Clinical trial NCT04682639
Conditions: Eosinophilic Esophagitis
Keywords: Eosinophilic esophagitis Esophageal eosinophilia Etrasimod APD334 EoE Eosinophilic oesophagitis
Sponsor: Pfizer
Start date: 2020-12-15; Completion date: 2023-06-30
Enrollment: 108 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to determine whether oral etrasimod is a safe and effective treatment for active eosinophilic esophagitis (EoE) in adult participants.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: Participants will receive etrasimod matching placebo tablet during the Double-Blind Treatment Period and etrasimod tablet during the Extension Treatment Period.
Interventions: intervention 1: Etrasimod intervention 2: Placebo intervention 3: Etrasimod
Intervention descriptions: intervention 1: Participants will receive etrasimod tablet by mouth, once daily during the 24-week Double-Blind and 28-week Extension Treatment Periods. intervention 2: Participants will receive etrasimod matching placebo tablet by mouth, once daily during the 24-week Double-Blind Treatment Period. intervention 3: Participants will receive etrasimod tablet by mouth, once daily during the 28-week Extension Treatment Period.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Protocol title:
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Assess 
the Safety and Efficacy of Etrasimod in Adult Subjects with Eosinophilic 
Esophagitis
Protocol number:
APD334-206 (C5041009)
Version:
Amendment 3.0, dated 04 January 2023
Compound name or 
number:
Etrasimod (APD334)
Study phase:
2
Indication:
Eosinophilic esophagitis
EudraCT number:
2020-003226-23
Sponsor name:
Arena Pharmaceuticals, Inc., a wholly owned subsidiary of Pfizer Inc.
Sponsor approval:
This protocol was approved by the Sponsor’s Responsible Medical Officer 
or delegate. The electronic signature manifest is appended.
Confidentiality Statement
This document contains confidential information of Arena Pharmaceuticals, Inc, a wholly owned 
subsidiary of Pfizer Inc. Unauthorized distribution, copying, or disclosure is strictly prohibited 
unless required by applicable law. Persons receiving this information must be notified that it is 
confidential and may not be further distributed, copied, or disclosed.


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PROTOCOL HISTORY
Document
Amendment Type
Date
Amendment 3.0
Global
04 January 2023
Amendment 2.1
Regional
22 October 2021
Amendment 2.0
Global
20 October 2021
Amendment 1.1
Regional
24 March 2021
Amendment 1.0
Global
24 September 2020
Original 0.0
Not applicable
10 July 2020


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PROTOCOL SYNOPSIS
Sponsor: Arena Pharmaceuticals, Inc.
Name of Investigational Study Drug: APD334 (etrasimod)
Protocol Title: A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Assess 
the Safety and Efficacy of Etrasimod in Adult Subjects with Eosinophilic Esophagitis
Protocol Number: APD334-206
Phase: 2
Countries/Regions (planned): North America, European Union, Australia
Objectives:
Primary:

To evaluate the effects of etrasimod on esophageal eosinophilia in adult subjects with 
active eosinophilic esophagitis (EoE)

To evaluate the dose-response relationship of 2 doses of etrasimod versus placebo in adult 
subjects with active EoE

To select an etrasimod dose based on efficacy and safety for continued development
Secondary:

To evaluate the effect of etrasimod on dysphagia symptoms in adult subjects with active 
EoE
Study Design:
This Phase 2, randomized, double-blind, multi-center study will evaluate the efficacy, safety, 
and pharmacokinetics (PK) of etrasimod compared with placebo in adults with active EoE.
The study will consist of a Screening Period of up to 35 days, 24 weeks of double-blind 
treatment (Double-Blind Treatment Period), 28 weeks of active extended treatment (Extension 
Treatment Period), and 4 weeks of follow-up (Safety Follow-Up Period) for a total study 
duration of up to 61 weeks.
Eligible subjects will be randomized in a double-blind fashion (3:3:2 ratio) to etrasimod 1 mg, 
etrasimod 2 mg, or matching placebo once daily. Randomization will be stratified by baseline 
history of esophageal dilation (yes/no) and concurrent proton pump inhibitor (PPI) therapy 
(yes/no).
All subjects who complete the Double-Blind Treatment Period and meet eligibility criteria for 
the Extension Treatment Period may enter the Extension Treatment Period. Subjects who were 
in the etrasimod 1 mg or etrasimod 2 mg groups in the Double-Blind Treatment Period will 
continue the same etrasimod dose in the Extension Treatment Period. Subjects who were in the 
placebo group during the Double-Blind Treatment Period will be re-randomized (1:1 ratio) to 
etrasimod 1 mg or etrasimod 2 mg at entry into the Extension Treatment Period. 
Subjects will have follow-up visits at 2 and 4 weeks after the last dose of study treatment after 
Week 52 or the Early Termination (ET) Visit.


