Clinical trial NCT03633617
Conditions: Eosinophilic Esophagitis
Sponsor: Regeneron Pharmaceuticals
Start date: 2018-09-24; Completion date: 2022-06-07
Enrollment: 321 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objectives of the study by study part are:

Part A:

To determine the treatment effect of dupilumab compared with placebo in adult and adolescent patients with EoE after 24 weeks of treatment as assessed by histological and clinical measures and to inform/confirm the final sample size determination for Part B.

Part B:

To demonstrate the efficacy of dupilumab treatment compared with placebo in adult and adolescent patients with EoE after 24 weeks of treatment as assessed by histological and clinical measures.

Part C:

To assess the safety and efficacy of dupilumab treatment in adult and adolescent patients with EoE after up to 52 weeks of treatment as assessed by histological and clinical measures.

The secondary objectives of the study are:

* To evaluate the safety, tolerability, and immunogenicity of dupilumab treatment for up to 52 weeks in adult and adolescent patients with EoE
* To explore the relationship between dupilumab concentration and responses in adult and adolescent patients with EoE, using descriptive analyses
* To evaluate the effects of dupilumab on transcriptomic signatures associated with EoE and type 2 inflammation
* To demonstrate the efficacy of dupilumab treatment compared to placebo after 24 weeks and 52 weeks of treatment in adult and adolescent patients with EoE who have previously received swallowed topical corticosteroids

Detailed description:

Arms: arm 1: Part A consists of a 24-week double-blind treatment period. Participants will be randomized to receive dupilumab or placebo. At the end of the double-blind treatment visit (week 24), eligible participants may enter Part C. Participants who do not enter Part C will enter a 12-week follow-up period. arm 2: Part B consists of a 24-week double-blind treatment period. Participants will be randomized to receive dupilumab dosing regimen 1, dupilumab dosing regimen 2 or placebo. At the end of the double-blind treatment visit (week 24), eligible participants may enter Part C. Participants who do not enter Part C will enter a 12-week follow-up period. arm 3: Part C is a 28-week extended active treatment period. Participants will receive dupilumab dosing regimen 1, dupilumab dosing regimen 2. At the end of the treatment period (week 52), participants will enter a 12-week follow-up period.
Interventions: intervention 1: Dupilumab intervention 2: Placebo
Intervention descriptions: intervention 1: Solution for injection administered subcutaneously intervention 2: Matching placebo

Protocol documents:
SAP_002.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 101 
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 Phase 3, Randomized, 3-Part Study to Investigate the Efficacy and Safety of Dupilumab 
in Adult and Adolescent Patients with Eosinophilic Esophagitis 
Part B/Part C 
Compound:  
Dupilumab (REGN668) 
Protocol Number: 
R668-EE-1774.05 
Clinical Phase:   
Phase 3 
Sponsor:  
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
 
Clinical Trial Manager: 
  
Study Medical Director:
 
Version/Date: 
Amendment 1/ September 14, 2021 
VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00
NCT Number:  NCT03633617


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 2 of 101 
 
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 
Study Biostatistician  
 
 
 
 
See appended electronic signature page 
Study Medical Director 
  
 
 
 
See appended electronic signature page 
Head of BDM or designee  
 
 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 3 of 101 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
OVERVIEW ...............................................................................................................10 
1.1. 
Background/Rationale ................................................................................................10 
1.2. 
Study Objectives .........................................................................................................11 
1.2.1. 
Primary Objectives .....................................................................................................11 
1.2.2. 
Secondary Objectives .................................................................................................12 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ................................12 
1.2.4. 
Revision History for SAP Amendments .....................................................................12 
2. 
INVESTIGATION PLAN ..........................................................................................14 
2.1. 
Study Design and Randomization ..............................................................................14 
2.2. 
Statistical Hypothesis ..................................................................................................15 
2.3. 
Sample Size and Power Considerations .....................................................................16 
2.4. 
Study Plan ...................................................................................................................16 
3. 
ANALYSIS POPULATIONS ....................................................................................20 
3.1. 
The Full Analysis Set (FAS) .......................................................................................20 
3.2. 
The Safety Analysis Set (SAF) ...................................................................................20 
3.3. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................21 
3.4. 
The Immunogenicity Analysis Set..............................................................................21 
3.5. 
Subgroups ...................................................................................................................22 
4. 
ANALYSIS VARIABLES .........................................................................................23 
4.1. 
Demographic and Baseline Characteristics ................................................................23 
4.2. 
Medical History ..........................................................................................................25 
4.3. 
Pre-treatment / Concomitant Medications and Procedures ........................................25 
4.4. 
Efficacy Variable ........................................................................................................27 
4.4.1. 
Primary Efficacy Variable (s) .....................................................................................27 
4.4.2. 
Secondary Efficacy Variable(s) ..................................................................................29 
4.4.3. 
Exploratory Efficacy Variable(s) ................................................................................34 
4.5. 
Safety Variables ..........................................................................................................39 
4.5.1. 
Adverse Events and Serious Adverse Events .............................................................39 
4.5.2. 
Laboratory Safety Variables .......................................................................................40 
4.5.3. 
Vital Signs ..................................................................................................................41 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 4 of 101 
4.5.4. 
12-Lead Electrocardiography (ECG) ..........................................................................41 
4.5.5. 
Physical Examination Variables .................................................................................41 
4.6. 
Pharmacokinetic Variables .........................................................................................41 
4.7. 
Immunogenicity Variables ..........................................................................................41 
4.8. 
Biomarker Variables ...................................................................................................42 
4.9. 
Patient Reported Outcomes for Psychometric Validity Assessment ..........................42 
5. 
STATISTICAL METHODS .......................................................................................43 
5.1. 
Demographics and Baseline Characteristics ...............................................................43 
5.2. 
Medical History ..........................................................................................................43 
5.3. 
Prior/Concomitant Medications/Procedures ...............................................................43 
5.4. 
Subject Disposition .....................................................................................................44 
5.5. 
Extent of Study Treatment Exposure and Compliance ...............................................45 
5.5.1. 
Measurement of Compliance ......................................................................................45 
5.5.2. 
Exposure to Study Drug and Observation Period .......................................................45 
5.6. 
Analyses of Efficacy Variables ..................................................................................46 
5.6.1. 
Analysis of Co-Primary Efficacy Variable(s) .............................................................46 
5.6.2. 
Analysis of Secondary Efficacy Variables .................................................................51 
5.6.3. 
Adjustment for Multiple Comparison .........................................................................52 
5.6.4. 
Subgroup Analysis ......................................................................................................53 
5.6.5. 
Analysis of Exploratory Efficacy Variables ...............................................................53 
5.7. 
Analysis of Safety Data ..............................................................................................53 
5.7.1. 
Adverse Events  ..........................................................................................................54 
5.7.2. 
Clinical Laboratory Measurements.............................................................................55 
5.7.3. 
Analysis of Vital Signs ...............................................................................................56 
5.7.4. 
Analysis of 12-Lead ECG ...........................................................................................56 
5.7.5. 
Physical Exams ...........................................................................................................56 
5.8. 
Analysis of Pharmacokinetic Data ..............................................................................56 
5.9. 
Analysis of Immunogenicity Data ..............................................................................56 
5.9.1. 
Analysis of ADA ........................................................................................................56 
5.9.2. 
Analysis of Neutralizing Antibody (NAb) Data .........................................................57 
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................57 
5.10.1. 
Association of immunogenicity with exposure ..........................................................57 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 5 of 101 
5.10.2. 
Immunogenicity and Safety/Efficacy .........................................................................57 
5.11. 
Analysis of Biomarker Data .......................................................................................58 
5.12. 
Analysis of Psychometric Validity of Patient Reported Outcome Measures .............59 
6. 
DATA CONVENTIONS ............................................................................................60 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................60 
6.2. 
General Data Handling Conventions ..........................................................................60 
6.3. 
Data Handling Convention for Missing Data .............................................................60 
6.4. 
Analysis Visit Windows .............................................................................................62 
6.5. 
Statistical Technical Issues .........................................................................................66 
7. 
INTERIM ANALYSIS ...............................................................................................67 
8. 
TIMING OF STATISTICAL ANALYSIS .................................................................68 
9. 
SOFTWARE ...............................................................................................................69 
10. 
REFERENCES ...........................................................................................................70 
11. 
APPENDIX.................................................................................................................72 
11.1. 
Summary of Statistical Analyses ................................................................................72 
11.1.1. 
Summary of Primary Estimand for Co-primary Endpoints and Secondary 
Endpoints in Part B .....................................................................................................72 
11.1.2. 
Summary of Efficacy Analyses ..................................................................................74 
11.1.3. 
Summary of Safety Analyses ......................................................................................75 
11.2. 
Schedule of Time and Events .....................................................................................76 
11.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................88 
11.4. 
Search Criteria for TEAEs of Special Interest ............................................................94 
11.5. 
EoE Histology Scoring System (EoEHSS) Feature Evaluation Per Colllins et 
al. 2017 .......................................................................................................................96 
11.6. 
Gene Lists Comprising Each Transcriptome Endpoint ..............................................98 
11.7. 
List of Part B Subjects Affected by Electronic Handheld Device Navigation 
Malfunction ...............................................................................................................100 
11.8. 
EQ-5D-3L Utility Index scoring (UK Tariff) ...........................................................100 
 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 6 of 101 
LIST OF TABLES 
Table 1: Analysis Visit Window for Efficacy Endpoints in Part B ...............................................63 
Table 2: Analysis Visit Window for Safety and Biomarkers in Part B .........................................64 
Table 3: Analysis Visit Window for Efficacy Endpoints in Part C ...............................................64 
Table 4: Analysis Visit Window for Safety and Biomarkers in Part C .........................................65 
Table 5: Analysis Visit Window for 12-week follow-up period after Part B/Part C end of 
treatment .....................................................................................................................65 
Table 6: Parts B Schedule of Events – Screening Period and Placebo-controlled, Double-
Blind Treatment Period ...............................................................................................76 
Table 7: Part C Schedule of Events – Extended Active Treatment Period ....................................78 
Table 8: Follow-up Period, Early Termination Visit, and Unscheduled Visit...............................80 
Table 9: Coefficients of Regression Model Based on UK population.........................................100 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Design ..................................................................................................15 
Figure 2: 
Study Flow Diagram for Part B and Part C ................................................................17 
Figure 3: 
Flow Diagram of DSQ eDiary ....................................................................................48 
Figure 4: 
Response Patterns of DSQ eDiary ..............................................................................49 
 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 7 of 101 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Ab 
Antibody 
ACQ-5 
Asthma Control Questionnaire-5 
AD 
Atopic dermatitis 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BID 
Twice (two times) a day 
BUN 
Blood urea nitrogen 
CMH 
Cochran-Mantel-Haenszel (test) 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
Ctrough 
Trough concentration 
DMC 
Data monitoring committee 
DSQ 
Dysphagia Symptom Questionnaire 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eCOA 
Electronic clinical outcome assessment 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EndoFLIP 
Endolumenal functional lumen imaging probe 
EoE 
Eosinophilic esophagitis 
EoE-EREFS 
Eosinophilic Esophagitis-Endoscopic Reference Score 
EoEHSS 
EoE Histology Scoring System 
EoE-IQ 
EoE Impact Questionnaire 
EoE-SQ 
EoE Symtom Questionnaire 
EOS 
End of study (visit) 
eos/hpf 
Eosinophils/high power field 
EOT 
End of treatment 
EQ-5D 
European Quality of Life 5-Dimensional Scale 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 8 of 101 
ET 
Early termination 
FAS 
Full analysis set 
FSH 
Follicle stimulating hormone 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
IA 
Interim analysis 
IAF 
Informed assent form 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IgE 
Immunoglobulin E 
IgG4 
Immunoglobulin G4 
IL 
Interleukin 
IL-4Rα 
Interleukin-4 receptor alpha 
ISR 
Injection site reaction 
IWRS 
Interactive voice/web response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model repeated measure 
NAb 
Neutralizing antibody 
OIT 
Oral immunotherapy 
PCSV 
Potentially clinically significant value 
PGIC 
Patient Global Impression of Change of Dysphagia 
PGIS 
Patient Global Impression of Severity of Dysphagia 
PK 
Pharmacokinetic 
POEM 
Patient-Oriented Eczema Measure 
PPI 
Proton pump inhibitor 
PRO 
Patient-reported outcome 
PT 
Preferred term (MedDRA) 
QOL 
Quality of life 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 9 of 101 
Q2W 
Once every two weeks 
QW 
Once weekly 
RBC 
Red blood cell 
RQLQ(s)+12 
Rhinoconjunctivitis Quality of Life Questionnaires for 12 years and older 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SD 
Standard deviation 
SLIT 
Sublingual immunotherapy 
SOC 
System organ class 
STC 
Swallowed topical corticosteroids 
TARC 
Thymus and activation-regulated chemokine 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
Th2 
Type 2 helper T cell 
TNSS 
Total Nasal Symptom Score 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCF 
Worst observation carried forward 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 10 of 101 
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 analysis of data for R668-EE-1774 study Part B, as well as Part B 
patients’ data in Part C as extended active treatment and in the 12-week follow-up period. A 
separate Part A SAP was finalized on 21April2020 for the analysis of data from Part A, and Part 
A patients’ data in Part C and 12-week follow-up period before Part A DBL. 
This plan will be finalized prior to the data lock for the end of Part B, i.e., the last Part B patient 
reaching week 24 visit. 
1.1. 
Background/Rationale 
Eosinophilic esophagitis (EoE) is a chronic, inflammatory, allergic/immune-mediated disease of 
the esophagus. The disease is characterized by local eosinophilic inflammation leading to 
symptoms of esophageal dysfunction. The primary clinical manifestations of EoE in both adults 
and adolescents are dysphagia and food impaction (Hudgens, 2017). Growing evidence suggests 
that a type 2 cytokine-mediated immune response plays an important role in the pathogenesis of 
EoE. The inflammatory damage to the esophageal epithelium results in symptoms of esophageal 
dysfunction, such as dysphagia. Chronic inflammation of the esophagus may also lead to 
remodeling, stricture formation, and fibrosis.  
Current therapeutic approaches include high dose proton pump inhibitors, dietary modification 
with specific food elimination, swallowed topical corticosteroids (not approved for the treatment 
of EoE in adolescents or in adults outside the European Union [EU]), and esophageal dilation when 
esophageal narrowing/or strictures develop. The therapies for eosinophilic esophagitis are limited 
by variable response rates, relapse after therapy cessation, and adverse effects on quality of life. 
High dose proton pump inhibitors lead to histologic remission in approximately half of the patients 
(Lucendo, 2016). Swallowed topical corticosteroids have shown variable response, and 
maintainance of compliance is challenging due to the potential risks of side effects. Endoscopic 
dilation for prolonged and/or painful food impaction is an emergency procedure utilized for 
symptomatic relief if the patient cannot pass the food or induce vomiting. It is associated with a 
risk of severe esophageal injury and does not alter the underlying pathogenesis or progression of 
the disease.  As such, there is a significant unmet need for new treatments across the age spectrum 
targeting key pathways driving the inflammation in EoE (Rothenberg, 2015, Spergel, 2012, 
Greuter, 2017).  
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 
cytokine-induced responses, including the release of pro-inflammatory cytokines, chemokines, 
and IgE. Additionally, preclinical data demonstrate that treatment with dupilumab prevents 
infiltration of eosinophils into tissues. For these reasons, dupilumab was evaluated in adult patients 
with EoE in a phase 2, multicenter, double-blind, randomized, placebo-controlled study (R668-
EE-1324), where it demonstrated substantial improvements in clinical (based on the Straumann 
Dysphagia Instrument), histologic, and endoscopic aspects of the disease. Dupilumab was well 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 11 of 101 
tolerated in the study, with safety data generally consistent with other dupilumab studies in patients 
with AD, in patients with asthma, and patients with chronic rhinosinusitis with nasal polyps.  No 
new safety signal associated with dupilumab use was identified in the EoE patient population. The 
results from phase 2 support the phase 3 evaluation of dupilumab in EoE. 
Additional background information on the study drug and development program can be found in 
the most recent Investigator’s Brochure. 
This phase 3 study was to investigate the efficacy and safety of dupilumab in adult and adolescent 
patients with EoE in a 3-part study. Part A and Part B are 24-week treatment, randomized, double-
blind, placebo-controlled studies. In Part A, patients were randomized to receive dupilumab 
300 mg QW or placebo; In Part B, patients were to be randomized to receive dupilumab 300 mg 
Q2W, dupilumab 300 mg QW, or placebo. Patients who had participated in Part A would not be 
eligible to participate in Part B. At the end of Part A, eligible patients were offered an option to 
enter Part C for an extended treatment period to receive dupilumab 300 mg QW. At the end of Part 
B, eligible patients were to be provided with an option to enter Part C to receive dupilumab 300 mg 
Q2W or dupilumab 300 mg QW in a blinded fashion for an additional 28 weeks. Patients in Parts 
A/B who not entering Part C would enter a 12-week post-treatment follow-up period immediately 
after Part A/B.  
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
Parts A and B  
To demonstrate the efficacy of dupilumab treatment compared with placebo in adult and 
adolescent patients with EoE after 24 weeks of treatment as assessed by histological and clinical 
measures. 
Part C 
To assess the safety and efficacy of dupilumab treatment in adult and adolescent patients with EoE 
after up to 52 weeks of treatment as assessed by histological and clinical measures. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 12 of 101 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the safety, tolerability, and immunogenicity of dupilumab treatment for up 
to 52 weeks in adult and adolescent patients with EoE 
• To explore the relationship between dupilumab concentration and responses in adult 
and adolescent patients with EoE, using descriptive analyses 
• To evaluate the molecular effects of dupilumab on transcriptomic signatures associated 
with EoE and type 2 inflammation 
• To demonstrate the efficacy of dupilumab treatment compared with placebo after 24 
weeks and 52 weeks of treatment in adult and adolescent patients with EoE who have 
previously received  swallowed topical corticosteroids  
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
The Part B per protocol analysis set (PPS) is removed since estimands are constructed, with 
aligned method of analysis, that better address the objective and analysis of PPS might not add 
additional insights.  
1.2.4. 
Revision History for SAP Amendments 
The purpose of this SAP amendment is to  
(1) add analyses per feedback received from a Health Authority  
(2) clarify the analysis of EoE-EREFS and update the hierarchical testing order before 
database lock. 
Description of Change 
Rationale 
Section Changed 
To add 2 supplemental 
analyses for co-primary 
endpoint of absolute 
change in DSQ score 
from baseline to week 24 
As per Health Authority 
recommendation 
Section 5.6.1 Analysis of Co-
Primary Efficacy Variable(s) 
To add DSQ-related 
analyses 
As per Health Authority 
recomendation 
Section 4.4.3 Exploratory 
Efficacy Variable (s) 
Section 5.6.5 Analysis of 
Exploratory Efficacy Variables 
To update the hierarchical 
testing order 
To address a Health Authority 
recommendation 
Section 5.6.3 Adjustment for 
Multiple Comparison 
To clarify the analysis of 
EoE-EREFS  
To be consistent in the analysis 
between Part A and Part B and 
to be in line with the intent of 
the protocol to utilize 
investigator assessed EoE-
EREFS data for the analysis if 
the images for central reading 
are not available (e.g. due to 
Section 4.4.2 Secondary 
Efficacy Variable(s) 
Section 5.6.2 Analysis of 
Secondary Efficacy Variables 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 13 of 101 
technical and image quality 
issues) 
Editorial changes  
To clarify that the the analysis 
of psychometric validity of 
patient reported outcome 
measures is described in a 
separate Psychometric 
Analysis Plan 
Section 5.12 Analysis of 
Psychometric Validity of Patient 
Reported Outcome Measures 
To clarify that the Part B CSR 
will be written separated from 
the Part B patients’ Part C 
CSR 
Section 8 Timing of Statistical 
Analysis 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 14 of 101 
2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
Part B is a 24-week treatment, randomized, double-blind, placebo-controlled study phase to 
determine the treatment effect of dupilumab compared with placebo in adult and adolescent 
patients with EoE as assessed by histological and clinical measures. After a screening period up to 
12 weeks, patients were centrally randomized via interactive web response system (IWRS) in a 
1:1:1 ratio to dupilumab 300 mg SC QW, dupilumab 300 mg SC Q2W or placebo SC and treated 
double-blind for 24 weeks in Part B. Randomization was stratified by age (≥18 vs. ≥12 to <18 
years of age) and use of PPI at randomization (yes vs. no). At the end of Part B, eligible patients 
were to be provided an option to enter Part C, which consists of a 28-week period of active 
treatment with dupilumab. Patients from Part B who were randomized to placebo during the 
double-blind treatment period would be re-randomized in a 1:1 ratio to dupilumab 300 mg QW or 
dupilumab 300 mg Q2W. Patients from Part B who were randomized to dupilumab during the 
double-blind treatment period would remain on the same dupilumab treatment in Part C. Treatment 
assignment in Part C were managed by an interactive web response system (IWRS) to maintain 
blinding of treatment assignment in Part B. All patients would be followed up for an additional 12 
weeks after completing Part C. Patients in Part B who do not enter Part C would enter a 12-week 
follow-up period immediately after Part B. Patients who participated in Part A were not eligible to 
participate in Part B. 
Approximately 210 patients (70 per treatment group) are planned to be randomized in Part B from 
multiple global sites.  
The design of the overall study is depicted below in Figure 1. As Part A and Part B are carried out 
as 2 separate sub-studies with no overlap in patients, Part A and Part B will each have a separate 
2-sided alpha level of 0.05.  
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 15 of 101 
Figure 1: 
Overall Study Design 
 
 
2.2. 
Statistical Hypothesis 
For the comparison of each of the 2 dupilumab treatment groups to placebo, the following 
hypotheses of the co-primary endpoints will be tested, where pd is the true proportion of patients 
achieving peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 24 and μd is the 
true mean change from baseline in the DSQ total score at week 24 in the dupilumab group; and pp 
and μp are the corresponding true values in the placebo group. 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 
eos/hpf at week 24 
− Null hypothesis (H0): pp = pd, ie, the proportion of patients achieving peak 
esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 24 is the same 
between the dupilumab group and the placebo group. 
− Alternative hypothesis (H1): pp ≠ pd, ie, the proportion of patients achieving peak 
esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 24 is different 
between the dupilumab group and the placebo group. 
•  Change from baseline in the DSQ total score at week 24 
− Null hypothesis (H0): μp = μd, ie, the mean change from baseline in the DSQ total 
score at week 24 is the same between the dupilumab group and the placebo group. 
− Alternative hypothesis (H1): μp ≠ μd, ie, the mean change from baseline in the DSQ 
total score at week 24 is different between the dupilumab group and the placebo 
group. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 16 of 101 
2.3. 
Sample Size and Power Considerations 
Efficacy assessment employs the following co-primary endpoints measuring histologic and 
clinical symptoms of disease, respectively: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 
eos/hpf at week 24 
• Absolute change in Dysphagia Symptom Questionnaire (DSQ) score from baseline to 
week 24 
The assumptions used in sample size calculations are based on results from Part A of the study as 
below: 
• The proportion of patients achieving peak esophageal intraepithelial eosinophil count 
of ≤6 eos/hpf at 24 weeks was 5.1% in placebo group and 59.5% in dupilumab 300mg 
QW group with a treatment difference of 55.4% 
• The mean (standard deviation [SD]) of change from baseline in DSQ total score at week 
24 was -9.6 (15.2) in placebo and -21.9 (14.6) in the dupilumab 300mg QW group with 
a treatment group difference of -12.3.   
Based on the Part A study results, the planned sample size for Part B is approximately 70 patients 
in each treatment group such that for the comparison of each dupilumab treatment group to 
placebo:  
• This sample size will yield >99.9% power to detect a treatment difference of 55.4% in 
the proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤6 eos/hpf at week 24 between placebo (5.1%) and each dupilumab treatment group 
(59.5% ) at a 2-sided significant level of 5% using Fisher’s exact test.   
• This sample size will provide >99.9% power to detect a treatment difference of -12.3 
points in the mean change from baseline in the total DSQ score to week 24 at a 2-sided 
significance level of 5% using a two-sample t-test, assuming a common SD of 15.0.   
Therefore, the sample size of  70 patients/arm will provide an overall power of >99.9% (99.9% × 
99.9%) for the co-primary endpoints, assuming no negative correlation between the two endpoints. 
In Part B, the same treatment effect for the two 300 mg dupilumab dose regimens (ie, QW and 
Q2W) is assumed. 
A dropout rate of 15% is assumed for the sample size calculations. 
Sample size calculations were made using nQuery Advisor 7.0. 
2.4. 
Study Plan 
Patients will undergo a screening period (up to 12 weeks), a double-blind treatment period of 24 
weeks (Part B), a 28-week extended active treatment period (Part C), and a 12-week follow-up 
period as depicted in Figure 2. All patients will be followed up for an additional 12 weeks after 
completing Part C.  Patients in Parts B who choose not to participate in or are ineligible for Part C 
will be followed for an additional 12 weeks immediately after Part B. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 17 of 101 
Figure 2: 
Study Flow Diagram for Part B and Part C 
 
DB = double-blind. 
Note:  For patients who do not have at least 11 daily entries during the 14 days immediately preceding the planned 
randomization date (baseline), randomization should be postponed until this requirement is met, but without 
exceeding the 85-day maximum duration for screening. 
After adult patients provide informed consent and adolescent patients and/or their legal 
parents/legal guardians provide informed consent and informed assent (as appropriate), patients 
will be assessed for study eligibility at visit 1.  
Study participants are required to have a conﬁrmed diagnosis of EoE which may be established 
either by a prior historical biopsy showing ≥15 intraepithelial eosinophils per high-power ﬁeld 
(eos/hpf) from at least one esophageal region after at least 8 weeks of treatment with a high-dose 
proton pump inhibitor (PPI) using any approved PPI or by biopsies performed after approximately 
8 weeks of high-dose PPI treatment initiated prior to screening or during the screening period, 
which demonstrate ≥15 intraepithelial eos/hpf in at least 2 out of 3 esophageal regions (proximal, 
mid, and distal); see Protocol Figure 3 for endoscopy/biopsy procedure flow chart. Patients who 
are on PPIs during the screening period and are eligible to enroll in the study must continue a 
high-dose PPI regimen during the study (see details in Protocol Section 7.2). Patients are allowed 
to switch among the approved background therapy options for high-dose PPI use during the study. 
All patients who meet the other clinical and laboratory eligibility criteria will undergo endoscopy 
with biopsies at visit 2 (day -21±7) both to establish a baseline reference measure and to ensure 
eligibility. For patients without a historical biopsy, the visit 2 biopsy will serve as both 
confirmation of EoE diagnosis and the baseline reference measure. 
All biopsies performed during this study will be evaluated by pathologists at a central pathology 
laboratory who will be blinded to treatment assignment. 
Note: Biopsy specimens from the stomach and/or duodenum will be obtained in all patients 
<18 years of age to rule out alternate etiologies of esophageal eosinophilia. Targeted, stomach 
and/or duodenal biopsies will be obtained in adults only in the event of abnormal endoscopic 
findings (other than typical EoE findings) or clinical suspicion of alternate etiologies. All 
randomized patients found to have stomach and/or duodenal abnormalities at baseline will have 
follow-up stomach and/or duodenal biopsies at week 24 and week 52. 
Part B 
Part C 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 18 of 101 
After confirmation of EoE diagnosis, patients will be given an electronic diary (eDiary) to record 
dysphagia symptoms on a daily basis during the 2 weeks prior to the baseline visit (visit 3). 
Patients may be re-screened once if they fail the screening evaluation, unless the reason for screen 
failure is related to histologic or clinical disease severity inclusion criteria. The baseline endoscopy 
with biopsy and EoE-EREFS scoring will not be repeated for re-screened patients.  These results 
will continue to be valid baseline data.  Re-screening must occur within 6 months of the screen 
failure. 
For patients whose DSQ diary compliance does not meet eligibility requirements within the 21-
day interval between Visit 2 and Visit 3 (at least 11 daily entries during the 14 days immediately 
preceding the planned randomization date), randomization may be postponed as long as the total 
duration of the screening period does not exceed the 85-day maximum. 
At the baseline visit (visit 3), patients who continue to meet eligibility criteria will enter the 
24week, placebo-controlled, double-blind treatment period and be randomized in a 1:1:1 ratio to 
dupilumab 300 mg SC QW, dupilumab 300 mg SC Q2W or placebo SC. Randomization will be 
stratified by age (≥18 vs. ≥12 to <18 years of age) and use of PPI at randomization (yes vs. no). 
During the 24-week, placebo controlled, double-blind treatment period, clinic visits are scheduled 
per the schedule of events (Section 11.2). Patients and parents/caregivers will be trained on 
injecting study drug at the first 3 visits during the double-blind treatment period. Patients will be 
closely monitored at the study site at visits 3 to 6 (baseline visit, study weeks 1, 2, and 4) for a 
minimum of 30 minutes after the administration of study drug. During weeks when no clinic visit 
is scheduled, the patient or parent/caregiver will administer study drug. Doses of study drug 
administered at home should be administered one week after the prior dose of study drug.  Study 
drug administration that occurs in clinic should occur per the Schedule of Events in Section 11.2. 
Patients and parents/caregivers who prefer to have clinic staff administer study drug may choose 
to have injections administered in the clinic. 
The end of treatment visit for the double-blind treatment period is at week 24. The co-primary 
endpoints will be assessed at week 24, one week after the last dose of study drug during the double-
blind treatment period.  
Patients who prematurely discontinue study treatment will be encouraged to remain in the study 
and attend all subsequent scheduled visits. 
At the end of the double-blind treatment visit (week 24), eligible patients in Part B may enter Part 
C, which consists of a 28-week extended active treatment period. Patients from Part B who are 
randomized to placebo during the double-blind treatment period will be re-randomized in a 1:1 
ratio to dupilumab 300 mg QW or dupilumab 300 mg Q2W.  Patients randomized to dupilumab 
300 mg Q2W will also receive matching placebo alternating with dupilumab doses so the injection 
frequency will be identical for both groups for regimen-blinding purposes.  All other patients will 
remain on the same dupilumab dose regimen to which they are randomized during the double-
blind treatment period. Patients who do not enter Part C may enter a 12-week follow-up period. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 19 of 101 
Due to the COVID-19 pandemic, the Sponsor allows study procedures to occur outside the 
protocol specified timepoint and/or outside of the clinic environment and will remain in effect only 
for the duration of the public health emergency: 
• Endoscopy with biopsies may be delayed for visit 11/week 24, visit 19/week 52, early 
termination, and before initiating rescue treatment 
• At-home study drug dosing is permitted for all visits except for visit 3/day 1 and visit 
11/week 24 
• If the for-cause endoscopy with biopsies cannot occur due to COVID-19 restrictions, 
rescue treatment should be initiated without delay and these patients will be eligible to 
participate in Part C 
• Safety and laboratory procedures (vital signs, weight, PK/ADA sample collection, 
hematology and chemistry urine sample collection) may be delayed or occur at-home 
when possible 
• The patient reported outcome questionnaires that are intended to be completed during 
clinic visits may be conducted via phone interviews after visit 3/day 1 
Patients are allowed to extend their current assigned dose regimen of study drug (Parts B and/or 
C) until the post-baseline esophageal biopsy procedure(s) are performed. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 20 of 101 
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 B efficacy analyses. The 
Part B safety analysis set (SAF) is the basis for Part B safety analyses.  
The Part C SAF is the basis for both efficacy and safety analyses of Part C. 
3.1. 
The Full Analysis Set (FAS) 
The Part B full analysis set (FAS) includes all randomized patients in Part B. Efficacy analyses 
will be based on the treatment allocated by the IWRS at randomization (as randomized).  
3.2. 
The Safety Analysis Set (SAF) 
Part B: 
The Part B safety analysis set (SAF) includes all randomized patients who received any study drug 
in Part B; it is based on the treatment received (as treated). Treatment compliance/administration 
and all clinical safety variables in Part B will be analyzed using the Part B SAF. 
Part C: 
The Part C SAF includes all patients who were randomized in Part B, entered Part C, and 
received any study drug in Part C. Efficacy, treatment compliance/administration, and all clinical 
safety data from Part C  through a pre-specified cut-off date around the time of Part B 
completion will be analyzed for Part C SAF patients who entered Part C from Part B. 
 
The actual treatment group as treated for Part B is defined by the following rules: 
• For a patient randomized to dupilumab 300 mg QW or dupilumab 300 mg Q2W, if the 
patient received all placebo injections in Part B, the actual treatment will be assigned 
as placebo. 
• For a patient randomized to dupilumab 300 mg QW or dupilumab 300 mg Q2W, if the 
patient received at least one dupilumab injections in Part B, 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 B, the actual treatment will be assigned as dupilumab 300 mg Q2W. 
The Part B treatment group assignment for analysis of Part C data will be the same as the SAF for 
Part B.  
For safety summaries, the following analysis periods are defined: 
• Part B week 24 treatment period is defined as  
− For patients who entered Part C: Day 1 to the date of first dose of Part C study drug 
(or week 24 visit if patient entered Part C but never received any Part C study drug).  
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 21 of 101 
− For patients who did not enter Part C:  
▪ Day 1 to the week 24 visit if patients completed week 24 visit with known 
visit date. 
▪ Day 1 to study day 169 (24 weeks times 7 days/week), or to patient’s last 
study participation date, whichever comes earlier, if patients did not 
complete week 24 visit or had missing week 24 visit date. 
• Part C extended treatment period for patients who entered Part C is defined as 
▪ Time after the first dose of study drug in Part C to the date of week 52 visit 
if patients completed week 52 with known visit date. 
▪ Time after the first dose of study drug in Part C to study day 365 (52 weeks 
times 7 days/week), or to patient’s last study participation date, whichever 
comes earlier, if patients did not complete week 52 visit or had missing 
week 52 visit date. 
• Follow-up period is defined as 
− For patients who entered Part C: the day after the end of Part C extended treatment 
period to the patient last study participation date. 
− For patients who did not enter Part C: the day after the end of Part B week 24 
treatment period to the patient last study participation date. 
The Part B and Part C SAFs will be the basis for the analyses for the Part B treatment period and 
Part C treatment period, respectively; however, for the analyses for 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 24 visit (for Part B SAF) and week 52 
visit (for Part C SAF). 
Due to COVID-19 pandemic, patients are allowed to extend their current assigned dose regimen 
of study drug (Part B and/or Part C) until endoscopy with biopsy can be performed at week 24 
visit and/or week 52 visit. The safety data during the extended dosing period will also be presented 
in the corresponding analysis period.  
3.3. 
The Pharmacokinetic Analysis Set (PKAS) 
The PK analysis set for Part B and Part C includes all randomized patients who received any study 
drug and who had at least one non-missing drug concentration result following the first dose of 
study drug in the corresponding study part.  
3.4. 
The Immunogenicity Analysis Set 
The ADA analysis set (AAS) for Part B and Part C includes all patients who received any study 
drug and had at least one non-missing ADA result from the dupilumab ADA assay after first dose 
of the study drug in the corresponding study part.  Patients will be analyzed according to the 
treatment actually received. 
The neutralizing antibody (NAb) analysis set (NAS) for Part B and Part C includes all treated 
patients who received any study drug (active or placebo), have at least one non-missing ADA 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 22 of 101 
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) in the corresponding study part. Patients who are 
ADA negative are set to negative in the NAb analysis set. Patients will be analyzed according to 
the treatment actually received. 
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 efficacy and safety analyses: 
• Age group (years; 12 to <18, ≥18)  
• Sex (Male, Female) 
• Duration of EoE (years from start date of EoE to randomization date; <5, ≥5) 
• Baseline weight group (<60 kg, ≥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 or No)  
• History of atopic dermatitis (Yes, No)  
• History of asthma (Yes, No) 
• History of allergic rhinitis (Yes, No) 
• History of food allergy (Yes, No) 
Note: subgroups defined by race, ethnicity, and region are not included as majority of patients in 
Part B are anticipated to be in one major category of these demographic factors. The analysis for 
the subgroups defined above may not be performed if the number of patients within the subgroup 
is small, e.g. <20 patients per arm. 
Subgroups to be considered for efficacy analyses only: 
• Baseline BMI group (<25, ≥25-<30, ≥30) 
• 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) 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 23 of 101 
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;12 to <18, ≥18 to <40, ≥40 to <65, ≥65), Sex (Male, Female), Ethnicity with 
grouping (Hispanic or Latino, Not-Hispanic or Latino), Race with grouping (White, 
Black or African American, Asian, Other), Region (North America, or Rest of World), 
Country, Baseline weight as a continuous variable and with grouping (kg; <60, ≥60), 
Height (m), and calculated BMI (kg/m2; <15, ≥15-<25, ≥25-<30, ≥30), age [years; 12 
to <18, ≥18] and use of PPI at randomization [Yes, No]. 
• Baseline characteristics:  
− DSQ total score 
− Number of days with dysphagia in the 2 weeks prior to baseline as a continuous 
variable and with group (4, 5, 6, 7, 8, etc.) 
− Amount of pain patient had experienced when swallowing food from DSQ 
− Peak esophageal intraepithelial eosinophil count (eos/hpf) of three regions 
(proximal, mid, and distal) 
− Eosinophilic Esophagitis-Endoscopic Reference Score (EREFS) total score 
− Mean stage score from the EoE Histology Scoring System (EoEHSS) summed over 
3 regions  
− Mean grade score from the EoEHSS summered over 3 regions  
− Total EoEHSS histology stage score (excluding lamina propria fibrosis) summed 
over 3 regions  
− Total EoEHSS histology grade score (excluding lamina propria fibrosis) summed 
over 3 regions  
− Patient global impression of severity (PGIS) level (none, mild, moderate, or severe) 
− EoE Impact Questionnaire (EoE-IQ) score 
− EoE Symptom Questionnaire (EoE-SQ) frequency score and severity score 
− Total Nasal Symptom Score (TNSS) for patients with history of allergic rhinitis  
− Rhinoconjunctivitis Quality of Life Questionnaire score for patients aged 12+ years 
[RQLQ(S)+12] for patients with history of allergic rhinitis 
− Asthma Control Questionnaire-5 (ACQ-5) score for patients with history of asthma 
− Patient-Oriented Eczema Measure (POEM) score for patients with history of atopic 
dermatitis 
− European quality of life 5-dimensional scale (EQ-5D) utility index score 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 24 of 101 
− European quality visual analogue scale (EQ VAS) 
− Baseline blood eosinophil count as a continuous variable and with grouping 
(Giga/L; <0.15, ≥0.15; <0.30, ≥0.30; <0.50, ≥0.50) 
− Baseline serum total immunoglobulin E (IgE) as a continuous variable and with 
grouping (IU/mL; <100, ≥100) 
− Patients treated with PPI at randomization (Yes, No) 
− Prior use of STC for EoE (Yes, No) 
− Effectiveness of prior use of swallowed topical corticosteroids for EoE (Yes, No) 
− Inadequate response, intolerant and/or contraindicated to STC (Yes or No) 
− Prior esophageal dilations (Yes, No) 
− Prior use of STC for EoE and prior esophageal dilation (Yes, No) 
− Number of prior esophageal dilations  
− Age at the first esophageal dilation with grouping (years; 0 to 11, 12 to 18, 19 to 
24, 25 to 50, >50), calculated as the number of years between patient birth year and 
the year of the first esophageal dilation (prior to screening)  
− Duration of EoE as a continuous variable and with grouping (years; <5, ≥5)  
− Age at EoE onset with grouping (years; 0 to 11, 12 to 18, 19 to 24, 25 to 50, >50), 
calculated as the number of years between patient birth year and the start year of 
EoE  
− Historical esophageal biopsy showing ≥ 15 (eso/hpf [400 X]) after 8 weeks of high-
dose PPI (Yes, No) 
− Patient on food elimination diet in past (Yes, No) 
− Patient on food elimination diet at screening (Yes, No) 
European Quality of Life 5-Dimensional Scale (EQ-5D) 
The European Quality of Life 5-dimension (EQ-5D) scale is a standardized questionnaire used to 
assess health status (Rabin R, Gudex C, Selai C, Herdman M. From translation to version 
management: a history and review of methods for the cultural adaptation of the EuroQol five-
dimensional questionnaire, Value Health 2014 Jan;17(1):70-76.) (Brooks R. EuroQol: the current 
state of play, Health Policy. 1996 Jul;37(1):53-72.). It consists of a descriptive system and the 
EQ visual analogue scale (EQ VAS). The EQ-5D-3L (3-level) descriptive system comprises of 
the following 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. For each dimension, patients select one of 3 levels: no problems, some 
problems, and extreme problems. Health states defined by the 5-dimension classification can be 
converted into corresponding index scores that quantify health status. This utility index score is 
ranged from -0.594 to 1 (perfect health). The algorithm and SAS code for the utility index 
scoring are provided in Appendix 11.8. The EQ VAS records the patient’s self-rated health on a 
vertical visual analogue scale where the endpoints are labelled ‘Best imaginable health state’ 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 25 of 101 
(100) and ‘Worst imaginable health state’ (0). The EQ-5D-3L will be completed at screening or 
baseline visit by patients screened under protocol amendment 3 or later. 
4.2. 
Medical History 
Medical history will be coded using MedDRA. Same MedDRA version will be used for Part B 
data and Part B patients’s data in Part C within the scope of DBL. Information related to EoE and 
other atopic medical conditions includes diagnosis of EoE, atopic dermatitis, asthma, allergic 
rhinitis, allergic conjunctivitis, chronic rhinosinusitis, nasal polyps, food allergy, hives, contact 
dermatitis, and 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 is on 
food elimination diet, food type eliminated, and reason for elimination of specific food.  
4.3. 
Pre-treatment / Concomitant Medications and Procedures 
Medications/Procedures will be recorded from the day of informed consent until the EOS visit. 
Medications will be coded using WHO Drug Dictionary (WHODD). Patients will be counted once 
in each medication class linked to the medication. Medications of interest include PPIs and 
swallowed topical/systemic corticosteroids for the treatment of EoE.  
Procedures will be coded per MedDRA. 
Pre-treatment medications/procedures: medications taken or procedures performed prior to 
administration of the first dose of study drug. 
Concomitant medications/procedures (CMs/CPs): medications taken or procedures performed 
following the first dose of study drug through the EOS visit. This includes medications 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 B week 24 treatment period 
• CMs/CPs taken during the Part C extended active treatment period 
• CMs/CPs taken during the follow-up period 
Prohibited concomitant medications/procedures during the study:  
Treatment with the following concomitant medications is prohibited through week 52:  
• Swallowed topical corticosteroids (may be used as rescue treatment for EoE) 
• Systemic corticosteroids (may be used as rescue treatment for EoE) 
• Systemic immunosuppressive/immunomodulating drugs (including, but not limited to, 
omalizumab, cyclosporine, mycophenolate-mofetil, azathioprine, methotrexate, IFN-γ, 
or other biologics) 
• Treatment with an investigational drug (other than dupilumab) 
• Initiation, discontinuation, or change in dosage regimen of the following medications 
within 8 weeks prior to the baseline endoscopy (stable doses of these medications are 
allowed) 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 26 of 101 
− Proton pump inhibitors, unless used for a required PPI trial during the screening 
period or in patients who present at the initial screening visit with current use of 
PPIs 
− Systemic leukotriene inhibitors 
− Nasal and/or inhaled corticosteroids 
• Initiation of SCIT, or change in dose for those patients on a stable dose of SCIT within 
1 year prior to screening  
• SLIT 
• OIT 
• Treatment with an investigational drug (other than dupilumab) 
• Treatment with a live (attenuated) vaccine (see protocol Section 7.1.1 for the list of 
vaccine). 
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 
monitor before database locks with documented procedures.  
Rescue treatments (including both medications 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 in Part B and C. 
If possible, an endoscopy with biopsy will be performed prior to the initiation of rescue therapy. 
Patients who undergo an endoscopy with biopsy due to the initiation of rescue therapy will not 
undergo the scheduled end of treatment visit endoscopy/biopsy at weeks 24 and 52. Patients who 
receive rescue treatment in Part B will not be eligible for the Part C extended active treatment 
period unless an endoscopy with biopsy is performed prior to the initiation of rescue treatment. 
However, if the endoscopy with biopsies cannot occur due to COVID-19 restrictions, rescue 
treatment should not be delayed, and these patients will be eligible for Part C. 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 and participate in all assessments for these 
visits except for endoscopy/biopsy, as noted above.  
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 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 27 of 101 
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/or duodenum will be obtained at visit 2 in all patients 
<18 years of age to rule out alternate etiologies of esophageal eosinophilia. Stomach and/or 
duodenal biopsies will be obtained in adults only in the event of abnormal endoscopic findings 
(other than typical EoE findings) or clinical suspicion of alternate etiologies. All randomized 
patients found to have stomach and/or duodenal abnormalities at baseline will have follow-up 
stomach and/or duodenal biopsies at week 24 and week 52. 
4.4. 
Efficacy Variable 
4.4.1. 
Primary Efficacy Variable (s) 
The co-primary endpoints for Part B are: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count 
(from all 3 regions) of ≤6 eos/hpf at week 24 
• Absolute change in DSQ score from baseline to week 24 
Peak esophageal intraepithelial eosinophil count 
Peak esophageal intraepithelial eosinophil count will be measured from esophageal biopsies. A 
total of 9 mucosal pinch biopsies will be collected at each time point from 3 esophageal regions: 
3 proximal, 3 mid, and 3 distal. Two samples from each region will be used for the histology and 
other tissue analyses. The third sample from each region will be processed for RNA analyses. The 
quantity of eosinophils in the most inflamed high power field (HPF) for each of the 3 esophageal 
regions (proximal, mid and distal) will be determined by a pathologist at a central pathology 
reading center who will be blinded to the treatment assignment. The peak esophageal 
intraepithelial eosinophil count at each visit is the maximum of the quantities of eosinophils in the 
most inflamed HPFs across the 3 regions. For example, if for a particular patient, at week 24, 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 24. 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. 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. 
Esophageal biopsies will be obtained by endoscopy at the second screening visit (visit 2), week 24 
and week 52 (EOS) or ET visits. For patients who receive rescue treatment during Part B, the 
endoscopy/biopsy procedures should be performed prior to the initiation of rescue treatment; 
however, Protocol Amendment #4 allows for rescue treatment to be initiated if, due to the COVID-
19, an endoscopy procedure can not occur. Patients undergoing endoscopy/biopsy due to the 
initiation of rescue will not undergo the scheduled endoscopy/biopsy at weeks 24 and 52.  
Due to COVID-19 restrictions, patients may postpone the week 24 visit until an in-clinic visit can 
be done for biopsy. Data handling for the biopsy data from those delayed week 24 visits will be 
detailed in section 5.6.1.  
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 28 of 101 
Dysphagia Symptom Questionnaire (DSQ) Score 
The DSQ is a validated PRO that has been used in clinical studies to measure the frequency and 
intensity of dysphagia (Hudgens, 2017). For patients who respond “No” to question 1 (“Since you 
woke up this morning, did you eat solid food?”), a modification was made to the DSQ by asking 
a follow-up question to probe if patients avoided solid food due to their problems with swallowing 
solid food. The DSQ uses a daily recall period and will be completed by the patient daily using an 
eDiary from screening through end of study or ET visit.  
The questions and scoring of DSQ are presented in the table below. Question 1 is a screening 
question; patients will proceed with the questionnaire depending on their response to question 1: 
• If the response to question 1 is ‘No’, question 1a will be asked to collect reason for not 
eating solid food and the remaining items on the DSQ are not scored. Data for that day 
is considered to be missing for analysis but diary completion is considered compliant 
for that day. 
• If the response to question 1 is ‘Yes’, patient will skip question 1a and move on to 
questions 2, 3 and 4. Only questions on the frequency (question 2) and severity 
(question 3) of dysphagia contribute to the total DSQ score. Although question 4 related 
to pain was included in the DSQ, pain was not highlighted as an important symptomatic 
factor based on interviews of adolescent and adult patients with EoE. Thus, question 4 
was considered as a standalone item for exploratory analysis.   
Dysphagia Symptom Questionnaire (DSQ) (Adapted from Hudgens, 2017) 
Question Number 
Response Option 
Score 
1. Since you woke up this morning, did 
you eat solid food? 
No 
No score assigned 
Yes 
No score assigned 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
2. Since you woke up this morning, has 
food gone down slowly or been stuck 
in your throat? 
No 
0 
Yes  
2 
3. For the most difficult time you had 
swallowing food today (during the 
past 24 hours), did you have to do 
anything to make the food go down or 
to get relief? 
No, it got better or cleared up on its own 
0 
Yes, I had to drink liquid to get relief 
1 
Yes, I had to cough and/or gag to get relief 
2 
Yes, I had to vomit to get relief 
3 
Yes, I had to seek medical attention to get 
relief 
4 
4. The following question concerns the 
amount of pain you have experienced 
when swallowing food. What was the 
worse pain you had while swallowing 
food over the past 24 hours?b 
None, I had no pain 
0 
Mild 
1 
Moderate 
2 
Severe 
3 
Very Severe 
4 
a DSQ is modified with the addition of Question 1a when response to Question 1 is ‘No’.  
b Question 4 does not assess dysphagia and is considered a standalone item to be evaluated as an exploratory 
outcome. 
The DSQ score is calculated based on the daily responses to question 2 (frequency) and question 
3 (severity) over a 14-day period using the formula from (Hudgens, 2017): 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 29 of 101 
DSQ Score=
(sum of points from questions 2 and 3 from daily DSQ diary)×14 days
number of diary days reported with non-missing data
 
To calculate the DSQ score, a minimum of 8 diary entries (including days when patient responded 
‘No’ to question 1) is required for each 14-day period to derive a standardized total score based on 
the cumulative scores through 14 days. If there are less than 8 diary entries for a 14-day period, 
the DSQ score is considered to be missing for that period. The primary analysis will be based on 
DSQ score calculated using this algorithm. If there are multiple diary entries on the same day, the 
first entry on that day will be used in calculating DSQ score for analysis. DSQ scores can 
theoretically range from 0 to 84, with a lower score indicating less-frequent or less-severe 
dysphagia. 
As a sensitivity analysis, DSQ will be scored using an alternative algorithm that takes into account 
patient’s response to question 1a about reason for not eating solid food: 
• If not eating solid food because of patient problems with swallowing solid food, a daily 
score of 6 will be assigned for that day for analysis but not for consideration of 
eligibility and used in the formula given above to calculate DSQ score over a 14-day 
period after randomization.  
• If the patient responds to question 1a by indicating that he/she did not eat solid food 
since waking up in the morning because of something NOT related to their problems 
with swallowing solid food, no score will be assigned. Data for that day is considered 
to be missing for analysis but diary completion is considered compliant for that day. 
Baseline DSQ scores will be calculated from daily responses recorded during the 14 days just prior 
to the first dose date. For example, if a patient is randomized and takes the first dose of study drug 
on Jan 15th, DSQ score will be calculated from daily responses recorded during Jan 1st through Jan 
14th as baseline. DSQ scores at time points after baseline will be calculated for each 14-day period 
starting from the day of patient receiving their first dose of study drug (see detailed analysis time 
point window in Section 6.4). 
4.4.2. 
Secondary Efficacy Variable(s) 
The key secondary endpoints for Part B are: 
• Absolute change in EoE EREFS total score from baseline to week 24 
• Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from 
baseline to week 24 
• Absolute change in EoEHSS mean grade score from baseline to week 24 
• Absolute change in EoEHSS mean stage score from baseline to week 24 
Eosinophilic Esophagitis-Endoscopic Reference Score (EoE EREFS) 
EoE-EREFS is a validated scoring system for inflammatory and remodeling features of disease 
that are visible through endoscopy (Hirano, 2013). The proximal and distal esophageal regions 
will be scored separately. The score for each region is the sum of assigned scores for each of the 
5 major features and ranges from 0 to 9. The total score (summing scores for the proximal and 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 30 of 101 
distal regions) ranges from 0 to 18 and is the final score used for the analysis. If score is available 
only from 1 of the 2 regions, that available score will be used as total score. For example, if score 
is 8 from the proximal region and missing from the distal region, the total score will be 8. 
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 EoE-EREFS should be performed by the physician conducting the endoscopy procedure 
before biopsies. For Part B enrolled patients, EoE-EREFS will be performed by both the 
investigators who perform the endoscopies as well as a centralized reading center who will provide 
EoE-EREFS analysis and scoring from endoscopy imaging. The centralized reading will be used 
for analysis, if available. Given centralized readings were introduced for the first time for part B 
patients of this study, if the centralized reading is not possible (e.g. technical issues) for a given 
proportion of the FAS (e.g. >20% patients in FAS with either baseline or week 24 unavailable 
(Dziura, 2013)), the EoE-EREFS performed by the investigator will be used for analysis, which 
will be consistent with part A. 
In addition to the major features above, data for the following minor features will also be captured 
but not included in the EoE-EREFS scoring: 
• 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 (but not 
included in the EoE-EREFS scoring) 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 the second screening visit, week 24 and week 52 
(EOS) or ET visits, and immediately prior to start of rescue medication or procedures. Patients 
undergoing endoscopy/biopsy prior to rescue will not undergo the scheduled endoscopy/biopsy at 
weeks 24 and 52. 
Eosinophilic Esophagitis Histology Scoring System (EoEHSS) 
The EoEHSS is a method for evaluating the grade and stage of multiple pathologic features in 
esophageal biopsies from EoE patients that extend observations beyond the presence of tissue 
eosinophils (Collins, 2017). EoEHSS evaluates eight features: eosinophil inflammation (EI), basal 
zone hyperplasia (BZH), eosinophil abscess (EA), eosinophil surface layering (SL), dilated 
intercellular spaces (DIS), surface epithelial alteration (SEA), dyskeratotic epithelial cells (DEC), 
and lamina propria fibrosis (LPF). Severity (grade) and extent (stage) of abnormalities will be 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 31 of 101 
scored by a central, blinded pathologist for each feature 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 EoEHSS for each biopsy is the ratio of the sum of the 
assigned scores for each feature evaluated divided by the maximum possible score for that biopsy 
(the maximum possible score for each biopsy is 24). For example, if all 8 features have maximum 
grade of 3 for a biopsy, the mean grade score will be 24/24 = 1. If a feature is not evaluated, the 
maximum possible score is reduced by 3. Most maximum possible score reductions may occur 
because lamina propria is not present; if all other features are evaluable, the maximum possible 
score for a biopsy lacking lamina propria is reduced from 24 to 21 because 7 instead of 8 features 
were evaluated. Both mean grade and mean stage scores will be determined for biopsies from 3 
esophageal regions (proximal, mid and distal). The mean grade and mean stage scores summed 
across the 3 regions is the final score used in the primary analysis of these endpoints. In the 
example given in the table below, the mean grade score 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 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 (EI) 
3 
3 
3 
Basal zone hyperplasia (BZH) 
2 
3 
3 
Eosinophil abscess (EA) 
2 
2 
3 
Surface layering (SL) 
0 
0 
0 
Dilated intercellular spaces (DIS) 
0 
0 
0 
Surface epithelial alteration (SEA) 
0 
0 
0 
Dyskeratotic epithelial cells (DEC) 
0 
0 
0 
Lamina propria fibrosis (LPF) 
missing 
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 
Due to the anticipation that lamina propria may not be present in many biopsies, a total grade or 
total stage score by summing scores from the other 7 individual features will be calculated for an 
exploratory analysis. In the example given above, the total grade score excluding lamina propia is 
(3 + 2 +2) + (3 + 3 + 2) + (3 +  3 + 3 ) = 24.  
Esophageal biopsies will be obtained by endoscopy at the second screening visit (visit 2, day -21 
± 7), week 24 and week 52 (EOS) or ET visits, and immediately prior to the start of rescue 
medication or procedures. Patients undergoing endoscopy/biopsy prior to or due to the initiation 
of rescue will not undergo the scheduled endoscopy/biopsy at weeks 24 and 52. 
The other secondary endpoints are: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
<15 eos/hpf at week 24 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤1 eos/hpf at week 24 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 32 of 101 
• Percent change in DSQ from baseline to week 24 
• Normalized Enrichment Scores (NES) for the relative change from baseline to week 24 
in the EoE diagnostic panel (EDP)  
• NES of the relative change from baseline to week 24 in the type 2 inflammation 
signature 
• Absolute change from baseline to week 24 in health-related QOL average score as 
measured by EoE Impact Questionnaire (EoE-IQ) 
• Absolute change from baseline to week 24 in severity of EoE symptoms other than 
dysphagia and pain with swallowing as measured by EoE Symptom Questionnaire 
(EoE-SQ) 
• Absolute change from baseline to week 24 in frequency of EoE symptoms other than 
dysphagia and pain with swallowing as measured by EoE Symptom Questionnaire 
(EoE-SQ) 
• Proportion of patients who receive rescue medications or procedures during the 
24-week placebo-controlled treatment period 
• Absolute change from baseline to week 24 in esophageal distensibility plateau 
measured by endolumenal functional lumen imaging probe (EndoFLIP), if collected. 
• All the above co-primary and secondary endpoints assessed at week 24 will be assessed 
at week 52 as additional secondary endpoints. 
• All the above co-primary and secondary endpoints at week 24 and week 52 will be 
assessed in patients who have previously received swallowed topical corticosteroids as 
additional secondary endpoints. 
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, 2017a).  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 (unpublished). The gene lists comprising each 
one of these transcriptomes can be found in Section 11.6. 
Normalized Enrichment Score (NES) reflects the degree to which the activity level of a set of 
transcripts is overrepresented at the extremes (top or bottom) of the entire ranked list of transcripts 
within a sample and is normalized by accounting for the number of transcripts in the set 
(Subramanian, 2005, Barbie, 2009). NES of the relative change from baseline to week 24 will be 
calculated for the respective gene sets based on expression levels of each individual gene averaged 
over 3 esophageal regions (proximal, mid, and distal). If data are missing from region(s), the 
average will be taken from the available regions for each individual gene. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 33 of 101 
EoE Impact Questionnaire (EoE-IQ) 
The EoE-IQ is a disease-specific measure of health-related QoL in EoE patients developed by the 
sponsor. The EoE-IQ measures EoE impact on emotional, social, work and school, and sleep 
aspect of a patient. Patient is asked to respond to 11 questions based on experience living with EoE 
during the past 7 days.  
Item No. 
Question 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Response to each item is on a 5-point scale (1 = ‘Not at all’, 2 = ‘A little’, 3 = ‘Somewhat’, 4 = 
‘Quite a bit’, 5 = ‘Extremely’). The EoE-IQ average score is the sum of the non-missing responses 
divided by the number of items with non-missing response (note: response of “I do not go to school 
or work at a paying job” to item 9 or 10 is considered as missing response). The average score 
could range from 1 to 5; a higher score is indicative of a more negative impact of EoE on patient 
QoL.  
The EoE Impact Questionnaire will be recorded by the patient using electronic questionnaire at 
baseline visit (visit 3), week 12, week 24, week 36, week 52 (EOS) or ET visits, and immediately 
prior to start of rescue medication or procedures.  
EoE Symptom Questionnaire (EoE-SQ) 
The EoE-SQ is a questionnaire measuring the frequency and severity of symptoms other than 
dysphagia and pain with swallowing. It is developed by the sponsor. The EoE-SQ asks about 
symptoms that patients with EoE may have (chest pain, stomach pain, burning feeling in your 
chest, food or liquid coming back up into your throat, throwing up) during the past 7 days. 
Response to the frequency of each symptom is on a 5-point scale (1 = ‘Never’, 2 = ‘One day’, 3 = 
‘ 2-6 days’, 4 = ‘Once a day’, 5 = ‘More than once a day’). The EoE-SQ frequency score is 
calculated as the sum of the frequency scores from the 5 items which could range from 5 to 25; a 
higher score is indicative of higher frequency of symptoms. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 34 of 101 
Response to the severity of each symptom based on the worst experience in the past 7 days is on 
a scale of 0 to 10 (higher is worse), with 0 and 10 indicating severity levels for the respective 
symptoms as follows: 
Questions 
Severity Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
’ 
a Questions 4 and 5 are not included in EoE severity scoring. 
The EoE-SQ severity score is calculated as the sum of the severity scores from questions 1 to 3, 
which could range from 0 to 30; a higher score is indicative of more severe symptoms.  If patient 
answers ‘Not at all’ to an item question about frequency, they will not be asked to answer the 
corresponding severity question and in that case a severity score of 0 will be assigned for that item. 
The EoE Symptom Questionnaire will be recorded by the patient using electronic questionnaire at 
baseline visit (visit 3), week 12, week 24, week 36, week 52 (EOS) or ET visits, and immediately 
prior to start of rescue medication or procedures. 
Proportion of patients who receive rescue medications or procedures 
Rescue medications or procedures are described in Section 0. 
4.4.3. 
Exploratory Efficacy Variable(s) 
Exploratory efficacy endpoints include: 
• Percent change from baseline to week 24 in average esophageal intraepithelial 
eosinophil count (eos/hpf) of 3 esophageal regions  
• Percent change in EoE EREFS total score from baseline to week 24 
• Absolute change from baseline to week 24 in EREFS (excluding stricture) 
• Absolute change from baseline to week 24 in EREFS inflammation subscore 
• Absolute change from baseline to week 24 in EREFS remodeling subscore 
• Absolute change in EoEHSS total grade score (excluding lamina propria) from baseline 
to week 24 
• Absolute change in EoEHSS total stage score (excluding lamina propria) from baseline 
to week 24 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 35 of 101 
• Patient global impression of change (PGIC) of dysphagia: proportion of patients who 
rate their dysphagia symptoms as “a little better”, “moderately better”, or “very much 
better” at week 24 
• Patient global impression of severity (PGIS) of dysphagia: proportion of patients with 
no symptom and proportion of patients with no symptom or mild symptoms at week 
24 
• Absolute change in TNSS from baseline to week 24 
• Absolute change in POEM from baseline to week 24 
• Absolute change in ACQ-5 from baseline to week 24 
• Absolute change in RQLQ 12+ from baseline to week 24 
• Absolute change in pain related to dysphagia (based on question 4 of the DSQ) from 
baseline to week 24 
• All the above exploratory endpoints assessed at week 24 will be assessed at week 52 
as additional exploratory endpoints. 
The following DSQ variables (prorated and un-prorated) will be analyzed: 
• Absolute change in the prorated 7-day average DSQ score from baseline to week 24 
• Absolute change in the un-prorated 7-day average DSQ score from baseline to week 
24 
• Absolute change in the un-prorated 14-day average DSQ score from baseline to week 
24 
More details including calculations of DSQ variables are provided below, “Prorated/un-prorated 
DSQ score”.  
Average esophageal intraepithelial eosinophil count (eos/hpf) of 3 esophageal regions 
The average esophageal intraepithelial eosinophil count at each visit is the average of the 
quantities of eosinophils in the most inflamed HPFs across the 3 esophageal regions. For 
example, if for a particular patient, at week 24, 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 
average eosinophil count is 3/hpf (mean of 2, 3, 4/hpf) for week 24. 
EREFS (excluding stricture), Inflammation, and Remodeling Sub-scores 
The EREFS (excluding stricture), inflammation, and remodeling sub-scores 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 subscore 
Edema + Exudates + Furrows 
0-5 
0-10 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 36 of 101 
Remodeling subscore 
Rings + Stricture 
0-4 
0-8 
Patient Global Impression of Severity (PGIS) of Dysphagia 
The PGIS is a one-item questionnaire that asks patients to provide the overall self-assessment of 
difficulty of swallowing food on a 4-point scale for the past week. Response choices are: 1 = 
‘none’, 2 = ‘Mild’, 3 = ‘Moderate’, 4 = ‘Severe’. The PGIS will be completed by patients using 
electronic questionnaire at baseline visit (visit 3), week 12, week 20, week 24, week 36, week 52 
(EOS) or ET visits, and immediately prior to start of rescue medication or procedures. 
Patient Global Impression of Change (PGIC) of Dysphagia 
The PGIC is a one-item questionnaire that asks patients to provide the overall self-assessment of 
change in difficulty of swallowing food on a 7-point scale, compared to just before patient started 
taking the study injection. Response choices are: 0 = ‘Very much better’,  1 = ‘Moderately better’,  
2  = ‘A little better’, 3 = ‘No change’, 4 = ‘A little worse’, 5 = ‘Moderately worse’, 6 = ‘Very 
much worse’.  
The PGIC will be completed by patients using electronic questionnaire at week 12, week 20, week 
24, week 36, week 52 (EOS) or ET visits, and immediately prior to start of rescue medication or 
procedures. 
Total Nasal Symptom Score (TNSS) 
The Total Nasal Symptom Score (TNSS) is a 3-item composite symptom assessment of 
congestion, itching/sneezing, and rhinorrhea for the last week. Each symptom is graded on a 0-3 
scale as below: 
Score 
Symptoms 
0 
No symptoms 
1 = mild 
Awareness but not troubled 
2 = moderate 
Troublesome but not interfering with normal daily activities or sleep 
3 = severe 
Interfering with normal daily activities or sleep 
The TNSS total score is the sum of scores for each of the symptoms (congestion, itching/sneezing, 
rhinorrhea) and could range from 0 to 9 (a higher score suggests worse nasal symptoms).  
The TNSS will be administered only to patients with a documented history of allergic rhinitis 
and who fluently speak a language in which the questionnaire is presented (based on availability 
of translations in participating countries). It will be completed by patients at the baseline visit 
(visit 3), week 12, week 24, week 36, and week 52 (EOS) or ET visits, and immediately prior to 
start of rescue medication or procedures. 
Patient-Oriented Eczema Measure (POEM) 
The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess 
disease symptoms in children and adults with AD (Charman, 2004). The format is a response to 7 
items (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) using a 5-point scale, 
based on frequency of occurrence during the past week. The possible scores for each question 
were: 0 (no days), 1 (1 to 2 days), 2 (3 to 4 days), 3 (5 to 6 days), and 4 (every day). The total score 
is the sum of scores for each of the 7 items; a higher score is indicative of more severe AD. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 37 of 101 
The following POEM banding scores have been established (Charman, 2004): 0 to 2=clear or 
almost clear; 3 to 7=mild eczema; 8 to 16=moderate eczema; 17 to 24=severe eczema; and 25 to 
28=very severe eczema.  
If one question of the seven is left unanswered, then that question is scored as 0 and the scores are 
summed and expressed as usual out of a maximum of 28. If two or more questions are left 
unanswered, then the questionnaire is not scored and is set to missing. 
The POEM will be administered only to patients with a documented history of AD and who 
fluently speak a language in which the questionnaire is presented (based on availability of 
validated translations in participating countries). It will be completed by patients at the baseline 
visit (visit 3), week 12, week 24, week 36, and week 52 (EOS) or ET visits, and immediately prior 
to start of rescue medication or procedures. 
Juniper Asthma Control Questionnaire (ACQ) 
The 5-question version of the Juniper ACQ (ACQ-5) is a validated questionnaire to evaluate 
asthma control. The ACQ-5 has 5 questions which assess the top-scoring five asthma symptoms:  
• Frequency in past week awoken by asthma during the night 
• Severity of asthma symptoms in the morning 
• Limitation of daily activities due to asthma 
• Shortness of breath due to asthma 
• Frequency of wheezing 
Patients are asked to recall how their asthma has been during the previous week and to respond to 
the symptom questions on a 7-point scale (0=no impairment, 6= maximum impairment). 
A global score is calculated: the questions are equally weighted and the ACQ-5 score is the mean 
of the 5 questions and, therefore, between 0 (totally controlled) and 6 (severely uncontrolled). A 
higher score indicates lower asthma control. Scores less than 1.0 reflect adequately controlled 
asthma, and scores 1.0 or greater reflect inadequately controlled asthma. On the 7-point scale of 
the ACQ-5, a change or difference in a score of 0.5 is the smallest change that can be considered 
clinically important, corresponding to the Minimal Clinically Important Difference (MCID) 
defined by the developer. The recommended change of 0.50 is a reasonable threshold to define a 
meaningful individual-level change. 
Based on the manual of ACQ, any more than one missing value is not acceptable. If more than one 
of the questions has a missing value, the global score is invalid and will be considered as missing. 
If only one question has a missing value, it will be interpolated (pro-rated) using the completed 
questionnaires from the previous visit. For example, if answer to question 5 is missing at week 24 
visit and all questions are completed at week 12 visit, the score for question 5 at week 24 visit will 
be imputed as: (sum of score at week 24 visit/sum of scores excluding question 5 at week 12 visit) 
× score of question 5 at week 12 visit. If the questionnaire from the previous visit is not complete, 
the missing value will be imputed as the average of the completed questions within the current 
visit. 
The ACQ-5 will be administered only to patients with a documented history of asthma. It will be 
completed by patients using electronic questionnaires at the baseline visit (visit 3), week 12, week 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 38 of 101 
24, week 36, and week 52 (EOS) or ET visits, and immediately prior to start of rescue medication 
or procedures. 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire for ages 12+ [RQLQ(S)+12] 
RQLQ(S)+12 is a self-administered questionnaire to measure health-related QOL in those 12 years 
of age and above, as a result of perennial or seasonal allergic rhinitis. There are 28 items on the 
RQLQ(S) in 7 domains: activity limitation, sleep problems, nasal symptoms, eye symptoms, non-
nasal/eye symptoms, practical problems, and emotional function. The RQLQ(S)+12 responses are 
based on a 7-point Likert scale with responses ranging from 0 (not troubled) to 6 (extremely 
troubled). The overall RQLQ(S)+12 score is the mean of all 28 responses and the individual 
domain scores are the means of the items in those domains. No interpolation will be performed for 
missing scores. Higher scores indicated more health-related QOL impairment (lower scores were 
better). A change of 0.5 point or more in total score is considered to be clinically meaningful. 
The RQLQ(S)+12 will be administered only to patients with a documented history of allergic 
rhinitis. It will be completed by patients using electronic questionnaires at the baseline visit (visit 
3), week 12, week 24, week 36, and week 52 (EOS) or ET visits, and immediately prior to start of 
rescue medication or procedures. 
Pain related to dysphagia  
Pain related to dysphagia is assessed daily by question 4 in the DSQ questionnaire. Patient will 
respond to this question only when they answer Yes to question 2 “Since you woke up this 
morning, has food gone down slowly or been stuck in your throat?”. If the answer is No to question 
2, a score of 0 will be assigned to pain related to dysphagia. The pain score over a 14-day period 
is calculated using the formula: 
Dysphagia Related Pain Score=
( sum of points from question 4  from daily DSQ diary)×14 days
number of diary days reported with non-missing data
 
The rules for a minimum of 8 diary entries and non-missing data are the same as used for DSQ 
score calculation as described in Section 4.4.1. 
Endolumenal Functional Lumen Imaging Probe (EndoFLIP) 
The endolumenal functional lumen imaging probe (EndoFLIP, Medtronic, USA) device is a 
catheter-based procedure that measures the cross-sectional area at multiple sites along the 
esophagus with simultaneous intraluminal pressure recordings during volumetric distension of the 
esophagus. The analyses of cross sectional area versus pressure relationships of the esophagus 
allow for determination of esophageal compliance as well as the distensibility plateau. 
Distensibility Plateau (DP), Restricting Diameter 40mmHg (RD40) and Restricting Diameter 
30mmHg (RD30) are collected to evaluate the distensibility of the esophageal body using 
EndoFLIP in the study. DP is the number at which the narrowest diameter measurement fails to 
expand anymore despite increasing intra-balloon pressure. RD40/RD30 is the narrowest diameter 
in the esophageal body at an intra-balloon pressure of 40mmHg/30mmHg (+/- 2mmHg). 
EndoFLIP may be performed for patients at selected North American, with measurements taken 
as part of the esophagogastroscopy procedure performed at screening, week 24 and week 52. 
Procedural order should be: EREFS/imaging, EndoFLIP, then biopsies.  
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 39 of 101 
Prorated/un-prorated DSQ score 
The prorated 7-day average DSQ score is calculated over a 7-day period using the formula as 
below: 
The prorated 7-day average DSQ score=
(sum of points from questions 2 and 3 from daily DSQ diary) ∗7
number of diary days reported with non-missing data
 
The un-prorated 7-day average DSQ score is calculated over a 7-day period using the formula as 
below: 
The un-prorated 7-day average DSQ score= (sum of points from questions 2 and 3 from daily DSQ diary)
number of diary days reported with non-missing data
 
If there are less than 4 diary entries for a 7-day period, both the prorated and un-prorated 7-day 
average DSQ scores are considered to be missing for that period.  
The un-prorated 14-day average DSQ score is calculated over a 14-day period using the formula 
as below: 
The un-prorated 14-day average DSQ score=
(sum of points from questions 2 and 3 from daily DSQ diary)
number of diary days reported with non-missing data
 
