Clinical trial NCT02379052
Conditions: Eosinophilic Esophagitis
Sponsor: Regeneron Pharmaceuticals
Start date: 2015-05-12; Completion date: 2017-07-10
Enrollment: 47 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to assess the clinical efficacy of repeat subcutaneous (SC) doses of dupilumab, compared with placebo, to relieve symptoms in adult participants with active, moderate to severe Eosinophilic Esophagitis (EoE).

The secondary objectives of the study are:

* To assess the safety, tolerability, and immunogenicity of SC doses of dupilumab in adult participants with active, moderate to severe EoE
* To assess the effect of dupilumab on esophageal eosinophilic infiltration
* To evaluate the pharmacokinetics (PK) of dupilumab in adult participants with EoE

Detailed description:

Arms: arm 1: Participants received SC dupilumab 300 mg during the 12-week double-blind treatment phase. Participants received 2 injections (300-mg initial dose, followed by a 300-mg loading dose) on day 1, followed by weekly injections. arm 2: Participants received matching placebo once weekly (qw) during the 12-week double-blind treatment phase. Participants received 2 injections on day 1, followed by weekly injections.
Interventions: intervention 1: Dupilumab intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
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To the best of my knowledge, this report accurately describes the conduct of the study. 
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SAP_001.pdf: 
CONFIDENTIAL 
Page 1 of 57 
VV-RIM-00013092-1.0 Approved - 14 Apr 2017 GMT-5:00 
 
 
 
 
Clinical and Regulatory Development 
 
Biostatistics and Data Management 
NCT02379052 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Title: A phase 2 Randomized, Double-Blind, Parallel, Placebo-Controlled Study of the Efficacy, 
Safety and Tolerability of Dupilumab in Adult Patients with Active Eosinophilic Esophagitis 
 
 
 
Protocol: R668-EE-1324.04 
 
Investigational product: Dupilumab (REGN668) 
Sponsor: Regeneron Pharmaceuticals, Inc. 
Statistician: 
Clinical Trial Manager: 
Clinical Study Director: 
 
Version/Date: Version 1 / 12Apr2017 


CONFIDENTIAL 
Page 2 of 57 
VV-RIM-00013092-1.0 Approved - 14 Apr 2017 GMT-5:00 
Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-EE-1324 
Apr 12, 2017 
 
 
 
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. 
 
 
 
Study Biostatistician 
 
 
 
See appended electronic signature page 
 
 
 
Study Medical Director 
 
 
 
See appended electronic signature page 
 
 
 
Head of BDM or designee 
 
 
 
See appended electronic signature page 


CONFIDENTIAL 
Page 3 of 57 
VV-RIM-00013092-1.0 Approved - 14 Apr 2017 GMT-5:00 
Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-EE-1324 
Apr 12, 2017 
 
 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................6 
 
1. 
OVERVIEW .................................................................................................................8 
 
1.1. 
Background and Rationale............................................................................................8 
 
1.2. 
Study Objectives ...........................................................................................................9 
 
1.2.1. 
Primary Objective .........................................................................................................9 
 
1.2.2. 
Secondary Objectives ...................................................................................................9 
 
1.2.3. 
Exploratory Objective...................................................................................................9 
 
1.3. 
Modifications from the Statistical Plan in the Final Protocol.......................................9 
 
1.4. 
Modifications from the Previously Approved SAP ......................................................9 
 
2. 
INVESTIGATIONAL PLAN.....................................................................................10 
 
2.1. 
Study Design and Randomization ..............................................................................10 
 
2.2. 
Sample Size and Power Considerations .....................................................................10 
 
2.3. 
Study Plan ...................................................................................................................10 
 
3. 
ANALYSIS POPULATIONS ....................................................................................12 
 
3.1. 
The Full Analysis Set (FAS).......................................................................................12 
 
3.2. 
Per Protocol Analysis Set (PPS) .................................................................................12 
 
3.3. 
The Safety Analysis Set (SAF) ...................................................................................12 
 
3.4. 
The Pharmacokinetic Analysis Set (PKAS) ...............................................................13 
 
3.5. 
The ADA Analysis Set (AAS)....................................................................................13 
 
3.6. 
Subgroups ...................................................................................................................13 
 
4. 
ANALYSIS VARIABLES .........................................................................................14 
 
4.1. 
Demographic and Baseline Characteristics ................................................................14 
 
4.2. 
Medical History and EoE Disease Medical History ...................................................14 
 
4.3. 
Pre-treatment/ Concomitant Medications and Procedures .........................................14 
 
4.4. 
Efficacy Variables ......................................................................................................15 
 
4.4.1. 
Primary Efficacy Variables.........................................................................................15 
 
4.4.2. 
Secondary Efficacy Variables.....................................................................................16 
 
4.4.3. 
Exploratory Efficacy Variables ..................................................................................18 
 
4.5. 
Safety Variables ..........................................................................................................19 
 
4.5.1. 
Adverse Events and Serious Adverse Events Variables .............................................19 
 
4.5.2. 
Laboratory Safety Variables .......................................................................................20 


CONFIDENTIAL 
Page 4 of 57 
VV-RIM-00013092-1.0 Approved - 14 Apr 2017 GMT-5:00 
Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-EE-1324 
Apr 12, 2017 
 
 
 
4.5.3. 
Vital Sign Variables....................................................................................................21 
 
4.5.4. 
12-Lead Electrocardiography (ECG) Variables .........................................................21 
 
4.5.5. 
Physical Examination Variables .................................................................................21 
 
4.5.6. 
Pharmacokinetic (PK) Variables ................................................................................21 
 
4.6. 
Antibody (ADA) Variable ..........................................................................................22 
 
5. 
STATISTICAL METHODS.......................................................................................23 
 
5.1. 
Demographics and Baseline Characteristics...............................................................23 
 
5.2. 
Medical and EoE History............................................................................................23 
 
5.3. 
Pre-treatment/Concomitant Medications/Procedures .................................................23 
 
5.4. 
Subject Disposition .....................................................................................................23 
 
5.5. 
Dose administration ....................................................................................................24 
 
5.6. 
Treatment Exposure and Observation Period .............................................................24 
 
5.7. 
Analyses of Efficacy Variables ..................................................................................25 
 
5.7.1. 
Hypothesis Testing and Multiplicity Control .............................................................25 
 
5.7.2. 
Analysis of Primary Efficacy Variables .....................................................................25 
 
5.7.3. 
Analyses of Secondary Efficacy Variables.................................................................27 
 
5.7.4. 
Analyses of Exploratory Efficacy Variables ..............................................................27 
 
5.7.5. 
Subgroup Analysis ......................................................................................................27 
 
5.8. 
Analysis of Safety Data ..............................................................................................27 
 
5.8.1. 
Analysis of Adverse Events ........................................................................................27 
 
5.8.2. 
Analysis of Clinical Laboratory Measurements .........................................................30 
 
5.8.3. 
Analysis of Vital Signs ...............................................................................................30 
 
5.8.4. 
Analysis of Physical Exams........................................................................................31 
 
5.8.5. 
Analysis of 12-Lead ECG...........................................................................................31 
 
5.9. 
Analysis of Pharmacokinetic Data..............................................................................31 
 
5.10. 
Analysis of ADA Data ................................................................................................31 
 
6. 
DATA CONVENTIONS ............................................................................................33 
 
6.1. 
Definition of Baseline for Efficacy/Safety Variables .................................................33 
 
6.2. 
General Data Handling Conventions ..........................................................................33 
 
6.3. 
Data Handling Convention Missing Data ...................................................................33 
 
6.4. 
Analysis Visit Window ...............................................................................................35 
 
7. 
INTERIM ANALYSIS ...............................................................................................40 
 
8. 
SOFTWARE...............................................................................................................40 


CONFIDENTIAL 
Page 5 of 57 
VV-RIM-00013092-1.0 Approved - 14 Apr 2017 GMT-5:00 
Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-EE-1324 
Apr 12, 2017 
 
 
 
9. 
REFERENCES ...........................................................................................................41 
 
10. 
APPENDIX.................................................................................................................42 
 
10.1. 
Summary of Statistical Analyses ................................................................................42 
 
10.2. 
Schedule of Events .....................................................................................................44 
 
10.3. 
Criteria for Treatment-Emergent Potentially Clinical Significant Value 
(PCSV) for Dupilumab studies ...................................................................................49 
 
10.4. 
Search Criteria for TEAE of Special Interest/TEAE Syndrome ................................53 
 
10.5. 
EEsAI Score................................................................................................................55 
 
10.6. 
Medication for RESCUE TREATMENTS.................................................................57 
 
 
 
 
 
LIST OF TABLES 
 
Table 1: 
Schedule of Events – Screening and Treatment Period ..............................................44 
 
Table 2: 
Schedule of Events – Follow-up Period .....................................................................47 


CONFIDENTIAL 
Page 6 of 57 
VV-RIM-00013092-1.0 Approved - 14 Apr 2017 GMT-5:00 
Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-EE-1324 
Apr 12, 2017 
 
 
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AD 
Atopic dermatitis 
ADA 
Anti-Drug Antibodies 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALT (SGOT) 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST (SGPT) 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CRF 
Case report form 
EEsAI 
Eosinophilic Esophagitis Activity Index 
EndoFLIP 
Endolumenal functional lumen imaging probe 
EoE 
Eosinophilic esophagitis 
EoE-EREFS 
Eosinophilic Esophagitis-Endoscopic Reference Score 
EoEHSS 
Eosinophilic Esophagitis Histology Scoring System 
EoE-QOL-A 
Adult Eosinophilic Esophagitis Quality of Life (questionnaire) 
ECG 
Electrocardiogram 
EOS 
End of study EOT
 
End of treatment 
ET 
Early termination 
FAS 
Full analysis set 
HLT 
High Level Term 
ICF 
Informed consent form 
ICH 
International conference on harmonization 
LDH 
Lactate dehydrogenase 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MMRM 
Mixed effect model with repeated measures 
PCSV 
Potentially clinically significant value 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic analysis set 
PPS 
Per protocol set 
PT 
Preferred term 


CONFIDENTIAL 
Page 7 of 57 
VV-RIM-00013092-1.0 Approved - 14 Apr 2017 GMT-5:00 
Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-EE-1324 
Apr 12, 2017 
 
 
 
qw 
Weekly 
RBC 
Red blood cell 
Regeneron 
Regeneron Pharmaceuticals, Inc. 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software 
SC 
Subcutaneous 
SD 
Standard deviation 
SDI 
Straumann Dysphagia Instrument 
SOC 
System organ class 
TEAE 
Treatment emergent adverse event 
WHODD 
World health organization drug dictionary 


CONFIDENTIAL 
Page 8 of 57 
VV-RIM-00013092-1.0 Approved - 14 Apr 2017 GMT-5:00 
Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-EE-1324 
Apr 12, 2017 
 
 
 
 
1.            OVERVIEW 
 
The purpose of the statistical analysis plan (SAP) is to ensure the credibility of the study results 
by pre-specifying statistical approaches for the analysis of this study. The SAP is intended to be 
a comprehensive and detailed description of strategy and statistical techniques to be used to 
realize the analysis of data for R668-EE-1324 study. 
 
This plan may be revised during the study to accommodate protocol amendments and to adapt to 
unexpected issues in study execution or data that affect planned analyses. The plan will be based 
on blinded data and will be finalized prior to the database lock. 
 
1.1.         Background and Rationale 
 
Eosinophilic esophagitis (EoE) is an emerging, chronic, immune-/antigen-mediated disease 
characterized  by  esophageal  dysfunction  and  eosinophil  inflammation  in  the  esophagus 
(Liacouras 2011,  Weinbrand-Goichberg  2013,  Zhang  2013).    Adult  patients  with  EoE  have 
substantially impaired quality of life (QOL) due to dysphagia and the possible risk of food 
impaction (DeBrosse 2011, Falk 2014, Straumann 2008, Straumann 2003).   Emergency 
endoscopy for prolonged food impactions is associated with a risk of severe esophageal injury. 
The prevalence of EoE in the general population was reported to range from 0.5 to 1 case 
per 100,000 persons (Dellon 2014a). 
 