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Number of Subjects (planned):
Approximately 96 subjects are planned to be enrolled.
Eligibility Criteria for the Double-Blind Treatment Period:
Key Inclusion Criteria (Full Inclusion Criteria Are Provided in the Protocol)

Men or women between 18 and 65 years of age at the time of informed consent (IC)

Have an EoE diagnosis prior to screening and histologically active disease with an 
esophageal peak eosinophil count (PEC) of ≥15 eosinophils (eos)/high power field 
(hpf) (~60 eos/mm2) from any level (proximal, mid, or distal) of the esophagus at the 
Screening esophagogastroduodenoscopy (EGD)

Have dysphagia, defined as solid food going down slowly or getting stuck in the throat 
with an average frequency of ≥2 episodes per week over 2 weeks (as documented 
using the Dysphagia Symptom Questionnaire (DSQ) during the Screening period)
Key Exclusion Criteria (Full Exclusion Criteria Are Provided in the Protocol)

History of any of the following non-EoE conditions or procedures that may interfere 
with the evaluation of or affect the histologic, endoscopic, or symptom endpoints of the 
study: 
a.
Conditions that substantially contribute to esophageal eosinophilia (eg, eosinophilic 
gastritis or enteritis [ie, eosinophilic duodenitis or colitis] with esophageal 
involvement, achalasia, hypereosinophilic syndrome, Crohn’s disease [CD] with 
esophageal involvement, esophageal infection [fungal, viral], eosinophilic 
granulomatosis with polyangiitis (formally known as Churg-Strauss Syndrome),  
pemphigus, with esophageal involvement, pill esophagitis, graft versus host 
disease, Mendelian disorders [eg, Marfan syndrome Type II, 
hyper-immunoglobulin E (IgE) syndrome, phosphatase and tensin homolog 
(PTEN) hamartoma tumor syndrome, Netherton syndrome, severe atopy metabolic 
wasting (SAM) syndrome])
b. Conditions that interfere with the evaluation of the esophagus (eg, esophageal 
varices with risk of spontaneous bleed, high-grade esophageal stenosis where an 
8- to 10-mm endoscope could not pass through the stricture without dilation at the 
time of Screening EGD)
c.
Conditions or procedures that substantially contribute to dysphagia (eg, 
histologically active Barrett’s esophagitis, active erosive esophagitis Los Angeles 
Grade B or above, significant hiatal hernia [≥4 cm], esophageal resection)

Undergone dilation of an esophageal stricture within 12 weeks prior to Screening 
EGD.

Use of corticosteroids for the treatment of EoE within 8 weeks prior to Screening 
EGD.

Discontinue, initiate, or change dosing (dosage/frequency) of the following therapies 
for EoE within 8 weeks prior to Screening EGD. Subjects on any of the following 
therapy need to stay on a stable regimen during study participation:


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d. Elemental diet
e.
EoE food trigger elimination diet
f.
PPI therapy

Used any immunotherapy/desensitization including oral immunotherapy (OIT) or 
sublingual immunotherapy (SLIT) within 12 months prior to the Screening EGD.
Note: Stable (ie, ≥6 months prior to the Screening EGD) subcutaneous 
immunotherapy (SCIT) is permitted. Subjects on SCIT need to stay on a stable 
treatment during study participation.

Used any of the following immunomodulatory therapies within the timeframes prior to 
Baseline as indicated below. The Medical Monitor should be consulted with any 
questions related to prior use of unlisted immunomodulatory therapies.
Time Frame
Therapies
Within 2 weeks
Antimetabolites (eg, AZA, 6-MP, MTX, 6-TG), calcineurin inhibitors (eg, 
cyclosporine, tacrolimus), MMF
Within 12 weeks (or 
5 half-lives if shorter)
Anti-IL-5 antibodies (eg, mepolizumab, reslizumab, benralizumab), anti-IL-4/13 
antibodies (eg, dupilumab), anti-IgE antibodies (eg, omalizumab), TNFα 
inhibitors (eg, infliximab), JAK inhibitors (eg, tofacitinib, oclacitinib)
Within 24 weeks 
Anti-CD20 antibodies (eg, rituximab, ocrelizumab), anti-CD52 antibodies (eg, 
alemtuzumab), other cell-depleting therapies (eg, bone marrow transplantation, 
total body irradiation)
Any time prior to Baseline
Sphingosine 1-phosphate receptor modulators (eg, fingolimod, siponimod, 
ozanimod), natalizumab
AZA, azacytidine; IgE, immunoglobulin E; IL-4/13, interleukin-4/13; IL-5, interleukin-5; JAK, Janus kinase; 6-MP, 
6-mercaptopurine; MMF, mycophenolate mofetil; MTX, methotrexate; 6-TG, 6-thioguanine; TNFα, tumor necrosis factor 
alpha
Eligibility Criteria for the Extension Treatment Period:
Inclusion Criteria

Completion of the Week 24 study visit (including EGD) including subjects who 
discontinued study treatment due to lack of clinical efficacy and started rescue therapy 
between Weeks 16 and 24. Rescue therapy must be discontinued on the day etrasimod 
is initiated in the Extension Treatment Period.