If there are less than 8 diary entries for a 14-day period, the un-prorated 14-day average DSQ score 
is considered to be missing for that period. 
The prorated DSQ scores are basecally identical with the un-prorated DSQ scores with multiplier 
(7 or 14). 
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 referred to protocol section 9.3.1 
and section 9.3.2. The pre-treatment AE and treatment-emergent AE (TEAE) is defined as 
following: 
• Pre-treatment signs and symptoms (Pre-treatment AEs) are AEs that developed or 
worsened in severity during the pre-treatment period. 
• Treatment-emergent AEs (TEAEs) are AEs that developed or worsened in severity 
compared to the baseline during the treatment-emergent period. As the worsening pre-
existing AEs and new AEs that occur during the treatment and follow-up period will 
be collected on the AE case report form, all AEs with an onset date during the treatment 
and follow-up periods are considered as TEAEs. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 40 of 101 
The following AESIs will be analyzed:  
• 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. 
4.5.2. 
Laboratory Safety Variables 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory. Samples will be collected predose at the initial screening visit (visit 1), baseline visit 
(visit 3), week 12, week 24, week 36, week 52 (EOS) or ET visits. Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total and indirect bilirubin 
Potassium 
Creatinine 
Total cholesterol 
Chloride 
Blood urea nitrogen (BUN) 
Low-density lipoprotein (LDL) 
Carbon dioxide 
AST 
High-density lipoprotein (HDL) 
Calcium 
ALT 
Triglycerides 
Glucose 
Alkaline phosphatase 
Uric acid 
Albumin 
Lactate dehydrogenase (LDH) 
Creatine phosphokinase (CPK)1 
1 CPK isoenzymes will be measured when CPK >5 × ULN  
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 41 of 101 
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 
4.5.3. 
Vital Signs 
Vital signs, including heart rate, blood pressure, respiration rate, and body temperature will be 
collected predose and 30 minutes post-dose at the initial screening visit (visit 1), every scheduled 
visit and the unscheduled visit before rescue treatment. 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. Weight is measured at the initial screening visit (visit 1), every scheduled visit (except 
week 1, week 40, week 44, and week 48 visits). Height is measured at the initial screening visit 
(visit 1), week 24, and week 52 (EOS) or ET visits. 
4.5.4. 
12-Lead Electrocardiography (ECG) 
Standard 12-Lead ECG parameters include: Ventricular HR, PR interval, QRS interval, corrected 
QT interval (QTc Fridericia [QTcF] =QT/√𝑅𝑅
3
 and QTc Bazett [QTcB]=QT/√𝑅𝑅). 
Electrocardiogram results will be interpreted by a central reading center and categorized to: 
normal, abnormal not clinical significant or abnormal clinical significant 
ECG will be performed predose at the initial screening visit (visit 1), week 24, and week 52 (EOS) 
or ET visits. ECG will be performed before blood is drawn during visits requiring blood draws.  
4.5.5. 
Physical Examination Variables 
The physical examination variable values are dichotomized to normal and abnormal.  
A thorough and complete physical examination will be performed at the initial screening visit (visit 
1), week 24, and week 52 (EOS) or ET visits.  
4.6. 
Pharmacokinetic Variables 
Serum samples for measuring functional dupilumab concentrations will be collected at time points 
according to Section 11.2. PK variables consist of functional dupilumab concentration and time 
(both actual and nominal).  
4.7. 
Immunogenicity Variables 
The immunogenicity variables are ADA response status, titer, NAb response status, and time-
point/visit.   
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 42 of 101 
ADA response are specifically defined as follows: 
• ADA Negative, defined as an ADA negative response in the ADA assay at all time 
points collected, regardless of any missing samples. 
• Pre-existing immunoreactivity, defined as either an ADA positive response in the 
dupilumab ADA assay at baseline with all post first dose ADA results negative, OR a 
positive response at baseline with all post first dose ADA responses less than 4-fold 
over baseline titer levels. 
• Treatment-emergent response, defined as a positive response in the dupilumab ADA 
assay post first dose when baseline results are negative or missing. The treatment-
emergent responses will be further characterized as Persistent, Indeterminate or 
Transient.   
− Persistent Response: Treatment-emergent ADA positive response with two or more 
consecutive ADA positive sampling time points, separated by greater than 12-week 
period (based on nominal sampling time), with no ADA negative samples in 
between, regardless of any missing samples. 
− Indeterminate Response: Treatment-emergent ADA positive response with only the 
last collected sample positive in the ADA assay.  
− Transient Response: Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate, regardless of any missing samples. 
• Treatment-boosted response, defined as a positive response in the dupilumab ADA 
assay post first dose that is greater than or equal to 4-fold over baseline titer levels, 
when baseline results are positive 
Serum samples for ADA will be collected at the clinic visits specified in Section 11.2. 
4.8. 
Biomarker Variables 
Biomarkers to be analyzed in this study are:  
• TARC  
• Total serum IgE 
• Allergen specific IgEs 
• Allergen specific IgG4s 
• Eotaxin-3 
Serum 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. 
Patient Reported Outcomes for Psychometric Validity Assessment 
The psychometric validity of 3 patient-reported outcome measures (DSQ, EoE-SQ, and EoE-IQ 
as described in Section 4.4.1 and Section 4.4.2) will be assessed.  
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 43 of 101 
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 part: 
1. Part B 
• Dupilumab 300mg Q2W 
• Dupilumab 300mg QW 
• Combined Dupilumab Group (For safety analysis only) 
• Placebo 
2. Part C (Treatment in Part B/Treatment in Part C) 
• Dupilumab 300mg Q2W/Dupilumab 300mg Q2W 
• Dupilumab 300mg QW/Dupilumab 300mg QW 
• Combined Dupilumab Group (For safety analysis only) 
• Placebo/ Dupilumab 300mg Q2W 
• Placebo/ Dupilumab 300mg QW 
• Placebo/Dupilumab (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 C SAF patients who entered 
Part C from Part B.  
5.2. 
Medical History 
Medical history will be summarized by primary SOC and PT for each treatment group and for 
study total based on the SAF. The table will be sorted by decreasing frequency of SOC followed 
by PT based on the overall incidence across treatment groups. 
5.3. 
Prior/Concomitant Medications/Procedures 
Number and proportion of subjects taking prior/concomitant medications, prohibited 
medications/procedures and rescue medications/procedures will be summarized for each treatment 
group and study total, based on the study part specific SAFs, by ATC Level 2 and ATC Level 4, 
sorted by decreasing frequency of ATC Level 2 and ATC level 4 in the dupilumab treatment group. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 44 of 101 
Number and proportion of subjects taking PPIs for the treatment of EoE will be summarized by 
PPI therapy name.  
Number and proportion of subjects undergoing prior/concomitant procedures will be summarized 
for each treatment group and study total, based on the study part specific SAFs, by system organ 
class (SOC) and preferred term (PT), and sorted by decreasing frequency of SOC and PT in the 
dupilumab treatment group.  
In addition, the summary of prior/concomitant medications/procedures will be performed for 
subjects who were impacted by COVID-19 pandemic and not impacted by COVID-19 pandemic 
in each study period, respectively. The summary will be performed for pre-, during, and post-
COVID-19 periods for subjects impacted by COVID-19, if applicable. 
The detailed information of rescue medications/procedures including duration of use and incidence 
of use will be summarized, particularly for swallowed topical/systemic corticosteroids used to treat 
EoE. Kaplan Meier curves for time to first rescue use will be generated. 
Separate summaries will be provided for Part B and Part C concomitant medications/procedures. 
For CMs/CPs taken during the follow-up period, separate summaries will be provided for patients 
who entered follow-up after Part C vs. patients who entered follow-up immediately after Part B. 
If there is a limited number of patients entering follow-up immediately after Part B, only listing 
will be provided. 
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 B and the 
reasons for discontinuation (including COVID-19 related reasons) 
• The total number of patients who discontinued the study during Part B, and the reasons 
for discontinuation (including COVID-19 related reasons) 
• Number of patients who entered into Part C 
• The total number of patients who discontinued the study treatment in Part C and the 
reasons for discontinuation (including COVID-19 related reasons) 
• The total number of patients who discontinued the study during Part C, and the reasons 
for discontinuation (including COVID-19 related reasons) 
• Number of patients who entered the 12-week follow-up period from Part B and Part C, 
respectively 
• Number of patients who had occurrence(s) of visits impacted by the COVID-19 
pandemic and reasons  
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 45 of 101 
 Summary table of protocol deviations in each study treatment period will be provided. 
5.5. 
Extent of Study Treatment Exposure and Compliance 
5.5.1. 
Measurement of Compliance 
Compliance with protocol-defined study drug administration will be calculated separately for Part 
B and Part C as follows: 
Treatment Compliance = (Number of study drug injections during the respective study 
part)/(Number of planned study drug injections during the respective study part) x 100% 
The extended dosing will be also be counted as QW for calculation of treatment compliance.  
Treatment compliance will be summarized separately for Part B and Part C as a continuous 
variable with descriptive statistics for each treatment group. Treatment compliance will also be 
presented by the following specific ranges for each treatment group: <80% and ≥80%.  
5.5.2. 
Exposure to Study Drug and Observation Period 
The duration of exposure to study drug is calculated separately for Part B, Part C, and the overall 
study as follows: 
(Date of last study drug injection in the respective study part – date of first study drug 
injection in the respective study part) + 7 
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 24 
weeks for Part B or 28 weeks for Part C 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 
number of patients, mean, SD, minimum, median, Q1, Q3, and maximum. These summaries will 
be provided for Part B and Part C separately. 
In addition, the duration of exposure will be summarized categorically by counts and percentages 
for each of the following categories and cumulatively by these categories as well: 
≥ 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, with an increment 
of 1 week for each subsequent category. 
In addition, for patients who received at least 1 dose of dupilumab, the total duration of exposure 
to dupilumab during the study (throughout Part B and Part C) is calculated as: 
(Date of last study drug injection in the study – date of first dupilumab injection) + 7 
The duration of observation period during the study is calculated as: 
[Date of the last study visit – date of the first study injection] +1. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 46 of 101 
The duration of observation period will be summarized descriptively using number of 
patients, mean, SD, median, Q1, Q3, minimum and maximum. In addition, the number (%) of 
subjects with observation periods will be presented by specific time periods. The time periods of 
interest is specified as: ≥ 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, ≥ 183 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 estimands of interest for the co-primary endpoints and selected 
secondary endpoint are provided in Appendix 11.1.1. 
5.6.1. 
Analysis of Co-Primary Efficacy Variable(s) 
Histologic response (binary endpoint) 
The proportion of patients achieving a histologic response of peak esophageal intraepithelial 
eosinophil (eos) count (from all 3 regions) of ≤6 eos/hpf at week 24 will be analyzed using the 
Cochran-Mantel-Haenszel (CMH) test to assess the difference in the proportion of responders in 
the FAS adjusting for the randomization stratification factors (age group [≥18 vs. ≥12 to <18 years 
of age] and use of PPI at randomization [yes vs. no]). Estimates of treatment difference and its 
95% confidence interval will be presented. 
Data may be collected after the patient discontinued treatment and will be included in the analyses. 
To account for use of rescue treatment (see Section 0), patients will be considered as non-responder 
for all time points subsequent to the use of rescue treatment in the primary analysis.  
If week 24 biopsy is performed after the date when the first dose of Part C study drug is 
administered, patients will be considered as non-responder in the analysis. 
Due to COVID-19 restrictions, patients may postpone the week 24 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 24 visits will be used in the primary analysis as long as the patients 
keep the extended dosing before biopsy.  However, for patients in whom extended dosing due to 
COVID-19 is interrupted (i.e. 2 or more consecutive doses or 5 or more doses in total missing 
during extended dosing period), their week 24 biopsy data will be set to missing and then imputed 
using MI. 
Missing data at week 24 will be handled according to the reason for missingness as follows: 
• If the peak esophageal intraepithelial eosinophil count at week 24 is missing due to 
COVID-19 pandemic, the data will be imputed by multiple imputation (MI) using a 
random seed number of 6681774 for 10 times based on patients who have non-missing 
eosinophil counts at week 24. The MI will utilize the regression method with treatment 
group, randomization stratification, baseline eosinophil count, and week 24 eosinophil 
count included in the regression model. The imputed week 24 eosinophil counts will 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 47 of 101 
determine whether that patient will be classified as a responder or non-responder. The 
results from each imputed dataset will be combined according to Rubin’s formula 
(Rubin, 1987).  
• If a patient has missing value for the histological response (peak esophageal 
intraepithelial eosinophil count) at week 24 due to reasons not related to the COVID-
19 pandemic, the patient will be classified as a non-responder at week 24. 
The complete dataset after the above steps will be analyzed by the CMH test. 
DSQ total score (continuous endpoint) 
The absolute change from baseline in the DSQ total score at week 24 will be analyzed using an 
analysis of covariance (ANCOVA) model for the FAS with treatment group, randomization 
stratification factors, and relevant baseline measurement as covariates included in the model. The 
cumulative distribution function (CDF) of the absolute change from baseline in the DSQ total score 
at week 24 will be graphed to present the between-treatment-group differences at each level of the 
change. 
Data may be collected after the patient discontinued treatment and will be included in the analyses. 
To account for use of rescue treatment (see Section 0), data will be set to missing for all time points 
subsequent to the use of rescue treatment in the primary analysis.  
For patient with missing value or data set to missing after rescue for the DSQ total score at week 
24, their data for Week 24 will be imputed by MI based on patients who remained in the trial with 
observed values relevant to analysis. To account for the uncertainty in the imputation, missing data 
at week 24 will be imputed 50 times to generate 50 complete datasets by using the MI procedure 
in Statistical Analysis Software (SAS).  
MI will follow the 2 steps below using a random seed number of 6681774 in both steps: 
1. Step 1: Use the Markov Chain Monte Carlo (MCMC) method to fill in intermittent missing 
values (ie, those missing values followed by observed values at subsequent visits) so that 
a monotone missing pattern will be formed. 
2. Step 2: Using the datasets from step 1, missing data through week 24 will be imputed using 
the regression method with treatment group, randomization stratification, relevant baseline 
measurement, and post-baseline measurement up to week 24 included in the regression 
model.  
SAS syntax code for MI: 
proc mi data=mi1 out=mi2 noprint nimpute=50 seed=6681774;  
    mcmc impute=monotone; 
    var val_:; 
run; 
proc mi data=mi3 out=mi4 nimpute=1 seed=6681774; 
  class trtpn ASTRAT1 ASTRAT2 ; 
  monotone reg; 
  var  trtpn ASTRAT1 ASTRAT2 val_:; 
  by _imputation_; 
run; 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 48 of 101 
Once imputations are made, the week 24 data of each of the complete datasets will be analyzed 
using ANCOVA. The results from the 50 analyses on the complete datasets will be combined to 
generate a valid overall statistical inference according to Rubin’s formula (Rubin, 1987) using the 
SAS MIANALYZE procedure. 
During the COVID-19 pandemic, DSQ data continued to be collected by the electronic handheld 
devices that were with the patients at home. This is consistent with how the DSQ data was collected 
for the entirety of the study and does not require consideration for COVID-19 impact in the 
analysis. 
Handling of DSQ Data Collected During the Electronic Handheld Device Malfunction Period 
In the normal flow of DSQ diary question on the electronic handheld device, patients are directed 
to question 2 if they answer Yes to question 1 and will be directed to question 1a only if they 
answer No to question 1 (Figure 3). 
Figure 3: Flow Diagram of DSQ eDiary 
When the YPrime Change Control Form (CCF) 023 update was released on 13Mar2020, it 
caused a DSQ navigation error issue to some devices (listed in Section Section 11.7) after 
patients synchronized their devices with the YPrime eCOA system (this marks the start of the 
period when patient’s device did not direct DSQ questions properly). Details are reported in a 
note to file for this issue (documented on 15Jan2021 by eCOA vendor). 
A software update to resolve this malfunction was sent to devices on 27Mar2020 and impacted 
patients were instructed to upgrade the device software to fix the issue. The date when each 
affected patient upgraded the software on their device is provided in Section 11.7.  
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 49 of 101 
As a result, the devices of 6 patients randomized in Part B were affected by this navigation 
malfunction and irregular response patterns (as shown in Figure 4) were observed from all these 6 
patients using the affected devices.  
Figure 4: 
Response Patterns of DSQ eDiary 
 
In the primary analysis, for patients using the affected devices, the daily DSQ scores will be set to 
missing for all days during the time when patient’s device did not direct DSQ questions properly. 
Diary entries are considered as “not completed” on the affected days and thus will not contribute 
to the requirement of a minimum of 8 diary entries during a 14-day period to calculate the DSQ 
total score for that period. 
Sensitivity analyses  
Sensitivity analyses will assess alternative methods to impute missing data and include the 
following for the co-primary endpoints. 
Histologic responder: 
1. Tipping point analysis: 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 co-primary endpoints. The impact from 
missing data on the comparisons in proportion of patients achieving peak esophageal 
intraepithelial eosinophil count (from all 3 regions) of ≤6 eos/hpf at week 24 between each 
Dupilumab group and placebo control group will be examined, by adjusting for 
stratification factors: 
• A sequence of analyses will be performed with the adjustment to artificially decrease 
the response rate in active treatment group and increase the response rate in placebo 
group with a fixed and definite set of values for data imputation. 
• For each combination of increasing response rate in placebo and decreasing response 
rate in , multiple imputed datasets will be generated and analyzed using CMH test. The 
results obtained from multiple imputed datasets will be combined to generate statistical 
inference, i.e. p-value and treatment difference between active treatment group and 
placebo group. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 50 of 101 
• A “tipping point” will be identified while the result is no longer statistically significant 
(i.e. p-value >0.05). 
2. Sensitivity analyses for different methods of data handling from delayed week 24 biopsy: 
a. All the observed data from week 24 biopsy will be used regardless of dosing 
interruption or out of week 24 window per protocol. Then the same rule on the missing 
data handling in primary analysis will be applied. 
b. Data will be set to missing for patients with week 24 biopsy performed 3 weeks or more 
later than target date due to COVID-19, i.e. study day of week 24 biopsy > 190. The 
missing for those patients will be considered as missing due to COVID-19. Then the 
same rule on the missing data handling in primary analysis will be applied. 
c. Data will be set to missing for patients with week 24 biopsy performed out of window 
per protocol. The missing for those patients will be considered as missing due to 
COVID-19. Then the same rule on the missing data handling in primary analysis will 
be applied. 
An exploraroty analysis will also be performed for patients with week 24 biopsy performed out of 
window per protocol due to COVID-19, i.e. study of week 24 biopsy > 176. 
DSQ total score: 
1. Tipping point analysis: 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 co-primary endpoints. The impact from 
missing data on comparisons in absolute change in DSQ score from baseline to week 24 
between each Dupilumab group and placebo control group will be examined, by adjusting 
for stratification factors:  
• A sequence of analyses will be performed by adding a sequence of positive values in 
placebo group and subtracting a sequence of positive values in active treatment group 
for data imputation. 
• For each combination of adding and subtracting values, multiple imputed datasets will 
be generated and analyzed with the ANCOVA model. The results obtained from 
multiple imputed datasets will be combined using Rubin’s formula to generate 
statistical inference, i.e. p-value and LSmean of treatment difference between active 
treatment group and placebo group. 
• A “tipping point” will be identified while the result is no longer statistically significant 
(i.e. p-value >0.05). 
2. A minimum of 4 diary entries (including days when patient responded ‘No’ to question 1) 
per week is required to derive a standardized total score for each 14-day period. The 
analysis method will be as same as the primary analysis. 
3. DSQ will be scored using an alternative algorithm (detailed in section 4.4.1), i.e. assigning 
a DSQ daily score of 6 if patients do not eat solid food due to EoE. The analysis method 
will be as same as the primary analysis. 
As in the primary analysis, DSQ data collected during the time when patient’s device did not 
direct DSQ questions properly will not be used in the above sensitivity analyses. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 51 of 101 
Supplemental analyses  
DSQ total score: 
Two supplemental analyses for different strategy of use of rescue treatment will be performed: 
1. Composite strategy for rescue: Worst observation carried forward (WOCF) approach will 
be used for  data after the use of rescue treatment.  
2. Treatment policy for rescue: Data collected after the use of rescue treatment will be 
included in the analysis.   
The missing data will be imputed by the MI method as described in primary analysis for the 
supplemental analyses above. 
5.6.2. 
Analysis of Secondary Efficacy Variables 
Binary endpoints at week 24: 
Secondary efficacy endpoints that measure binary responses at week 24 will be analyzed in the 
same fashion as the co-primary endpoint of histologic response of peak esophageal intraepithelial 
eosinophil count of ≤6 eos/hpf, including the method to handle missing data .  
Continuous endpoints at week 24: 
Continuous secondary efficacy endpoints at week 24 will be analyzed using ANCOVA in a similar 
fashion to the co-primary endpoint of change from baseline in the DSQ total score. In the main 
analyses of these endpoint, data will be set to missing for all time points subsequent to the use of 
rescue treatment. For endoscopy/biopsy-based endpoints (i.e., esophageal intraepithelial eos count, 
EREFS, EoE-HSS), if week 24 endoscopy/biopsy is performed after the date when the first dose 
of Part C study drug is administered, data from that endoscopy/biopsy will be set to missing in the 
analysis.  
For continuous efficacy data that are scheduled to be measured repeatedly post-baseline up to week 
24 (eg, percent change in DSQ score from baseline to week 24), as a primary analysis, missing 
data will be imputed by MI as described in the primary efficacy analysis of the DSQ co-primary 
endpoint.  
In the  analysis of EoE-IQ and EoE-SQ endpoints, the missing baseline will be imputed using the 
mean score of FAS.  
During the COVID-19 pandemic, readability of Patient-reported outcomes (PROs) that were 
originally intended to be completed during clinic visits were permitted to be conducted via phone 
interviews. Data collected via phone interview will be included in the primary analysis of these 
PRO endpoints. 
For continuous efficacy data that are to be measured only once post-baseline up to week 24 (eg, 
percent change in peak eos/hpf from baseline to week 24), as a primary analysis, a hybrid approach 
WOCF-MI will be used to handle missing data. That is, missing values at week 24 due to the 
COVID-19 pandemic will be imputed using MI as described in the primary analysis of the co-
primary endpoint of histologic response in Section 5.6.1, and missing values at week 24 due to 
reasons not related to the COVID-19 pandemic will be imputed with patient’s baseline value or 
the available post-baseline value up to week 24, whichever is worse, ie, a worst observation carried 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 52 of 101 
forward (WOCF) approach. 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 reading of EoE-EREFS used in the primary analysis is specified in Section 4.4.2. 
For transcriptome endpoints, the Wilcoxon rank-sum test will be used for patients with NES data 
collected to test if the difference in median NES of the relative change from baseline to week 24 
between the dupilumab and placebo groups is statistically significant. Missing NES data will be 
imputed by LOCF. P-values will be reported.  
The endpoints from EndoFLIP will be summarized with descriptive statistics using all observed 
data. 
Secondary endpoints in Part C: 
Secondary endpoints assessed in Part C (through week 52) will be summarized with descriptive 
statistics for Part C SAF patients who entered Part C from Part B by the treatment groups received 
in Part C, as well as based on the treatment assignment in Part B (as randomized). Descriptive 
statistics will include number of patients, mean, median, Q1, Q3, standard deviation, minimum, 
and maximum for continuous efficacy variables; and patient counts and proportions for categorical 
efficacy variables. No formal statistical hypothesis testing will be performed. Inferential statistics 
will only be provided as needed.  
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 C 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 [visit 3]). Part C baseline is the last available valid measurement taken prior to or on 
the date of the first dose of extended active treatment (scheduled to be administered at week 24 
visit [visit 11]). For DSQ, Part C baseline; is defined in section 6.4; if it is missing, the latest 
available DSQ score prior to first Part C injection will be Part C baseline. 
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. 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 as below (all comparisons are with the placebo). 
 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 53 of 101 
 
Endpoints 
Dupilumab 
 
300mg QW 
group 
300mg Q2W 
group 
Co-Primary 
endpoints  
Proportion of patients achieving peak esophageal 
intraepithelial eosinophil count of ≤6 eos/hpf at week 24 
1 
3 
 
Absolute change in DSQ score from baseline to week 24 
Secondary 
endpoints 
Percent change in DSQ from baseline to week 24 
2 
4 
Percent change in peak esophageal intraepithelial 
eosinophil count (eos/hpf) from baseline to week 24 
5 
8 
Absolute change in EoEHSS mean grade score from 
baseline to week 24 
6 
9 
Absolute change in EoEHSS mean stage score from 
baseline to week 24 
7 
10 
Absolute change in EoE EREFS total score from 
baseline to week 24 
11 
12 
 
Proportion of patients achieving peak esophageal 
intraepithelial eosinophil count of <15 eos/hpf at week 
24 
13 
14 
NES for the relative change from baseline to week 24 in 
the EoE diagnostic panel (EDP) transcriptome signature 
15 
17 
NES of the relative change from baseline to week 24 in 
the type 2 inflammation transcriptome signature 
16 
18 
 
5.6.4. 
Subgroup Analysis 
Subgroups described in Section 3.5 for the primary and key secondary efficacy endpoints (as listed 
in Section 4.4.1 and Section 4.4.2) will be summarized. Treatment difference and its 95% 
confidence interval in subgroups of patients will be presented in forest plots. Interactions between 
the subgroups and treatment groups will be tested.  
5.6.5. 
Analysis of Exploratory Efficacy Variables 
The analysis of other efficacy variables will be the same as the primary analysis described in 
Section 5.6.1 Section 5.6.2.  
The prorated and un-prorated DSQ scores will be analyzed using the same method as the co-
primary endpoint of absolute change from baseline in DSQ. Descriptive statistics and the CDF 
plots will also be provided for adults and adolescents separately. 
5.7. 
Analysis of Safety Data 
The analysis of safety and tolerability will be performed on the SAF, as defined in Section 3.2. 
The safety analysis will be based on the reported AEs, clinical laboratory evaluations, vital signs 
and 12-lead ECG.  
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 54 of 101 
Thresholds for treatment-emergent Potential Clinically Significant Values (PCSVs) in laboratory 
variables, vital signs and ECG 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 C, baseline is the last 
available valid measurement taken prior to the first dose of extended active treatment in Part C 
(scheduled to be administered at week 24 visit [visit 11]). 
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 study part by treatment received in the 
corresponding part. For safety variables/summaries involving baseline values, e.g., absolute 
change from baseline or shift table, study part specific baselines will be used. Summaries for PartB 
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 C and follow-up period will use Part C baseline (i.e., 
the last available valid measurement prior to the first dose of extended active treatment in Part C). 
In addition, the summary of safety results (including TEAEs, clinical laboratory, vital signs and 
ECG) will be performed for subjects who were impacted by COVID-19 pandemic and not 
impacted by COVID-19 pandemic in each study part, respectively.  
5.7.1. 
Adverse Events  
The number and proportion of patients reporting TEAEs will be summarized for Part B week 24 
treatment period, Part C extended active treatment period, and follow-up period, as described in 
Section 3.2. 
• For the summary of Part B treatment period, TEAEs with onset date during the Part B 
treatment period will be included. TEAEs that had an onset during the Part B treatment 
period and continued afterwards into Part C treatment period or the follow-up period 
will be counted only once as TEAEs during the Part B treatment period. 
• For the summary of Part C extended treatment period, TEAEs with onset during the 
Part C extended treatment period will be included. TEAEs that had an onset during the 
Part C treatment period and continued afterwards into the follow-up period will be 
counted only once as TEAEs during the Part C extended treatment period. 
• For the follow-up period, TEAEs with onset during the follow-up period will be 
included.  
AE incidence tables will be presented by treatment group for the SAF as well as for selected 
subgroups. TEAE summaries will present the number (n) and percentage (%) of subjects 
experiencing an TEAE by SOC and PT, sorted by decreasing frequency of SOC and PT for the 
dupilumab treatment group. Multiple occurrences of AEs of the same PT (or SOC) in the same 
subject will be counted only once for that PT (or SOC). For tables presenting severity of events, 
the worst severity will be chosen for subjects 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. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 55 of 101 
An overall summary of TEAEs will be provided with number and proportions of patients with any: 
• TEAE 
• Serious TEAE 
• TEAE of special interest (AESI) 
• TEAE leading to death 
• TEAE leading to permanent treatment discontinuation 
Detailed summaries of TEAEs will include: 
• TEAEs 
− TEAEs by SOC/PT 
− TEAEs by PT 
− TEAEs by SOC/PT with incidence of PT ≥5% in any treatment group 
− TEAEs by severity by SOC/PT 
− TEAEs related to study medication as assessed by the investigator by SOC/PT 
− TEAE of special interest by category (see Section 11.4) 
• Serious TEAEs: 
− Serious TEAEs by SOC/PT 
− Serious TEAEs related to study medication as assessed by the investigator by 
SOC/PT 
• TEAEs leading to permanent discontinuation of study treatment by SOC/PT 
• Fatal TEAEs by SOC/PT 
The time to first AESIs (TEAE by category) will be assessed by Kaplan-Meier estimates (K-M 
plot).  Graphs of cumulative incidence rate over time will be presented by treatment group. 
5.7.2. 
Clinical Laboratory Measurements  
Laboratory measurements include clinical chemistry, hematology and urinalysis results, and will 
be converted to values in standard international units. Summaries of laboratory variables will 
include: 
• Descriptive statistics of laboratory result and change from baseline by visit.  
• The number (n) and percentage (%) of subjects with treatment-emergent PCSVs. This 
summary will be provided based on all patients in the SAF as well as in the subgroup 
of SAF patients who did not meet the PCSV criterion at 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 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 56 of 101 
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 
• 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. 
Analysis of 12-Lead ECG 
Summaries of 12-lead ECG parameters will include: 
• Descriptive statistics for each ECG parameter and change from baseline 
• The number (n) and percentage (%) of subjects with PCSV 
• ECG status (i.e. normal, abnormal) summarized by a shift table  
5.7.5. 
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 treatment group 
• Graphical presentations of median and mean (+/- SD) functional dupilumab 
concentration in serum vs nominal time  
• Graphical presentations of individual functional dupilumab concentration in serum vs 
actual sampling time   
• Assessment of the impact of anti-drug antibodies on functional dupilumab 
concentrations in serum. 
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 responses as defined in Section 4.7 and 
titers observed in patients in the ADA analysis set.  
The following listings will be provided: 
• Number (n) and percent (%) of ADA-negative patients that are negative in the ADA 
assay at all time points by treatment groups 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 57 of 101 
• Number (n) and percent (%) of patients with Pre-existing immunoreactivity by 
treatment groups  
• Number (n) and percent (%) of treatment-emergent ADA positive patients by treatment 
groups and ADA titer categories 
− 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 by treatment 
groups and ADA titer categories  
 Titer categories (Maximum titer values) 
− Low (titer <1,000) 
− Moderate (1,000 ≤ titer ≤ 10,000) 
− High (titer >10,000) 
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.  
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy 
The analyses in this section will only be performed if 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 ADA responses 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 response status, titer and NAb on individual patient drug 
concentration profile.  
5.10.2. 
Immunogenicity and Safety/Efficacy 
Potential association between ADA responses 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 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 58 of 101 
• Injection site reaction (HLT=’ Injection site reaction’) 
• Hypersensitivity (AESI category ‘Hypersensitivity’) 
• Anaphylaxis (SMQ: Anaphylactic Reaction [Narrow]) 
Potential association between ADA responses and impact on individual patient 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 negative patients, that is patients with pre-existing immunoreactivity or 
negative in the ADA assay at all time points. 
• ADA positive patients, that is patients with treatment-emergent or treatment-boosted 
response. 
• Patients with persistent treatment-emergent ADA response 
• NAb positive patients, that is ADA positive patients who were positive in the NAb 
assay at any time point analyzed.  
• Maximum post-first dose titer in treatment-emergent or treatment-boosted ADA 
positive patients:  
− Low (titer <1,000) 
− Moderate (1,000 ≤ titer ≤ 10,000) 
− High (titer >10,000) 
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. 
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. 
For Part B, exploratory analyses for the difference between the dupilumab groups and the placebo 
group in the change and percent change from baseline values will be performed using a rank-based 
ANCOVA model, with treatment group and randomization stratification factors as fixed factors, 
and the relevant baseline value as a covariate. Missing value will be imputed by LOCF method 
using available post-baseline data for visits up to week 24. P-value for differences from placebo 
will be provided. 
Correlation of baseline TARC (measured value), Eotaxin-3, and IgE (measured value) with the 
following clinical endpoints will be explored using ANCOVA model. The model will include the 
below clinical endpoint as the dependent variable, with randomization stratification factors, the 
log10 transformed baseline biomarker value, 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. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 59 of 101 
• Change from baseline to week 24 in DSQ total score 
• Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from 
baseline to week 24 
• Absolute change in EoE EREFS total score from baseline to week 24 
• Absolute change in EoEHSS mean grade score from baseline to week 24 
• Absolute change in EoEHSS mean stage score from baseline to week 24 
Correlation of baseline TARC (measured value), Eotaxin-3, IgE (measured value), and positivity 
to at least one antigen-specific IgE (The threshold for positivity being ≥ 0.35 kU/L) with the 
histologic responder (histologic response of esophageal intraepithelial eosinophil count of 
≤6 eos/hpf at week 24) will be explored using the logistic model. The model will include the 
histologic responder/non-responder as the dependent variable, with randomization stratification 
factors, 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. 
Association of the DSQ score with the histology measures and EREFS score will be explored. 
Specifically, Pearson's correlation coefficient will be provided for the correlation of the following 
pairs within each treatment group: 
• Total EoEHSS grade and stage scores (excluding lamina propria) vs. DSQ score at 
week 24 
• Peak eos count vs. DSQ score at week 24 
• Total EREFS score vs. DSQ score at week 24 
• Change from baseline in total EoEHSS grade and stage scores (excluding lamina 
propria) vs. change from baseline in DSQ score at week 24 
• Change from baseline in peak eos count vs. change from baseline in DSQ score at 
week 24 
• Change from baseline in total EREFS score vs. change from baseline in DSQ score at 
week 24 
All the above correlation/association analyses will be performed on the FAS for  
• All observed data, regardless of the use of rescue treatment  
• Observed data, with data set to missing for all time points subsequent to the use of 
rescue treatment 
5.12. 
Analysis of Psychometric Validity of Patient Reported Outcome 
Measures 
The Sponsor will submit evidence of questionnaire measurement properties using Part B data by 
conducting the analyses described in a separate Psychometric Analysis Plan (PAP).  
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 60 of 101 
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 study baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the first administration of study drug. If any randomized 
patients are not treated, the baseline will be the last value on or prior to the randomization. In 
addition, Part C baseline is defined as the last available valid measurement taken prior to the first 
dose of extended treatment in Part C. The baseline of DSQ is defined in Section 6.4.  
The following rules specify the determination by both date/time information: 
1. For AE, lab (including biomarker), PK and ADA data, both date and time of the 
measurement will be used to determine baseline by comparing with the first injection 
date and time. 
2. For other data except AE, lab (including biomarker), PK or ADA, only date of the 
measurement will be used to determine baseline by comparing with the first injection 
date. 
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 subject ID or enrolled subject ID. 
6.2. 
General Data Handling Conventions 
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 TEAE. 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 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 61 of 101 
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’. 
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 01 January. 
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.  
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 62 of 101 
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 DM and study MD. 
PCSV 
Patients who had post-baseline PCSV but missing baseline value will be regarded as having 
treatment emergent PCSV. 
6.4. 
Analysis Visit Windows 
Data analyzed by-visit-analysis (efficacy [excluding daily diary data], laboratory data, vital sign, 
ECG, ADA) will be summarized by the study scheduled visits described in study protocol and 
SAP Section 11.2, “Schedule of Event”.   
The analysis visit windows will be created per study schedule of events (SOE) 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 
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. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 63 of 101 
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 exist on the same day, the first unscheduled visit will 
be used.  
4. If mapping distance is greater than 4 weeks, the unscheduled visit will not be mapped.  
Unscheduled visits and early termination (ET) visit will be mapped per the analysis visit windows 
for Part B and Part C (Table 1-5) based on the study day/visit of each parameter, respectively.  
Due to COVID-19 pandemic, patients may have delayed week 24 visit and week 52 visit. The two 
visits will not be remapped for primary analysis of efficacy.  
Part B (data collected after the first injection in Part C will not be used for Part B analysis) 
Table 1: Analysis Visit Window for Efficacy Endpoints in Part B 
Visit from SOE 
Target 
Study Day 
in Part Ba 
Analysis Visit Window based on Study Day in Part B 
Histology endpoints, 
Transcriptome 
endpoints, EREFS,  
EndoFLIP endpoints 
PGIC, PGIS 
EOE-IQ, EoE-
SQ, TNSS, 
RQLQ(S)+12, 
ACQ-5, POEM 
Baseline 
1 
≤1 
≤1 
≤1 
Week 12 
85 
 
[2, 113] 
[2, 127] 
Week 20 
141 
 
[114, 155] 
 
Week 24  
(Part B end of treatment) 
169 
[2, 190] Error! Reference 
source not found. 
[156, 190] 
Error! Reference 
source not found. 
[128, 190] Error! 
Reference source not 
found. 
Week 28c  
(Extended period of Part B) 
197 
[191, 204] 
Week 30c  
(Extended period of Part B) 
211 
[205, 218] 
Week 32c  
(Extended period of Part B) 
225 
[219, 232] 
Week 34c  
(Extended period of Part B) 
239 
[233, 246] 
Week 36c  
(Extended period of Part B) 
253 
>=247 
Error! Reference source not found. 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 ≥ 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. 
Error! Reference source not found. If unscheduled or ET visit occurs in this window and it is after the first dose of Part C, it 
will be considered for Week 26 in Part C.  
c  Those are dummy analysis visit windows for patients with extended dosing in Part B. ET or unscheduled visit 
occurred after week 24 visit and before first dose of part C will be mapped per Table 5. 
 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 64 of 101 
Table 2: Analysis Visit Window for Safety and Biomarkers in Part B 
Visit from SOE 
Target 
Study 
Day in 
Part Ba 
Analysis Window based on Study Day in Part B 
Vital signs 
Weight 
Physical 
examinati
on, ECG, 
Height 
Laboratory, 
PK, ADA 
Eotaxin-3, 
Total IgE, 
Allergen-
specific IgE, 
IgG4 
TARC 
Baseline 
1 
≤1 
≤1 
≤1 
≤1 
≤1 
≤1 
Week 1 
8 
[2, 11] 
 
 
 
 
 
Week 2 
15 
[12, 22] 
[2, 22] 
 
 
 
 
Week 4 
29 
[23, 43] 
[23, 43] 
 
 
[2, 57] 
[2, 89] 
Week 8 
57 
[44, 71] 
[44, 71] 
 
 
 
 
Week 12 
85 
[72, 99] 
[72, 99] 
 
[2, 113] 
[58, 127] 
 
Week 16 
113 
[100, 127] 
[100, 127] 
 
 
 
 
Week 20 
141 
[128, 155] 
[128, 155] 
 
[114, 155] 
 
 
Week 24  
(Part B end of treatment) 
169 
[156, 
190]Error! 
Reference source 
not found. 
[156, 
190]Error! 
Reference 
source not 
found. 
[2, 
190]Error! 
Reference 
source not 
found. 
[156, 190] 
Error! Reference 
source not found. 
[128, 
190]Error! 
Reference source 
not found. 
[90, 
190]Error! 
Reference 
source not 
found. 
Week 28c  
(Extended period of Part B) 
197 
[191, 204] 
Week 30c  
(Extended period of Part B) 
211 
[205, 218] 
Week 32c  
(Extended period of Part B) 
225 
[219, 232] 
Week 34c  
(Extended period of Part B) 
239 
[233, 246] 
Week 36c  
(Extended period of Part B) 
253 
>=247 
Error! Reference source not found. 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 ≥ 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. 
Error! Reference source not found. If unscheduled or ET visit occurs in this window and it is after the first dose of Part C, it 
will be considered for Week 26.  
c  Those are dummy analysis visits windows for patients with extended dosing in Part B. ET or unscheduled visit 
occurred after week 24 visit and before first dose of part C will be mapped per Table 5. 
Part C (only applies to patients who received at least 1 dose of Part C study drug) 
Table 3: Analysis Visit Window for Efficacy Endpoints in Part C 
Visit from SOE 
Target Study 
Day in Part 
Ca 
Analysis Window based on Study Day in Part C 
Histology endpoints, 
Transcriptome endpoints, 
EREFS,  
EndoFLIP endpoints 
PRO endpoints 
Baseline of Part C 
1 
≤1 
≤1 
Week 36 
85 
 
[2, 141] 
Week 52 (Part C end of treatment) 
197 
[2, 218] 
[142, 218] 
Week 56b (Extended period of Part C) 
225 
[219, 232] 
Week 58b (Extended period of Part C) 
239 
[233, 246] 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 65 of 101 
Visit from SOE 
Target Study 
Day in Part 
Ca 
Analysis Window based on Study Day in Part C 
Histology endpoints, 
Transcriptome endpoints, 
EREFS,  
EndoFLIP endpoints 
PRO endpoints 
Week 60b (Extended period of Part C) 
253 
[247, 260] 
Week 62b (Extended period of Part C) 
267 
[261, 274] 
Week 64b (Extended period of Part C) 
281 
>=275 
Error! Reference source not found. Study days are calculated from the day of 1st injection of Part C. Study day = (date of 
assessment – 1st injection date +1) when date of assessment ≥ 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  Those are dummy analysis visits windows for patients with extended dosing in Part C. ET or unscheduled visit 
occurred after week 52 visit will be mapped per Table 5. 
Table 4: 
Analysis Visit Window for Safety and Biomarkers in Part C 
Visit from SOE 
Target 
Study 
Day in 
Part Ca 
Analysis Window based on Study Day in Part C 
Vital Signs 
Weight 
Physical 
examination, 
ECG, Height, 
TARC 
Laborator
y 
PK, ADA 
Eotaxin-3, 
Total IgE, 
Allergen-
specific 
IgE, IgG4 
Baseline of Part C 
1 
≤1 
≤1 
≤1 
≤1 
≤1 
≤1 
Week 26 
15 
[2, 22] 
[2, 22] 
 
 
 
[2, 36] 
Week 28 
29 
[23, 43] 
[23, 43] 
 
 
 
 
Week 32 
57 
[44, 71] 
[44, 71] 
 
 
[2, 127] 
[37, 127] 
Week 36 
85 
[72, 99] 
[72, 141] 
 
[2, 141] 
 
 
Week 40 
113 
[100, 127] 
 
 
 
 
 
Week 44 
141 
[128, 155] 
 
 
 
 
 
Week 48 
169 
[156, 183] 
 
 
 
 
 
Week 52 
(Part C end of treatment) 
197 
[184, 218] [142, 218] 
[2, 218] 
[142, 218] [128, 218] [128, 218] 
Week 56b 
(Extended period of Part C) 
225 
[219, 232] 
Week 58b 
(Extended period of Part C) 
239 
[233, 246] 
Week 60b 
(Extended period of Part C) 
253 
[247, 260] 
Week 62b 
(Extended period of Part C) 
267 
[261, 274] 
Week 64b 
(Extended period of Part C) 
281 
>=275 
Error! Reference source not found. Study days are calculated from the day of 1st injection of Part C. Study day = (date of 
assessment – 1st injection date +1) when date of assessment ≥ 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  Those are dummy analysis visits windows for patients with extended dosing in Part C. ET or unscheduled visit 
occurred after week 52 visit will be mapped per Table 5. 
12-week follow-up period after Part B/Part C end of treatment 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 66 of 101 
Table 5: Analysis Visit Window for 12-week follow-up period after Part B/Part C end of 
treatment 
Visit from SOE 
Target Study 
Day after 
EOT Visita 
Analysis Window based on Study Day after EOT 
12-week Follow-up EOS Visit (Patient 
not entering Part C) 
85 (relative to 
week 24 visit) 
≥2 
12-week Follow-up EOS Visit (Patient 
entering Part C) 
85 (relative to 
week 52 visit) 
≥2 
Error! Reference source not found. Study days are calculated from the day of week 24 visit for patients not entering Part C 
and the day of week 52 visit for patients entering Part C. Study day = (date of assessment – week 24/52 visit +1) 
when date of assessment ≥  week 24/52 visit. If patient dose not complete week 24/52 visit, 12-week Follow-up 
EOS Visit will be not applicable for this patient. 
For DSQ data (collected daily by eDiary), the analysis visit windows will be implemented 
following the procedures below: 
Part B (diaries collected after the first injection in Part C will not be used for Part B 
analysis) 
Step 1: Derive the study day  
• If diary date ≥ 1st injection date in the study Part B and < 1st injection date in Part C, 
then Part B diary study day = diary date – 1st injection date in the study +1;  
• If diary date < 1st injection date in the study Part B, Part B diary study day = diary 
date – 1st injection date in the study 
Step 2: Windows are defined as -14 to -1 = BL, 1 to 14 = week 2, 15 to 28 = week 4, etc, with 14-
day intervals between visit windows, through 155 to 168 = week 24. For patients who never entered 
Part C, windows in the 12-week follow-up period will continue with the 14-day intervals as 169 
to 182 = week 26, 183 to 196 = week 28, etc. 
Part C (only applies to patients who received at least 1 dose of Part C study drug) 
Step 1: Derive the study day,  
• For diary date ≥ 1st injection date in the study Part C, Part C diary study day = diary 
date – 1st injection date in Part C +1;  
• If diary date < 1st injection date in the study Part C, Part C diary study day = diary 
date – 1st injection date in Part C 
Step 2: Windows are defined as -14 to -1 = Part C BL, 1 to 14 = week 26, 15 to 28 = week 28, etc, 
with 14-day intervals between visit windows, through 183 to 196 = week 52. For patients who 
entered 12-week follow-up period after Part C, windows will continue with the 14-day intervals 
as 197 to 210 = week 54, 211 to 224 = week 56, etc. 
6.5. 
Statistical Technical Issues 
None. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 67 of 101 
7. 
INTERIM ANALYSIS 
No interim analysis is planned. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 68 of 101 
8. 
TIMING OF STATISTICAL ANALYSIS 
Primary analysis and final analysis are planned for Part B patients.  The primary analysis will be 
performed when the last Part B patient has completed their end of Part B visit including patients 
who have terminated early in Part B. The assessments of primary, secondary, and exploratory 
efficacy endpoints through the end of Part B 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 patients’ Part C data will also be analyzed and evaluated, 
including assessment of secondary endpoints at week 52 for patients for whom this is evaluable 
at time last patient completes end of Part B. The final analysis for Part B patients will occur 
when all patients who entered the 12-week follow-up period immediately from Part B or Part C 
completed the follow-up period. The Part B CSR will be written separately from Part B patients’ 
Part C CSR. 
To maintain study integrity with respect to the post Part B visits and analyses, a dissemination plan 
will be written. This plan will clearly identify the team (including the statistician) that will perform 
the Part B 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 post treatment analyses.  However, the dedicated team can participate in the analysis 
following the final database lock. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 69 of 101 
9. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or higher. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 70 of 101 
10. 
REFERENCES 
1. Barbie, DA, P Tamayo, JS Boehm, SY Kim, S E Moody, IF Dunn, AC Schinzel, P Sandy, 
E Meylan, C Scholl, S Frohling, EM Chan, ML Sos, K Michel, C Mermel, SJ Silver, BA 
Weir, JH Reiling, Q Sheng, PB Gupta, RC Wadlow, H Le, S Hoersch, BS Wittner, S 
Ramaswamy, DM Livingston, DM Sabatini, MMeyerson, RK Thomas, ES Lander, JP 
Mesirov, DE Root, DG Gilliland, T Jacks, and WC Hahn. Systematic Rna Interference 
Reveals That Oncogenic Kras-Driven Cancers Require Tbk1. Nature 462, no 7269. 2009 
5 Nov: 108-12. PMID: 19847166 
2. Brooks R. EuroQol: the current state of play, Health Policy. 1996 Jul;37(1):53-72. 
3. Charman CR, Venn AJ, and Williams, HC. The patient-oriented eczema measure. Arch 
Dermatol 2004; 140:1513-1519. 
4. Collins MH, Martin LJ, Alexander ES, Todd Boyd J, 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 Feb 1;30(3):1-8  
5. Dellon ES, Katzka DA, Collins MH, Hamdani M, Gupta SK, Hirano I; MP-101-06 
Investigators. Budesonide Oral Suspension Improves Symptomatic, Endoscopic, and 
Histologic Parameters Compared With Placebo in Patients With Eosinophilic Esophagitis. 
Gastroenterology. 2017 Mar;152(4):776-786.e5. doi: 10.1053/j.gastro.2016.11.021. Epub 
2016 Nov 23. PMID: 27889574 
6. Dellon, ES, Veerappan R, Selitsky SR, Parker JS, Higgins LL, Beitia RM,, Robert M. 
Genta RM , and Lash RH, MDA 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. 
7. Dziura JD, Post LA, Zhao Q, Fu Z, Peduzzi P. Strategies for dealing with missing data in 
clinical trials: from design to analysis. Yale J Biol Med. 2013 Sep 20;86(3):343-58. PMID: 
24058309; PMCID: PMC3767219. 
8. Greuter T, Bussmann C, Safroneeva E, Schoepfer AM, Biedermann L, Vavricka SR, 
Straumann A. Long-Term Treatment of Eosinophilic Esophagitis With Swallowed Topical 
Corticosteroids: Development and Evaluation of a Therapeutic Concept. Am J 
Gastroenterol. 2017 Oct;112(10):1527-1535. 
9. 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. 
10. Hudgens S, Evans C, Phillips E, Hill M. Psychometric validation of the Dysphagia 
Symptom Questionnaire in patients with eosinophilic esophagitis treated with budesonide 
oral suspension. J Patient Rep Outcomes. 2017;1(1):3. doi: 10.1186/s41687-017-0006-5. 
Epub 2017 Sep 12. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 71 of 101 
11. 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. 
12. Lucendo AJ, Arias A, Molina-Infante J. Efficacy of Proton Pump Inhibitor Drugs for 
Inducing Clinical and Histologic Remission in Patients With Symptomatic Esophageal 
Eosinophilia: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol. 2016 
Jan;14(1):13-22.e1. 
13. Rabin R, Gudex C, Selai C, Herdman M. From translation to version management: a 
history and review of methods for the cultural adaptation of the EuroQol five-
dimensional questionnaire, Value Health 2014 Jan;17(1):70-76. 
14. 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. 
15. Rothenberg ME. Molecular, genetic, and cellular bases for treating eosinophilic 
esophagitis. Gastroenterology. 2015 May;148(6):1143-57. 
16. Rubin, D.B. (1987) Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons 
Inc., New York.  
17. Spergel JM, Brown-Whitehorn TF, Cianferoni A, Shuker M, Wang ML, Verma R, 
Liacouras CA. Identification of causative foods in children with eosinophilic esophagitis 
treated with an elimination diet.J Allergy Clin Immunol. 2012 Aug;130(2):461-7.e5. 
18. Subramanian, A, P Tamayo, VK Mootha, S Mukherjee, BL Ebert, MA Gillette, A 
Paulovich, SL Pomeroy, TR Golub, ES Lander, and JP Mesirov. Gene Set Enrichment 
Analysis: A Knowledge-Based Approach for Interpreting Genome-Wide Expression 
Profiles. Proc Natl Acad Sci U S A 102, no. 43. 2005 25 Oct: 15545-50. PMID: 16199517 
19. Sherrill JD, Kiran KC, Blanchard C, Stucke EM, Kemme KA, Collins MH, Abonia JP, 
Putnam PE, Mukkada VA, Kaul A, Kocoshis SA, Kushner JP, Plassard AJ, Karns RA, 
Dexheimer PJ, Aronow BJ, Rothenberg ME.Analysis and expansion of the eosinophilic 
esophagitis transcriptome by RNA sequencing. Genes Immun. 2014 Sep;15(6):361-9. doi: 
10.1038/gene.2014.27. 
 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 72 of 101 
11. 
APPENDIX 
11.1. 
Summary of Statistical Analyses 
11.1.1. 
Summary of Primary Estimand for Co-primary Endpoints and Secondary Endpoints in Part B 
Endpoints 
Intercurrent event(s) 
Strategy 
Missing data handling 
method 
Co-Primary Endpoints 
Proportion of patients 
achieving a histologic 
response of esophageal 
intraepithelial eosinophil 
count of ≤6 eos/hpf at week 
24 visit 
Initiation of systemic 
and/or swallowed topical 
corticosteroids drugs or 
emergency dilation for 
EoE (rescue treatment) 
Composite strategy: Patients will be considered as non-
responders after such events. 
1. Missing data due to 
COVID-19 will be 
imputed by multiple 
imputation (MI). 
2. Missing data due to 
reasons not related to 
COVID-19 will be 
imputed as non-
responder. 
Initiation of treatment 
with systemic 
corticosteroid drugs for 
conditions other than EoE 
(prohibited medications) 
Treatment policy strategy: Data collected after the patient 
received treatment with systemic corticosteroid drugs for 
conditions other than EoE will be included in the analyses. 
Treatment 
discontinuation 
Treatment policy strategy: Data collected after the patient 
discontinued treatment will be included in the analyses. 
Absolute change from 
baseline in the DSQ total 
score at week 24 
Initiation of systemic 
and/or swallowed topical 
corticosteroids drugs or 
emergency dilation for 
EoE (rescue treatment) 
Hypothetical strategy: Data after such events will be assigned 
using MI.  
Missing data will be 
imputed by MI, 
including the data set to 
missing after rescue 
treatment. 
 
Initiation of treatment 
with systemic 
corticosteroid drugs for 
conditions other than EoE 
(prohibited medications) 
Treatment policy strategy: Data collected after the patient 
received treatment with systemic corticosteroid drugs for 
conditions other than EoE will be included in the analyses. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 73 of 101 
Endpoints 
Intercurrent event(s) 
Strategy 
Missing data handling 
method 
Treatment 
discontinuation 
Treatment policy strategy: Data collected after the patient 
discontinued treatment will be included in the analyses. 
Secondary endpoints 
Continuous Endpoints that 
are scheduled to be 
measured only once post-
baseline up to week 24 (e.g. 
Absolute change in EoE-
EREFS from baseline to 
week 24) 
Initiation of systemic 
and/or swallowed topical 
corticosteroids drugs or 
emergency dilation for 
EoE (rescue treatment) 
Composite strategy: data after rescue treatment will be 
assigned by the worst possible value 
1. Missing data due to 
COVID-19 will be 
imputed by multiple 
imputation (MI). 
2. Missing data due to 
reasons not related to 
COVID-19 will be 
imputed by WOCF. 
Initiation of treatment 
with systemic 
corticosteroid drugs for 
conditions other than 
EoE (prohibited 
medications) 
Treatment policy strategy: Data collected after the patient 
received treatment with systemic corticosteroid drugs for 
conditions other than EoE will be included in the analyses. 
Treatment 
discontinuation 
Treatment policy strategy: Data collected after the patient 
discontinued treatment will be included in the analyses. 
Continuous Endpoints that 
are scheduled to be 
measured repeatedly post-
baseline up to week 24 (e.g. 
Percent change in DSQ from 
baseline to week 24) 
Will be analyzed with the same fasion as the co-primary endpoint of absolute change from baseline in the DSQ total 
score at week 24 
Binary Endpoints (e.g. 
Proportion of patients 
achieving peak esophageal 
intraepithelial eosinophil 
count of <15 eos/hpf at week 
24) 
Will be analyzed with the same fasion as the co-primary endpoint of histologic response of peak esophageal 
intraepithelial eosinophil count of ≤6 eos/hpf 
 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 74 of 101 
11.1.2. 
Summary of Efficacy Analyses 
Endpoint 
Analysis 
Populations 
Primary Statistical Method 
Supportive/Sens
itive Statistical 
Method 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoints 
Proportion of patients 
achieving a histologic response 
of esophageal intraepithelial 
eosinophil count of ≤6 eos/hpf 
at week 24 
FAS 
Cochran-Mantel-Haenszel test / 
MI for missing due to the 
COVID-19 pandemic, otherwise 
define missing as non-responder 
Cochran-Mantel-
Haenszel test on 
LOCF-MI, valid 
week 24, week 
24 regardless of 
any delay 
Yes 
Histogram 
Absolute change from baseline in 
the DSQ total score at week 24 
FAS 
MI+ANCOVA 
ANCOVA with 
LOCF, WOCF, 
requiring 4/7 
diariy entries per 
week 
Yes 
Line plot 
Secondary Endpoints 
Secondary continuous variables 
FAS 
MI+ANCOVA for endpoints 
measured repeatedly (eg, DSQ); 
ANCOVA with WOCF-MI for 
endpoints measured only once 
post-baseline in Part B (eg, peak 
eos count) 
ANCOVA with 
LOCF, LOCF-MI 
Yes for key 
secondary 
efficacy  
Line plot 
Secondary binary variables 
FAS 
Cochran-Mantel-Haenszel test / 
MI for missing due to the 
COVID-19 pandemic, otherwise 
define missing as non-responder 
Cochran-Mantel-
Haenszel test on 
LOCF-MI 
No 
Histogram 
 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 75 of 101 
11.1.3. 
Summary of Safety Analyses 
Endpoint 
Analysis 
Populations 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Adverse Events 
SAF 
Descriptive statistics and 
model-based analyses 
No 
No 
No 
Laboratory Measures 
SAF 
Descriptive Statistics 
No 
No 
No 
Vital sign 
SAF 
Descriptive Statistics 
No 
No 
No 
ECG 
SAF 
Descriptive Statistics 
No 
No 
No 
 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 76 of 101 
11.2. 
Schedule of Time and Events 
Table 6: Parts B Schedule of Events – Screening Period and Placebo-controlled, Double-Blind Treatment Period 
 
Screening Period 
24-Week Double-Blind Treatment Period18 
Study Procedure 
Screening1 
V1 
Screening 
Endoscopy/ 
Biopsy2 
V2 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
DB 
EOT 
V113 
Week (W) 
 
 
 
W1 
W2 
W4 
W8 
W12 
W16 
W20 
W243 
Day (D) 
D-85 to  
D-291 
D-212 
D1 
D8 
D15 
D29 
D57 
D85 
D113 
D141 
D169 
Visit Window (Days [d]) 
 
±7 d 
 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
+7 d 
Screening4/Baseline: 
Informed consent and assent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
Med. history, Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Randomization2a 
 
 
X2a 
 
 
 
 
 
 
 
 
Treatment: 
Training for self-injection5 
 
 
X 
X6a 
X6a 
 
 
 
 
 
 
Administer study drug6, 6a 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug dispensation6, 6a 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Study drug accountability 
 
 
 
X6a 
X6a 
X 
X 
X 
X 
X 
X 
Concomitant medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy:7 
DSQ PRO (daily)8 
assessed by patient daily using eDiary  
PGIC9 
 
 
 
 
 
 
 
X  
 
X  
X 
PGIS9 
 
 
X 
 
 
 
 
X  
 
X  
X 
EoE Impact Questionnaire 10 
 
 
X 
 
 
 
 
X 
 
 
X 
EoE Symptom Questionnaire10 
 
 
X 
 
 
 
 
X 
 
 
X 
TNSS11 
 
 
X 
 
 
 
 
X 
 
 
X 
RQLQ(S)+1211 
 
 
X 
 
 
 
 
X 
 
 
X 
ACQ-511 
 
 
X 
 
 
 
 
X 
 
 
X 
POEM11 
 
 
X 
 
 
 
 
X 
 
 
X 
EQ-5D-3L 
X17 
 
X17 
 
 
 
 
 
 
 
  
EoE-EREFS2,12 
 
X2, 2a, 4 
 
 
 
 
 
 
 
 
X2, 2b 
Endoscopy with biopsies (histology, IHC, 
RNA, EndoFLIP)2 
 
X2, 2a, 4 
 
 
 
 
 
 
 
 
X2, 2b 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 77 of 101 
 
Screening Period 
24-Week Double-Blind Treatment Period18 
Study Procedure 
Screening1 
V1 
Screening 
Endoscopy/ 
Biopsy2 
V2 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
DB 
EOT 
V113 
Week (W) 
 
 
 
W1 
W2 
W4 
W8 
W12 
W16 
W20 
W243 
Day (D) 
D-85 to  
D-291 
D-212 
D1 
D8 
D15 
D29 
D57 
D85 
D113 
D141 
D169 
Visit Window (Days [d]) 
 
±7 d 
 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
+7 d 
Safety: 7, 7a, 19 
Vital signs13 
X 
X 
X13 
X13, 13a 
X13, 13a 
X13, 13a 
X13a 
X13a 
X13a 
X13a 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
X14 
Weight 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
x 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing:7, 7a 
Hematology, Chemistry 
X 
 
X 
 
 
 
 
X 
 
 
X 
Serology tests 15  
X 
 
 
 
 
 
 
 
 
 
 
Serum FSH 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test16 
Serum 
Urine 
Urine 
 
 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urinalysis 
X 
 
X 
 
 
 
 
X 
 
 
X 
PK and ADA:7, 7a 
PK sample 
 
 
X 
 
  
  
 
X 
 
 
X 
ADA sample 
 
 
X 
 
 
  
 
X 
 
 
X 
Biomarkers and Genomics:7, 7a 
Whole blood DNA (optional) 
 
 
X 
 
 
 
 
 
 
 
 
Whole blood RNA (optional) 
X 
 
X 
 
 
 
 
 
 
 
X 
Eotaxin-3 
X 
 
X 
 
 
X 
 
X 
 
 
X 
TARC 
X 
 
X 
 
 
X 
 
 
 
 
X 
Total IgE 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Allergen-specific IgE, IgG4  
X 
 
X 
 
 
X 
 
X 
 
 
X 
Future Biomarker Serum/Plasma 
X 
 
X 
 
 
X 
 
X 
 
 
X 
ADA = anti-drug antibody; DB EOT = end of double-blind treatment period; DSQ = Dysphagia Symptom Questionnaire; ECG = electrocardiogram; EoE-
EREFS = Eosinophilic Esophagitis-Endoscopic Reference Score; IHC = immunohistochemistry; PGIC = Patient Global Impression of Change of Dysphagia; 
PGIS = Patient Global Impression of Severity of Dysphagia; POEM = Patient-Oriented Eczema Measure; PRO = patient-reported outcome; PK = 
pharmacokinetic; RQLQ(S)+12 = Rhinoconjunctivitis Quality of Life Questionnaire for patients aged 12+ years; TNSS = Total Nasal Symptom Score; V = visit 
 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 78 of 101 
Table 7: Part C Schedule of Events – Extended Active Treatment Period 
 
28-Week Extended Active Treatment Period 14 
Study Procedure 
V111 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
EOT 
V19 
Week (W) 
W241 
W26 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
Day (D) 
D169 
D183 
D197 
D225 
D253 
D281 
D309 
D337 
D365 
Visit Window (Days [d]) 
+7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
+7 d 
Treatment:2 
Administer study drug 3, 4, 4a 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug dispensation 4, 4a 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/procedures 
 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy:2 
DSQ eDiary5 
--------------------------- completed daily by patient --------------------------------→ 
PGIC6 
 
 
 
 
X 
 
 
 
X 
PGIS6 
 
 
 
 
X 
 
 
 
X 
EoE Impact Questionnaire7 
 
 
 
 
X 
 
 
 
X 
EoE Symptom Questionnaire 7 
 
 
 
 
X 
 
 
 
X 
TNSS 8 
 
 
 
 
X 
 
 
 
X 
RQLQ(S)+12 8 
 
 
 
 
X 
 
 
 
X 
POEM 8 
 
 
 
 
X 
 
 
 
X 
ACQ-5 8 
 
 
 
 
X 
 
 
 
X 
EoE-EREFS 9, 10 
 
 
 
 
 
 
 
 
X10, 10a 
Endoscopy with biopsies (histology, 
IHC, RNA, EndoFLIP)10 
 
 
 
 
 
 
 
 
X10, 10a 
Safety: 2, 2a, 15 
Vital signs 11 
X11 
X11 
X 
X 
X 
X 
X 
X 
X 
Height 12 
 
 
 
 
 
 
 
 
X 
Weight 
 
X 
X 
X 
X 
 
 
 
X 
Physical examination 
 
 
 
 
 
 
 
 
X 
ECG 
 
 
 
 
 
 
 
 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 79 of 101 
 
28-Week Extended Active Treatment Period 14 
Study Procedure 
V111 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
EOT 
V19 
Week (W) 
W241 
W26 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
Day (D) 
D169 
D183 
D197 
D225 
D253 
D281 
D309 
D337 
D365 
Visit Window (Days [d]) 
+7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
+7 d 
Laboratory Testing:2, 2a 
Hematology, Chemistry 
 
 
 
 
X 
 
 
 
X 
Pregnancy test 13 
 
Urine 
 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urinalysis 
 
  
 
  
X 
 
 
 
X 
PK and ADA:2, 2a   
PK Sample 
 
 
 
X 
 
 
 
 
X 
ADA sample 
 
 
 
X 
 
 
 
 
X 
Biomarkers:2, 2a 
Whole blood RNA (optional) 
 
 
 
 
 
 
 
 
X 
Eotaxin-3 
 
X 
 
X 
 
 
 
 
X 
TARC 
 
 
 
 
 
 
 
 
X 
Total IgE 
 
X 
 
X 
 
 
 
 
X 
Allergen-specific IgE, IgG4  
 
X 
 
X 
 
 
 
 
X 
Future Biomarker Serum/Plasma 
 
X 
 
X 
 
 
 
 
X 
ADA = anti-drug antibody; DSQ = Dysphagia Symptom Questionnaire; ECG = electrocardiogram; EoE-EREFS = Eosinophilic Esophagitis-Endoscopic 
Reference Score; EOT = end of extended active treatment period; IHC = immunohistochemistry; POEM = Patient-Oriented Eczema Measure; PRO = patient 
reported outcome; PGA = physician global assessment; PGIC = Patient Global Impression of Change of Dysphagia; PGIS = Patient Global Impression of 
Severity of Dysphagia; PK = pharmacokinetic; RQLQ(S)+12 = Rhinoconjunctivitis Quality of Life Questionnaire for patients aged 12+ years; TNSS = Total 
Nasal Symptom Score; V = visit 
 
 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 80 of 101 
Table 8: Follow-up Period, Early Termination Visit, and Unscheduled Visit 
Study Procedure 
12-Week Follow-Up 
EOS Visit 
Early 
Termination 
during 12-
Week Follow-
Up1 
Early 
Termination 
during Parts 
A, B, or C1 
Unscheduled Visit before 
Rescue Treatment 
Unscheduled 
Visit for Other 
Reasons 
Week (W) 
12 weeks after EOT visit 
 
 
 
 
Day (D) 
84 days after EOT visit 
 
 
 
 
Visit Window (Days [d]) 
±7 d 
 
 
 
 
Concomitant 
medications/procedures10 
X 
X 
X 
X 
X 
Efficacy: 
DSQ eDiary2 
completed daily by 
patient→ 
 
X 
X 
 
PGIC3 
 
 
X 
X 
 
PGIS3 
 
 
X 
X 
 
EoE Impact Questionnaire 4 
 
 
X 
X 
 
EoE Symptom Questionnaire 4 
 
 
X 
X 
 
TNSS 5 
 
 
X 
X 
 
RQLQ(S)+12 5 
 
 
X 
X 
 
ACQ-5 5 
 
 
X 
X 
 
POEM 5 
 
 
X 
X 
 
EoE-EREFS 6, 7 
 
 
X 7, 7a 
X 8 
 
Endoscopy with biopsies (histology, 
IHC, RNA)7 
 
 
X 7, 7a 
X 8 
 
Safety10:  
Vital signs  
X 
X 
X 
X 
 
Height 9 
 
 
X 
 
 
Weight 
X 
X 
X 
 
 
Physical examination 
 
 
X 
 
 
ECG 
 
 
X 
 
 
Adverse events 
X 
X 
X 
X 
X 
Laboratory Testing10: 
Hematology, Chemistry 
X 
X 
X 
 
 
Pregnancy test 
Urine 
Urine 
Urine 
 
 
Urinalysis 
X 
X 
X 
 
 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 81 of 101 
PK and ADA10: 
PK Sample 
X 
X 
X 
X 
 
ADA sample 
X 
X 
X 
X 
X 
Biomarkers: 
Future Biomarker Serum/Plasma 
(optional) 
 
 
X 
 
 
ADA = anti-drug antibody; DSQ = Dysphagia Symptom Questionnaire; ECG = electrocardiogram; EoE-EREFS = Eosinophilic Esophagitis-Endoscopic 
Reference Score; EOS = end of study (visit); EOT = end of treatment period; POEM = Patient-Oriented Eczema Measure; PRO = patient-reported outcome; 
PGA = physician global assessment; PGIC = Patient Global Impression of Change of Dysphagia; PGIS = Patient Global Impression of Severity of Dysphagia; 
PK = pharmacokinetic; RQLQ(S)+12 = Rhinoconjunctivitis Quality of Life Questionnaire for patients aged 12+ years; TNSS = Total Nasal Symptom Score 
 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 82 of 101 
Footnotes for the Schedule of Events Tables 
Footnotes for Table 1 
1. For patients without a satisfactory prior endoscopy/biopsy (eg, histological criteria were 
not met, or the biopsy was not performed while patient was on at least 8 weeks of high-dose 
PPI treatment), the screening period will be extended for up to 12 weeks (day -85) to allow 
for at least 8 weeks of high-dose PPI treatment prior to the screening endoscopy/biopsies.  
For all other patients, the screening period will be shorter, with sufficient time to allow 
screening assessments and laboratory test results to be available prior to the baseline 
endoscopy/biopsies. 
2. The endoscopy/EoE-EREFS/biopsy procedures should be performed after all other 
efficacy and safety assessments. 
a. The baseline endoscopy with biopsies should be performed at approximately 
day -21±7 days to allow for availability of the intraepithelial eosinophil count result 
from the central pathology laboratory prior to day 1.  For patients without a 
satisfactory prior historical endoscopy/biopsy, the baseline endoscopy/biopsies must 
be performed after at least 8 weeks of high-dose PPI.  Patients may be randomized as 
soon as their endoscopy/biopsy results are available and DSQ eDiary entries are 
completed. 
Note:  Biopsy specimens from the stomach and/or duodenum will be obtained in all 
patients <18 years of age to rule out alternate etiologies.  Stomach and/or duodenal 
biopsies will be obtained in adults only in the event of abnormal endoscopic findings 
(other than typical EoE findings) or clinical suspicion of alternate etiologies. 
b. For patients who receive rescue treatment during the double-blind treatment period, 
the endoscopy/EoE-EREFS/biopsy procedures will be performed prior to the 
initiation of rescue treatment.  Patients undergoing endoscopy/biopsy prior to rescue 
will not undergo the scheduled endoscopy/biopsy at week 24 
Note:  All randomized patients found to have stomach and/or duodenal abnormalities 
at baseline will have follow-up stomach and/or duodenal biopsies at week 24 and 
week 52. 
c. The EndoFLIP procedure to measure esophageal distensibility may be performed 
during the esophagogastroscopy procedures at selected North American sites in 
approximately 150 adult patients. 
3. Assessments indicated for this week 24 (end of treatment) visit should be performed for all 
patients in Parts B.  For patients who will enter Part C, there are additional events listed in 
week 24 visit in Table 7 for Part C. 
4. Patients may be re-screened once if they fail the screening evaluation, unless the reason for 
screen failure is related to histologic or clinical disease severity inclusion criteria. The 
baseline endoscopy with biopsy and EoE-EREFS scoring will not be repeated for re-
screened patients.  These results will continue to be valid baseline data.  Re-screening must 
occur within 6 months of the screen failure. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 83 of 101 
5. Patients and/or caregivers will be trained on administration of study drug at a minimum at 
visit 3/day 1 
6. On scheduled in-clinic study visit days, study drug will be administered in the clinic (by 
the patient, site staff, or caregiver).  Study drug will be provided for those doses scheduled 
to be administered at home before the next in-clinic visit.  Doses of study drug administered 
at home should be administered 1 week after the prior dose of study drug.  Study drug 
administration that occurs in clinic should occur per the Schedule of Events in Table 6 and 
Table 7.  Patients will be closely monitored at the study site at visits 3 to 6 for a minimum 
of 30 minutes after the administration of study drug.  In addition to the predose 
assessments, AEs and vital signs (body temperature, blood pressure, respiratory rate and 
heart rate) will be assessed at 30 minutes (±10 minutes) post-dose. 
a. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic 
visits, after visit 3/day 1 patients/caregivers may be dispensed study drug for at-home 
dosing.  Additionally, if the visit 11/week 24 endoscopy with biopsies is delayed due 
to COVID-19 restrictions, extended blinded dosing of study drug is allowed until this 
visit can occur.  If extended dosing of the study drug occurs beyond week 23, the 
clinic staff must contact the patient every 4 weeks (at a minimum) to collect any AE 
(including ISRs), any change in concomitant medications and/or procedures, and 
monthly pregnancy test results, if required. 
7. Assessments will be performed and blood samples will be collected before the 
administration of study drug. 
a. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic 
visits, procedures/sample collection should occur at the next available in-clinic visit.  
Pregnancy testing must be performed as indicated (in-clinic or at-home) monthly (at a 
minimum) and results reported in a timely manner. 
8. DSQ eDiary will be completed once daily by the patients after their last meal of the day 
but before they go to bed.  Site personnel should conduct regular checks of patient eDiary 
compliance.  
9. Patient Global Impression of Change (PGIC) of Dysphagia and Patient Global Impression 
of Severity (PGIS) of Dysphagia will be completed by the patient via electronic 
questionnaire at the indicated site visits.  
10. EoE Impact Questionnaire and EoE Symptom Questionnaire will be completed by the 
patient via electronic questionnaire at the indicated site visits.  
11. Total Nasal Symptom Score (TNSS) and Rhinoconjunctivitis Quality of Life Questionnaire 
for patients aged 12+ years [RQLQ(S)+12] will be administered only to patients with a 
documented history of allergic rhinitis; Asthma Control Questionnaire-5 (ACQ-5) will be 
administered only to patients with a documented history of asthma; Patient-Oriented 
Eczema Measure (POEM) will be administered only to patients with a documented history 
of AD.  TNSS, POEM, ACQ-5 and RQLQ(S)+12 will be completed via electronic 
questionnaire and at the indicated site visits.   The questionnaires will be administered only 
to the subset of patients who fluently speak the language in which the questionnaire is 
presented (based on the availability of validated translations in participating countries).  
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 84 of 101 
12. EoE-EREFS should be completed by the investigator before biopsies for all patients are 
performed. For Part B enrolled patients, EoE-EREFS will be performed by both the 
investigators who perform the endoscopies as well as a centralized reading center, that will 
provide EoE-EREFS analysis and scoring from endoscopy imaging. For all endoscopies, 
the investigators will assess minor esophageal features including mucosal inflammatory 
and remodeling features.  
13.  At visits 3 through 6, vital signs (body temperature, blood pressure, respiratory rate, heart 
rate) should be taken predose and 30 minutes (±10 minutes) post-dose.  Vital signs should 
be taken predose at all other indicated visits.  
a. If study drug administration is not possible in-clinic due to staff or patient availability 
due to COVID-19 restrictions, vital signs pre- and post-dose may not be performed. 
14. For adolescent patients only. 
15. Includes HIV Ab, HBsAg, HBsAb, HBcAb, HCV Ab, and TB.  Tuberculosis testing will 
be performed on a country-by-country basis according to local guidelines if required by 
regulatory authorities or ECs. 
16. Not required if post-menopausal status confirmed at screening.  A negative result must be 
obtained prior to the randomization visit.  In case of a positive urine test, the study treatment 
will be withheld and a serum pregnancy test to confirm the pregnancy should be performed 
as soon as possible.  A confirmed pregnancy will lead to study drug discontinuation in all 
cases. 
17. The EQ-5D-3L should be administered one time at either visit 1 or visit 3 for newly 
screened patients. 
18. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, 
the clinic staff should make every effort to contact the patient at the timepoint of the 
expected in-clinic visit to collect any AEs (including ISRs), any change in concomitant 
medications and/or procedures, and monthly pregnancy test results, if required. 
Footnotes for Table 2 
1. This visit is the same as the week 24 visit for Parts B (Table 6), and all other assessments 
indicated for week 24 of Parts B (Table 6) should be performed. All pre-dosing procedures 
(including endoscopy with biopsy) at visit 11/week 24 must be completed prior to 
administration of study drug for Part C extended active treatment. 
2. Study assessments will be performed and blood samples will be collected prior to 
administration of study drug. 
a. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic 
visits, procedures/sample collection should occur at the next available in-clinic visit.  
Pregnancy testing must be performed as indicated (in-clinic or at-home) monthly (at a 
minimum) and results reported in a timely manner. 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 85 of 101 
3. Patients will be closely monitored at the study site at visits 11 (at a minimum) and 12, if 
possible, for a minimum of 30 minutes after the administration of study drug.  In addition 
to predose assessments, AEs and vital signs (body temperature, blood pressure, respiratory 
rate, and heart rate) will be assessed at 30 minutes (±10 minutes) post-dose.  
4. All pre-dosing procedures (including endoscopy with biopsy) at the scheduled visit 
11/week 24 must occur prior to dosing with Part C / extended active treatment study drug.  
On scheduled in-clinic study visit days, study drug will be administered in the clinic (by 
the patient, site staff, or caregiver).  Study drug will be provided for those scheduled doses 
to be administered at home before the next in-clinic visit. Doses of study drug administered 
at home should be administered 1 week after the prior dose of study drug.  Study drug 
administration that occurs in clinic should occur per the Schedule of Events in Table 6 and 
Table 7. 
a. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic 
visits, after visit 11/week 24 patients/caregivers may be dispensed study drug for at-
home dosing.  Additionally, if the visit 19/ week 52 endoscopy with biopsies is 
delayed due to COVID-19 restrictions, extended dosing of study drug is allowed until 
this visit can occur.  If extended dosing of the study drug occurs beyond week 51, the 
clinic staff must contact the patient every 4 weeks (at a minimum) to collect any AEs 
(including ISRs any change in concomitant medications and/or procedures, and 
monthly pregnancy test results, if required. 
5. DSQ eDiary will be completed once daily by the patients after their last meal of the day 
but before they go to bed.  Site personnel should conduct regular checks of patient eDiary 
compliance.   
6. PGIC and PGIS will be completed by the patient via electronic questionnaire at the 
indicated site visits. 
7. EoE Impact Questionnaire and EoE Symptom Questionnaire will be completed by the 
patient via electronic questionnaire at the indicated site visits.  
8. TNSS and RQLQ(S)+12 will be administered only to patients with a documented history 
of allergic rhinitis; ACQ-5 will be administered only to patients with a documented history 
of asthma, and POEM will be administered only to patients with a documented history of 
AD.  TNSS, POEM, ACQ-5 and RQLQ(S)+12 will be completed via electronic 
questionnaire and at the indicated site visits.  The questionnaires will be administered only 
to the subset of patients who fluently speak the language in which the questionnaire is 
presented (based on the availability of validated translations in participating countries).  
9. EoE-EREFS should be completed by the investigator before biopsies for all patients are 
performed. For Part B enrolled patients, EoE-EREFS will be performed by both the 
investigators who perform the endoscopies as well as a centralized reading center who will 
provide EoE-EREFS analysis and scoring from endoscopy imaging. For all endoscopies, 
the investigators will assess minor esophageal features including mucosal inflammatory 
and remodeling features.  
10. Endoscopy/EoE-EREFS/biopsy procedures should be performed after all other efficacy 
and safety assessments. The EndoFLIP procedure to measure esophageal distensibility may 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 86 of 101 
be performed during the esophagogastroscopy procedures at selected North American sites 
in approximately 150 adult patients. 
Note:  All randomized patients found to have stomach and/or duodenal abnormalities at 
baseline will have follow-up stomach and/or duodenal biopsies at weeks 24 and 52. 
a. For patients who receive rescue treatment, endoscopy/EoE-EREFS/biopsy procedures 
will be performed prior to initiation of rescue treatment.  Patients undergoing 
endoscopy/biopsy prior to rescue will not undergo the scheduled endoscopy/biopsy at 
weeks 24 and 52. 
11. At visits 11 and 12, vital signs (body temperature, blood pressure, respiratory rate, heart 
rate) should be taken predose and 30 minutes (±10 minutes) post-dose.  Only predose vital 
signs are required at subsequent visits. 
12. For adolescents only 
13. In case of a positive urine pregnancy test, the study treatment will be withheld and a serum 
pregnancy test to confirm the pregnancy should be performed as soon as possible.  A 
confirmed pregnancy will lead to study drug discontinuation in all cases. 
14. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, 
the clinic staff should make every effort to contact the patient at the timepoint of the 
expected in-clinic visit to collect any AEs (including ISRs), any change in concomitant 
medications and/or procedures, and monthly pregnancy test results, if required. 
Footnotes for Table 3 
1. Patients who are withdrawn from study drug will be asked to complete the 12-week follow-
up period and the end of study visit. 
2. DSQ eDiary will be completed once daily by the patients after their last meal of the day 
but before they go to bed.  Site personnel should conduct regular checks of patient eDiary 
compliance.   
3. PGIC and PGIS will be completed by the patient via electronic questionnaire at the 
indicated site visits.  
4. EoE Impact Questionnaire and EoE Symptom Questionnaire will be completed by the 
patient via electronic questionnaire at the indicated site visits.  
5. TNSS and RQLQ(S)+12 will be administered only to patients with a documented history 
of allergic rhinitis; ACQ-5 will be administered only to patients with a documented history 
of asthma, and only in countries in which a valid translation is available; POEM will be 
administered only to patients with a documented history of AD.  TNSS, POEM, ACQ-5 
and RQLQ(S)+12 will be completed via electronic questionnaire and at the indicated site 
visits.  
6. EoE-EREFS should be completed by the investigator before biopsies for all patients are 
performed. For Part B enrolled patients, EoE-EREFS will be performed by both the 
investigators who perform the endoscopies as well as a centralized reading center who 
will provide EoE-EREFS analysis and scoring from endoscopy imaging. For all 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 87 of 101 
endoscopies, the investigators will assess minor esophageal features including mucosal 
inflammatory and remodeling features.  
7. Endoscopy/EoE-EREFS/biopsy procedures should be performed after all other efficacy 
and safety assessments.  The EndoFLIP procedure to measure esophageal distensibility 
may be performed during the esophagogastroscopy procedures at selected North American 
sites in approximately 150 adult patients. 
Note:  All randomized patients found to have stomach and/or duodenal abnormalities at 
baseline will have follow-up stomach and/or duodenal biopsies at weeks 24 and 52 or ET 
visit. 
a. For patients who receive rescue treatment during the double-blind treatment period, 
endoscopy/EoE-EREFS/biopsy procedures will be performed prior to initiation of 
rescue treatment.  Rescue treatment should not be delayed if an endoscopy with 
biopsies cannot occur due to COVID-19 restrictions.  Patients undergoing 
endoscopy/biopsy prior to rescue will not undergo the scheduled endoscopy/biopsy at 
weeks 24 and 52. 
8. Endoscopy/EoE-EREFS/biopsy will be performed only if the Unscheduled Visit is for the 
purpose of administering rescue therapy. 
9. For adolescents only. 
10. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, 
the clinic staff should make every effort to contact the patient at the timepoint of the 
expected in-clinic visit to collect any AEs (including ISRs), any change in concomitant 
medications and/or procedures, and monthly pregnancy test results, if required. 
 