The pathogenesis of EoE is still unclear, however, growing evidence suggests that type 2 helper 
T cell (Th2)-mediated immune response plays an important role in the pathogenesis of EoE. 
Mutations in downstream Th2 functional genes including eotaxin-3 (chemokine [C-C motif] 
ligand [CCL26]), thymic and stromal lymphopoeitin (TSLP), and filaggrin (FLG) have been 
associated with EoE risk. Impaired barrier function of the esophageal epithelium is also thought 
to play a role in EoE pathogenesis. The data suggest that Th2 cytokines may be driving not only 
an inflammatory response, but also epithelial barrier dysfunction in the esophagus. 
 
Consistent with the Th2-mediated inflammation observed in esophageal tissue, patients with EoE 
have high rates of comorbid Type 2 immune diseases, especially food allergies, atopic dermatitis 
(AD), asthma, and allergic rhinitis. 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 chronic dietary elimination, swallowed topical 
formulation corticosteroids (not approved for the treatment of EoE in the US), and esophageal 
dilation.  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. 
There are currently no approved drug therapies for EoE. 
 
Dupilumab  is  a  human  monoclonal  antibody  that  targets  the  IL-4  receptor  alpha  subunit 
(IL-4Rα), a component of IL-4 receptors Type I and Type II, as well as the IL-13 receptor 
system. The binding of dupilumab to IL-4Rα results in blockade of the function of both IL-4 and 
IL-13 signal transduction. Dupilumab has demonstrated preliminary efficacy in 3 other Type 
2/Th2 immune diseases: asthma, chronic sinusitis with nasal polyps, and moderate-to-severe 


CONFIDENTIAL 
Page 9 of 57 
VV-RIM-00013092-1.0 Approved - 14 Apr 2017 GMT-5:00 
Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-EE-1324 
Apr 12, 2017 
 
 
 
atopic dermatitis. Because IL-4 and IL-13 are likely key pathomechanisms in EoE, dupilumab 
treatment may improve inflammation and clinical symptoms. 
 
This  is  a  multicenter,  randomized,  double-blind,  placebo-controlled,  2-arm,  parallel-group, 
proof-of-concept  study.  This  study will  evaluate  the  effect  of  dupilumab  on  relieving  EoE 
clinical symptoms and reducing esophageal inflammation in adults. Efficacy in this study will be 
assessed based on clinical signs and symptoms using the EoE-specific PROs currently in 
development,  as  well  as  on  anatomical  and  histological  findings  from  endoscopy  with 
esophageal biopsies. The placebo control will provide a reliable reference for any apparent 
effects of the study treatment with active IL-4Rα inhibition. Repeat SC dose regimens as high as 
300 mg qw (with or without a loading dose) for up to 16 weeks have previously been studied in 
phase 1, 2 and phase 3 clinical trials in healthy subjects as well as in patients with AD or asthma 
and were well tolerated. Therefore, a SC 600 mg loading dose followed by   the repeat SC 
300 mg qw dose, the highest SC repeat dose studied to date, was selected for this study. 
 
1.2.         Study Objectives 
 
1.2.1.         Primary Objective 
 
The primary objective of the study is to assess the clinical efficacy of repeat SC doses of 
dupilumab, compared with placebo, to relieve symptoms in adult patients with active, moderate 
to severe EoE. 
 
1.2.2.         Secondary Objectives 
 
The secondary objectives of the study are: 
 
• To assess the safety, tolerability, and immunogenicity of SC doses of dupilumab in 
adult patients with active, moderate to severe EoE 
 
• To assess the effect of dupilumab on esophageal eosinophilic infiltration 
 
• To evaluate the PK of dupilumab in adult patients with EoE 
 
1.2.3.         Exploratory Objective 
 
The exploratory objective of the study is to assess the effect of dupilumab on other esophageal 
biopsy pathologic features associated with EoE, as well as esophageal distensibility, which is 
reduced in EoE patients. 
 
1.3.         Modifications from the Statistical Plan in the Final Protocol 
 
NA 
 
1.4.         Modifications from the Previously Approved SAP 
 
NA 


CONFIDENTIAL 
Page 10 of 57 
VV-RIM-00013092-1.0 Approved - 14 Apr 2017 GMT-5:00 
Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-EE-1324 
Apr 12, 2017 
 
 
 
 
2.            INVESTIGATIONAL PLAN 
 
2.1.         Study Design and Randomization 
 
This is a phase 2, multicenter, double-blind, randomized, placebo-controlled study investigating 
the efficacy, safety, tolerability, PK, and immunogenicity of dupilumab in adult patients with 
EoE. Patients will be randomized in a 1:1 ratio to receive SC 600 mg dupilumab or  SC placebo 
loading dose followed by weekly SC 300 mg dupilumab or SC placebo during the 12-week 
double-blind treatment phase. The randomization will be stratified by baseline Straumann 
Dysphagia Instrument (SDI) PRO score (≥5 and ≤7 versus >7). 
 
2.2.         Sample Size and Power Considerations 
 
The sample size calculations are based on the change from baseline in SDI score to week 12. The 
study of Straumann 2010 has a 2-week treatment period and the 3-point improvement from 
baseline is observed at end of week 2. A 3-point improvement from baseline is assumed for the 
study at both week 10 and week 12, so the power calculation for change from baseline in SDI 
score to week 12 is the same as the one at week 10.  In the Straumann adult study, change from 
baseline in SDI score for active and placebo treatment group are -3.39 (2.46) [mean (maximum 
possible SD)] and -0.61 (2.19) [mean (maximum possible SD)] respectively. 
 
A sample size of 18 patients per treatment arm will provide 94% power to detect a treatment 
effect, with an expected mean difference of 3 points in change from baseline to week 12 in SDI 
score between dupilumab and placebo at a 2-sided t-test with 5% significance level and an 
assumed SD of 2.46. Taking into account the assumed 15% dropouts, 22 patients per treatment 
arm will be enrolled. 
 
2.3.         Study Plan 
 
The study will consist of 3 periods: screening, 12 week double-blind treatment, double-blind 
follow-up: 
 
Screening 
Treatment Period (Weeks)a,b 
Follow-upc 
1 
2 
3 
4 
5d 
6 d 
7 d 
8 
9 d 
10 d 
11 d 
B/R 
EOT 
EOS 
(Day -35 to -1) 
(Day 1) 
(Week 12) 
(Week 28) 
 
B/R = baseline/randomization; EOT = end of treatment; EOS = end of study. 
Note: The scale is not linear. 
a  Patients will receive a weekly injection of study drug from day 1 through week 12 (with the last dose at week 11). 
b  Patients will be monitored at the study site for 30 minutes after each of the first 5 doses (visits 2 to 6) of study 
drug. 
c  Follow-up visits will occur every 4 weeks. 
d  Weeks 5, 6, 7, 9, 10, and 11 will be telephone visits. 
 
After providing informed consent, patient eligibility will be assessed at the screening visit (to 
occur between day -35 and day -1).   Patients who meet eligibility criteria will undergo day 1 
baseline assessments.  Patients will be randomized in a 1:1 ratio to receive dupilumab or placebo 


CONFIDENTIAL 
Page 11 of 57 
VV-RIM-00013092-1.0 Approved - 14 Apr 2017 GMT-5:00 
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Statistical Analysis Plan 
R668-EE-1324 
Apr 12, 2017 
 
 
 
during the 12-week double-blind treatment phase. After the 12-week double-blind treatment 
phase, patients will be followed off-study drug for an additional 16 weeks. 
 
Patients may receive concomitant medications (except for prohibited medications) as needed, at 
the discretion of the investigator, while continuing study treatment.  Frequency of use and type 
of product will be documented.   If medically necessary, rescue medications or emergency 
esophageal dilation may be provided to study patients.  Patients receiving rescue therapy will be 
discontinued from study treatment.   These patients will remain blinded and will be asked to 
return to the clinic for all remaining study treatment visits and participate in all follow-up 
assessments according to the visit schedule. 
 
Efficacy,  safety,  and  laboratory  assessments  will  be  performed  at  specified  time  points 
throughout the study. Samples for the assessments of dupilumab concentration and assessment of 
anti-drug antibody (ADA) response to dupilumab, as well as research samples will be collected 
at specified time points throughout the study. In response to AE’s of special interest like 
anaphylaxis or hypersensitivity additional samples closer to the event may be collected and 
analyzed for ADA, based on the judgement of the medical investigator and/or medical monitor. 
 
The end of the double-blind treatment period visit occurs at week 12, 1 week after the last dose 
of study drug.  The maximum duration of the double-blind study is approximately 33 weeks 
including screening and follow-up. 


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3.            ANALYSIS POPULATIONS 
 
In accordance with guidance from the International Conference of Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for  Human  Use (ICH)  guideline  ICH E9 
Statistical Principles for Clinical Trials (1998), the following populations of analysis will be used 
for all statistical analyses. 
 
3.1.         The Full Analysis Set (FAS) 
 
The full analysis set (FAS) includes all randomized patients. Efficacy analyses will be based on 
the treatment allocated by the IVRS/IWRS at randomization (as randomized). This is the primary 
analysis population for efficacy analyses. 
 
3.2.         Per Protocol Analysis Set (PPS) 
 
The per protocol analysis set (PPS) includes all patients in the FAS except for those who are 
excluded from this analysis because of major efficacy-related protocol violations. 
 
A major efficacy-related protocol violation is one that may affect the interpretation of study 
efficacy results.   The criteria of major efficacy-related protocol deviation are defined as 
following: 
 
• Any major violations of efficacy-related entry criteria 
 
− Inclusion criteria 2, 3, 5 
 
− Exclusion criteria 8, 12 
 
• Patients who received <80% of the scheduled doses during the double blind treatment 
period 
 
Final determination of the PPS will be made in the blinded manner prior to the database lock. 
 
3.3.         The Safety Analysis Set (SAF) 
 
The safety analysis set (SAF) includes all randomized patients who receive any study drug, and 
will be analyzed as treated. 
 
The actual treatment group as treated is defined by the following rules: 
 
• For a patient randomized to dupilumab, 
 
− if the patient received all placebo injections, the actual treatment will be assigned 
as placebo 
 
− if the patient received at least one dupilumab injection, the actual treatment will 
be assigned as dupilumab 
 
• For a patient randomized to placebo, 
 
− if the patient accidentally received one or more dupilumab injections, the actual 
treatment will be assigned as dupilumab; otherwise it will remain as placebo 
 
The safety analyses will be based on the SAF. 


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For safety summaries, three analysis periods are defined as follows: 
 
• 
Week 12 treatment period is defined as 
Day 1 from start of administration of the first dose of study drug through week 12 of 
the double-blind period (85 days starting from the first dose of study drug if the date 
of week 12 treatment visit is unavailable). 
• Follow-up period is defined as from week 12 of the double-blind period to the last 
visit of the double-blind period. 
• Overall study Period is defined as day 1 to the date of the end of study visit, 
consisting of both the treatment and follow-up periods 
3.4. 
The Pharmacokinetic Analysis Set (PKAS) 
The PK analysis set includes all randomized patients who received any study drug and who had 
at least one non-missing PK sample result following the first dose of study drug, and will be 
analyzed as the treated groups defined in the SAF. 
 
3.5.         The ADA Analysis Set (AAS) 
 
The ADA analysis set includes all treated patients who received any study drug and had at least 
1 non-missing ADA result in the ADA assay following the first dose of the study drug. 
 