Compliance with study procedures during the Double-Blind Treatment Period as 
assessed by the Investigator

No notable safety concerns during the Double-Blind Treatment Period, as determined 
by the Investigator 

Willing to comply with all study visits and procedures for the Extension Treatment 
Period
Test Product, Dose, and Mode of Administration:
Etrasimod 1 mg and 2 mg tablets taken once daily by mouth in the Double-Blind Treatment 
Period and the Extension Treatment Period.
Duration of Study:


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The overall duration of the study will be up to 61 weeks, including:
Up to 5-Week Screening Period
24-Week Double-Blind Treatment Period
28-Week Extension Treatment Period
Safety Follow-Up Visits 2 and 4 weeks after the last dose of study treatment
Reference Therapy, Dose, and Mode of Administration
Matching placebo tablets taken once daily by mouth in the Double-Blind Treatment Period. 
There is no reference therapy (no placebo) during the Extension Treatment Period.
Efficacy Assessments:
Esophageal peak eosinophil count (PEC), EoE Histology Scoring System (HSS), DSQ, Food 
Avoidance Question (FAQ); Eosinophilic Esophagitis Endoscopic Reference Score (EREFS), 
Adult Eosinophilic Esophagitis Quality of Life (EoE-QOL-A), the Patient Global Impression 
of Change (PGIC), and Patient Global Impression of Severity (PGIS).
Primary efficacy endpoint:

Percent change from Baseline in esophageal PEC at Week 16
Secondary efficacy endpoints:

Absolute change from Baseline in DSQ score at Week 16

Absolute change from Baseline in esophageal PEC at Week 16

Proportion of subjects with esophageal PEC < 15 eos/hpf at Week 16

Proportion of subjects with esophageal PEC ≤6 eos/hpf at Week 16
A complete list of efficacy endpoints and definitions, as well as analysis methods will be 
provided in the Statistical Analysis Plan (SAP).
Pharmacokinetic Assessments:
Etrasimod plasma concentrations will be determined on Day 1 (predose and 
4 hours ± 15 minutes postdose) and before dosing at subsequent study visits and at the 
follow-up visits.
Collected blood for PK may also be used for profiling of drug binding proteins, bioanalytical 
method validation purposes, stability assessments, metabolite assessments, or to assess other 
actions of etrasimod with plasma constituents. Not all collected PK samples from 
placebo-treated subjects during the Double-Blind Treatment Period will be assayed.
Safety Assessments:
Safety will be assessed through the incidence of adverse events (AEs), clinical laboratory 
findings, 12-lead electrocardiograms (ECGs) (for first-dose monitoring, on treatment 
re-initiation after a defined period of treatment interruption, and at the start of the Extension 
Treatment Period, to be done predose and at 4 hours following the first dose), physical 
examinations, vital signs (measured hourly for at least 4 hours following the first dose), 
pulmonary function tests (PFTs), ophthalmoscopy and optical coherence tomography (OCT).
Statistical Methods:


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Testing Strategy:
Unadjusted p-values for any hypothesis tests related to the comparisons of etrasimod dose 
group versus placebo will be reported. Estimated difference between etrasimod dose group and 
placebo as well as the associated 95% confidence intervals will be reported.
Statistical Analysis:
The primary and secondary endpoints will be analyzed using the Full Analysis Set (FAS) and 
demographic and safety analyses will be performed using the Safety Set. Other important 
statistical considerations, such as handling rescue medication/rescue procedure uses during 
study treatment, missing data imputation strategies, sensitivity analyses, and subgroup
analyses will be described in the protocol and the SAP.
The endpoints of percentage change in esophageal PEC from Baseline to Week 16 and Week 
24 will be analyzed using analysis of covariance (ANCOVA) model based on rank scores due 
to the skewed distribution of the data and possible outliers. The ANCOVA model will include 
treatment group and randomization stratification factors as factors and Baseline eosinophil 
PEC as a covariate. PEC after rescue medication/rescue procedure uses will be set to missing; 
all missing data will be imputed in the FAS using multiple imputation (MI) procedure as 
appropriate. Multiple results of ANCOVA (least square [LS] mean rank scores and LS mean 
rank score difference from placebo) for each MI dataset will be analyzed and reported along 
with final p-value using Rubin’s method [1]. In addition, a descriptive summary of percentage 
change in esophageal PEC from baseline as well as the difference between treatment groups 
will be presented by treatment group. When applying the same ANCOVA model to key 
secondary continuous variables, no rank transformation will be used. 
Proportion-based secondary endpoints (eg, histologic responders or symptomatic responders) 
at Week 16 will be analyzed in the FAS; subjects who use rescue medication or have a rescue 
procedure, or with missing data for any reason will be considered a “nonresponder” or 
“failure.” The analyses will be performed using the Cochran-Mantel-Haenszel (CMH) method 
adjusted for randomization stratification factors. The number and percentage of subjects 
achieving the goal and the difference in proportion between treatment groups achieving the 
goal, along with p-value and the 95% CIs will be reported.
Longitudinal continuous endpoints will also be analyzed up to Week 24 using a linear mixed 
effects model. The model will include treatment group, visit, interaction of treatment-by-visit, 
and randomization stratification factors as factors and Baseline measure value as covariates. 
An unstructured covariance matrix will be specified for the within-subject measurements. LS 
means and LS mean differences between treatment group with unadjusted p-values and 
corresponding 95% CIs will be reported at each scheduled visit.
No hypothesis tests between treatment groups will be performed for endpoints measured 
during the Extension Treatment Period. Only descriptive statistics will be provided. 
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Continuous variables will be summarized using the number of observations, mean, SD, 
median, minimum, and maximum. Categorical variables will be summarized using frequency 
counts and percentages.
Subjects receiving any rescue therapy will have efficacy assessments after rescue therapy set 
to missing (continuous variable) or considered as treatment failures/non-responders at 
subsequent timepoints (dichotomous variables). Details and handling of rescue therapy for 
analysis will be contained in the protocol and SAP.
Safety Analysis:
All safety data will be listed and summarized by treatment group. All treatment-emergent AEs 
(TEAEs) will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and 
tabulated by System Organ Class and Preferred Term. Incidence of AEs, serious adverse 
events, adverse events of special interest, and AEs leading to study treatment discontinuation 
will be summarized and presented in descending order of frequency. In addition, details 
regarding risk-based safety analyses (eg, risk difference, hazard ratio) and exposure adjusted 
incidence rates will be described in the SAP. Laboratory parameters will be summarized by 
treatment group at each scheduled assessment timepoint using descriptive statistics. 
Associated laboratory parameters such as hepatic enzymes, renal function, and hematology 
values will be grouped and presented together. Individual subject values will be listed and 
values outside of the standard reference range will be noted. Shift tables and analyses of 
changes from Baseline will be produced. The change from Baseline for each of the vital signs 
and ECG parameters will be summarized. Incidence of abnormal vital signs parameters and 
outlier ECG results will be tabulated.
Pharmacokinetic Analysis:
A descriptive summary of observed plasma concentration will be displayed by time and by 
treatment group. The Pharmacokinetic Set will be used to analyze plasma levels.
Interim Analysis:
No formal interim analyses for efficacy are planned. Full details of the efficacy, safety, and PK 
analysis will be provided in the SAP.


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TABLE OF CONTENTS
CLINICAL STUDY PROTOCOL ............................................................................................1
PROTOCOL HISTORY............................................................................................................2
PROTOCOL SYNOPSIS ..........................................................................................................3
LIST OF APPENDICES..........................................................................................................15
LIST OF TABLES...................................................................................................................15
LIST OF FIGURES .................................................................................................................16
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................17
1. INTRODUCTION ...............................................................................................................22
1.1. Background .............................................................................................................22
1.1.1. Eosinophilic Esophagitis ............................................................................22
1.1.2. Etrasimod....................................................................................................23
1.2. Benefit-Risk Considerations ...................................................................................24
2. OBJECTIVES......................................................................................................................26
3. STUDY DESIGN.................................................................................................................26
3.1. Overall Design.........................................................................................................26
3.2. Discussion and Scientific Rationale for Study Design............................................27
3.3. Rationale for Dose Selection...................................................................................28
3.4. End of Study............................................................................................................29
4. STUDY POPULATION......................................................................................................29
4.1. Inclusion Criteria.....................................................................................................29
4.2. Exclusion Criteria....................................................................................................30
4.3. Eligibility Criteria for the Extension Treatment Period..........................................34
5. SUBJECT RESTRICTIONS ...............................................................................................34
6. STUDY TREATMENT.......................................................................................................34
6.1. Study Treatments Administered..............................................................................34
6.2. Identity of Study Treatments...................................................................................35
6.2.1. Etrasimod....................................................................................................35
6.2.2. Placebo........................................................................................................35
6.3. Dosage and Administration.....................................................................................35
6.3.1. Instructions for Missed Dose(s)..................................................................35
6.3.2. Dose Interruptions ......................................................................................36
6.4. Method of Assigning Subjects to Treatment...........................................................36