 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 88 of 101 
11.3. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Where adolescent criteria (age >12 to <18) are different than adult criteria (>18), the adolescent 
criteria are provided in [parentheses] in the combined column. The criteria inside the “Combined” 
column will be used for display in the reporting outputs. Applicable criteria will be applied to 
parameters collected in the study to identify treatment-emergent PCSV cases.  
Parameter 
Adults (≥18)a 
Adolescents (≥12 to <18) a 
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 
Alkaline 
Phosphatase 
>1.5 ULN and baseline ≤ 1.5 
ULN 
≥1.5 ULN and baseline <1.5 
ULN 
>1.5 [≥1.5] ULN and baseline ≤ 
1.5[<1.5] ULN  
Total Bilirubin 
>1.5 and ≤ 2 ULN and 
baseline ≤ 1.5 ULN 
>2 ULN and baseline ≤ 2.0 
ULN 
>1.3 ULN and baseline <  1.3 
ULN 
>1.5 [>1.3] and ≤ 2 ULN and 
baseline ≤ 1.5 [ < 1.3] ULN 
>2 ULN and baseline ≤ 2.0 ULN  
Conjugated 
Bilirubinb 
(Direct Bilirubin >35% Total 
Bilirubin and Total Bilirubin 
>1.5 ULN) and (Direct 
Bilirubin <35%  Total 
Bilirubin or  Total Bilirubin 
<1.5 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 
>1.5 [>1.3] ULN) and (Direct 
Bilirubin <35%  Total Bilirubin 
or  Total Bilirubin <1.5 [<1.3] 
ULN) at baseline 
ALT or AST and 
Total Bilirubin 
((ALT>3 ULN or AST>3 
ULN) and TBILI>2 ULN) 
and baseline ((ALT <3 ULN 
and AST<3 ULN) or TBILI 
<2 ULN) 
((ALT>3 ULN or AST>3 
ULN) and TBILI>2 ULN) 
and baseline ((ALT <3 ULN 
and AST<3 ULN) or TBILI 
<2 ULN) 
((ALT>3 ULN or AST>3 ULN) 
and TBILI>2 ULN) and baseline 
((ALT <3 ULN and AST<3 
ULN) or TBILI <2 ULN) 
CPK 
>3 and ≤ 10 ULN and 
baseline ≤ 3ULN 
>10 ULN and baseline ≤ 
10ULN 
≥3 ULN and baseline < 
3ULN 
>3 [≥3] and ≤ 10 ULN and 
baseline ≤ 3 [<3] ULN 
>10 ULN and baseline ≤ 10ULN 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 89 of 101 
Parameter 
Adults (≥18)a 
Adolescents (≥12 to <18) a 
Combined 
Creatinine 
≥150 μmol/L (Adults) and 
baseline < 150 μmol/L 
>=30%  change from baseline 
and <100% change from 
baseline 
≥100% change from baseline 
≥132µmol/L and baseline < 
132µmol/L 
 (or ≥1.5 mg/dL and baseline 
<1.5 mg/dL) 
>=30%  change from baseline 
>150 [>132] μmol/L and baseline 
< 150 [<132] μmol/L 
>=30%  change from baseline 
and <100% change from baseline 
≥100% change from baseline 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L and <=408 
μmol/L at baseline 
<120 μmol/L and >= 120 
μmol/L at baseline 
 
>8.0 mg/dL and <8.0 mg/dl 
at baseline ( or >476 µmol/L 
and <476 µmol/L at baseline 
≤2 mg/dL and >2 mg/dL at 
baseline (or <119 µmol/L and 
baseline > 119 µmol/L) 
 
>408 [>476] μmol/L and <408 
[<476] μmol/L at baseline 
<120 μmol/L and > 120 μmol/L 
at baseline  
Blood Urea 
Nitrogen 
≥17 mmol/L and <17 mmol/L 
at baseline 
≥7.14 mmol/L and <7.14 
mmol/L at baseline 
≥17 [≥7.14] mmol/L and <17 
[<7.14] mmol/L at baseline 
Chloride 
Hypochloremia 
Hyperchloremia 
<80 mmol/L and baseline ≥ 
80 mmol/L  
>115 mmol/L and baseline ≤ 
115 mmol/L  
<80 mmol/L and baseline ≥ 
80 mmol/L  
≥115 mmol/L and baseline < 
115 mmol/L 
<80 mmol/L and baseline ≥ 80 
mmol/L  
>115 mmol/L and baseline ≤ 115 
mmol/L 
Sodium 
Hyponatremia 
Hypernatremia 
≤129 mmol/L  and baseline > 
129 mmol/L  
≥160 mmol/L  and baseline 
<160 mmol/L  
≤129 mmol/L  and baseline 
>129 mmol/L  
≥150 mmol/L  and baseline 
<150 mmol/L 
≤129 mmol/L  and baseline > 
129 mmol/L  
≥160 [≥150] mmol/L  and 
baseline <160 [<150] mmol/L 
Potassium 
Hypokalemia 
Hyperkalemia 
 
<3 mmol/L and baseline ≥ 3 
mmol/L  
≥5.5 mmol/L and baseline 
<5.5 mmol/L  
 
≤3.5 mmol/L and baseline 
>3.5 mmol/L  
≥5.5 mmol/L and baseline 
<5.5 mmol/L 
<3 [≤3.5] mmol/L and baseline ≥ 
3 [>3.5] mmol/L  
≥5.5 mmol/L and baseline <5.5 
mmol/L 
Total Cholesterol 
≥7.74 mmol/L and < 7.74 
mmol/L at baseline 
≥ 6.20 mmol/Land < 6.20 
mmol/L at baseline  
 
≥7.74 [≥6.20] mmol/L and < 7.74 
[<6.20] mmol/L at baseline 
Triglycerides 
≥4.6 mmol/L and < 4.6 
mmol/L at baseline 
Fasted level ≥5.64 mmol/L 
and < 5.64 mmol/L at 
baseline 
≥4.6 [≥5.64 fasted] mmol/L and 
< 4.6 [<5.64 fasted] mmol/L at 
baseline 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 90 of 101 
Parameter 
Adults (≥18)a 
Adolescents (≥12 to <18) a 
Combined 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
(≤3.9 mmol/L and <LLN) and 
(>3.9 mmol/L or >=LLN) at 
baseline 
≥11.1 mmol/L (unfasted) and 
<11.1 mmol/L (unfasted) at 
baseline; ≥7 mmol/L (fasted) 
and <7 mmol/L (fasted) at 
baseline 
<2.7 mmol/L and ≥2.7 
mmol/L at baseline (or < 50 
mg/dL and ≥ 50 mg/dL at 
baseline)  
≥10 mmol/L (unfasted) and < 
10 mmol/L (unfasted) at 
baseline (or ≥180 mg/dl and 
<180 mg/dl at baseline);  ; ≥7 
mmol/L (fasted) and <7 
mmol/L (fasted) at baseline 
(or ≥120 mg/dL and <120 
mg/dL at baseline) 
 
(≤3.9 [<2.7] mmol/L and <LLN) 
and (>3.9 [>2.7] mmol/L or 
>=LLN) at baseline 
≥11.1 [≥10] mmol/L (unfasted) 
and <11.1 [<10] mmol/L 
(unfasted) at baseline; ≥7 
mmol/L (fasted) and <7 mmol/L 
(fasted) at baseline 
HbA1cb 
>8% and <= 8% at baseline 
>6.5% and <= 6.5% at 
baseline 
>8% [>6.5%] and < 8% [<6.5%] 
at baseline 
Albumin 
≤25 g/L and >25 g/L at 
baseline 
≤25 g/L and >25 g/L at 
baseline 
≤25 g/L and >25 g/L at baseline  
CRPb 
>2 ULN or >10 mg/L (if ULN 
not provided) and 
<=2 ULN or <=10 mg/L (if 
ULN not provided) at baseline 
NONE 
 >2 ULN or >10 mg/L (if ULN 
not provided) and <=2 ULN or 
<=10 mg/L (if ULN not 
provided) at baseline  (adults 
only) 
Calcium total 
NONE 
<2 mmol/L and baseline ≥2 
mmol/L  (or ≤ 8 mg/dL and 
baseline >8 mg/dL) 
≥2.9 mmol/L and baseline 
<2.9 mmol/L (or ≥11.6 
mg/dL and baseline <11.6 
mg/dL) 
<2 mmol/L and baseline ≥2 
mmol/L  (adolescents only)  
≥2.9 mmol/L and baseline <2.9 
mmol/L (adolescents only) 
LDL Cholesterol 
NONE 
≥4.91 mmol/L and <4.91 
mmol/L at baseline (≥ 190 
mg/dl and <190 mg/dl at 
baseline) 
≥4.91 mmol/L and <4.91 mmol/L 
at baseline (adolescents only) 
Hematology 
WBC 
<3.0 Giga/L and >=3.0 
Giga/L at baseline (Non-
Black);  
<2.0 Giga/L and >=2.0 
Giga/L at baseline (Black) 
≥16.0 Giga/L and < 16 Giga/L 
at baseline 
<4.0 Giga/L and ≥4.0 Giga/L 
at baseline  
 
>13.5 Giga/L and ≤13.5 
Giga/L at baseline 
<3.0 Giga/L and >=3.0 Giga/L at 
baseline (Non-Black); <2.0 
Giga/L and >=2.0 Giga/L at 
baseline (Black) [<4.0 Giga/L 
and ≥4.0 Giga/L at baseline]  
 
≥16.0 [>13.5] Giga/L and < 16 
[<13.5] Giga/L at baseline 
Lymphocytes 
>4.0 Giga/L and <= 4.0 
Giga/L at baseline 
<0.6 Giga/L and ≥0.6 Giga/L 
at baseline  
 
>6.0 Giga/L and ≤6.0 Giga/L 
at baseline   
<0.6 Giga/L and ≥0.6 Giga/L at 
baseline (adolescents only) 
 
>4.0 [>6.0] Giga/L and ≤4.0 
[≤6.0] Giga/L at baseline   
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 91 of 101 
Parameter 
Adults (≥18)a 
Adolescents (≥12 to <18) a 
Combined 
Neutrophils 
<1.5 Giga/L and >=1.5 
Giga/L at baseline (Non-
Black);  
<1.0 Giga/L and >=1.0 
Giga/L at baseline (Black) 
<1.2 Giga/L and ≥1.2 Giga/L 
at baseline  
>ULN and baseline ≤ ULN 
<1.5 Giga/L and >=1.5 Giga/L at 
baseline (Non-Black); <1.0 
Giga/L and >=1.0 Giga/L at 
baseline (Black) [<1.2 Giga/L 
and ≥1.2 Giga/L at baseline] 
 
 >ULN and baseline ≤ ULN 
(adolescents only) 
Monocytes 
>0.7 Giga/L <= 0.7 Giga/L at 
baseline 
>1.2 Giga/L and <= 1.2 
Giga/L at baseline 
>0.7 [1.2] Giga/L <= 0.7 [1.2] 
Giga/L at baseline 
Basophils 
>0.1 Giga/L <= 0.1 Giga/L at 
baseline 
NONE 
>0.1 Giga/L <= 0.1 Giga/L at 
baseline (adults 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) 
Hemoglobin 
≤115 g/L and > 115 g/L at 
baseline for male; 
≤95 g/L and> 95 g/L at 
baseline for Female. 
 
≥185 g/L and <185 g/L at 
baseline for Male; 
 ≥165 g/L and < 165 g/L at 
baseline for Female 
 
Decrease from Baseline ≥20 
g/L 
 
<100 g/L and >=100 g/L at 
baseline 
 
>200 g/L and <200 g/L at 
baseline 
≤115 g/L and > 115 g/L at 
baseline for male; ≤95 g/L and> 
95 g/L at baseline for Female. 
[<100 g/L and >=100 g/L at 
baseline] 
  
≥185 g/L and <185 g/L at 
baseline for Male;  ≥165 g/L and 
< 165 g/L at baseline for Female 
[>200 g/L and <200 g/L at 
baseline] 
 
Decrease from Baseline ≥20 g/L  
Hematocrit 
≤0.37 v/v and > 0.37 v/v at 
baseline for Male ; ≤0.32 v/v 
and > 0.32 v/v at baseline for 
Female 
≥0.55 v/v and < 0.55 v/v at 
baseline for Male ; ≥0.5 v/v 
and < 0.5 v/v at baseline for 
Female 
≤0.37 v/v and >0.37 v/v at 
baseline for Male; ≤0.33 v/v 
and >0.33 v/v at baseline for 
Female 
≥0.52 v/v and <0.52 v/v at 
baseline for Male; ≥0.47 v/v 
and <0.47 v/v at baseline for 
Female 
≤0.37 v/v and > 0.37 v/v at 
baseline for Male ; ≤0.32 [≤0.33] 
v/v and > 0.32 [>0.33] v/v at 
baseline for Female 
≥0.55 [≥0.52] v/v and < 0.55 
[<0.52] v/v at baseline for Male ; 
≥0.5 [≥0.47] v/v and < 0.5 
[<0.47] v/v at baseline for 
Female 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 92 of 101 
Parameter 
Adults (≥18)a 
Adolescents (≥12 to <18) a 
Combined 
RBC 
<4 Tera/L and baseline ≥4 
Tera/L 
For Male; <3 Tera/L and 
baseline ≥3 Tera/L for Female 
 
≥7 Tera/L and baseline < 7 
Tera/L for Male; ≥6 Tera/L 
and baseline < 6 Tera/L for 
Female 
 
 
 
NONE 
 
 
 
<4 Tera/L and baseline ≥4 Tera/L 
For Male; <3 Tera/L and baseline 
≥3 Tera/L for Female 
 
≥7 Tera/L and baseline < 7 
Tera/L for Male; ≥6 Tera/L and 
baseline < 6 Tera/L for Female 
 
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 
pH 
≤4.6 and > 4.6 at baseline 
≥8 and < 8 at baseline 
 
NONE 
≤4.6 and > 4.6 at baseline (adults 
only) 
≥8 and < 8 at baseline (adults 
only) 
Ketonuria 
NONE 
Presence and absence at 
baseline 
Presence and absence at baseline 
(adolescents only) 
Glycosuria 
NONE 
Presence and absence at 
baseline 
Presence and absence at baseline 
(adolescents only) 
Microscopic 
Hematuria 
NONE 
> 5 RBCs/ HPF and ≤5 
RBCs/ HPF at baseline 
> 5 RBCs/ HPF and ≤5 RBCs/ 
HPF at baseline (adolescents 
only) 
Proteinuria 
NONE 
≥ 1+ and <1 at baseline 
≥ 1+ and <1 at baseline 
(adolescents only) 
Vital signs 
 
HR 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline≥20 bpm 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline≥20 bpm 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline≥20 bpm 
SBP 
≤95 mmHg and decrease from 
baseline ≥20mmHg 
≥160 mmHg and increase 
from baseline ≥20 mmHg 
≤90 mmHg and decrease 
from baseline ≥20 mmHg 
≥119 mmHg and increase 
from baseline ≥20 mmHg 
≤95 mmHg [≤90 mmHg] and 
decrease from baseline 
≥20mmHg  
 
≥160 mmHg [≥119 mmHg] and 
increase from baseline ≥20 
mmHg 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 93 of 101 
Parameter 
Adults (≥18)a 
Adolescents (≥12 to <18) a 
Combined 
DBP 
≤45 mmHg and decrease from 
baseline ≥10 mmHg 
≥110 mmHg and increase 
from baseline ≥10 mmHg 
≤54 mmHg and decrease 
from baseline ≥10 mmHg  
≥78 mmHg and increase from 
baseline ≥10 mmHg 
≤45 mmHg [≤54 mmHg] and 
decrease from baseline ≥10 
mmHg 
≥110 mmHg [≥78 mmHg] and 
increase from baseline ≥10 
mmHg 
Temperature 
Rectal, ear: >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: >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: >100.4 °F/38.0 °C 
Oral: >99.5 °F/37.5 °C  
Axillary or skin infrared: 
>99 °F/37.2 °C 
Respiratory rate 
<12 per minute and ≥12 per 
minute at baseline 
 
>20 per minute and ≤20 per 
minute at baseline 
 
<12 per minute and ≥12 per 
minute at baseline 
 
>20 per minute and ≤20 per 
minute at baseline 
 
<12 per minute and ≥12 per 
minute at baseline 
 
>20 per minute and ≤20 per 
minute at baseline 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
 
≥5% weight loss from 
baseline 
≥5% increase from baseline 
(adults only) 
≥5% decrease from baseline  
ECG 
 
Ref.: CPMP 1997 guideline. 
HR 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline ≥20 bpm 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline ≥20 bpm 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline ≥20 bpm 
PR 
≥220 ms and increase from 
baseline ≥20 ms 
≥200 ms and < 200 ms at 
baseline 
 
≥220 ms and increase from 
baseline ≥20 ms [≥200 ms and < 
200 ms at baseline] 
QRS 
≥120 ms & < 120 ms at 
baseline 
≥110 ms & < 110 ms at 
baseline 
≥120 [≥110] ms and  < 120 
[<110] ms at baseline 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 94 of 101 
Parameter 
Adults (≥18)a 
Adolescents (≥12 to <18) a 
Combined 
QTc 
Borderline 
Prolonged 
Additional 
 
Absolute values (ms)  
Borderline: 
431-450 ms and < 431ms at 
baseline for Male;  
451-470 ms and < 451 ms at 
baseline for Female 
Prolonged:  
>450 to  <500 ms and <= 450 
ms at baseline for Male;  
>470 to <500 ms and <= 470 
ms at baseline for Female 
Additional: 
≥500 ms and < 500 ms at 
baseline 
 
Increase from baseline 
Borderline: Increase from 
baseline 30-60 ms 
Prolonged: Increase from 
baseline >60 ms 
Absolute values (ms)  
Borderline: 
431-450 ms and < 431ms at 
baseline for Male;  
451-470 ms and < 451 ms at 
baseline for Female 
Prolonged:  
>450 to  <500 ms and <= 450 
ms at baseline for Male;  
 >470 to <500 ms and <= 470 
ms at baseline for Female 
Additional: 
 ≥500 ms and < 500 ms at 
baseline 
 
Increase from baseline 
Borderline: Increase from 
baseline 30-60 ms 
Prolonged: Increase from 
baseline >60 ms 
Absolute values (ms)  
Borderline: 
431-450 ms and < 431ms at 
baseline for Male;  
451-470 ms and < 451 ms at 
baseline for Female 
Prolonged:  
>450 to  <500 ms and <= 450 ms 
at baseline for Male;  
 >470 to <500 ms and <= 470 ms 
at baseline for Female 
Additional: 
 ≥500 ms and < 500 ms at 
baseline 
 
Increase from baseline 
Borderline: Increase from 
baseline 30-60 ms 
Prolonged: Increase from 
baseline >60 ms 
a The ULN is based upon central lab reference ranges. The reference range might be different for different age-
groups. For the purpose of this study in a particular patient the reference range based upon age at baseline will be 
used as reference throughout the study for determining PCSVs. 
b Lab parameters not collected in this study. 
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 
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 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 95 of 101 
AESI Category 
Search Criteria 
Serious AE= “Yes” OR Severity= “severe” 
Keratitis 
Narrow SMQ for corneal disorders 
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. 
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-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 96 of 101 
11.5. 
EoE Histology Scoring System (EoEHSS) Feature Evaluation Per 
Colllins 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 
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 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 97 of 101 
Feature 
Grade Score 
Stage Score 
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-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 98 of 101 
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 
KCNJ2 
ANO1 
SLC26A4 
TPSAB1 
TPSB2 
CPA3 
CMA1 
NEFM 
NEFL 
PNLIPRP3 
ENDOU 
IL4 
IL13 
 
IL4R 
IL5 
 
TSLP 
 
 
 
 
 
 
CCL26 
 
 
 
CCR3 
 
 
 
 
 
CLC 
ALOX15 
 
 
POSTN 
 
CMA1 
TPSAB1 
HRH1 
 
 
ARG1 
 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 99 of 101 
EoE diagnostic panel 
Type 2 inflammation signature 
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-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 100 of 101 
11.7. 
List of Part B Subjects Affected by Electronic Handheld Device 
Navigation Malfunction 
Subject ID 
Asset Tag 
Date of First 
Synchronization After 
13Mar2020 Update 
Release 
Date Device 
Upgrade/Replacement 
 
 
2020-03-14 
2020-03-30 
 
 
2020-03-13 
2020-03-27 
 
 
2020-03-13 
2020-04-16 
 
 
2020-03-13 
2020-04-07 
 
 
2020-03-13 
2020-04-14 
 
 
Replaced on 2020-08-07 
* The patient used a previous impacted device that was successfully upgraded during screening period. The patients 
had device replaced on 07Aug2020 and was randomized on 21Aug2020 with valid 14-day DSQ score. 
11.8. 
EQ-5D-3L Utility Index scoring (UK Tariff) 
Table 9: Coefficients of Regression Model Based on UK population 
Variable (Xi) 
Definition 
Coefficients in UK model (βi) 
Constant  
At least one level at 2 or 3 
0.081 
Mobility 
Level 2 
Mobility at level 2 
0.069 
Level 3 
Mobility at level 3 
0.314 
Self-care (S-C) 
Level 2 
S-C at level 2 
0.104 
Level 3 
S-C at level 3 
0.214 
Usual activities (UA) 
Level 2 
UA at level 2 
0.036 
Level 3 
UA at level 3 
0.094 
Pain or discomfort (P/D) 
Level 2 
P/D at level 2 
0.123 
Level 3 
P/D at level 3 
0.386 
Anxiety or depression (A/D) 
Level 2 
A/D at level 2 
0.071 
Level 3 
A/D at level 3 
0.236 
N3 
Any dimention at level 3 
0.269 
Model for Utility index score: 
utility index score = 1 − ∑
(𝛃𝐢∗Xi)
12
𝑖=1
, 
where Xi is a dummy variable  with value 1 if the definition for this variable is met and 0 otherwise 
(e.g X1 =1 if the patient has at lease one level at 2 or 3 from 5 demensions, otherwise X1 =0).  
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part B/C 
Statistical Analysis Plan 
Date: September 14th, 2021 
 
CONFIDENTIAL 
Page 101 of 101 
For example, if the patient only have mobility at level 2 (i.e. some problems in mobility) and others 
are level 1 (i.e. no problem on the other 4 dimensions), then only “At least one level at 2 or 3” and 
“Mobility at level 2” are met and the utility index score=1-(1*0.081+1*0.069)=0.85. 
SAS code 
data EUROQOL; set temp; 
profil= (10000*eqq1cd)+(1000*eqq2cd)+(100*eqq3cd)+(10*eqq4cd)+eqq5cd; 
eq5d=1; 
**********Mobility*********; 
if eqq1cd=2 then eq5d=eq5d-0.069; 
if eqq1cd=3 then eq5d=eq5d-0.314; 
********Self-care**********; 
if eqq2cd=2 then eq5d=eq5d-0.104; 
if eqq2cd=3 then eq5d=eq5d-0.214; 
******Usual activities*****; 
if eqq3cd=2 then eq5d=eq5d-0.036; 
if eqq3cd=3 then eq5d=eq5d-0.094; 
*****Pain/discomfort******; 
if eqq4cd=2 then eq5d=eq5d-0.123; 
if eqq4cd=3 then eq5d=eq5d-0.386; 
*****Anxiety/depression*****; 
if eqq5cd=2 then eq5d=eq5d-0.071; 
if eqq5cd=3 then eq5d=eq5d-0.236; 
if (eqq1cd ne 1 or eqq2cd ne 1 or eqq3cd ne 1 or eqq4cd ne 1 or eqq5cd ne 1) 
then eq5d=eq5d-0.081; 
if (eqq1cd=3 or eqq2cd=3 or eqq3cd=3 or eqq4cd=3 or eqq5cd=3) 
then eq5d=eq5d-0.269; 
if (eqq1cd=. or eqq2cd=. or eqq3cd=. or eqq4cd=. or eqq5cd=.) 
then eq5d=.; 
run; 
 
 
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00


Signature Page for VV-RIM-00168730 v1.0
Signature Page for VV-RIM-00168730 v1.0 Approved
ESig Approval
00
ESig Approval
00
ESig Approval
-2021 15:13:19 GMT+0000
                                        VV-RIM-00168730-1.0 Approved - 21 Sep 2021 GMT-5:00

Prot_000.pdf: 
IND Number:  136142 
EudraCT number:  2018-000844-25 
Regeneron Pharmaceuticals, Inc. 
Clinical Study Protocol 
A PHASE 3, RANDOMIZED, 3-PART STUDY TO INVESTIGATE THE 
EFFICACY AND SAFETY OF DUPILUMAB IN ADULT AND 
ADOLESCENT PATIENTS WITH EOSINOPHILIC ESOPHAGITIS 
Compound: 
Dupilumab 
Clinical Phase: 
3 
Protocol Number: 
R668-EE-1774 
Protocol Version: 
R668-EE-1774 Amendment 5 
Amendment 5 Date of Issue: 
See appended electronic signature page 
Amendment 4 Date of Issue: 
16 April 2020 
Amendment 3 Date of Issue: 
10 March 2020 
Amendment 2 Date of Issue: 
18 April 2019 
Amendment 1 Date of Issue: 
04 October 2018 
Original Date of Issue: 
21 June 2018 
Medical /Study Director: 
 
 
 
Regeneron Pharmaceuticals, Inc. 
777 Old Saw Mill River Road 
Tarrytown, NY 10591 
 
 
 
 
 
. 
VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00
NCT Number:  NCT03633617


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 2 of 113 
 
CONFIDENTIAL 
AMENDMENT HISTORY 
Amendment 5 
The purpose of this protocol amendment is to adjust the sample size for Part B based on the 
results of Part A of the study, and to add an additional database lock after all patients in Part A 
complete study week 52 of Part C. Other changes were made for clarification and consistency. 
The following table outlines the changes made to the protocol and the rationale.  
Description of Change 
Rationale 
Section Changed 
Decreased the required sample size for 
Part B from 345 patients to 210 
patients (70/arm) based on the sample 
size re-estimation for Part B, as 
previously outlined in Section 10.2 
Justification of Sample Size.  
 
This sample size re-
estimation for Part B 
was based on results 
from Part A of the 
study in which a larger 
treatment effect on the 
Dysphagia Symptom 
Questionnaire (DSQ) 
was observed than in a 
phase 2 study with 
budesonide, 
previously used for 
sample size 
estimation. 
Clinical Study Protocol Synopsis: 
Population, Statistical Plan 
Section 5.1 Study Description and Duration 
Figure 2 Study Design 
Section 6.1 Number of Patients Planned 
Section 7.5 Method of Treatment 
Assignment 
Section 10.2 Justification of Sample Size 
Added an additional database lock to 
occur after the last Part A patient has 
completed their week 52 visit of Part 
C, including patients who have 
terminated early in Part C.  
 
To provide safety and 
efficacy data for 
analyses of durability 
of treatment effect 
Section 10.4.9 Timing of Statistical Analysis 
Added a subgroup analysis of the co-
primary and secondary study variables 
in patients with previous swallowed 
topical corticosteroid use. 
 
To assess the 
treatment effects of 
dupilumab in a 
subgroup who 
received topical 
steroid therapy. 
Clinical Study Protocol Synopsis: 
Objective(s), Endpoint(s) 
Section 2.2 Secondary Objectives 
Section 4.2.2 Secondary Endpoints 
 
Revised the adverse events of special 
interest (AESIs) definitions and 
adverse drug reactions (ADRs) for the 
dupilumab clinical development 
program.  
 
For program 
consistency based on 
regulatory authority 
feedback and to align 
with the most recent 
Investigator’s 
Brochure. 
Section 3.2.3.2 Risks 
Section 9.4.3 Other Events that Require 
Accelerated Reporting to Sponsor 
Clarified that any additional analyses 
required to investigate the impact of 
COVID-19 on the safety evaluation 
will be specified in the SAP. 
To address guidance 
from the US and EU 
regarding the conduct 
of clinical trials during 
the COVID-19 
pandemic. 
Section 10.4.4 Safety Analysis 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 3 of 113 
 
CONFIDENTIAL 
Description of Change 
Rationale 
Section Changed 
Added the primary estimand for 
primary and key secondary endpoints 
and clarified the sensitivity analysis 
for co-primary endpoints including 
but not limited to the methods listed in 
protocol. 
 
To implement a 
concept estimand in 
the primary analysis 
approaches for the 
primary and key 
secondary endpoints 
based on ICH E9 (R1). 
Section 10.4.3.1 Primary Efficacy Analysis 
Table 4 Summary of Primary Estimand for 
Co-primary Endpoints  
Section 10.4.3.2.1 Analysis of Secondary 
Efficacy Endpoints in Part A and Part B 
Table 5 Summary of Primary Estimand for 
Key Secondary Endpoints  
Revised the Schedule of Events (SOE) 
to list TARC and Total IgE sample 
collection as separate rows, rather 
than listing in the same row with 
footnotes to clarify differences as 
before. 
 
For clarification only; 
there are no changes to 
sample collection. 
Table 1 Parts A and B Schedule of Events – 
Screening Period and Double-Blind 
Treatment Period 
Section 8.1.1.1 Footnotes for Table 1, 
footnote #17 (removed) 
Table 2 Table 2 Part C Schedule of Events – 
Extended Active Treatment Period 
Section 8.1.1.2 Footnotes for Table 2, 
footnote #14 (removed) 
Made minor clarifications and 
editorial corrections. 
For clarification. 
Throughout the document. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 4 of 113 
 
CONFIDENTIAL 
Amendment 4 
The purpose of this protocol amendment is to protect patient safety and data integrity during the 
COVID-19 pandemic by allowing for certain study procedures to occur at delayed time points 
and/or outside of the clinic environment. All temporary mechanisms utilized, and deviations 
from planned study procedures are to be documented as being related to COVID-19 and will 
remain in effect only for the duration of the public health emergency. The following table 
outlines the changes made to the protocol and the rationale.  
Description of Change 
Rationale 
Section Changed 
Added provisions allowing study 
procedures to occur at delayed 
timepoints and/or outside of the clinic 
environment. 
• 
Biopsy with endoscopies may be 
delayed for visit 11/week 24, visit 
19/week 52, early termination, 
and before initiating rescue 
treatment 
• 
At-home study drug dosing is 
permitted for all visits except for 
visit 3/day 1 and visit 11/week 24 
• 
If the endoscopy with biopsies 
cannot occur due to COVID-19 
restrictions, rescue treatment 
should be initiated without delay 
and these patients will be eligible 
to participate in Part C 
• 
Safety and laboratory procedures 
(vital signs, weight, PK/ADA 
sample collection, hematology 
and chemistry urine sample 
collection) may be delayed or 
occur at-home when possible 
• 
The patient-reported outcome 
questionnaires that are intended to 
be completed during clinic visits 
may be conducted via phone 
interviews after visit 3/day 1 
To protect 
patient safety 
and data 
integrity in 
the context of 
COVID-19 
restrictions. 
Clinical Study Protocol Synopsis: Study Design 
Section 3.2.3 Risk/Benefits of Participating in the 
Study 
Section 3.2.3.2 Risks 
Section 5.1 Study Description and Duration 
Section 5.1.1.3 Placebo-Controlled Double-Blind 
Treatment Period (24 Weeks) 
Section 6.2.3 Exclusion Criteria for Part C (the 
Extended Active Treatment Period), Criterion #5 
Section 7.3 Rescue Treatments 
Table 1 Parts A and B Schedule of Events – 
Screening Period and Double-Blind Treatment Period 
Table 2 Part C Schedule of Events – Extended Active 
Treatment Period 
Section 8.1 Schedule of Events 
Section 8.1.1.1 Footnotes for Table 1, footnote #5, 9, 
10, 11 (edited), footnote #6.a, 7.a, 13.a, 19 (added) 
Section 8.1.1.2 Footnotes for Table 2, footnote #3, 6, 
7, 8 (edited), footnote #2.a, 4.a, 15 (added) 
Section 8.1.1.3 Footnotes for Table 3, footnote #3, 4, 
5, 7.a (edited), footnote # 10 (added) 
Section 8.2.2.3 EoE Impact Questionnaire (EoE-IQ) 
Section 8.2.2.4 EoE Symptom Questionnaire 
Section 8.2.2.5 Patient Global Impression of Change 
(PGIC) 
Section 8.2.2.6 Patient Global Impression of Severity 
(PGIS) 
Section 8.2.2.7 Total Nasal Symptom Score (TNSS) 
Section 8.2.2.8 Standardized Rhinoconjunctivitis 
Quality of Life Questionnaire for ages 12+ 
[RQLQ(s)+12] 
Section 8.2.2.9 Juniper Asthma Control Questionnaire 
(ACQ) 
Section 8.2.2.10 Patient-Oriented Eczema Measure 
(POEM) 
Section 10.4.3.1 Primary Efficacy Analyses 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 5 of 113 
 
CONFIDENTIAL 
Description of Change 
Rationale 
Section Changed 
Added a provision allowing patients to 
extend their current assigned dose 
regimen of study drug (Parts A/B 
and/or C) until the post-baseline 
esophageal biopsy procedure(s) are 
performed.  
 
This change is detailed in the 
Footnotes for the Schedule of Events. 
Additionally, the word 
“approximately” was added 
throughout the protocol for time 
points related to duration of treatment. 
To protect 
patient safety 
and data 
integrity in 
the context of 
COVID-19 
restrictions. 
Section 3.2.1 Rationale for Study Design 
Section 5.1 Study Description and Duration 
Section 5.1.1.3 Placebo-Controlled Double-Blind 
Treatment Period (24 Weeks) 
Section 5.1.2.3 Placebo-Controlled Double-Blind 
Treatment Period (24 Weeks) 
Section 5.1.3 Part C (28-Week Extended Active 
Treatment Period 
Table 1 Parts A and B Schedule of Events – 
Screening Period and Double-Blind Treatment Period 
Table 2 Part C Schedule of Events – Extended Active 
Treatment Period 
Section 8.1.1.1 Footnotes for Table 1, footnote #6a 
(added) 
Section 8.1.1.2 Footnotes for Table 2, footnote #4a 
(added) 
Section 10.4.3.1 Primary Efficacy Analyses 
 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 6 of 113 
 
CONFIDENTIAL 
Amendment 3 
The purpose of this amendment is to add transcriptome sequencing for analyzing RNA 
expression of eosinophilic esophagitis (EoE) and type 2 inflammation to the study secondary 
objectives and endpoints, and to add the European Quality of Life 5-dimension 3-level (EQ-5D-
3L) Questionnaire to collect general health status of EoE patients. Additionally, the Eosinophilic 
Esophagitis-Endoscopic Reference Score (EoE-EREFS) procedure for Part B patients was 
revised to allow for centralized reading and scoring. Other minor changes were made to align 
with regulatory authority feedback and for general clarification. The following table outlines the 
changes made to the protocol and the rationale.  
Study status as of Amendment 3: Part A enrollment complete and Part B enrollment ongoing.  
Change 
Rationale 
Section Changed 
Added endpoints for EoE and type 2 
inflammation transcriptome 
signatures to the study secondary 
objectives and endpoints (from 
samples collected as a part of the 
original study procedures).  
Transcriptome sequencing 
was added as an important 
indicator of disease activity. 
Clinical Study Protocol Synopsis: 
Objective(s), Endpoint(s), Procedures 
and Assessments 
Section 2.2 Secondary Objectives 
Section 4.2.2 Secondary Endpoints 
Section 8.2.6.1 EoE Diagnostic Panel 
and Type 2 Inflammation 
Transcriptomics (section added) 
Section 10.4.3.2.1 Analysis of 
Secondary Efficacy Endpoints in Part A 
and Part B 
Section 22 References 
Added the EQ-5D-3L Questionnaire 
for newly screened patients at the 
screening or baseline visit only. 
 
In order to collect general 
health status of EoE 
patients. 
Table 1: Parts A and B Schedule of 
Events – Screening Period and Double-
Blind Treatment Period 
Section 8.1.1.1 Footnotes for Table 1, 
footnote #18 (footnote added) 
Section 8.2.2.11 European Quality of 
Life 5-Dimensional Scale (EQ-5D) 
(section added) 
Section 22 References 
Revised the EoE-EREFS procedure 
for Part B enrolled patients to allow 
for centralized reading and scoring. 
 
To minimize inter-rater 
variability for this endpoint. 
Clinical Study Protocol Synopsis: 
Procedures and Assessments 
Section 8.1.1.1 Footnotes for Table 1, 
footnote #12  
Section 8.1.1.2 Footnotes for Table 2, 
footnote #9 
Section 8.1.1.3 Footnotes for Table 3, 
footnote #6 
Section 8.2.2.1 Endoscopy with EoE-
EREFS and Biopsies, and Photographs 
Section 10.4.3.2.1 Analysis of 
Secondary Efficacy Endpoints in Part A 
and Part B 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 7 of 113 
 
CONFIDENTIAL 
Change 
Rationale 
Section Changed 
Revised the adverse events of special 
interest (AESIs) definitions for the 
dupilumab clinical development 
program.  
For program consistency 
based on regulatory 
authority feedback. 
Section 9.4.3 Other Events that Require 
Accelerated Reporting to Sponsor 
Revised the visit window for visit 
11/week 24 and visit 19/week 52 to 
change ±7 days to +7 days. 
For clarification to ensure 
the full 14 days of 
Dysphagia Symptom 
Questionnaire (DSQ) diary 
entries are collected just 
prior to these visits. 
Table 1: Parts A and B Schedule of 
Events – Screening Period and Double-
Blind Treatment Period 
Table 2: Part C Schedule of Events – 
Extended Active Treatment Period 
Revised an existing secondary 
endpoint to state: Proportion of 
patients achieving peak esophageal 
intraepithelial eosinophil count of 
<15 eos/hpf at week 24 (previously 
stated ≤15 eos/hpf). 
To correct a typographical 
error and thus align with the 
inclusion criteria of 
≥15 eos/hpf.  
Clinical Study Protocol Synopsis: 
Endpoint(s) 
Section 4.2.2 Secondary Endpoints 
 
Clarified exclusion criterion #14 and 
prohibited medications to allow for 
one-time steroid use with the 
anesthetic preparation (not for EoE) 
used during the endoscopy 
procedures.  
For clarification. 
Section 6.2.2 Exclusion Criteria for 
Parts A and B, #14  
Section 7.7.1 Prohibited Medications 
and Procedures 
Clarified the requirement that all pre-
dosing procedures (including 
endoscopy with biopsy) at the 
scheduled visit 11/week 24 must 
occur prior to dosing with Part C / 
Extended Active Treatment study 
drug. 
For clarification. 
Section 8.1.1.2 Footnotes for Table 2, 
footnotes #1 and #4  
 
Clarified the assumption used for 
Part A sample size calculation. 
For clarification. 
Section 10.2 Justification of Sample 
Size 
Minor language changes were made 
to clarify the definition of 
hospitalization. 
For clarification. 
Section 9.3.2 Serious Adverse Event 
Section heading was updated to add 
to word circulating before 
biomarkers. 
For clarification. 
Section 8.2.6.2 Type 2 Inflammatory 
and Disease-Related Circulating 
Biomarkers 
 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 8 of 113 
 
CONFIDENTIAL 
Amendment 2 
The following table outlines the changes made to the protocol and the affected sections: 
Change 
Section Changed 
Per Health Authority request, changed Part C from open-
label to a design with added placebo SC injections 
alternating with dupilumab 300 mg Q2W doses in order to 
mask the dosing regimen for Part B patients during this 
extended active treatment phase of the study. 
Clinical Study Protocol Synopsis – Objectives, Study 
Design, Study Duration, Treatment(s), Endpoint(s), 
Statistical Plan 
Section 3.2.1 Rationale for Study Design 
Section 3.2.3.1 Benefits 
Section 4.2.2 Secondary Endpoints 
Section 5.1 Study Description and Duration 
Figure 1 Study Flow Diagram 
Figure 2 Study Design 
Section 5.1.1.3 Placebo-Controlled, Double-Blind 
Treatment Period (24 Weeks) 
Section 5.1.2.3 Placebo-Controlled, Double-Blind 
Treatment Period (24 Weeks) 
Section 5.1.3 Part C (28-Week Extended Active 
Treatment Period) 
Section 5.2 Planned Interim Analysis 
Section 6.2.3 Exclusion Criteria for Part C (the 
Extended Active Treatment Period) 
Section 7.1 Investigational and Reference Treatments 
Section 7.3 Rescue Treatments 
Section 7.4.2 Study Drug Discontinuation 
Section 7.5 Method of Treatment Assignment 
Section 7.5.1 Blinding 
Section 7.6.1 Packaging, Labeling, and Storage 
Section 8.1 Schedule of Events 
Table 2 Part C Schedule of Events – Extended Active 
Treatment Period 
Section 10.3.1 Efficacy Analysis Sets 
Section 10.3.2 Safety Analysis Set 
Section 10.4.3.2.2 Analysis of Secondary Efficacy 
Endpoints in Part C 
Section 10.4.4.1 Adverse Events 
Section 10.4.4.3 Treatment Exposure 
Added a per protocol set to the defined efficacy analysis 
sets to assess the overall robustness of the analysis results. 
Added that any re-estimation of sample size for Part B 
will be documented in the Part B SAP before its database 
lock. If the re-estimated sample size requires an increase 
of the planned sample size in Part B by more than 86 total 
patients (25%), it will also be documented in a protocol 
amendment so as to inform Has, ECs, and investigators. 
 
Clinical Study Protocol Synopsis – Statistical Plan 
Section 6.1 Number of Patients Planned 
Section 10.2 Justification of Sample Size 
Section 10.3.1 Efficacy Analysis Sets 
Section 10.3.2 Safety Analysis Set 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 9 of 113 
 
CONFIDENTIAL 
Change 
Section Changed 
Clarified safety analyses of the Part C extended active 
treatment period will only include patients who received 
at least 1 dose of Part C study drug. 
Added a substudy which may be performed at select sites 
and a secondary endpoint to the study for the endolumenal 
functional lumen imaging probe (EndoFLIP) procedure to 
measure esophageal distensibility during the 
esophagogastroscopy procedures at selected sites in 
approximately 150 adult patients. 
Clinical Study Protocol Synopsis – Procedures and 
Assessments, Endpoint(s) 
List of Abbreviations 
Section 4.2.2 Secondary Endpoints 
Table 1 Parts A and B Schedule of Events – Screening 
Period and Double-Blind Treatment Period 
Table 2 Part C Schedule of Events – Extended Active 
Treatment Period 
Table 3 Follow-up Period, Early Termination Visit, and 
Unscheduled Visit 
Section 8.1.1.1 Footnotes for Table 1, footnote 2c 
Section 8.1.1.2 Footnotes for Table 2, footnote 10 
Section 8.1.1.3 Footnotes for Table 3, footnote 7 
Section 8.2.2.1 Endoscopy with EoE-EREFS and 
Biopsies, and Photographs 
Section 22 References 
Added additional secondary endpoints for proportion of 
patients who receive rescue medications or procedures 
during the 24-week placebo-controlled treatment period 
and absolute change in EoE Stage Score from the 
EoEHSS from baseline to week 24. 
Clinical Study Protocol Synopsis – Endpoint(s) 
Section 4.2.2 Secondary Endpoints 
Made revisions to sections related to patient screening and 
eligibility criteria to: 
• 
clarify that baseline endoscopy with biopsy and 
EoE-EREFS do not need to be repeated for 
patients eligible for rescreening. 
• 
clarify the requirement that all patients required 
to initiate high-dose PPI therapy prior to baseline 
may change to a different approved PPI 
medication during the study and to clarify the 
requirement for duration of treatment with high-
dose PPI regimen prior to the baseline endoscopy 
to account for patients who present at the 
screening visit already using an acceptable PPI 
regimen. 
• 
specify that exclusion of patients because of 
bleeding disorders or esophageal varices will be 
based on the opinion of the investigator if the 
condition would put the patient at undue risk for 
significant complications from an endoscopy 
procedure. 
Clinical Study Protocol Synopsis – Treatment(s) 
Section 5.1.1.1 Screening (Up to 12 Weeks) 
Figure 3 Endoscopy/Biopsy Procedure Flow Diagram 
Section 6.2.1 Inclusion Criteria for Parts A and B, #2 
Section 6.2.2 Exclusion Criteria for Parts A and B, #8 
Section 7.2 Background Treatment 
Table 1 Parts A and B Schedule of Events – Screening 
Period and Double-Blind Treatment Period 
Section 8.1.1.1 Footnotes for Table 1, footnote 4 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 10 of 113 
 
CONFIDENTIAL 
Change 
Section Changed 
Made the following changes to the Schedule of Events: 
• 
Added a column to the Schedule of Events 
specifying procedures for an Early Termination 
Visit that occurs during the 12-week safety 
follow-up period 
• 
Changed collection of blood samples for FBR 
and DNA and RNA extraction from mandatory 
to optional. 
• 
Changed the Visit Window for Visit 11 (from ±3 
days to ±7 days) for consistency with all other 
study visits requiring an endoscopy procedure. 
• 
Removed TARC analysis at Visit 8, Visit 12, and 
Visit 14 as well as removed Eotaxin-3 collection 
and analysis at Visit 5 
• 
Added respiratory rate to the list of vital signs to 
be collected pre/post dose.  
• 
Specified that the 21-day interval between visit 2 
and visit 3 may be extended for patients whose 
DSQ compliance does not meet eligibility 
criteria (at least 11 daily entries during the 14 
days immediately preceding the planned 
randomization/baseline date), as long as the total 
duration of the screening period does not exceed 
the 85-day maximum. 
• 
Added clarification for the collection of TNSS, 
POEM, ACQ-5 and RQLQ(S)+12 PROs. 
• 
Deleted reference to monthly visits from the 
Study Flow Diagram (Figure 1) for clarity. 
• 
Clarified the visit window for Self-
Administration of Study Drug at Home 
Section 5.1.1.1 Screening (Up to 12 Weeks) 
Figure 1 Study Flow Diagram  
Section 5.1.1.3 Placebo-Controlled Double-Blind 
Treatment Period (24 Weeks) 
Table 1 Parts A and B Schedule of Events – Screening 
Period and Double-Blind Treatment Period 
Table 2 Part C Schedule of Events – Extended Active 
Treatment Period 
Table 3 Follow-Up Period, Early Termination Visit, 
and Unscheduled Visit 
Section 8.1.1.1 Footnotes for Table 1, footnotes 6, 11, 
13, 17 
Section 8.1.1.2 Footnotes for Table 2, footnotes 3, 4, 8, 
11, 14 
Section 8.1.1.3 Footnotes for Table 3, footnote 5 
Section 8.2.3.1 Vital Signs 
Section 8.2.7 Future Biomedical Research (FBR) 
Serum/Plasma (Optional) 
Section 8.2.7.1 Genomics Substudy (Optional) 
Section 10.4.4.2 Other Safety 
 
Editorial changes were made throughout the protocol for 
further clarification, consistency, and completeness, and, 
if appropriate, correction. 
All references to the “study reference manual” have been 
replaced with 'study regulatory binders.’ 
Clinical Study Protocol Synopsis 
– Endpoints, 
Procedures and Assessments 
Section 4.2.2 Secondary Endpoints 
Section 5.1 Study Description and Duration 
Section 5.1.1.3 Placebo-Controlled Double-Blind 
Treatment Period (24 Weeks) 
Section 6.2.1  Inclusion Criteria for Parts A and B  
Section 7.5.1 Blinding 
Section 8.1.1.1  Footnotes for Table 1, footnote 15 
Section 8.2.2.1 Endoscopy with EoE-EREFS and 
Biopsies, and Photographs 
Section 8.2.2.2  Dysphagia Symptom Questionnaire 
(DSQ) - Patient-reported Outcome (PRO) 
Section 8.2.2.3  EoE Impact Questionnaire (EoE-IQ) 
Section 8.2.3.4  Electrocardiogram 
Section 8.2.3.5  Laboratory Testing 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 11 of 113 
 
CONFIDENTIAL 
Change 
Section Changed 
Section 8.2.6 Pharmacodynamic and Exploratory 
Biomarker Procedures 
Section 9.4.1 Adverse Events 
Section 9.4.2 Serious Adverse Events 
Section 9.4.4 Reporting Adverse Events Leading to 
Withdrawal from the Study 
Section 10.4.4.1 Adverse Events 
Section 10.4.4.3 Treatment Exposure 
Section 10.4.6 Analysis of Anti-Drug Antibody Data 
 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 12 of 113 
 
CONFIDENTIAL 
Amendment 1 
The following table outlines the changes made to the protocol and the affected sections: 
Change 
Section Changed 
Added an exclusion criterion:  known systemic 
hypersensitivity to dupilumab or the excipients of the drug 
product 
Section 6.2.2 Exclusion Criteria for Parts A and 
B, #34 (added) 
Section 6.2.3 Exclusion Criteria for Part C (the 
Open-Label Treatment Period), #6 (added) 
Exclusion Criterion # 26:  replaced serum creatinine 
threshold with estimated glomerular filtration rate (eGFR). 
Section 6.2.2 Exclusion Criteria for Parts A and 
B, #26 
Exclusion Criterion #27:  replaced the example for severe 
renal conditions of “patients on dialysis” with “severe 
nephrotic syndrome”. 
Section 6.2.2 Exclusion Criteria for Parts A and 
B, #27 
Exclusion Criterion #33:  Added clarification that the 
reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical trial and the preferred 
and usual lifestyle of the patient based on Clinical Trial 
Facilitation Group guideline on contraception. 
Section 6.2.2 Exclusion Criteria for Parts A and 
B, #33 
Clarified criteria for resumption of treatment after study drug 
has been temporarily discontinued because of a severe 
laboratory abnormality.  
Section 7.4.2.2 Reasons for Temporary 
Discontinuation of Study Drug 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 13 of 113 
 
CONFIDENTIAL 
CLINICAL STUDY PROTOCOL SYNOPSIS 
Title 
A Phase 3, Randomized, 3-Part Study to Investigate the Efficacy and Safety of 
Dupilumab in Adult and Adolescent Patients with Eosinophilic Esophagitis 
(EoE) 
Site Location(s) 
Global 
Objective(s) 
Primary Objectives 
This study consists of three parts:  Part A and Part B are 24-week treatment, 
randomized, double-blind, placebo-controlled study phases and Part C is a 
28-week, extended active treatment phase that will enroll patients from Part A 
and Part B. 
The primary objectives by study part are: 
• 
Part A: To determine the treatment effect of dupilumab compared 
with placebo in adult and adolescent patients with EoE after 24 weeks 
of treatment as assessed by histological and clinical measures and to 
inform/confirm the final sample size determination for Part B. 
• 
Note:  Patients enrolled in Part A may not participate in Part B. 
• 
Part B: To demonstrate the efficacy of dupilumab treatment compared 
with placebo in adult and adolescent patients with EoE after 24 weeks 
of treatment as assessed by histological and clinical measures. 
• 
Part C: To assess the safety and efficacy of dupilumab treatment in 
adult and adolescent patients with EoE after up to 52 weeks of 
treatment as assessed by histological and clinical measures. 
Secondary Objectives 
• 
To evaluate the safety, tolerability, and immunogenicity of 
dupilumab treatment for up to 52 weeks in adult and adolescent 
patients with EoE 
• 
To explore the relationship between dupilumab concentration and 
responses in adult and adolescent patients with EoE, using 
descriptive analyses 
• 
To evaluate the effects of dupilumab on transcriptomic signatures 
associated with EoE and type 2 inflammation  
• 
To demonstrate the efficacy of dupilumab treatment compared to 
placebo after 24 weeks and 52 weeks of treatment in adult and 
adolescent patients with EoE who have previously received 
swallowed topical corticosteroids 
Study Design 
Part A 
Screening (Up to 12 Weeks) 
After obtaining informed consent/assent, patients will initially be assessed for 
study eligibility at visit 1. 
Study participants are required to have a conﬁrmed diagnosis of EoE which 
may be established either by a prior historical biopsy or by biopsies performed 
during the screening period. 
All patients meeting clinical and laboratory eligibility criteria will undergo 
endoscopy with biopsies at visit 2 to establish a baseline reference measure. For 
patients without a historical biopsy, the visit 2 biopsies will serve as both 
confirmation of EoE diagnosis and the baseline reference measure. All biopsies 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 14 of 113 
 
CONFIDENTIAL 
performed during this study will be evaluated by pathologists at a central 
pathology laboratory who will be blinded to treatment assignment. 
After confirmation of EoE diagnosis, patients will be given an electronic diary 
(eDiary) to begin recording dysphagia symptoms on a daily basis. 
Randomization 
At the baseline visit (visit 3), patients who continue to meet eligibility criteria 
will enter the 24-week placebo-controlled, double-blind treatment period and 
will be randomized in a 1:1 ratio to dupilumab 300 mg once weekly (QW) or 
placebo administered subcutaneously (SC). 
Placebo-Controlled Double-Blind Treatment Period (24 Weeks) 
The co-primary endpoints will be assessed at week 24, one week after the last 
dose of study drug during the double-blind treatment period to inform/confirm 
the final sample size determination for Part B. 
At the end of the double-blind treatment visit (week 24), eligible patients in 
Part A may enter a 28-week extended active treatment period (Part C). Patients 
not participating in Part C will enter a 12-week follow-up period. 
Patients enrolled in Part A will not be eligible to participate in Part B. 
Part B 
Enrollment for Part B will begin immediately after the last patient is enrolled 
in Part A. 
Screening (Up to 12 Weeks) 
The screening procedures for Part B are identical to those described above for 
Part A. 
Randomization 
At the baseline visit (visit 3), patients who continue to meet eligibility criteria 
will enter the 24-week double-blind treatment period and will be randomized 
in a 1:1:1 ratio to dupilumab 300 mg QW, dupilumab 300 mg once every two 
weeks (Q2W), or placebo administered SC. 
Placebo-controlled Double-Blind Treatment Period (24 Weeks) 
Procedures for Part B are identical to those for Part A. 
At the end of the double-blind treatment visit (week 24), eligible patients in 
Part B may enter a 28-week extended active treatment period (Part C). Patients 
not participating in Part C will enter a 12-week follow-up period. 
Part C (28-Week Extended Active Treatment Period) 
At the end of the double-blind treatment visit (week 24), eligible patients in 
Part A and Part B may enter a 28-week extended active treatment period where 
all patients will receive active treatment with dupilumab but only patients in 
Part B will be blinded to treatment regimen in Part C. 
Patients from Part A who are randomized to placebo during the double-blind 
treatment period will receive dupilumab 300 mg QW during Part C. Patients 
from Part A who are randomized to dupilumab 300 mg QW during the 
double-blind treatment period will continue to receive dupilumab 300 mg QW 
during Part C. 
Patients from Part B who are randomized to placebo during the double-blind 
treatment period will be re-randomized in a 1:1 ratio to dupilumab 300 mg QW 
or dupilumab 300 mg Q2W.  
Patients randomized to dupilumab 300 mg Q2W will also receive matching 
placebo administered Q2W alternating with dupilumab doses so the injection 
frequency will match the other group for regimen-blinding purposes. All other 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 15 of 113 
 
CONFIDENTIAL 
patients will remain on the same dupilumab dose regimen to which they are 
randomized during the double-blind treatment period. 
Follow-up Period (12 Weeks) 
All patients will be followed up for an additional 12 weeks after completing 
Part C or, if ineligible for Part C, immediately following Part A or B. 
Rescue Treatment  
If medically necessary, rescue medications (systemic and/or swallowed topical 
corticosteroids) or emergency esophageal dilation are allowed in study patients 
in Parts A, B and C. An endoscopy with biopsies will be performed prior to the 
initiation of rescue therapy unless COVID-19 restrictions prohibit this 
procedure. If the endoscopy with biopsies cannot occur due to COVID-19 
restrictions, rescue treatment should not be delayed, and these patients will be 
eligible for Part C. Part C treatment will be initiated per the schedule of events 
and only at an in-clinic visit. Patients receiving rescue therapy may continue to 
receive study drug. They will remain blinded and will be asked to return to the 
clinic for all remaining study treatment visits and participate in all study 
assessments according to the schedule of events. However, they will not 
undergo any scheduled endoscopy/biopsies subsequent to the date of rescue. 
Study Duration 
The duration of the study for a patient (excluding the screening period) is 
approximately 64 weeks. This includes participation in the double-blind and 
extended active treatment part, and the follow-up period. For patients not 
entering Part C, the duration of the study is approximately 36 weeks. 
End of Study Definition 
The end of study is defined as the last visit of the last patient in the study. 
Population 
 
 
Sample Size: 
Part A:  Approximately 80 patients (40 per treatment group). Patients may be 
adults ≥18 years of age or adolescents ≥12 and <18 years of age. 
Part B:  Approximately 210 patients (70 in each treatment group).  
 
Target Population: 
The target population includes adult males and females ≥18 years of age and 
adolescent males and females ≥12 to <18 years of age at the time of study entry 
with EoE. At least 10% of patients enrolled in Part B will be adolescents ≥12 
to <18 years of age. At least 30% of patients enrolled in Part B must have a 
history of prior use of swallowed topical corticosteroids. 
 
Key Eligibility Criteria: 
Key Inclusion Criteria 
• A documented diagnosis of EoE by endoscopic biopsy prior to screening, as 
demonstrated by intraepithelial eosinophilic infiltration (peak cell count 
≥15 eosinophils/high power field [eos/hpf]) from at least one esophageal 
region and performed after at least 8 weeks of treatment with a high dose 
proton pump inhibitor (PPI) regimen. If the patient discontinued PPI 
therapy, the biopsy must have been performed within 2 weeks of the date of 
discontinuation. 
If a prior (historical) endoscopic biopsy meeting these criteria is not 
available (or no prior biopsy is available), patients who meet other clinical 
and laboratory eligibility criteria will undergo treatment with a high dose 
PPI regimen for at least 8 weeks during the screening period before their 
baseline endoscopy/biopsies.  
• Baseline endoscopic biopsies with a demonstration on central reading of 
intraepithelial eosinophilic infiltration (peak cell count ≥15 eos/hpf) in at 
least 2 of the 3 biopsied esophageal regions (proximal, mid, or distal) 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 16 of 113 
 
CONFIDENTIAL 
• History (by patient report) of an average of at least 2 episodes of dysphagia 
(with intake of solids) per week in the 4 weeks prior to screening 
• At least 4 episodes of dysphagia in the 2 weeks prior to baseline, 
documented via eDiary, at least 2 of which require liquids, coughing or 
gagging, vomiting, or medical attention to obtain relief 
• Completed at least 11 of 14 days of the Dysphagia Symptom Questionnaire 
(DSQ) eDiary data entry in the 2 weeks prior to the baseline visit (visit 3) 
• Baseline DSQ score ≥10  
 
Key Exclusion Criteria 
• Body weight ≤40 kg  
• Prior participation in a dupilumab clinical trial, or past or current treatment 
with dupilumab 
• Initiation or change of a food-elimination diet regimen or re-introduction of 
a previously eliminated food group in the 6 weeks prior to screening. 
Patients on a food-elimination diet must remain on the same diet throughout 
the study. 
• Other causes of esophageal eosinophilia or the following conditions:  
hypereosinophilic syndrome and eosinophilic granulomatosis with 
polyangiitis (Churg-Strauss syndrome)  
Note:  Patients with eosinophilic gastroenteritis are eligible, provided they 
meet other eligibility criteria. 
• Active Helicobacter pylori infection 
• History of achalasia, Crohn’s disease, ulcerative colitis, celiac disease, and 
prior esophageal surgery 
• Any esophageal stricture unable to be passed with a standard, diagnostic, 
9 to10 mm upper endoscope or any critical esophageal stricture that requires 
dilation at screening 
• History of bleeding disorders or esophageal varices that, in the opinion of 
the investigator, would put the patient at undue risk for significant 
complications from an endoscopy procedure 
• Treatment with swallowed topical corticosteroids within 8 weeks prior to 
baseline 
Treatment(s) 
 
 
Investigational Drug 
 
Dose/Route/Schedule: 
Part A 
• Dupilumab 300 mg SC QW 
Part B 
• Dupilumab 300 mg SC QW 
• Dupilumab 300 mg SC Q2W 
Part C 
• Dupilumab 300 mg SC QW 
• Dupilumab 300 mg SC Q2W 
 
Placebo 
 
Dose/Route/Schedule: 
• Placebo SC QW (Part A and Part B only) 
• Placebo SC Q2W alternating with Dupilumab Q2W for regimen-blinding 
purposes (Part B and Part C) 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 17 of 113 
 
CONFIDENTIAL 
 
Background Treatment 
 
Dose/Route/Schedule: 
For both Part A and Part B, patients who present at the initial screening visit 
with current use of PPIs initiated prior to screening or during the screening 
period must remain on the same or similar approved dosage regimen for the 
duration of their respective treatment period. Patients who initiate PPI therapy 
during the screening period must remain on the same or similar approved 
dosage regimen for the duration of the treatment period for their respective 
study part. Patients may change to a different approved PPI medication during 
the study. PPI therapy is prohibited for all other patients. 
Endpoint(s) 
 
 
Primary: 
The co-primary endpoints for both Part A and Part B are: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil 
count of ≤6 eos/hpf at week 24 
• Absolute change in DSQ score from baseline to week 24 
 
Key Secondary: 
The key secondary endpoints for both Part A and Part B of the study are: 
• Absolute change in Eosinophilic Esophagitis-Endoscopic Reference Score 
(EoE-EREFS) from baseline to week 24 
• Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) 
from baseline to week 24 
• Absolute change in EoE Grade Score from the Histology Scoring System 
(EoEHSS) from baseline to week 24 
• Absolute change in EoE Stage Score from the EoEHSS from baseline to 
week 24 
 
Other Secondary: 
Other secondary endpoints include the following: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil 
count of <15 eos/hpf at week 24 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil 
count of ≤1 eos/hpf at week 24 
• Percent change in DSQ from baseline to week 24 
• Normalized Enrichment Scores (NES) for the relative change from baseline 
to week 24 in the EoE diagnostic panel (EDP) transcriptome signature 
• NES for the relative change from baseline to week 24 in the type 2 
inflammation transcriptome signature 
• Absolute change from baseline to week 24 in health-related quality of life 
(QOL) as measured by EoE Impact Questionnaire (EoE-IQ) 
• Absolute change from baseline to week 24 in severity and/or frequency of 
EoE symptoms other than dysphagia  
• Proportion of patients who receive rescue medications or procedures during 
the 24-week placebo-controlled treatment period. 
• Absolute change from baseline in esophageal distensibility plateau 
measured by functional lumen imaging, if collected, at week 24. 
Note: All co-primary and secondary endpoints assessed at week 24 will be 
assessed at week 52 as secondary endpoints and summarized with 
descriptive statistics based on the treatment assignment in the double-blind 
treatment period as well as the extended active treatment assignment for 
patients previously in the placebo group. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 18 of 113 
 
CONFIDENTIAL 
Both co-primary and all secondary endpoints will be assessed at week 24 
and week 52 in in adult and adolescent patients with EoE who have 
previously received swallowed topical corticosteroids. 
Procedures and Assessments 
Efficacy assessments include the following: 
• Esophageal endoscopy with biopsies:  Biopsies will be obtained for 
histologic assessments including intraepithelial eosinophil count and 
EoEHSS (EoE Grade Score and EoE Stage Score). Biopsies will be 
evaluated by pathologists at a central pathology laboratory who will be 
blinded to treatment assignment. 
• For Part A enrolled patients, EoE-EREFS scoring will only be performed at 
the time of the endoscopies in Part A and Part C by the investigators who 
are performing the endoscopies (prior to biopsies). For Part B enrolled 
patients, EoE-EREFS scoring will be performed by both the investigators 
who perform the endoscopies in Part B and Part C as well as a centralized 
reading center. The centralized reading will be used for analysis, if available. 
If the centralized reading is not available, the EoE-EREFS performed by the 
investigator will be used for analysis. 
• For all endoscopies, the investigators will assess minor esophageal features 
including mucosal inflammatory and remodeling features. DSQ will be 
completed daily by patients in the eDiary to assess the frequency and 
severity of dysphagia. 
• The EoE-IQ, a disease-specific measure of health-related QOL in EoE 
patients, will be completed by patients at specified time points. 
• The EoE Symptom Questionnaire, a questionnaire measuring the frequency 
and severity of symptoms other than dysphagia and swallowing pain, will 
be completed by patients at specified time points. 
• The endolumenal functional lumen imaging probe (EndoFLIP) procedure 
to measure esophageal distensibility may be performed during the 
esophagogastroscopy procedures at selected North American sites in 
approximately 150 adult patients. 
Safety and tolerability will be assessed by physical examinations, vital signs, 
electrocardiograms (ECGs), clinical laboratory tests, and clinical evaluations. 
Patients will be asked to report all adverse events (AEs) experienced from the 
time of informed consent until their last study visit. 
Pharmacokinetics (PK):  Serum samples will be collected at specified time 
points for assay of dupilumab concentration. 
Anti-drug antibody (ADA):  Serum samples will be collected at specified time 
points for assay of ADA and exploratory analyses. 
Statistical Plan 
Sample Size  
Part A:  The planned sample size for Part A is approximately 40 patients in 
each treatment group. 
Part B:  Based on the Part A study results, the planned sample size for Part B 
is approximately 70 patients in each treatment group such that for the 
comparison of each dupilumab dose regimen to placebo: 
• 
This sample size will yield >99.9% power to detect a treatment difference 
of 55.4% in the proportion of patients achieving peak esophageal 
intraepithelial eosinophil count ≤6 eos/hpf at week 24 between placebo 
(5.1%) and the dupilumab treatment group (59.5%) at a 2-sided 
significance level of 5% using Fisher’s exact test. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 19 of 113 
 
CONFIDENTIAL 
• 
This sample size will provide >99.9% power to detect a treatment 
difference of -12.3 points in the mean change from baseline in the total 
DSQ score to week 24 at a 2-sided significance level of 5% using a two-
sample t-test, assuming a common standard deviation (SD) of 15.013.0. 
Therefore, the sample size of  70 patients/arm will provide an overall power 
of >99.9% (99.9% × 99.9%) for the co-primary endpoints, assuming no 
negative correlation between the two endpoints. In Part B, the same treatment 
effect for the two 300 mg dupilumab dose regimens (ie, QW and Q2W) is 
assumed. 
Efficacy Analysis Sets 
For Part A and Part B, the efficacy endpoints will be analyzed using the 
study-part-specific full analysis set (FAS) that includes all randomized patients 
in the corresponding study part. 
The efficacy endpoints in Part C (the extended active treatment period) will be 
summarized for all patients who received any extended active treatment study 
drug in that part. 
Safety Analysis Set 
For Part A and Part B, the study-part-specific safety analysis set (SAF) includes 
all randomized patients who received any study drug in the corresponding study 
part; it is based on the treatment received (as treated). Treatment 
compliance/administration and all clinical safety variables will be analyzed 
using the SAF. 
For safety analyses of the Part C extended treatment period, only a subset of 
SAF will be included, which is defined as those patients who received at least 
1 dose of Part C study drug. 
Statistical Analysis  
All statistical analyses will be conducted separately for Part A and Part B. 
Primary Efficacy Analysis (Part A and Part B): 
The co-primary endpoint of proportion of patients achieving a histologic 
response of peak esophageal intraepithelial eosinophil count ≤6 eos/hpf at 
week 24 will be analyzed using the Cochran-Mantel-Haenszel (CMH) test to 
assess the difference in the proportion of responders in the FAS, adjusting for 
the randomization stratification factors. 
The co-primary endpoint of absolute change from baseline in the DSQ total 
score at week 24 will be analyzed using an analysis of covariance (ANCOVA) 
model for the FAS with treatment group, randomization stratification factor, 
and relevant baseline measurement as covariates included in the model. 
To account for use of rescue treatment in the primary analysis, for peak 
esophageal intraepithelial eosinophil count of ≤6 eos/hpf, patients will be 
considered as non-responders after the use of rescue treatment. For absolute 
change from baseline in the DSQ total score, data will be imputed using 
multiple imputation (MI) for all time points subsequent to the use of rescue 
treatment.  
If a patient has missing value for the histological response (peak esophageal 
intraepithelial eosinophil count ≤6 eos/hpf) at week 24, the patient will be 
classified as a non-responder at week 24. 
If a patient has missing value for the DSQ total score at week 24, the missing 
data will be imputed by MI based on similar patients who remained in the trial 
with observed values relevant to analysis. Similarity is based on randomized 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 20 of 113 
 
CONFIDENTIAL 
treatment group, baseline value, stratification factors, and available post-
baseline values. 
Sensitivity analyses will assess alternative methods to impute missing data. For 
the eosinophil responder analysis, sensitivity methods may include utilizing 
peak eosinophil values from imputations to determine responder status. 
Sensitivity analyses will also include an analysis without setting data 
post-rescue to missing. 
Secondary Efficacy Analysis (Part A and Part B):  
Secondary efficacy endpoints will be analyzed in the same fashion as the 
co-primary endpoints depending on the type of data, unless otherwise specified.  
For continuous efficacy data that are scheduled to be measured only once 
post-baseline at week 24, missing values at week 24 will be imputed with 
patient’s baseline value or the available post-baseline value, whichever is 
worse, ie, a worst observation carried forward (WOCF) approach. 
Subgroup analysis (eg, by age group) will also be performed. 
Secondary Efficacy Analysis (Part C):  
Efficacy endpoints in Part C will be summarized with descriptive statistics by 
treatment received in Part C. Inferential statistics will only be provided as 
needed. 
Multiplicity Considerations: 
Part A and Part B will have separate and independent 2-sided alpha level of 
0.05. 
Part A:  Statistical significance of the co-primary endpoints at the 2-sided 
Type I error rate of 5% will be required before drawing inferential conclusions 
about any secondary efficacy endpoints.  
Part B:  The co-primary endpoints will be tested for the comparison of 
dupilumab QW dose regimen to placebo first and if both endpoints are 
statistically significant, the testing will proceed to the co-primary endpoints of 
dupilumab Q2W, or the secondary endpoints of dupilumab QW, with the exact 
order to be specified in Part B statistical analysis plan (SAP). 
Safety Analysis: 
Safety analysis will be based on the SAF. This includes reported 
treatment-emergent AEs (TEAEs) and other safety data (ie, clinical laboratory 
evaluations, vital signs, and 12-lead ECG results). A descriptive summary of 
safety results will be presented by treatment group for each study part. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 21 of 113 
 
CONFIDENTIAL 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Ab 
Antibody 
ACQ-5 
Asthma Control Questionnaire-5 
AD 
Atopic dermatitis 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BID 
Twice (two times) a day 
BUN 
Blood urea nitrogen 
CCL 
Chemokine (C-C motif) ligand 
CMH 
Cochran-Mantel-Haenszel (test) 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
Ctrough 
Trough concentration 
DMC 
Data monitoring committee 
DSQ 
Dysphagia Symptom Questionnaire 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EDP 
EoE Diagnostic Panel  
eGFR 
Estimated glomerular filtration rate 
EndoFLIP 
Endolumenal functional lumen imaging probe 
EoE 
Eosinophilic esophagitis 
EoE-EREFS 
Eosinophilic Esophagitis-Endoscopic Reference Score 
EoEHSS 
EoE Histology Scoring System 
EoE-IQ 
EoE Impact Questionnaire 
EOS 
End of study (visit) 
eos/hpf 
Eosinophils/high power field 
EOT 
End of treatment 
EQ-5D-3L 
European Quality of Life 5-dimension (version 3L; 3-level) 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 22 of 113 
 
CONFIDENTIAL 
ET 
Early termination 
 
 
EU 
European Union 
FAS 
Full analysis set 
FBR 
Future biomedical research 
FLG 
Filaggrin 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
IA 
Interim analysis 
IAF 
Informed assent form 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IFN-γ 
Interferon-gamma 
IgE 
Immunoglobulin E 
IgG4 
Immunoglobulin G4 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IL-4Rα 
Interleukin-4 receptor alpha 
IRB 
Institutional Review Board 
ISR 
Injection site reaction 
IVRS/IWRS 
Interactive voice/web response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation  
MMRM 
Mixed-effect model repeated measure 
NES 
Normalized Enrichment Scores  
OIT 
Oral immunotherapy 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 23 of 113 
 
CONFIDENTIAL 
PCSV 
Potentially clinically significant value 
PGIC 
Patient Global Impression of Change of Dysphagia 
PGIS 
Patient Global Impression of Severity of Dysphagia 
PK 
Pharmacokinetic 
POEM 
Patient-Oriented Eczema Measure 
PPI 
Proton pump inhibitor 
PPS 
Per protocol set 
PRO 
Patient-reported outcome 
PT 
Preferred term (MedDRA) 
PVRM 
Pharmacovigilance and Risk Management 
QD 
Once a day 
QOL 
Quality of life 
Q2W 
Once every two weeks 
QW 
Once weekly 
RBC 
Red blood cell 
RQLQ(s)+12 
Rhinoconjunctivitis Quality of Life Questionnaires for 12 years and older 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SCIT 
Subcutaneous immunotherapy 
SD 
Standard deviation 
SLIT 
Sublingual immunotherapy 
SOC 
System organ class 
SPRR3 
Small proline-rich protein 3 
SUSAR 
Suspected unexpected serious adverse reaction 
TARC 
Thymus and activation-regulated chemokine 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
Th2 
Type 2 helper T cell 
TNSS 
Total Nasal Symptom Score 
TSLP 
Thymic stromal lymphopoietin 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCF 
Worst observation carried forward 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 24 of 113 
 