3.6.         Subgroups 
 
Subgroups are defined by key baseline factors recorded on the CRF and listed as follows 
 
Subgroups to be considered for efficacy/safety analyses: 
 
• Age group (≥18-<40, ≥40-<65, ≥65) 
 
• Sex (Male, Female) 
 
• Baseline weight group (<70 kg, ≥70-<100 kg, ≥100 kg) 
 
93% patients enrolled for this study are white so no subgroup for  ethnicity or race as all patients 
are not Hispanic or Latino 


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4. 
ANALYSIS VARIABLES 
 
4.1. 
Demographic and Baseline Characteristics 
 
The following demographic and Baseline characteristics variables will be summarized: 
 
• Demographic variables: Age at screening with grouping (year; ≥18-<40, ≥40-<65, 
≥65), Sex, Ethnicity with grouping (Hispanic or Latino, Not-Hispanic or Latino), 
Race with grouping (White, Black, Asian, Other), Baseline weight with grouping (kg, 
<70; ≥70-<100,  ≥100), Height (m), and BMI (kg/m2; <15, ≥15-<25, ≥25-<30, ≥30), 
• Baseline characteristics: Age at EOE diagnosis, Duration of EoE, age at first 
esophageal dilation, number of documented dysphagia episodes, SDI PRO score, 
EEsAI PRO score, EoE-QOL-A PRO score, EoE-EREFS, distensibility plateau, peak 
eosinophils/hpf, EoEHSS stage, EoEHSS grade, allergic disease, peripheral 
eosinophil counts, serum total Immunoglobulin E (IgE). 
4.2. 
Medical History and EoE Disease Medical History 
Medical history will be coded to a Preferred Term (PT) and associated primary System Organ 
Class  (SOC)  according  to  MedDRA  version  19.1  at  the  coding  of  CRO.  Information  on 
conditions related to EoE includes diagnosis of EoE and EoE treatment history. 
 
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) version Sep 2016 at the coding of CRO Patients will be counted once in 
all ATC categories linked to the medication. 
 
Pre-treatment medications/procedures: medications taken or procedures performed prior to 
administration of the first study drug. 
 
Concomitant medications/procedures: medications taken or procedures performed following the 
first dose of study drug through the EOS visit. 
 
Prohibited concomitant medications/procedures during week 12 treatment period Treatment with 
the following concomitant medications is prohibited: 
 
• Medications used for the treatment of EoE . 
 
• Allergen immunotherapy. 
 
• Patients who are not using PPI in the 8 weeks prior to screening cannot start PPI 
therapy prior to EOT visit 
 
• Treatment with a live (attenuated) vaccine 
 
• Treatment with an investigational drug (other than dupilumab) 


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Treatment with the following concomitant procedures is prohibited: 
 
• Major elective surgical procedures 
 
• Esophageal dilation (considered rescue procedure) 
 
• Diet change. 
 
If medically necessary (eg, for treatment of intolerable EoE symptoms) patients may be rescued 
with a prohibited medication or procedure at the discretion of the investigator. Patients who 
receive rescue treatment with a prohibited medication or procedure through week 12 will be 
permanently discontinued from study drug. 
 
Rescue treatments for EoE:   Blinded adjudication of rescue treatments will be implemented 
before database locks by considering the type of medications.  A predetermined algorithm for 
rescue  medications  listed  in  Appendix 10.6  will  be  used  to  programmatically  search  the 
concomitant medications (CMs).  The rescue CMs will be reviewed and adjudicated by the 
medical monitor in a blinded fashion. 
 
All patients will complete the schedule of study visits and assessments whether or not they 
complete study treatment. Investigators should make every attempt to conduct efficacy and 
safety assessments immediately before administering any rescue treatment. An unscheduled visit 
may be used for this purpose if necessary. 
 
4.4.         Efficacy Variables 
 
Due to failure with electronic diaries, data from many patients are missing for the week 12 
analysis. Week 10 timepoint is therefore chosen  as endpoints for SDI and EEsAI in a blinded 
fashion prior to database lock to increase available data for analysis. Week 12 remains the 
endpoints for other efficacy endpoints. 
 
4.4.1.         Primary Efficacy Variables 
 
The primary efficacy endpoint is the change in the Straumann Dysphagia Instrument (SDI) 
patient reported outcome (PRO) score from baseline to week 10. 
Straumann Dysphagia Instrument (SDI) 
The SDI is a  PRO that has been used in clinical studies to determine the frequency and intensity 
of dysphagia. The SDI has a 1-week recall period. Frequency of dysphagia events is graded on a 
5-point scale: 0 = none, 1 = once per week, 2 = several times per week, 3 = once per day, and 
4 = several  times  per  day,  and  intensity of  dysphagia  events  is  graded  on  a  6-point  scale: 
0 = swallowing unrestricted, 1 = slight sensation of resistance, 2 = slight retching with delayed 
passage, 3 = short period of obstruction necessitating intervention (eg, drinking, breathing), 
4 = longer-lasting period obstruction only removable by vomiting, and 5 = long-lasting complete 
obstruction requiring endoscopic intervention. The SDI total score is the sum of scores of 
frequency of dysphagia and intensity of dysphagia, and ranges from 0 to 9. In the Straumann 
adult study of swallowed budesonide TCS (Straumann, Gastroenterology 2010), a clinical 
response (improvement)  was  defined  as  a decrease in  SDI score of at  least  3  points from 
baseline.  SDI  score  is  the  sum  of  scores  of  frequency  of  dysphagia  and  intensity  of 
dysphagia.  SDI score will be set to missing if score of frequency of dysphagia or score of 


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intensity of dysphagia is missing. If intensity of dysphagia event is greater than 0 and frequency 
of dysphagia is 0, then frequency of dysphagia will be set to 1. 
 
4.4.2.         Secondary Efficacy Variables 
The secondary endpoints are: 
 
 •  Percent  change in weekly Eosinophilic Esophagitis Activity Index  (EEsAI) PRO 
score from baseline to week 10 
 
• Change in weekly EEsAI PRO score from baseline to week 10 
 
• Percent change in weekly EEsAI PRO score from baseline to week 12 
 
• Change in weekly EEsAI PRO score from baseline to week 12 
 
• Percent change in the SDI PRO score from baseline to week 10 
 
• Percent change in the SDI PRO score from baseline to week 12 
 
• Change in the SDI PRO score from baseline to week 12 
 
• Change in EoE-QOL-A PRO score from baseline to week 12 
 
• Percentage of patients with SDI PRO response at week 10; where response is defined 
as a decrease of at least 3 points on the SDI compared to baseline 
 
 •  Percentage of patients who achieve ≥40% improvement in EEsAI score from baseline 
to week 10 
 
 •  Percent  change  in  overall  peak  esophageal  intraepithelial  eos/hpf  (400X)  from 
baseline to week 12 
 
• Change in EoE-EREFs (endoscopy visual anatomical score) from baseline to week 12 
 
• Percentage of patients with use of rescue medication or procedure (eg, esophageal 
dilation) through week 12 
 
 •  Incidence of treatment-emergent AEs 
 
Eosinophilic Esophagitis Activity Index (EEsAI) PRO 
 
The EEsAI is a multimodular index in development at University Hospital Inselspital (Berne, 
Switzerland), a part of the international EEsAI study group. The EEsAI PRO module 
(questionnaire) used in this study includes items related to the intensity and frequency of 
dysphagia, and the influence of specific food groups on dysphagia symptoms. The PRO 
instrument contains 5 domains addressing symptoms while eating or drinking includes items on 
duration, frequency, and severity of dysphagia, time required for meal intake, dysphagia upon 
consuming liquids, and pain when swallowing. The visual dysphagia question (VDQ) addresses 
the severity of dysphagia when consuming food of 8 distinct consistencies. The 8 food 
consistencies and examples of foods to illustrate those consistencies are: (1) solid meat (such as 
steak, chicken, turkey, and lamb), (2) soft foods (such as pudding, jelly, and apple sauce), (3) dry 
rice or sticky Asian rice, (4) ground meat (hamburger and meatloaf), (5) fresh white untoasted 
bread or similar foods (such as doughnuts, mufﬁns, and cake), (6) grits, porridge (oatmeal), or 
rice pudding, (7) raw ﬁbrous foods (such as apples, carrots, and celery), and (8) French fries. The 


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behavioral adaptations (avoidance, modiﬁcation, and slow eating [AMS] of various foods) are 
assessed in the context of consuming 8 distinct food consistencies. The total EEsAI PRO score 
ranges from 0 to 100. The details of the calculation are provided in Appendix 10.5 . The EEsAI 
PRO utilizes 24-hour and 1-week recall periods. Patients will electronically complete this 
questionnaire daily and weekly from the beginning of screening through end of study or early 
termination. EEsAI score will be set to missing if one of 5 domain scores is missing. 
 
Derived weekly EEsAI score will be produced by average daily EEsAI score for each patient and 
calculated as the prorated average of the daily EEsAI score. For example, if there are 4 daily 
EEsAI score in a week, the prorated average = (score1 + score2 + score3  + score4)/4. A 
minimum of 4 days nonmissing daily score in a week is required to calculate the derived weekly 
score. If there are <4 days of daily score, the derived weekly score will be missing. Derived 
weekly EEsAI score will cover the same time period as the weekly EEsAI score. 
 
Details for calculation EEsAI score can be found in Appendix 10.5. 
Endoscopy with Esophageal Biopsies 
Esophageal biopsies will be obtained by endoscopy at the screening and week 12 visits.  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. To 
participate in the study, patients must have a peak intraepithelial eosinophil count ≥15 eos/hpf 
(400X) in at least 2 of the 3 esophageal regions sampled.  Peak esophageal eos/hpf (400X) will 
be determined for each of the 3 esophageal regions (proximal, mid, and distal) and overall at 
each time point.   Mean peak of esophageal eos/hpf (400X) will be calculated from the peak 
count at each of the 3 esophageal regions for each patient at each time point. 
 
EoE-EREFS 
 
The EoE-EREFS (endoscopy visual anatomical score: Exudates, Rings, Edema, Furrows, 
Stricture) will be used to measure the endoscopically identified EoE esophageal mucosal 
inflammatory and remodeling features. This instrument includes a total of 12 items related to the 
presence and severity of esophageal features. The specific esophageal features include: rings 
(absent, mild, moderate, severe, not applicable); stricture (yes, no, not applicable); diameter of 
the stricture (if applicable); exudates (absent, mild, severe), furrows (absent, present); edema 
(absent, present). Total scores for edema, rings, furrows and exudate, stricture scores will be 
calculated,  will  range  from  0  to  9.  Also  total  scores  excluding  stricture  and  inflammation 
subscore (edema+exudate+furrows) and remodeling subscore (ring+stricture) will be calculated. 
Estimated diameter of stricture will be stratified into group (>=18 mm, 15-17, 12-14, 9-11, 6-8) 
and assigned severity scores from 0 to 4. 
 
Adult Eosinophilic Esophagitis Quality of Life Questionnaire 
 
The EoE-QOL-A questionnaire is a validated disease-specific measure of health-related quality 
of life in EoE patients.  The instrument used in this study, the EoE-QOL-A v.3.0, includes 30 
items related to 5 established domains such as social functioning, emotional functioning, and 
disease impact of daily life experiences.  The EoE-QOL-A has a 1-week recall period.  The items 
are graded on a 5-point scale from 1 to 5 as:   ‘Not at All’=5, ‘Slightly’=4, ‘Moderately’=3, 
‘Quite a bit’=2, and ‘Extremely’ =1. 


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Subscales 
Score Range 
Items 
Eating/Diet Impact 
0-40 
Q2, Q9, Q16, Q24, Q25, Q26, Q27, Q28, Q29, Q30 
Social Impact 
0-16 
Q14, Q17, Q19, Q22 
Emotional Impact 
0-32 
Q1, Q5, Q6, Q7, Q11, Q13, Q21, Q23 
Disease Anxiety 
0-20 
Q4, Q10, Q12, Q15, Q18, 
Swallowing Anxiety 
0-12 
Q3, Q8, Q20 
Overall Score 
0-120 
Q1-Q30 
 
If less than 40% of EoE-QOL-A questionnaire for a domain are missing, the score for the 
domain will be imputed by a weighted average calculated by dividing sum of scores by the total 
number of items answered, recommended by the developer of the instrument. If more than 40% 
of questionnaire for a domain are missing, the total score for the domain will be set to missing. 
 
This assessment will be recorded by the patient in a questionnaire at baseline and then monthly 
through end of study or early termination. 
 