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6.5. Blinding...................................................................................................................36
6.6. Treatment Compliance ............................................................................................37
6.7. Concomitant Therapy..............................................................................................37
6.7.1. Required Concomitant Therapy..................................................................37
6.7.2. Permitted Therapy ......................................................................................37
6.7.3. Prohibited Concomitant Therapy................................................................38
6.7.4. Rescue Therapy ..........................................................................................39
7. STUDY TREATMENT MATERIALS MANAGEMENT .................................................39
7.1. Packaging and Labeling ..........................................................................................39
7.2. Storage and Handling..............................................................................................39
7.3. Preparation ..............................................................................................................39
7.4. Accountability.........................................................................................................39
7.5. Retention and Disposal............................................................................................40
8. REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT...............................40
8.1. Discontinuation of Study Treatment .......................................................................40
8.2. Reasons for Discontinuation from the Study ..........................................................40
8.3. Lost to Follow-Up ...................................................................................................41
8.4. Premature Termination of the Study or a Study Site ..............................................41
9. STUDY PERIODS...............................................................................................................42
9.1. General Instructions ................................................................................................42
9.2. Screening.................................................................................................................42
9.3. Double-Blind Treatment Period..............................................................................43
9.3.1. Day 1 Pre-Randomization and Predose......................................................43
9.3.2. Day 1 Randomization and Postdose ...........................................................43
9.4. Extension Treatment Period....................................................................................43
9.4.1. Week 24 Visit .............................................................................................43
9.5. Follow-Up/End of Study.........................................................................................44
9.6. Early Termination ...................................................................................................44
9.7. Telehealth and Hybrid Visits...................................................................................44
9.7.1. Telehealth Visits.........................................................................................44
9.7.2. Home Health Visits.....................................................................................45
9.7.3. Hybrid Visits...............................................................................................45
10. STUDY ASSESSMENTS AND PROCEDURES.............................................................45


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10.1. Virtual and In-Person Assessments.......................................................................45
10.2. Subject Informed Consent.....................................................................................46
10.3. Screening and Eligibility.......................................................................................47
10.3.1. Demography and Other Subject Characteristics.......................................47
10.3.2. Social and Family History ........................................................................47
10.3.3. Prior Therapies..........................................................................................47
10.3.4. Medical History ........................................................................................47
10.3.5. Pregnancy Testing ....................................................................................48
10.3.6. Esophagogastroduodenoscopy..................................................................48
10.3.6.1. Biopsy Collection....................................................................49
10.3.7. Rescreening...............................................................................................49
10.4. Efficacy Assessments............................................................................................49
10.4.1. Histology...................................................................................................49
10.4.1.1. Esophageal Peak Eosinophil Count.........................................50
10.4.1.2. Eosinophilic Esophagitis Histology Scoring System..............50
10.4.2. Endoscopy.................................................................................................50
10.4.2.1. Eosinophilic Esophagitis Endoscopic Reference Score..........50
10.4.3. Clinical Outcome Assessments.................................................................50
10.4.3.1. Dysphagia Symptom Questionnaire........................................50
10.4.3.2. Food Avoidance Question.......................................................51
10.4.3.3. EoE-QOL-A ............................................................................51
10.4.3.4. Patient Global Impression of Severity ....................................51
10.4.3.5. Patient Global Impression of Change......................................51
10.5. Pharmacokinetic Assessments...............................................................................51
10.6. Safety Assessments ...............................................................................................52
10.6.1. Vital Signs ................................................................................................52
10.6.2. Physical Examinations..............................................................................52
10.6.3. Electrocardiography..................................................................................53
10.6.4. Clinical Laboratory Assessments .............................................................53
10.6.5. Pulmonary Function Test..........................................................................55
10.6.6. Ophthalmoscopy and Optical Coherence Tomography............................55
10.6.7. Safety Monitoring Guidance.....................................................................56
10.6.7.1. Drug-Induced Liver Injury......................................................56