CONFIDENTIAL 
TABLE OF CONTENTS 
AMENDMENT HISTORY .............................................................................................................2 
CLINICAL STUDY PROTOCOL SYNOPSIS.............................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................21 
1. 
INTRODUCTION ......................................................................................................31 
2. 
STUDY OBJECTIVES ..............................................................................................33 
2.1. 
Primary Objectives .....................................................................................................33 
2.2. 
Secondary Objectives .................................................................................................33 
3. 
HYPOTHESIS AND RATIONALE ..........................................................................33 
3.1. 
Hypothesis ..................................................................................................................33 
3.2. 
Rationale .....................................................................................................................34 
3.2.1. 
Rationale for Study Design .........................................................................................34 
3.2.2. 
Rationale for Dose Selection ......................................................................................35 
3.2.3. 
Risk/Benefits of Participating in the Study ................................................................36 
3.2.3.1. 
Benefits .......................................................................................................................36 
3.2.3.2. 
Risks ...........................................................................................................................37 
3.2.3.3. 
Benefit/Risk Conclusion .............................................................................................37 
4. 
STUDY VARIABLES................................................................................................37 
4.1. 
Demographic and Baseline Characteristics ................................................................37 
4.2. 
Primary and Secondary Endpoints..............................................................................38 
4.2.1. 
Primary Endpoints ......................................................................................................38 
4.2.2. 
Secondary Endpoints ..................................................................................................38 
4.3. 
Pharmacokinetic Variables .........................................................................................39 
4.4. 
Anti-Drug Antibody Variables ...................................................................................39 
5. 
STUDY DESIGN .......................................................................................................39 
5.1. 
Study Description and Duration .................................................................................39 
5.1.1. 
Part A ..........................................................................................................................42 
5.1.1.1. 
Screening (Up to 12 Weeks) .......................................................................................42 
5.1.1.2. 
Randomization ............................................................................................................43 
5.1.1.3. 
Placebo-Controlled Double-Blind Treatment Period (24 Weeks) ..............................43 
5.1.2. 
Part B ..........................................................................................................................44 
5.1.2.1. 
Screening (Up to 12 Weeks) .......................................................................................44 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 25 of 113 
 
CONFIDENTIAL 
5.1.2.2. 
Randomization ............................................................................................................44 
5.1.2.3. 
Placebo-Controlled Double-Blind Treatment Period (24 Weeks) ..............................44 
5.1.3. 
Part C (28-Week Extended Active Treatment Period) ...............................................45 
5.1.4. 
Follow-Up Period (12 Weeks) ....................................................................................45 
5.1.5. 
End of Study Definition ..............................................................................................45 
5.2. 
Planned Interim Analysis ............................................................................................45 
5.3. 
Study Committees .......................................................................................................45 
5.3.1. 
Independent Data Monitoring Committee ..................................................................45 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF PATIENTS ..............46 
6.1. 
Number of Patients Planned .......................................................................................46 
6.2. 
Study Population .........................................................................................................46 
6.2.1. 
Inclusion Criteria for Parts A and B ...........................................................................46 
6.2.2. 
Exclusion Criteria for Parts A and B ..........................................................................47 
6.2.3. 
Exclusion Criteria for Part C (the Extended Active Treatment Period) .....................51 
6.3. 
Premature Withdrawal from the Study .......................................................................51 
6.4. 
Replacement of Patient ...............................................................................................51 
7. 
STUDY TREATMENTS............................................................................................52 
7.1. 
Investigational and Reference Treatments ..................................................................52 
7.2. 
Background Treatment ...............................................................................................52 
7.3. 
Rescue Treatments ......................................................................................................53 
7.4. 
Dose Modification and Study Treatment Discontinuation Rules ...............................53 
7.4.1. 
Dose Modification ......................................................................................................53 
7.4.2. 
Study Drug Discontinuation .......................................................................................53 
7.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug .............................................53 
7.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug ............................................54 
7.5. 
Method of Treatment Assignment ..............................................................................55 
7.5.1. 
Blinding ......................................................................................................................55 
7.5.2. 
Emergency Unblinding ...............................................................................................56 
7.5.3. 
Unblinding for Regulatory Reporting Purposes .........................................................56 
7.6. 
Treatment Logistics and Accountability .....................................................................56 
7.6.1. 
Packaging, Labeling, and Storage ..............................................................................56 
7.6.2. 
Supply and Disposition of Treatments .......................................................................56 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 26 of 113 
 
CONFIDENTIAL 
7.6.3. 
Treatment Accountability ...........................................................................................57 
7.6.4. 
Treatment Compliance ................................................................................................57 
7.7. 
Concomitant Medications and Procedures .................................................................57 
7.7.1. 
Prohibited Medications and Procedures .....................................................................57 
7.7.2. 
Permitted Medications and Procedures ......................................................................58 
7.7.3. 
Restricted Medications and Procedures during the Follow-Up Period ......................58 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES ......................................59 
8.1. 
Schedule of Events .....................................................................................................59 
8.1.1. 
Footnotes for the Schedule of Events Tables .............................................................66 
8.1.1.1. 
Footnotes for Table 1 ..................................................................................................66 
8.1.1.2. 
Footnotes for Table 2 ..................................................................................................68 
8.1.1.3. 
Footnotes for Table 3 ..................................................................................................70 
8.1.2. 
Early Termination Visit ..............................................................................................71 
8.1.3. 
Unscheduled Visits before Rescue Treatment ............................................................71 
8.1.4. 
Unscheduled Visits for Other Reasons .......................................................................71 
8.2. 
Study Procedures ........................................................................................................72 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit .....................................72 
8.2.2. 
Efficacy Procedures ....................................................................................................72 
8.2.2.1. 
Endoscopy with EoE-EREFS and Biopsies, and Photographs ...................................72 
8.2.2.2. 
Dysphagia Symptom Questionnaire (DSQ) - Patient-reported Outcome 
(PRO) ..........................................................................................................................74 
8.2.2.3. 
EoE Impact Questionnaire (EoE-IQ) ..........................................................................75 
8.2.2.4. 
EoE Symptom Questionnaire .....................................................................................75 
8.2.2.5. 
Patient Global Impression of Change (PGIC) of Dysphagia ......................................75 
8.2.2.6. 
Patient Global Impression of Severity (PGIS) of Dysphagia .....................................76 
8.2.2.7. 
Total Nasal Symptom Score (TNSS) ..........................................................................76 
8.2.2.8. 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire for ages 12+ 
[RQLQ(S)+12] ............................................................................................................76 
8.2.2.9. 
Juniper Asthma Control Questionnaire (ACQ) ..........................................................77 
8.2.2.10. 
Patient-Oriented Eczema Measure (POEM) ...............................................................77 
8.2.2.11. 
European Quality of Life 5-Dimensional Scale (EQ-5D) ..........................................78 
8.2.3. 
Safety Procedures .......................................................................................................78 
8.2.3.1. 
Vital Signs ..................................................................................................................78 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 27 of 113 
 
CONFIDENTIAL 
8.2.3.2. 
Physical Examination .................................................................................................78 
8.2.3.3. 
Body Weight and Height ............................................................................................78 
8.2.3.4. 
Electrocardiogram .......................................................................................................78 
8.2.3.5. 
Laboratory Testing ......................................................................................................78 
8.2.4. 
Drug Concentration and Measurements .....................................................................80 
8.2.5. 
Anti-Drug Antibody Measurements and Samples ......................................................80 
8.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures .......................................80 
8.2.6.1. 
EoE Diagnostic Panel and Type 2 Inflammation Transcriptomics ............................80 
8.2.6.2. 
Type 2 Inflammatory and Disease-Related Circulating Biomarkers ..........................81 
8.2.7. 
Future Biomedical Research (FBR) Serum/Plasma (Optional) ..................................82 
8.2.7.1. 
Genomics Substudy (Optional) ...................................................................................82 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING .............................83 
9.1. 
Obligations of Investigator .........................................................................................83 
9.2. 
Obligations of Sponsor ...............................................................................................83 
9.3. 
Definitions ..................................................................................................................83 
9.3.1. 
Adverse Event .............................................................................................................83 
9.3.2. 
Serious Adverse Event ................................................................................................83 
9.3.3. 
Adverse Events of Special Interest .............................................................................84 
9.4. 
Recording and Reporting Adverse Events ..................................................................84 
9.4.1. 
Adverse Events ...........................................................................................................84 
9.4.2. 
Serious Adverse Events ..............................................................................................84 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor ...................................85 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study ...........................86 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results .............................86 
9.4.6. 
Follow-up ....................................................................................................................86 
9.5. 
Evaluation of Severity and Causality .........................................................................86 
9.5.1. 
Evaluation of Severity ................................................................................................86 
9.5.2. 
Evaluation of Causality ...............................................................................................87 
9.6. 
Safety Monitoring .......................................................................................................88 
9.7. 
Investigator Alert Notification ....................................................................................89 
10. 
STATISTICAL PLAN................................................................................................89 
10.1. 
Statistical Hypothesis ..................................................................................................89 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 28 of 113 
 
CONFIDENTIAL 
10.2. 
Justification of Sample Size........................................................................................89 
10.3. 
Analysis Sets ...............................................................................................................91 
10.3.1. 
Efficacy Analysis Sets ................................................................................................91 
10.3.2. 
Safety Analysis Set .....................................................................................................91 
10.3.3. 
Pharmacokinetic Analysis Sets ...................................................................................91 
10.3.4. 
Anti-Drug Antibody Analysis Sets .............................................................................91 
10.4. 
Statistical Methods ......................................................................................................91 
10.4.1. 
Patient Disposition ......................................................................................................92 
10.4.2. 
Demography and Baseline Characteristics .................................................................92 
10.4.3. 
Efficacy Analyses .......................................................................................................92 
10.4.3.1. 
Primary Efficacy Analysis ..........................................................................................92 
10.4.3.2. 
Secondary Efficacy Analysis ......................................................................................94 
10.4.3.3. 
Multiplicity Considerations ........................................................................................96 
10.4.4. 
Safety Analysis ...........................................................................................................97 
10.4.4.1. 
Adverse Events ...........................................................................................................97 
10.4.4.2. 
Other Safety ................................................................................................................98 
10.4.4.3. 
Treatment Exposure ....................................................................................................98 
10.4.4.4. 
Treatment Compliance ................................................................................................99 
10.4.5. 
Pharmacokinetics ........................................................................................................99 
10.4.5.1. 
Analysis of Drug Concentration Data .........................................................................99 
10.4.6. 
Analysis of Anti-Drug Antibody Data ........................................................................99 
10.4.7. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data ..............................99 
10.4.8. 
Analysis of Quality of Life Data ................................................................................99 
10.4.9. 
Timing of Statistical Analysis ....................................................................................99 
10.5. 
Additional Statistical Data Handling Conventions ...................................................100 
10.6. 
Statistical Considerations Surrounding the Premature Termination of a Study .......100 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS ...................................100 
11.1. 
Data Management .....................................................................................................100 
11.2. 
Electronic Systems ....................................................................................................101 
12. 
STUDY MONITORING ..........................................................................................101 
12.1. 
Monitoring of Study Sites .........................................................................................101 
12.2. 
Source Document Requirements ..............................................................................101 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 29 of 113 
 
CONFIDENTIAL 
12.3. 
Case Report Form Requirements ..............................................................................102 
13. 
AUDITS AND INSPECTIONS ...............................................................................102 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................102 
14.1. 
Good Clinical Practice Statement .............................................................................102 
14.2. 
Informed Consent .....................................................................................................103 
14.3. 
Patients Confidentiality and Data Protection ............................................................103 
14.4. 
Institutional Review Board/Ethics Committee .........................................................104 
15. 
PROTOCOL AMENDMENTS ................................................................................104 
16. 
PREMATURE TERMINATION OF THE STUDY OR CLOSE-OUT OF A 
SITE ..........................................................................................................................104 
16.1. 
Premature Termination of the Study .........................................................................104 
16.2. 
Close-out of a Site ....................................................................................................105 
17. 
STUDY DOCUMENTATION .................................................................................105 
17.1. 
Certification of Accuracy of Data .............................................................................105 
17.2. 
Retention of Records ................................................................................................105 
18. 
DATA QUALITY ASSURANCE ............................................................................106 
19. 
CONFIDENTIALITY ..............................................................................................106 
20. 
FINANCING AND INSURANCE ...........................................................................106 
21. 
PUBLICATION POLICY ........................................................................................107 
22. 
REFERENCES .........................................................................................................107 
23. 
INVESTIGATOR’S AGREEMENT ........................................................................112 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS ...................................................113 
 
LIST OF TABLES 
Table 1: 
Parts A and B Schedule of Events – Screening Period and Double-Blind 
Treatment Period ........................................................................................................60 
Table 2: 
Part C Schedule of Events – Extended Active Treatment Period ...............................62 
Table 3: 
Follow-up Period, Early Termination Visit, and Unscheduled Visit ..........................64 
Table 4: 
Summary of Primary Estimand for Co-primary Endpoints ........................................93 
Table 5: 
Summary of Primary Estimand for Key Secondary Endpoints ..................................95 
 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 30 of 113 
 
CONFIDENTIAL 
LIST OF FIGURES 
Figure 1: 
Study Flow Diagram ...................................................................................................40 
Figure 2: 
Study Design ...............................................................................................................41 
Figure 3: 
Endoscopy/Biopsy Procedure Flow Diagram .............................................................43 
 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 31 of 113 
 
CONFIDENTIAL 
1. 
INTRODUCTION 
Eosinophilic esophagitis (EoE) is a chronic, inflammatory, allergic/immune-mediated disease of 
the esophagus. The disease is characterized by local eosinophilic inflammation leading to 
symptoms of esophageal dysfunction (Furuta, 2017) (Liacouras, 2011) (DeBrosse, 2011) 
(Falk, 2014). Although considered a rare disease, the current prevalence is estimated at 22.7 per 
100,000 worldwide (Arias, 2016) and appears to be on the increase (Dellon, 2014a). Eosinophilic 
esophagitis has been reported in all ages; however, most cases are in children and adults younger 
than 50 years (Dellon, 2014a) (Dellon, 2014b) (Dellon, 2007) (Kapel, 2008) (Liacouras, 2011) 
(Spergel, 2009). Gender differences in EoE have been consistently reported, with males affected 
3 to 4 times more often than females (Dellon, 2014a), but there are no gender-related differences 
in the clinical symptoms (Kapel, 2008) (Prasad, 2009) (Veerappan, 2009) (Hruz, 2011) 
(Ally, 2015). 
The primary clinical manifestations of EoE in both adults and children over 10 years of age are 
dysphagia and food impaction (Lucendo, 2017). These symptoms lead to substantially impaired 
quality of life (QOL) (DeBrosse, 2011) (Falk, 2014) (Straumann, 2008) (Straumann, 2003). 
Endoscopic findings are related to the inflammation in the esophagus and consist of fixed or 
transient concentric rings, longitudinal furrows, white plaques, reduced mucosal vascularity, 
fragile or crepe-like mucosa, and strictures. Rings and furrows are the most common, seen in nearly 
half of patients (Singla, 2016). 
Growing evidence suggests that a Type 2 cytokine-mediated immune response plays an important 
role in the development of EoE. This is thought to occur by provoking chronic eosinophil, mast 
cell, T cell, and lymphocyte-induced inflammation via cytokines known to regulate eosinophilic 
accumulation in the esophagus, such as interleukin (IL)-4, IL-5, IL-13, and eotaxin-1, -2, and -3 
(Abonia, 2010) (Abonia, 2012) (Blanchard, 2006) (Blanchard, 2008) (Blanchard, 2010) 
(Bullock, 2007) (Mishra, 2003) (Mishra, 2009`) (Straumann, 2001). Th2 cells are a subgroup of 
the T cells that regulate the activity of other immune cells by releasing Type 2 cytokines. IL-13 
has been found to be upregulated in the esophageal epithelium of EoE patients (Blanchard, 2007). 
The induction of eotaxin-3, an eosinophil chemoattractant, is thought to be an important factor in 
EoE pathogenesis (Blanchard, 2006) (Blanchard, 2007). The 2 most up-regulated genes in 
esophageal biopsies from EoE patients (compared to normal controls) encode eotaxin-3 and 
periostin, another protein induced by Type 2 cytokines and thought to promote inflammation and 
remodeling (Blanchard, 2006) (Blanchard, 2008). Furthermore, esophageal biopsies and blood 
samples of patients with active EoE have increased levels of cytokines and chemokines associated 
with Type 2 inflammation, including IL-4 and IL-13, thymic and stromal lymphopoeitin (TSLP), 
and eotaxin-3 secreted by the typical cells involved in allergic inflammation:  T cells, mast cells, 
basophils, invariant natural killer T cells (iNKTs), and esophageal epithelial cells. Mutations in 
the eotaxin-3 and TSLP genes, whose functions propagate Type 2 inflammation, have been 
associated with EoE risk (Cianferoni, 2016). 
Impaired barrier function of the esophageal epithelium is thought to play a role in EoE 
pathogenesis. Several genes in the epidermal differentiation complex, known to be down-regulated 
by Type 2 cytokines with resultant barrier dysfunction of the skin, are also down-regulated in 
primary esophageal epithelial cells in vitro. Furthermore, decreased mRNA expression of the 
epidermal differentiation complex gene filaggrin (FLG), and the esophagus-specific esophagin 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 32 of 113 
 
CONFIDENTIAL 
(small proline-rich protein 3 [SPRR3]), was observed in esophageal biopsies from EoE patients 
compared to normal controls (Blanchard, 2010). The increased frequency at which FLG null alleles 
were found in EoE patients compared to controls provides further evidence of the barrier 
hypothesis in EoE (Blanchard, 2010). It is also known that FLG mRNA expression is directly 
suppressed by IL-4 and IL-13 in keratinocytes (Howell, 2007). The data suggest that Type 2 
cytokines may be driving not only an inflammatory response, but also epithelial barrier 
dysfunction in the esophagus. 
Consistent with the Type 2-mediated inflammation observed in esophageal tissue, patients with 
EoE have high rates of comorbid allergic diseases which are also associated with enhanced IL-4 
and IL-13 signaling, especially food allergies, atopic dermatitis (AD), asthma, and allergic rhinitis 
(Arora, 2012) (Assa’ad, 2008) (Liacouras, 2011) (Moawad, 2010) (Roy-Ghanta, 2008) 
(Weinbrand-Goichberg, 2013).  
The inflammatory damage to the esophageal epithelium results in symptoms of esophageal 
dysfunction, such as dysphagia. Chronic inflammation of the esophagus may also lead to 
remodeling, stricture formation, and fibrosis (Hirano, 2014). The fibrotic aspect of progressed 
disease is not well understood, and whether or not this can be reversed with treatment is unknown. 
Current therapeutic approaches include chronic dietary elimination, swallowed topical formulation 
corticosteroids (not approved for the treatment of EoE outside the European Union [EU]), and 
esophageal dilation. Emergency endoscopy for prolonged and/or painful food impaction is 
associated with a risk of severe esophageal injury and does not alter the underlying pathogenesis 
or progression of the disease. Although swallowed topical corticosteroids have been reported in 
clinical trials to induce partial clinical responses and histologic remission, they are not uniformly 
effective and can be associated with fungal infections as well as disease recurrence after 
discontinuation. 
Dupilumab is a human monoclonal immunoglobulin G4 (IgG4) antibody (Ab) that inhibits IL-4 
and IL-13 signaling by specifically binding to the IL-4 receptor alpha (IL-4Rα) subunit shared by 
the IL-4 and IL-13 receptor complexes. Blocking IL-4Rα with dupilumab inhibits IL-4 and IL-13 
Type 2 cytokine-induced responses, including the release of pro-inflammatory cytokines, 
chemokines, and IgE. Additionally, preclinical data demonstrate that treatment with dupilumab 
prevents infiltration of eosinophils into tissues. For these reasons, dupilumab was evaluated in 
adult patients with EoE in a phase 2, multicenter, double-blind, randomized, placebo-controlled 
study (R668-EE-1324), where it demonstrated substantial improvements in clinical, histologic, 
and endoscopic aspects of the disease. Dupilumab was well tolerated in the study, with safety data 
generally consistent with other dupilumab studies in AD patients and no particular safety signal 
associated with use in the EoE patient population. The results support the phase 3 evaluation of 
dupilumab in EoE. 
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 33 of 113 
 
CONFIDENTIAL 
2. 
STUDY OBJECTIVES  
2.1. 
Primary Objectives 
The primary objectives of the study by study part are: 
• Part A: To determine the treatment effect of dupilumab compared with placebo in 
adult and adolescent patients with EoE after 24 weeks of treatment as assessed by 
histological and clinical measures, and to inform/confirm the final sample size 
determination for Part B. 
• Part B: To demonstrate the efficacy of dupilumab treatment compared with placebo 
in adult and adolescent patients with EoE after 24 weeks of treatment as assessed by 
histological and clinical measures. 
• Part C: To assess the safety and efficacy of dupilumab treatment in adult and 
adolescent patients with EoE after up to 52 weeks of treatment as assessed by 
histological and clinical measures. 
2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• To evaluate the safety, tolerability, and immunogenicity of dupilumab treatment for up 
to 52 weeks in adult and adolescent patients with EoE 
• To explore the relationship between dupilumab concentration and responses in adult 
and adolescent patients with EoE, using descriptive analyses 
• To evaluate the effects of dupilumab on transcriptomic signatures associated with 
EoE and type 2 inflammation  
• To demonstrate the efficacy of dupilumab treatment compared to placebo after 
24 weeks and 52 weeks of treatment in adult and adolescent patients with EoE who 
have previously received swallowed topical corticosteroids 
3. 
HYPOTHESIS AND RATIONALE  
3.1. 
Hypothesis 
In adult and adolescent patients ≥12 years of age with EoE, treatment with dupilumab will result 
in a statistically significant benefit compared to treatment with placebo, as measured by: 
• Relief of dysphagia, assessed by change in the Dysphagia Symptom Questionnaire 
(DSQ) score. 
• Reduction in eosinophilic esophageal infiltration, assessed by change in esophageal 
intraepithelial eosinophil count 
• Improvement in endoscopically identified esophageal mucosal inflammatory and 
remodeling features, assessed by change in the Eosinophilic Esophagitis-Endoscopic 
Reference Score (EoE-EREFS) 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 34 of 113 
 
CONFIDENTIAL 
3.2. 
Rationale  
3.2.1. 
Rationale for Study Design 
The study is divided into 3 parts:   
• Part A consists of a screening period of up to 12 weeks, followed by a randomized, 
double-blind, placebo-controlled, 2-arm, parallel-group, 24-week treatment period. 
Patients who complete Part A will either enter Part C or continue to a 12-week follow-
up period (for patients who do not go on to Part C). 
• Part B consists of a screening period of up to 12 weeks, followed by a randomized, 
double-blind, placebo-controlled, 3-arm, parallel-group, 24-week treatment period. 
Patients who complete Part B will either enter Part C or continue to a 12-week follow-
up period (for patients who do not go on to Part C). Enrollment in Part B will begin 
immediately after the last patient has been randomized in Part A. 
• Part C is an extended active treatment period and consists of a 2-arm, 28-week 
treatment period. Patients who complete Part C will continue to a 12-week follow-up 
period. 
The co-primary endpoints selected for Parts A and B of the study (proportion of patients achieving 
peak esophageal intraepithelial eosinophil count of ≤6 eos/high power field [hpf] at week 24 and 
change in DSQ score from baseline to week 24) assess important clinical and histological measures 
of dysphagia symptoms and disease activity and progression. Eosinophilic infiltration of the 
esophageal mucosa is the hallmark of the disease and, in conjunction with characteristic clinical 
symptoms of esophageal dysfunction (solid food dysphagia, food impaction), is considered 
pathognomonic for EoE.  
Solid food dysphagia is the most common presenting symptom of EoE and food impaction 
necessitating endoscopic bolus removal occurs in 33% to 54% of adult EoE patients 
(Dellon, 2013). The DSQ is a daily patient-reported outcome (PRO) measure that has been 
validated for the measurement of dysphagia frequency and severity in patients with EoE 
(Dellon, 2013) (Hudgens, 2017). The questions ask whether solid food has been eaten; whether 
food has gone down slowly or become stuck; and what, if any, measures have been taken to achieve 
relief. 
Since the gross appearance of the esophageal mucosa assessed by endoscopy reflects both the 
inflammatory and fibrotic nature of the disease, EoE-EREFS is a key secondary endpoint. The 
EoE-EREFS is a validated classiﬁcation and grading system designed to standardize nomenclature 
for the major endoscopically identiﬁed esophageal features of EoE (edema, rings, exudates, 
furrows, and strictures) (Hirano, 2013). Recent studies have demonstrated the clinical relevance 
of endoscopic severity assessment in EoE. The severity of each of the EoE-EREFS subscores has 
been shown to be associated with patient-reported global symptom activity (Schoepfer, 2014). The 
use of a visual endoscopy score is consistent with the emphasis on endoscopic mucosal healing as 
a primary endpoint of therapeutics in inflammatory bowel disease, peptide ulcer disease and 
GERD (Hirano, 2017). 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 35 of 113 
 
CONFIDENTIAL 
The study will include adolescents ≥12 years of age. The primary clinical manifestation of EoE in 
children and adolescents ≥10 years of age is dysphagia and food impaction, similar to adult patients 
(Lucendo, 2017). In addition, the disease appears to have the same underlying pathophysiology 
regardless of age; similar high rates of atopy as well as a genetic predisposition have been 
demonstrated in both the pediatric and adult populations. A unique genetic signature for EoE has 
been identified that is conserved in all patients with the disease, suggesting the biological 
manifestations of disease are the same across all age groups (Blanchard, 2006). Additional work 
demonstrated that a transcriptome of 96 genes in EoE patients was similar between both adults and 
children (Wen, 2013). 
Study treatment will be administered for approximately 24 weeks in the double-blind, placebo-
controlled phase to adequately assess the risk/benefit profile of a drug intended for chronic use. In 
the phase 2, multicenter, double-blind, randomized, placebo-controlled study in patients with EoE 
(R668-EE-1324), a plateau in clinical effect had not been observed by week 12 with a dose of 300 
mg once weekly (QW). An additional 28 weeks of extended active treatment in Part C for an 
overall exposure of approximately 52 weeks will provide data on the long-term efficacy and safety 
of dupilumab in patients with EoE. 
There are several justifications for the inclusion of a placebo control group in this study. Although 
there is an approved swallowed topical steroid treatment for EoE in the EU, it is only indicated for 
short-term use in adults, not for chronic treatment or treatment of pediatric patients (EMA Jorveza 
Assessment Report, 2017). Furthermore, it is only approved in this region and thus considered 
inappropriate for use in a global study. Studies show that patients with EoE frequently relapse, 
even while maintained on long-term topical steroid therapy (Eluri, 2017). Furthermore, although 
studies have shown that a prolonged delay in the diagnosis and treatment of EoE increases the risk 
of stricture formation in a time-dependent manner, the median delay in EoE diagnosis in these 
studies was 6 years, and duration of follow-up was over 20 years (Schoepfer, 2013). It is unlikely 
that a 24-week period of untreated disease will lead to irreversible stricture formation. Hence, 
while allocation to a placebo arm may result in temporary continuation of symptoms, it should not 
impact a patient’s long-term prognosis. In addition, rescue treatment (including swallowed steroids 
and dilation) is allowed for any patient who experiences intolerable symptoms during the study. 
Finally, study patients will be offered the opportunity to participate in the 28-week extended active 
treatment phase, thus offering some potential for direct benefit, even for patients initially enrolled 
in the placebo treatment arm. 
3.2.2. 
Rationale for Dose Selection  
Patients in Part A will receive either 300 mg dupilumab or placebo QW administered 
subcutaneously (SC). In the phase 2 study R668-EE-1324, dupilumab 300 mg QW was 
demonstrated to be efficacious with clinically significant improvements in histologic, endoscopic, 
and patient-reported symptoms after 12 weeks of treatment. Dupilumab was well tolerated with a 
favorable profile with no particular safety signal associated with use in the EoE patient population.  
Patients in Part B will receive 300 mg dupilumab SC once every two weeks (Q2W), 300 mg 
dupilumab SC QW or placebo SC QW. The 300 mg Q2W was chosen to provide dose-ranging 
information. Based on pharmacokinetic (PK) considerations, this dose is expected to achieve 
target-saturating concentrations over the dosing interval, and hence provide clinical benefit. The 
approved dose regimen for treatment of AD is 300 mg Q2W. In addition, this dose regimen 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 36 of 113 
 
CONFIDENTIAL 
provided significant benefit in phase 3 studies of dupilumab for the treatment of adults and 
adolescents with moderate-to-severe asthma, and is currently being tested in adults with nasal 
polyposis. Dosing regimens with inter-dose intervals longer than Q2W have been suboptimal in 
AD and asthma and are not proposed for this trial, as the end of interval concentrations would be 
expected to be below those required for target saturation, and hence may not yield optimal benefit 
in patients with EoE. 
Both dupilumab 300 mg QW and Q2W have a well understood and favorable safety profile. 
Approximately 2500 AD patients were exposed to dupilumab; 645 AD patients have been exposed 
to 300 mg QW for ≥364 days, and 58 have been exposed to 300 mg Q2W for ≥364 days as of the 
27 April 2016 biologics license application cut-off. In completed/unblinded Phase 2/3 studies of 
dupilumab in asthma patients (as of 30 September 2017), 2649 asthma patients were exposed to 
dupilumab; 1035 of these patients have been exposed to 300 mg Q2W for ≥1 year, 662 have been 
exposed for ≥1.5 years, and 473 have been exposed for ≥2 years. 
In both the AD and asthma programs, as is typical for monoclonal antibodies, body weight was 
found to be the most significant covariate affecting the PK of dupilumab, with patients of a lower 
body weight achieving higher concentrations of dupilumab. In the pivotal phase 3 studies in AD 
(R668-AD-1334, R668-AD-1416, and R668-AD-1224), adults with body weights of 41 kg or more 
received dupilumab doses of 300 mg Q2W and 300 mg QW, which were found to be well tolerated 
for 16 to 52 weeks. In Study EFC13579, 33 adolescent patients with asthma (median age of 
14 years with a range of 12 to 17 years; median weight 55 kg) received dupilumab 300 mg Q2W; 
a similar PK profile was observed between adolescent and adult patients with asthma. 
As dupilumab 300 mg QW has not been studied in lighter patients, subjects (adults or adolescents) 
with body weight <40 kg will be excluded from the study. 
3.2.3. 
Risk/Benefits of Participating in the Study 
Recognizing that the “Coronavirus Disease 2019” (COVID-19) pandemic will have an impact on 
the conduct of clinical trials, the sponsor does not intend to screen any new patients in this study 
unless the impact of the COVID-19 pandemic is deemed manageable and no longer interfering 
with the conduct of trials at individual sites, and patients can safely participate in this study. Until 
then, the sponsor plans to obtain approvals from health authorities/ethics committees to enable 
continuation of study sites for this study, as allowed by local laws and regulations. 
3.2.3.1. 
Benefits 
The efficacy and safety of dupilumab in adults with EoE were evaluated in a phase 2, randomized, 
double-blind, placebo-controlled study (R668-EE-1324). Treatment with weekly dupilumab 
300 mg SC for 12 weeks in patients with EoE reduced the frequency and intensity of dysphagia, 
the cardinal symptom of EoE. Improvement in clinical symptoms was accompanied by endoscopic 
and biopsy histologic evidence of reduced esophageal intraepithelial eosinophil infiltration, 
esophageal mucosal inflammation, and improved esophageal distensibility. Study patients could 
potentially benefit from dupilumab treatment, including patients randomized to receive placebo in 
Parts A and B, as all patients have the opportunity to receive dupilumab in the extended active 
treatment Part C of the study. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 37 of 113 
 
CONFIDENTIAL 
3.2.3.2. 
Risks 
As of 28 March 2020, over 8000 subjects have been enrolled into the dupilumab development 
program for the indications of AD, asthma, chromic rhinosinusitis with nasal polyps (CRSwNP), 
grass allergy, peanut allergy, bullous pemphigoid, and EoE (Investigator's Brochure Version 14). 
Based upon currently available data, 1 important identified risk, “Systemic Hypersensitivity 
(including those events associated with immunogenicity),” has been established. One serious case 
each of serum sickness and serum sickness-like reaction (both associated with high anti-drug 
antibody [ADA] titers) were reported in adult AD studies, however none were seen in the asthma 
development program. Additionally, there has been one report of anaphylaxis considered related 
to study drug by the Investigator in an asthma study. Based on the review of post-marketing data, 
signals of anaphylactic reaction and angioedema were confirmed and considered as adverse drug 
reactions (ADRs). 
A higher incidence of Injection Site reactions (ISRs) has been observed in the dupilumab-treated 
subjects, consistent with the SC injection of a protein biologic. Most ISRs were mild to moderate 
in intensity, and less than 2% were severe or led to treatment discontinuation. The proportion of 
patients experiencing ISRs diminished over time during the treatment period. 
Conjunctivitis, Conjunctivitis Allergic, Conjunctivitis Bacterial, Blepharitis, Dry Eye, Eye 
Pruritus, Herpes Simplex (primarily mucocutaneous in nature), and Oral Herpes have been 
identified as adverse drug reactions for the AD indication. There was no increase in incidence of 
these events observed in the completed asthma study. Conjunctivitis was also observed in the 
completed CRSwNP studies but with lower incidence than in the AD studies and without keratitis 
or increase in other ophthalmic events. Most events were mild in intensity and transient in nature, 
and did not necessitate treatment discontinuation. Based on the post-marketing safety data, events 
of angioedema, arthralgia, keratitis and ulcerative keratitis are now considered as ADRs. 
The purpose of protocol amendment 4 was to account for the COVID-19 pandemic and to 
minimize the risks to the patients in the trial as well as healthcare providers by allowing flexibility 
in the visit schedule while social distancing suggestions are in place. Allowing for this flexibility 
does not increase the risk of participating in this trial as there will be continued contact between 
the patients and study personnel despite postponement of in-person clinic visits. 
3.2.3.3. 
Benefit/Risk Conclusion 
The safety data available to date across multiple indications in conjunction with the clinical benefit 
of dupilumab demonstrated in the phase 2 EoE study support a favorable benefit-risk profile for 
dupilumab. 
4. 
STUDY VARIABLES  
4.1. 
Demographic and Baseline Characteristics 
Baseline characteristics will include standard demography (eg, age, race, weight, height, etc.), 
disease characteristics including medical history, and medication history. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 38 of 113 
 
CONFIDENTIAL 
4.2. 
Primary and Secondary Endpoints 
4.2.1. 
Primary Endpoints 
The co-primary endpoints for both Parts A and B of the study are: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤6 eos/hpf at week 24 
• Absolute change in DSQ score from baseline to week 24  
4.2.2. 
Secondary Endpoints 
The key secondary endpoints for both Parts A and B of the study are: 
• Absolute change in EoE-EREFS from baseline to week 24 
• Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from 
baseline to week 24 
• Absolute change in EoE Grade Score from the EoE Histology Scoring System 
(EoEHSS) from baseline to week 24  
• Absolute change in EoE Stage Score from the EoEHSS from baseline to week 24 
The other secondary endpoints are: 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
<15 eos/hpf at week 24 
• Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤1 eos/hpf at week 24 
• Percent change in DSQ from baseline to week 24 
• Normalized Enrichment Scores (NES) for the relative change from baseline to week 
24 in the EoE diagnostic panel (EDP) transcriptome signature 
• NES for the relative change from baseline to week 24 in the type 2 inflammation 
transcriptome signature 
• Absolute change from baseline to week 24 in health-related QOL as measured by EoE 
Impact Questionnaire (EoE-IQ) 
• Absolute change from baseline to week 24 in severity and/or frequency of EoE 
symptoms other than dysphagia  
• Proportion of patients who receive rescue medications or procedures during the 
24-week placebo-controlled treatment period  
• Absolute change from baseline in esophageal distensibility plateau measured by 
functional lumen imaging, if collected, at week 24.  
Note:  All the above co-primary and secondary endpoints assessed at week 24 will be 
assessed at week 52 as secondary endpoints and summarized with descriptive statistics 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 39 of 113 
 
CONFIDENTIAL 
based on the treatment assignment in the double-blind treatment period as well as the 
extended active treatment assignment for patients previously in the placebo group.  
Both co-primary and all secondary endpoints will be assessed at week 24 and week 52 in 
in adult and adolescent patients with EoE who have previously received swallowed 
topical corticosteroids. 
4.3. 
Pharmacokinetic Variables 
The pharmacokinetic variable is the trough concentration (Ctrough) of functional dupilumab in 
serum at each time point. Samples in this study will be collected using a sparse sampling schedule, 
eg, only 1 blood sample for drug concentration measurement is collected at any single clinic visit. 
These sampling time points (prior to dosing at each time point) are specified in Table 1, Table 2, 
and Table 3. 
4.4. 
Anti-Drug Antibody Variables 
The ADA variables are ADA status, titer, and time point/visit. Samples in this study will be 
collected at the clinic visits specified in Table 1, Table 2, and Table 3. 
5. 
STUDY DESIGN  
5.1. 
Study Description and Duration 
This study will investigate the efficacy and safety of dupilumab in adult and adolescent patients 
with EoE. The study will consist of 3 parts and a follow-up period:  Part A and Part B (each 
consisting of a 24-week double-blind treatment period), Part C (a 28-week extended active 
treatment period), and a 12-week follow-up period following the end of the extended active 
treatment period for patients who enter into Part C or following the end of Parts A and B of the 
double-blind treatment period for patients who do not enter Part C. 
Approximately 80 patients (40 per treatment group) are planned to be enrolled in Part A. 
Approximately 210 patients (70 per treatment group) are planned to be enrolled in Part B. At least 
10% of patients enrolled in Part B will be adolescents ≥12 years of age and at least 30% of patients 
enrolled in Part B must have a history of prior use of swallowed topical corticosteroids. At the end 
of the double-blind treatment visit (week 24) of Part A or Part B, eligible patients may enter Part C.  
The study flow diagram is provided in Figure 1. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 40 of 113 
 
CONFIDENTIAL 
Figure 1: 
Study Flow Diagram 
End of 
Study
Visit 1
D-85 to 
D-29
Baseline
Double-Blind Treatment Period
(24 weeks)
Screening Period
(up to 12 weeks)
Extended Treatment Period
(28 weeks)
Follow-Up Period
(12 weeks)
End of 
Extended 
Treatment
End of DB 
Treatment
Visit 2
D-21±7
(endoscopy 
with biopsies)
Visit 3
D1
Visit 11
D169
W24
(endoscopy 
with biopsies)
Visit 19
D365
W52
(endoscopy 
with 
biopsies)
Visit 20
D421
W64
Visit 7
D57
W8
Home e-Diary
 
DB = double-blind. 
Note:  For patients who do not have at least 11 daily entries during the 14 days immediately preceding the planned 
randomization date (baseline), randomization should be postponed until this requirement is met, but without 
exceeding the 85-day maximum duration for screening. 
This study consists of 3 parts:  Part A and Part B are 24-week treatment, randomized, double-blind, 
placebo-controlled study phases, and Part C is a 28-week, extended active treatment phase that 
will enroll patients from Part A and Part B. A depiction of the randomization scheme for this study 
is below in Figure 2 . 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 41 of 113 
 
CONFIDENTIAL 
Figure 2: 
Study Design 
 
Note: If there are restrictions to the clinical study as a result of the COVID-19 pandemic, it may 
be necessary to adjust the visit schedule, convert in-person visits to telephone contacts, and 
postpone study procedures until the next available in clinic study visit. It is necessary that the 
randomization visit (V3) and the first visit of Part C (V11) occur in the clinic. Endoscopies with 
biopsies are required at approximately week 24 and week 52. If it is not possible to complete the 
endoscopies with biopsies due to COVID-19 restrictions and provided there are no specific safety 
concerns for the patient, patients may continue their current study medication regimen until the 
endoscopies with biopsies can be performed. All temporary mechanisms utilized, and deviations 
from planned study procedures are to be documented as being related to COVID-19 and will 
remain in effect only for the duration of the public health emergency. Once COVID-19 conditions 
resolve, all study visits and procedures should follow the schedule of events as specified in Table 1, 
Table 2, and Table 3. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 42 of 113 
 
CONFIDENTIAL 
5.1.1. 
Part A 
5.1.1.1. 
Screening (Up to 12 Weeks) 
After adult patients provide informed consent and adolescent patients and/or their legal 
parents/legal guardians provide informed consent and informed assent (as appropriate), patients 
will be assessed for study eligibility at visit 1.  
Study participants are required to have a conﬁrmed diagnosis of EoE which may be established 
either by a prior historical biopsy showing ≥15 intraepithelial eosinophils per high-power ﬁeld 
(eos/hpf) from at least one esophageal region after at least 8 weeks of treatment with a high-dose 
proton pump inhibitor (PPI) using any approved PPI or by biopsies performed after approximately 
8 weeks of high-dose PPI treatment initiated prior to screening or during the screening period, 
which demonstrate ≥15 intraepithelial eos/hpf in at least 2 out of 3 esophageal regions (proximal, 
mid, and distal); see Figure 3 for endoscopy/biopsy procedure flow chart. Patients who are on PPIs 
during the screening period and are eligible to enroll in the study must continue a high-dose PPI 
regimen during the study (see details in Section 7.2). Patients are allowed to switch among the 
approved background therapy options for high-dose PPI use during the study.  
All patients who meet the other clinical and laboratory eligibility criteria will undergo endoscopy 
with biopsies at visit 2 (day -21±7) to establish a baseline reference measure. For patients without 
a historical biopsy, the visit 2 biopsy will serve as both confirmation of EoE diagnosis and the 
baseline reference measure. 
All biopsies performed during this study will be evaluated by pathologists at a central pathology 
laboratory who will be blinded to treatment assignment. 
Note:  Biopsy specimens from the stomach and/or duodenum will be obtained in all patients 
<18 years of age to rule out alternate etiologies of esophageal eosinophilia. Targeted, stomach, 
and/or duodenal biopsies will be obtained in adults only in the event of abnormal endoscopic 
findings (other than typical EoE findings) or clinical suspicion of alternate etiologies. All 
randomized patients found to have stomach and/or duodenal abnormalities at baseline will have 
follow-up stomach and/or duodenal biopsies at week 24 and week 52. 
After confirmation of EoE diagnosis, patients will be given an electronic diary (eDiary) to record 
dysphagia symptoms on a daily basis during the 2 weeks prior to the baseline visit (visit 3). 
Patients may be re-screened once if they fail the screening evaluation, unless the reason for screen 
failure is related to histologic or clinical disease severity inclusion criteria. The baseline endoscopy 
with biopsy and EoE-EREFS scoring will not be repeated for re-screened patients. These results 
will continue to be valid baseline data. Re-screening must occur within 6 months of the screen 
failure. 
For patients whose DSQ diary compliance does not meet eligibility requirements within the 21-day 
interval between Visit 2 and Visit 3 (at least 11 daily entries during the 14 days immediately 
preceding the planned randomization date), randomization may be postponed as long as the total 
duration of the screening period does not exceed the 85-day maximum. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 43 of 113 
 
CONFIDENTIAL 
Figure 3: 
Endoscopy/Biopsy Procedure Flow Diagram 
Historical esophageal biopsy showing at least 15 (eos/hpf) after 8-weeks of high-dose PPI
Proceed to Screening Endoscopy/Biopsies* at visit 2
If other clinical and laboratory eligibility criteria are met
Yes
No
Proceed to Screening Endoscopy/Biopsies* at visit 2
Endoscopy/Biopsies must be performed while on PPI
Histology results of the biopsies evaluated by a qualified 
central histology laboratory*
Peak intraepithelial eosinophil count sent to study site for 
eligibility assessment at baseline (visit 3)
*Biopsy specimens from the antrum and/or duodenum will be obtained in all patients <18 years of age to rule out alternate etiologies. 
Antral and/or duodenal biopsies will be obtained in adults only in the event of abnormal endoscopic findings (other than typical EoE 
findings) or clinical suspicion of alternate etiologies.  All randomized patients found to have stomach and/or duodenal abnormalities 
at baseline will have follow-up stomach and/or duodenal biopsies at week 24 and week 52.
If other clinical and laboratory eligibility criteria are met
8-week trial of high dose PPIs
Note:  the PPI trial can be initiated prior to screening
 
5.1.1.2. 
Randomization 
At the baseline visit (visit 3), patients who continue to meet eligibility criteria will enter the 
24-week treatment period and be randomized in a 1:1 ratio to dupilumab 300 mg SC QW or 
placebo SC. Patients may be randomized as soon as their baseline endoscopy/biopsy results are 
available and DSQ eDiary entries are completed. 
Randomization will be stratified by age (≥18 vs. ≥12 to <18 years of age) and use of PPI at 
randomization (yes vs. no). 
5.1.1.3. 
Placebo-Controlled Double-Blind Treatment Period (24 Weeks) 
During the approximately 24-week, placebo-controlled, double-blind treatment period, clinic visits 
are scheduled per the schedule of events (Table 1). Patients and parents/caregivers will be trained 
on injecting study drug at the first 3 visits during the double-blind treatment period. Patients will 
be closely monitored at the study site at visits 3 to 6 (baseline visit, study weeks 1, 2, and 4) for a 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 44 of 113 
 
CONFIDENTIAL 
minimum of 30 minutes after the administration of study drug. During weeks when no clinic visit 
is scheduled or if a scheduled visit cannot occur due to COVID-19 restrictions, the patient or 
parent/caregiver will administer study drug. Doses of study drug administered at home should be 
administered one week after the prior dose of study drug. Study drug administration that occurs in 
clinic should occur per the Schedule of Events in Tables 1 and 2. Patients and parents/caregivers 
who prefer to have clinic staff administer study drug may choose to have injections administered 
in the clinic. Study drug may be shipped from the clinical site to the patient's home if necessary.  
The planned end of treatment visit for the double-blind treatment period is at approximately week 
24. The co-primary endpoints will be assessed at week 24, one week after the last dose of study 
drug during the double-blind treatment period.  
Patients who prematurely discontinue study treatment will be encouraged to remain in the study 
and attend all subsequent scheduled visits. 
At the end of double-blind treatment visit (week 24), eligible patients in Part A may enter Part C, 
which consists of an approximately 28-week extended active treatment period. Eligibility 
requirements for the extended active treatment period are provided in Section 6.2.3. Patients who 
do not enter Part C may enter a 12-week follow-up period (Section 5.1.4). 
Patients who participate in Part A are not eligible to participate in Part B. 
5.1.2. 
Part B 
Enrollment for Part B will begin immediately after the last patient is enrolled in Part A. 
5.1.2.1. 
Screening (Up to 12 Weeks) 
The screening procedures for Part B are identical to those described above for Part A. 
5.1.2.2. 
Randomization 
At the baseline visit (visit 3), patients who continue to meet eligibility criteria will enter the 
24-week double-blind treatment period and will be randomized in a 1:1:1 ratio to dupilumab 
300 mg SC QW, dupilumab 300 mg SC Q2W, or placebo SC. Eligible patients may be randomized 
as soon as their baseline endoscopy/biopsy results are available and DSQ eDiary entries are 
completed. 
Randomization will be stratified by age (≥18 vs ≥12 to <18 years of age) and use of PPI at 
randomization (yes vs. no).  
5.1.2.3. 
Placebo-Controlled Double-Blind Treatment Period (24 Weeks) 
Procedures for Part B are identical to those described above for Part A. 
Patients who prematurely discontinue study treatment will be encouraged to remain in the study 
and attend all subsequent scheduled visits. 
At the end of double-blind treatment visit (week 24), eligible patients in Part B may enter Part C, 
which consists of an approximately 28-week extended active treatment period. Eligibility 
requirements for the extended active treatment period are provided in Section 6.2.3. Patients who 
do not enter Part C will enter a 12-week follow-up period (Section 5.1.4). 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 45 of 113 
 
CONFIDENTIAL 
5.1.3. 
Part C (28-Week Extended Active Treatment Period) 
At the end of the double-blind treatment visit (week 24), eligible patients in Parts A and B may 
enter an approximately 28-week extended active treatment period where all patients will receive 
active treatment with dupilumab but only patients in Part B will be blinded to treatment regimen 
in Part C. The eligibility criteria for Part C are provided in Section 6.2.3. 
Patients from Part A who are randomized to placebo during the double-blind treatment period will 
receive dupilumab 300 mg QW during Part C. Patients from Part A who are randomized to 
dupilumab 300 mg QW during the double-blind treatment period will continue to receive 
dupilumab 300 mg QW during Part C.  
Patients from Part B who are randomized to placebo during the double-blind treatment period will 
be re-randomized in a 1:1 ratio to dupilumab 300 mg QW or dupilumab 300 mg Q2W. Patients 
randomized to dupilumab 300 mg Q2W will also receive matching placebo alternating with 
dupilumab doses so the injection frequency will be identical for both groups for regimen-blinding 
purposes. All other patients will remain on the same dupilumab dose regimen to which they are 
randomized during the double-blind treatment period. Treatment assignment in Part C will be 
managed by an interactive voice/web response system (IVRS/IWRS) to maintain blinding of 
treatment assignment in Part B. 
5.1.4. 
Follow-Up Period (12 Weeks) 
All patients will be followed up for an additional 12 weeks after completing Part C. Patients in 
Parts A and B who choose not to participate in or are ineligible for Part C will be followed for an 
additional 12 weeks immediately after their respective trial part.  
5.1.5. 
End of Study Definition 
The end of study is defined as the last visit of the last patient in the study. 
5.2. 
Planned Interim Analysis  
No interim analysis (IA) is planned.  
Timing of the double-blind treatment period and extended active treatment period analyses are 
described in Section 10.4.9. 
5.3. 
Study Committees  
5.3.1. 
Independent Data Monitoring Committee 
An independent Data Monitoring Committee (DMC), composed of members who are independent 
from the sponsor and the study investigators, will monitor patient safety by conducting formal 
reviews of accumulated safety data that will be blinded by treatment group; if requested, the DMC 
may have access to the treatment allocation code or any other requested data for the purposes of a 
risk-benefit assessment. 
The DMC will provide the sponsor with appropriate recommendations on the conduct of the 
clinical study to ensure the protection and safety of the patients enrolled in the study. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 46 of 113 
 
CONFIDENTIAL 
All activities and responsibilities of the DMC are described in the DMC charter. 
6. 
SELECTION, WITHDRAWAL, AND REPLACEMENT OF 
PATIENTS 
6.1. 
Number of Patients Planned 
Approximately 80 patients (40 per treatment group) are planned to be enrolled in Part A. 
Approximately 210 patients (70 per treatment group) are planned to be enrolled in Part B at 
multiple global sites.  
6.2. 
Study Population  
Eligible patients for this study consist of adult males and females ≥18 years of age and adolescent 
males and females ≥12 to <18 years of age at the time of study entry with EoE. At least 10% of 
patients enrolled in Part B will be adolescents ≥12 to <18 years of age. At least 30% of patients 
enrolled in Part B must have a history of prior use of swallowed topical corticosteroids for the 
treatment of EoE. 
6.2.1. 
Inclusion Criteria for Parts A and B 
A patient must meet the following criteria to be eligible for inclusion in Part A and Part B of the 
study: 
1. 
Male or female, ≥12 years of age 
2. 
A documented diagnosis of EoE by endoscopic biopsy prior to screening, as demonstrated 
by intraepithelial eosinophilic infiltration (peak cell count ≥15 eos/hpf) from at least one 
esophageal region and performed after at least 8 weeks of treatment with a high-dose PPI 
regimen. If the patient discontinued PPI therapy, the biopsy must have been performed 
within 2 weeks of the date of discontinuation. 
If a prior (historical) endoscopic biopsy meeting these criteria is not available (or no prior 
biopsy is available), patients who meet other clinical and laboratory eligibility criteria will 
undergo treatment with a high-dose PPI regimen for at least 8 weeks before their baseline 
endoscopy/biopsies. (See Section 7.2 for acceptable high-dose PPI regimens). 
Note: If the patient is already using an acceptable high dose PPI regimen at the time of the 
screening visit, the baseline endoscopy may be scheduled at any point during the screening 
period after 8 weeks of treatment have been documented.  
3. 
Baseline endoscopic biopsies with a demonstration on central reading of intraepithelial 
eosinophilic infiltration (peak cell count ≥15 eos/hpf) in at least 2 of the 3 biopsied 
esophageal regions (proximal, mid, or distal) 
4. 
History (by patient report) of an average of at least 2 episodes of dysphagia (with intake of 
solids) per week in the 4 weeks prior to screening 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 47 of 113 
 
CONFIDENTIAL 
5. 
At least 4 episodes of dysphagia in the 2 weeks prior to baseline, documented via eDiary, 
at least 2 of which require liquids, coughing or gagging, vomiting, or medical attention to 
obtain relief 
6. 
Completed at least 11 of 14 days of DSQ eDiary data entry in the 2 weeks prior to the 
baseline visit (visit 3) 
7. 
Baseline DSQ score ≥10. 
8. 
Able to understand and complete study-related questionnaires 
9. 
Willing and able to comply with clinic visits and study-related procedures 
10. Provide informed consent signed by study patient or legally acceptable representative. For 
adolescents, parent or legal guardian must provide signed informed consent (patients must 
also provide separate informed assent to enroll in the study, and the assent documented 
either in a separate informed assent form [IAF] or in the informed consent form [ICF] 
signed by the parent(s)/legal guardian [as appropriate based on local regulations and 
requirements]). 
6.2.2. 
Exclusion Criteria for Parts A and B 
A patient who meets any of the following criteria will be excluded from Part A and Part B of the 
study: 
1. 
Body weight ≤40 kg 
2. 
Prior participation in a dupilumab clinical trial, or past or current treatment with dupilumab 
3. 
Initiation or change of a food-elimination diet regimen or re-introduction of a previously 
eliminated food group in the 6 weeks prior to screening. Patients on a food-elimination diet 
must remain on the same diet throughout the study. 
4. 
Other causes of esophageal eosinophilia or the following conditions:  hypereosinophilic 
syndrome and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) 
Note:  Patients with eosinophilic gastroenteritis are eligible, provided they meet other 
eligibility criteria. 
5. 
Active Helicobacter pylori infection 
6. 
History of achalasia, Crohn’s disease, ulcerative colitis, celiac disease, and prior 
esophageal surgery 
7. 
Any esophageal stricture unable to be passed with a standard, diagnostic, 9 to10 mm upper 
endoscope or any critical esophageal stricture that requires dilation at screening 
8. History of bleeding disorders or esophageal varices that, in the opinion of the investigator, 
would put the patient at undue risk for significant complications from an endoscopy 
procedure  
9. 
Treatment with swallowed topical corticosteroids within 8 weeks prior to baseline 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 48 of 113 
 
CONFIDENTIAL 
10. Initiation, discontinuation, or change in the dosage regimen of the following medications 
within 8 weeks prior to the baseline endoscopy: 
• Proton pump inhibitors (except for patients who require a PPI trial prior to baseline 
endoscopy) 
• Leukotriene inhibitors 
• Nasal and/or inhaled corticosteroids 
• Patients on a stable dose of these medications for at least 8 weeks prior to the baseline 
endoscopy may be included in the study, but must not change the dose during the 
study. 
11. Initiation, discontinuation, or change in the dosage regimen of SC immunotherapy (SCIT) 
• Patients on a stable dose of these medications for at least 1 year prior to visit 1 may 
be included in the study, but must not change the dose during the study. 
12. Treatment with sublingual immunotherapy (SLIT) 
13. Treatment with oral immunotherapy (OIT) within 6 months prior to visit 1 
14. The following treatments within 3 months prior to screening, or any condition that, in the 
opinion of the investigator, is likely to require such treatment(s) during the study: 
• Systemic immunosuppressant/immunomodulating drugs, including but not limited to 
systemic 
corticosteroids, 
omalizumab, 
cyclosporine, 
mycophenolate-mofetil, 
interferon-gamma [IFN-γ], Janus kinase inhibitors, azathioprine, and methotrexate  
− Note: One-time use of a corticosteroid as a part of the anesthetic preparation used 
during each endoscopy procedure is allowed. 
15. Treatment with an investigational drug within 2 months or within 5 half-lives (if known), 
whichever is longer, prior to visit 1 
16. Planned or anticipated use of any prohibited medications and procedures during the study 
17. Planned or anticipated major surgical procedure during the study 
18. Treatment with a live (attenuated) vaccine within 4 weeks prior to the baseline visit 
19. Active parasitic infection or suspected parasitic infection, unless clinical and (if necessary) 
laboratory assessments have ruled out active infection before randomization 
20. Chronic or acute infection requiring treatment with systemic antibiotics, antivirals, or 
antifungals within 2 weeks before baseline visit. 
Note:  A patient may be re-screened after the infection resolves. 
21. Known or suspected immunodeficiency disorder, including history of invasive 
opportunistic infections (eg, tuberculosis [TB], non-tuberculous mycobacterial infections, 
histoplasmosis, listeriosis, coccidioidomycosis, pneumocystosis, aspergillosis) despite 
infection resolution, or otherwise recurrent infections of abnormal frequency, or prolonged 
infections suggesting an immune-compromised status, as judged by the investigator. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 49 of 113 
 
CONFIDENTIAL 
Tuberculosis testing will be performed on a country-by-country basis according to local 
guidelines if required by regulatory authorities or ethics committees (ECs). 
22. Known history of human immunodeficiency virus (HIV) infection 
23. Established diagnosis of hepatitis B viral infection at the time of screening or positive for 
hepatitis B surface antigen (HBsAg) at the time of screening 
• Patients who have gained immunity for hepatitis B virus infection after vaccination 
(patients who are HBsAg negative, hepatitis B surface antibody [HBsAb] positive, and 
hepatitis B core antibody [HBcAb] negative are eligible for the study). 
• Patients with positive HBcAb are eligible for the study only if hepatitis B virus DNA 
level is undetectable.  
24. Established diagnosis of hepatitis C viral (HCV) infection at the time of screening Patients 
positive for hepatitis C Ab are eligible for the study only if HCV RNA is negative. 
25. On current treatment for hepatic disease including but not limited to acute or chronic 
hepatitis, cirrhosis, or hepatic failure, or has evidence of liver disease as indicated by 
persistent (confirmed by repeated tests ≥2 weeks apart) elevated transaminases (alanine 
aminotransferase [ALT] and/or aspartate aminotransferase [AST]) more than 3 times the 
upper limit of normal [ULN] during the screening period) 
26. Any of the following abnormal lab values at screening: 
• Platelets <100 ×103/μL 
• Neutrophils <1.5 × 103/μL 
• Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 
Note:  If an abnormal value is detected at screening, a repeat test should be performed to 
confirm the abnormality. Only if the repeat test confirms the abnormality would the 
patient be categorized as a screen failure. eGFR will be calculated using the Modification 
of Diet in Renal Disease (MDRD) equation in adult patients and using the Bedside 
Schwartz formula in patients <18 years of age. 
27. Severe concomitant illness(es) that, in the investigator’s judgment, would adversely affect 
the patient’s participation in the study. Examples include but are not limited to short life 
expectancy, uncontrolled diabetes, cardiovascular conditions (eg, NYHA Class III or IV 
cardiac failure), severe renal conditions (eg, severe nephrotic syndrome), hepatobiliary 
conditions (eg, Child-Pugh class B or C), neurological conditions (eg, demyelinating 
diseases), active major autoimmune diseases (eg, lupus, inflammatory bowel disease, 
rheumatoid arthritis, etc.), other severe endocrinologic, gastrointestinal, metabolic, 
pulmonary, or lymphatic diseases. The specific justification for patients excluded under 
this criterion will be noted in study documents (chart notes, case report forms [CRF], etc).  
28. History of malignancy within 5 years prior to screening, except completely treated in situ 
carcinoma of the cervix and completely treated non-metastatic squamous or basal cell 
carcinoma of the skin 
29. History of alcohol or drug abuse within 6 months prior to screening 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 50 of 113 
 
CONFIDENTIAL 
30. Any other medical or psychological condition including relevant laboratory abnormalities 
at screening that, in the opinion of the investigator, suggest a new and/or insufficiently 
understood disease, may present an unreasonable risk to the study patient as a result of 
his/her participation in this clinical trial, may make patient’s participation unreliable, or 
may interfere with study assessments. The specific justification for patients excluded under 
this criterion will be noted in study documents. 
31. Patient or his/her immediate family is a member of the investigational team 
32. Pregnant or breastfeeding women, or women planning to become pregnant or breastfeed 
during the study 
33. Women of childbearing potential* who are unwilling to practice highly effective 
contraception prior to the initial dose/start of the first treatment, during the study, and for 
at least 12 weeks after the last dose. Highly effective contraceptive measures include:  
a. Stable use of combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, 
injectable, implantable) associated with inhibition of ovulation initiated 2 or more 
menstrual cycles prior to screening 
b. Intrauterine device; intrauterine hormone-releasing system 
c. Bilateral tubal ligation 
d. Vasectomized partner 
e. And/or sexual abstinence†, ‡. 
*Postmenopausal women must be amenorrheic for at least 12 months in order not to be 
considered of childbearing potential. Pregnancy testing and contraception are not 
required for women with documented hysterectomy or tubal ligation. 
†Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
‡Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method are not 
acceptable methods of contraception. Female condom and male condom should not be 
used together.  
34. Known systemic hypersensitivity to dupilumab or the excipients of the drug product 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 51 of 113 
 
CONFIDENTIAL 
6.2.3. 
Exclusion Criteria for Part C (the Extended Active Treatment Period) 
A patient who meets any of the following criteria will not be permitted to enter Part C (the extended 
active treatment period): 
1. 
Patients who, during the double-blind treatment period, developed a serious adverse event 
(SAE) and/or adverse event (AE) deemed related to study drug, which in the opinion of the 
investigator could indicate that continued treatment with study drug may present an 
unreasonable risk for the patient 
2. 
Patients who, during the double-blind treatment period, were prematurely withdrawn 
because of a protocol violation, poor compliance, or inability to complete required study 
assessments 
3. 
Patients who became pregnant during the double-blind treatment period 
4. 
Patients who are prematurely discontinued from study drug due to an AE (patients who are 
prematurely discontinued from study drug due to lack of efficacy are eligible to enter 
Part C) 
5. 
Patients who did not undergo endoscopy with biopsies prior to receiving rescue treatment 
Note: If the endoscopy with biopsies cannot occur due to COVID-19 restrictions, 
rescue treatment should be initiated without delay and these patients will be 
eligible to participate in Part C when the patient can next return to the clinic.  
6. 
Systemic hypersensitivity to dupilumab or the excipients of the drug product based on 
participation in Part A or Part B 
6.3. 
Premature Withdrawal from the Study  
A patient has the right to withdraw from the study at any time, for any reason, and without 
repercussion. 
The investigator and/or sponsor have the right to withdraw a patient from the study if it is no longer 
in the interest of the patient to continue in the study, or if the patient’s continuation in the study 
places the scientific outcome of the study at risk (eg, if a patient does not or cannot follow study 
procedures). An excessive rate of withdrawals would render the study uninterpretable; therefore, 
unnecessary withdrawal of patients should be avoided. 
Patient who are withdrawn prematurely from the study will be asked to complete study 
assessments, as described in Section 8.1.2. 
Rules for discontinuation of study treatment (permanent or temporary) are discussed in 
Section 7.4.2. 
6.4. 
Replacement of Patient 
Patient prematurely discontinued from study/study drug will not be replaced. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 52 of 113 
 
CONFIDENTIAL 
7. 
STUDY TREATMENTS  
7.1. 
Investigational and Reference Treatments 
Dupilumab drug product is supplied for this study in the following concentration:   
• Dupilumab 150 mg/mL:  Each 2.0 mL single-use prefilled glass syringe with snap-off 
cap delivers 300 mg of study drug (2.0 mL of a 150 mg/mL solution) 
Placebo matching dupilumab is prepared in the same formulation without the addition of protein 
(ie, active substance, anti-IL-4Rα monoclonal Ab). 
In the double-blind placebo-controlled Parts A and B, as well as Part C, all patients will receive 
QW SC injections. For the dupilumab 300 mg SC Q2W group, in order to maintain the blind, there 
will be an SC injection of placebo in between dupilumab doses so the injection frequency will 
match the other 2 groups (dupilumab QW and placebo) (see randomization/treatment assignment 
in Section 5.1.1.2 for Part A, Section 5.1.2.2 for Part B, Section 5.1.3 for Part C, and Section 7.5). 
In the extended active treatment Part C, patients will receive dupilumab injections at the frequency 
(QW or Q2W with matching placebo alternating with  dupilumab doses so the injection frequency 
will be identical for both groups for regimen-blinding purposes) per their treatment assignment 
(see Section 5.1.3 and Section 7.5). 
Study drug will be administered by SC injections. Subcutaneous injection sites of study drug 
should be alternated among the different quadrants of the abdomen (avoiding navel and waist 
areas), upper thighs, and upper arms so that the same site is not injected for 2 consecutive 
administrations. 
Instructions on dose preparation are provided in the pharmacy manual. 
7.2. 
Background Treatment 
Patients who undergo a trial of high-dose PPI therapy initiated prior to screening or during the 
screening period of Part A or Part B must remain on a dosage regimen listed below for the duration 
of the 52-week treatment period. A high-dose PPI regimen is defined as follows: 
• omeprazole 40 mg once a day (QD) or 20 mg twice a day (BID) 
• esomeprazole 40 mg QD or 20 mg BID 
• lansoprazole 60 mg QD or 30 mg BID 
• dexlansoprazole 60 mg QD  
• rabeprazole 40 mg QD or 20 mg BID  
• pantoprazole 80 mg QD or 40 mg BID 
Patients who present at the initial screening visit with current use of PPIs must also remain on the 
same or similar approved dosage regimen for the duration of the 52-week treatment period. 
Patients may change to a different approved PPI medication during the study. PPI therapy is 
prohibited for all other patients. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 53 of 113 
 
CONFIDENTIAL 
7.3. 
Rescue Treatments 
If medically necessary (eg, for treatment of intolerable EoE symptoms), rescue medications 
(systemic and/or swallowed topical corticosteroids) or emergency esophageal dilation are allowed 
for study patients in Parts A, B, and C. An endoscopy with biopsy will be performed prior to the 
initiation of rescue therapy. Patients who undergo an endoscopy with biopsy due to the initiation 
of rescue therapy will not undergo the scheduled end of treatment visit endoscopy/biopsy at weeks 
24 and 52. Patients who receive rescue treatment during the double-blind period of the study will 
not be eligible for the extended active treatment period unless an endoscopy with biopsy is 
performed prior to the initiation of rescue treatment. However, if the endoscopy with biopsies 
cannot occur due to COVID-19 restrictions, rescue treatment should not be delayed, and these 
patients will be eligible for Part C. Part C treatment will be initiated per the schedule of events and 
only at an in-clinic visit.  
Patients receiving rescue therapy may continue to receive study drug. They will remain blinded 
and will be asked to return to the clinic for all remaining study visits for the double-blind treatment 
period and the follow-up period, and participate in all assessments for these visits according to the 
schedule of events specified in Table 1, Table 2, and Table 3, except for endoscopy/biopsy, as 
noted above. For the purpose of efficacy analyses, patients who receive rescue treatment during 
the study will be considered treatment failures. 
7.4. 
Dose Modification and Study Treatment Discontinuation Rules 
7.4.1. 
Dose Modification 
Dose modification for an individual patient is not allowed.  
7.4.2. 
Study Drug Discontinuation 
Patients who permanently discontinue from study drug during the double-blind treatment period 
will be asked to return to the clinic for all remaining study visits for the double-blind treatment 
period and follow-up period per the visit schedule. 
Patients who permanently discontinue from study drug during the extended active treatment period 
will be asked to return to the clinic for all remaining study visits per the visit schedule. 
Patients who permanently discontinue from study drug and who opt to withdraw from the study 
will be asked to complete an early termination (ET) visit, per Section 8.1.2. 
7.4.2.1. 
Reasons for Permanent Discontinuation of Study Drug 
Study drug dosing will be permanently stopped in the event of: 
• Evidence of pregnancy 
• Anaphylactic reaction or other severe systemic reaction deemed related to study drug  
• Diagnosis of a malignancy during study, excluding carcinoma in situ of the cervix or 
squamous or basal cell carcinoma of the skin. Patient must be withdrawn for these latter 
malignancies if they cannot be adequately treated by local resection. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 54 of 113 
 
CONFIDENTIAL 
• Any infection that is opportunistic, such as TB and other infections whose nature or 
course may suggest an immunocompromised status 
• Severe laboratory abnormalities assessed as related to study drug: 
− Neutrophil count ≤0.5 × 103/µL 
− Platelet count ≤50 × 103/µL 
− ALT and/or AST values >3 × ULN with total bilirubin >2 × ULN, excluding 
confirmed Gilbert’s Syndrome 
− Confirmed AST and/or ALT >5 × ULN (for more than 2 weeks) 
7.4.2.2. 
Reasons for Temporary Discontinuation of Study Drug 
Study drug dosing may be temporarily discontinued in the event of: 
• Severe laboratory abnormalities (as noted in Section 7.4.2.1) where a causal 
relationship to study drug can be reasonably excluded, (ie, an alternative cause is 
evident):  study drug will be discontinued but may be resumed when the laboratory 
abnormality is sufficiently normalized. At minimum, the laboratory value(s) must 
return to a level that no longer meets the specified criteria for discontinuation, as 
defined in Section 7.4.2.1. A decision to resume study treatment will be made jointly 
by the investigator and medical monitor (medical monitor’s written approval is 
required). 
• An infection that requires parenteral treatment with antibiotic, antifungal, antiviral, 
antiparasitic, or antiprotozoal agents, or requires oral treatment with such agents for 
longer than 2 weeks 
• Other intercurrent illnesses or major surgery which could, in the opinion of the 
investigator, present an unreasonable risk to the patient as a result of his/her continued 
participation in the study 
After the condition leading to suspension of dosing normalizes sufficiently, study treatment may 
resume at the discretion of the principal investigator in consultation with the medical monitor. 
A decision to temporarily discontinue study drug and/or to reinstitute study treatment should be 
discussed with the medical monitor. The investigator may suspend study treatment at any time, 
even without consultation with the medical monitor if the urgency of the situation requires 
immediate action and if this is determined to be in the patient’s best interest. However, the medical 
monitor should be contacted as soon as possible in any case of study drug discontinuation. 
Resumption of study treatment after temporary discontinuation requires consultation and 
agreement between the investigator and the medical monitor. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 55 of 113 
 
CONFIDENTIAL 
7.5. 
Method of Treatment Assignment  
In Part A, approximately 80 patients (40 per group) will be randomized in a 1:1 ratio to receive 
dupilumab 300 mg QW or placebo according to a central randomization scheme provided by an 
IVRS/IWRS to the designated study pharmacist (or qualified designee). 
In Part B, approximately 210 patients will be randomized in a 1:1:1 ratio to receive dupilumab 
300 mg QW, dupilumab 300 mg Q2W, or placebo (approximately 70 patients per group) according 
to a central randomization scheme provided by IVRS/IWRS to the designated study pharmacist 
(or qualified designee). 
Randomization for both Part A and Part B will be stratified according to age at the time of the 
screening visit (≥12 to <18 years of age vs. ≥18 years of age) and use of PPI at randomization (yes 
vs. no).  
For patients entering Part C from Part B, those who are randomized to placebo during Part B will 
be re-randomized in a 1:1 ratio to receive dupilumab 300 mg QW or dupilumab 300 mg Q2W 
(with matching placebo alternating with dupilumab doses so the injection frequency will be 
identical for both groups for regimen-blinding purposes) in Part C, and those who are randomized 
to one of the dupilumab dose regimens in Part B will remain on the same dupilumab dose regimen 
in Part C. Patients who received 300 mg Q2W in Part B will also continue with matching placebo 
alternating with dupilumab doses so the injection frequency will be identical for both groups for 
regimen-blinding purposes. Treatment assignment in Part C for all patients from Part B, regardless 
of their previously assigned treatment in Part B, will be managed by IVRS/IWRS to maintain 
blinding. 
7.5.1. 
Blinding  
Study patients, the principal investigators, and study site personnel will remain blinded to all 
randomization assignments throughout the study. The blinded Regeneron Medical/Study Director, 
Study Monitor, and any other Regeneron and contract research organization (CRO) personnel who 
are in regular contact with the study site will remain blinded to all patient randomization 
assignments. 
All study personnel will be blinded to data during each study part until the respective database 
lock. Part A will be unblinded while Part B is ongoing. 
Blinded study drug kits coded with a medication numbering system will be used. In order to 
maintain the blind, lists linking these codes with product lot numbers will not be accessible to 
individuals involved in study conduct. 
Anti-drug antibody, drug concentration results, and any post-treatment tissue eosinophil counts 
and histologic results, and biomarker results (eotaxin-3, thymus and activation-regulated 
chemokine [TARC], total IgE and allergen-specific IgEs) will not be communicated to the sites, 
and the sponsor’s blinded operational team will not have access to results associated with patient 
identification until after the database is locked for the respective study part. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 56 of 113 
 
CONFIDENTIAL 
7.5.2. 
Emergency Unblinding 
Unblinding of treatment assignment for a patient may be necessary due to a medical emergency or 
any other significant medical event (eg, pregnancy). 
• If unblinding is required: 
− Only the investigator will make the decision to unblind the treatment assignment. 
− Only the affected patients will be unblinded. 
− The designated study pharmacist(s)/designee at the study site will provide the 
treatment assignment to the investigator. If there is no study pharmacist, the 
investigator for the site will unblind the patient. 
− The investigator will notify Regeneron and/or designee as soon as possible after 
unblinding the patient. 
Treatment assignment is not to be provided to site personnel, other than the unblinded study 
pharmacist (when applicable), at any time during the conduct of the study, except in the case of a 
true emergency. In the event that there is no study pharmacist, the individual at the site fulfilling 
that role will be the only unblinded member of the site personnel. 
7.5.3. 
Unblinding for Regulatory Reporting Purposes 
Treatment assignments for certain patients may be unblinded to Pharmacovigilance personnel for 
the purpose of regulatory reporting of suspected unexpected serious adverse reactions (SUSARs) 
to health authorities in accordance with local regulations. 
7.6. 
Treatment Logistics and Accountability 
7.6.1. 
Packaging, Labeling, and Storage 
A medication numbering system will be used to label blinded investigational study drug. Lists 
linking medication numbers with product lot numbers will be maintained by the groups (or 
companies) responsible for study drug packaging. In order to maintain the blind, these lists will 
not be accessible to individuals involved in study conduct.  
Study drug will be stored at the site at a temperature of 2ºC to 8ºC; storage instructions will be 
provided in the pharmacy manual. 
7.6.2. 
Supply and Disposition of Treatments 
Study drug will be shipped at a temperature of 2ºC to 8ºC to the investigator or designee at regular 
intervals or as needed during the study. At specified time points during the study (eg, interim site 
monitoring visits), at the site close-out visit, and following drug reconciliation and documentation 
by the site monitor, all opened and unopened study drug will be returned to the sponsor or designee 
for destruction, unless it’s specified that the site may perform their own destruction. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 57 of 113 
 