4.4.3.         Exploratory Efficacy Variables 
 
Exploratory efficacy variables include: 
 
• Change in mean esophageal intraepithelial eosinophil counts (eos/hpf) [calculated 
using peak count from each esophageal site] from baseline to week 12 
 
• Proportion  of  patients  who  achieve  esophageal  intraepithelial  eosinophil  count 
<1 eos/hpf at week 12 
 
• Change in Collins Histology Score from baseline to week 12 
 
• Change  in  esophageal  distensibility  plateau  as 
measured  by  functional  lumen 
imaging from baseline to week 12 
 
Collins Histology Score 
 
The  Collins  Histology  Score,  also  known  as  the eosinophilic esophagitis  histology  scoring 
system (EoEHSS), is a method for evaluating the grade and stage of multiple pathologic features 
in esophageal biopsies from EoE patients (Collins et al. 2016). EoEHSS evaluates 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. Severity (grade) and extent (stage) of abnormalities were scored by a central, 
blinded pathologist for each parameter using a 4-point scale (0 normal; 3 maximum change). 
Composite scores for both grade and stage at 3 esophageal regions (proximal, mid, and distal) 
will be created by summing the individual 8 features scores.  Due to anticipation of at least 
50% missing data for LPF (lamina propria will likely be absent in at least 50% of biopsies), 
composite scores based on the other 7 features will be produced after excluding lamina propria 
score. An overall peak EoEHSS grade and stage score for a patient, as well as the peak grade and 
stage score for each individual region (proximal, mid and distal) will be generated. 


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Esophageal distensibility 
 
The assessment of esophageal distensibility utilizing the endolumenal functional lumen imaging 
probe (EndoFLIP, Crospon, Ireland) will also be performed, with measurements taken as part of 
the endoscopy procedure performed at screening and week 12.   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 
(DP). 
 
4.5.         Safety Variables 
 
4.5.1.         Adverse Events and Serious Adverse Events Variables 
 
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”, “High Level Term” and the associated primary “System Organ Class (SOC)” 
according to MedDRA version 19.1. 
 
An Adverse Event is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product. An AE can, therefore, be any unfavorable and 
unintended sign (including abnormal laboratory finding), symptom, or disease temporally 
associated  with  the  use  of  a  medicinal  product,  whether  or  not  considered  related  to  the 
medicinal (investigational) product. 
 
AEs also include: any worsening (i.e., 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; 
abnormal laboratory findings considered by the investigator to be clinically significant; and any 
untoward medical occurrence. 
 
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; is a congenital anomaly/ birth defect; or 
is an important medical event. 
 
The criteria for determining whether an abnormal laboratory, vital sign or ECG finding should be 
reported as an AE are as follows: 
 
• Test result is associated with accompanying symptoms, and/or 
 
• Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or 
 
• Test result leads to a change in dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy 
 
Treatment-emergent adverse events are defined as those that are not present at baseline or those 
that represent an exacerbation of a preexisting condition during the double blind period, follow 
up period. 


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4.5.2. 
Laboratory Safety Variables 
 
Hematology, chemistry, urinalysis, and pregnancy testing samples will be analyzed by a central 
laboratory. 
 
Blood samples for serum chemistry and hematology testing will be collected at time points 
according to the schedule in Appendix 10.2. 
 
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) 
CPK 
 
 
Hematology with Differential 
 
Hemoglobin 
Differential: 
Hematocrit 
 
Neutrophils 
Red blood cells (RBCs) 
 
Lymphocytes 
White blood cells (WBCs) 
 
Monocytes 
Red cell indices 
 
Basophils 
Platelet count 
 
Eosinophils 
 
 
 
Urinalysis 
 
Urine samples for urinalysis will be collected to measure overall patient health at time points 
according to the schedule in Appendix 10.2. 
 
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 


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4.5.3.         Vital Sign Variables 
 
The following vital signs parameters will be collected: 
 
• Weight (kg) and height (cm) 
 
• Respiratory rate (bpm) 
 
• Heart rate (beats/min) 
 
• Sitting systolic and diastolic blood pressures (mmHg) 
 
• Body temperature (oC) 
 
Height is only measured at screening. Other vital signs are collected pre-dose at every scheduled 
and unscheduled clinic visit. 
 
4.5.4.         12-Lead Electrocardiography (ECG) Variables 
 
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]) ECG 
status: normal, abnormal not 
clinical significant or 
abnormal 
clinical significant. 
Electrocardiograms should be performed before blood is drawn during visits requiring blood 
draws.  A  standard  12-lead  ECG  will  be  performed  at  scheduled  time  points  indicated  in 
Appendix 10.2 Schedule of Events. 
 
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 time points according to the 
schedule in Appendix 10.2. 
 
4.5.6.         Pharmacokinetic (PK) Variables 
 
Samples  for  drug  concentration  will  be  collected  at  scheduled  time  points  indicated  in 
Appendix 10.2  Schedule  of  Events.  Due  to  the  sparse  nature  of  the  data,  only  descriptive 
analyses will be performed.   Pharmacokinetic variables may include but not limited to Ctrough 
over time, Clast  and Tlast. 


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4.6. 
Antibody (ADA) Variable 
 
ADA samples collected at day 1 (baseline) , Week 12 (EOT), Week 28 (EOS) and at early 
termination (ET) will be analyzed for ADA. 
 
The variables include ADA response status  and titer as follows: 
 
• Total subjects negative in the ADA assay at all time points analyzed 
 
• Total subjects with pre-existing immunoreactivity - defined as either an ADA positive 
response in the assay at baseline, with all post first dose ADA results negative, OR a 
positive response at baseline with all post first dose ADA results less than 4-fold over 
baseline titer levels. 
 
• Total subjects with treatment-emergent response, defined as a positive response in the 
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 – defined as a treatment emergent ADA response with two or 
more consecutive ADA positive sampling time points separated by greater than 
(>) 12-week period, with no ADA negative samples or any missing sample in 
between. 
 
− Indeterminate Response – defined as a treatment-emergent  response with only 
the last collected sample positive in the ADA assay 
 
− Transient Response - defined as a treatment emergent ADA positive assay 
response that is not considered persistent or indeterminate. 
 
• Total subjects with treatment-boosted response, defined as a positive response in the 
ADA assay post first dose that is greater than or equal to 4-fold over baseline titer 
levels, when baseline results are positive 
 
• Titer Values (Titer value category) 
 
− Low (titer <1,000) 
 
− Moderate (1,000 ≤ titer ≤ 10,000) 
 
− High (titer >10,000) 
 
ADA  positive  samples  will  be  further  characterized  for  presence  of  neutralizing  antibody 
response in the NAb assay. 


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5.            STATISTICAL METHODS 
 
For continuous variables, descriptive statistics will include the following: the number of subjects 
reflected in the calculation (n), mean, median, standard deviation, Q1 and Q3, minimum, and 
maximum. 
 
For categorical or ordinal data, frequencies and percentages will be displayed for each category. 
 
5.1.         Demographics and Baseline Characteristics 
 
Demographics and Baseline Characteristics will be summarized by treatment groups based on 
FAS. Listing of demographics and baseline characteristics will be presented. 
 
5.2.         Medical and EoE History 
 
Medical history will be summarized by primary SOC and PT for each treatment group. 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 SAF. 
 
5.3.         Pre-treatment/Concomitant Medications/Procedures 
 
Number and proportion of subjects taking prior/concomitant medications, prohibited 
medications/procedures and rescue medications/procedures will be summarized, sorted by 
decreasing frequency of ATC Level 2 and ATC level 4, based on the overall incidence for the 
dupilumab treatment group. 
 
The procedure will be summarized by treatment group to MedDRA version 19.1 by system 
organ class (SOC) and preferred term (PT) and sorted by decreasing frequency of SOC and PT, 
based on the overall incidence for dupilumab treatment group. 
 
Listing of pre-treatment medication and concomitant medications will include generic name and 
ATC levels 2 and 4, indication, study day onset (for medications started before treatment, the 
study day onset (defined as date of medication start - date of the first dose; for medications 
started on or after treatment, the study day onset = date of medication start - date of the first dose 
+1),  the  study  end  date  (defined  similarly  as  for  study  day  onset),  ongoing  status,  dose, 
frequency, route. 
 
The detailed information of rescue medications/procedures including duration of use and 
incidence of use will be summarized. Kaplan Meier curves for time to first rescue use may be 
generated. 
 
5.4.         Subject Disposition 
 
The following summaries by table will be provided: 
 
• The total number of screened patients 
 
• The total number of randomized patients: received a randomization number 
 
• The total number of patients in each analysis set 


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• The total number of patients who discontinued the study treatment and the reasons for 
the discontinuation 
 
• The total number of patients who discontinued the study, and the reasons for 
discontinuation 
• Number of patients who entered into follow-up period. 
The following listings will be provided: 
 
• Listing of subject disposition including: date of randomization, date of the last visit, 
received dose, completed study drug 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. 
• A listing of patients prematurely discontinued from the study or treatment, along with 
reasons for discontinuation, summary tables of reasons will be provided 
• Summary table with listing of protocol deviations will be provided 
5.5. 
Dose administration 
The compliance with protocol-defined study drug will be calculated as follows: 
Treatment Compliance = 
(Number of investigational product injections])/(Number of planned investigational product 
injections]) x 100% 
 
Loading doses for the same patient will be counted as 1 study drug administration. 
 
Summary of study drug administration will include the number of study drug doses administered 
and treatment compliance. The treatment compliance will be presented by the following specific 
ranges for each treatment group for the double blind period: <80% and ≥80%. 
 
Listing of dose administration: including date/time, study day, number of injections, locations of 
injections, dosing information and whether or not the total dose is administered for each dose 
will be presented. 
 
If subjects received treatment different from the randomized treatment or stopped treatment due 
to an AE, or overdosed, the listings will be provided. 
 
5.6.         Treatment Exposure and Observation Period 
 
The duration of treatment during the study, in days, will be presented by treatment group and 
calculated as: 
 
(Date of last study drug injection– date of first study drug injection) + 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. 
 
The duration of exposure during the study will be summarized for each treatment group using 
number of patients, means, SD, minimums, Q1, medians, Q3, and maximums. 


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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. 
 
The duration of observation period during the study, in days, is calculated as: 
[Date of the last visit of double blind and follow up period – date of the first study injection] +1. 
The duration of observation period will be summarized descriptively as a quantitative data (n, 
mean, SD, median, Q1 and 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, ≥113 days, ≥141 days,  ≥169 days, 
≥197 days. 
 
5.7.         Analyses of Efficacy Variables 
 
5.7.1.         Hypothesis Testing and Multiplicity Control 
 
For all efficacy variables, the analysis will be a comparison of dupilumab and the placebo 
treatment groups. The following null and alternative hypotheses for the primary endpoint will be 
tested for dupilumab group and the placebo group: 
 
Let μ0  and μ1 be the population mean of the primary endpoint at week 10 under placebo and 
dupilumab, respectively. The hypothesis that will be tested is “H0: µ0 =µ1” versus “H1: µ0≠µ1”. 
 
To account for the impact of rescue medication on the efficacy effect during 12 week double 
blinded period: 
 
• Continuous efficacy endpoints: if a patient receives rescue medication, the data 
collected after rescue medication initiated will be treated as missing. 
 
• Categorical efficacy endpoints: responder data will be counted as non-responders 
after use of rescue medication or procedure. 
 
The analyses of efficacy variables are described in the subsections below and summarized in 
Appendix 10.1. 
 
There will be no adjustment of multiplicity for the secondary efficacy endpoints in this proof-of- 
concept study. 
 
The efficacy data endpoints for the follow-up period will be summarized descriptively.  No 
formal statistical test will be performed for efficacy endpoints in the follow-up period. 
 
5.7.2.         Analysis of Primary Efficacy Variables 
 
The change in the SDI score at week 10 from baseline will be analyzed in the full analysis set 
(FAS) using multiple imputation (MI), with an analysis of covariance (ANCOVA) model with 
treatment group as fixed effect, and the baseline SDI value as continuous covariate. (primary 
approach). 