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10.6.7.2. Guidance on Management of Lymphocyte, Neutrophil, and 
White Blood Cell Counts, and Monitoring for Infections.................57
10.6.7.3. Guidance on Monitoring Subjects for Infections ....................57
10.6.7.4. Guidance for Cardiac Monitoring Following Treatment 
Initiation or Re-Initiation...................................................................58
10.6.7.5. Pulmonary Function Monitoring.............................................61
10.6.7.6. Ophthalmic Symptom Monitoring ..........................................61
10.6.8. Adverse Events.........................................................................................62
10.6.8.1. Definitions...............................................................................62
10.6.9. Pregnancy and Lactation...........................................................................66
10.6.9.1. Exposure During Pregnancy....................................................67
10.6.9.2. Exposure During Breastfeeding ..............................................67
10.6.9.3. Occupational Exposure ...........................................................67
10.6.10. Lack of Efficacy .....................................................................................67
10.6.11. Medication Errors ...................................................................................68
10.7. Procedures for Overdose .......................................................................................68
10.8. Genetic Testing .....................................................................................................68
10.10. Qualitative Interview...........................................................................................70
11. PLANNED STATISTICAL METHODS ..........................................................................70
11.1. General Considerations .........................................................................................70
11.3. Analysis Sets .........................................................................................................71
11.4. Missing Data .........................................................................................................72
11.4.1. Primary Methods of Handling Missing Data and Rescue 
Medication/Rescue Procedure Usage ..............................................................72
11.4.2. Sensitivity Analyses..................................................................................73
11.5. Efficacy Analyses..................................................................................................74
11.5.1. Efficacy Endpoints....................................................................................75
11.5.1.1. Primary Endpoint ....................................................................75
11.5.1.2. Secondary Endpoints...............................................................75
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11.6. Subgroup Analyses................................................................................................76
11.7. Testing Strategy.....................................................................................................77
11.8. Interim Analysis ....................................................................................................77
11.9. Safety Analyses.....................................................................................................77
11.9.1. Safety Endpoints.......................................................................................77
11.9.2. Adverse Events .........................................................................................78
11.9.3. Extent of Exposure ...................................................................................78
11.9.4. Clinical Laboratory Parameters ................................................................78
11.9.5. Electrocardiograms...................................................................................78
11.9.6. Vital Signs ................................................................................................78
11.9.7. Physical Examination ...............................................................................79
11.10. Pharmacokinetic Analyses ..................................................................................79
11.10.1. Pharmacokinetic Endpoint......................................................................79
11.11. Clinical Outcome Assessments ...........................................................................79
12. REGULATORY AND ETHICAL CONSIDERATIONS.................................................79
12.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ...80
12.2. Informed Consent and Assent ...............................................................................80
12.3. Confidentiality.......................................................................................................80
12.4. Protocol Compliance.............................................................................................81
13. QUALITY CONTROL AND QUALITY ASSURANCE.................................................81
13.1. Training of Study Site Personnel ..........................................................................81
13.2. Monitoring.............................................................................................................82
13.3. Audit......................................................................................................................82
14. DATA HANDLING AND RECORD KEEPING .............................................................82
14.1. Data Management .................................................................................................82
14.1.1. Case Report Forms ...................................................................................82
14.1.2. Source Documents....................................................................................83
14.2. Study Documentation and Records Retention ......................................................83
14.3. Clinical Study Report............................................................................................83
14.4. Disclosure of Study Results ..................................................................................84
15. RESPONSIBILITIES ........................................................................................................84
15.1. Investigator Responsibilities .................................................................................84
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15.2. Sponsor’s Medically Qualified Individual ............................................................84
15.3. Sponsor Responsibilities .......................................................................................84
16. REFERENCES ..................................................................................................................85


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LIST OF APPENDICES
APPENDIX 1:
SCHEDULES OF ASSESSMENTS ........................................................91
APPENDIX 2:
EOSINOPHILIC ESOPHAGITIS HISTOLOGY SCORING SYSTEM.97
APPENDIX 3:
EOSINOPHILIC ESOPHAGITIS ENDOSCOPIC REFERENCE 
SCORE .....................................................................................................98
APPENDIX 4:
DYSPHAGIA SYMPTOM QUESTIONNAIRE .....................................99
APPENDIX 5:
FOOD AVOIDANCE QUESTION........................................................100
APPENDIX 6:
PATIENT GLOBAL IMPRESSION OF SEVERITY ...........................101
APPENDIX 7:
PATIENT GLOBAL IMPRESSION OF CHANGE..............................102
APPENDIX 8:
GRADING OF CLINICAL AND LABORATORY ADVERSE
EVENTS.................................................................................................103
APPENDIX 9:
GUIDANCE FOR THE MANAGEMENT OF CLINICAL AND 
LABORATORY ADVERSE EVENTS .................................................105
APPENDIX 10:
GUIDANCE FOR THE ASSESSMENT OF POTENTIAL 
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY.......106
APPENDIX 11:
GUIDANCE ON CLINICAL TRIAL CONDUCT DURING THE 
COVID-19 PANDEMIC ........................................................................107
LIST OF TABLES
Table 1:
Required Washout Period of Immunomodulatory Therapies...................31
Table 2:
Study Treatments......................................................................................34
Table 3:
Clinical Laboratory Tests .........................................................................54
Table 4:
Procedures to Be Performed During the Cardiac Monitoring Period.......59
Table 5:
Discharge Criteria After Cardiac Monitoring...........................................60
Table 6:
Analysis Sets.............................................................................................72
Table 7:
Schedule of Assessments – Screening, Double-Blind Treatment Period, 
and Safety Follow-Up Period ...................................................................91
Table 8:
Schedule of Assessments – Extension Treatment Period and Safety 
Follow-Up Period .....................................................................................95
Table 9:
Eosinophilic Esophagitis Histology Scoring System Definitions ............97
Table 10:
Example of CTCAE Terms and Grading for Clinical Adverse Events..103
Table 11:
Example of CTCAE Terms and Grading for Laboratory Abnormalities 
and Pulmonary Functions Tests..............................................................104


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LIST OF FIGURES
Figure 1:
Study Design.............................................................................................27
Figure 2:
Algorithm for the Management of Clinical and Safety 
Assessment-Related Adverse Events......................................................105


