before database lock 
Helminthic infections 
HLT = Cestode infections 
HLT = Helminthic infections NEC 
HLT = Nematode infections 
HLT = Trematode infections 
Clinically symptomatic 
eosinophilia (or eosinophilia 
associated with clinical 
symptoms)  
HLT = Eosinophilic disorders  
PT = Eosinophil count increased 
Note: manual adjudication of relevant PTs will be required by the study 
medical monitor, before database lock. 
Any severe type of conjunctivitis 
or blepharitis 
Broad CMQ conjunctivitis PTs 
1. Conjunctivitis   2. Conjunctivitis allergic   3. Conjunctivitis bacterial   4. 
Conjunctivitis viral   5. Atopic keratoconjunctivitis   6. Blepharitis   7. Dry eye   
8. Eye irritation   9. Eye pruritus   10. Lacrimation increased   11. Eye discharge   
12. Foreign body sensation in eyes   13. Photophobia   14. Ocular hyperaemia   
15. Conjunctival hyperaemia   16. Xerophthalmia 
Blepharitis PTs  
1. Blepharitis allergic    2. Bacterial blepharitis 
AND 
Serious AE= “Yes” OR Severity= “severe” 
Keratitis 
Narrow SMQ for corneal disorders 
Severe injection site reactions 
HLT=Injection Site Reactions 
AND 
Serious AE= “Yes” OR Severity= “severe” 
Herpes simplex infection 
HLT=Herpes viral infections  
Arthralgia 
PT=Arthralgia  
Note: The search criteria are meant to assist the process of identification of TEAE of Special Interest/TEAE Syndrome. 
However, since these criteria might not be exhaustive in some cases or may not be specific in other cases, an additional 
blinded review of all PTs in the database may be performed by the medical monitor, based on medical judgement, to 
identify any TEAE of Special Interest/TEAE Syndrome that might have been missed by the criteria or to identify any 
TEAE may been inaccurately assigned as AESI by the algorithmic search.  
                                        VV-RIM-00199013-1.0 Approved - 03 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan Amendment 1 
 
Date: June 2, 2022 
 
CONFIDENTIAL 
Page 95 of 100 
11.5. 
EoE Histology Scoring System (EoE-HSS) Feature Evaluation Per 
Collins et al. 2017 
Feature 
Grade Score 
Stage Score 
Eosinophilic inflammation (EI) 
0 = intraepithelial eosinophils not 
present 
1 = PEC <15/HPF 
2 = PEC 15-59/HPF 
3 = PEC >60/HPF  
0 = intraepithelial eosinophils 0-
14/HPF, 
1 = PEC ≥15/HPF in <33% of 
HPFs 
2 = PEC ≥15/HPF in 33-66% of 
HPFs 
3 = PEC ≥15/HPF in >66% of 
HPFs 
Basal zone hyperplasia (BZH) 
0 = BZH not present  
1 = basal zone occupies >15% but 
<33% of total epithelial thickness  
2 = basal zone occupies 33-66% of 
total epithelial thickness  
3 = basal zone occupies >66% of 
total epithelial thickness  
0 = BZH not present 
1 = BZH (any grade >0) in <33% of 
epithelium 
2 = BZH (any grade >0) in 33-66% 
of epithelium 
3 = BZH (any grade >0) in >66% of 
epithelium 
Eosinophil abscess (EA) 
0 = groups or aggregates of 
eosinophils not present 
1 = group of 4-9 eosinophils 
2 = group of 10-20 eosinophils 
3 = group of >20 eosinophils 
0 = groups or aggregates of 
eosinophils not present 
1 = EA (any grade >0) in <33% of 
epithelium 
2 = EA (any grade >0) in 33-66% 
of epithelium 
3 = EA (any grade >0) in > 66% of 
epithelium 
Surface layering (SL) 
0 = absent SL (fewer than 3 aligned 
eosinophils) 
1 = SL of 3-4 eosinophils 
2 = SL of 5-10 eosinophils 
3 = SL of >10 eosinophils 
0 = absent SL 
1 = SL (any grade >0) in <33% of 
epithelium 
2 = SL (any grade >0) in 33-66% of 
epithelium 
3 = SL (any grade >0) in >66% of 
epithelium. 
Dilated intercellular spaces (DIS) 
0 = DIS not seen at any 
magnification 
1 = intercellular bridges in DIS 
visible at 400X magnification only 
2 = intercellular bridges in DIS 
visible at 200X magnification 
3 = intercellular bridges in DIS 
visible at 100X magnification or 
lower 
0 = DIS not seen at any 
magnification 
1 = DIS (any grade >0) in <33% of 
epithelium 
2 = DIS (any grade >0) in 33-66% 
of epithelium 
3 = DIS (any grade >0) in >66% of 
epithelium 
                                        VV-RIM-00199013-1.0 Approved - 03 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan Amendment 1 
 