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Due to the substantial imbalance at baseline in the number of patients in the two randomization 
strata (only 12.8% patients in the strata of baseline SDI > 7), the multiple imputation and 
ANCOVA model will not use randomization strata as a factor. 
 
Patients’ efficacy data through week 12 after  rescue medication usage will be set to missing first, 
and then be imputed by the MI method. 
 
Missing data from the FAS will be imputed 50 times to generate 50 complete data sets by using 
the SAS procedure MI following the 2 steps below: 
 
Step  1:  The  monotone  missing  pattern  is  induced  by  Markov  Chain  Monte  Carlo 
(MCMC) method in MI procedure. The monotone missing pattern means that if a patient 
has missing value for a variable at a visit, then the values at all subsequent visits for the 
same variable are all missing for the patient. 
 
Step 2: The missing data at subsequent visits will be imputed using the regression method 
for the monotone pattern with adjustment for covariates including treatment groups, and 
baseline SDI score. 
 
Data of each of the 50 complete datasets will be analyzed using an analysis of covariance 
(ANCOVA)  model  with  treatment  group  as  fixed  effect,  and  the  baseline  SDI  value  as 
continuous covariate. SAS MIANALYZE procedure will be used to generate valid statistical 
inferences by combining results from these multiple analyses using Rubin’s formula. 
 
The imputation model will include: 
 
• The covariates included in the ANCOVA model, including the treatment group and 
the baseline SDI value. 
 
•    Observed efficacy values from every clinic visit up to week 10 
 
The ANCOVA model will provide least-squares means at week 10, and at other time points for 
each treatment group, with the corresponding standard error, confidence interval, and the p-value 
for treatment comparisons. The graph of LS-mean +/- SE by visit will be provided. 
 
Sensitivity analyses 
 
In addition to the MI method described previously, sensitivity analyses for the primary efficacy 
endpoint will be conducted as described below: 
 
1.   The  sensitivity  analysis  will  use  MI  method,  followed  by  ANCOVA  based  on  all 
observed data no matter if rescue medication is used. 
 
2.   This sensitivity analysis will use ANCOVA model. The efficacy data will be set to 
missing after rescue medication is used. The post-baseline last-observed-case-forward 
(LOCF) method will then be used to impute missing values. 
 
3.   This sensitivity analysis will use ANCOVA model. The efficacy data will be set to 
missing after rescue medication is used. The post-baseline worst observation carried 
forward (WOCF) method will then be used to impute missing values. 
 
4.   This sensitivity analysis will use ANCOVA model, including all observed data, no matter 
if rescue medication is used. 


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5.7.3.         Analyses of Secondary Efficacy Variables 
 
The continuous secondary efficacy endpoints listed in Section 4.4.2 will be analyzed using the 
same approach as that used for the analysis of the primary endpoints. Inside step 2 of MI 
procedure, the missing data at subsequent visits will be imputed using the regression method for 
the monotone pattern with adjustment for covariates including treatment groups, baseline SDI 
score and relevant baseline value. Data of each of the 50 complete datasets will be analyzed 
using an analysis of covariance (ANCOVA) model with treatment group as fixed effect, and the 
baseline SDI value  and relevant baseline value as continuous covariates. 
 
Due to the substantial imbalance at baseline in the number of patients in the two randomization 
strata (only 12.8% patients in the strata of baseline SDI > 7), the imputation and ANCOVA will 
not use randomization strata as a factor. Instead the model includes the baseline SDI score as a 
continuous covarate. 
 
Categorical analyses will be performed on responder data.  Comparisons between dupilumab and 
placebo will be done using the Fisher exact test.  Patients with early withdrawals or use of rescue 
medication or procedure will be counted as non-responders. 
 
5.7.4.         Analyses of Exploratory Efficacy Variables 
 
The exploratory efficacy endpoints listed in Section 4.4.3 will be analyzed in the same method as 
the analysis method used for primary endpoint and secondary endpoint. 
 
5.7.5.         Subgroup Analysis 
 
Subgroups described in Section 3.6 for the primary and key secondary efficacy endpoints listed 
in  Section 4.4.1  and  Section 4.4.2  will  be  analyzed.  The  analysis  method  for  the  subgroup 
analysis will be conducted using the primary analysis of continuous and category endpoints 
described in Section 5.7.1 and Section 5.7.2.  Interactions between the subgroups and treatment 
groups will also be tested. 
 
5.8.         Analysis of Safety Data 
 
The summary of safety and tolerance will be performed based on SAF. 
 
The safety analysis will be based on the reported AEs, clinical laboratory evaluations, physical 
examination, vital signs, and 12-lead ECG. 
 
Thresholds for treatment-emergent Potentially Clinically Significant Values (PCSVs) in 
laboratory variables, vital signs and ECG are defined in Appendix 10.3. Treatment-emergent 
PCSV is any PCSV developed or worsened in severity compared to the baseline during the 
treatment and follow-up period. 
 
The time interval to detect any event or abnormality is between the first injection of study 
medication and EOS. 
 
5.8.1.         Analysis of Adverse Events 
 
The number and proportion of patients will be summarized separately for the week 12 treatment 
period, the follow-up period, and overall study period, described in Section 3.3. Adverse event 
(AE) incidence tables will be presented for each treatment group, including the number (n) and 


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percentage (%) of patients experiencing an AE, where multiple instances of the same event occur 
in the same patient the event will be counted only once for that patient. The denominator for 
computation of percentages is the number of patients in each treatment group. 
 
The number and proportion of patients reporting TEAEs will be summarized, sorted by 
decreasing frequency of SOC and PT for the dupilumab group. The number and proportions of 
patients reporting TEAEs will also be summarized, sorted by decreasing frequency of SOC, HLT 
and PT for the dupilumab group. 
 
Patient 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 
 
• Age/sex/race 
 
• System Organ Class (SOC) 
 
• High Level Term (HLT) 
 
• Preferred Term (PT) 
 
• Verbatim Term 
 
• AE start date and end date/ongoing (using both calendar days and study days) 
 
• AE Duration 
 
• Relationship of AE to study drug: unrelated or related 
 
• Action taken: Dose withdrawn temporarily, Dose reduced, Dose withdrawn 
permanently, Dose not changed, Not known 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 
 
Overall TEAE summary 
 
The overall summary of TEAEs will be provided with number and proportions of patients with 
any: 
 
• TEAE 
 
• TEAE related to study drug 
 
• Serious TEAE 
 
• TEAE of special interest (AESI) 
 
• TEAE leading to death 


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AESI 
 
• TEAE leading to permanent treatment discontinuation 
 
 
 
• Anaphylactic reactions 
 
• Acute allergic reactions that require immediate treatment 
 
• Severe injection site reactions that last longer than 24 hours 
 
• Mycosis fungoides 
 
• Cutaneous T-cell dyscrasia 
 
• Any severe infection 
 
• Any infection requiring treatment with parenteral antibiotics 
 
• Any infection requiring treatment with oral antibiotics/anti-viral/anti-fungal for 
longer than 2 weeks 
 
• Any clinical endoparasitisis 
 
• Any opportunistic infection 
 
• Suicidal behavior 
 
Appendix 10.5 provides a list of AESIs search criteria. 
TEAE Incidence 
Number and proportions of patients reporting TEAEs will be summarized for the following 
TEAEs: 
 
• TEAEs 
 
− TEAEs by SOC/PT 
 
− TEAEs by SOC/HLT/PT 
 
− TEAEs by PT 
 
− TEAEs by SOC/HLT/PT with HLT ≥5% in any treatment groups 
 
− TEAEs by SOC/PT with PT ≥5% in any treatment groups 
 
− TEAEs by severity by SOC/PT 
 
− Severe TEAEs by SOC/PT 
 
− Severe TEAEs by SOC/HLT/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 
 
• Serious TEAEs 


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− 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 
 
Summary of the most frequent (≥5%) TEAEs by SOC, HLT, PT, respectively, in the dupilumab 
groups and in the overall study population will be provided. 
 
SAEs/AESI during the Week 12 treatment period, follow-up period, and overall period will be 
listed. 
 
5.8.2.         Analysis of Clinical Laboratory Measurements 
 
Laboratory measurements include clinical chemistry, hematology and urinalysis results, and will 
be converted to standard international units and US conventional 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 abnormal lab value during study 
whose screening and baseline values are normal (overall and per each lab parameter) 
 
• The number (n) and percentage (%) of subjects with treatment-emergent PCSVs 
during study, depending on data 
 
• Shift tables based on baseline normal/abnormal may be used to present the results for 
parameters of interest 
 
Listing of all laboratory parameters value, normal range, abnormal flag and treatment-emergent 
PCSV by subject and visit will be provided. 
 
5.8.3.         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, 
depending on data 
 
• Shift tables based on baseline normal/abnormal may be used to present the results for 
parameters of interest 
 
Listings will be provided with flags indicating the treatment-emergent PCSVs, depending on 
data. 


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5.8.4.         Analysis of Physical Exams 
 
The number (n) and percentage (%) of subjects with abnormal physical exams will be 
summarized at time points according to the schedule in Appendix 10.2. by treatment group. A 
summary of treatment-emergent abnormal findings will be provided. 
 
5.8.5.         Analysis of 12-Lead ECG 
 
Summaries of 12-lead ECG parameters by treatment group will include: 
 
• Each ECG parameter and change from baseline 
 
• The number (n) and percentage (%) of subjects with PCSV, depending on data 
 
• ECG status (i.e. normal, abnormal) summarized by a shift table 
 
Listings will be provided with flags indicating PCSVs, depending on data. 
 
5.9.         Analysis of Pharmacokinetic Data 
 
Due to the sparse nature of the drug concentration data, only descriptive analyses will be 
performed. Concentrations will be summarized at each time point. Pharmacokinetic variables 
may include but not limited to Ctrough over time, Clast   and Tlast, as appropriate. Results will be 
described in the Clinical Pharmacology report. 
 
No formal statistical analysis will be performed. 
 
Impact of Drug Concentration on Safety and Efficacy 
 
The association of drug concentration and efficacy and/or safety endpoints may be performed, as 
appropriate. 
 
 
 
5.10.       Analysis of ADA Data 
 
The ADA variables described in Section 4.6 will be summarized using descriptive statistics by 
treatment arm in the ADA analysis set. Frequency tables of the proportion of patients with pre- 
existing immunoreactivity, treatment-emergent ADA response, persistent ADA response, and 
titers will be presented as absolute occurrence (n) and percent of patients (%), presented by 
treatment  groups.  Listing  of  all  ADA  titer  levels  and  neutralizing  antibody  status  will  be 
provided for patients with a positive response in the ADA assay. 
 
The following summaries will be performed on the AAS: 
 
• Number (%) of patients with pre-existing immunoreactivity, treatment-emergent 
ADA, and persistent ADA response by treatment group 
 
• Number (%) of patients with ADA peak titer achieved in each of the three ADA Titer 
value category (Low, Medium and High) as mentioned in Section 4.6, by treatment 
group 
 
 •  ADA peak titers using descriptive statistics (median, minimum and maximum) for 
treatment-emergent and persistent ADA response by treatment group 


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 •  ADA titers using descriptive statistics (median, minimum and maximum) by 
treatment group and at each ADA time point analyzed 
 
 •  Number (%) of patients with NAb status (negative or positive in the NAb assay) in 
treatment-emergent and persistent ADA response subjects by treatment group 
 
Association between ADA variables (e.g. ADA peak titer, treatment-emergent, persistent ADA 
responses, and NAb status) and functional dupilumab concentrations may also be explored. 
plotting and comparing mean functional dupilumab concentrations over time by ADA response 
(treatment emergent and persistent) and NAb status and by peak titer category. 
 
 
 
Impact of ADA on Safety and Efficacy 
 
Analysis of the association of of treatment emergent and persistent ADA response and NAb 
status with safety endpoints may be performed on SAF. 
 
The safety assessment will primarily focus on the following events: 
 
• Hypersensitivity (SMQ: Hypersensitivity [Narrow]) 
 
• Anaphylaxis (SMQ: Anaphylaxis [Narrow]) 
 
Number (%) of patients with the above mentioned safety events will be summarized by treatment 
emergent, persistent ADA response status and neutralizing antibody status during the TEAE 
period. 
 