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Explanation
ADL
activities of daily living
ADR
adverse drug reaction
AE
adverse event
AESI
adverse event of special interest
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AV
atrioventricular
AZA
azacytidine
β-hCG
beta-human chorionic gonadotropin
BP
blood pressure
bpm
beats per minute
CBC
complete blood count
CD
Crohn’s disease
CFR
Code of Federal Regulations
cGMP
current Good Manufacturing Practices
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CMH
Cochran-Mantel-Haenszel
CMP
Clinical Monitoring Plan
COPD
chronic obstructive pulmonary disease
COVID-19
coronavirus disease 2019
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CT
clinical trial
CTCAE
Common Terminology Criteria for Adverse Events
CYP
cytochrome P450
DILI
drug-induced liver injury


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Abbreviation
Explanation
DLCO
diffusing capacity of the lungs for carbon monoxide
DNA
deoxyribonucleic acid
DSQ
Dysphagia Symptom Questionnaire
ECC
Emergency Contact Card
ECG
electrocardiogram
eCRF
electronic case report form
EDB
exposure during breastfeeding
EDP
exposure during pregnancy
eDiary
electronic diary
EEn
eosinophilic enteritis
EG
eosinophilic gastritis
EGD
esophagogastroduodenoscopy
eGFR
estimated glomerular filtration rate
EGID
eosinophilic gastrointestinal disease
EoE
eosinophilic esophagitis
EoE-HSS
Eosinophilic Esophagitis Histology Scoring System
EoE-QOL-A
Adult Eosinophilic Esophagitis Quality of Life
eos
eosinophils
EREFS
Eosinophilic Esophagitis Endoscopic Reference Score
ET
Early Termination
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
FA
fluorescein angiogram
FAQ
Food Avoidance Question
FAS
Full Analysis Set
FCS
fully conditional specification
FDA
Food and Drug Administration
FEV1
forced expiratory volume at 1 second
FSH
follicle-stimulating hormone
FVC
forced vital capacity
GCP
Good Clinical Practice
GERD
gastroesophageal reflux disease
GGT
gamma glutamyl transferase


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Abbreviation
Explanation
GI
gastrointestinal
GWAS
genome-wide association studies
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
hpf
high power field
HR
heart rate
HSS
Histology Scoring System
IAC
independent adjudication committee
IB
Investigator’s Brochure
IC
informed consent
ICD
Informed Consent Document
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgE
immunoglobulin E
IL
interleukin
IMID
immune-mediated inflammatory disorder
IND
Investigational New Drug
INR
international normalized ratio
IRB
Institutional Review Board
IUD
intrauterine device
IV
intravenous
IWRS
Interactive Web Response System
JAK
Janus kinase
LFT
liver function test
LS
least square
6-MP
6-mercaptopurine
MAR
missing at random
MedDRA
Medical Dictionary for Regulatory Activities
mFAS
modified Full Analysis Set


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Abbreviation
Explanation
MI
multiple imputation
MMF
mycophenolate mofetil
MQI
Medically Qualified Individual
MTX
methotrexate
NASH
nonalcoholic steatohepatitis
OCT
optical coherence tomography
OIT
oral immunotherapy
PD
pharmacodynamic(s)
PEC
peak eosinophil count
PFT
pulmonary function test
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PHE
public health emergency
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PPI
proton pump inhibitor
PPI-REE
proton pump inhibitor-responsive esophageal eosinophilia
PRES
posterior reversible encephalopathy syndrome
PT
prothrombin time
PTEN
phosphatase and tensin homolog
qd
once daily
QOL
quality of life
QTcB
Bazett’s corrected QT interval
QTcF
Fridericia’s corrected QT interval
RNA
ribonucleic acid
S1P
sphingosine 1-phosphate
S1P1,4,5
sphingosine 1-phosphate receptors 1, 4, 5
SAE
serious adverse event
SAM
severe atopy metabolic wasting
SAP
Statistical Analysis Plan
SCIT
subcutaneous immunotherapy
SD
standard deviation


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Abbreviation
Explanation
SLIT
sublingual immunotherapy
SOP
standard operating procedure
SpO2
arterial oxygen saturation
SRSD
Single Reference Safety Document
6-TG
6-thioguanine
T bili
total bilirubin
TBNK
T, B, NK, CD4+ T cell and CD8+ T cell count (absolute number and percentage)
TEAE
treatment-emergent adverse event
TGF-β
transforming growth factor-beta
Th2
type 2 helper T
TNFα
tumor necrosis factor alpha
TSLP
thymic stromal lymphopoietin
UC
ulcerative colitis
ULN
upper limit of normal
WBC
white blood cell
WOCBP
woman of child-bearing potential