Date: June 2, 2022 
 
CONFIDENTIAL 
Page 96 of 100 
Feature 
Grade Score 
Stage Score 
Surface epithelial alteration (SEA) 
0 = SEA not present 
1= SEA without eosinophils 
2 = SEA with any eosinophils 
3 = shed altered surface epithelium 
admixed with numerous eosinophils 
consistent with exudate 
0 = SEA not present 
1 = SEA (any grade >0) in <33% of 
epithelium 
2 = SEA (any grade >0) in 33-66% 
of epithelium 
3 = SEA (any grade >0) in >66% of 
epithelium 
Dyskeratotic epithelial cells (DEC) 
0 = DEC not present 
1 = 1 DEC/HPF 
2 = 2-5 DEC/HPF 
3 = >5 DEC/HPF 
0 = DEC not present 
1 = DEC (any grade >0) in <33% of 
epithelium 
2 = DEC (any grade >0) in 33-66% 
of epithelium 
3 = DEC (any grade >0) in >66% of 
epithelium 
Lamina propria fibrosis (LPF) 
0 = LPF not present 
1 = fibers are cohesive and 
interfiber spaces cannot be 
demarcated 
2 = fiber diameter equals the 
diameter of a basal cell nucleus 
3 = fiber diameter exceeds the 
diameter of a basal cell nucleus 
0 = LPF not present 
1 = LPF (any grade >0) in <33% of 
lamina propria 
2 = LPF (any grade >0) in 33-66% 
of lamina propria 
3 = LPF (any grade >0) in >66% of 
lamina propria 
PEC = peak eosinophil count (quantity of eosinophils in the most inflamed high power field) 
                                        VV-RIM-00199013-1.0 Approved - 03 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan Amendment 1 
 
Date: June 2, 2022 
 
CONFIDENTIAL 
Page 97 of 100 
11.6. 
Gene Lists Comprising Each Transcriptome Endpoint 
EoE diagnostic panel 
Type 2 inflammation signature 
CDH26 
CDH20 
CLDN10 
CTNNAL1 
DSG1 
CHL1 
CXCL6 
CCL26 
CXCL1 
IL8 
IL5 
IL13 
CCR3 
CLC 
IL5RA 
CRISP2 
FLG 
UPK1A 
SPINK7 
CRISP3 
ACPP 
UPK1B 
CA2 
PHLDB2 
MUC4 
GCNT3 
EPPK1 
ZNF365 
CITED2 
ARG1 
ALOX12 
IGJ 
TNFAIP6 
CFB 
HRH1 
CFI 
APOBEC3A 
MMP12 
CD200R1 
HPGDS 
FCGR3A 
FCGR3B 
RUNX2 
ALOX15 
GRK5 
SAMSN1 
PMCH  
SLC16A6 
IL4 
IL13 
IL13RA1 
IL4R 
IL5 
IL33 
TSLP 
IL25 
CCL11 
CCL13 
CCL17 
CCL18 
CCL24 
CCL26 
IL1RL1 
FCER1A 
FCER2 
CCR3 
CCR4 
SIGLEC8 
HDC 
PTGDS 
PTGDR2 
CLC 
ALOX15 
MUC5B 
MUC5AC 
POSTN 
DPP4 
CMA1 
TPSAB1 
HRH1 
GATA1 
GATA3 
ARG1 
STAT6 
                                        VV-RIM-00199013-1.0 Approved - 03 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan Amendment 1 
 
Date: June 2, 2022 
 
CONFIDENTIAL 
Page 98 of 100 
EoE diagnostic panel 
Type 2 inflammation signature 
KCNJ2 
ANO1 
SLC26A4 
TPSAB1 
TPSB2 
CPA3 
CMA1 
NEFM 
NEFL 
PNLIPRP3 
ENDOU 
CDA  
EML1 
SUSD2 
GPR160 
TSPAN12 
LRRC31 
GLDC  
GYS2 
IGFL1 
MT1M    
CRYM 
UBD 
GRPEL2 
RTP4 
ACTG2 
CTSC   
POSTN 
KRT23 
COL8A2 
IL32 
IL4 
MSRB3 
CCL8 
EPX  
EPB41L3 
SYNPO2 
COL1A2 
TRIM2 
SYNPO2L 
NCAM1 
F3 
TSLP  
H19 
FKBP5 
SLAMF7 
PTGFRN  
 
                                        VV-RIM-00199013-1.0 Approved - 03 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan Amendment 1 
 
Date: June 2, 2022 
 
CONFIDENTIAL 
Page 99 of 100 
11.7. 
SAS Syntax Code for Multiple Imputation with CMH Test  
The multiple imputation with CMH test for the primary analysis of proportion of patients achieving 
a histologic response of peak esophageal intraepithelial eosinophil count ≤6 eos/hpf at week 16 
will be taken the following 5 steps:  
Step 1: Use the MCMC method to fill in intermittent missing values so that a monotone missing 
pattern will be formed.  
Step 2: Using the datasets from step 1, missing data through week 16 will be imputed using the 
regression method with treatment group, randomization stratification, relevant baseline 
measurement, and post-baseline measurement up to week 16 included in the regression model.  
SAS syntax code for MI: 
  
    
 
 
 
 
 
 
 
 
 
 
Note: From Steps 1 and 2, missing data at week 16 will be imputed 10 times to generate 10 
complete datasets using the MI procedure in SAS with seed number of 6681877. 
Step 3: Analyze each of the 10 complete datasets using SAS FREQ procedure with CMH test.  
SAS syntax code for CMH 
 
  
 
 
  
Step 4: Apply Wilson-Hilferty (WH) transformation to normalize the test statistic  
SAS syntax code for WH transformation 
  
 
 
 
  
Step 5: Use Rubin’s rule to combine the odds ratio and WH transformation for p-value using 
SAS MIANALYZE procedure 
SAS syntax code for Rubin’s rule 
 
  
  
  
  
  
                                        VV-RIM-00199013-1.0 Approved - 03 Jun 2022 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
 
Protocol: R668-EE-1877 
Statistical Analysis Plan Amendment 1 
 
Date: June 2, 2022 
 
CONFIDENTIAL 
Page 100 of 100 
 
 
 
  
 
  
    
                           
 
       
 
     
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
                                        VV-RIM-00199013-1.0 Approved - 03 Jun 2022 GMT-5:00


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