Associations between ADA variables (e.g. ADA peak titer, treatment-emergent, persistent ADA 
responses  and  NAb  status),  and  efficacy endpoints  (clinical  response)  may be  explored  by 
plotting and comparing the mean % change from baseline in clinical response over time by ADA 
response (treatment emergent and persistent) and NAb status and by peak titer category. 


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6.            DATA CONVENTIONS 
 
The following analysis conventions will be used in the statistical analysis. 
 
6.1.         Definition of Baseline for Efficacy/Safety Variables 
 
Unless otherwise specified, the baseline assessment for all measurements will be the latest 
available valid measurement taken prior to the administration of study drug. If any randomized 
patients are not treated, the baseline will be the last value on or prior to the randomization. The 
following rules specify the determination by both date/time information: 
 
1.   For the AE, lab (including biomarker), drug concentration 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), drug concentration or ADA, only 
date of the measurement will be used to determine baseline by comparing with the first 
injection date. 
 
For the rescreened patients, all data from the same patient will be used to derive baseline 
regardless if the data is 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 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 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 investigational product is 
missing, it will be classified as “related” in the frequency tables by relation to the investigational 
product. 
 
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 


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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’. 
 
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 AE starting date imputation, 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 last 
study visit 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 
last study visit date instead. 
 
If AE end year is missing: Impute AE end date using the end of follow up 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. 


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Prior medication end date 
 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date on or after first dose intake date, use first dose intake date -1 
instead. Imputation flag is ‘D’. 
 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date on or after first dose intake date, use first dose intake date - 
1 instead. Imputation flag is ‘M’ 
 
If end year is missing: Impute end date using the first dose intake date –1. Imputation flag is ‘Y’. 
 
Concomitant medication start date 
 
The imputation rule for concomitant medication start date is the same as AE start date. 
Concomitant medication end date 
If end day is missing, and end month and year are not missing: Impute end date using the last day 
of the month. If this leads to a date after end of study follow up date, use the last visit study date 
instead. Imputation flag is ‘D’. 
 
If end month is missing, and end year is not missing: Impute end date using 31 December as the 
day and month. If this leads to a date after end of study follow up date, use the last study visit 
date instead. Imputation flag is ‘M’. 
 
If end year is missing: Impute date using the end of last study visit date. Imputation flag is ‘Y’. 
 
Medication coding 
 
Medications whose ATC level 4 cannot be coded will be summarized by setting ATC4=ATC2 in 
the table programs. However, these uncoded ATC level 4 records still need to be confirmed with 
study 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 Window 
 
Data analyzed by-visit-analysis (including efficacy, laboratory data, visit sign, ECG, ADA) will 
be summarized by the study scheduled visits described Appendix 10.2, “Schedule of Event”. The 
analysis visit windows will be exhaustive so that all available values obtained from unscheduled 
visits, early termination visit (ETV) and end of treatment (EOT)/end of study (EOS) have the 
potential to be summarized. No analysis visit windows will be applied for the study scheduled 
visits. 


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The following analysis visit windows will be used to map the unscheduled visits, ETV and EOT 
visits for weekly SDI and EEsAI, based on the study day during the double blind period: 
 
Visit 
No. 
visit 
Targeted 
Study Days* 
Analysis Window in Study 
Days 
1 
Screening 
<1 
<1 
2 
Baseline 
1 
1 
3 
Week 1 
8 
[2,11] 
4 
Week 2 
15 
[12,18] 
5 
Week 3 
22 
[19, 25] 
6 
Week 4 
29 
[26, 32] 
7 
Week 5 
36 
[33, 39] 
8 
Week 6 
43 
[40, 46] 
9 
Week7 
50 
[47, 53] 
10 
Week 8 
57 
[54, 60] 
11 
Week 9 
64 
[61, 67] 
12 
Week 10 
71 
[68, 74] 
13 
Week 11 
78 
[75, 81] 
14 
Week 12 (End of double 
blindTreatment) 
85 
[82, 88] 
15 
Week 13 
92 
[89, 95] 
16 
Week 14 
99 
[96, 102] 
17 
Week 15 
106 
[103, 109] 
18 
Week 16 
113 
[110, 116] 
19 
Week 17 
120 
[117, 123] 
20 
Week 18 
127 
[124, 130] 
21 
Week 19 
134 
[131, 137] 
22 
Week 20 
141 
[138, 144] 
23 
Week 21 
148 
[145, 151] 
24 
Week 22 
155 
[152, 158] 
25 
Week 23 
162 
[159, 165] 
26 
Week 24 
169 
[166, 172] 
27 
Week 25 
176 
[173, 179] 
28 
Week 26 
183 
[180, 186] 
29 
Week 27 
190 
[187, 193] 
30 
Week 28(End of follow-up 
period) 
197 
[>= 194] 
*Study days are calculated from 1st day of dupilumab injection during the double blind period. 


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Apr 12, 2017 
 
 
 
The following analysis visit windows will be used to map the unscheduled visits, ETV and EOT 
visits for EoE-QOL-A questionnaire, based on the study day during the double blind period: 
 
Visit 
No. 
visit 
Targeted 
Study Days* 
Analysis Window in Study 
Days 
1 
Screening 
<1 
<1 
2 
Baseline 
1 
1 
3 
Week 4 
29 
[2, 43] 
4 
Week 8 
57 
[44, 71] 
5 
Week 12 (End of double 
blindTreatment) 
85 
[72, 88] 
6 
Week 16 
113 
[89, 127] 
7 
Week 20 
141 
[128, 155] 
8 
Week 24 
169 
[156, 183] 
9 
Week 28 (End of follow-up 
period) 
197 
>=184 
*Study days are calculated from 1st day of dupilumab injection during the double blind period. 
 
 
 
The following analysis visit windows will be used to map the unscheduled visits, ETV and EOT 
visits for endoscopy related efficacy variables, based on the study day during the double blind 
period: 
 
Visit 
No. 
visit 
Targeted 
Study Days* 
Analysis Window in Study 
Days 
1 
Screening 
<1 
<1 
2 
Baseline 
1 
1 
3 
Week 12 (End of double 
blindTreatment) 
85 
[2, 99] 
*Study days are calculated from 1st day of dupilumab injection during the double blind period. 
 
 
 
The following analysis visit windows will be used to map the unscheduled visits, ETV and EOT 
visits for lab, based on the study day during the double blind period: 
 
Visit 
No. 
visit 
Targeted 
Study Days* 
Analysis Window in Study 
Days 
1 
Screening 
<1 
<1 
2 
Baseline 
1 
1 
3 
Week 2 
15 
[2, 22] 
4 
Week 4 
29 
[23, 43] 
5 
Week 8 
57 
[44, 71] 
6 
Week 12 (End of double 
blindTreatment) 
85 
[72, 88] 
7 
Week 16 
113 
[89, 127] 
8 
Week 20 
141 
[128, 155] 
9 
Week 24 
169 
[156, 183] 


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Regeneron Pharmaceuticals, Inc. 
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Apr 12, 2017 
 
 
 
10 
Week 28 (End of follow-up 
period) 
197 
>=184 
*Study days are calculated from 1st day of dupilumab injection during the double blind period. 
 
 
 
The following analysis visit windows will be used to map the unscheduled visits, ETV and EOT 
visits for vital sign, Physical examination and ECG, based on the study day during the double 
blind period: 
 
Visit 
No. 
Visit 
Targeted 
Study Days* 
Analysis Window in Study 
Days 
1 
Screening 
<1 
<1 
2 
Baseline 
1 
1 
3 
Week 12 (End of double 
blindTreatment) 
85 
[2, 88] 
4 
Week 28 (End of follow-up 
period) 
197 
>=88 
*Study days are calculated from 1st day of dupilumab injection during the double blind period. 
 
 
 
The following analysis visit windows will be used to map the unscheduled visits, ETV and EOT 
visits for body weight , based on the study day during the double blind period: 
 
Visit 
No. 
visit 
Targeted 
Study Days* 
Analysis Window in Study 
Days 
1 
Screening 
<1 
<1 
2 
Baseline 
1 
1 
3 
Week 1 
8 
[2,11] 
4 
Week 2 
15 
[12,18] 
5 
Week 3 
22 
[19, 25] 
6 
Week 4 
29 
[26, 43] 
7 
Week 8 
57 
[44, 71] 
8 
Week 12 (End of double 
blindTreatment) 
85 
[72, 88] 
9 
Week 16 
113 
[89, 127] 
10 
Week 20 
141 
[128, 155] 
11 
Week 24 
169 
[156, 183] 
12 
Week 28 (End of follow-up 
period) 
197 
>=184 
*Study days are calculated from 1st day of dupilumab injection during the double blind period. 


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Statistical Analysis Plan 
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Apr 12, 2017 
 
 
 
In general, the following order will be used to select the record for analysis at given visit: 
 
1.   Scheduled visit 
 
2.   Early termination (ET) or end of study (EOS), whichever comes first if scheduled visit 
not available 
 
3.   Unscheduled visit if both scheduled visit and ETV/EOT/EOS are not available 
 
For the multiple measurements of the same test in the same window, the following rules will be 
used to pick up the analysis value: 
 
• If multiple valid values of a variable 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 the ePRO data collected daily via IVRS, the analysis visit windows will be implemented 
following the procedures below: 
 
Step 1: Derive the study day, 
 
• If diary date ≥ 1st injection date, then diary study day=diary date – 1st injection date 
+1; 
 
• Otherwise diary study day=diary date – 1st injection date 
 
Step 2: Windows are defined as -6 to 1 = BL, 2 to 8 = week 1, 9 to 15 = week 2, etc, with 7 days 
interval between visit windows. 


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Apr 12, 2017 
 
 
 
 
7.            INTERIM ANALYSIS 
 
No formal interim analysis is planned. 
 
There will be 2 database locks for this study. The first database lock will occur when the last 
patient completes the week 12 visit. The analyses of  primary and secondary efficacy endpoints 
at the first database lock are considered  the final analyses. The second database lock will occur 
when the last patient completes the last visit of the study. For the first database lock, a designated 
unblinding team (eg, statisticians, SAS programmers, etc.) that is not involved in the conduct of 
the study will perform the analysis of week 12 outcomes. The study conduct will not be affected 
by the unblinded week-12 results. The analysis results will be made available only to a limited 
group of people who are not involved in the daily conduct of the study. Individuals involved in 
the continuing conduct of the study will remain blinded until after the final database lock. 
Following the second database lock, efficacy and safety results during the follow-up period will 
be summarized. 
 
 
8.            SOFTWARE 
 
All analyses will be done using SAS Version 9.2 or above. 


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Apr 12, 2017 
 
 
 
 
 
9.            REFERENCES 
 
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. 
 
Falk GW. Clinical presentation of eosinophilic esophagitis in adults. Gastroenterology Clinics of 
North America. 2014 Jun;43(2):231-42. PubMed PMID: 24813512. 
 
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. 
 
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. 
 
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, 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. 
 
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. 
 
Zhang Z, Sferra TJ, Eroglu Y. T cell co-stimulatory molecules: a co-conspirator in the 
pathogenesis      of      eosinophilic      esophagitis?      Digestive      Diseases      and      Sciences. 
2013 Jun;58(6):1497-506. PubMed PMID: 23456499. 