CONFIDENTIAL 
7.6.3. 
Treatment Accountability 
All drug accountability records must be kept current. 
The investigator must be able to account for all opened and unopened study drug. These records 
should contain the dates, quantity, and study drug that is: 
• dispensed to each patient, 
• returned from each patient (if applicable), or 
• disposed of at the site or returned to the sponsor or designee. 
All accountability records must be made available for inspection by the sponsor and regulatory 
agency inspectors; photocopies must be provided to the sponsor at the conclusion of the study. 
7.6.4. 
Treatment Compliance 
All drug compliance records must be kept current and made available for inspection by the sponsor 
and regulatory agency inspectors. 
7.7. 
Concomitant Medications and Procedures  
Any treatment administered from the time of informed consent to the final study visit will be 
recorded. Any treatment administered from the time of first dose of study drug to the final study 
visit will be considered concomitant medication; this includes medications that were started before 
the study and are ongoing during the study. 
7.7.1. 
Prohibited Medications and Procedures  
Treatment with the following concomitant medications is prohibited through week 52:   
• Swallowed topical corticosteroids (may be used as rescue treatment for EoE) 
• Systemic corticosteroids (may be used as rescue treatment for EoE)  
− Note: One-time use of a corticosteroid as a part of the anesthetic preparation used 
during each endoscopy procedure is allowed. 
• Systemic immunosuppressive/immunomodulating drugs (including, but not limited to, 
omalizumab, cyclosporine, mycophenolate-mofetil, azathioprine, methotrexate, IFN-γ, 
or other biologics)  
• Treatment with an investigational drug (other than dupilumab) 
• Initiation, discontinuation, or change in dosage regimen of the following medications 
within 8 weeks prior to the baseline endoscopy (stable doses of these medications are 
allowed) 
− Proton pump inhibitors, unless used for a required PPI trial during the screening 
period or in patients who present at the initial screening visit with current use of 
PPIs 
− Systemic leukotriene inhibitors 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 58 of 113 
 
CONFIDENTIAL 
− Nasal and/or inhaled corticosteroids 
• Initiation of SCIT, or change in dose for those patients on a stable dose of SCIT within 
1 year prior to screening  
• SLIT 
• OIT 
• Treatment with an investigational drug (other than dupilumab) 
• Treatment with a live (attenuated) vaccine 
Chickenpox (varicella) 
FluMist-Influenza 
Intranasal influenza 
Measles (rubeola) 
Measles-mumps-rubella combination 
Measles-mumps-rubella-varicella combination 
Mumps 
Oral polio (Sabin) 
Oral typhoid 
Rubella 
Smallpox (vaccinia) 
Yellow fever 
Bacille Calmette-Guerin 
Rotavirus 
Varicella zoster (shingles) 
The following concomitant procedures are prohibited during study treatment (through week 52): 
• Major elective surgical procedures 
• Esophageal dilation (may be used as rescue procedure) 
• Initiation or change of food-elimination diet regimen 
7.7.2. 
Permitted Medications and Procedures  
Other than the prohibited medications listed in Section 7.7.1, treatment with concomitant 
medications are permitted during the study. Medications used to treat chronic disease such as 
diabetes and hypertension are also permitted. If there is any question regarding whether a 
concomitant medication may be used during the study, the study site should contact the medical 
monitor. 
7.7.3. 
Restricted Medications and Procedures during the Follow-Up Period 
Patients may receive the prohibited medications/procedures listed in Section 7.7.1 as needed 
during the follow-up period, with the exception of live (attenuated) vaccine, which should not be 
used within 3 months after the last dose of study drug. Investigators are advised to prescribe 
prohibited medications/procedures judiciously, only when they are absolutely required for the 
appropriate management of study patients. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 59 of 113 
 
CONFIDENTIAL 
8. 
STUDY SCHEDULE OF EVENTS AND PROCEDURES 
8.1. 
Schedule of Events 
Study assessments and procedures are presented by study period and visit in Table 1 for the 
screening period and double-blind treatment period in Parts A and B, in Table 2 for the extended 
active treatment period in Part C, and in Table 3 for the follow-up period, ET visit, and 
unscheduled visit. 
In light of the public health emergency related to COVID-19, the continuity of clinical study 
conduct and oversight may require implementation of temporary or alternative mechanisms. 
Examples of such mechanisms may include, but are not limited to, any of the following:  phone 
contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring 
devices, use of local clinic or laboratory locations, and home visits by skilled staff. Additionally, 
no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All 
temporary mechanisms utilized, and deviations from planned study procedures are to be 
documented as being related to COVID-19 and will remain in effect only for the duration of the 
public health emergency. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 60 of 113 
 
CONFIDENTIAL 
Table 1: 
Parts A and B Schedule of Events – Screening Period and Double-Blind Treatment Period 
 
Screening Period 
24-Week Double-Blind Treatment Period18 
Study Procedure 
Screening1 
V1 
Screening 
Endoscopy/ 
Biopsy2 
V2 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
DB 
EOT 
V113 
Week (W) 
 
 
 
W1 
W2 
W4 
W8 
W12 
W16 
W20 
W243 
Day (D) 
D-85 to  
D-291 
D-212 
D1 
D8 
D15 
D29 
D57 
D85 
D113 
D141 
D169 
Visit Window (Days [d]) 
 
±7 d 
 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
+7 d 
Screening4/Baseline: 
Informed consent and assent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
Med. history, Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Randomization2a 
 
 
X2a 
 
 
 
 
 
 
 
 
Treatment: 
Training for self-injection5 
 
 
X 
X6a 
X6a 
 
 
 
 
 
 
Administer study drug6, 6a 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug dispensation6, 6a 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
Study drug accountability 
 
 
 
X6a 
X6a 
X 
X 
X 
X 
X 
X 
Concomitant medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy:7 
DSQ PRO (daily)8 
assessed by patient daily using eDiary  
PGIC9 
 
 
 
 
 
 
 
X  
 
X  
X 
PGIS9 
 
 
X 
 
 
 
 
X  
 
X  
X 
EoE Impact Questionnaire 10 
 
 
X 
 
 
 
 
X 
 
 
X 
EoE Symptom Questionnaire10 
 
 
X 
 
 
 
 
X 
 
 
X 
TNSS11 
 
 
X 
 
 
 
 
X 
 
 
X 
RQLQ(S)+1211 
 
 
X 
 
 
 
 
X 
 
 
X 
ACQ-511 
 
 
X 
 
 
 
 
X 
 
 
X 
POEM11 
 
 
X 
 
 
 
 
X 
 
 
X 
EQ-5D-3L 
X17 
 
X17 
 
 
 
 
 
 
 
  
EoE-EREFS2,12 
 
X2, 2a, 4 
 
 
 
 
 
 
 
 
X2, 2b 
Endoscopy with biopsies (histology, IHC, 
RNA, EndoFLIP)2 
 
X2, 2a, 4 
 
 
 
 
 
 
 
 
X2, 2b 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 61 of 113 
 
CONFIDENTIAL 
 
Screening Period 
24-Week Double-Blind Treatment Period18 
Study Procedure 
Screening1 
V1 
Screening 
Endoscopy/ 
Biopsy2 
V2 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
DB 
EOT 
V113 
Week (W) 
 
 
 
W1 
W2 
W4 
W8 
W12 
W16 
W20 
W243 
Day (D) 
D-85 to  
D-291 
D-212 
D1 
D8 
D15 
D29 
D57 
D85 
D113 
D141 
D169 
Visit Window (Days [d]) 
 
±7 d 
 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
+7 d 
Safety: 7, 7a, 18 
Vital signs13 
X 
X 
X13 
X13, 13a 
X13, 13a 
X13, 13a 
X13a 
X13a 
X13a 
X13a 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
X14 
Weight 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
x 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing:7, 7a 
Hematology, Chemistry 
X 
 
X 
 
 
 
 
X 
 
 
X 
Serology tests 15  
X 
 
 
 
 
 
 
 
 
 
 
Serum FSH 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test16 
Serum 
Urine 
Urine 
 
 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urinalysis 
X 
 
X 
 
 
 
 
X 
 
 
X 
PK and ADA:7, 7a 
PK sample 
 
 
X 
 
  
  
 
X 
 
 
X 
ADA sample 
 
 
X 
 
 
  
 
X 
 
 
X 
Biomarkers and Genomics:7, 7a 
Whole blood DNA (optional) 
 
 
X 
 
 
 
 
 
 
 
 
Whole blood RNA (optional) 
X 
 
X 
 
 
 
 
 
 
 
X 
Plasma Eotaxin-3 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Serum TARC 
X 
 
X 
 
 
X 
 
 
 
 
X 
Serum Total IgE 
X 
 
X 
 
 
X 
 
X 
 
 
X 
Allergen-specific IgE, IgG4  
X 
 
X 
 
 
X 
 
X 
 
 
X 
Future Biomarker Serum/Plasma 
X 
 
X 
 
 
X 
 
X 
 
 
X 
ADA = anti-drug antibody; DB EOT = end of double-blind treatment period; DSQ = Dysphagia Symptom Questionnaire; ECG = electrocardiogram; 
EoE-EREFS = Eosinophilic Esophagitis-Endoscopic Reference Score; EQ-5D-3L = European Quality of Life 5-dimension (version 3L; 3-level); IHC = 
immunohistochemistry; PGIC = Patient Global Impression of Change of Dysphagia; PGIS = Patient Global Impression of Severity of Dysphagia; POEM = 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 62 of 113 
 
CONFIDENTIAL 
Patient-Oriented Eczema Measure; PRO = patient-reported outcome; PK = pharmacokinetic; RQLQ(S)+12 = Rhinoconjunctivitis Quality of Life Questionnaire 
for patients aged 12+ years; TNSS = Total Nasal Symptom Score; V = visit 
Table 2: 
Part C Schedule of Events – Extended Active Treatment Period 
 
28-Week Extended Active Treatment Period 14 
Study Procedure 
V111 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
EOT 
V19 
Week (W) 
W241 
W26 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
Day (D) 
D169 
D183 
D197 
D225 
D253 
D281 
D309 
D337 
D365 
Visit Window (Days [d]) 
+7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
+7 d 
Treatment:2 
Administer study drug 3, 4, 4a 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug dispensation 4, 4a 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/procedures 
 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy:2 
DSQ eDiary5 
--------------------------- completed daily by patient --------------------------------→ 
PGIC6 
 
 
 
 
X 
 
 
 
X 
PGIS6 
 
 
 
 
X 
 
 
 
X 
EoE Impact Questionnaire7 
 
 
 
 
X 
 
 
 
X 
EoE Symptom Questionnaire 7 
 
 
 
 
X 
 
 
 
X 
TNSS 8 
 
 
 
 
X 
 
 
 
X 
RQLQ(S)+12 8 
 
 
 
 
X 
 
 
 
X 
POEM 8 
 
 
 
 
X 
 
 
 
X 
ACQ-5 8 
 
 
 
 
X 
 
 
 
X 
EoE-EREFS 9, 10 
 
 
 
 
 
 
 
 
X10, 10a 
Endoscopy with biopsies (histology, 
IHC, RNA, EndoFLIP)10 
 
 
 
 
 
 
 
 
X10, 10a 
Safety: 2, 2a, 14 
Vital signs 11 
X11 
X11 
X 
X 
X 
X 
X 
X 
X 
Height 12 
 
 
 
 
 
 
 
 
X 
Weight 
 
X 
X 
X 
X 
 
 
 
X 
Physical examination 
 
 
 
 
 
 
 
 
X 
ECG 
 
 
 
 
 
 
 
 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 63 of 113 
 
CONFIDENTIAL 
 
28-Week Extended Active Treatment Period 14 
Study Procedure 
V111 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
EOT 
V19 
Week (W) 
W241 
W26 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
Day (D) 
D169 
D183 
D197 
D225 
D253 
D281 
D309 
D337 
D365 
Visit Window (Days [d]) 
+7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
+7 d 
Laboratory Testing:2, 2a 
Hematology, Chemistry 
 
 
 
 
X 
 
 
 
X 
Pregnancy test 13 
 
Urine 
 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urinalysis 
 
  
 
  
X 
 
 
 
X 
PK and ADA:2, 2a   
PK Sample 
 
 
 
X 
 
 
 
 
X 
ADA sample 
 
 
 
X 
 
 
 
 
X 
Biomarkers:2, 2a 
Whole blood RNA (optional) 
 
 
 
 
 
 
 
 
X 
Plasma Eotaxin-3 
 
X 
 
X 
 
 
 
 
X 
Serum TARC 
 
 
 
 
 
 
 
 
X 
Serum Total IgE 
 
X 
 
X 
 
 
 
 
X 
Allergen-specific IgE, IgG4  
 
X 
 
X 
 
 
 
 
X 
Future Biomarker Serum/Plasma 
 
X 
 
X 
 
 
 
 
X 
ADA = anti-drug antibody; DSQ = Dysphagia Symptom Questionnaire; ECG = electrocardiogram; EoE-EREFS = Eosinophilic Esophagitis-Endoscopic 
Reference Score; EOT = end of extended active treatment period; IHC = immunohistochemistry; POEM = Patient-Oriented Eczema Measure; PRO = patient 
reported outcome; PGA = physician global assessment; PGIC = Patient Global Impression of Change of Dysphagia; PGIS = Patient Global Impression of 
Severity of Dysphagia; PK = pharmacokinetic; RQLQ(S)+12 = Rhinoconjunctivitis Quality of Life Questionnaire for patients aged 12+ years; TNSS = Total 
Nasal Symptom Score; V = visit 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 64 of 113 
 
CONFIDENTIAL 
Table 3: 
Follow-up Period, Early Termination Visit, and Unscheduled Visit 
Study Procedure 
12-Week Follow-Up 
EOS Visit 
Early 
Termination 
during 12-
Week Follow-
Up1 
Early 
Termination 
during Parts 
A, B, or C1 
Unscheduled Visit before 
Rescue Treatment 
Unscheduled 
Visit for Other 
Reasons 
Week (W) 
12 weeks after EOT visit 
 
 
 
 
Day (D) 
84 days after EOT visit 
 
 
 
 
Visit Window (Days [d]) 
±7 d 
 
 
 
 
Concomitant 
medications/procedures10 
X 
X 
X 
X 
X 
Efficacy: 
DSQ eDiary2 
completed daily by 
patient→ 
 
X 
X 
 
PGIC3 
 
 
X 
X 
 
PGIS3 
 
 
X 
X 
 
EoE Impact Questionnaire 4 
 
 
X 
X 
 
EoE Symptom Questionnaire 4 
 
 
X 
X 
 
TNSS 5 
 
 
X 
X 
 
RQLQ(S)+12 5 
 
 
X 
X 
 
ACQ-5 5 
 
 
X 
X 
 
POEM 5 
 
 
X 
X 
 
EoE-EREFS 6, 7 
 
 
X 7, 7a 
X 8 
 
Endoscopy with biopsies (histology, 
IHC, RNA)7 
 
 
X 7, 7a 
X 8 
 
Safety10:  
Vital signs  
X 
X 
X 
X 
 
Height 9 
 
 
X 
 
 
Weight 
X 
X 
X 
 
 
Physical examination 
 
 
X 
 
 
ECG 
 
 
X 
 
 
Adverse events 
X 
X 
X 
X 
X 
Laboratory Testing10: 
Hematology, Chemistry 
X 
X 
X 
 
 
Pregnancy test 
Urine 
Urine 
Urine 
 
 
Urinalysis 
X 
X 
X 
 
 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 65 of 113 
 
CONFIDENTIAL 
Study Procedure 
12-Week Follow-Up 
EOS Visit 
Early 
Termination 
during 12-
Week Follow-
Up1 
Early 
Termination 
during Parts 
A, B, or C1 
Unscheduled Visit before 
Rescue Treatment 
Unscheduled 
Visit for Other 
Reasons 
Week (W) 
12 weeks after EOT visit 
 
 
 
 
Day (D) 
84 days after EOT visit 
 
 
 
 
Visit Window (Days [d]) 
±7 d 
 
 
 
 
PK and ADA10: 
PK Sample 
X 
X 
X 
X 
 
ADA sample 
X 
X 
X 
X 
X 
Biomarkers: 
Future Biomarker Serum/Plasma 
(optional) 
 
 
X 
 
 
ADA = anti-drug antibody; DSQ = Dysphagia Symptom Questionnaire; ECG = electrocardiogram; EoE-EREFS = Eosinophilic Esophagitis-Endoscopic 
Reference Score; EOS = end of study (visit); EOT = end of treatment period; POEM = Patient-Oriented Eczema Measure; PRO = patient-reported outcome; 
PGA = physician global assessment; PGIC = Patient Global Impression of Change of Dysphagia; PGIS = Patient Global Impression of Severity of Dysphagia; 
PK = pharmacokinetic; RQLQ(S)+12 = Rhinoconjunctivitis Quality of Life Questionnaire for patients aged 12+ years; TNSS = Total Nasal Symptom Score 
 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 66 of 113 
 
CONFIDENTIAL 
8.1.1. 
Footnotes for the Schedule of Events Tables 
8.1.1.1. 
Footnotes for Table 1 
1. For patients without a satisfactory prior endoscopy/biopsy (eg, histological criteria were 
not met, or the biopsy was not performed while patient was on at least 8 weeks of high-dose 
PPI treatment), the screening period will be extended for up to 12 weeks (day -85) to allow 
for at least 8 weeks of high-dose PPI treatment prior to the screening endoscopy/biopsies. 
For all other patients, the screening period will be shorter, with sufficient time to allow 
screening assessments and laboratory test results to be available prior to the baseline 
endoscopy/biopsies. 
2. The endoscopy/EoE-EREFS/biopsy procedures should be performed after all other 
efficacy and safety assessments. 
a. The baseline endoscopy with biopsies should be performed at approximately 
day -21±7 days to allow for availability of the intraepithelial eosinophil count result 
from the central pathology laboratory prior to day 1. For patients without a 
satisfactory prior historical endoscopy/biopsy, the baseline endoscopy/biopsies must 
be performed after at least 8 weeks of high-dose PPI. Patients may be randomized as 
soon as their endoscopy/biopsy results are available and DSQ eDiary entries are 
completed. 
Note:  Biopsy specimens from the stomach and/or duodenum will be obtained in all 
patients <18 years of age to rule out alternate etiologies. Stomach and/or duodenal 
biopsies will be obtained in adults only in the event of abnormal endoscopic findings 
(other than typical EoE findings) or clinical suspicion of alternate etiologies. 
b. For patients who receive rescue treatment during the double-blind treatment period, 
the endoscopy/EoE-EREFS/biopsy procedures will be performed prior to the 
initiation of rescue treatment. Patients undergoing endoscopy/biopsy prior to rescue 
will not undergo the scheduled endoscopy/biopsy at week 24 
Note:  All randomized patients found to have stomach and/or duodenal abnormalities 
at baseline will have follow-up stomach and/or duodenal biopsies at week 24 and 
week 52. 
c. The EndoFLIP procedure to measure esophageal distensibility may be performed 
during the esophagogastroscopy procedures at selected North American sites in 
approximately 150 adult patients. 
3. Assessments indicated for this week 24 (end of treatment) visit should be performed for all 
patients in Parts A and B. For patients who will enter Part C, there are additional events 
listed in week 24 visit in Table 2 for Part C. 
4. Patients may be re-screened once if they fail the screening evaluation, unless the reason for 
screen failure is related to histologic or clinical disease severity inclusion criteria. The 
baseline endoscopy with biopsy and EoE-EREFS scoring will not be repeated for re-
screened patients. These results will continue to be valid baseline data. Re-screening must 
occur within 6 months of the screen failure. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 67 of 113 
 
CONFIDENTIAL 
5. Patients and/or caregivers will be trained on administration of study drug at a minimum at 
visit 3/day 1 
6. On scheduled in-clinic study visit days, study drug will be administered in the clinic (by 
the patient, site staff, or caregiver). Study drug will be provided for those doses scheduled 
to be administered at home before the next in-clinic visit. Doses of study drug administered 
at home should be administered 1 week after the prior dose of study drug. Study drug 
administration that occurs in clinic should occur per the Schedule of Events in Table 1 and 
Table 2. Patients will be closely monitored at the study site at visits 3 to 6 for a minimum 
of 30 minutes after the administration of study drug. In addition to the predose assessments, 
AEs and vital signs (body temperature, blood pressure, respiratory rate and heart rate) will 
be assessed at 30 minutes (±10 minutes) post-dose. 
a. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic 
visits, after visit 3/day 1 patients/caregivers may be dispensed study drug for at-home 
dosing. Additionally, if the visit 11/week 24 endoscopy with biopsies is delayed due 
to COVID-19 restrictions, extended blinded dosing of study drug is allowed until this 
visit can occur. If extended dosing of the study drug occurs beyond week 23, the 
clinic staff must contact the patient every 4 weeks (at a minimum) to collect any AE 
(including ISRs), any change in concomitant medications and/or procedures, and 
monthly pregnancy test results, if required. 
7. Assessments will be performed and blood samples will be collected before the 
administration of study drug. 
a. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic 
visits, procedures/sample collection should occur at the next available in-clinic visit. 
Pregnancy testing must be performed as indicated (in-clinic or at-home) monthly (at a 
minimum) and results reported in a timely manner. 
8. DSQ eDiary will be completed once daily by the patients after their last meal of the day 
but before they go to bed. Site personnel should conduct regular checks of patient eDiary 
compliance.  
9. Patient Global Impression of Change (PGIC) of Dysphagia and Patient Global Impression 
of Severity (PGIS) of Dysphagia will be completed by the patient via electronic 
questionnaire at the indicated site visits. See Section 8.2.2.5 and Section 8.2.2.6.  
10. EoE Impact Questionnaire and EoE Symptom Questionnaire will be completed by the 
patient via electronic questionnaire at the indicated site visits. See Section 8.2.2.3 and 
Section 8.2.2.4.  
11. Total Nasal Symptom Score (TNSS) and Rhinoconjunctivitis Quality of Life Questionnaire 
for patients aged 12+ years [RQLQ(S)+12] will be administered only to patients with a 
documented history of allergic rhinitis; Asthma Control Questionnaire-5 (ACQ-5) will be 
administered only to patients with a documented history of asthma; Patient-Oriented 
Eczema Measure (POEM) will be administered only to patients with a documented history 
of AD. TNSS, POEM, ACQ-5 and RQLQ(S)+12 will be completed via electronic 
questionnaire and at the indicated site visits. The questionnaires will be administered only 
to the subset of patients who fluently speak the language in which the questionnaire is 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 68 of 113 
 
CONFIDENTIAL 
presented (based on the availability of validated translations in participating countries). See 
Section 8.2.2.7, Section 8.2.2.8, Section 8.2.2.9, and Section 8.2.2.10. 
12. EoE-EREFS should be completed by the investigator before biopsies for all patients are 
performed. For Part B enrolled patients, EoE-EREFS will be performed by both the 
investigators who perform the endoscopies as well as a centralized reading center, that will 
provide EoE-EREFS analysis and scoring from endoscopy imaging. For all endoscopies, 
the investigators will assess minor esophageal features including mucosal inflammatory 
and remodeling features.  
13.  At visits 3 through 6, vital signs (body temperature, blood pressure, respiratory rate, heart 
rate) should be taken predose and 30 minutes (±10 minutes) post-dose. Vital signs should 
be taken predose at all other indicated visits.  
a. If study drug administration is not possible in-clinic due to staff or patient availability 
due to COVID-19 restrictions, vital signs pre- and post-dose may not be performed. 
14. For adolescent patients only. 
15. Includes HIV Ab, HBsAg, HBsAb, HBcAb, HCV Ab, and TB. Tuberculosis testing will 
be performed on a country-by-country basis according to local guidelines if required by 
regulatory authorities or ECs. 
16. Not required if post-menopausal status confirmed at screening. A negative result must be 
obtained prior to the randomization visit. In case of a positive urine test, the study treatment 
will be withheld and a serum pregnancy test to confirm the pregnancy should be performed 
as soon as possible. A confirmed pregnancy will lead to study drug discontinuation in all 
cases. 
17. The EQ-5D-3L should be administered one time at either visit 1 or visit 3 for newly 
screened patients. 
18. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, 
the clinic staff should make every effort to contact the patient at the timepoint of the 
expected in-clinic visit to collect any AEs (including ISRs), any change in concomitant 
medications and/or procedures, and monthly pregnancy test results, if required. 
8.1.1.2. 
Footnotes for Table 2 
1. This visit is the same as the week 24 visit for Parts A and B (Table 1), and all other 
assessments indicated for week 24 of Parts A and B (Table 1) should be performed. All 
pre-dosing procedures (including endoscopy with biopsy) at visit 11/week 24 must be 
completed prior to administration of study drug for Part C extended active treatment. 
2. Study assessments will be performed and blood samples will be collected prior to 
administration of study drug. 
a. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic 
visits, procedures/sample collection should occur at the next available in-clinic visit. 
Pregnancy testing must be performed as indicated (in-clinic or at-home) monthly (at a 
minimum) and results reported in a timely manner. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 69 of 113 
 
CONFIDENTIAL 
3. Patients will be closely monitored at the study site at visits 11 (at a minimum) and 12, if 
possible, for a minimum of 30 minutes after the administration of study drug. In addition 
to predose assessments, AEs and vital signs (body temperature, blood pressure, respiratory 
rate, and heart rate) will be assessed at 30 minutes (±10 minutes) post-dose.  
4. All pre-dosing procedures (including endoscopy with biopsy) at the scheduled visit 
11/week 24 must occur prior to dosing with Part C / extended active treatment study drug. 
On scheduled in-clinic study visit days, study drug will be administered in the clinic (by 
the patient, site staff, or caregiver). Study drug will be provided for those scheduled doses 
to be administered at home before the next in-clinic visit. Doses of study drug administered 
at home should be administered 1 week after the prior dose of study drug. Study drug 
administration that occurs in clinic should occur per the Schedule of Events in Table 1 and 
Table 2. 
a. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic 
visits, after visit 11/week 24 patients/caregivers may be dispensed study drug for at-
home dosing. Additionally, if the visit 19/ week 52 endoscopy with biopsies is 
delayed due to COVID-19 restrictions, extended dosing of study drug is allowed until 
this visit can occur. If extended dosing of the study drug occurs beyond week 51, the 
clinic staff must contact the patient every 4 weeks (at a minimum) to collect any AEs 
(including ISRs any change in concomitant medications and/or procedures, and 
monthly pregnancy test results, if required. 
5. DSQ eDiary will be completed once daily by the patients after their last meal of the day 
but before they go to bed. Site personnel should conduct regular checks of patient eDiary 
compliance.  
6. PGIC and PGIS will be completed by the patient via electronic questionnaire at the 
indicated site visits. See Section 8.2.2.5 and Section 8.2.2.6. 
7. EoE Impact Questionnaire and EoE Symptom Questionnaire will be completed by the 
patient via electronic questionnaire at the indicated site visits. See Section 8.2.2.3 and 
Section 8.2.2.4. 
8. TNSS and RQLQ(S)+12 will be administered only to patients with a documented history 
of allergic rhinitis; ACQ-5 will be administered only to patients with a documented history 
of asthma, and POEM will be administered only to patients with a documented history of 
AD. TNSS, POEM, ACQ-5 and RQLQ(S)+12 will be completed via electronic 
questionnaire and at the indicated site visits. The questionnaires will be administered only 
to the subset of patients who fluently speak the language in which the questionnaire is 
presented (based on the availability of validated translations in participating countries). See 
Section 8.2.2.7, Section 8.2.2.8, Section 8.2.2.9, and Section 8.2.2.10. 
9. EoE-EREFS should be completed by the investigator before biopsies for all patients are 
performed. For Part B enrolled patients, EoE-EREFS will be performed by both the 
investigators who perform the endoscopies as well as a centralized reading center who will 
provide EoE-EREFS analysis and scoring from endoscopy imaging. For all endoscopies, 
the investigators will assess minor esophageal features including mucosal inflammatory 
and remodeling features.  
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 70 of 113 
 
CONFIDENTIAL 
10. Endoscopy/EoE-EREFS/biopsy procedures should be performed after all other efficacy 
and safety assessments. The EndoFLIP procedure to measure esophageal distensibility may 
be performed during the esophagogastroscopy procedures at selected North American sites 
in approximately 150 adult patients. 
Note:  All randomized patients found to have stomach and/or duodenal abnormalities at 
baseline will have follow-up stomach and/or duodenal biopsies at weeks 24 and 52. 
a. For patients who receive rescue treatment, endoscopy/EoE-EREFS/biopsy procedures 
will be performed prior to initiation of rescue treatment. Patients undergoing 
endoscopy/biopsy prior to rescue will not undergo the scheduled endoscopy/biopsy at 
weeks 24 and 52. 
11. At visits 11 and 12, vital signs (body temperature, blood pressure, respiratory rate, heart 
rate) should be taken predose and 30 minutes (±10 minutes) post-dose. Only predose vital 
signs are required at subsequent visits. 
12. For adolescents only 
13. In case of a positive urine pregnancy test, the study treatment will be withheld and a serum 
pregnancy test to confirm the pregnancy should be performed as soon as possible. A 
confirmed pregnancy will lead to study drug discontinuation in all cases. 
14. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, 
the clinic staff should make every effort to contact the patient at the timepoint of the 
expected in-clinic visit to collect any AEs (including ISRs), any change in concomitant 
medications and/or procedures, and monthly pregnancy test results, if required. 
8.1.1.3. 
Footnotes for Table 3 
1. Patients who are withdrawn from study drug will be asked to complete the 12-week follow-
up period and the end of study visit. 
2. DSQ eDiary will be completed once daily by the patients after their last meal of the day 
but before they go to bed. Site personnel should conduct regular checks of patient eDiary 
compliance.  
3. PGIC and PGIS will be completed by the patient via electronic questionnaire at the 
indicated site visits. See Section 8.2.2.5 and Section 8.2.2.6. 
4. EoE Impact Questionnaire and EoE Symptom Questionnaire will be completed by the 
patient via electronic questionnaire at the indicated site visits. See Section 8.2.2.3 and 
Section 8.2.2.4. 
5. TNSS and RQLQ(S)+12 will be administered only to patients with a documented history 
of allergic rhinitis; ACQ-5 will be administered only to patients with a documented history 
of asthma, and only in countries in which a valid translation is available; POEM will be 
administered only to patients with a documented history of AD. TNSS, POEM, ACQ-5 
and RQLQ(S)+12 will be completed via electronic questionnaire and at the indicated site 
visits. See Section 8.2.2.7, Section 8.2.2.8, Section 8.2.2.9, and Section 8.2.2.10. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 71 of 113 
 
CONFIDENTIAL 
6. EoE-EREFS should be completed by the investigator before biopsies for all patients are 
performed. For Part B enrolled patients, EoE-EREFS will be performed by both the 
investigators who perform the endoscopies as well as a centralized reading center who 
will provide EoE-EREFS analysis and scoring from endoscopy imaging. For all 
endoscopies, the investigators will assess minor esophageal features including mucosal 
inflammatory and remodeling features.  
7. Endoscopy/EoE-EREFS/biopsy procedures should be performed after all other efficacy 
and safety assessments. The EndoFLIP procedure to measure esophageal distensibility may 
be performed during the esophagogastroscopy procedures at selected North American sites 
in approximately 150 adult patients. 
Note:  All randomized patients found to have stomach and/or duodenal abnormalities at 
baseline will have follow-up stomach and/or duodenal biopsies at weeks 24 and 52 or ET 
visit. 
a. For patients who receive rescue treatment during the double-blind treatment period, 
endoscopy/EoE-EREFS/biopsy procedures will be performed prior to initiation of 
rescue treatment. Rescue treatment should not be delayed if an endoscopy with 
biopsies cannot occur due to COVID-19 restrictions. Patients undergoing 
endoscopy/biopsy prior to rescue will not undergo the scheduled endoscopy/biopsy at 
weeks 24 and 52. 
8. Endoscopy/EoE-EREFS/biopsy will be performed only if the Unscheduled Visit is for the 
purpose of administering rescue therapy. 
9. For adolescents only. 
10. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, 
the clinic staff should make every effort to contact the patient at the timepoint of the 
expected in-clinic visit to collect any AEs (including ISRs), any change in concomitant 
medications and/or procedures, and monthly pregnancy test results, if required. 
8.1.2. 
Early Termination Visit 
Patients who are withdrawn from the study will be asked to return to the clinic for an ET visit 
consisting of the assessments described in Table 3. 
8.1.3. 
Unscheduled Visits before Rescue Treatment 
Before patients receive rescue treatment, efficacy assessments, PK and ADA sampling specified 
in Table 3 should be performed. 
8.1.4. 
Unscheduled Visits for Other Reasons 
All attempts should be made to keep patients on the study schedule. Unscheduled visits may be 
necessary to repeat testing following abnormal laboratory results, for follow-up of AEs, or for any 
other reason, as warranted. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 72 of 113 
 
CONFIDENTIAL 
8.2. 
Study Procedures 
8.2.1. 
Procedures Performed Only at the Screening/Baseline Visit 
The following procedures will be performed for the sole purpose of determining study eligibility 
or characterizing the baseline population:  serum follicle stimulating hormone (FSH) (for 
confirmation of menopausal status) and serology tests (HIV Ab, HBsAg, HBcAb, HCV Ab, and 
TB). Tuberculosis testing will be performed on a country-by-country basis according to local 
guidelines if required by regulatory authorities or ECs. 
8.2.2. 
Efficacy Procedures  
8.2.2.1. 
Endoscopy with EoE-EREFS and Biopsies, and Photographs 
During the endoscopy procedure, EoE-EREFS and biopsies will be performed in the listed order. 
Training will be provided to study sites on performing this procedure. All biopsies performed 
during this study will be evaluated by a qualified central histology laboratory. Photographs and/or 
video may be taken as part of the endoscopic procedure and biopsy collection. For Part B enrolled 
patients, video imaging should be collected for EoE-EREFS analysis and scoring by a centralized 
reading center. 
The endoscopy/EoE-EREFS/biopsy procedure will be performed per the Schedule of Events in 
Table 1, Table 2, and Table 3. 
EoE-EREFS 
The EoE esophageal characteristics will be analyzed based on the EoE-EREFS, a validated scoring 
system for inflammatory and remodeling features of disease using both overall scores and scores 
for each individual characteristic (Hirano, 2013). The proximal and distal esophageal regions will 
be scored separately; the score for each region ranges from 0 to 9 and the overall score ranges from 
0 to 18. The major esophageal features include:   
• Edema (absent, present) 
• Rings (absent, mild, moderate, severe) 
• Exudates (absent, mild, severe) 
• Furrows (absent, mild, severe) 
• Stricture (absent, present) 
EoE-EREFS should be completed by the investigator before biopsies for all patients are performed. 
For Part B enrolled patients, EoE-EREFS will be performed by both the investigators who perform 
the endoscopies as well as a centralized reading center who will provide EoE-EREFS analysis and 
scoring from endoscopy imaging. The centralized reading will be used for analysis, if available. If 
the centralized reading is not available, the EoE-EREFS performed by the investigator will be used 
for analysis. A copy of the EoE-EREFS is provided in the study regulatory binders. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 73 of 113 
 
CONFIDENTIAL 
In addition to the major features above, data for the following minor features will also be captured 
by the physician performing the endoscopy procedure: 
• Crepe paper esophagus (mucosal fragility or laceration upon passage of diagnostic 
endoscope): absent, present 
• Narrow caliber esophagus (reduced luminal diameter of the majority of the tubular 
esophagus): absent, present 
• Stricture diameter 
Mucosal changes associated with gastroesophageal reflux disease will also be recorded using the 
Los Angeles classification system for erosions (No Erosions or Grade A, B, C, or D). 
Biopsies 
Biopsies will be obtained by endoscopy at the second screening visit (visit 2, day -21 ± 7), week 24 
and week 52 visits, and immediately prior to start of rescue medication or procedures during the 
double-blind treatment period. The screening endoscopy should be performed at a time during the 
screening period that will allow results to be available prior to day -1 for assessment of eligibility. 
A total of 9 mucosal pinch biopsies will be collected at each time point from 3 esophageal regions:  
3 proximal, 3 mid, and 3 distal. Two samples from each region will be used for the histology 
(needed for study inclusion criteria, as well as endpoint assessment) and other tissue analyses (may 
include but not limited, to immunohistochemistry [IHC], RNA scope (in situ hybridization), and 
RNA sequencing). To participate in the study, patients must have a peak intraepithelial eosinophil 
count ≥15 eos/hpf (400×) in at least 2 of the 3 esophageal regions sampled. Any remaining tissue 
blocks will be banked for exploratory research. The third sample from each region will be 
processed for RNA analyses.  
In addition, biopsy specimens from the stomach and/or duodenum will be obtained at visit 2 in all 
patients <18 years of age to rule out alternate etiologies of esophageal eosinophilia. Targeted, 
stomach and/or duodenal biopsies will be obtained in adults only in the event of abnormal 
endoscopic findings (other than typical EoE findings) or clinical suspicion of alternate etiologies. 
Gastric biopsy samples should include 2 samples from the antrum and 2 samples from the body. 
Duodenal biopsy samples should include 2 bulb samples and 2 from another portion of the 
duodenum. All randomized patients found to have stomach and/or duodenal abnormalities at 
baseline will have follow-up stomach and/or duodenal biopsies at week 24 and week 52. 
Biopsy samples will be sent to a central pathology laboratory for processing and analysis. If 
required by the investigator institution, biopsy samples will be processed and analyzed by the local 
laboratory, and the processed specimen will be sent to the central pathology laboratory for central 
reading. These samples will be assessed for peak eos per hpf and EoE Grade Scores and Stage 
Scores will be assigned. EoE Grade and Stage Scores evaluate eight features: eosinophil density, 
basal zone hyperplasia, eosinophil abscesses, eosinophil surface layering, dilated intercellular 
spaces, surface epithelial alteration, dyskeratotic epithelial cells, and lamina propria fibrosis 
(absent/present). Additional analyses on these data may also be performed. 
Assessment of lamina propria fibrosis may not be possible if the esophageal biopsy specimens do 
not contain adequate amounts of subepithelium lamina propria and then will not be included in the 
overall EoE Grade and Stage Scores. Severity (grade) and extent (stage) of abnormalities will be 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 74 of 113 
 
CONFIDENTIAL 
scored using a 4-point scale (0 normal; 3 maximum change). The endoscopy with biopsies 
procedure will be performed the same way at all scheduled visits. 
Histology results will be interpreted by a pathologist at a central pathology reading center who will 
be blinded to the treatment assignment. Detailed instructions for biopsy sample collection and 
handling will be provided in the study regulatory binders. 
EndoFLIP 
A substudy of esopohageal distensibility utilizing the endolumenal functional lumen imaging 
probe (EndoFLIP, Medtronic, USA) may also be performed at selected North American sites in 
approximately 150 adult patients, with measurements taken as part of the esophagogastroscopy 
procedure performed at screening, week 24 and week 52. The EndoFLIP procedure must be 
performed before biopsies are collected. Procedural order should be: EREFS/imaging, EndoFLIP, 
then biopsies. The EndoFLIP device is a catheter-based procedure that measures the cross-
sectional area at multiple sites along the esophagus with simultaneous intraluminal pressure 
recordings during volumetric distension of the esophagus. The analyses of cross sectional area 
versus pressure relationships of the esophagus allow for determination of esophageal compliance 
as well as the distensibility plateau. The distensibility plateau has been shown to be significantly 
reduced in adult patients with EoE compared to healthy controls (Kwiatek, 2011). Moreover, the 
esophageal distensibility has been associated with outcomes of both food impaction and need for 
esophageal dilation (Nicodème, 2013). Details of the EndoFLIP procedure will be provided in the 
study regulatory binders. 
Photographs and/or Video 
Photographs and/or video may be taken by the site as part of the endoscopic procedure and biopsy 
collection. A copy of these photographs and/or video will be requested from the study sites. Details 
for collecting and sending these photographs and/or video will be provided in the study regulatory 
binders. For Part B enrolled patients, video imaging should be collected for EoE-EREFS analysis 
and scoring by a centralized reading center. 
8.2.2.2. 
Dysphagia Symptom Questionnaire (DSQ) - Patient-reported Outcome (PRO) 
The DSQ is a validated PRO that has been used in clinical studies to measure the frequency and 
intensity of dysphagia (Hudgens, 2017). For patients who respond “No” to Question 1 (“Since you 
woke up this morning, did you eat solid food?”), a modification was made to the DSQ by asking 
a follow-up question to probe if patients avoided solid food due to their problems with swallowing 
solid food. This modified DSQ will be completed by the patient daily using an eDiary from 
screening through end of study or ET visit. A copy of the DSQ is provided in the study regulatory 
binders. 
The DSQ uses a daily recall period and comprises 3 questions on the presence and severity of EoE 
dysphagia. All patients respond to questions 1 and 2 and are required to have eaten solid foods 
(‘Yes’ to question 1: “Since you woke up this morning, did you eat solid food?”) in order to 
proceed with the questionnaire. If a patient answers “No” to question 1, the remaining items on 
the DSQ are not scored. Patients who respond “No” to question 2 (“Since you woke up this 
morning, has food gone down slowly or been stuck in your throat?”) are given a score of zero, and 
do not go on to answer question 3 (the diary is recorded as completed for that day). Those who 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 75 of 113 
 
CONFIDENTIAL 
respond ‘Yes’ to questions 1 and 2 move on to question 3, which is scored on a 5-point scale that 
infers severity of dysphagia based on the patient’s action to alleviate symptoms, ranging from no 
action to seeking medical attention. The DSQ scoring algorithm is therefore constructed from the 
responses to questions 2 and 3, to ensure that the final score is driven by the frequency and severity 
of dysphagia. To calculate the DSQ score, a minimum of 8 diary entries is required for each 14-day 
period to derive a standardized total score based on the cumulative scores through 14 days. DSQ 
scores can theoretically range from 0 to 84, with a lower score indicating less-frequent or less-
severe dysphagia.  
Although Question 4 related to pain was included in the DSQ, it is considered as a standalone item 
for exploratory analysis.  
8.2.2.3. 
EoE Impact Questionnaire (EoE-IQ) 
The EoE-IQ is a disease-specific measure of health-related QOL in EoE patients developed by the 
sponsor. The EoE-IQ measures EoE impact on emotional, social, work and school, and sleep 
aspect of a patient. 
This assessment will be recorded by the patient using electronic questionnaire per the Schedule of 
Events in Table 1, Table 2, and Table 3. A copy of the EoE-IQ is provided in the study regulatory 
binders. If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, 
after visit 3/day 1, site staff should make every effort to conduct telephone interviews to complete 
these questionnaires. Site staff should conduct the telephone interviews on the date of scheduled 
site visit by following an interview guide provided by the sponsor. Patient responses from the 
interviewer administered questionnaires will be captured by the site staff on a paper-copy print-
out of the questionnaire screenshots.  
8.2.2.4. 
EoE Symptom Questionnaire 
The EOE Symptom Questionnaire is a questionnaire measuring the frequency and severity of 
symptoms other than dysphagia and pain with swallowing. It is developed by the sponsor. The 
EoE Symptom Questionnaire will be completed by patients using electronic questionnaire per the 
Schedule of Events in Table 1, Table 2, and Table 3. 
If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, after 
visit 3/day 1, site staff should make every effort to conduct telephone interviews to complete these 
questionnaires. Site staff should conduct the telephone interviews on the date of scheduled site 
visit by following an interview guide provided by the sponsor. Patient responses from the 
interviewer administered questionnaires will be captured by the site staff on a paper-copy print-
out of the questionnaire screenshots.  
8.2.2.5. 
Patient Global Impression of Change (PGIC) of Dysphagia 
The PGIC is a one-item questionnaire that asks patients to provide the overall self-assessment of 
change of difficulty swallowing food. The PGIC will be completed by patients using electronic 
questionnaire per the Schedule of Events in Table 1, Table 2, and Table 3. 
If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, after 
visit 3/day 1, site staff should make every effort to conduct telephone interviews to complete these 
questionnaires. Site staff should conduct the telephone interviews on the date of scheduled site 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 76 of 113 
 
CONFIDENTIAL 
visit by following an interview guide provided by the sponsor. Patient responses from the 
interviewer administered questionnaires will be captured by the site staff on a paper-copy print-
out of the questionnaire screenshots.  
8.2.2.6. 
Patient Global Impression of Severity (PGIS) of Dysphagia 
The PGIS is a one-item questionnaire that asks patients to provide the overall self-assessment of 
difficulty of swallowing food. The PGIS will be completed by patients using electronic 
questionnaire per the Schedule of Events in Table 1, Table 2, and Table 3. 
If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, after 
visit 3/day 1, site staff should make every effort to conduct telephone interviews to complete these 
questionnaires. Site staff should conduct the telephone interviews on the date of scheduled site 
visit by following an interview guide provided by the sponsor. Patient responses from the 
interviewer administered questionnaires will be captured by the site staff on a paper-copy print-
out of the questionnaire screenshots.  
8.2.2.7. 
Total Nasal Symptom Score (TNSS) 
The Total Nasal Symptom Score (TNSS), measured on a 0-9 scale, is a composite symptom 
assessment of congestion, itching/sneezing, and rhinorrhea (each graded on a 0-3 scale, 3 being 
severe). The TNSS will be administered only to patients with a documented history of allergic 
rhinitis and who fluently speak a language in which the questionnaire is presented (based on 
availability of translations in participating countries). The TNSS will be completed by patients per 
the Schedule of Events in Table 1, Table 2, and Table 3. 
If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, after 
visit 3/day 1, site staff should make every effort to conduct telephone interviews to complete these 
questionnaires. Site staff should conduct the telephone interviews on the date of scheduled site 
visit by following an interview guide provided by the sponsor. Patient responses from the 
interviewer administered questionnaires will be captured by the site staff on a paper-copy print-
out of the questionnaire screenshots.  
8.2.2.8. 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire for ages 12+ 
[RQLQ(S)+12] 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire for ages 12+ [RQLQ(S)+12] is a 
self-administered questionnaire to measure health-related QOL in those 12 years of age and above, 
as a result of perennial or seasonal allergic rhinitis. There are 28 items on the RQLQ(S) in 
7 domains:  activity limitation, sleep problems, nasal symptoms, eye symptoms, non-nasal/eye 
symptoms, practical problems, and emotional function. The RQLQ(S)+12 responses are based on 
a 7-point Likert scale with responses ranging from 0 (not troubled) to 6 (extremely troubled). The 
overall RQLQ(S)+12 score is the mean of all 28 responses and the individual domain scores are 
the means of the items in those domains. Higher scores indicated more health-related QOL 
impairment (lower scores were better). A change of 0.5 point or more in total score is considered 
to be clinically meaningful. 
The RQLQ(S)+12 will be performed per the Schedule of Events in Table 1, Table 2, and Table 3. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 77 of 113 
 
CONFIDENTIAL 
If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, after 
visit 3/day 1, site staff should make every effort to conduct telephone interviews to complete these 
questionnaires. Site staff should conduct the telephone interviews on the date of scheduled site 
visit by following an interview guide provided by the sponsor. Patient responses from the 
interviewer administered questionnaires will be captured by the site staff on a paper-copy print-
out of the questionnaire screenshots.  
8.2.2.9. 
Juniper Asthma Control Questionnaire (ACQ) 
The 5-question version of the Juniper ACQ (ACQ-5) is a validated questionnaire to evaluate 
asthma control. The ACQ-5 score is the mean of the scores of the 5 items and ranges from 0 (totally 
controlled) to 6 (severely uncontrolled). Scores less than 1.0 reflect adequately controlled asthma, 
and scores 1.0 or greater reflect inadequately controlled asthma. Higher score indicates lower 
asthma control. The recommended change of 0.50 is a reasonable threshold to define a meaningful 
individual-level change. The ACQ-5 will be administered only to patients with a documented 
history of asthma and who fluently speak a language in which the questionnaire is presented (based 
on availability of validated translations in participating countries). The ACQ-5 will be completed 
by patients using electronic questionnaire per the Schedule of Events in Table 1, Table 2, and 
Table 3. 
If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, after 
visit 3/day 1, site staff should make every effort to conduct telephone interviews to complete these 
questionnaires. Site staff should conduct the telephone interviews on the date of scheduled site 
visit by following an interview guide provided by the sponsor. Patient responses from the 
interviewer administered questionnaires will be captured by the site staff on a paper-copy print-
out of the questionnaire screenshots.  
8.2.2.10. Patient-Oriented Eczema Measure (POEM) 
The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess 
disease symptoms in children and adults with AD (Charman, 2004). The format is a response to 
7 items (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) using a 5-point 
scale, based on frequency of occurrence during the past week. The possible scores for each 
question were:  0 (no days), 1 (1 to 2 days), 2 (3 to 4 days), 3 (5 to 6 days), and 4 (every day), with 
a composite scoring system of 0 to 28; a higher score is indicative of more severe AD. 
The following POEM banding scores have been established (Charman, 2004):  0 to 2=clear or 
almost clear; 3 to 7=mild eczema; 8 to 16=moderate eczema; 17 to 24=severe eczema; and 25 to 
28=very severe eczema. 
The POEM will be administered only to patients with a documented history of AD and who 
fluently speak a language in which the questionnaire is presented (based on availability of 
validated translations in participating countries). The POEM will be completed by patients per the 
Schedule of Events in Table 1, Table 2, and Table 3. 
If COVID-19 restrictions limit the availability of staff or the patient to have in-clinic visits, after 
visit 3/day 1, site staff should make every effort to conduct telephone interviews to complete these 
questionnaires. Site staff should conduct the telephone interviews on the date of scheduled site 
visit by following an interview guide provided by the sponsor. Patient responses from the 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 78 of 113 
 
CONFIDENTIAL 
interviewer administered questionnaires will be captured by the site staff on a paper-copy print-
out of the questionnaire screenshots.  
8.2.2.11. European Quality of Life 5-Dimensional Scale (EQ-5D) 
The European Quality of Life 5-dimension (EQ-5D) scale is a standardized questionnaire used to 
assess health status (Rabin, 2014) (Brooks, 1996). It consists of a descriptive system and the EQ 
visual analogue scale (EQ VAS). The EQ-5D-3L (3-level) descriptive system comprises of the 
following 
5 
dimensions: 
mobility, 
self-care, 
usual 
activities, pain/discomfort, 
and 
anxiety/depression. For each dimension, patients select one of 3 levels: no problems, some 
problems, and extreme problems. The EQ VAS records the patient’s self-rated health on a vertical 
visual analogue scale where the endpoints are labelled ‘Best imaginable health state’ and ‘Worst 
imaginable health state’. The EQ-5D-3L will be completed by patients per the Schedule of Events 
in Table 1. 
8.2.3. 
Safety Procedures  
8.2.3.1. 
Vital Signs 
Vital signs, including heart rate, blood pressure, respiratory rate, and body temperature will be 
collected predose and 30 minutes post-dose at time points listed in Table 1, Table 2, and Table 3. 
Heart rate and blood pressure will be measured with the patient in a sitting position, after the 
patient has rested comfortably for at least 5 minutes. 
8.2.3.2. 
Physical Examination 
A thorough and complete physical examination will be performed at time points according to 
Table 1, Table 2, and Table 3. Care should be taken to examine and assess any abnormalities that 
may be present, as indicated by the patient’s medical history. 
8.2.3.3. 
Body Weight and Height 
Body weight and height will be measured at time points according to Table 1, Table 2, and Table 3. 
8.2.3.4. 
Electrocardiogram 
Electrocardiograms (ECG) will be performed before blood is drawn during visits requiring blood 
draws. A standard 12-lead ECG will be performed predose at time points listed in Table 1, Table 2, 
and Table 3. Heart rate will be recorded from the ventricular rate and the PR, QRS, and QT 
(identify QTcB or QTcF) intervals will be recorded. The ECG strips or reports will be retained 
with the source documentation, and the results will be documented in the electronic case report 
form (eCRF). 
Electrocardiogram results will be interpreted by a central reading center. Instructions for 
performing the assessment and transmitting ECG data are provided in the study regulatory binders. 
8.2.3.5. 
Laboratory Testing 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory. Samples will be collected predose at time points listed in Table 1, Table 2, and Table 3. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 79 of 113 
 
CONFIDENTIAL 
Detailed instructions for blood sample collection are in the laboratory manual provided to study 
sites. Tests will include: 
Blood Chemistry 
Sodium 
Total protein, serum 
Total and indirect bilirubin 
Potassium 
Creatinine 
Total cholesterol 
Chloride 
Blood urea nitrogen (BUN) 
Low-density lipoprotein (LDL) 
Carbon dioxide 
AST 
High-density lipoprotein (HDL) 
Calcium 
ALT 
Triglycerides 
Glucose 
Alkaline phosphatase 
Uric acid 
Albumin 
Lactate dehydrogenase (LDH) 
Estimated glomerular filtration rate (eGFR) 
Creatine phosphokinase (CPK)1 
 
1 CPK isoenzymes will be measured when CPK >5 × ULN  
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Microscopic analysis will only be done in the event of abnormal dipstick results. 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
Other Laboratory Tests 
• Pregnancy testing will be performed for all women of childbearing potential. Serum or 
urine pregnancy testing will be performed at time points listed in Table 1, Table 2, and 
Table 3. A serum FSH test will be performed if menopausal status is in question. 
• The following tests will be performed at screening:  HIV, HBsAg, HBsAb, HBcAb, 
hepatitis C Ab, TB (will be performed on a country-by-country basis according to local 
guidelines if required by regulatory authorities or ethics boards), and alcohol and drug 
screen test. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 80 of 113 
 
CONFIDENTIAL 
Abnormal Laboratory Values and Laboratory Adverse Events 
All laboratory values must be reviewed by the investigator or authorized designee. 
Significantly abnormal test results that occur after start of treatment must be repeated to confirm 
the nature and degree of the abnormality. When necessary, appropriate ancillary investigations 
should be initiated. If the abnormality fails to resolve or cannot be explained by events or 
conditions unrelated to the study medication or its administration, the Medical/Study Director must 
be consulted.  
The clinical significance of an abnormal test value, within the context of the disease under study, 
must be determined by the investigator. 
Criteria for reporting laboratory values as an AE are provided in Section 9.4.5. 
8.2.4. 
Drug Concentration and Measurements 
Samples for functional dupilumab concentration in serum will be collected predose at visits listed 
in Table 1, Table 2, and Table 3. Detailed instructions for blood sample collection are included in 
the laboratory manual provided to study sites 
Any unused samples may be used for exploratory biomarker research. 
8.2.5. 
Anti-Drug Antibody Measurements and Samples 
Samples for ADA assessment will be collected predose at time points listed in Table 1, Table 2, 
and Table 3. Detailed instructions for blood sample collection are included in the laboratory 
manual provided to study sites. 
Any unused samples may be used for exploratory biomarker research. 
8.2.6. 
Pharmacodynamic and Exploratory Biomarker Procedures 
In this study, research assessments will be performed to explore EoE, how dupilumab may modify 
the underlying disease process in EoE, type 2 inflammation, and predictors of dupilumab safety 
and efficacy.  
Samples for eotaxin-3 (heparinized plasma); serum TARC, total IgE, and allergen-specific IgE and 
IgG4s will be collected at time points according to Table 1 and Table 2. The biomarkers studied 
are believed to be relevant to the pathophysiology of EoE, response to treatment (ie, assessment 
of type 2 inflammation) and baseline predictors of response and dupilumab mechanism of action. 
8.2.6.1. 
EoE Diagnostic Panel and Type 2 Inflammation Transcriptomics 
The differential gene expression profiles of esophageal biopsies of EoE patients compared to 
healthy controls is the EoE disease transcriptome (Sherrill, 2014). This disease gene expression 
signature was further refined to a smaller gene set to be used as an EoE diagnostic panel (EDP) 
(Dellon, 2017). A gene signature representing type 2 inflammation has been curated from the 
literature, preclinical experiments performed at Regeneron, and dupilumab response signatures 
from atopic dermatitis and a phase 2 study of EoE (Regeneron unpublished data). The gene lists 
comprising the EDP and type 2 transcriptomes can be found in the statistical analysis plan (SAP). 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 81 of 113 
 
CONFIDENTIAL 
In a phase 2 study of EoE (R668-EE-1324), dupilumab significantly decreased the disease, EDP, 
and type 2 transcriptome signatures (Regeneron unpublished data).  
Normalized Enrichment Score (NES) reflects the degree to which the activity level of a set of 
transcripts is overrepresented at the extremes (top or bottom) of the entire ranked list of transcripts 
within a sample and is normalized by accounting for the number of transcripts in the set 
(Subramanian, 2005) (Barbie, 2009). NES scores will be calculated for each transcriptome 
signature for each sample for statistical analyses, collected as part of procedures in Table 1, 
Table 2, and Table 3. 
8.2.6.2. 
Type 2 Inflammatory and Disease-Related Circulating Biomarkers 
Eotaxin-3, Thymus and Activation Regulated Chemokine (TARC), and IgE (total and specific) are 
measures of type 2 inflammation, and are known pharmacodynamic markers for dupilumab in AD, 
asthma, and nasal polyposis. 
8.2.6.2.1. Eotaxin-3 
Eotaxin-3 (also known as CCL26), an eosinophil chemokine, is up-regulated in esophageal mucosa 
of EoE patients relative to controls (Blanchard, 2006), and variants in the gene have been 
associated with disease risk. Eotaxin-3 mRNA expression in skin is down-regulated by dupilumab 
in AD (Hamilton, 2014). Circulating concentrations have been shown to decrease in asthma and 
nasal polyposis patients treated with dupilumab. Eotaxin-3 will be measured in heparinized plasma 
from samples collected at time points indicated in Table 1 and Table 2. Modulation of eotaxin-3 
is an exploratory measure. Data analysis will be described in the SAP and the results will be 
provided in the clinical study report (CSR).  
8.2.6.2.2. Thymus and Activation Regulated Chemokine (TARC) 
TARC is a type 2 chemokine for Th2 cells and other inflammatory cells expressing the CCR4 
receptor. TARC expression is regulated by IL4 and IL13, and rapidly decreases upon dupilumab 
treatment in AD, asthma, and nasal polyps. Serum TARC will be measured at time points indicated 
in Table 1 and Table 2. Modulation of TARC is an exploratory measure. Data analysis will be 
described in the SAP and the results will be provided in the CSR. 
8.2.6.2.3. Total and Allergen-Specific IgEs 
IL4 and IL13 regulate B cell class switching to, as well as production of, IgE. Dupilumab has been 
shown to suppress IgE (total and allergen-specific) in AD, asthma, and nasal polyposis patients. 
Serum concentrations of IgE (total and a panel of allergen-specific) will be measured at time points 
indicated in Table 1. Modulation of IgE is an exploratory measure. Data analysis will be described 
in the SAP and the results will be provided in the CSR. 
8.2.6.2.4. Allergen-Specific IgG4s 
Allergen-specific IgG4s have been found to be elevated in esophageal tissue and in circulation of 
EoE patients. Because the factors driving histological abnormalities and symptoms are unclear, 
IgG4 has been proposed as a pathological driver in the disease (Clayton, 2014) (Wright, 2016). To 
evaluate the potential role of IgG4 in EoE pathogenesis, as well as whether or not dupilumab 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 82 of 113 
 
CONFIDENTIAL 
modulates these markers, a panel of serum allergen-specific IgG4s will be measured in samples 
collected at times indicated in Table 1 and Table 2. Modulation of allergen-specific IgG4s is an 
exploratory measure. Data analysis will be described in the SAP and results will be provided in 
the CSR. 
8.2.7. 
Future Biomedical Research (FBR) Serum/Plasma (Optional) 
Patients/parents or legal guardians who agree to participate in the future biomedical research 
(FBR) substudy will be required to consent to this optional substudy before FBR samples are 
collected and banked in long-term storage. The unused biomarker samples for study-related 
research, as well as unused PK and ADA samples, will be stored for up to 15 years after the final 
date of the database lock. The FBR samples may be utilized for future biomedical research of EoE 
and related diseases, and the effects of dupilumab on target pathway modulation. Additional 
samples will be collected for future biomedical research according to Schedule of Events in 
Table 1, Table 2, and Table 3. After 15 years, any residual samples will be destroyed. The results 
of these future biomedical research analyses will not be presented in the CSR. Patients are not 
required to participate in the FBR substudy in order to enroll in the primary study. 
8.2.7.1. 
Genomics Substudy (Optional) 
Patients/parent or legal guardians who agree to participate in the genomics substudy will be 
required to consent to this optional substudy before collection of the samples. Patients are not 
required to participate in the genomics substudy in order to enroll in the primary study. 
Whole blood samples for DNA extraction should be collected on day 1/baseline (predose), but can 
be collected at a later study visit. Whole blood samples for RNA extraction will be collected at 
time points according to Table 1. 
DNA and blood RNA samples will be collected for the pharmacogenomics analyses to understand 
the genetic determinants of efficacy and safety associated with the treatments in this study, and the 
molecular basis of EoE and related diseases. These samples will be single-coded as defined by the 
International Council on Harmonisation (ICH) guideline E15. Samples will be stored for up to 
15 years after the final date of the database lock.  
The purpose of the pharmacogenomic analyses is to identify genomic associations with clinical or 
biomarker response to dupilumab, other EoE clinical outcome measures, and possible AEs. In 
addition, associations between genomic variants and prognosis or progression of EoE as well as 
related allergic/atopic diseases may also be studied. These data may be used or combined with data 
collected from other studies to identify and validate genomic markers related to the study drug or 
EoE and related diseases.  
Analyses may include sequence determination or single nucleotide polymorphism studies of 
candidate genes and surrounding genomic regions. Other methods, including whole-exome 
sequencing, whole-genome sequencing, DNA copy number variation, and transcriptome 
sequencing (or other methods for quantitating RNA expression) may also be performed. The list 
of methods may be expanded to include novel methodology that may be developed during the 
course of this study or sample storage period. Results from the genomic analyses will not be 
reported in the CSR. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 83 of 113 
 
CONFIDENTIAL 
9. 
SAFETY DEFINITIONS, REPORTING, AND MONITORING 
9.1. 
Obligations of Investigator 
The investigator must promptly report to the Institutional Review Board (IRB)/EC all 
unanticipated problems involving risks to patients/subjects, according to local regulations. This 
may include death from any cause and all SAEs related to the use of the study drug. It is 
recommended that all SAEs be reported to the IRB/EC, according to local regulations. 
9.2. 
Obligations of Sponsor 
During the course of the study, the sponsor will report in an expedited manner all SAEs that are 
both unexpected and at least reasonably related to the study drug (SUSAR), to the health 
authorities, ECs/IRBs as appropriate, and to the investigators (in a blinded manner).  
Any AE not listed as an expected event in the Reference Safety Information section of the 
Investigator’s Brochure will be considered as unexpected. Any worsening of or new onset of 
symptoms related to EoE during the screening period prior to study drug administration will be 
considered expected. 
At the completion of the study, the sponsor will report all safety observations made during the 
conduct of the trial in the CSR to health authorities and ECs/IRBs as appropriate.  
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE is any untoward medical occurrence in a patient administered a study drug which may or 
may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally 
associated with the use of a study drug, whether or not considered related to the study drug. 
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
9.3.2. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death – includes all deaths, even those that appear to be completely unrelated 
to study drug (eg, a car accident in which a patient is a passenger). 
• Is life-threatening – in the view of the investigator, the patient is at immediate risk of 
death at the time of the event. This does not include an AE that had it occurred in a 
more severe form, might have caused death. 
• Requires in-patient hospitalization or prolongation of existing hospitalization. 
In-patient hospitalization is defined as admission to a hospital (any duration) or an 
emergency room visit for longer than 24 hours. Prolongation of existing hospitalization 
is defined as a hospital stay that is longer than was originally anticipated for the event, 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 84 of 113 
 
CONFIDENTIAL 
or is prolonged due to the development of a new AE as determined by the investigator 
or treating physician. 
• Results in persistent or significant disability/incapacity (substantial disruption of 
one’s ability to conduct normal life functions). 
• Is a congenital anomaly/birth defect 
• Is an important medical event – Important medical events may not be immediately 
life-threatening or result in death or hospitalization, but may jeopardize the patient or 
may require intervention to prevent one of the other serious outcomes listed above 
(eg, intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse). 
Criteria for reporting SAEs must be followed for these events. See Section 9.4 for more 
information on recording and reporting SAEs. 
9.3.3. 
Adverse Events of Special Interest 
An adverse event of special interest (AESI; serious or non-serious) is one of scientific and medical 
concern specific to the sponsor’s product or program, for which ongoing monitoring and rapid 
communication by the investigator to the sponsor can be appropriate. Such an event might warrant 
further investigation in order to characterize and understand it. Depending on the nature of the 
event, rapid communication by the trial sponsor to other parties (eg, regulators) might also be 
warranted (Section 9.4.3). 
9.4. 
Recording and Reporting Adverse Events  
9.4.1. 
Adverse Events 
The investigator (or designee) will record all AEs that occur from the time the informed consent 
is signed until the end of study. Refer to the study regulatory binders for the procedures to be 
followed. 
Information on follow-up for AEs is provided in Section 9.4.6. Laboratory, vital signs, or ECG 
abnormalities are to be recorded as AEs as outlined in Section 9.4.5. 
9.4.2. 
Serious Adverse Events 
All SAEs, regardless of assessment of causal relationship to study drug, must be reported to the 
sponsor (or designee) within 24 hours. Refer to the study regulatory binders for the procedure to 
be followed. 
Information not available at the time of the initial report must be documented in a follow-up report. 
Substantiating data such as relevant hospital or medical records and diagnostic test reports may 
also be requested. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 85 of 113 
 
CONFIDENTIAL 
In the event the investigator is informed of an SAE after the patient completes the study, the 
following will apply: 
• SAE with an onset within 30 days of the end of study or within 84 days (12 weeks) of 
last study drug administration if the patient early terminated from the study – the SAE 
will be reported to the sponsor. The investigator should make every effort to obtain 
follow-up information on the outcome until the event is considered chronic and/or 
stable. 
• SAE with an onset day greater than 30 days from the end of study or ET visit – only 
fatal SAEs and those deemed by the investigator to be drug-related SAEs will be 
reported to the sponsor. The investigator should make every effort to obtain follow-up 
information on the outcome of a drug-related SAE until the event is considered chronic 
and/or stable. 
9.4.3. 
Other Events that Require Accelerated Reporting to Sponsor 
The following events also require reporting to the sponsor (or designee) within 24 hours of learning 
of the event: 
Symptomatic Overdose of Study Drug: 
Accidental or intentional overdose of at least 2 times 
the intended dose of study drug within the intended therapeutic window, if 
associated with an AE. 
Pregnancy: 
Although pregnancy is not considered an AE, it is the responsibility of the 
investigator to report to the sponsor (or designee), within 24 hours of identification, 
any pregnancy occurring in a female study patient, during the study or within 
12 weeks of the last dose of study drug. Any complication of pregnancy affecting 
a female study patient and/or fetus and/or newborn that meets the SAE criteria must 
be reported as an SAE. Outcome for all pregnancies should be reported to the 
sponsor. 
Adverse Events of Special Interest: All AESI, serious and non-serious, must be reported within 
24 hours of identification using the same reporting process as for SAE reporting, 
per Section 9.4.2. Adverse events of special interest for this study include the 
following:   
• Anaphylactic reactions  
• Systemic hypersensitivity reactions  
• Helminthic infections 
• Any severe type of conjunctivitis or blepharitis 
• Keratitis 
• Clinically symptomatic eosinophilia (or eosinophilia associated with clinical 
symptoms)  
• Severe injection site reactions 
• Herpes simplex infection 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 86 of 113 
 
CONFIDENTIAL 
• Arthralgia 
Refer to the study manual for the procedures to be followed. 
9.4.4. 
Reporting Adverse Events Leading to Withdrawal from the Study 
All AEs that lead to a patient’s withdrawal from the study must be reported to the sponsor’s 
Medical/Study Director within 30 days. 
Refer to the study regulatory binders for the procedures to be followed. 
9.4.5. 
Abnormal Laboratory, Vital Signs, or Electrocardiogram Results 
The criteria for determining whether an abnormal objective test finding should be reported as an 
AE include: 
• The test result is associated with accompanying symptoms, and/or 
• The test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
• The test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments), discontinuation from the study, significant additional concomitant drug 
treatment, or other therapy 
Contact the Medical/Study Director in the event the investigator feels that an abnormal test finding 
should be reported as an AE, although it does not meet any of the above criteria. 
Repeating an abnormal test, in the absence of any of the above conditions, does not constitute an 
AE. Any abnormal test result that is determined to be an error does not require reporting as an AE. 
Evaluation of severity of laboratory abnormalities will be assessed according to the scale outlined 
in Section 9.5.1. 
9.4.6. 
Follow-up 
Adverse event information will be collected until the patient’s last study visit. 
Serious adverse event information will be followed up until the event is resolved or considered 
chronic and/or stable. 
9.5. 
Evaluation of Severity and Causality 
9.5.1. 
Evaluation of Severity 
The severity of AEs will be graded according to the following scale: 
Mild:  Does not interfere in a significant manner with the patient’s normal functioning level. It 
may be an annoyance. Prescription drugs are not ordinarily needed for relief of symptoms, but may 
be given because of personality of the patient. 
Moderate:  Produces some impairment of functioning but is not hazardous to health. It is 
uncomfortable or an embarrassment. Treatment for symptom may be needed. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 87 of 113 
 
CONFIDENTIAL 
Severe:  Produces significant impairment of functioning or incapacitation and is a definite hazard 
to the subject’s health. Treatment for symptom may be given and/or patient hospitalized. 
If a laboratory value is considered an AE, its severity should be based on the degree of 
physiological impairment the value indicates. 
Injection Site Reactions 
The severity of ISRs will be graded according to the following scale (semi-colon indicates “or” 
within description of grade): 
Mild:  Pain that does not interfere with activity; mild discomfort to touch; <5 cm of erythema or 
induration that does not interfere with activity 
Moderate:  Pain that requires repeated use of non-narcotic pain reliever >24 hours or interferes 
with activity; discomfort with movement; 5.1 cm to 10 cm erythema or induration or induration 
that interferes with activity 
Severe:  Pain that requires any use of narcotic pain reliever or that prevents daily activity; 
significant discomfort at rest; >10 cm erythema or induration; prevents daily activity; requires ER 
visit or hospitalization; necrosis or exfoliative dermatitis 
9.5.2. 
Evaluation of Causality 
Relationship of Adverse Events to Study Drug: 
The relationship of AEs to study drug will be assessed by the blinded investigator, and will be a 
clinical decision based on all available information. The following question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the study drug? 
The possible answers are: 
Not Related: 
There is no reasonable possibility that the event may have been caused by 
the study drug. 
Related: There is a reasonable possibility that the event may have been caused by the study 
drug. 
The investigator should justify the causality assessment of each SAE. 
A list of factors to consider when assessing the relationship of AEs to study drug is provided below. 
Please note that this list is not exhaustive. 
Is there a reasonable possibility that the event may have been caused by the study drug? 
No: 
• Due to external causes such as environmental factors or other treatment(s) being 
administered 
• Due to the patient’s disease state or clinical condition 
• Do not follow a reasonable temporal sequence following the time of administration of 
the dose of study drug 
• Do not reappear or worsen when dosing with study drug is resumed 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 88 of 113 
 
CONFIDENTIAL 
• Are not a suspected response to the study drug based upon preclinical data or prior 
clinical data 
Yes: 
• Could not be explained by environmental factors or other treatment(s) being 
administered 
• Could not be explained by the patient’s disease state or clinical condition 
• Follow a reasonable temporal sequence following the time of administration of the dose 
of study drug  
• Resolve or improve after discontinuation of study drug  
• Reappear or worsen when dosing with study drug  
• Are known or suspected to be a response to the study drug based upon preclinical data 
or prior clinical data 
Relationship of Adverse Events to Study Procedure:  
The relationship of AEs to study procedure (eg, endoscopy or biopsy) will be assessed by the 
investigator, and will be a clinical decision based on all available information. The following 
question will be addressed: 
Is there a reasonable possibility that the AE may have been caused by the procedure? 
The possible answers are: 
Not Related: 
There is no reasonable possibility that the event may have been caused by 
the procedure. 
Related: 
There is a reasonable possibility that the event may have been caused by the 
procedure. 
The sponsor will request information to justify the causality assessment of SAEs, as needed. 
9.6. 
Safety Monitoring 
The investigator will monitor the safety of study patient at his/her site(s) as per the requirements 
of this protocol and consistent with current Good Clinical Practice (GCP). Any questions or 
concerns should be discussed with the sponsor in a timely fashion. The sponsor will monitor the 
safety data from across all study sites. The Medical/Study Director will have primary responsibility 
for the emerging safety profile of the compound, but will be supported by other departments (eg, 
Pharmacovigilance and Risk Management (PVRM); Biostatistics and Data Management). Safety 
monitoring will be performed on an ongoing basis (eg, individual review of SAEs) and on a 
periodic cumulative aggregate basis. 
In addition, the DMC will conduct safety reviews for all dupilumab studies (see details in 
Section 5.3.1). 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 89 of 113 
 
CONFIDENTIAL 
9.7. 
Investigator Alert Notification 
Regeneron (or designee) will inform all investigators participating in this clinical trial, as well as 
in any other clinical trial using the same investigational drug, of any SAE that meets the relevant 
requirements for expedited reporting (an AE that is serious, unexpected based on the reference 
safety information in the Investigator’s Brochure, and has a reasonable suspected causal 
relationship to the study drug). 
10. 
STATISTICAL PLAN 
This section provides the basis for the SAPs for the study. The part-specific SAP(s) may be revised 
during the study to accommodate amendments to the clinical study protocol and to make changes 
to adapt to unexpected issues in study execution and data that may affect the planned analyses. 
The final SAP(s) will be issued before the database is locked for respective part. 
Analysis variables are listed in Section 4. 
Results from different parts of this study will be summarized and/or analyzed separately unless 
otherwise specified. 
10.1. 
Statistical Hypothesis  
For comparisons of each of the 2 dupilumab treatment groups to placebo, the following hypotheses 
of the co-primary endpoints will be tested, where pd is the true proportion of patients achieving 
peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 24 and μd is the true mean 
change from baseline in the DSQ total score at week 24 in each of the dupilumab group; and pp 
and μp are the corresponding true values in the placebo group. 
• Null hypothesis (H0):  pp = pd or μp = μd, ie, the proportion of patients achieving peak 
esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 24 OR the mean 
change from baseline in the DSQ total score at week 24 is the same between the 
dupilumab group and the placebo group. 
• Alternative hypothesis (H1):  pp ≠ pd and μp ≠ μd, ie, the proportion of patients 
achieving peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 24 
AND the mean change from baseline in the DSQ total score at week 24 is different 
between the dupilumab group and the placebo group. 
10.2. 
Justification of Sample Size 
The assumptions used in sample size calculations for Part A are based on results from a phase 2 
study of dupilumab (R668-EE-1324) and reported data of a phase 2 study of budesonide 
(Dellon, 2017) in patients with EoE as follows: 
• In the study of dupilumab, a treatment difference of 65.2% was observed in the 
proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤6 eos/hpf after 12 weeks of treatment (placebo 0% vs. dupilumab 65.2%). DSQ was 
not assessed in this study. The overall dropout rate was 8.5% during the 12-week 
treatment period. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 90 of 113 
 
CONFIDENTIAL 
• In the study of budesonide oral suspension, a treatment difference of 36% was observed 
in the proportion of patients achieving peak esophageal intraepithelial eosinophil count 
of ≤6 eos/hpf after 12 weeks of treatment (placebo 3% vs. budesonide 39%). The mean 
(standard deviation [SD]) of change from baseline in DSQ total score at week 12 
was -7.5 (10.7) in placebo and -14.3 (13.0) in the budesonide group, corresponding to 
a treatment group difference of -6.8. The overall dropout rate was 6.5% during the 
12-week treatment period. 
With the consideration that a higher dropout rate may be observed for a longer treatment period, a 
dropout rate of 15% is assumed for all sample size calculations provided below. 
Part A 
The planned sample size for Part A is approximately 40 patients in each treatment group such that 
for the comparison of each dupilumab dose regimen to placebo: 
• This sample size will yield >99% power to detect a treatment difference of 62% in the 
proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤6 eos/hpf at week 24 (placebo 3% vs. dupilumab 65%) at a 2-sided significance level 
of 5% using Fisher’s exact test.  
• With respect to the treatment group difference in the mean change from baseline in 
DSQ total score, assuming a common SD of 13.0, this sample size is expected to 
generate a 95% confidence interval whose half-width is 5.7. If the true treatment 
difference is -9.0 points, the statistical power for the co-primary endpoint of DSQ will 
be 80% using a two-sample t-test. 
Part B 
The study includes two double-blind placebo-controlled randomized parts: Part A and Part B. An 
objective of Part A was to evaluate the Part B sample size. Part A database lock occurred on 
20 May 2020 and the study results for the co-primary endpoints from Part A are below: 
• The proportion of patients achieving peak esophageal intraepithelial eosinophil count 
of ≤6 eos/hpf at 24 weeks was 5.1% in placebo group and 59.5% in dupilumab 300mg 
QW group with a treatment difference of 55.4% 
• The mean (standard deviation [SD]) of change from baseline in DSQ total score at week 
24 was -9.6 (15.2) in placebo and -21.9 (14.6) in the dupilumab 300mg QW group with 
a treatment group difference of -12.3.  
Based on the Part A study results, the planned sample size for Part B is approximately 70 patients 
in each treatment group such that for the comparison of each dupilumab dose regimen to placebo: 
• This sample size will yield >99.9% power to detect a treatment difference of 55.4% in 
the proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤6 eos/hpf at week 24 between placebo (5.1% ) and each dupilumab treatment group 
(59.5%) at a 2-sided significance level of 5% using Fisher’s exact test.  
• This sample size will provide >99.9% power to detect a treatment difference of -12.3 
points in the mean change from baseline in the total DSQ score to week 24 at a 2-sided 
significance level of 5% using a two-sample t-test, assuming a common SD of 15.0.  
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 91 of 113 
 
CONFIDENTIAL 
Therefore, the sample size of 70 patients/arm will provide an overall power of >99.9% (99.9% × 
99.9%) for the co-primary endpoints, assuming no negative correlation between the two endpoints. 
In Part B, the same treatment effect for the two 300 mg dupilumab dose regimens (ie, QW and 
Q2W) is assumed. 
Sample size calculations were made using nQuery Advisor 7.0. 
10.3. 
Analysis Sets  
10.3.1. 
Efficacy Analysis Sets 
Part A and Part B 
For Part A and Part B, the efficacy endpoints will be analyzed using the study part-specific full 
analysis set (FAS) that includes all randomized patients in the corresponding study part. Efficacy 
analyses for these 2 parts will be based on the treatment allocated by the randomization and carried 
out separately for each part. Analysis on the FAS will be considered to be primary. 
The study-part specific per protocol set (PPS) will include all patients in the corresponding FAS 
except for those who are excluded due to important protocol violations.  
All efficacy endpoints will be evaluated on the FAS; the co-primary endpoints will also be 
evaluated on the PPS.  
Part C 
The efficacy endpoints in Part C (the extended active treatment period) will be summarized for all 
patients who received any extended active treatment study drug in that part. 
10.3.2. 
Safety Analysis Set 
For Part A and Part B, the study part-specific safety analysis set (SAF) includes all randomized 
patients who received any study drug; it is based on the treatment received (as treated). Treatment 
compliance/administration and all clinical safety variables will be analyzed using the SAF. 
For safety analyses of the Part C extended active treatment period, only a subset of SAF will be 
included, which is defined as those patients who received at least 1 dose of Part C study drug. 
10.3.3. 
Pharmacokinetic Analysis Sets 
The PK analysis set includes all treated patients who received any study drug and who had at 
least 1 non-missing result following the first dose of study drug.  
10.3.4. 
Anti-Drug Antibody Analysis Sets 
The ADA analysis set includes all treated patients who received any study drug and who had at 
least 1 non-missing ADA result following the first dose of study drug.  
10.4. 
Statistical Methods  
For continuous variables, descriptive statistics will include the following information:  the number 
of patients reflected in the calculation (n), mean, median, SD, minimum, first and third quartiles, 
and maximum.  
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 92 of 113 
 
CONFIDENTIAL 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
10.4.1. 
Patient Disposition 
The following will be provided: 
• The total number of screened patients: met the inclusion criteria regarding the target 
indication and signed the ICF 
• The total number of randomized patients:  received a randomization number 
• The total number of patients in each analysis set (eg, FAS, provided in Section 10.3) 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• The total number of patients who discontinued study treatment, and the reasons for 
discontinuation 
• The total number of patients who took rescue medications/procedures  
• A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized 
• A listing of patients prematurely discontinued from study treatment, along with reasons 
for discontinuation 
10.4.2. 
Demography and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group, 
and by all patients combined.  
10.4.3. 
Efficacy Analyses 
10.4.3.1. Primary Efficacy Analysis 
The co-primary endpoint of proportion of patients achieving a histologic response of esophageal 
intraepithelial eosinophil count of ≤6 eos/hpf at week 24 visit will be analyzed using the Cochran-
Mantel-Haenszel (CMH) test to assess the difference in the proportion of responders in the FAS 
adjusting for the randomization stratification factors. In anticipation of sparse responders in the 
placebo group, the Fisher’s exact test will be performed as a supportive analysis to confirm the 
results from the CMH test. 
The co-primary endpoint of absolute change from baseline in the DSQ total score at week 24 will 
be analyzed using an analysis of covariance (ANCOVA) model for the FAS with treatment group, 
randomization stratification factor, and relevant baseline measurement as covariates included in 
the model. The cumulative proportion of responders over the entire range of possible cut-off points 
will be graphed to present the between-treatment-group differences at any responder level. 
The intercurrent events, strategies, and the corresponding missing data handling approaches for 
the primary estimands of interest for the co-primary endpoints are provided in Table 4. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 93 of 113 
 
CONFIDENTIAL 
Table 4: 
Summary of Primary Estimand for Co-primary Endpoints 
Co-Primary Endpoint Intercurrent event(s) 
Strategy 
Missing data handling 
method 
Proportion of patients 
achieving a histologic 
response of esophageal 
intraepithelial 
eosinophil count of ≤6 
eos/hpf at week 24 visit 
Initiation of treatment 
with systemic and/or 
swallowed topical 
corticosteroids drugs 
for EoE (rescue 
treatment) 
Composite strategy: Patients 
will be considered as non-
responders after such events. 
(1) Missing data due to 
COVID-19 will be imputed 
by multiple imputation 
(MI). 
(2) Missing data due to reasons 
not related to COVID-19 
will be imputed as non-
responder. 
Initiation or change of 
treatment with 
systemic 
corticosteroid drugs 
for conditions other 
than EoE (prohibited 
medications)  
Treatment policy strategy: 
Data collected after the 
patient received treatment 
with systemic corticosteroid 
drugs for conditions other 
than EoE will be included in 
the analyses. 
Treatment 
discontinuation 
Treatment policy strategy: 
Data collected after the 
patient discontinued treatment 
will be included in the 
analyses. 
Absolute change from 
baseline in the DSQ 
total score at week 24 
Initiation of treatment 
with systemic and/or 
swallowed topical 
corticosteroids drugs 
for EoE (rescue 
treatment) 
Hypothetical strategy: Data 
will be assigned using MI 
after such events.  
Missing data will be imputed by 
multiple imputation (MI). 
 