Regeneron Pharmaceuticals, Inc. 
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10. 
APPENDIX 
 
10.1. 
Summary of Statistical Analyses 
 
Efficacy Analysis: 
 
Endpoint 
Analysis 
Population 
Primary Statistical Method 
Supportive/Sensitive 
Statistical Method 
Subgroup 
Analysis 
Other Analyses 
Change  in  the  SDI  score  at 
week 10 from baseline 
FAS 
MI + ANCOVA 
MI+ANCOVA 
regardless of 
rescue, ANCOVA 
on LOCF, WOCF 
and OC, and 
primary efficacy 
analysis on PPS 
Yes 
Line plot 
Secondary continuous variables 
FAS 
MI + ANCOVA 
NO 
No 
Line plot 
Categorical variables 
FAS 
Fisher exact test / define 
missing as treatment failure 
No 
Histogram 


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Safety Analyses: 
 
Endpoint 
Analysis 
Populations 
Statistical 
Method 
Supportive 
Analysis 
Subgroup 
Analysis 
Other 
Analyses 
Adverse Events 
SAF 
Descriptive statistics 
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 


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10.2. 
Schedule of Events 
 
Table 1: 
Schedule of Events – Screening and Treatment Period 
 
Study Procedures 
Screening 
Treatment Period 
In-Clinic Visit (V) or 
Telephone Visit (TV) 
Screening 
V1 
Baseline 
V2 
V3 
V4 
V5 
V6 
TV71 
TV81 
TV91 
V10 
TV111 TV121 TV131 
EOT 
V14 
Week (Wk) 
Wk1 
Wk2 
Wk3 
Wk4 
Wk5 
Wk6 
Wk7 
Wk8 
Wk9 
Wk10 
Wk11 
Wk12 
Day (D) D-35 to D-1 
D1 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D64 
D71 
D78 
D85 
Visit Window in days (d) 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
Screening/Baseline: 
Informed consent2 
X 
Inclusion/exclusion 
X 
X 
Medical history/demographics/height 
X 
Randomization 
X 
Treatment: 
Training for self-injection3 
X 
X 
X 
X 
X 
Administer study drug 
X4 
X4 
X4 
X4 
X4 
X1 
X1 
X1 
X4 
X1 
X1 
X1 
Con meds/procedures 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy:5 
SDI/EEsAI (PRO), 6,7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
EoE-QOL-A (PRO) 7,8 
X 
X 
X 
X 
EoE-EREFS9 
X 
X 
Safety:5 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X10 
X 
Diet History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination; ECG 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Study Procedures 
Screening 
Treatment Period 
In-Clinic Visit (V) or 
Telephone Visit (TV) 
Screening 
V1 
Baseline 
V2 
V3 
V4 
V5 
V6 
TV71 
TV81 
TV91 
V10 
TV111 TV121 TV131 
EOT 
V14 
Week (Wk) 
Wk1 
Wk2 
Wk3 
Wk4 
Wk5 
Wk6 
Wk7 
Wk8 
Wk9 
Wk10 
Wk11 
Wk12 
Day (D) D-35 to D-1 
D1 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D64 
D71 
D78 
D85 
Visit Window in days (d) 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
±3 d 
Laboratory Testing:5 
Hematology and serum chemistry 
X 
X 
X 
X 
X 
X 
Coagulation11 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
HBsAg and hepatitis C Ab 
X 
Pregnancy testing 
Serum 
Urine 
Urine 
Urine 
Urine 
Serum FSH to confirm menopausal 
status 
X 
Endoscopy with esophageal biopsies12 
X13 
X 
Serum total IgE 
X 
Research samples (serum/plasma) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK and ADA Testing:5 
PK sample 
X 
X 
X 
X 
X 
X 
X 
ADA sample 
X 
X 
ADA = anti-drug antibody; ECG = electrocardiogram; EEsAI = Eosinophilic Esophagitis Activity Index; EoE-EREFS = Eosinophilic Esophagitis-Endoscopic 
Reference Score; EoE-QOL-A = Adult Eosinophilic Esophagitis Quality of Life (questionnaire); EOT = end of treatment; PK = pharmacokinetic; 
PRO = patient-reported outcome; SDI = Straumann Dysphagia Instrument; TV = telephone visit; V = visit. 
 
1  The site will contact the patient by telephone to conduct these visits. The patient/caregiver will self-administer study drug outside clinic on these days. Patients 
will complete a dosing diary to document compliance with self-injection of study drug and to document any ISRs and concomitant medications. Patients may 
return to the clinic on a weekly basis if unable to self-administer study drug. 


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3  Patients and/or caregivers will be trained on self-administration of study drug. Patients will be closely monitored at the study site at visits 2, 3, 4, 5, and 6 for a 
minimum of 30 minutes after the administration of study drug. In addition to the predose assessments, AEs will be assessed at 30 minutes (±10 minutes) 
postdose. 
4  On scheduled in-clinic study visit days, the study drug will be administered in the clinic (by site staff, the patient, or a caregiver). 
5  Assessments will be performed before the administration of study drug. 
6  Questionnaires will be completed before any other assessments or procedures. 
7  The SDI/EEsAI PROs should be done by the patient electronically, weekly for SDI, and daily and weekly for EEsAI from the begi nning of screening through 
EOS or ET. Site should confirm patient compliance at each clinic visit. 
8  The EoE-QOL-A PRO should be recorded at baseline and then monthly through EOS or ET. 
9  EoE-EREFS should be completed when endoscopy with esophageal biopsies procedure is performed. 
10 Vital signs at predose and 30 (±10) minutes postdose. 
11 Coagulation tests should be performed before the procedure of endoscopy with esophageal biopsies on days the procedure is per formed. 
12 The EndoFLIP procedure, with photographs, to measure esophageal distensibility will be performed during the endoscopy procedures. 
13 Screening endoscopy with esophageal biopsies, and photographs are to be performed during screening period to allow results to be available prior to day -1. 


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Table 2: 
Schedule of Events – Follow-up Period 
 
Study Procedures 
Follow-Up Period 
ET Visit 
(if applicable) 
In-Clinic Visit (V) 
V15 
V16 
V17 
EOS Visit 
V18 
Week (Wk) 
Wk16 
Wk20 
Wk24 
Wk28 
Day (D) 
D113 
D141 
D169 
D197 
Visit Window in days (d) 
±3 d 
±3 d 
±3 d 
±3 d 
Treatment: 
Concomitant medications/procedures 
X 
X 
X 
X 
X 
Efficacy: 
SDI/EEsAI (PRO)1,2 
X 
X 
X 
X 
X 
EoE-QOL-A (PRO)1,3 
X 
X 
X 
X 
X 
EoE-EREFS 4 
X 
Safety: 
Weight 
X 
X 
X 
X 
X 
Diet History 
X 
X 
X 
X 
X 
Physical examination; ECG 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
Laboratory Testing: 
Hematology and serum chemistry 
X 
X 
X 
X 
X 
Coagulation 
X 
Urinalysis 
X 
X 
X 
X 
X 
Pregnancy testing 
Urine 
Serum 
Serum 
Endoscopy with esophageal biopsies 5 
X 
Research samples (serum/plasma) 
X 
X 
PK and ADA Testing: 
PK sample 
X 
X 
X 
X 
X 
ADA sample 6 
X 6 
X 6 


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ADA = anti-drug antibody; ECG = electrocardiogram; EEsAI = Eosinophilic Esophagitis Activity Index; EoE-EREFS = Eosinophilic Esophagitis-Endoscopic 
Reference Score; EoE-QOL-A = Adult Eosinophilic Esophagitis Quality of Life (questionnaire); EOS = end of study; ET = early termination; 
PK = pharmacokinetic; PRO = patient-reported outcome; SDI = Straumann Dysphagia Instrument. 
1  Questionnaires will be completed before any other assessments or procedures. 
2  The SDI/EEsAI PROs should be done by the patient electronically, weekly for SDI, and daily and weekly for EEsAI from the begi nning of screening through 
EOS or ET. Site should confirm patient compliance at each clinic visit. 
3  The EoE-QOL-A PRO should be recorded at baseline and then monthly through EOS or ET. 
4  EoE-EREFS should be completed when endoscopy with esophageal biopsies procedure is performed. 
5  The EndoFLIP procedure, with photographs, to measure esophageal distensibility will be performed during the endoscopy procedures. 


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10.3. 
Criteria for Treatment-Emergent Potentially Clinical Significant 
  
Value (PCSV) for Dupilumab studies  
 
Parameter 
Treatment Emergent PCSV 
Comments 
 
Clinical Chemistry 
 
ALT* 
>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 
 
Enzyme activity must be expressed in ULN, 
not in IU/L. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Each category is calculated independently. 
* At least one level is required, multiple 
levels are optional for phase 2/3 studies. If it 
is desirable to get the distribution across the 
different PCSV levels, additional shift table 
on ≤3, >3 to ≤5, > 5 to ≤10, >10 to ≤20, and 
> 20 category for baseline vs. post baseline 
may be provided 
 
AST* 
>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 
 
Enzyme activity must be expressed in ULN, 
not in IU/L. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
Each category is calculated independently. 
* At least one level is required, multiple 
levels are optional for phase 2/3 studies. If it 
is desirable to get the distribution across the 
different PCSV levels, additional shift table 
on ≤3, >3 to ≤5, > 5 to ≤10, >10 to ≤20, and 
> 20 category for baseline vs. post baseline 
may be provided 
 
Alkaline 
Phosphatase 
 
>1.5 ULN and baseline ≤ 1.5 ULN 
Enzyme activity must be expressed in ULN, 
not in IU/L. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
 
 
Total Bilirubin* 
>1.5 and ≤ 2 ULN and baseline ≤ 1.5 ULN* 
>2 ULN and baseline ≤ 2.0 ULN 
Must be expressed in ULN, not in µmol/L or 
mg/L. Categories are cumulative. 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
* At least one level is required, multiple 
levels are optional for phase 2/3 studies. If it 
is desirable to get the distribution of 
significant level, additional shift table on 
≤1.5, >1.5 to ≤2.0 and > 2.0 category for 
baseline vs. post baseline may be provided 
 
Conjugated 
 
(Direct Bilirubin >35% Total Bilirubin and 
 
Conjugated bilirubin dosed on a case-by-case 
Bilirubin 
Total Bilirubin >1.5 ULN) and (Direct Bilirubin basis. 
<=35% Total Bilirubin or Total Bilirubin 
<=1.5 ULN) at baseline 


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Parameter 
Treatment Emergent PCSV 
Comments 
 
ALT and Total 
Bilirubin 
 
(ALT>3 ULN and TBILI>2 ULN) and baseline 
(ALT <=3 ULN or TBILI <=2 ULN) 
 
Concept paper on DILI – FDA draft Guidance 
Oct 2007. 
 
 
CPK* 
>3 and ≤ 10 ULN and baseline ≤ 3ULN* 
>10 ULN and baseline ≤ 10ULN 
FDA Feb 2005. 
Am J Cardiol April 2006. 
Categories are cumulative. 
* At least one level is required, multiple 
levels are optional for phase 2/3 studies. If it 
is desirable to get the distribution of 
significant level, additional shift table on ≤3, 
>3 to ≤10, and > 10 category for baseline vs. 
post baseline may be provided 
 
Creatinine 
≥150 μmol/L (Adults) and baseline < 150 
μmol/L 
>=30% change from baseline and <100% 
change from baseline 
≥100% change from baseline 
 
Uric Acid 
Benichou C., 1994. 
3 independent criteria 
 
 
 
 
 
Harrison- Principles of internal Medicine 17th 
Hyperuricemia 
Hypouricemia 
>408 μmol/L and <=408 μmol/L at baseline 
<120 μmol/L and >= 120 μmol/L at baseline 
Ed., 2008. 
Two independent criteria 
 
Blood Urea 
Nitrogen 
≥17 mmol/L and <17 mmol/L at baseline 
Two independent criteria 
 
Chloride 
Hypochloremia 
Hyperchloremia 
 
 
<80 mmol/L and baseline ≥ 80 mmol/L 
>115 mmol/L and baseline ≤ 115 mmol/L 
 
Two independent criteria 
 
Sodium 
Hyponatremia 
Hypernatremia 
 
 
≤129 mmol/L and baseline > 129 mmol/L 
≥160 mmol/L and baseline <160 mmol/L 
 
Two independent criteria 
 
Potassium 
Hypokalemia 
Hyperkalemia 
 
 
<3 mmol/L and baseline ≥ 3 mmol/L 
≥5.5 mmol/L and baseline <5.5 mmol/L 
FDA Feb 2005. 
Two independent criteria 
 
Total Cholesterol  ≥7.74 mmol/L and < 7.74 mmol/L at baseline 
Threshold for therapeutic intervention. 
 
Triglycerides 
≥4.6 mmol/L and < 4.6 mmol/L at baseline 
Threshold for therapeutic intervention. 
 
Glucose 
Hypoglycaemia 
Hyperglycaemia 
 
 
(≤3.9 mmol/L and <LLN) and (>3.9 mmol/L or 
>=LLN) at baseline 
≥11.1 mmol/L (unfasted); ≥7 mmol/L (fasted) 
and < 11.1 mmol/L (unfasted); <7 mmol/L 
(fasted) at baseline 
 
 
ADA May 2005. 
ADA Jan 2008. 
 
HbA1c 
>8% and <= 8% at baseline 


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Parameter 
Treatment Emergent PCSV 
Comments 
 
Albumin 
≤25 g/L and >25 g/L at baseline 
 
CRP 
>2 ULN or >10 mg/L (if ULN not provided) and 
<=2 ULN or <=10 mg/L (if ULN not provided) 
at baseline 
FDA Sept 2005. 
 
Hematology 
 
WBC 
<3.0 Giga/L and >=3.0 Giga/L at baseline (Non- Increase in WBC: not relevant. 
Black); 
<2.0 Giga/L and >=2.0 Giga/L at baseline 
(Black) 
≥16.0 Giga/L and < 16 Giga/L at baseline 
 
To be interpreted only if no differential count 
available. 
 
Lymphocytes 
>4.0 Giga/L and <= 4.0 Giga/L at baseline 
 
Neutrophils 
<1.5 Giga/L and >=1.5 Giga/L at baseline (Non- International Consensus meeting on drug- 
Black); 
<1.0 Giga/L and >=1.0 Giga/L at baseline 
(Black) 
induced blood cytopenias, 1991. 
FDA criteria. 
 
Monocytes 
>0.7 Giga/L <= 0.7 Giga/L at baseline 
 
Basophils 
>0.1 Giga/L <= 0.1 Giga/L at baseline 
 
Eosinophils 
(>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 
 
 
 
 
Harrison- Principles of internal Medicine 17th 
Ed., 2008. 
 
Three criteria are independent. 
 
 
 
Criteria based upon decrease from baseline 
are more relevant than based on absolute 
value. Other categories for decrease from 
baseline can be used (≥30 g/L, ≥40 g/L, 
≥50 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 forFemale 
≥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 
Two Criteria are independent 
 
RBC 
Female 
<3 Tera/L and baseline ≥3 Tera/L 
≥6 Tera/L and baseline < 6 Tera/L 
Male 
<4 Tera/L and baseline ≥4 Tera/L 
≥7 Tera/L and baseline < 7 Tera/L 
Unless specifically required for particular 
drug development, the analysis is redundant 
with that of Hb. 
Otherwise, consider FDA criteria. 
 
Platelets 
<100 Giga/L and >=100 Giga/L at baseline 
≥700 Giga/L and < 700 Giga/L at baseline 
International Consensus meeting on drug- 
induced blood cytopenias, 1991. 
Two independent criteria 


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Apr 12, 2017 
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VV-RIM-00013092-1.0 Approved - 14 Apr 2017 GMT-5:00 
 
 
 
Parameter 
Treatment Emergent PCSV 
Comments 
 
Urinalysis 
 
pH 
≤4.6 and > 4.6 at baseline 
≥8 and < 8 at baseline 
 
Two independent criteria 
 
Vital signs 
 
HR 
≤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 
 
 
To be applied for all positions (including 
missing) except STANDING. 
 
To be applied for all positions (including 
missing) except STANDING. 
 
DBP 
≤45 mmHg and decrease from baseline ≥10 
mmHg 
≥110 mmHg and increase from baseline ≥10 
mmHg 
To be applied for all positions (including 
missing) except STANDING. 
 
Weight 
≥5% increase from baseline 
≥5% decrease from baseline 
FDA Feb 2007. 
ECG 
 
Ref.: CPMP 1997 guideline. 
HR 
≤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 
 
QRS 
≥120 ms & < 120 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 
≥500 ms and < 500 ms at baseline 
 
 
Increase from baseline 
Borderline: Increase from baseline 30-60 ms 
Prolonged: Increase from baseline >60 ms 
To be applied to any kind of QT correction 
formula. 
 
 
 
 
 
*QTc prolonged and QTc>60 ms are the 
PCSA to be identified in individual 
subjects/patients listings. 
 
 
5 independent criteria 


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10.4. 
Search Criteria for TEAE of Special Interest/TEAE Syndrome 
AESI 
Search Criteria 
Anaphylactic reactions 
Narrow SMQ for “anaphylactic reaction” 
Acute allergic reactions 
that require treatment 
• Narrow SMQ for “hypersensitivity” 
• TEAE occurred due to the medication taken  and 
recoded on ConMed CRF page 
Note: Blinded manual adjudication of relevant PTs will be 
required by the study medical monitor,  before database 
locks 
Severe ISRs that last 
longer than 24 hours 
-HLT = Injection site reactions 
- Severity = “severe” 
Mycosis fungoides or 
other forms of cutaneous 
T cell lymphoma 
-HLT = “Mycosis fungoides” 
• Includes LLT = Sezary syndrome 
• Includes LLT = Cutaneous T-cell lymphoma 
-PT = “Cutaneous T-cell dyscrasia 
Any severe infection 
-SOC = Infections and infestations 
-Severity = “severe 
Any infection requiring 
treatment with parenteral 
antibiotics 
-SOC = Infection and infestations 
-Action taken for AE = “medication” 
- ConMed: ATC3= “Antiinfectives” during the TEAE 
course (between start and stop dates), Route = IV, IM 
Any infection requiring 
treatment with oral 
antibiotic/anti-viral/anti- 
fungal for longer than 2 
weeks 
-SOC = Infection and infestations 
-Action taken for AE = “medication” 
-Check CM: ATC3= “Antiinfectives” during the TEAE 
course (between start and stop dates), Route = PO and 
Treatment duration >14 days 
Any clinical 
endoparasitosis 
-HLT = Cestode infections 
-HLT = Helminthic infections NEC 
-HLT = Nematode infections 
-HLT = Trematode infection 
Any opportunistic 
infectiona 
The following HLTs plus PTs 
-HLT = Pneumocystis infection 
-HLT* = Fungal infections NEC 
-HLT* = Pseudallescheria infections 
-HLT = Herpes viral infections 
-HLT = Paracoccidioides infections 


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-HLT = Sporothrix infections 
-HLT = Cryptosporidia infections 
-HLT* = Trypanosomal infections 
-HLT* = Campylobacter infections 
-HLT* = Shigella infections 
-HLT* = Vibrio infections 
Plus the following PTs 
-Polyomavirus-associated nephropathy 
-BK virus infection 
-Cytomegalovirus infection 
-Post transplant lymphoproliferative disorder 
-Progressive multifocal leukoencephalopathy 
-*Bartonellosis 
-Blastomycosis 
-Toxoplasmosis 
-Coccidioidomycosis 
-Histoplasmosis 
-*Aspergillus infection 
-Systemic candida 
-Oropharyngeal candidiasis 
-Cryptococcosis 
-Listeriosis 
-Tuberculosis 
-Nocardiosis 
-Mycobacterial infection 
-*Salmonellosis 
-*Hepatitis B 
-Herpes zoster 
-*Strongyloidiasis 
-Microsporidia infection 
-Visceral leishmaniasis 
-*Hepatitis C 
Note: *Blinded manual adjudication of relevant PTs under 
each of HLTs listed above will be required by the study 
medical monitor,  before database locks 
Suicidal behavior 
Include the following PTs 
-Completed suicide 
-Suicidal ideation 
a  The definition of opportunistic infections is referring to the recent consensus guidance for opportunistic infections 
in the setting of biologic therapy ( K L Winthrop et al, 2015) 


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Apr 12, 2017 
CONFIDENTIAL 
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VV-RIM-00013092-1.0 Approved - 14 Apr 2017 GMT-5:00 
 
 
 
10.5. 
EEsAI Score 
 
The tables and fomular below are used to calculate the EEsAI score. 
Weekly EEsAI score 
Item 
Score (total 
set to 100) 
Frequency of trouble swallowing 
Never 
0 
1–3 times/wk 
15 
4–6 times/wk 
27 
Daily 
31 
Duration of trouble swallowing 
<=5 min 
0 
>5 min 
6 
Pain when swallowing 
No 
0 
Yes 
15 
VDQ score 
0 
0 
0.1–2.5 
12 
2.6–5.0 
19 
5.1–7.5 
21 
7.6–10.0 
23 
AMS score 
0 
0 
0.1–2.5 
0 
2.6–5.0 
0 
5.1–7.5 
9 
7.6–10.0 
25 
Total 
100 


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Apr 12, 2017 
CONFIDENTIAL 
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VV-RIM-00013092-1.0 Approved - 14 Apr 2017 GMT-5:00 
 
 
 
Daily EEsAI score 
 
Item 
Score (total 
set to 100) 
Frequency of trouble swallowing 
Never 
0 
Present 
11 
Duration of trouble swallowing 
<=5 min 
0 
>5 min 
14 
Pain when swallowing 
No 
0 
Yes 
6 
VDQ score 
0 
0 
0.1–2.5 
1 
2.6–5.0 
17 
5.1–7.5 
27 
7.6–10.0 
51 
AMS score 
0 
0 
0.1–2.5 
0 
2.6–5.0 
0 
5.1–7.5 
2 
7.6–10.0 
18 
Total 
100 
 
1. VDQ score - one should get a number from 0 to 10. 
VDQ = 10∗ (N1 ∗ 1 + N2 ∗ 2 + N3 ∗ 3)/(D ∗ 3)
 
Where: 
1. N1 = number of food consistencies graded with ‘Mild difficulties’ 
2. N2 = number of food consistencies graded with ‘Moderate difficulties’ 
3. N3 = number of food consistencies graded with ‘Severe difficulties’ 
4. D = number of relevant food consistencies (different than ‘Not applicable’) 
 
2. AMS score - one should get a number from 0 to 10. 
AMS = 10∗ (N1 ∗ 1 + N2 ∗ 2 + N3 ∗ 3+ N4 ∗ 5)/(D ∗ 5)
 
Where: 
1. N1 = number of food consistencies with ‘Yes’ to ‘Eating slowly’ only 
2. N2 = number of food consistencies with ‘Yes’ to ‘Modification’ only 
3. N3 = number of food consistencies with ‘Yes’ to both ‘Eating slowly’ and 
‘Modification’ 
4. N4 = number of food consistencies with ‘Yes’ to ‘Avoidance’ only 
5. D = number of relevant food consistencies (different than ‘Not applicable’) 


Regeneron Pharmaceuticals, Inc. 
Statistical Analysis Plan 
R668-EE-1324 
Apr 12, 2017 
VV-RIM-00013092-1.0 Approved - 14 Apr 2017 GMT-5:00 
 
 
 
 
10.6. 
Medication for RESCUE TREATMENTS 
 
The medications given post-baseline are considered rescue Medication. 
 
Therapeutic Class 
Chemical Class 
ANTINEOPLASTIC AGENTS 
MONOCLONAL ANTIBODIES 
Check if patient 
took Omalzumab 
(Anti IgE) 
CORTICOSTEROIDS FOR 
SYSTEMIC USE 
GLUCOCORTICOIDS 
Except route of 
administration as 
topical 
DRUGS FOR ACID RELATED 
DISORDERS 
PROTON PUMP INHIBITORS 
DRUGS FOR OBSTRUCTIVE 
AIRWAY DISEASES 
GLUCOCORTICOIDS 
Except route of 
administration as 
topical 
DRUGS FOR OBSTRUCTIVE 
AIRWAY DISEASES 
LEUKOTRIENE RECEPTOR 
ANTAGONISTS 
IMMUNOSUPPRESSANTS 
INTERLEUKIN INHIBITORS 
Check if patient took 
Anti IL5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
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Signature Page for VV-RIM-00013092 v1.0 Approved