Initiation or change of 
treatment with 
systemic 
corticosteroid drugs 
for conditions other 
than EoE (prohibited 
medications) 
Treatment policy strategy: 
Data collected after the 
patient received treatment 
with systemic corticosteroid 
drugs for conditions other 
than EoE conditions will be 
included in the analyses. 
Treatment 
discontinuation 
Treatment policy strategy: 
Data collected after the 
patient discontinued treatment 
will be included in the 
analyses. 
To account for use of rescue treatment in the primary analysis, for peak esophageal intraepithelial 
eosinophil count of ≤6 eos/hpf, patients will be considered as non-responders after the use of rescue 
treatment. For absolute change from baseline in the DSQ total score, data will be imputed using 
multiple imputation (MI) for all time points subsequent to the use of rescue treatment.  
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 94 of 113 
 
CONFIDENTIAL 
If a patient has missing value for the histological response (peak esophageal intraepithelial 
eosinophil count of ≤6 eos/hpf) at week 24 visit due to reasons not related to COVID-19, the 
patient will be classified as a non-responder at week 24. Multiple imputation (MI) will be used for 
missing histological response due to COVID-19. 
If a patient has missing value for the DSQ total score at week 24, their missing data will be imputed 
by multiple imputation (MI) based on similar patients who remained in the trial with observed 
values relevant to analysis. Similarity is based on randomized treatment group, baseline value, 
stratification factors, and available post-baseline values. To account for the uncertainty in the 
imputation, missing data at week 24 will be imputed 50 times to generate 50 complete datasets by 
using the MI procedure in Statistical Analysis Software (SAS).  
MI will follow the 2 steps below using a random seed number of 6681774 in both steps: 
• Step 1:  Use the Markov Chain Monte Carlo (MCMC) method to fill in intermittent 
missing values (ie, those missing values followed by observed values at subsequent 
visits) so that a monotone missing pattern will be formed. 
• Step 2:  Using the datasets from step 1, missing data through week 24 will be imputed 
using the regression method with treatment group, randomization stratification, 
relevant baseline measurement, and post-baseline measurement up to week 24 included 
in the regression model.  
Once imputations are made, the week 24 data of each of the complete datasets will be analyzed 
using ANCOVA. The results from the 50 analyses on the complete datasets will be combined to 
generate a valid overall statistical inference according to Rubin’s formula (Rubin, 1987) using the 
SAS MIANALYZE procedure. 
Sensitivity analyses will assess alternative methods to impute missing data under the assumption 
of missing at random or missing not at random. For the esophageal-intraepithelial-eosinophil 
responder analysis, alternative methods may include utilizing peak esophageal intraepithelial 
eosinophil count values from imputations to determine responder status. For the analysis of change 
from baseline in the DSQ total score, alternative methods may include mixed-effect model for 
repeated measures (MMRM), last observation carried forward (LOCF), and tipping point analysis. 
Sensitivity analyses will also include an analysis without setting data post-rescue to missing. 
Sensitivity analyses may include but are not limited to the methods specified above. Details will 
be specified in the SAP. 
Handling of missing data or delayed procedures due to COVID-19 and any additional analyses 
required to investigate the impact of COVID-19 to understand estimated treatment effect will be 
detailed in the SAP. 
10.4.3.2. Secondary Efficacy Analysis 
10.4.3.2.1. Analysis of Secondary Efficacy Endpoints in Part A and Part B 
Binary endpoints: 
Secondary efficacy endpoints that measure binary responses at week 24 will be analyzed in the 
same fashion as the co-primary endpoint of histologic response of peak esophageal intraepithelial 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 95 of 113 
 
CONFIDENTIAL 
eosinophil count of ≤6 eos/hpf, including the method to handle missing data and planned 
sensitivity analyses.  
Continuous endpoints: 
For Part A enrolled patients, EoE-EREFS assessed by investigators will be used in the analysis (no 
centralized readings available). For Part B enrolled patients, the primary analysis of EoE-EREFS 
will be based on centralized readings, if available. If the centralized reading is not available, the 
EoE-EREFS performed by the investigator will be used for analysis. 
Continuous secondary efficacy endpoints at week 24 will be analyzed using ANCOVA in a similar 
fashion to the co-primary endpoint of change from baseline in the DSQ total score.  
For continuous efficacy data that are scheduled to be measured repeatedly post-baseline up to week 
24 (eg, percent change in DSQ score from baseline to week 24), missing data will be imputed by 
MI as described in the primary efficacy analysis of the DSQ co-primary endpoint. Sensitivity 
analyses similar to those specified for the DSQ co-primary endpoint will be conducted. 
For continuous efficacy data that are to be measured only once post-baseline up to week 24 
(eg, percent change in peak eos/hpf from baseline to week 24), missing values at week 24 will be 
imputed with patient’s baseline value or the available post-baseline value, whichever is worse, 
ie, a worst observation carried forward (WOCF) approach. MI approach is not suitable for 
handling missing data in this case due to the fact that the complete case patients will not have 
measurements available at the time points when measurements are obtained for ET patients 
(designed to be at their ET visits) to enable the imputation of week 24 missing values for early 
terminated patients. A sensitivity analysis, using the LOCF approach to impute missing values at 
week 24, will be performed. 
To account for use of rescue treatment, data will be imputed by MI for continuous endpoints 
repeatedly measured or by WOCF for continuous endpoints measured only once up to week 24 
visit after the use of rescue treatment.  
For the four key secondary endpoints, the primary estimand and details about the intercurrent 
events strategy and missing data handling are presented in Table 5. 
Table 5: 
Summary of Primary Estimand for Key Secondary Endpoints 
Key Secondary Endpoint 
Intercurrent event(s) 
Strategy 
Missing data handling 
method 
• 
Absolute change in EoE-
EREFS from baseline to 
week 24 
• 
Percent change in peak 
esophageal intraepithelial 
eosinophil count 
(eos/hpf) from baseline 
to week 24 
• 
Absolute change in EoE 
Grade Score from the 
EoEHSS from baseline 
to week 24  
Initiation of treatment with 
systemic and/or swallowed 
topical corticosteroids 
drugs for EoE (rescue 
treatment) 
Composite strategy: data 
after rescue treatment 
will be assigned by the 
worst possible value 
Missing values at week 24 
will be imputed with 
WOCF approach 
including baseline. 
Initiation or change of 
treatment with systemic 
corticosteroid drugs for 
conditions other than EoE 
(prohibited medications) 
Treatment policy 
strategy: Data collected 
after the patient received 
treatment with systemic 
corticosteroid drugs for 
conditions other than 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 96 of 113 
 
CONFIDENTIAL 
Key Secondary Endpoint 
Intercurrent event(s) 
Strategy 
Missing data handling 
method 
• 
Absolute change in EoE 
Stage Score from the 
EoEHSS from baseline 
to week 24 
EoE will be included in 
the analyses. 
Treatment discontinuation 
Treatment policy 
strategy: Data collected 
after the patient 
discontinued treatment 
will be included in the 
analyses. 
Sensitivity analyses will also include an analysis without setting data post-rescue to missing. 
Subgroup analysis (eg, by age group) will also be performed and details will be specified in SAP. 
For transcriptome endpoints, the Wilcoxon rank-sum test will be used to test if the difference in 
median NES of the relative change from baseline to week 24 between the dupilumab and placebo 
groups is statistically significant. P-values will be reported. 
10.4.3.2.2. Analysis of Secondary Efficacy Endpoints in Part C  
Efficacy variables measured in Part C will use the last non-missing value prior to the first dose of 
extended active treatment study drug as their baseline assessments. These efficacy variables will 
be summarized with descriptive statistics by received treatment in Part C. Inferential statistics will 
only be conducted as needed. 
10.4.3.3. Multiplicity Considerations 
Part A and Part B will be carried out as 2 separate sub-studies with no overlap in patients. 
Therefore, each study part will have separate and independent 2-sided alpha level of 0.05. In the 
event that sample size of Part B is changed based on observed data from Part A, there will be no 
alpha adjustment as data from Part A are considered external information to Part B. 
To demonstrate efficacy for a dupilumab dose regimen, both of the individual co-primary 
endpoints need to be statistically significant at the 2-sided 0.05 level for that dose regimen.  
Part A: Statistical significance of both co-primary efficacy endpoints will be required before 
drawing inferential conclusions about any secondary efficacy endpoints. The hierarchical order of 
secondary endpoints will be specified in Part A SAP. 
Part B: Type I error rate will be controlled using a hierarchical testing procedure. The co-primary 
endpoints will be tested for the comparison of dupilumab QW dose regimen to placebo first and if 
both endpoints are statistically significant, the testing will proceed to the co-primary endpoints of 
dupilumab Q2W, or the secondary endpoints of dupilumab QW, with the exact order to be 
specified in Part B SAP. 
As Part C data will be summarized using descriptive statistics, there is no multiplicity issue. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 97 of 113 
 
CONFIDENTIAL 
10.4.4. 
Safety Analysis 
Safety analysis will be based on the SAF. This includes reported treatment-emergent adverse 
events (TEAEs) and other safety data (ie, clinical laboratory evaluations, vital signs, and 12-lead 
ECG results). A descriptive summary of safety results will be presented by treatment group for 
each study part. The use of rescue treatment will be summarized. 
Any additional analyses and methods required to investigate the impact of COVID-19, including 
extended dosing, on the safety evaluation will be specified in the SAP. 
10.4.4.1. Adverse Events 
Definitions 
For AEs, 2 observation periods are defined: 
• The pre-treatment period is defined as the time from signing the ICF to before the first 
dose of study drug. 
• The treatment-emergent period is defined as the day from the first dose of study 
treatment through the end of study including the follow-up period. The treatment-
emergent period includes the placebo-controlled treatment period plus the extended 
active treatment period (52 weeks in total) and the 12-week follow-up period. 
− Treatment period: date of the first dose of study drug to the end of the 52-week 
treatment period (placebo-controlled plus extended-active treatment) 
− Follow-up period: day after the end of the treatment period to the end of study. 
Treatment-emergent adverse events are defined as those that are not present at baseline or represent 
the exacerbation of a preexisting condition during the treatment-emergent period. 
Analysis 
All AEs reported in this study will be coded using the currently available version of the Medical 
Dictionary for Regulatory Activities (MedDRA®). Coding will be to lowest level terms. The 
verbatim text, the preferred term (PT), and the primary system organ class (SOC) will be listed. 
Summaries of the TEAEs will include the following for each study part: 
• The number (n) and percentage (%) of patients with at least 1 TEAE by SOC and PT 
• TEAEs by severity (according to the grading scale outlined in Section 9.5.1), presented 
by SOC and PT 
• TEAEs by relationship to treatment (related, not related), presented by SOC and PT 
• Treatment-emergent AESIs (defined with a PT or a pre-specified grouping) 
Deaths and other SAEs will be listed and summarized. The summary will include the number (n) 
and percentage (%) of patients with at least 1 SAE as well as the number of SAEs. 
Treatment-emergent adverse events leading to permanent treatment discontinuation will be listed 
and summarized. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 98 of 113 
 
CONFIDENTIAL 
TEAEs that occurred in Part A or Part B will be summarized by the treatment patient received in 
the respective part, and also for combined dupilumab QW and Q2W treatment groups. 
TEAEs that occurred in Part C will be summarized by treatment received in Part C.  
10.4.4.2. Other Safety 
Vital Signs 
Vital signs (temperature, pulse, blood pressure, and respiratory rate) will be summarized by 
baseline and change from baseline to each scheduled assessment time with descriptive statistics.  
Number and percentage of patients with a treatment-emergent potentially clinically significant 
value (PCSV) will be summarized for each vital sign variable. The criteria for treatment-emergent 
PCSV will be defined in the SAP. 
Laboratory Tests 
Laboratory test results will be summarized by baseline and change from baseline to each scheduled 
assessment time with descriptive statistics. 
Number and percentage of patients with a treatment-emergent PCSV will be summarized for each 
clinical laboratory test. The criteria for treatment-emergent PCSV will be defined in the SAP. 
Shift tables based on baseline normal/abnormal and other tabular and graphical methods may be 
used to present the results for laboratory tests of interest. 
Listings will be provided with flags indicating the out-of-range laboratory values. 
10.4.4.3. Treatment Exposure 
The duration of exposure during each study part will be calculated as follows: 
• (date of last dose of study drug in the specific study part – date of first dose of study 
drug in the specific study part) + 7 days 
In addition, duration of cumulative exposure to dupilumab across study parts will be calculated for 
patients who participate in both the double-blind treatment period (Part A or Part B) and the 
extended active treatment period as follows: 
• (date of last dose of study drug – date of first dose of dupilumab in the study) + 7 days. 
Number and percentage of patients exposed to study drug within a study part and across study 
parts will be summarized by time periods of specific lengths for each treatment group. The lengths 
of interest will be specified in the SAP.  
In addition, duration of exposure within a study part and across study parts will be summarized as 
a continuous variable for each treatment group with the number of patients reflected in the 
calculation (n), mean, median, SD, minimum, the first and third quartiles, and maximum. 
A summary of the number of study-part-specific doses for each treatment group will be provided. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 99 of 113 
 
CONFIDENTIAL 
10.4.4.4. Treatment Compliance 
The compliance with protocol-defined study treatment will be calculated for each of the 3 study 
parts separately as follows: 
Treatment compliance = 
number of administered doses of study drug   
number of planned doses of study drug 
×100% 
The treatment compliance will be summarized descriptively by specific ranges for each treatment 
group. The ranges of interest will be specified in the SAP. 
10.4.5. 
Pharmacokinetics 
10.4.5.1. Analysis of Drug Concentration Data 
For this study, sampling will be sparse and the types of analyses will be descriptive statistics at 
each sampling time. No formal statistical analysis will be performed. 
10.4.6. 
Analysis of Anti-Drug Antibody Data 
ADA data will be summarized using descriptive statistics by treatment group. Samples that are 
positive in the ADA assay will be further characterized for the presence of neutralizing antibody.  
Plots of drug concentrations will be examined and the influence of ADAs on individual PK profiles 
may be evaluated. Where appropriate, assessment of impact of ADA on safety and efficacy will 
be provided. 
10.4.7. 
Analysis of Pharmacodynamic and Exploratory Biomarker Data 
Biomarker results will be summarized by baseline, measured values, change from baseline, and 
percent change from baseline to each scheduled assessment time point with descriptive statistics. 
10.4.8. 
Analysis of Quality of Life Data 
Quality of life data will be analyzed using the same method as specified for the continuous 
secondary efficacy variables.  
10.4.9. 
Timing of Statistical Analysis 
Multiple steps of analyses are planned for this study.  
• The first database lock will occur after the last Part A patient has completed their end 
of Part A visit including patients who have terminated early in Part A.  
• The second database lock will occur after the last Part A patient has completed their 
week 52 visit of Part C including Part A patients who have terminated early in Part A 
or Part C.  
• The third database lock will occur after the last Part B patient has completed their end 
of Part B visit including patients who have terminated early in Part B.  
• After the last patient completes the last visit in Part C, analysis of all week 52 efficacy 
and safety endpoints may be performed. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 100 of 113 
 
CONFIDENTIAL 
• The last database lock will occur after the last patient completes their last end of study 
visit. The end-of-study analysis will include data through the end of the 12-week 
follow-up period. 
10.5. 
Additional Statistical Data Handling Conventions 
The following analysis and data conventions will be followed: 
Definition of baseline:  
• The baseline assessment for each study part will be the latest, valid predose assessment 
available for the corresponding study part, respectively 
General rules for handling missing data:  
• If the start date of an AE or concomitant medication is incomplete or missing, it will 
be assumed to have occurred on or after the intake of study medication, except if an 
incomplete date (eg, month and year) clearly indicates that the event started prior to 
treatment. If the partial date indicates the same month or year of the intake of study 
medication date, then the start date by the study medication intake date will be imputed; 
otherwise, the missing day or month by the first day or the first month will be imputed.  
• No imputations for missing laboratory data, ECG data, vital sign data, or physical 
examination data will be made. 
Unscheduled assessments: 
• Extra assessments (laboratory data or vital signs associated with non-protocol clinical 
visits or obtained in the course of investigating or managing AEs) will be included in 
listings and summaries. If more than 1 laboratory value is available for a given visit, 
the first observation will be used in summaries and all observations will be presented 
in listings.  
10.6. 
Statistical Considerations Surrounding the Premature Termination 
of a Study  
If the study is terminated prematurely for other reasons, only those parameters required for the 
development program and/or reporting to regulatory authorities will be summarized. Investigator 
and sponsor responsibilities surrounding the premature termination of a study are presented in 
Section 16.1. 
11. 
DATA MANAGEMENT AND ELECTRONIC SYSTEMS 
11.1. 
Data Management 
A data management plan specifying all relevant aspects of data processing for the study (including 
data validation [quality-checking], cleaning, correcting, releasing) will be maintained and stored 
at Regeneron (Sponsor). 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 101 of 113 
 
CONFIDENTIAL 
A medical coding plan (included in the data management plan) will specify the processes and the 
dictionary used for coding. All data coding (eg, AEs, baseline findings, medication, medical 
history/surgical history/EoE comorbidity history, etc.) will be done using internationally 
recognized and accepted dictionaries. 
The CRF data for this study will be collected with an electronic data capture (EDC) system 
Medidata Rave. 
11.2. 
Electronic Systems 
Electronic systems that may be used to process and/or collect data in this study will include the 
following: 
• IVRS/IWRS system – randomization and study drug supply 
• EDC system – data capture/uploading  
• Electronic patient diary – data capture/uploading 
• Central ECG reading center-digital images 
• nQuery Advisor – sample size calculations 
• Statistical Analysis System (SAS) – statistical review and analysis 
• Pharmacovigilance and Risk Management (PVRM) safety system 
• Digital archive system for endoscopic photographic and video images 
12. 
STUDY MONITORING 
12.1. 
Monitoring of Study Sites 
The study monitor and/or designee (eg, CRO monitor) will visit each site prior to enrollment of 
the first patient, and periodically during the study.  
The investigator must allow study-related monitoring. 
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements. 
12.2. 
Source Document Requirements 
Investigators are required to prepare and maintain adequate and accurate patient records (source 
documents). 
The investigator must keep all source documents on file with the CRF (throughout this protocol, 
CRF refers to either a paper CRF or an electronic CRF). Case report forms and source documents 
must be available at all times for inspection by authorized representatives of the sponsor and 
regulatory authorities. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 102 of 113 
 
CONFIDENTIAL 
12.3. 
Case Report Form Requirements 
Study data obtained in the course of the clinical study will be recorded on eCRFs within the EDC 
system by trained site personnel. All required CRFs must be completed for each and every patient 
enrolled in the study. After review of the clinical data for each patient, the investigator must 
provide an electronic signature. A copy of each patient CRF casebook is to be retained by the 
investigator as part of the study record and must be available at all times for inspection by 
authorized representatives of the sponsor and regulatory authorities. 
Corrections to the CRF will be entered in the CRF by the investigator or an authorized designee. 
All changes, including date and person performing corrections, will be available via the audit trail, 
which is part of the EDC system. For corrections made via data queries, a reason for any alteration 
must be provided. 
13. 
AUDITS AND INSPECTIONS 
This study may be subject to a quality assurance audit or inspection by the sponsor or regulatory 
authorities. Should this occur, the investigator is responsible for: 
• Informing the sponsor of a planned inspection by the authorities as soon as notification 
is received, and authorizing the sponsor’s participation in the inspection 
• Providing access to all necessary facilities, study data, and documents for the inspection 
or audit 
• Communicating any information arising from inspection by the regulatory authorities 
to the sponsor immediately 
• Taking all appropriate measures requested by the sponsor to resolve the problems found 
during the audit or inspection 
Documents subject to audit or inspection include but are not limited to all source documents, CRFs, 
medical records, correspondence, ICFs, IRB/EC files, documentation of certification and quality 
control of supporting laboratories, and records relevant to the study maintained in any supporting 
pharmacy facilities. Conditions of study material storage are also subject to inspection. In addition, 
representatives of the sponsor may observe the conduct of any aspect of the clinical study or its 
supporting activities both within and outside of the investigator's institution. 
In all instances, the confidentiality of the data must be respected. 
14. 
ETHICAL AND REGULATORY CONSIDERATIONS  
14.1. 
Good Clinical Practice Statement 
It is the responsibility of both the sponsor and the investigators to ensure that this clinical study 
will be conducted in accordance with the ethical principles that have their origin in the Declaration 
of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory 
requirements. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 103 of 113 
 
CONFIDENTIAL 
14.2. 
Informed Consent 
The principles of informed consent are described in ICH guidelines for GCP. 
The ICF used by the investigator must be reviewed and approved by the sponsor prior to 
submission to the appropriate IRB/EC. A copy of the IRB- or EC-approved ICF and documentation 
of approval must be provided to the sponsor before study drug will be shipped to the study site. 
It is the responsibility of the investigator or designee (if acceptable by local regulations) to obtain 
written informed consent from each adult patient, and written informed consent or assent from 
each adolescent patient and written informed consent from his/her parent(s) or legal guardian(s), 
prior to patient’s participation in the study and after the aims, methods, objectives, and potential 
hazards of the study have been explained to the patient and adolescent patient’s parent(s) or legal 
guardian(s) in language that he/she can understand. The ICF should be signed and dated by the 
adult patient, and the ICF/IAF by adolescent patient and his/her parent(s) or legal guardian(s), and 
by the investigator or authorized designee who reviewed the ICF/IAF with the patient/patient’s 
parent(s) or legal guardian(s).  
For adolescent patients, local law must be observed in deciding whether the consent of 1 or both 
parents/guardians is required. If only 1 parent or guardian signs the consent form, the investigator 
must document the reason the other parent or guardian did not sign. The patient may also be 
required to sign and date the ICF, as determined by the IRB or EC and in accordance with the local 
regulations and requirements. 
• Patients/parents/guardians who can write but cannot read will have the ICF/IAF read 
to them before signing and dating the ICF/IAF. 
• Patients who can understand but who can neither write nor read will have the ICF/IAF 
read to them in presence of an impartial witness, who will sign and date the ICF/IAF 
to confirm that informed consent/assent was given. 
The original ICF/IAF must be retained by the investigator as part of the patient’s study record, and 
a copy of the signed ICF must be given to the adult patient, or to the adolescent patient and his/her 
parent(s) or legal guardian(s). 
If new safety information results in significant changes in the risk/benefit assessment, the ICF/IAF 
must be reviewed and updated appropriately. All study patients (and adolescent patients’ parent[s] 
or legal guardian[s]) must be informed of the new information and provide their written 
consent/assent if they wish to continue in the study. The original signed revised ICF/IAF must be 
maintained in the patient’s study record and a copy must be given to the adult patient, and the 
adolescent patient and his/her parent(s) or legal guardian(s). 
14.3. 
Patients Confidentiality and Data Protection 
The investigator must take all appropriate measures to ensure that the anonymity of each study 
patient will be maintained. Patients should be identified by a patient identification number only, 
on CRFs or other documents submitted to the sponsor. Documents that will not be submitted to 
the sponsor (eg, signed ICF/IAF) must be kept in strict confidence. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 104 of 113 
 
CONFIDENTIAL 
The patient’s and investigator’s personal data, which may be included in the sponsor database, will 
be treated in compliance with all applicable laws and regulations. The sponsor shall take all 
appropriate measures to safeguard and prevent access to this data by any unauthorized third party. 
14.4. 
Institutional Review Board/Ethics Committee 
An appropriately constituted IRB or EC, as described in ICH guidelines for GCP, must review and 
approve: 
• The protocol, ICF/IAF, and any other materials to be provided to the patients 
(eg, advertising) before any patient may be enrolled in the study 
• Any amendment or modification to the study protocol or ICF before implementation, 
unless the change is necessary to eliminate an immediate hazard to the patient, in which 
case the IRB or EC should be informed as soon as possible  
• Ongoing studies on an annual basis or at intervals appropriate to the degree of risk  
In addition, the IRB or EC should be informed of any event likely to affect the safety of patients 
or the continued conduct of the clinical study. 
A copy of the IRB or EC approval letter with a current list of the IRB or EC members and their 
functions must be received by the sponsor prior to shipment of drug supplies to the investigator. 
The approval letter should include the study number and title, the documents reviewed, and the 
date of the review. 
Records of the IRB or EC review and approval of all study documents (including approval of 
ongoing studies) must be kept on file by the investigator. 
15. 
PROTOCOL AMENDMENTS 
The sponsor may not implement a change in the design of the protocol or ICF without an IRB- or 
EC-approved amendment. All substantial protocol amendments will be approved by the competent 
authorities before changes are implemented according to national regulations. 
16. 
PREMATURE TERMINATION OF THE STUDY OR 
CLOSE-OUT OF A SITE 
16.1. 
Premature Termination of the Study 
The sponsor has the right to terminate the study prematurely. Reasons may include efficacy, safety, 
or futility, among others. Should the sponsor decide to terminate the study, the investigator(s) will 
be notified in writing. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 105 of 113 
 
CONFIDENTIAL 
16.2. 
Close-out of a Site 
The sponsor and the investigator have the right to close-out a site prematurely. 
Investigator’s Decision 
The investigator must notify the sponsor of a desire to close-out a site in writing, providing at least 
30 days’ notice. The final decision should be made through mutual agreement with the sponsor. 
Both parties will arrange the close-out procedures after review and consultation. 
Sponsor’s Decision 
The sponsor will notify the investigator(s) of a decision to close-out a study site in writing. Reasons 
may include the following, among others:  
• The investigator has received all items and information necessary to perform the study, 
but has not enrolled any patient within a reasonable period of time 
• The investigator has violated any fundamental obligation in the study agreement, 
including but not limited to, breach of this protocol (and any applicable amendments), 
breach of the applicable laws and regulations, or breach of any applicable ICH 
guidelines  
• The total number of patients required for the study are enrolled earlier than expected 
In all cases, the appropriate IRB or EC and Health Authorities must be informed according to 
applicable regulatory requirements, and adequate consideration must be given to the protection of 
the patients’ interests. 
17. 
STUDY DOCUMENTATION 
17.1. 
Certification of Accuracy of Data 
A declaration assuring the accuracy and content of the data recorded on the eCRF must be signed 
electronically by the investigator. This signed declaration accompanies each set of patient final 
eCRF that will be provided to the sponsor. 
17.2. 
Retention of Records 
The investigator must retain all essential study documents, including ICFs/IAFs, source 
documents, investigator copies of CRFs, and drug accountability records for at least 15 years 
following the completion or discontinuation of the study, or longer, if a longer period is required 
by relevant regulatory authorities. The investigator must obtain written approval from the sponsor 
before discarding or destroying any essential study documents during the retention period 
following study completion or discontinuation. Records must be destroyed in a manner that 
ensures confidentiality. 
If the investigator's personal situation is such that archiving can no longer be ensured, the 
investigator must inform the sponsor (written notification) and the relevant records will be 
transferred to a mutually agreed-upon destination.  
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 106 of 113 
 
CONFIDENTIAL 
18. 
DATA QUALITY ASSURANCE 
In accordance with ICH E6, the sponsor is responsible for quality assurance to ensure that the 
study is conducted and the data generated, recorded, and reported in compliance with the protocol, 
GCP, and any applicable regulatory requirement(s). The planned quality assurance and quality 
control procedures for the study are summarized.  
Data Management 
The sponsor is responsible for the data management of this study including quality checking of the 
data (Section 11.1). 
Study Monitoring 
The investigator must allow study-related monitoring, IRB/EC review, audits, and inspections 
from relevant health regulatory authorities, and provide direct access to source data documents 
(Section 12.1, Section 12.2, and Section 13)   
The study monitors will perform ongoing source data review to verify that data recorded in the 
CRF by authorized site personnel are accurate, complete, and verifiable from source documents, 
that the safety and rights of patients are being protected, and that the study is being conducted in 
accordance with the current approved protocol version and any other study agreements, ICH GCP, 
and all applicable regulatory requirements (Section 12.1).  
All subject/patient data collected during the study will be recorded on paper or electronic CRF 
unless the data are transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for affirming that data entries in the CRF are accurate and correct by 
electronically signing a declaration that accompanies each set of patient/subject final CRF 
(Section 12.3 and Section 17.1).  
Study Documentation 
The investigator must maintain accurate documentation (source data) that supports the information 
entered in the CRF (Section 12.2).  
The investigator will retain all records and documents, including signed ICFs, pertaining to the 
conduct of this study for at least 15 years after study completion, unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of the sponsor. No records may be transferred to 
another location or party without written notification to the sponsor (Section 17.2).  
19. 
CONFIDENTIALITY 
Confidentiality of information is provided as a separate agreement. 
20. 
FINANCING AND INSURANCE 
Financing and insurance information is provided as a separate agreement. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 107 of 113 
 
CONFIDENTIAL 
21. 
PUBLICATION POLICY 
Publication rights and procedures will be outlined in a separate clinical study agreement. 
22. 
REFERENCES  
Abonia JP, Blanchard C, Butz BB, Rainey HF, Collins MH, Stringer K, et al. Involvement of mast 
cells in eosinophilic esophagitis. The Journal of Allergy and Clinical Immunology. 
2010 Jul;126(1):140-9. PubMed PMID: 20538331. Pubmed Central PMCID: 2902643. 
Abonia JP, Rothenberg ME. Eosinophilic esophagitis: rapidly advancing insights. Annual Review 
of Medicine. 2012;63:421-34. PubMed PMID: 22034864. 
Ally MR, Maydonovitch CL, Betteridge JD, Veerappan GR, Moawad FJ. Prevalence of 
eosinophilic esophagitis in a United States military health-care population. Dis Esophagus. 2015 
Aug-Sep;28(6):505-11. PubMed PMID: 24827543. 
Arias Á1, Pérez-Martínez I2, Tenías JM3, Lucendo AJ4. Systematic review with meta-analysis: 
the incidence and prevalence of eosinophilic oesophagitis in children and adults in population-
based studies. Aliment Pharmacol Ther. 2016 Jan;43(1):3-15. doi: 10.1111/apt.13441. Epub 2015 
Oct 28. 
Arora AA, Weiler CR, Katzka DA. Eosinophilic esophagitis: allergic contribution, testing, and 
management. Current Gastroenterology Reports. 2012 Jun;14(3):206-15. PubMed PMID: 
22422505. 
Assa’ad A. Eosinophilic esophagitis: association with allergic disorders. Gastrointestinal 
Endoscopy Clinics of North America. 2008 Jan;18(1):119-32; x. PubMed PMID: 18061106. 
Barbie, DA, P Tamayo, JS Boehm, SY Kim, S E Moody, IF Dunn, AC Schinzel, P Sandy, E 
Meylan, C Scholl, S Frohling, EM Chan, ML Sos, K Michel, C Mermel, SJ Silver, BA Weir, JH 
Reiling, Q Sheng, PB Gupta, RC Wadlow, H Le, S Hoersch, BS Wittner, S Ramaswamy, DM 
Livingston, DM Sabatini, MMeyerson, RK Thomas, ES Lander, JP Mesirov, DE Root, DG 
Gilliland, T Jacks, and WC Hahn. Systematic Rna Interference Reveals That Oncogenic Kras-
Driven Cancers Require Tbk1. Nature 462, no 7269. 2009 5 Nov: 108-12. PMID: 19847166 
Blanchard C, Rothenberg ME. Basic pathogenesis of eosinophilic esophagitis. Gastrointestinal 
Endoscopy Clinics of North America. 2008 Jan;18(1):133-43; x. PubMed PMID: 18061107. 
Pubmed Central PMCID: 2194642. 
Blanchard C, Stucke EM, Burwinkel K, Caldwell JM, Collins MH, Ahrens A, et al. Coordinate 
interaction between IL-13 and epithelial differentiation cluster genes in eosinophilic esophagitis. 
Journal of Immunology. 2010 Apr 1;184(7):4033-41. PubMed PMID: 20208004. Pubmed Central 
PMCID: 3807813. 
Blanchard C, Wang N, Stringer KF, Mishra A, Fulkerson PC, Abonia JP, et al. Eotaxin-3 and a 
uniquely conserved gene-expression profile in eosinophilic esophagitis. The Journal of Clinical 
Investigation. 2006 Feb;116(2):536-47. PubMed PMID: 16453027. Pubmed Central PMCID: 
1359059. 
Blanchard C, Mingler MK, Vicario M, Abonia JP, Wu YY, Lu TX, et al. IL-13 involvement in 
eosinophilic esophagitis: transcriptome analysis and reversibility with glucocorticoids. The 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 108 of 113 
 
CONFIDENTIAL 
Journal of Allergy and Clinical Immunology. 2007 Dec;120(6):1292-300. PubMed PMID: 
18073124. 
Brooks R. EuroQol: the current state of play, Health Policy. 1996 Jul;37(1):53-72. 
Bullock JZ, Villanueva JM, Blanchard C, Filipovich AH, Putnam PE, Collins MH, et al. Interplay 
of adaptive th2 immunity with eotaxin-3/c-C chemokine receptor 3 in eosinophilic esophagitis. 
Journal of Pediatric Gastroenterology and Nutrition. 2007 Jul;45(1):22-31. PubMed PMID: 
17592361. 
Charman CR, Venn AJ, et al. The patient-oriented eczema measure. Arch Dermatol 2004; 
140:1513-1519. 
Cianferoni A, Spergel J. Eosinophilic Esophagitis: A Comprehensive Review. Clin Rev Allergy 
Immunol. 2016 Apr;50(2):159-74. PubMed PMID: 26194940 
Clayton F, Fang JC, Gleich GJ, Lucendo AJ, Olalla JM, Vinson LA, Lowichik A, Chen X, 
Emerson L, Cox K, O'Gorman MA, Peterson KA. Eosinophilic esophagitis in adults is associated 
with IgG4 and 
not 
mediated 
by 
IgE. 
Gastroenterology. 2014 Sep;147(3):602-9. 
doi: 
10.1053/j.gastro.2014.05.036. Epub 2014 Jun 4. 
DeBrosse CW, Franciosi JP, King EC, Butz BK, Greenberg AB, Collins MH, et al. Long-term 
outcomes in pediatric-onset esophageal eosinophilia. The Journal of Allergy and Clinical 
Immunology. 2011 Jul;128(1):132-8. PubMed PMID: 21636117. Pubmed Central PMCID: 
3130990. 
Dellon ES. Epidemiology of eosinophilic esophagitis. Gastroenterology Clinics of North America. 
2014a Jun;43(2):201-18. PubMed PMID: 24813510. Pubmed Central PMCID: 4019938. 
Dellon ES, Aderoju A, Woosley JT, Sandler RS, Shaheen NJ. Variability in diagnostic criteria for 
eosinophilic esophagitis: a systematic review. The American Journal of Gastroenterology. 2007 
Oct;102(10):2300-13. PubMed PMID: 17617209. 
Dellon ES, Jensen ET, Martin CF, Shaheen NJ, Kappelman MD. Prevalence of eosinophilic 
esophagitis in the United States. Clinical Gastroenterology and Hepatology : the official clinical 
practice journal of the American Gastroenterological Association. 2014b Apr;12(4):589-96 e1. 
PubMed PMID: 24035773. Pubmed Central PMCID: 3952040. 
Dellon ES, Irani AM, Hill MR, Hirano I. Development and field testing of a novel patient-reported 
outcome measure of dysphagia in patients with eosinophilic esophagitis. Aliment Pharmacol Ther. 
2013;38(6):634-642. 
Dellon ES, Katzka DA, Collins MH, Hamdani M, Gupta SK, Hirano I; MP-101-06 Investigators. 
Budesonide Oral Suspension Improves Symptomatic, Endoscopic, and Histologic Parameters 
Compared With Placebo in Patients With Eosinophilic Esophagitis. Gastroenterology. 2017 
Mar;152(4):776-786.e5. doi: 10.1053/j.gastro.2016.11.021. Epub 2016 Nov 23. PMID: 27889574 
Eluri S, Runge TM, Hansen J, Kochar B, Reed CC, Robey BS, Woosley JT, Shaheen NJ, Dellon 
ES. Diminishing Effectiveness of Long-Term Maintenance Topical Steroid Therapy in PPI Non-
Responsive Eosinophilic Esophagitis. Clin Transl Gastroenterol. 2017 Jun 15;8(6):e97. doi: 
10.1038/ctg.2017.27. PMID: 28617448 
EMA. Assessment Report – Jorveza. 09 November 2017, EMA/774645/2017 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 109 of 113 
 
CONFIDENTIAL 
Falk GW. Clinical presentation of eosinophilic esophagitis in adults. Gastroenterology Clinics of 
North America. 2014 Jun;43(2):231-42. PubMed PMID: 24813512. 
Furuta GT, Aceves SS, The National Biome Initiative: An Allergy Perspective. J Allergy Clin 
Immunol. 2017 Apr;139(4):1131-1134. 
Hamilton JD, Suárez-Fariñas M, Dhingra N, Cardinale I, Li X, Kostic A, Ming JE, Radin AR, 
Krueger JG, Graham N, Yancopoulos GD, Pirozzi G, Guttman-Yassky E. Dupilumab improves 
the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy 
Clin Immunol. 2014 Dec;134(6):1293-1300. doi: 10.1016/j.jaci.2014.10.013. 
Hirano I, Aceves SS. Clinical implications and pathogenesis of esophageal remodeling in 
eosinophilic esophagitis. Gastroenterology Clinics of North America. 2014 Jun;43(2):297-316. 
PubMed PMID: 24813517. 
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. 
Hirano D, Oka S, Tanaka S, Sumimoto K, Ninomiya Y, Tamaru Y, Shigita K, Hayashi N, Urabe 
Y, Kitadai Y, Shimamoto F, Arihiro K, Chayama K. Clinicopathologic and endoscopic features of 
early-stage colorectal serrated adenocarcinoma. BMC Gastroenterol. 2017 Dec 12;17(1):158. doi: 
10.1186/s12876-017-0702-x. PMID: 29233113 
Howell MD, Kim BE, Gao P, Grant AV, Boguniewicz M, Debenedetto A, et al. Cytokine 
modulation of atopic dermatitis filaggrin skin expression. The Journal of Allergy and Clinical 
Immunology. 2007 Jul;120(1):150-5. PubMed PMID: 17512043. Pubmed Central PMCID: 
2669594. 
Hruz P, Straumann A, Bussmann C, Heer P, Simon HU, Zwahlen M, Beglinger C, Schoepfer AM; 
Swiss EoE study group. Escalating incidence of eosinophilic esophagitis: a 20-year prospective, 
population-based study in Olten County, Switzerland. J Allergy Clin Immunol. 2011 
Dec;128(6):1349-1350.e5. PubMed PMID: 22019091 
Hudgens S1, Evans C2, Phillips E3, Hill M3. Psychometric validation of the Dysphagia Symptom 
Questionnaire in patients with eosinophilic esophagitis treated with budesonide oral suspension. J 
Patient Rep Outcomes. 2017;1(1):3. doi: 10.1186/s41687-017-0006-5. Epub 2017 Sep 12. 
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 May;134(5):1316-
21. PubMed PMID: 18471509. 
Kwiatek MA, Hirano I, Kahrilas PJ, Rothe J, Luger D, Pandolfino JE. Mechanical properties of 
the esophagus in eosinophilic esophagitis. Gastroenterology. 2011 Jan;140(1):82-90. doi: 
10.1053/j.gastro.2010.09.037. Epub 2010 Sep 19. 
Liacouras CA, Furuta GT, Hirano I, Atkins D, Attwood SE, Bonis PA, et al. Eosinophilic 
esophagitis: updated consensus recommendations for children and adults. The Journal of Allergy 
and Clinical Immunology. 2011 Jul;128(1):3-20 e6; quiz 1-2. PubMed PMID: 21477849. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 110 of 113 
 
CONFIDENTIAL 
Lucendo AJ,2, Molina-Infante J, Arias Á, et al, Guidelines on eosinophilic esophagitis: evidence-
based statements and recommendations for diagnosis and management in children and adults. 
United European Gastroenterol J. 2017 Apr;5(3):335-358 
Mishra A. Mechanism of eosinophilic esophagitis. Immunology and Allergy Clinics of North 
America. 2009 Feb;29(1):29-40, viii. PubMed PMID: 19141339. Pubmed Central PMCID: 
2650237. 
Mishra A, Rothenberg ME. Intratracheal IL-13 induces eosinophilic esophagitis by an IL-5, 
eotaxin-1, and STAT6-dependent mechanism. Gastroenterology. 2003 Nov;125(5):1419-27. 
PubMed PMID: 14598258. 
Moawad FJ, Veerappan GR, Lake JM, Maydonovitch CL, Haymore BR, Kosisky SE, et al. 
Correlation between eosinophilic oesophagitis and aeroallergens. Alimentary Pharmacology & 
Therapeutics. 2010 Feb 15;31(4):509-15. PubMed PMID: 19925501. 
Nicodème F, Hirano I, Chen J, Robinson K, Lin Z, Xiao Y, Gonsalves N, Kwasny MJ, Kahrilas 
PJ, Pandolfino JE. Esophageal distensibility as a measure of disease severity in patients with 
eosinophilic esophagitis. Clin Gastroenterol Hepatol. 2013 Sep;11(9):1101-1107.e1. doi: 
10.1016/j.cgh.2013.03.020. Epub 2013 Apr 13. 
Prasad GA, Alexander JA, Schleck CD, Zinsmeister AR, Smyrk TC, Elias RM, Locke GR 
3rd, Talley NJ. Epidemiology of eosinophilic esophagitis over three decades in Olmsted County, 
Minnesota. Clin Gastroenterol Hepatol. 2009 Oct;7(10):1055-61. doi: 10.1016/j.cgh.2009.06.023. 
Epub  2009 Jul 1. 
Rabin R, Gudex C, Selai C, Herdman M. From translation to version management: a history and 
review of methods for the cultural adaptation of the EuroQol five-dimensional questionnaire, 
Value Health 2014 Jan;17(1):70-76. 
Roy-Ghanta S, Larosa DF, Katzka DA. Atopic characteristics of adult patients with eosinophilic 
esophagitis. Clin Gastroenterol Hepatol. 2008 May;6(5):531-5. doi: 10.1016/j.cgh.2007.12.045. 
Epub 2008 Mar 4. 
Rubin, D.B. (1987), Multiple Imputation for Nonresponse in Surveys, New York: John Wiley & 
Sons, Inc. 
Schoepfer AM, Straumann A, Panczak R, et al. Development and Validation of a Symptom-Based 
Activity Index for Adults with Eosinophilic Esophagitis. Gastroenterology. 2014;147(6):1255-
1266. 
Schoepfer A. Development, validation and evaluation of an adult and pediatric Eosinophilic 
Esophagitis Activity Index (EEsAI). ClinicalTrials.gov. Last updated 2 September 2013. Available 
at:  
http://clinicaltrials.gov/ct2/show/NCT00939263?term=eosinophilic+esophagitis&recr=Open&ra
nk=19. Accessed 27 February 2014.  
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. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 111 of 113 
 
CONFIDENTIAL 
Singla MB1, Moawad FJ1. An Overview of the Diagnosis and Management of Eosinophilic 
Esophagitis. Clin Transl Gastroenterol. 2016 Mar 17;7:e155. doi: 10.1038/ctg.2016.4. 
Spergel JM, Brown-Whitehorn TF, Beausoleil JL, Franciosi J, Shuker M, Verma R, et al. 14 years 
of eosinophilic esophagitis: clinical features and prognosis. Journal of Pediatric Gastroenterology 
and Nutrition. 2009 Jan;48(1):30-6. PubMed PMID: 19172120. 
Straumann A. The natural history and complications of eosinophilic esophagitis. Gastrointestinal 
Endoscopy Clinics of North America. 2008 Jan;18(1):99-118; ix. PubMed PMID: 18061105. 
Straumann A, Bauer M, Fischer B, Blaser K, Simon HU. Idiopathic eosinophilic esophagitis is 
associated with a T(H)2-type allergic inflammatory response. The Journal of Allergy and Clinical 
Immunology. 2001 Dec;108(6):954-61. PubMed PMID: 11742273. 
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 Dec;125(6):1660-9. PubMed PMID: 14724818. 
Subramanian, A, P Tamayo, VK Mootha, S Mukherjee, BL Ebert, MA Gillette, A Paulovich, SL 
Pomeroy, TR Golub, ES Lander, and JP Mesirov. Gene Set Enrichment Analysis: A Knowledge-
Based Approach for Interpreting Genome-Wide Expression Profiles. Proc Natl Acad Sci U S A 
102, no. 43. 2005 25 Oct: 15545-50. PMID: 16199517 
Veerappan GR, Perry JL, Duncan TJ, Baker TP, Maydonovitch C, Lake JM, Wong RK, Osgard 
EM. Prevalence of eosinophilic esophagitis in an adult population undergoing upper endoscopy: a 
prospective study. Clin Gastroenterol Hepatol. 2009 Apr;7(4):420-6, 426.e1-2. PubMed PMID: 
19162236. 
Weinbrand-Goichberg J, Segal I, Ovadia A, Levine A, Dalal I. Eosinophilic esophagitis: an 
immune-mediated esophageal disease. Immunologic Research. 2013 Jul;56(2-3):249-60. PubMed 
PMID: 23579771. 
Wen T, Stucke EM, Grotjan TM, Kemme KA, Abonia JP, Putnam PE, Franciosi JP, Garza JM, 
Kaul A, King EC, Collins MH, Kushner JP, Rothenberg ME. Molecular diagnosis of eosinophilic 
esophagitis by gene expression profiling. Gastroenterology. 2013 Dec;145(6):1289-99. PubMed 
PMID: 23978633 
Wright BL, Kulis M, Guo R, Orgel KA, Wolf WA, Burks AW, Vickery BP, Dellon ES. Food-
specific 
IgG4 is 
associated 
with eosinophilic 
esophagitis. 
J 
Allergy 
Clin 
Immunol. 2016 Oct;138(4):1190-1192.e3. doi: 10.1016/j.jaci.2016.02.024. Epub 2016 Apr 6. 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 112 of 113 
 
CONFIDENTIAL 
23. 
INVESTIGATOR’S AGREEMENT 
I have read the attached protocol:  A PHASE 3, RANDOMIZED, 3-PART STUDY TO 
INVESTIGATE THE EFFICACY AND SAFETY OF DUPILUMAB IN ADULT AND 
ADOLESCENT PATIENTS WITH EOSINOPHILIC ESOPHAGITIS, and agree to abide by all 
provisions set forth therein. 
I agree to comply with the current International Council for Harmonisation Guideline for Good 
Clinical Practice and the laws, rules, regulations, and guidelines of the community, country, state, 
or locality relating to the conduct of the clinical study. 
I also agree that persons debarred from conducting or working on clinical studies by any court or 
regulatory agency will not be allowed to conduct or work on studies for the sponsor or a partnership 
in which the sponsor is involved. I will immediately disclose it in writing to the sponsor if any 
person who is involved in the study is debarred, or if any proceeding for debarment is pending, or, 
to the best of my knowledge, threatened. 
This document contains confidential information of the sponsor, which must not be disclosed to 
anyone other than the recipient study staff and members of the Institutional Review Board or Ethics 
Committee. I agree to ensure that this information will not be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written consent of the sponsor. 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
 
 
 
(Printed Name) 
 
 
 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


Clinical Study Protocol 
 
R668-EE-1774 Amendment 5 
 
 
Regeneron Pharmaceuticals, Inc. 
 
Page 113 of 113 
 
CONFIDENTIAL 
SIGNATURE OF SPONSOR’S RESPONSIBLE OFFICERS 
(Medical/Study Director, Regulatory Representative, Clinical Study Team Lead, and 
Biostatistician) 
To the best of my knowledge, this protocol accurately describes the conduct of the study. 
Study Title: 
A Phase 3, Randomized, 3-Part Study to Investigate the Efficacy and Safety 
of Dupilumab in Adult and Adolescent Patients with Eosinophilic Esophagitis 
Protocol Number: 
R668-EE-1774 
Protocol Version: 
R668-EE-1774 Amendment 5 
 
See appended electronic signature page 
Sponsor’s Responsible Medical/Study Director 
 
 
See appended electronic signature page 
Sponsor’s Responsible Regulatory Liaison 
 
 
See appended electronic signature page 
Sponsor’s Responsible Clinical Study Team Lead 
 
 
See appended electronic signature page 
Sponsor’s Responsible Biostatistician 
                                        VV-RIM-00127522-1.0 Approved - 05 Nov 2020 GMT-5:00


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

SAP_001.pdf: 
Clinical Development and Regulatory Affairs 
Biostatistics and Data Management 
CONFIDENTIAL 
Page 1 of 101 
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 Phase 3, Randomized, 3-Part Study To Investigate The Efficacy And Safety Of Dupilumab In 
Adult And Adolescent Patients With Eosinophilic Esophagitis 
Part A/Part C 
Compound:  
Dupilumab (REGN668) 
Protocol Number: 
R668-EE-1774.04 
Clinical Phase:   
Phase 3 
Sponsor:  
Regeneron Pharmaceuticals, Inc. 
Study Biostatistician: 
 
Clinical Trial Manager: 
  
Study Medical Director:
 
Version/Date: 
Version Amendment 1/ April 21, 2020 
VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00
NCT Number:  NCT03633617


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 2 of 101 
 
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 
Study Biostatistician  
 
 
 
 
See appended electronic signature page 
Study Medical Director 
  
 
 
 
See appended electronic signature page 
Head of BDM or designee  
 
 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 3 of 101 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................7 
1. 
OVERVIEW ...............................................................................................................10 
1.1. 
Background/Rationale ................................................................................................10 
1.2. 
Study Objectives .........................................................................................................11 
1.2.1. 
Primary Objectives .....................................................................................................11 
1.2.2. 
Secondary Objectives .................................................................................................12 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol ................................12 
1.2.4. 
Revision History for SAP Amendments .....................................................................12 
2. 
INVESTIGATION PLAN ..........................................................................................14 
2.1. 
Study Design and Randomization ..............................................................................14 
2.2. 
Statistical Hypothesis ..................................................................................................15 
2.3. 
Sample Size and Power Considerations .....................................................................16 
2.4. 
Study Plan ...................................................................................................................17 
3. 
ANALYSIS POPULATIONS ....................................................................................20 
3.1. 
The Full Analysis Set (FAS) .......................................................................................20 
3.2. 
The Per Protocol Set (PPS) .........................................................................................20 
3.3. 
The Safety Analysis Set (SAF) ...................................................................................20 
3.4. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................22 
3.5. 
The Immunogenicity Analysis Set..............................................................................22 
3.6. 
Subgroups ...................................................................................................................22 
4. 
ANALYSIS VARIABLES .........................................................................................23 
4.1. 
Demographic and Baseline Characteristics ................................................................23 
4.2. 
Medical History ..........................................................................................................24 
4.3. 
Pre-treatment / Concomitant Medications and Procedures ........................................25 
4.4. 
Efficacy Variable ........................................................................................................27 
4.4.1. 
Primary Efficacy Variable (s) .....................................................................................27 
4.4.2. 
Secondary Efficacy Variable(s) ..................................................................................29 
4.4.3. 
Exploratory Efficacy Variable(s) ................................................................................34 
4.5. 
Safety Variables ..........................................................................................................38 
4.5.1. 
Adverse Events and Serious Adverse Events .............................................................38 
4.5.2. 
Laboratory Safety Variables .......................................................................................38 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 4 of 101 
4.5.3. 
Vital Signs ..................................................................................................................39 
4.5.4. 
12-Lead Electrocardiography (ECG) ..........................................................................39 
4.5.5. 
Physical Examination Variables .................................................................................40 
4.6. 
Pharmacokinetic Variables .........................................................................................40 
4.7. 
Immunogenicity Variables ..........................................................................................40 
4.8. 
Biomarker Variables ...................................................................................................41 
4.9. 
Patient Reported Outcomes for Psychometric Validity Assessment ..........................41 
5. 
STATISTICAL METHODS .......................................................................................41 
5.1. 
Demographics and Baseline Characteristics ...............................................................41 
5.2. 
Medical History ..........................................................................................................41 
5.3. 
Prior/Concomitant Medications/Procedures ...............................................................41 
5.4. 
Subject Disposition .....................................................................................................42 
5.5. 
Extent of Study Treatment Exposure and Compliance ...............................................43 
5.5.1. 
Measurement of Compliance ......................................................................................43 
5.5.2. 
Exposure to Study Drug and Observation Period .......................................................43 
5.6. 
Analyses of Efficacy Variables ..................................................................................44 
5.6.1. 
Analysis of Co-Primary Efficacy Variable(s) .............................................................44 
5.6.2. 
Analysis of Secondary Efficacy Variables .................................................................49 
5.6.3. 
Adjustment for Multiple Comparison .........................................................................50 
5.6.4. 
Analysis of Exploratory Efficacy Variables ...............................................................51 
5.7. 
Analysis of Safety Data ..............................................................................................51 
5.7.1. 
Adverse Events ...........................................................................................................52 
5.7.2. 
Clinical Laboratory Measurements.............................................................................54 
5.7.3. 
Analysis of Vital Signs ...............................................................................................54 
5.7.4. 
Analysis of 12-Lead ECG ...........................................................................................54 
5.7.5. 
Physical Exams ...........................................................................................................55 
5.8. 
Analysis of Pharmacokinetic Data ..............................................................................55 
5.9. 
Analysis of Immunogenicity Data ..............................................................................55 
5.9.1. 
Analysis of ADA ........................................................................................................55 
5.9.2. 
Analysis of Neutralizing Antibody (NAb) Data .........................................................56 
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy ........................56 
5.10.1. 
Association of immunogenicity with exposure ..........................................................56 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 5 of 101 
5.10.2. 
Immunogenicity and Safety/Efficacy .........................................................................56 
5.11. 
Analysis of Biomarker Data .......................................................................................57 
5.12. 
Analysis of Psychometric Validity of Patient Reported Outcome Measures .............58 
6. 
DATA CONVENTIONS ............................................................................................59 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................59 
6.2. 
General Data Handling Conventions ..........................................................................59 
6.3. 
Data Handling Convention for Missing Data .............................................................59 
6.4. 
Analysis Visit Windows .............................................................................................61 
6.5. 
Statistical Technical Issues .........................................................................................63 
7. 
INTERIM ANALYSIS ...............................................................................................64 
8. 
SOFTWARE ...............................................................................................................65 
9. 
REFERENCES ...........................................................................................................66 
10. 
APPENDIX.................................................................................................................68 
10.1. 
Summary of Statistical Analyses ................................................................................68 
10.2. 
Schedule of Time and Events .....................................................................................70 
10.2.1. 
Footnotes for the Schedule of Events Tables .............................................................76 
10.2.1.1. 
Footnotes for Table 1 ..................................................................................................76 
10.2.1.2. 
Footnotes for Table 2 ..................................................................................................78 
10.2.1.3. 
Footnotes for Table 3 ..................................................................................................79 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) ...................................80 
10.4. 
Search Criteria for TEAEs of Special Interest ............................................................87 
10.5. 
Important Protocol Deviations that Exclude Patients from the Per Protocol 
Analysis Set ................................................................................................................88 
10.6. 
EoE Histology Scoring System (EoEHSS) Feature Evaluation Per Colllins et 
al. 2017 .......................................................................................................................97 
10.7. 
Gene Lists Comprising Each Transcriptome Endpoint ..............................................99 
10.8. 
List of Part A Subjects Affected by Electronic Handheld Device Navigation 
Malfunction ...............................................................................................................101 
 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 6 of 101 
LIST OF TABLES 
Table 1: 
Parts A Schedule of Events – Screening Period and Placebo-controlled, 
Double-Blind Treatment Period .................................................................................70 
Table 2: 
Part C Schedule of Events – Extended Active Treatment Period ...............................72 
Table 3: 
Follow-up Period, Early Termination Visit, and Unscheduled Visit ..........................74 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Design ..................................................................................................15 
Figure 2: 
Study Flow Diagram for Part A and Part C ................................................................17 
Figure 3: 
Flow Diagram of DSQ eDiary ....................................................................................46 
Figure 4: 
Response Patterns of DSQ eDiary ..............................................................................47 
 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 7 of 101 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Ab 
Antibody 
ACQ-5 
Asthma Control Questionnaire-5 
AD 
Atopic dermatitis 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BID 
Twice (two times) a day 
BUN 
Blood urea nitrogen 
CMH 
Cochran-Mantel-Haenszel (test) 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CRO 
Contract research organization 
CSR 
Clinical study report 
Ctrough 
Trough concentration 
DMC 
Data monitoring committee 
DSQ 
Dysphagia Symptom Questionnaire 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eCOA 
Electronic clinical outcome assessment 
EDC 
Electronic data capture 
eGFR 
Estimated glomerular filtration rate 
EoE 
Eosinophilic esophagitis 
EoE-EREFS 
Eosinophilic Esophagitis-Endoscopic Reference Score 
EoEHSS 
EoE Histology Scoring System 
EoE-IQ 
EoE Impact Questionnaire 
EoE-SQ 
EoE Symtom Questionnaire 
EOS 
End of study (visit) 
eos/hpf 
Eosinophils/high power field 
EOT 
End of treatment 
ET 
Early termination 
FAS 
Full analysis set 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 8 of 101 
FSH 
Follicle stimulating hormone 
HBcAb 
Hepatitis B core antibody 
HBsAb 
Hepatitis B surface antibody 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HDL 
High-density lipoprotein 
HIV 
Human immunodeficiency virus 
IA 
Interim analysis 
IAF 
Informed assent form 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IgE 
Immunoglobulin E 
IgG4 
Immunoglobulin G4 
IL 
Interleukin 
IL-4Rα 
Interleukin-4 receptor alpha 
ISR 
Injection site reaction 
IVRS/IWRS 
Interactive voice/web response system 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model repeated measure 
NAb 
Neutralizing antibody 
OIT 
Oral immunotherapy 
PCSV 
Potentially clinically significant value 
PGIC 
Patient Global Impression of Change of Dysphagia 
PGIS 
Patient Global Impression of Severity of Dysphagia 
PK 
Pharmacokinetic 
POEM 
Patient-Oriented Eczema Measure 
PPI 
Proton pump inhibitor 
PRO 
Patient-reported outcome 
PT 
Preferred term (MedDRA) 
QOL 
Quality of life 
Q2W 
Once every two weeks 
QW 
Once weekly 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 9 of 101 
RBC 
Red blood cell 
RQLQ(s)+12 
Rhinoconjunctivitis Quality of Life Questionnaires for 12 years and older 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis Software 
SC 
Subcutaneous 
SD 
Standard deviation 
SLIT 
Sublingual immunotherapy 
SOC 
System organ class 
TARC 
Thymus and activation-regulated chemokine 
TB 
Tuberculosis 
TEAE 
Treatment-emergent adverse event 
Th2 
Type 2 helper T cell 
TNSS 
Total Nasal Symptom Score 
ULN 
Upper limit of normal 
WBC 
White blood cell 
WOCF 
Worst observation carried forward 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 10 of 101 
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 analysis of data for R668-EE-1774 study Part A. This SAP will also 
describe the descriptive summary of Part A patients’ data in Part C as extended active treatment 
and in the 12-week follow-up period. A separate Part B SAP will be prepared for the analysis of 
data from Part B, and Part B patients’ data in Part C and 12-week follow-up period (no separate 
SAP for Part C). 
This plan may be revised during the conduct of study Part A to accommodate protocol amendments 
and/or to make changes to adapt to unexpected issues in study execution and/or data that affect 
planned analyses. These revisions will be based on blinded review of the study and data. This plan 
will be finalized prior to the data lock for end of Part A, i.e., the last Part A patient reaching week 
24 visit. 
1.1. 
Background/Rationale 
Eosinophilic esophagitis (EoE) is a chronic, inflammatory, allergic/immune-mediated disease of 
the esophagus. The disease is characterized by local eosinophilic inflammation leading to 
symptoms of esophageal dysfunction. The primary clinical manifestations of EoE in both adults 
and adolescents are dysphagia and food impaction (Hudgens, 2017). Growing evidence suggests 
that a Type 2 cytokine-mediated immune response plays an important role in the development of 
EoE. The inflammatory damage to the esophageal epithelium results in symptoms of esophageal 
dysfunction, such as dysphagia. Chronic inflammation of the esophagus may also lead to 
remodeling, stricture formation, and fibrosis.  
Current therapeutic approaches include high dose proton pump inhibitors, chronic dietary 
modification with specific food elimination, swallowed topical formulation corticosteroids (not 
approved for the treatment of EoE in adolescents or in adults outside the European Union [EU]), 
and esophageal dilation when esophageal narrowing occurs or strictures develop. The therapies 
for eosinophilic esophagitis are limited by variable response rates, relapse after therapy cessation, 
and adverse effects on quality of life. High dose proton pump inhibitors lead to histologic remission 
in approximately half of the patients (Lucendo, 2016).  Swallowed topical corticosteroids have 
been reported in clinical trials to induce partial clinical responses and histologic remission; 
however, they are not uniformly effective and have been associated with local fungal infections. 
Endoscopy for prolonged and/or painful food impaction is an emergent procedure utilized for 
symptomatic relief if the patient cannot pass the food or induce vomiting. It is associated with a 
risk of severe esophageal injury and does not alter the underlying pathogenesis or progression of 
the disease.  As such, there is a significant unmet need for new treatments across the age spectrum 
targeting key pathways driving the inflammation in EoE (Rothenberg, 2015, Spergel, 2012, 
Greuter, 2017).  
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, 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 11 of 101 
chemokines, and IgE. Additionally, preclinical data demonstrate that treatment with dupilumab 
prevents infiltration of eosinophils into tissues. For these reasons, dupilumab was evaluated in 
adult patients with EoE in a phase 2, multicenter, double-blind, randomized, placebo-controlled 
study (R668-EE-1324), where it demonstrated substantial improvements in clinical (based on the 
Straumann Dysphagia Instrument), histologic, and endoscopic aspects of the disease. Dupilumab 
was well tolerated in the study, with safety data generally consistent with other dupilumab studies 
in AD patients, asthma patients, and patients with chronic rhinosinusitis with nasal polyps.  No 
safety signal associated with dupilumab use was identified in the EoE patient population have been 
identified. The results from phase 2 support the phase 3 evaluation of dupilumab in EoE. 
Additional background information on the study drug and development program can be found in 
the Investigator’s Brochure. 
This phase 3 study will investigate the efficacy and safety of dupilumab in adult and adolescent 
patients with EoE in 3 study parts. Part A and Part B are 24-week treatment, randomized, double-
blind, placebo-controlled study phases. Patients are randomized in Part A to receive dupilumab 
300 mg QW or placebo; patients are randomized in Part B to receive dupilumab 300 mg Q2W, 
dupilumab 300 mg QW, or placebo. Patients who participate in Part A are not eligible to participate 
in Part B. At the end of Part A, eligible patients will enter Part C as an extended treatment period 
to receive dupilumab 300 mg QW. At the end of Part B, eligible patients will enter Part C to receive 
dupilumab 300 mg Q2W or dupilumab 300 mg QW in a blinded fashion. Patients in Parts A/B 
who do not enter Part C will enter a 12-week follow-up period immediately after Part A/B.  
Two SAPs will be prepared to describe the strategy and statistical methods to be used in the 
analysis of data for this study: 
 This SAP will cover Part A patients’ data in Part A, Part C, and the 12-week follow-
up period.  
 A separate SAP will cover Part B patients’ data in Part B, Part C and the 12-week 
follow-up period.  
1.2. 
Study Objectives  
1.2.1. 
Primary Objectives 
Part A  
To determine the treatment effect of dupilumab compared with placebo in adult and adolescent 
patients with EoE after 24 weeks of treatment as assessed by histological and clinical measures, 
and to inform/confirm the final sample size determination for Part B. 
Part C 
To assess the safety and efficacy of dupilumab treatment in adult and adolescent patients with EoE 
after up to 52 weeks of treatment as assessed by histological and clinical measures. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 12 of 101 
1.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
 To evaluate the safety, tolerability, and immunogenicity of dupilumab treatment for up 
to 52 weeks in adult and adolescent patients with EoE 
 To explore the relationship between dupilumab concentration and responses in adult 
and adolescent patients with EoE, using descriptive analyses 
 To evaluate the molecular effects of dupilumab on transcriptomic signatures associated 
with EoE and type 2 inflammation 
1.2.3. 
Modifications from the Statistical Section in the Final Protocol 
Modifications from protocol amendment 4: 
 Removed the sensitivity analysis using the Mixed Effect Model for Repeated 
Measure (MMRM) as it’s based on the same assumption for missing data (missing at 
random) as the primary analysis using multiple imputations (MI). 
1.2.4. 
Revision History for SAP Amendments 
The purpose of this amendment is to: (1) specify the methods for handling missing data due to the 
COVID-19 pandemic and additional analyses for potentially affected endpoints; and (2) describe 
the handling of DSQ data collected during the time when DSQ device navigation malfunctions 
occurred. 
Section 
Description of Additions/Updates 
1.2.3 Modifications 
from the Statistical 
Section in the Final 
Protocol 
Updated per protocol amendment 4. Removed items that are no 
longer modifications from the latest protocol amendment. 
2.4 Study plan 
Added provisions introduced in protocol amendment 4 allowing for 
certain study procedures to occur outside the protocol specified time 
points and/or outside of the clinic environment. 
5.4 Subject 
Disposition 
Added summaries of patient disposition due to the COVID-19 
pandemic 
5.6.1 Analysis of Co-
Primary Efficacy 
Variable(s) 
Specified that in the primary analysis of the co-primary endpoint of 
histologic response, patients with missing week 24 data due to the 
COVID-19 pandemic will be imputed by multiple imputation (MI). 
Sensitivity analysis considering patients with missing week 24 data 
due to the COVID-19 pandemic as non-responders is added. 
 
Clarified that DSQ data collection and analyses are not expected to 
be affected by the COVID-19 pandemic. 
 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 13 of 101 
Section 
Description of Additions/Updates 
Specified DSQ data collected during the time when some devices 
were impacted by navigation malfunction will not be used in the 
analyses.  
 
Specified that in the primary analyses of the secondary histological 
and endoscopic efficacy endpoints at week 24, missing data due to 
the COVID-19 pandemic will be imputed by MI. Sensitivity analysis 
where missing data due to the COVID-19 pandemic will be imputed 
by WOCF is added. 
 
Specified that for PRO endpoints intended to be collected at clinic 
visits, data collected via phone interview will be included in the 
primary summary. Additional summaries will be provided with 
exclusion of data collected through phone interviews. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 14 of 101 
2. 
INVESTIGATION PLAN 
2.1. 
Study Design and Randomization 
Part A is a 24-week treatment, randomized, double-blind, placebo-controlled study phase to 
determine the treatment effect of dupilumab compared with placebo in adult and adolescent 
patients with EoE as assessed by histological and clinical measures, and to inform/confirm the 
final sample size determination for Part B. After a screening period up to 12 weeks, patients will 
be centrally randomized via interactive web response system (IWRS) in a 1:1 ratio to dupilumab 
300 mg SC QW or placebo SC and treated double-blind for 24 weeks in Part A. At the end of Part 
A, eligible patients will enter Part C, which consists of a 28-week period of dupilumab 300 mg SC 
QW treatment. Patients in Parts A who do not enter Part C will enter a 12-week follow-up period 
immediately after Part A. Patients who participate in Part A are not eligible to participate in Part 
B. 
Approximately 80 patients (40 per treatment group) are planned to be randomized in Part A from 
multiple global sites. Approximately 345 patients (115 per treatment group) are planned to be 
randomized in Part B from multiple global sites. Any re-estimation of sample size for Part B will 
be documented in the Part B statistical analysis plane (SAP) before its database lock.   
The design of the overall study is depicted below in Figure 1. Detailed description of the design 
and analysis for Part B will be provide in a separate SAP. As Part A and Part B are carried out as 
2 separate sub-studies with no overlap in patients, Part A and Part B will each have a separate 2-
sided alpha level of 0.05.  
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 15 of 101 
Figure 1: 
Overall Study Design 
 
 
2.2. 
Statistical Hypothesis 
For the comparison of dupilumab 300 mg QW to placebo, the following hypotheses of the co-
primary endpoints will be tested, where pd is the true proportion of patients achieving peak 
esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 24 and μd is the true mean change 
from baseline in the DSQ total score at week 24 in the dupilumab group; and pp and μp are the 
corresponding true values in the placebo group. 
 Proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 
eos/hpf at week 24 
 Null hypothesis (H0): pp = pd, ie, the proportion of patients achieving peak 
esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 24 is the same 
between the dupilumab group and the placebo group. 
 Alternative hypothesis (H1): pp ≠ pd, ie, the proportion of patients achieving peak 
esophageal intraepithelial eosinophil count of ≤6 eos/hpf at week 24 is different 
between the dupilumab group and the placebo group. 
  Change from baseline in the DSQ total score at week 24 
 Null hypothesis (H0): μp = μd, ie, the mean change from baseline in the DSQ total 
score at week 24 is the same between the dupilumab group and the placebo group. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 16 of 101 
 Alternative hypothesis (H1): μp ≠ μd, ie, the mean change from baseline in the DSQ 
total score at week 24 is different between the dupilumab group and the placebo 
group. 
Part A is considered positive when the co-primary endpoints both achieve statistical significance 
with two-sided significance level 0.05. 
2.3. 
Sample Size and Power Considerations 
Efficacy assessment employs the following co-primary endpoints measuring histologic and 
clinical symptoms of disease, respectively: 
 Proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 
eos/hpf at week 24 
 Absolute change in Dysphagia Symptom Questionnaire (DSQ) score from baseline to 
week 24 
The assumptions used in sample size calculations are based on results from a phase 2 study of 
dupilumab (R668-EE-1324) and reported data of a phase 2 study of budesonide in patients with 
EoE as follows:  
(1) In the study of dupilumab, a treatment difference of 65.2% was observed in the proportion 
of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 eos/hpf after 
12 weeks of treatment (placebo 0% vs. dupilumab 65.2%). DSQ was not assessed in this 
study. The overall dropout rate was 8.5% during the 12-week treatment period.  
(2) In the study of budesonide oral suspension (Dellon, 2017b), a treatment difference of 36% 
was observed in the proportion of patients achieving peak esophageal intraepithelial 
eosinophil count of ≤6 eos/hpf after 12 weeks of treatment (placebo 3% vs. budesonide 
39%). The mean (standard deviation [SD]) of change from baseline in DSQ total score at 
week 12 was -7.5 (10.7) in placebo and -14.3 (13.0) in the budesonide group, corresponding 
to a treatment group difference of -6.8. The overall dropout rate was 6.5% during the 
12  week treatment period. 
With the data of two phase 2 studies from Dupilumab and budersonide, the planned sample size 
for Part A is approximately 40 patients in each treatment group such that for the comparison of 
dupilumab 300 mg QW to placebo:  
 This sample size will yield >99% power to detect a treatment difference of 62% in the 
proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤6 eos/hpf at week 24 (placebo 3% vs. dupilumab 65%) at a 2-sided significance level 
of 5% using Fisher’s exact test. 
 With respect to the treatment group difference in the mean change from baseline in 
DSQ total score, assuming a common SD of 13.0, this sample size is expected to 
generate a 95% confidence interval whose half-width is 5.7. If the true treatment 
difference is -9.0 points, the statistical power for the co-primary endpoint of DSQ will 
be 80% using a two-sample t-test. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 17 of 101 
A dropout rate of 15% is assumed for the calculations above considering that a higher dropout rate 
may be observed in Part A (24 weeks treatment period) than in the previous phase 2 dupilumab 
study (dropout rate of 8.5% in the 12-week treatment period) or budesonide study (dropout rate of 
5.4% in the 12-week treatment period).  
2.4. 
Study Plan 
Patients will undergo a screening period (up to 12 weeks), a double-blind treatment period of 24 
weeks (Part A), a 28-week extended active treatment period (Part C), and a 12-week follow-up 
period as depicted in Figure 2. All patients will be followed up for an additional 12 weeks after 
completing Part C.  Patients in Parts A who choose not to participate in or are ineligible for Part C 
will be followed for an additional 12 weeks immediately after Part A. 
Figure 2: 
Study Flow Diagram for Part A and Part C 
 
DB = double-blind. 
Note:  For patients who do not have at least 11 daily entries during the 14 days immediately preceding the planned 
randomization date (baseline), randomization should be postponed until this requirement is met, but without 
exceeding the 85-day maximum duration for screening. 
After adult patients provide informed consent and adolescent patients and/or their legal 
parents/legal guardians provide informed consent and informed assent (as appropriate), patients 
will be assessed for study eligibility at visit 1.  
Study participants are required to have a conﬁrmed diagnosis of EoE which may be established 
either by a prior historical biopsy showing ≥15 intraepithelial eosinophils per high-power ﬁeld 
(eos/hpf) from at least one esophageal region after at least 8 weeks of treatment with a high-dose 
proton pump inhibitor (PPI) using any approved PPI or by biopsies performed after approximately 
8 weeks of high-dose PPI treatment initiated prior to screening or during the screening period, 
which demonstrate ≥15 intraepithelial eos/hpf in at least 2 out of 3 esophageal regions (proximal, 
mid, and distal); see Protocol Figure 3 for endoscopy/biopsy procedure flow chart. Patients who 
are on PPIs during the screening period and are eligible to enroll in the study must continue a 
high-dose PPI regimen during the study (see details in Protocol Section 7.2). Patients are allowed 
to switch among the approved background therapy options for high-dose PPI use during the study. 
Part A 
Part C 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 18 of 101 
All patients who meet the other clinical and laboratory eligibility criteria will undergo endoscopy 
with biopsies at visit 2 (day -21±7) both to establish a baseline reference measure and to ensure 
eligibility. For patients without a historical biopsy, the visit 2 biopsy will serve as both 
confirmation of EoE diagnosis and the baseline reference measure. 
All biopsies performed during this study will be evaluated by pathologists at a central pathology 
laboratory who will be blinded to treatment assignment. 
Note: Biopsy specimens from the stomach and/or duodenum will be obtained in all patients 
<18 years of age to rule out alternate etiologies of esophageal eosinophilia. Targeted, stomach 
and/or duodenal biopsies will be obtained in adults only in the event of abnormal endoscopic 
findings (other than typical EoE findings) or clinical suspicion of alternate etiologies. All 
randomized patients found to have stomach and/or duodenal abnormalities at baseline will have 
follow-up stomach and/or duodenal biopsies at week 24 and week 52. 
After confirmation of EoE diagnosis, patients will be given an electronic diary (eDiary) to record 
dysphagia symptoms on a daily basis during the 2 weeks prior to the baseline visit (visit 3). 
Patients may be re-screened once if they fail the screening evaluation, unless the reason for screen 
failure is related to histologic or clinical disease severity inclusion criteria. The baseline endoscopy 
with biopsy and EoE-EREFS scoring will not be repeated for re-screened patients.  These results 
will continue to be valid baseline data.  Re-screening must occur within 6 months of the screen 
failure. 
For patients whose DSQ diary compliance does not meet eligibility requirements within the 21-
day interval between Visit 2 and Visit 3 (at least 11 daily entries during the 14 days immediately 
preceding the planned randomization date), randomization may be postponed as long as the total 
duration of the screening period does not exceed the 85-day maximum. 
At the baseline visit (visit 3), patients who continue to meet eligibility criteria will enter the 
24-week, placebo-controlled, double-blind treatment period and be randomized in a 1:1 ratio to 
dupilumab 300 mg SC QW or placebo SC. Randomization will be stratified by age (≥18 vs. ≥12 
to <18 years of age) and use of PPI at randomization (yes vs. no). 
During the 24-week, placebo controlled, double-blind treatment period, clinic visits are scheduled 
per the schedule of events (Section 10.2). Patients and parents/caregivers will be trained on 
injecting study drug at the first 3 visits during the double-blind treatment period. Patients will be 
closely monitored at the study site at visits 3 to 6 (baseline visit, study weeks 1, 2, and 4) for a 
minimum of 30 minutes after the administration of study drug. During weeks when no clinic visit 
is scheduled, the patient or parent/caregiver will administer study drug. Doses of study drug 
administered at home should be administered one week after the prior dose of study drug.  Study 
drug administration that occurs in clinic should occur per the Schedule of Events in Section 10.2. 
Patients and parents/caregivers who prefer to have clinic staff administer study drug may choose 
to have injections administered in the clinic. 
The end of treatment visit for the double-blind treatment period is at week 24. The co-primary 
endpoints will be assessed at week 24, one week after the last dose of study drug during the double-
blind treatment period.  
Patients who prematurely discontinue study treatment will be encouraged to remain in the study 
and attend all subsequent scheduled visits. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 19 of 101 
At the end of double-blind treatment visit (week 24), eligible patients in Part A may enter Part C, 
which consists of a 28-week extended active treatment period. Patients who do not enter Part C 
may enter a 12-week follow-up period. 
In protocol amendment 4, provisions were added to allow study procedures to occur at outside the 
protocol specified timepoint and/or outside of the clinic environment and will remain in effect only 
for the duration of the public health emergency due to the COVID-19 pandemic. 
 Endoscopy with biopsies may be delayed for visit 11/week 24, visit 19/week 52, early 
termination, and before initiating rescue treatment 
 At-home study drug dosing is permitted for all visits except for visit 3/day 1 and visit 
11/week 24 
 If the for-cause endoscopy with biopsies cannot occur due to COVID-19 restrictions, 
rescue treatment should be initiated without delay and these patients will be eligible to 
participate in Part C 
 Safety and laboratory procedures (vital signs, weight, PK/ADA sample collection, 
hematology and chemistry urine sample collection) may be delayed or occur at-home 
when possible 
 The patient reported outcome questionnaires that are intended to be completed during 
clinic visits may be conducted via phone interviews after visit 3/day 1 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 20 of 101 
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 per 
protocol set (PPS) is the supportive analysis population for Part A efficacy analyses. The Part A 
safety analysis set (SAF) is the basis for Part A safety analyses.  
The Part C SAF is the basis for both efficacy and safety analyses of Part C. 
3.1. 
The Full Analysis Set (FAS) 
The Part A full analysis set (FAS) includes all randomized patients in Part A. Efficacy analyses 
will be based on the treatment allocated by the IWRS at randomization (as randomized).  
Note: Two randomization transactions were made for Part A patient 840118002 at Visit 3 due to 
internet connection issues. Each transaction allocated a randomization number and a study drug 
kit to this patient. The patient was administered study drug from both kits at Visit 3. The patient 
continued participation in the study as randomized per the first randomization transaction and 
subsequent kits were dispensed based on that transaction. Details about this randomization 
irregularity is documented in a note-to-file. In efficacy analyses, this patient will be analyzed based 
on the treatment allocated by the first IWRS randomization transaction.  
3.2. 
The Per Protocol Set (PPS) 
The Part A per protocol analysis set (PPS) includes all patients in the Part A FAS except for those 
who are excluded because of specified important protocol violations in Part A. A preliminary list 
of such important protocol violations is provided in Section 10.5 and a final list of patients 
excluded from FAS will be generated prior to Part A database lock.   
Final determinations of the PPS will be made in the blinded manner prior to Part A database lock. 
There is no PPS for Part C. 
3.3. 
The Safety Analysis Set (SAF) 
Part A: 
The Part A safety analysis set (SAF) includes all randomized patients who received any study drug 
in Part A; it is based on the treatment received (as treated). Treatment compliance/administration 
and all clinical safety variables in Part A will be analyzed using the Part A SAF. 
Part C: 
The Part C SAF includes all patients who were randomized in Part A/B, entered Part C, and 
received any study drug in Part C. Efficacy, treatment compliance/administration, and all clinical 
safety data from Part C  through a pre-specified cut-off date (approximately March 15th, 2020) 
around the time of Part A completion will be analyzed for Part C SAF patients who entered Part 
C from Part A. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 21 of 101 
 
The actual treatment group as treated for Part A is defined by the following rules: 
 For a patient randomized to dupilumab 300 mg QW, if the patient received all placebo 
injections in Part A, the actual treatment will be assigned as placebo. 
 Regardless of the treatment group a patient is randomized to, if the patient received at 
least 1 dupilumab injection in Part A, the actual treatment will be assigned as 
dupilumab 300 mg QW. 
The Part A treatment group assignment for analysis of Part C data will be the same as the SAF for 
Part A.  
For safety summaries, the following analysis periods are defined: 
 Part A week 24 treatment period is defined as  
 For patients who entered Part C: Day 1 to the date of first dose of Part C study drug 
(or week 24 visit if patient entered Part C but never received any Part C study drug).  
 For patients who did not enter Part C:  
 Day 1 to the week 24 visit if patients completed week 24 visit with known 
visit date. 
 Day 1 to study day 169 (24 weeks times 7 days/week), or to patient’s last 
study participation date, whichever comes earlier, if patients did not 
complete week 24 visit or had missing week 24 visit date. 
 Part C extended treatment period for patients who entered Part C is defined as 
 Time after the first dose of study drug in Part C to the date of week 52 visit 
if patients completed week 52 with known visit date. 
 Time after the first dose of study drug in Part C to study day 365 (52 weeks 
times 7 days/week), or to patient’s last study participation date, whichever 
comes earlier, if patients did not complete week 52 visit or had missing 
week 52 visit date. 
 Follow-up period is defined as 
 For patients who entered Part C: the day after the end of Part C extended treatment 
period to the patient last study participation date. 
 For patients who did not enter Part C: the day after the end of Part A week 24 
treatment period to the patient last study participation date. 
The Part A and Part C SAFs will be the basis for the analyses for the Part A treatment period and 
Part C treatment period, respectively; however, for the analyses for 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 24 visit (for Part A SAF) and week 52 
visit (for Part C SAF). 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 22 of 101 
3.4. 
The Pharmacokinetic Analysis Set (PKAS) 
The PK analysis set for Part A and Part C includes all randomized patients who received any study 
drug and who had at least one non-missing drug concentration result following the first dose of 
study drug in the corresponding study part.  
3.5. 
The Immunogenicity Analysis Set 
The ADA analysis set (AAS) for Part A and Part C includes all patients who received any study 
drug and had at least one non-missing ADA result from the dupilumab ADA assay after first dose 
of the study drug in the corresponding study part.  Patients will be analyzed according to the 
treatment actually received. 
The neutralizing antibody (NAb) analysis set (NAS) for Part A and Part C includes all patients 
who received any study drug and who are negative in the dupilumab ADA assay or with at least 
one non-missing result in the dupilumab NAb assay after first dose of the study drug in the 
corresponding study part. Patients who are ADA negative are set to negative in the NAb analysis 
set. Patients will be analyzed according to the treatment actually received. 
3.6. 
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 efficacy and safety analyses: 
 Age group (years; 12 to <18, ≥18)  
 Sex (Male, Female) 
 Duration of EoE (years from start date of EoE to randomization date; <5, ≥5) 
 Baseline weight group (<60 kg, ≥60 kg) 
 Prior use of swallowed topical steroids for the treatment of EoE (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) 
Note: subgroups defined by race, ethnicity, and region are not included as majority of patients in 
Part A are anticipated to be in one major category of these demographic factors. 
Subgroups to be considered for efficacy analyses only: 
 Baseline BMI group (<25, ≥25-<30, ≥30) 
 Use of PPI at randomization (Yes, No) 
 Prior esophageal dilations (Yes, No) 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 23 of 101 
 Subject on a food elimination diet at the time of screening (Yes, No) 
 Subject on a food elimination diet in the past (Yes, No) 
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;12 to <18, ≥18 to <40, ≥40 to <65, ≥65), Sex (Male, Female), Ethnicity with 
grouping (Hispanic or Latino, Not-Hispanic or Latino), Race with grouping (White, 
Black or African American, Asian, Other), Region (North America, or Rest of World), 
Country, Baseline weight as a continuous variable and with grouping (kg; <60, ≥60), 
Height (m), and calculated BMI (kg/m2; <15, ≥15-<25, ≥25-<30, ≥30), randomization 
stratification factors (age [years; 12 to <18, ≥18] and use of PPI at randomization [Yes, 
No]). 
 Baseline characteristics:  
 DSQ total score 
 Number of days with dysphagia in the 2 weeks prior to baseline as a continuous 
variable and with group (4, 5, 6, 7, 8, etc.) 
 Amount of pain patient had experienced when swallowing food 
 Peak esophageal intraepithelial eosinophil count (eos/hpf) of three regions 
(proximal, mid, and distal) 
 Eosinophilic Esophagitis-Endoscopic Reference Score (EREFS) total score 
 Mean stage score from the EoE Histology Scoring System (EoEHSS) summed over 
3 regions  
 Mean grade score from the EoEHSS summered over 3 regions  
 Total EoEHSS histology stage score (excluding lamina propria fibrosis) summed 
over 3 regions  
 Total EoEHSS histology grade score (excluding lamina propria fibrosis) summed 
over 3 regions  
 Patient global impression of severity (PGIS) level (none, mild, moderate, or severe) 
 EoE Impact Questionnaire (EoE-IQ) score 
 EoE Symptom Questionnaire (EoE-SQ) frequency score and severity score 
 Total Nasal Symptom Score (TNSS) for patients with history of allergic rhinitis  
 Rhinoconjunctivitis Quality of Life Questionnaire score for patients aged 12+ years 
[RQLQ(S)+12] for patients with history of allergic rhinitis 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 24 of 101 
 Asthma Control Questionnaire-5 (ACQ-5) score for patients with history of asthma 
 Patient-Oriented Eczema Measure (POEM) score for patients with history of atopic 
dermatitis 
 Baseline blood eosinophil count as a continuous variable and with grouping 
(Giga/L; <0.15, ≥0.15; <0.30, ≥0.30; <0.50, ≥0.50) 
 Baseline serum total immunoglobulin E (IgE) as a continuous variable and with 
grouping (IU/mL; <100, ≥100) 
 Patients treated with PPI at randomization (Yes, No) 
 Prior use of swallowed topical corticosteroids for EoE (Yes, No) 
 Prior esophageal dilations (Yes, No) 
 Prior use of swallowed topical corticosteroids for EoE and prior esophageal dilation 
(Yes, No) 
 Number of prior esophageal dilations  
 Age at the first esophageal dilation with grouping (years; 0 to 11, 12 to 18, 19 to 
24, 25 to 50, >50), calculated as the number of years between patient birth year and 
the year of the first esophageal dilation (prior to screening)  
 Duration of EoE as a continuous variable and with grouping (years; <5, ≥5)  
 Age at EoE onset with grouping (years; 0 to 18, 19 to 24, 25 to 50, >50), calculated 
as the number of years between patient birth year and the start year of EoE  
 Historical esophageal biopsy showing ≥ 15 (eso/hpf [400 X]) after 8 weeks of high-
dose PPI (Yes, No) 
 Patient on food elimination diet in past (Yes, No) 
 Patient on food elimination diet at screening (Yes, No) 
4.2. 
Medical History 
Medical history will be coded to a Preferred Term (PT) and associated Primary System Organ 
Class (SOC) according to the latest available version of MedDRA at the coding CRO. Information 
related to EoE and other atopic medical conditions includes diagnosis of EoE, atopic dermatitis, 
asthma, allergic rhinitis, allergic conjunctivitis, chronic rhinosinusitis, nasal polyps, food allergy, 
hives, contact dermatitis, and 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 is on food elimination diet, food type eliminated, and reason for elimination of specific 
food.  
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 25 of 101 
4.3. 
Pre-treatment / Concomitant Medications and Procedures 
Medications/Procedures will be recorded from the day of informed consent until the EOS visit. 
Medications will be coded to the ATC level 2 (therapeutic main group) and ATC level 4 
(chemical/therapeutic subgroup), according to the latest available version of WHO Drug 
Dictionary (WHODD) at the coding CRO. Patients will be counted once in all ATC categories 
linked to the medication. Medications of interest include PPIs and swallowed topical/systemic 
corticosteroids for the treatment of EoE.  
Procedures will be coded to a Preferred Term (PT), High Level Term (HLT) and associated 
primary System Organ Class (SOC) according to the latest available version of MedDRA in effect. 
Pre-treatment medications/procedures: medications taken or procedures performed prior to 
administration of the first dose of study drug. 
Concomitant medications/procedures (CMs/CPs): medications taken or procedures performed 
following the first dose of study drug through the EOS visit. This includes medications 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 3.3): 
 CMs/CPs taken during the Part A week 24 treatment period 
 CMs/CPs taken during the Part C extended active treatment period 
 CMs/CPs taken during the follow-up period 
Prohibited concomitant medications/procedures during the study:  
Treatment with the following concomitant medications is prohibited through week 52:  
 Swallowed topical corticosteroids (may be used as rescue treatment for EoE) 
 Systemic corticosteroids (may be used as rescue treatment for EoE) 
 Systemic immunosuppressive/immunomodulating drugs (including, but not limited to, 
omalizumab, cyclosporine, mycophenolate-mofetil, azathioprine, methotrexate, IFN-γ, 
or other biologics) 
 Treatment with an investigational drug (other than dupilumab) 
 Initiation, discontinuation, or change in dosage regimen of the following medications 
within 8 weeks prior to the baseline endoscopy (stable doses of these medications are 
allowed) 
 Proton pump inhibitors, unless used for a required PPI trial during the screening 
period or in patients who present at the initial screening visit with current use of 
PPIs 
 Systemic leukotriene inhibitors 
 Nasal and/or inhaled corticosteroids 
 Initiation of SCIT, or change in dose for those patients on a stable dose of SCIT within 
1 year prior to screening  
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 26 of 101 
 SLIT 
 OIT 
 Treatment with an investigational drug (other than dupilumab) 
 Treatment with a live (attenuated) vaccine (see protocol Section 7.1.1 for the list of 
vaccine). 
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 
monitor before database locks with documented procedures.  
Rescue treatments (including both medications 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 in Parts A and C. 
An endoscopy with biopsy will be performed prior to the initiation of rescue therapy. Patients who 
undergo an endoscopy with biopsy due to the initiation of rescue therapy will not undergo the 
scheduled end of treatment visit endoscopy/biopsy at weeks 24 and 52. Patients who receive rescue 
treatment in Part A will not be eligible for the Part C 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 and will be asked to 
return to the clinic for all remaining study visits and participate in all assessments for these visits 
except for endoscopy/biopsy, as noted above.  
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/or duodenum will be obtained at visit 2 in all patients 
<18 years of age to rule out alternate etiologies of esophageal eosinophilia. Stomach and/or 
duodenal biopsies will be obtained in adults only in the event of abnormal endoscopic findings 
(other than typical EoE findings) or clinical suspicion of alternate etiologies. All randomized 
patients found to have stomach and/or duodenal abnormalities at baseline will have follow-up 
stomach and/or duodenal biopsies at week 24 and week 52. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 27 of 101 
4.4. 
Efficacy Variable 
4.4.1. 
Primary Efficacy Variable (s) 
The co-primary endpoints for Part A are: 
 Proportion of patients achieving peak esophageal intraepithelial eosinophil count (from all 
3 regions) of ≤6 eos/hpf at week 24 
 Absolute change in DSQ score from baseline to week 24 
Peak esophageal intraepithelial eosinophil count 
Peak esophageal intraepithelial eosinophil count will be measured from esophageal biopsies. A 
total of 9 mucosal pinch biopsies will be collected at each time point from 3 esophageal regions: 
3 proximal, 3 mid, and 3 distal. Two samples from each region will be used for the histology and 
other tissue analyses. The third sample from each region will be processed for RNA analyses. The 
quantity of eosinophils in the most inflamed high power field (HPF) for each of the 3 esophageal 
regions (proximal, mid and distal) will be determined by a pathologist at a central pathology 
reading center who will be blinded to the treatment assignment. The peak esophageal 
intraepithelial eosinophil count at each visit is the maximum of the quantities of eosinophils in the 
most inflamed HPFs across the 3 regions. For example, if for a particular patient, at week 24, 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 is 4/hpf for week 24. 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. 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. 
Esophageal biopsies will be obtained by endoscopy at the second screening visit (visit 2, day -21 
± 7), week 24 and week 52 (EOS) or ET visits. For patients who receive rescue treatment during 
Part A, the endoscopy/biopsy procedures will be performed prior to the initiation of rescue 
treatment. Patients undergoing endoscopy/biopsy prior to rescue will not undergo the scheduled 
endoscopy/biopsy at weeks 24 and 52. 
Dysphagia Symptom Questionnaire (DSQ) Score 
The DSQ is a validated PRO that has been used in clinical studies to measure the frequency and 
intensity of dysphagia (Hudgens, 2017). For patients who respond “No” to question 1 (“Since you 
woke up this morning, did you eat solid food?”), a modification was made to the DSQ by asking 
a follow-up question to probe if patients avoided solid food due to their problems with swallowing 
solid food. The DSQ uses a daily recall period and will be completed by the patient daily using an 
eDiary from screening through end of study or ET visit.  
The questions and scoring of DSQ are presented in the table below. Question 1 is a screening 
question; patients will proceed with the questionnaire depending on their response to question 1: 
 If the response to question 1 is ‘No’, question 1a will be asked to collect reason for not 
eating solid food and the remaining items on the DSQ are not scored. Data for that day 
is considered to be missing for analysis but diary completion is considered compliant 
for that day. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 28 of 101 
 If the response to question 1 is ‘Yes’, patient will skip question 1a and move on to 
questions 2, 3 and 4. Only questions on the frequency (question 2) and severity 
(question 3) of dysphagia contribute to the total DSQ score. Although question 4 related 
to pain was included in the DSQ, pain was not highlighted as an important symptomatic 
factor based on interviews of adolescent and adult patients with EoE. Thus, question 4 
was considered as a standalone item for exploratory analysis.   
Dysphagia Symptom Questionnaire (DSQ) (Adapted from Hudgens, 2017) 
Question Number 
Response Option 
Score 
1. Since you woke up this morning, did 
you eat solid food? 
No 
No score assigned 
Yes 
No score assigned 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
2. Since you woke up this morning, has 
food gone down slowly or been stuck 
in your throat? 
No 
0 
Yes  
2 
3. For the most difficult time you had 
swallowing food today (during the 
past 24 hours), did you have to do 
anything to make the food go down or 
to get relief? 
No, it got better or cleared up on its own 
0 
Yes, I had to drink liquid to get relief 
1 
Yes, I had to cough and/or gag to get relief 
2 
Yes, I had to vomit to get relief 
3 
Yes, I had to seek medical attention to get 
relief 
4 
4. The following question concerns the 
amount of pain you have experienced 
when swallowing food. What was the 
worse pain you had while swallowing 
food over the past 24 hours?b 
None, I had no pain 
0 
Mild 
1 
Moderate 
2 
Severe 
3 
Very Severe 
4 
a DSQ is modified with the addition of Question 1a when response to Question 1 is ‘No’.  
b Question 4 does not assess dysphagia and is considered a standalone item to be evaluated as an exploratory 
outcome. 
The DSQ score is calculated based on the daily responses to question 2 (frequency) and question 
3 (severity) over a 14-day period using the formula from (Hudgens, 2017): 
DSQ Score= (sum of points from questions 2 and 3 from daily DSQ diary)×14 days
number of diary days reported with non-missing data
 
To calculate the DSQ score, a minimum of 8 diary entries (including days when patient responded 
‘No’ to question 1) is required for each 14-day period to derive a standardized total score based on 
the cumulative scores through 14 days. If there are less than 8 diary entries for a 14-day period, 
the DSQ score is considered to be missing for that period. The primary analysis will be based on 
DSQ score calculated using this algorithm. If there are multiple diary entries on the same day, the 
first entry on that day will be used in calculating DSQ score for analysis. DSQ scores can 
theoretically range from 0 to 84, with a lower score indicating less-frequent or less-severe 
dysphagia. 
As a sensitivity analysis, DSQ will be scored using an alternative algorithm that takes into account 
patient’s response to question 1a about reason for not eating solid food: 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 29 of 101 
 If not eating solid food because of patient problems with swallowing solid food, a daily 
score of 6 will be assigned for that day for analysis but not for consideration of 
eligibility and used in the formula given above to calculate DSQ score over a 14-day 
period after randomization.  
 If the patient responds to question 1a by indicating that he/she did not eat solid food 
since waking up in the morning because of something NOT related to their problems 
with swallowing solid food, no score will be assigned. Data for that day is considered 
to be missing for analysis but diary completion is considered compliant for that day. 
Baseline DSQ scores will be calculated from daily responses recorded during the 14 days just prior 
to the first dose date. For example, if a patient is randomized and takes the first dose of study drug 
on Jan 15th, DSQ score will be calculated from daily responses recorded during Jan 1st through Jan 
14th as baseline. DSQ scores at time points after baseline will be calculated for each 14-day period 
starting from the day of patient receiving their first dose of study drug (see detailed analysis time 
point window in Section 6.4). 
4.4.2. 
Secondary Efficacy Variable(s) 
The key secondary endpoints for Part A are: 
 Absolute change in EoE EREFS total score from baseline to week 24 
 Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from baseline 
to week 24 
 Absolute change in EoEHSS mean grade score from baseline to week 24 
 Absolute change in EoEHSS mean stage score from baseline to week 24 
 
Eosinophilic Esophagitis-Endoscopic Reference Score (EoE EREFS) 
EoE-EREFS is a validated scoring system for inflammatory and remodeling features of disease 
that are visible through endoscopy (Hirano, 2013). The proximal and distal esophageal regions 
will be scored separately. The score for each region is the sum of assigned scores for each of the 
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 score is available 
only from 1 of the 2 regions, that available score will be used as total score. For example, if score 
is 8 from the proximal region and missing from the distal region, the total score will be 8. 
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]) 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 30 of 101 
The EoE-EREFS should be performed and scored by the physician conducting the endoscopy 
procedure before biopsies. In addition to the major features above, data for the following minor 
features will also be captured but not included in the EoE-EREFS scoring: 
 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 (but not 
included in the EoE-EREFS scoring) 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 the second screening visit, week 24 and week 52 
(EOS) or ET visits, and immediately prior to start of rescue medication or procedures. Patients 
undergoing endoscopy/biopsy prior to rescue will not undergo the scheduled endoscopy/biopsy at 
weeks 24 and 52. 
Eosinophilic Esophagitis Histology Scoring System (EoEHSS) 
The EoEHSS is a method for evaluating the grade and stage of multiple pathologic features in 
esophageal biopsies from EoE patients that extend observations beyond the presence of tissue 
eosinophils (Collins, 2017). EoEHSS evaluates eight features: eosinophil inflammation (EI), basal 
zone hyperplasia (BZH), eosinophil abscess (EA), eosinophil surface layering (SL), dilated 
intercellular spaces (DIS), surface epithelial alteration (SEA), dyskeratotic epithelial cells (DEC), 
and lamina propria fibrosis (LPF). Severity (grade) and extent (stage) of abnormalities will be 
scored by a central, blinded pathologist for each feature using a 4-point scale (0 normal; 3 
maximum change). The detailed scoring scheme for each feature is provided in Section 10.6.  
The mean grade or mean stage score from EoEHSS for each biopsy is the ratio of the sum of the 
assigned scores for each feature evaluated divided by the maximum possible score for that biopsy 
(the maximum possible score for each biopsy is 24). For example, if all 8 features have maximum 
grade of 3 for a biopsy, the mean grade score will be 24/24 = 1. If a feature is not evaluated, the 
maximum possible score is reduced by 3. Most maximum possible score reductions may occur 
because lamina propria is not present; if all other features are evaluable, the maximum possible 
score for a biopsy lacking lamina propria is reduced from 24 to 21 because 7 instead of 8 features 
were evaluated. Both mean grade and mean stage scores will be determined for biopsies from 3 
esophageal regions (proximal, mid and distal). The mean grade and mean stage scores summed 
across the 3 regions is the final score used in the primary analysis of these endpoints. In the 
example given in the table below, the mean grade score 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). 
 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 31 of 101 
Feature 
Esophageal region 
Proximal 
Mid 
Distal 
Eosinophilic inflammation (EI) 
3 
3 
3 
Basal zone hyperplasia (BZH) 
2 
3 
3 
Eosinophil abscess (EA) 
2 
2 
3 
Surface layering (SL) 
0 
0 
0 
Dilated intercellular spaces (DIS) 
0 
0 
0 
Surface epithelial alteration (SEA) 
0 
0 
0 
Dyskeratotic epithelial cells (DEC) 
0 
0 
0 
Lamina propria fibrosis (LPF) 
missing 
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 
Due to the anticipation that lamina propria may not be present in many biopsies, a total grade or 
total stage score by summing scores from the other 7 individual features will be calculated for an 
exploratory analysis. In the example given above, the total grade score excluding lamina propia is 
(3 + 2 +2) + (3 + 3 + 2) + (3 +  3 + 3 ) = 24.  
Esophageal biopsies will be obtained by endoscopy at the second screening visit (visit 2, day 21 ± 
7), week 24 and week 52 (EOS) or ET visits, and immediately prior to the start of rescue 
medication or procedures. Patients undergoing endoscopy/biopsy prior to rescue will not undergo 
the scheduled endoscopy/biopsy at weeks 24 and 52. 
The other secondary endpoints are: 
 Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
<15 eos/hpf at week 24 
 Proportion of patients achieving peak esophageal intraepithelial eosinophil count of 
≤1 eos/hpf at week 24 
 Percent change in DSQ from baseline to week 24 
 Normalized Enrichment Scores (NES) for the relative change from baseline to week 24 
in the EoE diagnostic panel (EDP)  
 NES of the relative change from baseline to week 24 in the type 2 inflammation 
signature 
 Absolute change from baseline to week 24 in health-related QOL average score as 
measured by EoE Impact Questionnaire (EoE-IQ) 
 Absolute change from baseline to week 24 in severity of EoE symptoms other than 
dysphagia and pain with swallowing as measured by EoE Symptom Questionnaire 
(EoE-SQ) 
 Absolute change from baseline to week 24 in frequency of EoE symptoms other than 
dysphagia and pain with swallowing as measured by EoE Symptom Questionnaire 
(EoE-SQ) 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 32 of 101 
 Proportion of patients who receive rescue medications or procedures during the 
24-week placebo-controlled treatment period 
 All the above co-primary and secondary endpoints assessed at week 24 will be assessed 
at week 52 as additional secondary endpoints. 
 
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, 2017a).  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 (unpublished). The gene lists comprising each 
one of these transcriptomes can be found in Section 10.7. 
Normalized Enrichment Score (NES) reflects the degree to which the activity level of a set of 
transcripts is overrepresented at the extremes (top or bottom) of the entire ranked list of transcripts 
within a sample and is normalized by accounting for the number of transcripts in the set 
(Subramanian, 2005, Barbie, 2009). NES of the relative change from baseline to week 24 will be 
calculated for the respective gene sets based on expression levels of each individual gene averaged 
over 3 esophageal regions (proximal, mid, and distal). If data are missing from region(s), the 
average will be taken from the available regions for each individual gene. 
EoE Impact Questionnaire (EoE-IQ) 
The EoE-IQ is a disease-specific measure of health-related QoL in EoE patients developed by the 
sponsor. The EoE-IQ measures EoE impact on emotional, social, work and school, and sleep 
aspect of a patient. Patient is asked to respond to 11 questions based on experience living with EoE 
during the past 7 days.  
Item No. 
Question 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 33 of 101 
Response to each item is on a 5-point scale (1 = ‘Not at all’, 2 = ‘A little’, 3 = ‘Somewhat’, 4 = 
‘Quite a bit’, 5 = ‘Extremely’). The EoE-IQ average score is the sum of the non-missing responses 
divided by the number of items with non-missing response (note: response of “I do not go to school 
or work at a paying job” to item 9 or 10 is considered as missing response). The average score 
could range from 1 to 5; a higher score is indicative of a more negative impact of EoE on patient 
QoL.  
The EoE Impact Questionnaire will be recorded by the patient using electronic questionnaire at 
baseline visit (visit 3), week 12, week 24, week 36, week 52 (EOS) or ET visits, and immediately 
prior to start of rescue medication or procedures.  
EoE Symptom Questionnaire (EoE-SQ) 
The EoE-SQ is a questionnaire measuring the frequency and severity of symptoms other than 
dysphagia and pain with swallowing. It is developed by the sponsor. The EoE-SQ asks about 
symptoms that patients with EoE may have (chest pain, stomach pain, burning feeling in your 
chest, food or liquid coming back up into your throat, throwing up) during the past 7 days. 
Response to the frequency of each symptom is on a 5-point scale (1 = ‘Never’, 2 = ‘One day’, 3 = 
‘ 2-6 days’, 4 = ‘Once a day’, 5 = ‘More than once a day’). The EoE-SQ frequency score is 
calculated as the sum of the frequency scores from the 5 items which could range from 5 to 25; a 
higher score is indicative of higher frequency of symptoms. 
Response to the severity of each symptom based on the worst experience in the past 7 days is on 
a scale of 0 to 10 (higher is worse), with 0 and 10 indicating severity levels for the respective 
symptoms as follows: 
Questions 
Severity Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Questions 4 and 5 are not included in EoE severity scoring. 
The EoE-SQ severity score is calculated as the sum of the severity scores from questions 1 to 3, 
which could range from 0 to 30; a higher score is indicative of more severe symptoms.  If patient 
answers ‘Not at all’ to an item question about frequency, they will not be asked to answer the 
corresponding severity question and in that case a severity score of 0 will be assigned for that item. 
The EoE Symptom Questionnaire will be recorded by the patient using electronic questionnaire at 
baseline visit (visit 3), week 12, week 24, week 36, week 52 (EOS) or ET visits, and immediately 
prior to start of rescue medication or procedures. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 34 of 101 
Proportion of patients who receive rescue medications or procedures 
Rescue medications or procedures are described in Section 4.3. 
4.4.3. 
Exploratory Efficacy Variable(s) 
Exploratory efficacy endpoints include: 
 Percent change from baseline to week 24 in average esophageal intraepithelial 
eosinophil count (eos/hpf) of 3 esophageal regions  
 Absolute change from baseline to week 24 in EREFS (excluding stricture) 
 Absolute change from baseline to week 24 in EREFS inflammation subscore 
 Absolute change from baseline to week 24 in EREFS remodeling subscore 
 Absolute change in EoEHSS total grade score (excluding lamina propria) from baseline 
to week 24 
 Absolute change in EoEHSS total stage score (excluding lamina propria) from baseline 
to week 24 
 Patient global impression of change (PGIC) of dysphagia: proportion of patients who 
rate their dysphagia symptoms as “a little better”, “moderately better”, or “very much 
better” at week 24 
 Patient global impression of severity (PGIS) of dysphagia: proportion of patients with 
no symptom and proportion of patients with no symptom or mild symptoms at week 
24 
 Absolute change in TNSS from baseline to week 24 
 Absolute change in POEM from baseline to week 24 
 Absolute change in ACQ-5 from baseline to week 24 
 Absolute change in RQLQ 12+ from baseline to week 24 
 Absolute change in pain related to dysphagia (based on question 4 of the DSQ) from 
baseline to week 24 
 All the above exploratory endpoints assessed at week 24 will be assessed at week 52 
as additional exploratory endpoints. 
Average esophageal intraepithelial eosinophil count (eos/hpf) of 3 esophageal regions 
The average esophageal intraepithelial eosinophil count at each visit is the average of the quantities 
of eosinophils in the most inflamed HPFs across the 3 esophageal regions. For example, if for a 
partifular patient, at week 24, 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 average eosinophil count 
is 3/hpf (mean of 2, 3, 4/hpf) for week 24. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 35 of 101 
EREFS (excluding stricture), Inflammation, and Remodeling Sub-scores 
The EREFS (excluding stricture), inflammation, and remodeling sub-scores 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 subscore 
Edema + Exudates + Furrows 
0-5 
0-10 
Remodeling subscore 
Rings + Stricture 
0-4 
0-8 
Patient Global Impression of Severity (PGIS) of Dysphagia 
The PGIS is a one-item questionnaire that asks patients to provide the overall self-assessment of 
difficulty of swallowing food on a 4-point scale for the past week. Response choices are: 1 = 
‘none’, 2 = ‘Mild’, 3 = ‘Moderate’, 4 = ‘Severe’. The PGIS will be completed by patients using 
electronic questionnaire at baseline visit (visit 3), week 12, week 20, week 24, week 36, week 52 
(EOS) or ET visits, and immediately prior to start of rescue medication or procedures. 
Patient Global Impression of Change (PGIC) of Dysphagia 
The PGIC is a one-item questionnaire that asks patients to provide the overall self-assessment of 
change in difficulty of swallowing food on a 7-point scale, compared to just before patient started 
taking the study injection. Response choices are: 0 = ‘Very much better’,  1 = ‘Moderately better’,  
2  = ‘A little better’, 3 = ‘No change’, 4 = ‘A little worse’, 5 = ‘Moderately worse’, 6 = ‘Very 
much worse’.  
The PGIC will be completed by patients using electronic questionnaire at week 12, week 20, week 
24, week 36, week 52 (EOS) or ET visits, and immediately prior to start of rescue medication or 
procedures. 
Total Nasal Symptom Score (TNSS) 
The Total Nasal Symptom Score (TNSS) is a 3-item composite symptom assessment of 
congestion, itching/sneezing, and rhinorrhea for the last week. Each symptom is graded on a 0-3 
scale as below: 
Score 
Symptoms 
0 
No symptoms 
1 = mild 
Awareness but not troubled 
2 = moderate 
Troublesome but not interfering with normal daily activities or sleep 
3 = severe 
Interfering with normal daily activities or sleep 
The TNSS total score is the sum of scores for each of the symptoms (congestion, itching/sneezing, 
rhinorrhea) and could range from 0 to 9 (a higher score suggests worse nasal symptoms).  
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 36 of 101 
The TNSS will be administered only to patients with a documented history of allergic rhinitis and 
who fluently speak a language in which the questionnaire is presented (based on availability of 
translations in participating countries). It will be completed by patients at the baseline visit (visit 
3), week 12, week 24, week 36, and week 52 (EOS) or ET visits, and immediately prior to start of 
rescue medication or procedures. 
Patient-Oriented Eczema Measure (POEM) 
The POEM is a 7-item, validated questionnaire used in clinical practice and clinical trials to assess 
disease symptoms in children and adults with AD (Charman, 2004). The format is a response to 7 
items (dryness, itching, flaking, cracking, sleep loss, bleeding, and weeping) using a 5-point scale, 
based on frequency of occurrence during the past week. The possible scores for each question 
were: 0 (no days), 1 (1 to 2 days), 2 (3 to 4 days), 3 (5 to 6 days), and 4 (every day). The total score 
is the sum of scores for each of the 7 items; a higher score is indicative of more severe AD. 
The following POEM banding scores have been established (Charman, 2004): 0 to 2=clear or 
almost clear; 3 to 7=mild eczema; 8 to 16=moderate eczema; 17 to 24=severe eczema; and 25 to 
28=very severe eczema.  
If one question of the seven is left unanswered, then that question is scored as 0 and the scores are 
summed and expressed as usual out of a maximum of 28. If two or more questions are left 
unanswered, then the questionnaire is not scored and is set to missing. 
The POEM will be administered only to patients with a documented history of AD and who 
fluently speak a language in which the questionnaire is presented (based on availability of 
validated translations in participating countries). It will be completed by patients at the baseline 
visit (visit 3), week 12, week 24, week 36, and week 52 (EOS) or ET visits, and immediately prior 
to start of rescue medication or procedures. 
Juniper Asthma Control Questionnaire (ACQ) 
The 5-question version of the Juniper ACQ (ACQ-5) is a validated questionnaire to evaluate 
asthma control. The ACQ-5 has 5 questions which assess the top-scoring five asthma symptoms:  
 Frequency in past week awoken by asthma during the night 
 Severity of asthma symptoms in the morning 
 Limitation of daily activities due to asthma 
 Shortness of breath due to asthma 
 Frequency of wheezing 
Patients are asked to recall how their asthma has been during the previous week and to respond to 
the symptom questions on a 7-point scale (0=no impairment, 6= maximum impairment). 
A global score is calculated: the questions are equally weighted and the ACQ-5 score is the mean 
of the 5 questions and, therefore, between 0 (totally controlled) and 6 (severely uncontrolled). A 
higher score indicates lower asthma control. Scores less than 1.0 reflect adequately controlled 
asthma, and scores 1.0 or greater reflect inadequately controlled asthma. On the 7-point scale of 
the ACQ-5, a change or difference in a score of 0.5 is the smallest change that can be considered 
clinically important, corresponding to the Minimal Clinically Important Difference (MCID) 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 37 of 101 
defined by the developer. The recommended change of 0.50 is a reasonable threshold to define a 
meaningful individual-level change. 
Based on the manual of ACQ, any more than one missing value is not acceptable. If more than one 
of the questions has a missing value, the global score is invalid and will be considered as missing. 
If only one question has a missing value, it will be interpolated (pro-rated) using the completed 
questionnaires from the previous visit. For example, if answer to question 5 is missing at week 24 
visit and all questions are completed at week 12 visit, the score for question 5 at week 24 visit will 
be imputed as: (sum of score at week 24 visit/sum of scores excluding question 5 at week 12 visit) 
× score of question 5 at week 12 visit. If the questionnaire from the previous visit is not complete, 
the missing value will be imputed as the average of the completed questions within the current 
visit. 
The ACQ-5 will be administered only to patients with a documented history of asthma. It will be 
completed by patients using electronic questionnaires at the baseline visit (visit 3), week 12, week 
24, week 36, and week 52 (EOS) or ET visits, and immediately prior to start of rescue medication 
or procedures. 
Standardized Rhinoconjunctivitis Quality of Life Questionnaire for ages 12+ [RQLQ(S)+12] 
RQLQ(S)+12 is a self-administered questionnaire to measure health-related QOL in those 12 years 
of age and above, as a result of perennial or seasonal allergic rhinitis. There are 28 items on the 
RQLQ(S) in 7 domains: activity limitation, sleep problems, nasal symptoms, eye symptoms, non-
nasal/eye symptoms, practical problems, and emotional function. The RQLQ(S)+12 responses are 
based on a 7-point Likert scale with responses ranging from 0 (not troubled) to 6 (extremely 
troubled). The overall RQLQ(S)+12 score is the mean of all 28 responses and the individual 
domain scores are the means of the items in those domains. No interpolation will be performed for 
missing scores. Higher scores indicated more health-related QOL impairment (lower scores were 
better). A change of 0.5 point or more in total score is considered to be clinically meaningful. 
The RQLQ(S)+12 will be administered only to patients with a documented history of allergic 
rhinitis. It will be completed by patients using electronic questionnaires at the baseline visit (visit 
3), week 12, week 24, week 36, and week 52 (EOS) or ET visits, and immediately prior to start of 
rescue medication or procedures. 
Pain related to dysphagia  
Pain related to dysphagia is assessed daily by question 4 in the DSQ questionnaire. Patient will 
respond to this question only when they answer Yes to question 2 “Since you woke up this 
morning, has food gone down slowly or been stuck in your throat?”. If the answer is No to question 
2, a score of 0 will be assigned to pain related to dysphagia. The pain score over a 14-day period 
is calculated using the formula: 
Dysphagia Related Pain Score= ( sum of points from question 4  from daily DSQ diary)×14 days
number of diary days reported with non-missing data
 
The rules for a minimum of 8 diary entries and non-missing data are the same as used for DSQ 
score calculation as described in Section 4.4.1. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 38 of 101 
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 to a 
“Preferred Term (PT),” “High Level Term,” and associated primary “System Organ Class (SOC)” 
according to the Medical Dictionary for Regulatory Activities (MedDRA, the latest available 
version in effect). 
An Adverse Event is any untoward medical occurrence in a patient administered a study drug 
which may or may not have a causal relationship with the study drug. Therefore, an AE is any 
unfavorable and unintended sign (including abnormal laboratory finding), symptom, or disease 
which is temporally associated with the use of a study drug, whether or not considered related to 
the study drug.  
An AE also includes any worsening (ie, any clinically significant change in frequency and/or 
intensity) of a pre-existing condition that is temporally associated with the use of the study drug. 
A Serious Adverse Event is any untoward medical occurrence that at any dose, results in death, 
is life-threatening, requires in-patient hospitalization or prolongation of existing hospitalization, 
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. 
More information on criteria for SAE is specified in the protocol. SAE is based on investigator 
report in the CRF. 
The pre-treatment AE and treatment-emergent AE (TEAE) is defined as following: 
 Pre-treatment signs and symptoms (Pre-treatment AEs) are AEs that developed or 
worsened in severity during the pre-treatment period. 
 Treatment-emergent AEs (TEAEs) are AEs that developed or worsened in severity 
compared to the baseline during the treatment-emergent period. As the worsening pre-
existing AEs and new AEs that occur during the treatment and follow-up period will 
be collected on the AE case report form, all AEs with an onset date during the treatment 
and follow-up periods are considered as TEAEs. 
The following AESIs (as revised in protocol amendment 3) will be analyzed:  
 Anaphylactic reactions  
 Systemic hypersensitivity reactions  
 Helminthic infections  
For detailed definition of these AESIs, please see Section 10.4. 
4.5.2. 
Laboratory Safety Variables 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory. Samples will be collected predose at the initial screening visit (visit 1), baseline visit 
(visit 3), week 12, week 24, week 36, week 52 (EOS) or ET visits. Tests will include: 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 39 of 101 
Blood Chemistry 
Sodium 
Total protein, serum 
Total and indirect bilirubin 
Potassium 
Creatinine 
Total cholesterol 
Chloride 
Blood urea nitrogen (BUN) 
Low-density lipoprotein (LDL) 
Carbon dioxide 
AST 
High-density lipoprotein (HDL) 
Calcium 
ALT 
Triglycerides 
Glucose 
Alkaline phosphatase 
Uric acid 
Albumin 
Lactate dehydrogenase (LDH) 
Creatine phosphokinase (CPK)1 
1 CPK isoenzymes will be measured when CPK >5 × ULN  
Hematology 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
Urinalysis 
Microscopic analysis will only be done in the event of abnormal dipstick results. 
Color 
Glucose 
RBC 
Clarity 
Blood 
Hyaline and other casts 
pH 
Bilirubin 
Bacteria 
Specific gravity 
Leukocyte esterase 
Epithelial cells 
Ketones 
Nitrite 
Crystals 
Protein 
WBC 
Yeast 
4.5.3. 
Vital Signs 
Vital signs, including heart rate, blood pressure, respiration rate, and body temperature will be 
collected predose and 30 minutes post-dose at the initial screening visit (visit 1), every scheduled 
visit and the unscheduled visit before rescue treatment. 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. Weight is measured at the initial screening visit (visit 1), every scheduled visit (except 
week 1, week 40, week 44, and week 48 visits). Height is measured at the initial screening visit 
(visit 1), week 24, and week 52 (EOS) or ET visits. 
4.5.4. 
12-Lead Electrocardiography (ECG) 
Standard 12-Lead ECG parameters include: Ventricular HR, PR interval, QRS interval, corrected 
QT interval (QTc Fridericia [QTcF] =QT/[RR0.33] and QTc Bazett [QTcB]=QT/[RR0.5]). 
Electrocardiogram results will be interpreted by a central reading center and categorized to: 
normal, abnormal not clinical significant or abnormal clinical significant 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 40 of 101 
ECG will be performed predose at the initial screening visit (visit 1), week 24, and week 52 (EOS) 
or ET visits. ECG will be performed before blood is drawn during visits requiring blood draws.  
4.5.5. 
Physical Examination Variables 
The physical examination variable values are dichotomized to normal and abnormal.  
A thorough and complete physical examination will be performed at the initial screening visit (visit 
1), week 24, and week 52 (EOS) or ET visits.  
4.6. 
Pharmacokinetic Variables 
Serum samples for measuring functional dupilumab concentrations will be collected at time points 
according to Section 10.2. PK variables consist of functional dupilumab concentration and time 
(both actual and nominal).  
4.7. 
Immunogenicity Variables 
The immunogenicity variables are ADA response status, titer, NAb response status, and time-
point/visit.   
ADA response are specifically defined as follows: 
 ADA Negative, defined as an ADA negative response in the ADA assay at all time 
points collected, regardless of any missing samples. 
 Pre-existing immunoreactivity, defined as either an ADA positive response in the 
dupilumab ADA assay at baseline with all post first dose ADA results negative, OR a 
positive response at baseline with all post first dose ADA responses less than 4-fold 
over baseline titer levels. 
 Treatment-emergent response, defined as a positive response in the dupilumab ADA 
assay post first dose when baseline results are negative or missing. The treatment-
emergent responses will be further characterized as Persistent, Indeterminate or 
Transient.   
 Persistent Response: Treatment-emergent ADA positive response with two or more 
consecutive ADA positive sampling time points, separated by greater than 12-week 
period (based on nominal sampling time), with no ADA negative samples in 
between, regardless of any missing samples. 
 Indeterminate Response: Treatment-emergent ADA positive response with only the 
last collected sample positive in the ADA assay.  
 Transient Response: Treatment-emergent ADA positive response that is not 
considered persistent or indeterminate, regardless of any missing samples. 
 Treatment-boosted response, defined as a positive response in the dupilumab ADA 
assay post first dose that is greater than or equal to 4-fold over baseline titer levels, 
when baseline results are positive 
Serum samples for ADA will be collected at the clinic visits specified in Section 10.2. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 41 of 101 
4.8. 
Biomarker Variables 
Biomarkers to be analyzed in this study are:  
 TARC  
 Total serum IgE 
 Allergen specific IgEs 
 Allergen specific IgG4s 
 Lactate dehydrogenase (LDH) [which will be measured as part of the blood chemistry] 
 Eotaxin-3 
Serum samples for measurements of biomarkers to study the pharmacodynamic activity of 
dupilumab in EoE patients will be collected at time points according to Section 10.2. 
4.9. 
Patient Reported Outcomes for Psychometric Validity Assessment 
The psychometric validity of 3 patient-reported outcome measures (DSQ, EoE-SQ, and EoE-IQ 
as described in Section 4.4.1 and Section 4.4.2) will be assessed.  
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. 
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 may be provided for Part C SAF patients who entered 
Part C from Part A. Listing of demographics and baseline characteristics will be presented. 
5.2. 
Medical History 
Medical history will be summarized by primary SOC and PT for each treatment group and for 
study total based on the SAF. The table will be sorted by decreasing frequency of SOC followed 
by PT based on the overall incidence across treatment groups. 
Medical history will be listed, sorted by treatment groups based on the SAFs. 
5.3. 
Prior/Concomitant Medications/Procedures 
Number and proportion of subjects taking prior/concomitant medications, prohibited 
medications/procedures and rescue medications/procedures will be summarized for each treatment 
group and study total, based on the study part specific SAFs, by ATC Level 2 and ATC Level 4, 
sorted by decreasing frequency of ATC Level 2 and ATC level 4 in the dupilumab treatment group. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 42 of 101 
Number and proportion of subjects taking PPIs for the treatment of EoE will be summarized by 
PPI therapy name.  
Number and proportion of subjects undergoing prior/concomitant procedures will be summarized 
for each treatment group and study total, based on the study part specific SAFs, by system organ 
class (SOC) and preferred term (PT), and sorted by decreasing frequency of SOC and PT in the 
dupilumab treatment group.  
The detailed information of rescue medications/procedures including duration of use and incidence 
of use will be summarized, particularly for swallowed topical/systemic corticosteroids used to treat 
EoE. Kaplan Meier curves for time to first rescue use will be generated. 
Separate summaries will be provided for Part A and Part C concomitant medications/procedures. 
For CMs/CPs taken during the follow-up period, separate summaries will be provided for patients 
who entered follow-up after Part C vs. patients who entered follow-up immediately after Part A. 
If there is a limited number of patients entering follow-up immediately after Part A, only listing 
will be provided. 
Listing of pre-treatment medication and concomitant medications will include generic name and 
ATC levels 2 and 4, indication, study day of onset (for medications started before treatment, the 
study day of onset = date of medication start - date of the first dose; for medications started on or 
after treatment, the study day of onset = date of medication start - date of the first dose+1), the 
study day of medication end date (defined similarly as for study day of onset), ongoing status, 
dose, frequency, route.  
A listing of protocol deviations with respect to prohibited medication use and prohibited 
procedures will be provided. 
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 
 The total number of patients who discontinued the study during Part A, and the reasons 
for discontinuation 
 Number of patients who entered into Part C 
 The total number of patients who discontinued the study treatment in Part C and the 
reasons for discontinuation 
 The total number of patients who discontinued the study during Part C, and the reasons 
for discontinuation 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 43 of 101 
 Number of patients who entered the 12-week follow-up period from Part A and Part C, 
respectively 
The following listings will be provided for Part A and Part C separately: 
 Listing of subject disposition including: date of randomization, date of the last visit, 
received dose, completed Part A study drug dosing or discontinued by reason, 
completed Part C study drug dosing or discontinued by reason, completed study or 
discontinued by reason 
 A listing of patients treated but not randomized, patients randomized but not treated, 
and patients randomized but not treated as randomized, if applicable 
 A listing of patients prematurely discontinued from the study or treatment, along with 
reasons for discontinuation 
 Summary table and listing of protocol deviations will be provided 
The following summaries will be provided for each treatment group and study total: 
 Number of patients who discontinued the treatment due to the COVID-19 pandemic 
and the reasons for discontinuation 
 Number of patients who discontinued the study due to the COVID-19 pandemic and 
reasons for discontinuation 
 Number of patients who had occurrence(s) of visits impacted by the COVID-19 
pandemic and reasons  
5.5. 
Extent of Study Treatment Exposure and Compliance 
5.5.1. 
Measurement of Compliance 
Compliance with protocol-defined study drug administration will be calculated separately for Part 
A and Part C as follows: 
Treatment Compliance = (Number of study drug injections during the respective study 
part)/(Number of planned study drug injections during the respective study part) x 100% 
Treatment compliance will be summarized separately for Part A and Part C as a continuous 
variable with descriptive statistics for each treatment group. Treatment compliance will also be 
presented by the following specific ranges for each treatment group: <80% and ≥80%.  
Listing of treatment compliance will be presented with information on first dose date/time, last 
dose date/time, treatment completed or discontinued, number of planned doses, number of doses 
taken, compliance rate. 
If subjects received Part A treatment different from their randomized treatment, listings will be 
provided. 
5.5.2. 
Exposure to Study Drug and Observation Period 
The duration of exposure to study drug is calculated separately for Part A, Part C, and the overall 
study as follows: 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 44 of 101 
(Date of last study drug injection in the respective study part – date of first study drug 
injection in the respective study part) + 7 
Note: exposure will be calculated based on the last study drug injection date and first study drug 
injection date regardless of temporary dosing interruption. 
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 
number of patients, mean, SD, minimum, median, Q1, Q3, and maximum. These summaries will 
be provided for Part A and Part C separately. 
In addition, the duration of exposure will be summarized categorically by counts and percentages 
for each of the following categories and cumulatively by these categories as well: 
≥ 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, with an increment 
of 2 weeks for each subsequent category. 
In addition, for patients who received at least 1 dose of dupilumab, the total duration of exposure 
to dupilumab during the study (throughout Part A and Part C) is calculated as: 
(Date of last study drug injection in the study – date of first dupilumab injection) + 7 
The duration of observation period during the study is calculated as: 
[Date of the last study visit – date of the first study injection] +1. 
The duration of observation period will be summarized descriptively using number of 
patients, mean, SD, median, Q1, Q3, minimum and maximum. In addition, the number (%) of 
subjects with observation periods will be presented by specific time periods. The time periods of 
interest is specified as: ≥ 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, ≥ 183 days, with an increment of 2 weeks for each subsequent category. 
Listing of dose administration will be presented with information on administration date/time, 
study day, locations of injections, kit numbers, and whether or not the total dose is administered 
for each dose will be presented. 
5.6. 
Analyses of Efficacy Variables 
The analyses of efficacy variables are described in the subsections below and summarized in 
Section 10.1. 
5.6.1. 
Analysis of Co-Primary Efficacy Variable(s) 
Histologic response (binary endpoint) 
The proportion of patients achieving a histologic response of peak esophageal intraepithelial 
eosinophil (eos) count (from all 3 regions) of ≤6 eos/hpf at week 24 will be analyzed using the 
Cochran-Mantel-Haenszel (CMH) test to assess the difference in the proportion of responders in 
the FAS adjusting for the randomization stratification factors (age group [≥18 vs. ≥12 to <18 years 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 45 of 101 
of age] and use of PPI at randomization [yes vs. no]). Estimates of treatment difference and its 
95% confidence interval will be presented. 
Data may be collected after the patient discontinued treatment and will be included in the analyses. 
To account for use of rescue treatment (see Section 4.3), data will be set to missing for all time 
points subsequent to the use of rescue treatment in the primary analysis.  
If week 24 biopsy is performed after the date when the first dose of Part C study drug is 
administered, data from that biopsy will be set to missing in the analysis. 
Missing data at week 24 will be handled according to the reason for missingness as follows: 
 Due to the COVID-19 pandemic, the last few Part A patients may not be able to return 
to site on schedule for their week 24 endoscopy with biopsies. In the primary analysis, 
the peak esophageal intraepithelial eosinophil count at week 24 will be missing for 
these patients and will be imputed by multiple imputation (MI) for 10 times based on 
patients who have non-missing eos counts at week 24. The MI will utilize the regression 
method with treatment group, randomization stratification, baseline eos count, and 
week 24 eos count included in the regression model. For each patient, the average value 
of the imputed week 24 eos counts across the 10 imputation sets 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 24 due to reasons not related to the COVID-
19 pandemic, the patient will be classified as a non-responder at week 24. 
The complete dataset after the above steps will be analyzed by the CMH test.  
In anticipation of sparse responders in the placebo group, the Fisher’s exact test will be performed. 
DSQ total score (continuous endpoint) 
The absolute change from baseline in the DSQ total score at week 24 will be analyzed using an 
analysis of covariance (ANCOVA) model for the FAS with treatment group, randomization 
stratification factor, and relevant baseline measurement as covariates included in the model. The 
cumulative distribution function (CDF) of the absolute change from baseline in the DSQ total score 
at week 24 will be graphed to present the between-treatment-group differences at each level of the 
change. 
Data may be collected after the patient discontinued treatment and will be included in the analyses. 
To account for use of rescue treatment (see Section 4.3), data will be set to missing for all time 
points subsequent to the use of rescue treatment in the primary analysis.  
If a patient has missing value for the DSQ total score at week 24, their data for Week 24 will be 
imputed by multiple imputation (MI) based on patients who remained in the trial with observed 
values relevant to analysis. To account for the uncertainty in the imputation, missing data at week 
24 will be imputed 50 times to generate 50 complete datasets by using the MI procedure in 
Statistical Analysis Software (SAS).  
MI will follow the 2 steps below using a random seed number of 6681774 in both steps: 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 46 of 101 
1. Step 1: Use the Markov Chain Monte Carlo (MCMC) method to fill in intermittent missing 
values (ie, those missing values followed by observed values at subsequent visits) so that 
a monotone missing pattern will be formed. 
2. Step 2: Using the datasets from step 1, missing data through week 24 will be imputed using 
the regression method with treatment group, randomization stratification, relevant baseline 
measurement, and post-baseline measurement up to week 24 included in the regression 
model.  
Once imputations are made, the week 24 data of each of the complete datasets will be analyzed 
using ANCOVA. The results from the 50 analyses on the complete datasets will be combined to 
generate a valid overall statistical inference according to Rubin’s formula (Rubin, 1987) using the 
SAS MIANALYZE procedure. 
During the COVID-19 pandemic, DSQ data continued to be collected by the electronic handheld 
devices that were with the patients at home. This is consistent with how the DSQ data was collected 
for the entirety of the study and does not require consideration for COVID-19 impact in the 
analysis. 
Handling of DSQ Data Collected During the Electronic Handheld Device Malfunction Period 
In the normal flow of DSQ diary question on the electronic handheld device, patients are directed 
to question 2 if they answer Yes to question 1 and will be directed to question 1a only if they 
answer No to question 1 (Figure 3). 
Figure 3: 
Flow Diagram of DSQ eDiary 
 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 47 of 101 
When the YPrime Change Control Form (CCF) 023 update was released on 13Mar2020, it caused 
a DSQ navigation error issue to some devices (listed in Section Section 10.8) after patients 
synchronized their devices with the YPrime eCOA system (this marks the start of the period 
when patient’s device did not direct DSQ questions properly). Details are reported in a note to file 
for this issue. 
As a result, the devices of 16 patients randomized in Part A were affected by this navigation 
malfunction and irregular response patterns (as shown in Figure 4) were observed from patients 
using the affected devices.  
A software update to resolve this malfunction was sent to devices on 27Mar2020 and impacted 
patients were instructed to upgrade the device software to fix the issue. The date when each 
affected patient upgraded the software on their device is provided in Section 10.8. 
Figure 4: 
Response Patterns of DSQ eDiary 
 
In the primary analysis, for patients using the affected devices, the daily DSQ scores will be set to 
missing for all days during the time when patient’s device did not direct DSQ questions properly. 
Diary entries are considered as “not completed” on the affected days and thus will not contribute 
to the requirement of a minimum of 8 diary entries during a 14-day period to calculate the DSQ 
total score for that period. 
Sensitivity analyses  
Sensitivity analyses will assess alternative methods to impute missing data and include the 
following for the co-primary endpoints. 
Histologic responder: 
1. Last observation carried forward-multiple imputation (LOCF-MI): data will be set to 
missing for all time points subsequent to the use of rescue treatment. Missing values of 
peak eos count at week 24 due to the COVID-19 pandemic will be imputed using MI as in 
the primary analysis. Missing values of peak eos count at week 24 due to reasons not related 
to the COVID-19 pandemic will be imputed with patient’s last available post-baseline 
value prior to week 24 (including eos counts taken just prior to initiation of rescue 
treatment). The baseline value will be carried forward if no post-baseline data. The imputed 
peak eos count at week 24 will determine patient’s responder status. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 48 of 101 
2. All observed data, regardless of whether rescue treatment is used, will be included in the 
analysis. Patients with missing data will be counted as non-responders. 
3. Data will be set to missing for all time points subsequent to the use of rescue treatment. 
Patients with missing week 24 data due to any reasons (regardless of whether related to the 
COVID-19 pandemic or not) will be considered as non-responders in the analysis.  
DSQ total score: 
1. MI regardless rescue treatment: All observed data, regardless of whether rescue treatment 
is used, will be included in the analysis. Missing data will be imputed using MI. Data after 
imputation will be analyzed by ANCOVA with treatment group, randomization 
stratification factor, and baseline DSQ in the model.  
2. Last observation carried forward (LOCF): data will be set to missing for all time points 
subsequent to the use of rescue treatment. Missing values will be imputed with patient’s 
last available post-baseline value. Baseline value will be carried forward if no post-baseline 
data. Data after imputation will be analyzed by ANCOVA with treatment group, 
randomization stratification factor, and baseline DSQ in the model. 
3. Worst observation carried forward (WOCF): data will be set to missing for all time points 
subsequent to the use of rescue treatment. Missing values will be imputed with patient’s 
worst available post-baseline value; baseline value will be used if no post-baseline value. 
Data after imputation will be analyzed by ANCOVA with treatment group, randomization 
stratification factor, and baseline DSQ in the model. 
4. Tipping point analysis: after Step 1 and Step 2 in the aforementioned MI procedure, for 
each imputed dataset, a positive amount d will be added to the imputed week 24 values in 
the dupilumab group and a negative amount p will be added to the imputed week 24 values 
in the placebo group. Change from baseline to week 24 will then be calculated and analyzed 
using the same ANCOVA model followed by the SAS MIANALYZE procedure as in the 
primary analysis. The steps of adding the positive and negative amounts to the dupilumab 
and placebo group will be repeated iteratively until the p-value for estimated treatment 
effect from the ANCOVA analysis is greater than 0.05. Note: the tipping point analysis 
may not be conducted if the rate of missing data is very low. 
Two DSQ data collection issues were noted and two sensitivity analyses are planned accordingly: 
 This study does not allow collection of DSQ responses from paper screen reports and 
entering such paper sourced data in the eDiary database. However, before this 
decision was taken, patient 
 had DSQ diary collected through the paper 
source for one day during the baseline period. A sensitivity analysis will be conducted 
by excluding this paper sourced DSQ data point when calculating DSQ score. 
 Two subjects at a site in Spain, 
 and 
, completed DSQ on 
handheld eDiary device with pre-linguistic validation screens (i.e., using certified 
translation screens which were not linguistically validated via patient interviews) 
during both the baseline period and part of the post-baseline periods. A sensitivity 
analysis will be conducted by excluding these two subjects from the analysis. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 49 of 101 
As in the primary analysis, DSQ data collected during the time when patient’s device did not 
direct DSQ questions properly will not be used in the above sensitivity analyses. 
5.6.2. 
Analysis of Secondary Efficacy Variables 
Binary endpoints at week 24: 
Secondary efficacy endpoints that measure binary responses at week 24 will be analyzed in the 
same fashion as the co-primary endpoint of histologic response of peak esophageal intraepithelial 
eosinophil count of ≤6 eos/hpf, including the method to handle missing data and planned 
sensitivity analyses.  
Continuous endpoints at week 24: 
Continuous secondary efficacy endpoints at week 24 will be analyzed using ANCOVA in a similar 
fashion to the co-primary endpoint of change from baseline in the DSQ total score. In the main 
analyses of these endpoint, data will be set to missing for all time points subsequent to the use of 
rescue treatment. For endoscopy/biopsy-based endpoints (i.e., esophageal intraepithelial eos count, 
EREFS, EoE-HSS), if week 24 endoscopy/biopsy is performed after the date when the first dose 
of Part C study drug is administered, data from that endoscopy/biopsy will be set to missing in the 
analysis. 
For continuous efficacy data that are scheduled to be measured repeatedly post-baseline up to week 
24 (eg, percent change in DSQ score from baseline to week 24), as a primary analysis, missing 
data will be imputed by MI as described in the primary efficacy analysis of the DSQ co-primary 
endpoint. Sensitivity analyses similar to those specified for the DSQ co-primary endpoint may be 
conducted.  
For continuous efficacy data that are to be measured only once post-baseline up to week 24 (eg, 
percent change in peak eos/hpf from baseline to week 24), as a primary analysis, a hybrid approach 
WOCF-MI will be used to handle missing data. That is, missing values at week 24 due to the 
COVID-19 pandemic will be imputed using MI as described in the primary analysis of the co-
primary endpoint of histologic response in Section 5.6.1, and missing values at week 24 due to 
reasons not related to the COVID-19 pandemic will be imputed with patient’s baseline value or 
the available post-baseline value up to week 24, whichever is worse, ie, a worst observation carried 
forward (WOCF) approach. 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. A sensitivity analysis, using the LOCF-MI approach to impute missing values at week 
24, will be performed (i.e., MI for missing data due to the COVID-19 pandemic and LOCF 
otherwise). Another senstitivity analysis will use WOCF to impute all missing data at week 24 
regardless of whether the missingness is related to the COVID-19 pandemic or not. ANCOVA 
with treatment group, randomization stratification factor, and relevant baseline value (e.g., for the 
analysis of absolute change in EREFS, baseline EREFS value will be used) in the model will be 
used for these sensitivity analyses. 
For transcriptome endpoints, the Wilcoxon rank-sum test will be used to test if the difference in 
median NES of the relative change from baseline to week 24 between the dupilumab and placebo 
groups is statistically significant. P-values will be reported. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 50 of 101 
Secondary endpoints in Part C 
Secondary endpoints assessed in Part C (through week 52) will be summarized with descriptive 
statistics for Part C SAF patients who entered Part C from Part A as a single group, as well as 
based on the treatment assignment in Part A (as randomized). Descriptive statistics will include 
number of patients, mean, median, Q1, Q3, standard deviation, minimum, and maximum for 
continuous efficacy variables; and patient counts and proportions for categorical efficacy 
variables. No formal statistical hypothesis testing will be performed. Inferential statistics will only 
be provided as needed.  
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 patient 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 C 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 [visit 3]). Part C baseline is the last available valid measurement taken prior to or on 
the date of the first dose of extended active treatment (scheduled to be administered at week 24 
visit [visit 11]). For DSQ, week 24 score will be used as Part C baseline; if week 24 score is 
missing, the latest available DSQ score prior to week 24 will be Part C baseline. 
Provision was introduced in protocol amendment 4, after the Part C cut-off date of March 15, 2020, 
to permit PROs, intended to be completed during clinic visits, to be conducted via phone interviews 
during the COVID-19 pandemic. This provision is implemented for Part A subjects who are 
ongoing in Part C during the COVID-19 pandemic. Data collected via phone interview will be 
included from the primary summary of these PRO endpoints. Additional summaries may be 
provided by excluding data collected via phone interview. A listing of PRO assessments conducted 
via phone interviews will be provided. 
5.6.3. 
Adjustment for Multiple Comparison 
Part A and Part B will be carried out as 2 separate sub-studies with no overlap in patients. 
Therefore, each of Part A and Part B will have their own 2-sided significance level of 0.05.  
Part A is considered positive when the co-primary endpoints both achieve statistical significance 
with two-sided significance level 0.05. 
Statistical significance of both co-primary efficacy endpoints will be required before drawing 
inferential conclusions about any secondary efficacy endpoints. If both co-primary endpoints are 
statistically significant, the testing will proceed to the key and other secondary efficacy endpoints 
following a hierarchical procedure. The hierarchical order is as follows at the 2-sided significance 
level of 0.05 for the comparison of dupilumab 300 mg qw to placebo: 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 51 of 101 
1. Co-primary endpoints: 
 Proportion of patients achieving peak esophageal intraepithelial eosinophil count of ≤6 
eos/hpf at week 24 
 Absolute change in DSQ score from baseline to week 24  
2. Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from 
baseline to week 24 
3. Absolute change in EoEHSS mean grade score from baseline to week 24 
4. Absolute change in EoEHSS mean stage score from baseline to week 24 
5. Absolute change in EoE EREFS total score from baseline to week 24 
6. Proportion of patients achieving peak esophageal intraepithelial eosinophil count of <15 
eos/hpf at week 24 
7. Percent change in DSQ from baseline to week 24 
8. Normalized Enrichment Scores (NES) for the relative change from baseline to week 24 in 
the EoE diagnostic panel (EDP) transcriptome signature 
9. NES of the relative change from baseline to week 24 in the type 2 inflammation 
transcriptome signature 
Subgroups described in Section 3.6 for the primary and key secondary efficacy endpoints (as listed 
in Section 4.4.1 and Section 4.4.2) will be summarized. Treatment difference and its 95% 
confidence interval in subgroups of patients will be presented in forest plots. Interactions between 
the subgroups and treatment groups will be tested.  
5.6.4. 
Analysis of Exploratory Efficacy Variables 
The analysis of other efficacy variables will be the same as the primary analysis described in 
Section 5.6.1 Section 5.6.2.  
5.7. 
Analysis of Safety Data 
The analysis of safety and tolerability will be performed on the SAF, as defined in Section 3.3. 
The safety analysis will be based on the reported AEs, clinical laboratory evaluations, vital signs 
and 12-lead ECG.  
Thresholds for treatment-emergent Potential Clinically Significant Values (PCSVs) in laboratory 
variables, vital signs and ECG are defined in Section 10.3. 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 C, baseline is the last 
available valid measurement taken prior to the first dose of extended active treatment in Part C 
(scheduled to be administered at week 24 visit [visit 11]). 
The time interval to detect any event or abnormality is between the first injection of study 
medication and EOS. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 52 of 101 
The summary of safety results will be presented for each study part by treatment received in the 
corresponding part. For safety variables/summaries involving baseline values, e.g., absolute 
change from baseline or shift table, study part specific baselines will be used. 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 C and follow-up period will use Part C baseline (i.e., 
the last available valid measurement prior to the first dose of extended active treatment in Part C). 
5.7.1. 
Adverse Events  
The number and proportion of patients reporting TEAEs will be summarized for Part A week 24 
treatment period, Part C extended active treatment period, and follow-up period, as described in 
Section 3.3. 
 For the summary of Part A treatment period, TEAEs with onset date during the Part A 
treatment period will be included. TEAEs that had an onset during the Part A treatment 
period and continued afterwards into Part C treatment period or the follow-up period 
will be counted only once as TEAEs during the Part A treatment period. 
 For the summary of Part C extended treatment period, TEAEs with onset during the 
Part C extended treatment period will be included. TEAEs that had an onset during the 
Part C treatment period and continued afterwards into the follow-up period will be 
counted only once as TEAEs during the Part C extended treatment period. 
 For the follow-up period, TEAEs with onset during the follow-up period will be 
included.  
AE incidence tables will be presented by treatment group for the SAF as well as for selected 
subgroups. TEAE summaries will present the number (n) and percentage (%) of subjects 
experiencing an TEAE by SOC and PT, sorted by decreasing frequency of SOC and PT for the 
dupilumab treatment group. Multiple occurrences of AEs of the same PT (or SOC) in the same 
subject will be counted only once for that PT (or SOC). For tables presenting severity of events, 
the worst severity will be chosen for subjects 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 3.3. 
An overall summary of TEAEs will be provided with number and proportions of patients with any: 
 TEAE 
 Serious TEAE 
 TEAE of special interest (AESI) 
 TEAE leading to death 
 TEAE leading to permanent treatment discontinuation 
Detailed summaries of TEAEs will include: 
 TEAEs 
 TEAEs by SOC/PT 
 TEAEs by SOC/HLT/PT 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 53 of 101 
 TEAEs by PT 
 TEAEs by SOC/HLT/PT with incidence of PT ≥5% in any treatment group 
 TEAEs by SOC/PT with incidence of PT ≥5% in any treatment group 
 TEAEs by severity by SOC/PT 
 Severe TEAEs by SOC/PT 
 TEAEs related to study medication as assessed by the investigator by SOC/PT 
 Severe TEAEs related to study medication as assessed by the investigator by 
SOC/PT 
 TEAE of special interest/TEAE by category (see Section 10.4) 
 Serious TEAEs: 
 Serious TEAEs by SOC/PT 
 Serious TEAEs by SOC/HLT/PT 
 Serious TEAEs related to study medication as assessed by the investigator by 
SOC/PT 
 TEAEs leading to permanent discontinuation of study treatment by SOC/PT 
 Death by SOC/PT 
The time to first AESIs (TEAE by category) or TEAE leading to permanent treatment 
discontinuation will be assessed by Kaplan-Meier estimates (K-M plot). In order to detect any 
safety signals, the hazard ratio (HR) will be provided together with the corresponding 95% 
confidence interval (CI) for the selected adverse events during the Part A treatment period. Hazard 
ratios will be calculated using a Cox model including factors of treatment group, and 
randomization strata. The time is defined as the date of first event – the date of first dose + 1. 
Patients without an event will be censored at the end of Part A treatment period. Graphs of 
cumulative incidence rate over time will be presented by treatment group. 
Patient data listings will be provided for all SAEs, death, and TEAEs leading to permanent 
treatment discontinuation.  The following variables will be included in the listing: 
 Patient ID 
 Treatment group 
 Study part 
 Age/sex/race 
 System Organ Class (SOC) 
 High Level Term (HLT) 
 Preferred Term (PT) 
 Verbatim Term 
 AE start date and end date/ongoing (including both calendar days and study days) 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 54 of 101 
 AE Duration 
 Relationship of AE to study drug: unrelated or related 
 Action taken: Dose withdrawn, Dose interrupted, Dose not changed, Dose increased, 
Dose reduced, Unknown, or Not applicable 
 Severity: using a 3–point scale (mild, moderate, or severe) 
 Treatment: none, medication, surgery, or others 
 Outcome: recovered/resolved, recovered/resolved with sequelae, recovering/ 
resolving, not recovered/not resolved, fatal, or unknown 
5.7.2. 
Clinical Laboratory Measurements  
Laboratory measurements include clinical chemistry, hematology and urinalysis results, and will 
be converted to values in standard international units. Summaries of laboratory variables will 
include: 
 Descriptive statistics of laboratory result and change from baseline by visit.  
 The number (n) and percentage (%) of subjects with treatment-emergent PCSVs. This 
summary will be provided based on all patients in the SAF as well as in the subgroup 
of SAF patients who did not meet the PCSV criterion at 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 
Listing of all laboratory parameters normal range, abnormal flag and treatment-emergent PCSV 
by subject and visit will be provided. 
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 
 Shift tables based on baseline normal/abnormal and other tabular and graphical 
methods may be used to present the results for parameters of interest 
Listings will be provided with flags indicating the treatment-emergent PCSVs. 
5.7.4. 
Analysis of 12-Lead ECG 
Summaries of 12-lead ECG parameters will include: 
 Descriptive statistics for each ECG parameter and change from baseline 
 The number (n) and percentage (%) of subjects with PCSV 
 ECG status (i.e. normal, abnormal) summarized by a shift table 
Listings will be provided with flags indicating PCSVs. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 55 of 101 
5.7.5. 
Physical Exams 
Shift tables based on baseline normal/abnormal status will be provided 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  
 Graphical presentations of individual functional dupilumab concentration in serum vs 
actual sampling time   
 Assessment of the impact of anti-drug antibodies on functional dupilumab 
concentrations in serum. 
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 responses as defined in Section 4.7 and 
titers observed in patients in the ADA analysis set.  
The following listings will be provided: 
 Number (n) and percent (%) of ADA-negative patients (i.e., pre-existing 
immunoreactivity or negative in the ADA assay at all time points) by treatment groups  
 Number (n) and percent (%) of treatment-emergent ADA positive patients by treatment 
groups and ADA titer categories 
 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 by treatment 
groups and ADA titer categories  
Listing of all ADA titer levels will be provided for pre-existing, treatment-emergent and treatment-
boosted ADA response patients. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 56 of 101 
Titer categories (Maximum titer values) 
 Low (titer <1,000) 
 Moderate (1,000 ≤ titer ≤ 10,000) 
 High (titer >10,000) 
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.  
5.10. 
Association of Immunogenicity with Exposure, Safety and Efficacy  
5.10.1. 
Association of immunogenicity with exposure 
Potential association between ADA responses 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 response status, titer and NAb on individual patient drug 
concentration profile.  
5.10.2. 
Immunogenicity and Safety/Efficacy 
Potential association between ADA responses and safety may be explored with a primary focus 
on the following safety events during the TEAE period:  
 Injection site reaction (serious or severe and lasting 24 hours or longer) 
 Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
 Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
Potential association between ADA responses and impact on individual patient 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 negative patients, that is patients with pre-existing immunoreactivity or 
negative in the ADA assay at all time points. 
 ADA positive patients, that is patients with treatment-emergent or treatment-boosted 
response. 
 Patients with persistent treatment-emergent ADA response 
 NAb positive patients, that is ADA positive patients who were positive in the NAb 
assay at any time point analyzed.  
 Maximum post-first dose titer in treatment-emergent or treatment-boosted ADA 
positive patients:  
 Low (titer <1,000) 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 57 of 101 
 Moderate (1,000 ≤ titer ≤ 10,000) 
 High (titer >10,000) 
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. 
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. 
For Part A, exploratory analyses for the difference between the dupilumab group and the placebo 
group in the change and percent change from baseline values will be performed using a rank-based 
ANCOVA model, with treatment group and randomization stratification factors as fixed factors, 
and the relevant baseline value as a covariate. Missing value will be imputed by LOCF method 
using available post-baseline data for visits up to week 24. P-value for difference from placebo 
will be provided. 
Correlation of baseline TARC (measured value), Eotaxin-3, and IgE (measured value) with the 
following clinical endpoints will be explored using ANCOVA model. The model will include the 
below clinical endpoint as the dependent variable, with randomization stratification factors, the 
log10 transformed baseline biomarker value, 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. 
 Change from baseline to week 24 in DSQ total score 
 Percent change in peak esophageal intraepithelial eosinophil count (eos/hpf) from 
baseline to week 24 
 Absolute change in EoE EREFS total score from baseline to week 24 
 Absolute change in EoEHSS mean grade score from baseline to week 24 
 Absolute change in EoEHSS mean stage score from baseline to week 24 
Correlation of baseline TARC (measured value), Eotaxin-3, IgE (measured value), and positivity 
to at least one antigen-specific IgE (The threshold for positivity being ≥ 0.35 kU/L) with the 
histologic responder (histologic response of esophageal intraepithelial eosinophil count of ≤6 
eos/hpf at week 24) will be explored using the logistic model. The model will include the histologic 
responder/non-responder as the dependent variable, with randomization stratification factors, 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. 
Association of the DSQ score with the histology measures and EREFS score will be explored. 
Specifically, Pearson's correlation coefficient will be provided for the correlation of the following 
pairs within each treatment group: 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 58 of 101 
 Total EoEHSS grade and stage scores (excluding lamina propria) vs. DSQ score at 
week 24 
 Peak eos count vs. DSQ score at week 24 
 Total EREFS score vs. DSQ score at week 24 
 Change from baseline in total EoEHSS grade and stage scores (excluding lamina 
propria) vs. change from baseline in DSQ score at week 24 
 Change from baseline in peak eos count vs. change from baseline in DSQ score at 
week 24 
 Change from baseline in total EREFS score vs. change from baseline in DSQ score at 
week 24 
All the above correlation/association analyses will be performed on the FAS for  
 All observed data, regardless of the use of rescue treatment  
 Observed data, with data set to missing for all time points subsequent to the use of 
rescue treatment 
5.12. 
Analysis of Psychometric Validity of Patient Reported Outcome 
Measures 
A series of analyses for assessing the psychometric validity of the DSQ, EoE-SQ and EoE-IQ 
will be performed with methods detailed in a separate Psychometric Analysis Plan (PAP). 
Results will be made available in a separate report. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 59 of 101 
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 study baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the first administration of study drug. If any randomized 
patients are not treated, the baseline will be the last value on or prior to the randomization. In 
addition, Part C baseline is defined as the last available valid measurement taken prior to the first 
dose of extended treatment in Part C. The baseline of DSQ is defined in Section 4.4.1.  
The following rules specify the determination by both date/time information: 
1. For AE, lab (including biomarker), PK and ADA data, both date and time of the 
measurement will be used to determine baseline by comparing with the first injection 
date and time. 
2. For other data except AE, lab (including biomarker), PK or ADA, only date of the 
measurement will be used to determine baseline by comparing with the first injection date. 
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 subject ID or enrolled subject ID. 
6.2. 
General Data Handling Conventions 
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 TEAE. 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’. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 60 of 101 
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 01 January. 
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.  
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’. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 61 of 101 
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 DM and study MD. 
PCSV 
Patients who had post-baseline PCSV but missing baseline value will be regarded as having 
treatment emergent PCSV. 
6.4. 
Analysis Visit Windows 
Data analyzed by-visit-analysis (efficacy [excluding daily diary data and data collected via 
biopsy/endoscopy procedures], laboratory data, visit sign, ECG, ADA) will be summarized by the 
study scheduled visits described Section 10.2, “Schedule of Event”.  The analysis visit windows 
will be exhaustive so that all available values obtained from unscheduled visits and early 
termination (ET) visit have the potential to be summarized.  
No analysis visit windows will be applied for the study scheduled visits. 
The following analysis visit windows will be used to map the unscheduled clinic visits and ET 
visit, based on the study day: 
Visit No. 
Visit 
Targeted Study Daysa 
Analysis Window in 
Study Days 
1 
Screening  
-85 to -29 
≤ -29 
2 
Screening Endoscopy/Biopsy 
-28 to -14 
-28 to -1 
3 
Baseline 
1 
1 
4 
Week 1 
8 
[2, 11] 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 62 of 101 
Visit No. 
Visit 
Targeted Study Daysa 
Analysis Window in 
Study Days 
5 
Week 2 
15 
[12, 22] 
6 
Week 4 
29 
[23, 43] 
7 
Week 8 
57 
[44, 71] 
8 
Week 12 
85 
[72, 99] 
9 
Week 16 
113 
[100, 127] 
10 
Week 20 
141 
[128, 155] 
11 
Week 24 (Part A end of 
treatment) 
169 
[156, 176]b 
Following windows only apply to patients who entered Part C and received at least 1 Part C dose 
12 
Week 26 
183 
[177, 190]c 
13 
Week 28 
197 
[191, 211] 
14 
Week 32 
225 
[212, 239] 
15 
Week 36 
253 
[240, 267] 
16 
Week 40 
281 
[268, 295] 
17 
Week 44 
309 
[296, 323] 
18 
Week 48 
337 
[324, 351] 
19 
Week 52 (Part C end of 
treatment) 
365 
[352, 379] 
Following window applies to all patients  
20 
12-week follow-up 
Patients not entering 
Part C: 253 
≥ 177 
Patients entering  
Part C: 449 
≥ 380 
a Study days are calculated from the day of 1st injection. Study day = (date of assessment – 1st injection date +1) 
when date of assessment ≥ 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 or ET visit occurs in this window and it’s after the first dose of Part C, it will be considered for 
Week 26. This rule also applies to Week 24 biopsy and endoscopy assessments. 
c If unscheduled visit occurs in this window and it’s before the first dose of Part C, it will be considered for Week 
24. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 63 of 101 
In general, the following order will be used to select the record for analysis at given visit: 
1. Scheduled visit  
2. Early termination (ET) if scheduled visit not available  
3. Unscheduled visit if both scheduled visit and ET visit are not available 
If there are multiple measurements of the same test in the same window, the following rules will 
be used to select the analysis value: 
 If multiple valid values of a variable exist within an analysis visit window, the closest 
from the target study day will be selected.  
 If the difference is a tie, the value after the targeted study day will be used.  
 If multiple available values of a variable exist within a same day, then the first value 
of the day will be selected. 
Both scheduled and unscheduled measurements will be considered for determining 
abnormal/PCSV values from laboratory, vital sign or ECG as well as the baseline values.  
For DSQ 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 C will not be used for Part A 
analysis) 
Step 1: Derive the study day  
 If diary date ≥ 1st injection date in the study and < 1st injection date in Part C, then 
Part A diary study day = diary date – 1st injection date in the study +1;  
 If diary date < 1st injection date in the study, Part A diary study day = diary date – 1st 
injection date in the study 
Step 2: Windows are defined as -14 to -1 = BL, 1 to 14 = week 2, 15 to 28 = week 4, etc, with 14-
day intervals between visit windows, through 155 to 168 = week 24. For patients who never entered 
Part C, windows in the 12-week follow-up period will continue with the 14-day intervals as 169 
to 182 = week 26, 183 to 196 = week 28, etc. 
Part C (only applies to patients who received at least 1 dose of Part C study drug) 
Step 1: Derive the study day,  
 For diary date ≥ 1st injection date in Part C, Part C diary study day = diary date – 1st 
injection date in Part C +1;  
Step 2: Windows are defined as 1 to 14 = week 26, 15 to 28 = week 28, etc, with 14-day intervals 
between visit windows, through 183 to 196 = week 52.  
6.5. 
Statistical Technical Issues 
None. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 64 of 101 
7. 
INTERIM ANALYSIS 
No interim analysis is planned. 
Primary analysis and final analysis are planned for Part A.  The primary analysis will be performed 
when the last Part A patient has completed their end of 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. The final analysis for Part A will occur when all patients who entered the 12-week follow-
up period immediately from Part A completed the follow-up period. 
Multiple steps of analyses will occur at the time when other study parts are completed and will be 
detailed in Part B SAP.  
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 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 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. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 65 of 101 
8. 
SOFTWARE 
All analyses will be done using SAS Version 9.4 or above. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 66 of 101 
9. 
REFERENCES 
1. Barbie, DA, P Tamayo, JS Boehm, SY Kim, S E Moody, IF Dunn, AC Schinzel, P Sandy, 
E Meylan, C Scholl, S Frohling, EM Chan, ML Sos, K Michel, C Mermel, SJ Silver, BA 
Weir, JH Reiling, Q Sheng, PB Gupta, RC Wadlow, H Le, S Hoersch, BS Wittner, S 
Ramaswamy, DM Livingston, DM Sabatini, MMeyerson, RK Thomas, ES Lander, JP 
Mesirov, DE Root, DG Gilliland, T Jacks, and WC Hahn. Systematic Rna Interference 
Reveals That Oncogenic Kras-Driven Cancers Require Tbk1. Nature 462, no 7269. 2009 
5 Nov: 108-12. PMID: 19847166 
2. Charman CR, Venn AJ, and Williams, HC. The patient-oriented eczema measure. Arch 
Dermatol 2004; 140:1513-1519. 
3. Collins MH, Martin LJ, Alexander ES, Todd Boyd J, 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 Feb 1;30(3):1-8  
4. Dellon ES, Katzka DA, Collins MH, Hamdani M, Gupta SK, Hirano I; MP-101-06 
Investigators. Budesonide Oral Suspension Improves Symptomatic, Endoscopic, and 
Histologic Parameters Compared With Placebo in Patients With Eosinophilic Esophagitis. 
Gastroenterology. 2017 Mar;152(4):776-786.e5. doi: 10.1053/j.gastro.2016.11.021. Epub 
2016 Nov 23. PMID: 27889574 
5. Dellon, ES, Veerappan R, Selitsky SR, Parker JS, Higgins LL, Beitia RM,, Robert M. 
Genta RM , and Lash RH, MDA 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. 
6. Greuter T, Bussmann C, Safroneeva E, Schoepfer AM, Biedermann L, Vavricka SR, 
Straumann A. Long-Term Treatment of Eosinophilic Esophagitis With Swallowed Topical 
Corticosteroids: Development and Evaluation of a Therapeutic Concept. Am J 
Gastroenterol. 2017 Oct;112(10):1527-1535. 
7. 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. 
8. Hudgens S, Evans C, Phillips E, Hill M. Psychometric validation of the Dysphagia 
Symptom Questionnaire in patients with eosinophilic esophagitis treated with budesonide 
oral suspension. J Patient Rep Outcomes. 2017;1(1):3. doi: 10.1186/s41687-017-0006-5. 
Epub 2017 Sep 12. 
9. 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. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 67 of 101 
10. Lucendo AJ, Arias A, Molina-Infante J. Efficacy of Proton Pump Inhibitor Drugs for 
Inducing Clinical and Histologic Remission in Patients With Symptomatic Esophageal 
Eosinophilia: A Systematic Review and Meta-Analysis. Clin Gastroenterol Hepatol. 2016 
Jan;14(1):13-22.e1. 
11. Rothenberg ME. Molecular, genetic, and cellular bases for treating eosinophilic 
esophagitis. Gastroenterology. 2015 May;148(6):1143-57. 
12. Rubin, D.B. (1987) Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons 
Inc., New York.  
13. Spergel JM, Brown-Whitehorn TF, Cianferoni A, Shuker M, Wang ML, Verma R, 
Liacouras CA. Identification of causative foods in children with eosinophilic esophagitis 
treated with an elimination diet.J Allergy Clin Immunol. 2012 Aug;130(2):461-7.e5. 
14. Subramanian, A, P Tamayo, VK Mootha, S Mukherjee, BL Ebert, MA Gillette, A 
Paulovich, SL Pomeroy, TR Golub, ES Lander, and JP Mesirov. Gene Set Enrichment 
Analysis: A Knowledge-Based Approach for Interpreting Genome-Wide Expression 
Profiles. Proc Natl Acad Sci U S A 102, no. 43. 2005 25 Oct: 15545-50. PMID: 16199517 
15. Sherrill JD, Kiran KC, Blanchard C, Stucke EM, Kemme KA, Collins MH, Abonia JP, 
Putnam PE, Mukkada VA, Kaul A, Kocoshis SA, Kushner JP, Plassard AJ, Karns RA, 
Dexheimer PJ, Aronow BJ, Rothenberg ME.Analysis and expansion of the eosinophilic 
esophagitis transcriptome by RNA sequencing. Genes Immun. 2014 Sep;15(6):361-9. doi: 
10.1038/gene.2014.27. 
 
 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 68 of 101 
10. 
APPENDIX 
10.1. 
Summary of Statistical Analyses 
Efficacy Analyses: 
Endpoint 
Analysis 
Populations 
Primary Statistical Method 
Supportive/Sens
itive 
Statistical 
Method 
Subgroup 
Analysis 
Other 
Analyses 
Primary Endpoints 
Proportion of patients 
achieving a histologic response 
of esophageal intraepithelial 
eosinophil count of ≤6 eos/hpf 
at week 24 
FAS 
Cochran-Mantel-Haenszel test / 
MI for missing due to the 
COVID-19 pandemic, otherwise 
define missing as non-responder 
Cochran-Mantel-
Haenszel test on 
LOCF-MI, and 
on PPS 
Yes 
Histogram 
Absolute change from baseline in 
the DSQ total score at week 24 
FAS 
MI+ANCOVA 
ANCOVA with 
LOCF and 
WOCF 
Yes 
Line plot 
Secondary Endpoints 
Secondary continuous variables 
FAS 
MI+ANCOVA for endpoints 
measured repeatedly (eg, DSQ); 
ANCOVA with WOCF-MI for 
endpoints measured only once 
post-baseline in Part A (eg, peak 
eos count) 
ANCOVA with 
LOCF, LOCF-MI 
Yes for key 
secondary 
efficacy  
Line plot 
Secondary binary variables 
FAS 
Cochran-Mantel-Haenszel test / 
MI for missing due to the 
COVID-19 pandemic, otherwise 
define missing as non-responder 
Cochran-Mantel-
Haenszel test on 
LOCF-MI 
No 
Histogram 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 69 of 101 
Safety Analyses: 
Endpoint 
Analysis 
Populations 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Adverse Events 
SAF 
Descriptive statistics and 
model-based analyses 
No 
No 
No 
Laboratory Measures 
SAF 
Descriptive Statistics 
No 
No 
No 
Vital sign 
SAF 
Descriptive Statistics 
No 
No 
No 
ECG 
SAF 
Descriptive Statistics 
No 
No 
No 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 70 of 101 
10.2. 
Schedule of Time and Events 
Table 1: 
Parts A Schedule of Events – Screening Period and Placebo-controlled, Double-Blind Treatment Period 
 
Screening Period 
24-Week Double-Blind Treatment Period 
Study Procedure 
Screening1 
V1 
Screening 
Endoscopy/Biopsy2 
V2 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
DB EOT 
V113 
Week (W) 
 
 
 
W1 
W2 
W4 
W8 
W12 
W16 
W20 
W243 
Day (D) 
D-85 to  
D-291 
D-212 
D1 
D8 
D15 
D29 
D57 
D85 
D113 
D141 
D169 
Visit Window (Days [d]) 
 
±7 d 
 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±7 d 
Screening4/Baseline: 
Informed consent and assent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
Med. history, Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Randomization2a 
 
 
X2a 
 
 
 
 
 
 
 
 
Treatment: 
Training for self-injection5 
 
 
X 
X 
X 
 
 
 
 
 
 
Administer study drug6 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug dispensation6 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Study drug accountability 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
Concomitant 
medications/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy:7 
DSQ PRO (daily)8 
assessed by patient daily using eDiary  
PGIC9 
 
 
 
 
 
 
 
X  
 
X  
X 
PGIS9 
 
 
X 
 
 
 
 
X  
 
X  
X 
EoE Impact Questionnaire 10 
 
 
X 
 
 
 
 
X 
 
 
X 
EoE Symptom Questionnaire10 
 
 
X 
 
 
 
 
X 
 
 
X 
TNSS11 
 
 
X 
 
 
 
 
X 
 
 
X 
RQLQ(S)+12 11 
 
 
X 
 
 
 
 
X 
 
 
X 
ACQ-511 
 
 
X 
 
 
 
 
X 
 
 
X 
POEM11 
 
 
X 
 
 
 
 
X 
 
 
X 
EoE-EREFS2,12 
 
X2, 2a, 4 
 
 
 
 
 
 
 
 
X2, 2b 
Endoscopy with biopsies 
(histology, IHC, RNA) 2 
 
X2, 2a, 4 
 
 
 
 
 
 
 
 
X2, 2b 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 71 of 101 
 
Screening Period 
24-Week Double-Blind Treatment Period 
Study Procedure 
Screening1 
V1 
Screening 
Endoscopy/Biopsy2 
V2 
Baseline 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V10 
DB EOT 
V113 
Week (W) 
 
 
 
W1 
W2 
W4 
W8 
W12 
W16 
W20 
W243 
Day (D) 
D-85 to  
D-291 
D-212 
D1 
D8 
D15 
D29 
D57 
D85 
D113 
D141 
D169 
Visit Window (Days [d]) 
 
±7 d 
 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±7 d 
Safety: 7 
Vital signs13 
X 
X 
X13 
X13 
X13 
X13 
X 
X 
X 
X 
X 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
X14 
Weight 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
x 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing:7 
Hematology, Chemistry 
X 
 
X 
 
 
 
 
X 
 
 
X 
Serology tests 15  
X 
 
 
 
 
 
 
 
 
 
 
Serum FSH 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy test16 
Serum 
Urine 
Urine 
 
 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urinalysis 
X 
 
X 
 
 
 
 
X 
 
 
X 
PK and ADA:7 
PK sample 
 
 
X 
 
  
  
 
X 
 
 
X 
ADA sample 
 
 
X 
 
 
  
 
X 
 
 
X 
Biomarkers and Genomics:7 
Whole blood DNA (optional) 
 
 
X 
 
 
 
 
 
 
 
 
Whole blood RNA (optional) 
X 
 
X 
 
 
 
 
 
 
 
X 
Eotaxin-3 
X 
 
X 
 
 
X 
 
X 
 
 
X 
TARC17, Total IgE 
X 
 
X 
 
 
X 
 
X17 
 
 
X 
Allergen-specific IgE, IgG4  
X 
 
X 
 
 
X 
 
X 
 
 
X 
Future Biomarker Serum/Plasma 
X 
 
X 
 
 
X 
 
X 
 
 
X 
ADA = anti-drug antibody; DB EOT = end of double-blind treatment period; DSQ = Dysphagia Symptom Questionnaire; ECG = electrocardiogram; EoE-
EREFS = Eosinophilic Esophagitis-Endoscopic Reference Score; IHC = immunohistochemistry; PGIC = Patient Global Impression of Change of Dysphagia; 
PGIS = Patient Global Impression of Severity of Dysphagia; POEM = Patient-Oriented Eczema Measure; PRO = patient-reported outcome; PK = 
pharmacokinetic; RQLQ(S)+12 = Rhinoconjunctivitis Quality of Life Questionnaire for patients aged 12+ years; TNSS = Total Nasal Symptom Score; V = visit 
 
 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 72 of 101 
Table 2: 
Part C Schedule of Events – Extended Active Treatment Period 
 
28-Week Extended Active Treatment Period 
Study Procedure 
V111 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
EOT 
V19 
Week (W) 
W241 
W26 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
Day (D) 
D169 
D183 
D197 
D225 
D253 
D281 
D309 
D337 
D365 
Visit Window (Days [d]) 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
Treatment:2 
Administer study drug 3, 4 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug dispensation 4 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug accountability 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications/procedures 
 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy:2 
DSQ eDiary5 
--------------------------- completed daily by patient -------------------------------- 
PGIC6 
 
 
 
 
X 
 
 
 
X 
PGIS6 
 
 
 
 
X 
 
 
 
X 
EoE Impact Questionnaire7 
 
 
 
 
X 
 
 
 
X 
EoE Symptom Questionnaire 7 
 
 
 
 
X 
 
 
 
X 
TNSS 8 
 
 
 
 
X 
 
 
 
X 
RQLQ(S)+12 8 
 
 
 
 
X 
 
 
 
X 
POEM 8 
 
 
 
 
X 
 
 
 
X 
ACQ-5 8 
 
 
 
 
X 
 
 
 
X 
EoE-EREFS 9, 10 
 
 
 
 
 
 
 
 
X10, 10a 
Endoscopy with biopsies (histology, 
IHC, RNA)10 
 
 
 
 
 
 
 
 
X10, 10a 
Safety: 2 
Vital signs 11 
X11 
X11 
X 
X 
X 
X 
X 
X 
X 
Height 12 
 
 
 
 
 
 
 
 
X 
Weight 
 
X 
X 
X 
X 
 
 
 
X 
Physical examination 
 
 
 
 
 
 
 
 
X 
ECG 
 
 
 
 
 
 
 
 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 73 of 101 
 
28-Week Extended Active Treatment Period 
Study Procedure 
V111 
V12 
V13 
V14 
V15 
V16 
V17 
V18 
EOT 
V19 
Week (W) 
W241 
W26 
W28 
W32 
W36 
W40 
W44 
W48 
W52 
Day (D) 
D169 
D183 
D197 
D225 
D253 
D281 
D309 
D337 
D365 
Visit Window (Days [d]) 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
±7 d 
Laboratory Testing:2 
Hematology, Chemistry 
 
 
 
 
X 
 
 
 
X 
Pregnancy test 13 
 
Urine 
 
Urine 
Urine 
Urine 
Urine 
Urine 
Urine 
Urinalysis 
 
  
 
  
X 
 
 
 
X 
PK and ADA:2  
PK Sample 
 
 
 
X 
 
 
 
 
X 
ADA sample 
 
 
 
X 
 
 
 
 
X 
Biomarkers:2 
Whole blood RNA (optional) 
 
 
 
 
 
 
 
 
X 
Eotaxin-3 
 
X 
 
X 
 
 
 
 
X 
TARC14, Total IgE 
 
X14 
 
X14 
 
 
 
 
X 
Allergen-specific IgE, IgG4  
 
X 
 
X 
 
 
 
 
X 
Future Biomarker Serum/Plasma 
 
X 
 
X 
 
 
 
 
X 
ADA = anti-drug antibody; DSQ = Dysphagia Symptom Questionnaire; ECG = electrocardiogram; EoE-EREFS = Eosinophilic Esophagitis-Endoscopic 
Reference Score; EOT = end of extended active treatment period; IHC = immunohistochemistry; POEM = Patient-Oriented Eczema Measure; PRO = patient 
reported outcome; PGA = physician global assessment; PGIC = Patient Global Impression of Change of Dysphagia; PGIS = Patient Global Impression of 
Severity of Dysphagia; PK = pharmacokinetic; RQLQ(S)+12 = Rhinoconjunctivitis Quality of Life Questionnaire for patients aged 12+ years; TNSS = Total 
Nasal Symptom Score; V = visit 
 
 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 74 of 101 
Table 3: 
Follow-up Period, Early Termination Visit, and Unscheduled Visit 
Study Procedure 
12-Week Follow-Up 
EOS Visit 
Early 
Termination 
during 12-Week 
Follow-Up1 
Early 
Termination 
during Parts A, B, 
or C1 
Unscheduled Visit 
before Rescue 
Treatment 
Unscheduled Visit 
for Other Reasons 
Week (W) 
12 weeks after EOT 
visit 
 
 
 
 
Day (D) 
84 days after EOT 
visit 
 
 
 
 
Visit Window (Days [d]) 
±7 d 
 
 
 
 
Concomitant medications/procedures 
X 
X 
X 
X 
X 
Efficacy: 
DSQ eDiary2 
completed daily by 
patient 
 
X 
X 
 
PGIC3 
 
 
X 
X 
 
PGIS3 
 
 
X 
X 
 
EoE Impact Questionnaire 4 
 
 
X 
X 
 
EoE Symptom Questionnaire 4 
 
 
X 
X 
 
TNSS 5 
 
 
X 
X 
 
RQLQ(S)+12 5 
 
 
X 
X 
 
ACQ-5 5 
 
 
X 
X 
 
POEM 5 
 
 
X 
X 
 
EoE-EREFS 6, 7 
 
 
X 7, 7a 
X 8 
 
Endoscopy with biopsies (histology, 
IHC, RNA)7 
 
 
X 7, 7a 
X 8 
 
Safety:  
Vital signs  
X 
X 
X 
X 
 
Height 9 
 
 
X 
 
 
Weight 
X 
X 
X 
 
 
Physical examination 
 
 
X 
 
 
ECG 
 
 
X 
 
 
Adverse events 
X 
X 
X 
X 
X 
Laboratory Testing: 
Hematology, Chemistry 
X 
X 
X 
 
 
Pregnancy test 
Urine 
Urine 
Urine 
 
 
Urinalysis 
X 
X 
X 
 
 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 75 of 101 
Study Procedure 
12-Week Follow-Up 
EOS Visit 
Early 
Termination 
during 12-Week 
Follow-Up1 
Early 
Termination 
during Parts A, B, 
or C1 
Unscheduled Visit 
before Rescue 
Treatment 
Unscheduled Visit 
for Other Reasons 
Week (W) 
12 weeks after EOT 
visit 
 
 
 
 
Day (D) 
84 days after EOT 
visit 
 
 
 
 
Visit Window (Days [d]) 
±7 d 
 
 
 
 
PK and ADA: 
PK Sample 
X 
X 
X 
X 
 
ADA  
X 
X 
X 
X 
X 
Biomarkers: 
Future Biomarker Serum/Plasma 
(optional) 
 
 
X 
 
 
ADA = anti-drug antibody; DSQ = Dysphagia Symptom Questionnaire; ECG = electrocardiogram; EoE-EREFS = Eosinophilic Esophagitis-Endoscopic 
Reference Score; EOS = end of study (visit); EOT = end of treatment period; POEM = Patient-Oriented Eczema Measure; PRO = patient-reported outcome; 
PGA = physician global assessment; PGIC = Patient Global Impression of Change of Dysphagia; PGIS = Patient Global Impression of Severity of Dysphagia; 
PK = pharmacokinetic; RQLQ(S)+12 = Rhinoconjunctivitis Quality of Life Questionnaire for patients aged 12+ years; TNSS = Total Nasal Symptom Score 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 76 of 101 
10.2.1. 
Footnotes for the Schedule of Events Tables 
10.2.1.1. Footnotes for Table 1 
1. For patients without a satisfactory prior endoscopy/biopsy (eg, histological criteria 
were not met, or the biopsy was not performed while patient was on at least 8 weeks of 
high-dose PPI treatment), the screening period will be extended for up to 12 weeks 
(day -85) to allow for at least 8 weeks of high-dose PPI treatment prior to the screening 
endoscopy/biopsies.  For all other patients, the screening period will be shorter, with 
sufficient time to allow screening assessments and laboratory test results to be available 
prior to the baseline endoscopy/biopsies. 
2. The endoscopy/EoE-EREFS/biopsy procedures should be performed after all other 
efficacy and safety assessments. 
2a. The baseline endoscopy with biopsies should be performed at approximately 
day -21±7 days to allow for availability of the intraepithelial eosinophil count result 
from the central pathology laboratory prior to day 1.  For patients without a satisfactory 
prior historical endoscopy/biopsy, the baseline endoscopy/biopsies must be performed 
after at least 8 weeks of high-dose PPI.  Patients may be randomized as soon as their 
endoscopy/biopsy results are available and DSQ eDiary entries are completed. 
Note:  Biopsy specimens from the stomach and/or duodenum will be obtained in all patients <18 
years of age to rule out alternate etiologies.  Stomach and/or duodenal biopsies will be obtained 
in adults only in the event of abnormal endoscopic findings (other than typical EoE findings) or 
clinical suspicion of alternate etiologies. 
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 scheduled endoscopy/biopsy at week 24. 
Note:  All randomized patients found to have stomach and/or duodenal abnormalities at baseline 
will have follow-up stomach and/or duodenal biopsies at week 24 and week 52. 
3. Assessments indicated for this week 24 (end of treatment) visit should be performed 
for all patients in Part A.  For patients who will enter Part C, there are additional 
events listed in week 24 visit in Table 2 for Part C. 
4. Patients may be re-screened once if they fail the screening evaluation, unless the reason 
for screen failure is related to histologic or clinical disease severity inclusion criteria. 
The baseline endoscopy with biopsy and EoE-EREFS scoring will not be repeated for 
re-screened patients.  These results will continue to be valid baseline data.  Re-
screening must occur within 6 months of the screen failure. 
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).  Study drug will be provided for those doses 
scheduled to be administered at home before the next in-clinic visit.  Doses of study 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 77 of 101 
drug administered at home should be administered 1 week after the prior dose of study 
drug.  Study drug administration that occurs in clinic should occur per the Schedule of 
Events in Tables 1 and 2.  Patients will be closely monitored at the study site at visits 
3 to 6 for a minimum of 30 minutes after the administration of study drug.  In addition 
to the predose assessments, AEs and vital signs (body temperature, blood pressure, 
respiratory rate and heart rate) will be assessed at 30 minutes (±10 minutes) post-dose. 
7. Assessments will be performed and blood samples will be collected before the 
administration of study drug. 
8. DSQ eDiary will be completed once daily by the patients after their last meal of the 
day but before they go to bed.  Site personnel should conduct regular checks of patient 
eDiary compliance.  
9. Patient Global Impression of Change (PGIC) of Dysphagia and Patient Global 
Impression of Severity (PGIS) of Dysphagia will be completed by the patient via 
electronic questionnaire at the indicated site visits. 
10. EoE Impact Questionnaire and EoE Symptom Questionnaire will be completed by the 
patient via electronic questionnaire at the indicated site visits. 
11. Total Nasal Symptom Score (TNSS) and Rhinoconjunctivitis Quality of Life 
Questionnaire for patients aged 12+ years [RQLQ(S)+12] will be administered only to 
patients with a documented history of allergic rhinitis; Asthma Control Questionnaire-
5 (ACQ-5) will be administered only to patients with a documented history of asthma; 
Patient-Oriented Eczema Measure (POEM) will be administered only to patients with 
a documented history of AD. TNSS, POEM, ACQ-5 and RQLQ(S)+12 will be 
completed via electronic questionnaire and at the indicated site visits. The 
questionnaires will be administered only to the subset of patients who fluently speak 
the language in which the questionnaire is presented (based on the availability of 
validated translations in participating countries). 
12. EoE-EREFS should be completed before biopsies are performed. 
13. At visits 3 through 6, vital signs (body temperature, blood pressure, respiratory rate, 
heart rate) should be taken predose and 30 minutes (±10 minutes) post-dose.  Vital 
signs should be taken predose at all other indicated visits. 
14. For adolescent patients only. 
15. Includes HIV Ab, HBsAg, HBsAb, HBcAb, HCV Ab, and TB.  Tuberculosis testing 
will be performed on a country-by-country basis according to local guidelines if 
required by regulatory authorities or ECs. 
16. Not required if post-menopausal status confirmed at screening.  A negative result must 
be obtained prior to the randomization visit.  In case of a positive urine test, the study 
treatment will be withheld and a serum pregnancy test to confirm the pregnancy should 
be performed as soon as possible.  A confirmed pregnancy will lead to study drug 
discontinuation in all cases. 
17. TARC analysis will occur only at visits 1, 3. 6, 11, and 19  
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 78 of 101 
10.2.1.2. Footnotes for Table 2 
1. This visit is the same as the week 24 visit for Part A (Table 1), and all other assessments 
indicated for week 24 of Part A (Table 1) should be performed. 
2. Study assessments will be performed and blood samples will be collected prior to 
administration of study drug. 
3. Patients will be closely monitored at the study site at visits 11 and 12 for a minimum 
of 30 minutes after the administration of study drug.  In addition to predose 
assessments, AEs and vital signs (body temperature, blood pressure, respiratory rate, 
and heart rate) will be assessed at 30 minutes (±10 minutes) post-dose. 
4. On scheduled in-clinic study visit days, study drug will be administered in the clinic 
(by the patient, site staff, or caregiver).  Study drug will be provided for those scheduled 
doses to be administered at home before the next in-clinic visit. Doses of study drug 
administered at home should be administered 1 week after the prior dose of study drug.  
Study drug administration that occurs in clinic should occur per the Schedule of Events 
in Table 1 and Table 2. 
5. DSQ eDiary will be completed once daily by the patients after their last meal of the 
day but before they go to bed.  Site personnel should conduct regular checks of patient 
eDiary compliance.   
6. PGIC and PGIS will be completed by the patient via electronic questionnaire at the 
indicated site visits. 
7. EoE Impact Questionnaire and EoE Symptom Questionnaire will be completed by the 
patient via electronic questionnaire at the indicated site visits. 
8. TNSS and RQLQ(S)+12 will be administered only to patients with a documented 
history of allergic rhinitis; ACQ-5 will be administered only to patients with a 
documented history of asthma, and POEM will be administered only to patients with a 
documented history of AD.  TNSS, POEM, ACQ-5 and RQLQ(S)+12 will be 
completed via electronic questionnaire and at the indicated site visits.  The 
questionnaires will be administered only to the subset of patients who fluently speak 
the language in which the questionnaire is presented (based on the availability of 
validated translations in participating countries). 
9. EoE-EREFS should be completed before biopsies are performed. 
10. Endoscopy/EoE-EREFS/biopsy procedures should be performed after all other efficacy 
and safety assessments. Note:  All randomized patients found to have stomach and/or 
duodenal abnormalities at baseline will have follow-up stomach and/or duodenal 
biopsies at weeks 24 and 52. 
10a. For patients who receive rescue treatment, endoscopy/EoE-EREFS/biopsy procedures 
will be performed prior to initiation of rescue treatment.  Patients undergoing 
endoscopy/biopsy prior to rescue will not undergo the scheduled endoscopy/biopsy at 
weeks 24 and 52. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 79 of 101 
11. At visits 11 and 12, vital signs (body temperature, blood pressure, respiratory rate, heart 
rate) should be taken predose and 30 minutes (±10 minutes) post-dose.  Only predose 
vital signs are required at subsequent visits. 
12. For adolescents only 
13. In case of a positive urine pregnancy test, the study treatment will be withheld and a 
serum pregnancy test to confirm the pregnancy should be performed as soon as 
possible.  A confirmed pregnancy will lead to study drug discontinuation in all cases. 
14. TARC analysis will occur only at visits 1, 3, 6, 11, and 19. 
10.2.1.3. Footnotes for Table 3 
1. Patients who are withdrawn from study drug will be asked to complete the 12-week 
follow-up period and the end of study visit. 
2. DSQ eDiary will be completed once daily by the patients after their last meal of the 
day but before they go to bed.  Site personnel should conduct regular checks of patient 
eDiary compliance.   
3. PGIC and PGIS will be completed by the patient via electronic questionnaire at the 
indicated site visits.   
4. EoE Impact Questionnaire and EoE Symptom Questionnaire will be completed by the 
patient via electronic questionnaire at the indicated site visits. 
5. TNSS and RQLQ(S)+12 will be administered only to patients with a documented 
history of allergic rhinitis; ACQ-5 will be administered only to patients with a 
documented history of asthma, and only in countries in which a valid translation is 
available; POEM will be administered only to patients with a documented history of 
AD.  TNSS, POEM, ACQ-5 and RQLQ(S)+12 will be completed via electronic 
questionnaire and at the indicated site visits. 
6. EoE-EREFS should be completed before biopsies are performed. 
7. Endoscopy/EoE-EREFS/biopsy procedures should be performed after all other efficacy 
and safety assessments.  
Note:  All randomized patients found to have stomach and/or duodenal abnormalities at 
baseline will have follow-up stomach and/or duodenal biopsies at weeks 24 and 52 or ET 
visit. 
7a. For patients who receive rescue treatment during the double-blind treatment period, 
endoscopy/EoE-EREFS/biopsy procedures will be performed prior to initiation of 
rescue treatment.  Patients undergoing endoscopy/biopsy prior to rescue will not 
undergo the scheduled endoscopy/biopsy at weeks 24 and 52. 
8. Endoscopy/EoE-EREFS/biopsy will be performed only if the Unscheduled Visit is for 
the purpose of administering rescue therapy. 
9. For adolescents only. 
 
 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 80 of 101 
10.3. 
Criteria for Potentially Clinically Significant Values (PCSV) 
Where adolescent criteria (age >12 to <18) are different than adult criteria (>18), the adolescent 
criteria are provided in [parentheses] in the combined column. The criteria inside the “Combined” 
column will be used for display in the reporting outputs. Applicable criteria will be applied to 
parameters collected in the study to identify treatment-emergent PCSV cases.  
Parameter 
Adults (≥18)a 
Adolescents (≥12 to <18) a 
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 
Alkaline 
Phosphatase 
>1.5 ULN and baseline ≤ 1.5 
ULN 
≥1.5 ULN and baseline <1.5 
ULN 
>1.5 [≥1.5] ULN and baseline ≤ 
1.5[<1.5] ULN  
Total Bilirubin 
>1.5 and ≤ 2 ULN and 
baseline ≤ 1.5 ULN 
>2 ULN and baseline ≤ 2.0 
ULN 
>1.3 ULN and baseline <  1.3 
ULN 
>1.5 [>1.3] and ≤ 2 ULN and 
baseline ≤ 1.5 [ < 1.3] ULN 
>2 ULN and baseline ≤ 2.0 ULN  
Conjugated 
Bilirubinb 
(Direct Bilirubin >35% Total 
Bilirubin and Total Bilirubin 
>1.5 ULN) and (Direct 
Bilirubin <35%  Total 
Bilirubin or  Total Bilirubin 
<1.5 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 
>1.5 [>1.3] ULN) and (Direct 
Bilirubin <35%  Total Bilirubin 
or  Total Bilirubin <1.5 [<1.3] 
ULN) at baseline 
ALT and Total 
Bilirubin 
(ALT>3 ULN and TBILI>2 
ULN) and baseline (ALT <3 
ULN or TBILI <2 ULN) 
(ALT>3 ULN and TBILI>2 
ULN) and baseline (ALT <3 
ULN or TBILI <2 ULN) 
(ALT>3 ULN and TBILI>2 
ULN) and baseline (ALT <3 
ULN or TBILI <2 ULN) 
CPK 
>3 and ≤ 10 ULN and 
baseline ≤ 3ULN 
>10 ULN and baseline ≤ 
10ULN 
≥3 ULN and baseline < 
3ULN 
>3 [≥3] and ≤ 10 ULN and 
baseline ≤ 3 [<3] ULN 
>10 ULN and baseline ≤ 10ULN 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 81 of 101 
Parameter 
Adults (≥18)a 
Adolescents (≥12 to <18) a 
Combined 
Creatinine 
≥150 μmol/L (Adults) and 
baseline < 150 μmol/L 
>=30%  change from baseline 
and <100% change from 
baseline 
≥100% change from baseline 
≥132µmol/L and baseline < 
132µmol/L 
 (or ≥1.5 mg/dL and baseline 
<1.5 mg/dL) 
>=30%  change from baseline 
>150 [>132] μmol/L and baseline 
< 150 [<132] μmol/L 
>=30%  change from baseline 
and <100% change from baseline 
≥100% change from baseline 
Uric Acid 
Hyperuricemia  
Hypouricemia  
 
>408 μmol/L and <=408 
μmol/L at baseline 
<120 μmol/L and >= 120 
μmol/L at baseline 
 
>8.0 mg/dL and <8.0 mg/dl 
at baseline ( or >476 µmol/L 
and <476 µmol/L at baseline 
≤2 mg/dL and >2 mg/dL at 
baseline (or <119 µmol/L and 
baseline > 119 µmol/L) 
 
>408 [>476] μmol/L and <408 
[<476] μmol/L at baseline 
<120 μmol/L and > 120 μmol/L 
at baseline  
Blood Urea 
Nitrogen 
≥17 mmol/L and <17 mmol/L 
at baseline 
≥7.14 mmol/L and <7.14 
mmol/L at baseline 
≥17 [≥7.14] mmol/L and <17 
[<7.14] mmol/L at baseline 
Chloride 
Hypochloremia 
Hyperchloremia 
<80 mmol/L and baseline ≥ 
80 mmol/L  
>115 mmol/L and baseline ≤ 
115 mmol/L  
<80 mmol/L and baseline ≥ 
80 mmol/L  
≥115 mmol/L and baseline < 
115 mmol/L 
<80 mmol/L and baseline ≥ 80 
mmol/L  
>115 mmol/L and baseline ≤ 115 
mmol/L 
Sodium 
Hyponatremia 
Hypernatremia 
≤129 mmol/L  and baseline > 
129 mmol/L  
≥160 mmol/L  and baseline 
<160 mmol/L  
≤129 mmol/L  and baseline 
>129 mmol/L  
≥150 mmol/L  and baseline 
<150 mmol/L 
≤129 mmol/L  and baseline > 
129 mmol/L  
≥160 [≥150] mmol/L  and 
baseline <160 [<150] mmol/L 
Potassium 
Hypokalemia 
Hyperkalemia 
 
<3 mmol/L and baseline ≥ 3 
mmol/L  
≥5.5 mmol/L and baseline 
<5.5 mmol/L  
 
≤3.5 mmol/L and baseline 
>3.5 mmol/L  
≥5.5 mmol/L and baseline 
<5.5 mmol/L 
<3 [≤3.5] mmol/L and baseline ≥ 
3 [>3.5] mmol/L  
≥5.5 mmol/L and baseline <5.5 
mmol/L 
Total Cholesterol 
≥7.74 mmol/L and < 7.74 
mmol/L at baseline 
≥ 6.20 mmol/Land < 6.20 
mmol/L at baseline  
 
≥7.74 [≥6.20] mmol/L and < 7.74 
[<6.20] mmol/L at baseline 
Triglycerides 
≥4.6 mmol/L and < 4.6 
mmol/L at baseline 
Fasted level ≥5.64 mmol/L 
and < 5.64 mmol/L at 
baseline 
≥4.6 [≥5.64 fasted] mmol/L and 
< 4.6 [<5.64 fasted] mmol/L at 
baseline 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 82 of 101 
Parameter 
Adults (≥18)a 
Adolescents (≥12 to <18) a 
Combined 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
(≤3.9 mmol/L and <LLN) and 
(>3.9 mmol/L or >=LLN) at 
baseline 
≥11.1 mmol/L (unfasted) and 
<11.1 mmol/L (unfasted) at 
baseline; ≥7 mmol/L (fasted) 
and <7 mmol/L (fasted) at 
baseline 
<2.7 mmol/L and ≥2.7 
mmol/L at baseline (or < 50 
mg/dL and ≥ 50 mg/dL at 
baseline)  
≥10 mmol/L (unfasted) and < 
10 mmol/L (unfasted) at 
baseline (or ≥180 mg/dl and 
<180 mg/dl at baseline);  ; ≥7 
mmol/L (fasted) and <7 
mmol/L (fasted) at baseline 
(or ≥120 mg/dL and <120 
mg/dL at baseline) 
 
(≤3.9 [<2.7] mmol/L and <LLN) 
and (>3.9 [>2.7] mmol/L or 
>=LLN) at baseline 
≥11.1 [≥10] mmol/L (unfasted) 
and <11.1 [<10] mmol/L 
(unfasted) at baseline; ≥7 
mmol/L (fasted) and <7 mmol/L 
(fasted) at baseline 
HbA1cb 
>8% and <= 8% at baseline 
>6.5% and <= 6.5% at 
baseline 
>8% [>6.5%] and < 8% [<6.5%] 
at baseline 
Albumin 
≤25 g/L and >25 g/L at 
baseline 
≤25 g/L and >25 g/L at 
baseline 
≤25 g/L and >25 g/L at baseline  
CRPb 
>2 ULN or >10 mg/L (if ULN 
not provided) and 
<=2 ULN or <=10 mg/L (if 
ULN not provided) at baseline 
NONE 
 >2 ULN or >10 mg/L (if ULN 
not provided) and <=2 ULN or 
<=10 mg/L (if ULN not 
provided) at baseline  (adults 
only) 
Calcium total 
NONE 
<2 mmol/L and baseline ≥2 
mmol/L  (or ≤ 8 mg/dL and 
baseline >8 mg/dL) 
≥2.9 mmol/L and baseline 
<2.9 mmol/L (or ≥11.6 
mg/dL and baseline <11.6 
mg/dL) 
<2 mmol/L and baseline ≥2 
mmol/L  (adolescents only)  
≥2.9 mmol/L and baseline <2.9 
mmol/L (adolescents only) 
LDL Cholesterol 
NONE 
≥4.91 mmol/L and <4.91 
mmol/L at baseline (≥ 190 
mg/dl and <190 mg/dl at 
baseline) 
≥4.91 mmol/L and <4.91 mmol/L 
at baseline (adolescents only) 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 83 of 101 
Parameter 
Adults (≥18)a 
Adolescents (≥12 to <18) a 
Combined 
Hematology 
WBC 
<3.0 Giga/L and >=3.0 
Giga/L at baseline (Non-
Black);  
<2.0 Giga/L and >=2.0 
Giga/L at baseline (Black) 
≥16.0 Giga/L and < 16 Giga/L 
at baseline 
<4.0 Giga/L and ≥4.0 Giga/L 
at baseline  
 
>13.5 Giga/L and ≤13.5 
Giga/L at baseline 
<3.0 Giga/L and >=3.0 Giga/L at 
baseline (Non-Black); <2.0 
Giga/L and >=2.0 Giga/L at 
baseline (Black) [<4.0 Giga/L 
and ≥4.0 Giga/L at baseline]  
 
≥16.0 [>13.5] Giga/L and < 16 
[<13.5] Giga/L at baseline 
Lymphocytes 
>4.0 Giga/L and <= 4.0 
Giga/L at baseline 
<0.6 Giga/L and ≥0.6 Giga/L 
at baseline  
 
>6.0 Giga/L and ≤6.0 Giga/L 
at baseline   
<0.6 Giga/L and ≥0.6 Giga/L at 
baseline (adolescents only) 
 
>4.0 [>6.0] Giga/L and ≤4.0 
[≤6.0] Giga/L at baseline   
Neutrophils 
<1.5 Giga/L and >=1.5 
Giga/L at baseline (Non-
Black);  
<1.0 Giga/L and >=1.0 
Giga/L at baseline (Black) 
<1.2 Giga/L and ≥1.2 Giga/L 
at baseline  
>ULN and baseline ≤ ULN 
<1.5 Giga/L and >=1.5 Giga/L at 
baseline (Non-Black); <1.0 
Giga/L and >=1.0 Giga/L at 
baseline (Black) [<1.2 Giga/L 
and ≥1.2 Giga/L at baseline] 
 
 >ULN and baseline ≤ ULN 
(adolescents only) 
Monocytes 
>0.7 Giga/L <= 0.7 Giga/L at 
baseline 
>1.2 Giga/L and <= 1.2 
Giga/L at baseline 
>0.7 [1.2] Giga/L <= 0.7 [1.2] 
Giga/L at baseline 
Basophils 
>0.1 Giga/L <= 0.1 Giga/L at 
baseline 
NONE 
>0.1 Giga/L <= 0.1 Giga/L at 
baseline (adults 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) 
Hemoglobin 
≤115 g/L and > 115 g/L at 
baseline for male; 
≤95 g/L and> 95 g/L at 
baseline for Female. 
 
≥185 g/L and <185 g/L at 
baseline for Male; 
 ≥165 g/L and < 165 g/L at 
baseline for Female 
 
Decrease from Baseline ≥20 
g/L 
 
<100 g/L and >=100 g/L at 
baseline 
 
>200 g/L and <200 g/L at 
baseline 
≤115 g/L and > 115 g/L at 
baseline for male; ≤95 g/L and> 
95 g/L at baseline for Female. 
[<100 g/L and >=100 g/L at 
baseline] 
  
≥185 g/L and <185 g/L at 
baseline for Male;  ≥165 g/L and 
< 165 g/L at baseline for Female 
[>200 g/L and <200 g/L at 
baseline] 
 
Decrease from Baseline ≥20 g/L  
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 84 of 101 
Parameter 
Adults (≥18)a 
Adolescents (≥12 to <18) a 
Combined 
Hematocrit 
≤0.37 v/v and > 0.37 v/v at 
baseline for Male ; ≤0.32 v/v 
and > 0.32 v/v at baseline for 
Female 
≥0.55 v/v and < 0.55 v/v at 
baseline for Male ; ≥0.5 v/v 
and < 0.5 v/v at baseline for 
Female 
≤0.37 v/v and >0.37 v/v at 
baseline for Male; ≤0.33 v/v 
and >0.33 v/v at baseline for 
Female 
≥0.52 v/v and <0.52 v/v at 
baseline for Male; ≥0.47 v/v 
and <0.47 v/v at baseline for 
Female 
≤0.37 v/v and > 0.37 v/v at 
baseline for Male ; ≤0.32 [≤0.33] 
v/v and > 0.32 [>0.33] v/v at 
baseline for Female 
≥0.55 [≥0.52] v/v and < 0.55 
[<0.52] v/v at baseline for Male ; 
≥0.5 [≥0.47] v/v and < 0.5 
[<0.47] v/v at baseline for 
Female 
RBC 
<4 Tera/L and baseline ≥4 
Tera/L 
For Male; <3 Tera/L and 
baseline ≥3 Tera/L for Female 
 
≥7 Tera/L and baseline < 7 
Tera/L for Male; ≥6 Tera/L 
and baseline < 6 Tera/L for 
Female 
 
 
 
NONE 
 
 
 
<4 Tera/L and baseline ≥4 Tera/L 
For Male; <3 Tera/L and baseline 
≥3 Tera/L for Female 
 
≥7 Tera/L and baseline < 7 
Tera/L for Male; ≥6 Tera/L and 
baseline < 6 Tera/L for Female 
 
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  
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 85 of 101 
Parameter 
Adults (≥18)a 
Adolescents (≥12 to <18) a 
Combined 
Urinalysis 
pH 
≤4.6 and > 4.6 at baseline 
≥8 and < 8 at baseline 
 
NONE 
≤4.6 and > 4.6 at baseline (adults 
only) 
≥8 and < 8 at baseline (adults 
only) 
Ketonuria 
NONE 
Presence and absence at 
baseline 
Presence and absence at baseline 
(adolescents only) 
Glycosuria 
NONE 
Presence and absence at 
baseline 
Presence and absence at baseline 
(adolescents only) 
Microscopic 
Hematuria 
NONE 
> 5 RBCs/ HPF and ≤5 
RBCs/ HPF at baseline 
> 5 RBCs/ HPF and ≤5 RBCs/ 
HPF at baseline (adolescents 
only) 
Proteinuria 
NONE 
≥ 1+ and <1 at baseline 
≥ 1+ and <1 at baseline 
(adolescents only) 
Vital signs 
 
HR 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline≥20 bpm 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline≥20 bpm 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline≥20 bpm 
SBP 
≤95 mmHg and decrease from 
baseline ≥20mmHg 
≥160 mmHg and increase 
from baseline ≥20 mmHg 
≤90 mmHg and decrease 
from baseline ≥20 mmHg 
≥119 mmHg and increase 
from baseline ≥20 mmHg 
≤95 mmHg [≤90 mmHg] and 
decrease from baseline 
≥20mmHg  
 
≥160 mmHg [≥119 mmHg] and 
increase from baseline ≥20 
mmHg 
DBP 
≤45 mmHg and decrease from 
baseline ≥10 mmHg 
≥110 mmHg and increase 
from baseline ≥10 mmHg 
≤54 mmHg and decrease 
from baseline ≥10 mmHg  
≥78 mmHg and increase from 
baseline ≥10 mmHg 
≤45 mmHg [≤54 mmHg] and 
decrease from baseline ≥10 
mmHg 
≥110 mmHg [≥78 mmHg] and 
increase from baseline ≥10 
mmHg 
Temperature 
Rectal, ear: >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: >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: >100.4 °F/38.0 °C 
Oral: >99.5 °F/37.5 °C  
Axillary or skin infrared: 
>99 °F/37.2 °C 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 86 of 101 
Parameter 
Adults (≥18)a 
Adolescents (≥12 to <18) a 
Combined 
Respiratory rate 
<12 per minute and ≥12 per 
minute at baseline 
 
>20 per minute and ≤20 per 
minute at baseline 
 
<12 per minute and ≥12 per 
minute at baseline 
 
>20 per minute and ≤20 per 
minute at baseline 
 
<12 per minute and ≥12 per 
minute at baseline 
 
>20 per minute and ≤20 per 
minute at baseline 
 
Weight 
≥5% increase from baseline  
≥5% decrease from baseline 
 
≥5% weight loss from 
baseline 
≥5% increase from baseline 
(adults only) 
≥5% decrease from baseline  
ECG 
 
Ref.: CPMP 1997 guideline. 
HR 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline ≥20 bpm 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline ≥20 bpm 
≤50 bpm and decrease from 
baseline ≥20 bpm 
≥120 bpm and increase from 
baseline ≥20 bpm 
PR 
≥220 ms and increase from 
baseline ≥20 ms 
≥200 ms and < 200 ms at 
baseline 
 
≥220 ms and increase from 
baseline ≥20 ms [≥200 ms and < 
200 ms at baseline] 
QRS 
≥120 ms & < 120 ms at 
baseline 
≥110 ms & < 110 ms at 
baseline 
≥120 [≥110] ms and  < 120 
[<110] ms at baseline 
QTc 
Borderline 
Prolonged 
Additional 
 
Absolute values (ms)  
Borderline: 
431-450 ms and < 431ms at 
baseline for Male;  
451-470 ms and < 451 ms at 
baseline for Female 
Prolonged:  
>450 to  <500 ms and <= 450 
ms at baseline for Male;  
>470 to <500 ms and <= 470 
ms at baseline for Female 
Additional: 
≥500 ms and < 500 ms at 
baseline 
 
Increase from baseline 
Borderline: Increase from 
baseline 30-60 ms 
Prolonged: Increase from 
baseline >60 ms 
Absolute values (ms)  
Borderline: 
431-450 ms and < 431ms at 
baseline for Male;  
451-470 ms and < 451 ms at 
baseline for Female 
Prolonged:  
>450 to  <500 ms and <= 450 
ms at baseline for Male;  
 >470 to <500 ms and <= 470 
ms at baseline for Female 
Additional: 
 ≥500 ms and < 500 ms at 
baseline 
 
Increase from baseline 
Borderline: Increase from 
baseline 30-60 ms 
Prolonged: Increase from 
baseline >60 ms 
Absolute values (ms)  
Borderline: 
431-450 ms and < 431ms at 
baseline for Male;  
451-470 ms and < 451 ms at 
baseline for Female 
Prolonged:  
>450 to  <500 ms and <= 450 ms 
at baseline for Male;  
 >470 to <500 ms and <= 470 ms 
at baseline for Female 
Additional: 
 ≥500 ms and < 500 ms at 
baseline 
 
Increase from baseline 
Borderline: Increase from 
baseline 30-60 ms 
Prolonged: Increase from 
baseline >60 ms 
a The ULN is based upon central lab reference ranges. The reference range might be different for different age-
groups. For the purpose of this study in a particular patient the reference range based upon age at baseline will be 
used as reference throughout the study for determining PCSVs. 
b Lab parameters not collected in this study. 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 87 of 101 
10.4. 
Search Criteria for TEAEs of Special Interest 
AESI 
Search Criteria 
Anaphylactic reactions  
 
For SMQ “anaphylactic reaction” An algorithmic approach will be 
used. A case must include either:  
1. A narrow term (a term from Category A);  
2. Patient with both a term from Category B AND a term from 
Category C;  
3. Patient with a term from Category D AND {a term from 
Category B -  OR a term from Category C } 
For bullets 2 and 3, the search terms that are included under the SMQ 
for a particular event need to have the same start date (for e.g. if search 
shows cough (category B term) occurring at day 3 and urticaria 
(category C term) occurring at day 7, this event is not adjudicated as 
anaphylactic reaction as this is inconsistent with the clinical presentation 
of anaphylaxis as an acute event with simultaneous involvement of 2 or 
more body systems. 
Note:  manual adjudication of relevant PTs will be required by the study 
medical monitor, before database lock 
Systemic hypersensitivity 
reactions  
 
Hypersensitivity: 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 
 
 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 88 of 101 
10.5. 
Important Protocol Deviations that Exclude Patients from the Per 
Protocol Analysis Set 
*Note: This is a preliminary list and the final list will be generated prior to database lock.  
Category 
Description of Protocol Deviation 
Notes 
Entered study even 
though entry criteria not 
satisfied 
Inclusion #1: Male or female >= 12 years of age at 
screening (V1) 
  
Entered study even 
though entry criteria not 
satisfied 
Inclusion #2: A documented diagnosis of EoE by 
endoscopic biopsy prior to screening, as 
demonstrated by intraepithelial eosinophilic 
infiltration (peak cell count >=15 eos/hpf) from >= 
1 region 
  
Entered study even 
though entry criteria not 
satisfied 
Inclusion #3: Baseline endoscopic biopsies with 
demonstration on central reading of intraepithelial 
eosinophilic infiltration (peak cell count >=15 
eos/hpf) in at least 2 of the 3 biopsied regions 
  
Entered study even 
though entry criteria not 
satisfied 
Inclusion #4: History (by patient report) of an 
average of at least 2 episodes of dysphagia (with 
intake of solids) per week in the 4 weeks prior to 
screening 
  
Entered study even 
though entry criteria not 
satisfied 
Inclusion #5: At least 4 episodes of dysphagia in 
the 2 wks prior to baseline, documented via eDiary, 
at least 2 of which require liquids, coughing or 
gagging, vomiting or medical attention to relieve 
  
Entered study even 
though entry criteria not 
satisfied 
Inclusion #7: Baseline DSQ score >=10 
  
Entered study even 
though entry criteria not 
satisfied 
Inclusion #8: Able to understand and complete 
study-related questionnaires 
  
Entered study even 
though entry criteria not 
satisfied 
Inclusion #9: Willing and able to comply with 
clinic visits and study-related procedures 
  
Entered study even 
though entry criteria not 
satisfied 
Inclusion #10: ICF signed by study patient or legal 
representative. For <=12 yrs, parent/guardian must 
provide signed ICF (patients must also provide 
separate informed assent to enroll in the study) 
  
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 89 of 101 
Category 
Description of Protocol Deviation 
Notes 
Entered study even 
though entry criteria not 
satisfied 
Exclusion #1: Body weight <= 40 kg 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #2: Prior participation in a dupilumab 
clinical trial, or past or current treatment with 
dupilumab 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #3: Initiation/change of food-elimination 
diet or reintroduction of previously eliminated food 
in 6 wks prior to screening. Patients on food-
elimination diet must remain through entire study 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #4: Other causes of esophageal 
eosinophilia or the following conditions: 
hypereosinophilic syndrome and eosinophilic 
granulomatosis with polyangiitis (Churg-Strauss 
syndrome) 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #5: Active Helicobacter pylori infection 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #6: History of achalasia, Crohn’s 
disease, ulcerative colitis, celiac disease, and prior 
esophageal surgery 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #7: Any esophageal stricture unable to 
be passed with a standard, diagnostic, 9 to10 mm 
upper endoscope or any critical esophageal stricture 
that requires dilation at screening 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #9: Treatment with swallowed topical 
corticosteroids within 8 weeks prior to baseline 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #10: Initiation, discontinuation, or 
change in the dosage of proton pump inhibitors, 
leukotriene inhibitors, nasal and/or inhaled 
corticosteroids within 8 wks prior to the baseline 
endoscopy 
  
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 90 of 101 
Category 
Description of Protocol Deviation 
Notes 
Entered study even 
though entry criteria not 
satisfied 
Exclusion #11: Initiation, discontinuation, or 
change in the dosage regimen of SC 
immunotherapy (SCIT) 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #12: Treatment with sublingual 
immunotherapy (SLIT) 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #13: Treatment with oral immunotherapy 
(OIT) within 6 months prior to visit 1 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #14: The following 3 months prior to 
screening: immunosuppressant/immunomodulating 
drugs, including but not limited to systemic 
corticosteroids, omalizumab, cyclosporine, etc. 
 One time 
dosing of a 
corticosteroid 
as part of 
anesthetic 
dosing during 
Visit 2 biopsy 
will be 
allowed. 
Entered study even 
though entry criteria not 
satisfied 
Exclusion #15: Treatment with an investigational 
drug within 2 months or within 5 half-lives (if 
known), whichever is longer, prior to visit 1 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #16: Planned or anticipated use of any 
prohibited medications and procedures during the 
study 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #17: Planned or anticipated major 
surgical procedure during the study 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #19: Active parasitic infection or 
suspected parasitic infection, unless clinical and (if 
necessary) laboratory assessments have ruled out 
active infection before randomization 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #20: Chronic or acute infection requiring 
treatment with systemic antibiotics, antivirals, or 
antifungals within 2 weeks before baseline visit (pt 
may be re-screened after the infection) 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #21: Known or suspected 
immunodeficiency disorder, including history of 
invasive opportunistic infections (eg, tuberculosis 
[TB], non-tuberculous mycobacterial infections, 
histoplasmosis, li 
  
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 91 of 101 
Category 
Description of Protocol Deviation 
Notes 
Entered study even 
though entry criteria not 
satisfied 
Exclusion #22: Known history of human 
immunodeficiency virus (HIV) infection 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #23: Established diagnosis of hepatitis B 
viral infection at the time of screening or positive 
for hepatitis B surface antigen (HBsAg) at the time 
of screening 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #24: Established diagnosis of hepatitis C 
viral (HCV) infection at the time of screening. 
Patients positive for hepatitis C Ab are eligible for 
the study only if HCV RNA is negative. 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #25: On current treatment for hepatic 
disease including but not limited to acute or chronic 
hepatitis, cirrhosis, or hepatic failure, or has 
evidence of liver disease 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #26: Any of the following abnormal lab 
values at screening: 1) Platelets <100 ×103/μL 2) 
Neutrophils <1.5 × 103/μL 3) Serum creatinine > 
1.5 ULN 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #27: Severe concomitant illness that, in 
the investigator’s judgment, would adversely affect 
the patient’s participation in the study (eg, short life 
expectancy, uncontrolled diabetes, etc) 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #28: History of malignancy within 5 
years prior to screening, except completely treated 
in situ carcinoma of the cervix and completely 
treated non-metastatic squamous or basal cell 
carcinoma 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #29: History of alcohol or drug abuse 
within 6 months prior to screening 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #30: Any other medical or psychological 
condition including relevant laboratory 
abnormalities at screening that, in the opinion of 
the investigator, suggest a new and/or insufficiently 
under 
  
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 92 of 101 
Category 
Description of Protocol Deviation 
Notes 
Entered study even 
though entry criteria not 
satisfied 
Exclusion #31: Patient or his/her immediate family 
is a member of the investigational team 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #32: Pregnant or breastfeeding women, 
or women planning to become pregnant or 
breastfeed during the study 
  
Entered study even 
though entry criteria not 
satisfied 
Exclusion #33: Women of childbearing potential 
who are unwilling to practice highly effective 
contraception prior to the initial dose, during the 
study & for at least 12 wks after last dose 
  
Received an excluded 
concomitant treatment 
Swallowed topical corticosteroids (may be used as 
rescue treatment for EoE) starting at V3 through 
Week 52 visit 
Only if 
occurred 
during Part 
A  
Received an excluded 
concomitant treatment 
Systemic corticosteroids (may be used as rescue 
treatment for EoE) starting at V3 through Week 52 
visit 
Only if 
occurred 
during Part 
A  
Received an excluded 
concomitant treatment 
Systemic immunosuppressive/immunomodulating 
drugs) starting at V3 through Week 52 visit 
Only if 
occurred 
during Part 
A  
Received an excluded 
concomitant treatment 
Treatment with an investigational drug (other than 
dupilumab) starting at V3 through Week 52 visit 
Only if 
occurred 
during Part 
A  
Received an excluded 
concomitant treatment 
Initiation, discontinuation, or change in dosage 
regimen of: Proton pump inhibitors; Systemic 
leukotriene inhibitors; Nasal and/or inhaled 
corticosteroids starting at V3 through Week 52 visit 
Only if 
occurred 
during Part 
A  
Received an excluded 
concomitant treatment 
Initiation of SCIT, or change in dose for those 
patients on a stable dose of SCIT post 
randomization starting at V3 through Week 52 visit 
Only if 
occurred 
during Part 
A  
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 93 of 101 
Category 
Description of Protocol Deviation 
Notes 
Received an excluded 
concomitant treatment 
Use of SLIT starting at V3 through Week 52 visit 
Only if 
occurred 
during Part 
A  
Received an excluded 
concomitant treatment 
Use of OIT starting at V3 through Week 52 visit 
Only if 
occurred 
during Part 
A  
Received an excluded 
concomitant treatment 
Major elective surgical procedures starting at V3 
through Week 52 visit 
Only if 
occurred 
during Part 
A  
Received an excluded 
concomitant treatment 
Esophageal dilation (may be used as rescue 
procedure) starting at V3 through Week 52 visit 
Only if 
occurred 
during Part 
A  
Received an excluded 
concomitant treatment 
Initiation or change of food-elimination diet 
regimen starting at V3 through Week 52 visit 
Only if 
occurred 
during Part 
A  
Received wrong 
treatment or incorrect 
dose 
Kit unassigned in IVR administered to patient 
Only if 
occurred 
during Part 
A  
Received wrong 
treatment or incorrect 
dose 
Incorrect Kit administered by site or subject (out of 
order)  
Only if 
occurred 
during Part 
A  
Received wrong 
treatment or incorrect 
dose 
Patient given study drug but patient not randomized Only if 
occurred 
during Part 
A  
Other Treatment 
compliance 
Patient was dosed with IP that had a temperature 
excursion and deemed unacceptable 
Only if 
occurred 
during Part 
A  
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 94 of 101 
Category 
Description of Protocol Deviation 
Notes 
Other Treatment 
compliance 
Staff inappropriately unblinded to treatment 
assignment 
Only if 
occurred 
during Part 
A  
Other Treatment 
compliance 
Treatment assignment inappropriately unblinded 
Only if 
occurred 
during Part 
A  
Other Treatment 
Compliance 
IP not administered for 2 consecutive visits or more 
than 5 total visits for non safety reasons (including 
home dosing) during the course of double blinded 
period (part A/ part B) 
  
Other Treatment 
Compliance 
IP for Part C dosed PRIOR to Biopsy collection at 
Visit 11/ Week 24 
  
Randomization Error 
Mis-stratification of subject  
  
Randomization Error 
Subject randomized twice in the same study part 
  
Randomization Error 
IVRS assigned two randomization numbers to one 
patient in the same study part 
  
Visit not performed 
Screening visit 1 not performed 
  
Visit not performed 
Visit 2 (Endoscopy/Biopsy) not performed 
  
Visit not performed 
Visit 3 (Baseline) Day 1 not performed 
  
Visit not performed 
Visit 11 Day 169 not performed (EOT Part A/Part 
B) 
  
Visit not performed 
Early Termination Visit not performed for subjects 
who early terminate before EOT part A/Part B 
(Exception: If reason is withdrew consent or lost to 
follow-up or death) 
  
Procedure not performed 
EREFS not performed by an Investigator 
Only if 
occurred 
during Part 
A  
Procedure not performed 
Missed DSQ assessment more than 6 times in a 14 
day block after Visit 3 
Only if 
occurred 
during Part 
A  
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 95 of 101 
Category 
Description of Protocol Deviation 
Notes 
Procedure not performed 
EoE-EREFS not performed at Visits 2, 11, 19 or 
ET 
Only if 
occurred 
during Part 
A  
Procedure not performed 
Esophageal Biopsy Collection not performed at 
Visit 2 
  
Procedure not performed 
Esophageal Biopsy Collection not performed at 
Visits 11, 19 or ET (if not rescued) 
Only if 
occurred 
during Part 
A  
Procedure not performed 
Esophageal Biopsy not collected prior to Rescue 
Treatment 
Only if 
occurred 
during Part 
A  
Procedure not performed 
Medical History not collected  
  
Procedure not performed 
EoE Medical History not collected 
  
Procedure not performed 
Physical Examination not performed at Visit 1 
  
Procedure not performed 
Hematology not performed prior to Visit 3 
  
Procedure not performed 
Chemistry not performed prior to Visit 3 
  
Procedure not performed 
Serum Pregnancy testing not performed at 
Screening visit 1 
  
Procedure not performed 
HIV Ab not performed prior to Visit 3 
  
Procedure not performed 
HBsAg not performed prior to Visit 3 
  
Procedure not performed 
HBcAb not performed prior to Visit 3 
  
Procedure not performed 
TB not performed, if required, prior to Visit 3 
  
Procedure not performed 
PGIS assessment not collected at baseline visit 
  
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 96 of 101 
Category 
Description of Protocol Deviation 
Notes 
Procedure performed 
outside of window 
PGIS not collected on same day of V3 study drug 
administration 
  
Inadequate Informed 
Consent administration 
Consent/Assent not collected 
  
Inadequate Informed 
Consent administration 
Assent and/or ICF signed after screening or any 
study procedures 
  
 
 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 97 of 101 
10.6. 
EoE Histology Scoring System (EoEHSS) Feature Evaluation Per 
Colllins 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 
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 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 98 of 101 
Feature 
Grade Score 
Stage Score 
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-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 99 of 101 
10.7. 
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 
KCNJ2 
ANO1 
SLC26A4 
TPSAB1 
TPSB2 
CPA3 
CMA1 
NEFM 
NEFL 
PNLIPRP3 
ENDOU 
IL4 
IL13 
 
IL4R 
IL5 
 
TSLP 
 
 
 
 
 
 
CCL26 
 
 
 
CCR3 
 
 
 
 
CLC 
ALOX15 
 
POSTN 
 
CMA1 
TPSAB1 
HRH1 
 
 
ARG1 
 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 100 of 101 
EoE diagnostic panel 
Type 2 inflammation signature 
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-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Regeneron Pharmaceuticals, Inc. 
Protocol: R668-EE-1774 Part A/C 
Statistical Analysis Plan 
Date: April 21st, 2020 
 
CONFIDENTIAL 
Page 101 of 101 
10.8. 
List of Part A Subjects Affected by Electronic Handheld Device 
Navigation Malfunction 
Subject ID 
Asset Tag 
Date of First Synchronization After 
13Mar2020 Update Release   
Date Device Updated 
 
 
2020-03-14 
16-Apr-2020 
 
 
2020-03-13 
14-Apr-2020 
 
 
2020-03-15 
30-Mar-2020 
 
 
2020-03-13 
30-Mar-2020 
 
 
2020-03-14 
31-Mar-2020 
 
 
2020-03-14 
31-Mar-2020 
 
 
2020-03-13 
13-Apr-2020 
 
 
2020-03-13 
31-Mar-2020 
 
 
2020-03-13 
01-Apr-2020 
 
 
2020-03-14 
06-Apr-2020 
 
 
2020-03-13 
15-Apr-2020 
 
 
2020-03-14 
03-Apr-2020 
 
 
2020-03-13 
07-Apr-2020 
 
 
2020-03-13 
02-Apr-2020 
 
 
2020-03-18 
07-Apr-2020 
 
 
2020-03-16 
07-Apr-2020 
 
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00


Signature Page for VV-RIM-00107607 v1.0
Signature Page for VV-RIM-00107607 v1.0 Approved
ESig Approval
ESig Approval
ESig Approval
                                        VV-RIM-00107607-1.0 Approved - 24 Apr 2020 GMT-5:00