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1. INTRODUCTION
1.1. Background
1.1.1. Eosinophilic Esophagitis
Eosinophilic esophagitis (EoE) is a chronic and progressive, allergen-driven, immune-mediated 
disease of the esophagus. Histologically, EoE is characterized by the accumulation of eosinophils 
in the lining of the esophagus, a tissue that under normal conditions lacks these cells [2-4]. The 
presence of these unwelcome eosinophils has been shown to have a direct effect on immune 
function and tissue damage [3]. The eosinophilic predominant inflammation characteristic of 
EoE results in a variety of symptoms including but not limited to difficulty swallowing 
(dysphagia and/or odynophagia) and regurgitation, central chest pain, upper abdominal pain, 
food impaction, food refusal, and malnutrition [2,5,6]. Endoscopic abnormalities common to 
patients with EoE include esophageal linear furrows with loss of vascularity, trachealization, a 
small-caliber lumen, strictures, and mucosal exudates [2,3]. If left untreated, the natural course of 
disease ultimately progresses from chronic esophageal inflammation to fibrostenosis in the 
esophageal lining that increases tissue dysmotility and rigidity [7-9]. Spontaneous remission or 
development of tolerance to food allergies appears to be uncommon [9,10] and the disease 
commonly relapses in the absence of maintenance treatment [11-13]. Both pediatric and adult 
populations can develop EoE, however, the disorder is most common in individuals between the 
ages of 20 and 40 years old [14]. EoE also exhibits a strong hereditability pattern and 
predominance for males and for Caucasians, and principally affects those in socioeconomically 
developed countries [3,8,14]. Risk factors for EoE include atopy and other allergic diseases, 
including asthma, allergic rhinitis, and atopic dermatitis [2,15].
Though the etiology of EoE is not yet completely understood, EoE is considered a type 2 
helper T (Th2) cell-mediated atopic disease. EoE onset is thought to arise from a multifactorial 
interaction between genetic susceptibility and inappropriate immune-driven inflammatory 
responses to food antigens (predominantly non-immunoglobulin E [IgE]-mediated), 
aeroallergens, and environmental factors [2,5,16,17]. A genetic predisposition to disturbed 
barrier function, which is observed in esophageal tissue from EoE patients, permits allergenic 
molecules easy entry through the epithelium and subsequent Th2-driven allergic hypersensitivity 
[3,8,16]. Dendritic cells localized within the esophageal epithelium sample allergenic molecules 
and induce the activation and maturation of Th2 cells [4]. This Th2 cell-mediated activity leads 
to cytokine production (including interleukin [IL]-4, IL-5, and IL-13) and subsequent eosinophil 
activation and recruitment to the esophagus (eosinophilic inflammation) where the eosinophils 
release harmful secretory products that cause esophageal symptoms, further reinforcing the 
inflammatory cycle [3,8,18]. Thus, medical intervention that reduces esophageal inflammation, 
restores epithelial barrier integrity, and induces histologic remodeling can result in symptom 
improvement [7].
Genome-wide association studies (GWAS) have identified candidate genes involved in the 
pathogenesis of EoE including, but not limited to, thymic stromal lymphopoietin (TSLP) and 
calpain 14 (CAPN14), that when overexpressed can disrupt barrier integrity and increase allergic 
inflammation [5,8]. GWAS have also identified links between EoE and overexpression of 
eotaxin-3, an eosinophil-specific chemoattractant [3,17]. This genetic profile therefore supports 
an allergic etiology for EoE where a genetic predisposition enhances inappropriate immune 
responses to potential triggering events [8,16].


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Diagnostic criteria currently required for the diagnosis of EoE include 1) symptoms of 
esophageal dysfunction; 2) eosinophilic esophageal inflammation with at least 15 eosinophils per 
high power field (hpf) affecting the esophagus alone; and 3) exclusion of other causes of 
esophageal eosinophilia. The other causes may include non-EoE eosinophilic gastrointestinal 
diseases (EGIDs) such as eosinophilic gastritis (EG) or eosinophilic enteritis (EEn), Crohn’s 
disease (CD), infection, achalasia, and hypereosinophilic syndrome [6,9,16,19].
The differential diagnosis for EoE has historically included gastroesophageal reflux disease 
(GERD) and proton pump inhibitor (PPI)-responsive esophageal eosinophilia (PPI-REE), where 
responsiveness to an 8-week PPI study was considered an exclusion of an EoE diagnosis 
[5,6,20]. However, research suggested that EoE and GERD were not necessarily mutually 
exclusive and that PPIs may have an acid-independent anti-inflammatory effect that promotes the 
reduction of esophageal eosinophilia [5,6,21]. With the similarities in phenotypic, molecular, and 
pathophysiologic characteristics and responses to treatment, PPI-REE emerged rather as a 
subtype of EoE in some patients. Based on these findings, PPI trial requirement was removed 
from the diagnostic algorithm [6] and PPIs are considered a treatment option, although off-label, 
for EoE.
Current treatment options for EoE may be dietary, pharmacologic, or endoscopic in nature. 
These treatments are subject to a variety of disadvantages including difficulty in adhering to 
dietary therapy, potential negative side effects associated with systemic corticosteroids, partial 
efficacy of topical steroids, and invasiveness and risks of endoscopic treatment, including 
esophageal dilation [7,21,22]. In 2018, budesonide was approved in Europe as orodispersible
tablet formulation [23] for the treatment of EoE, but there are no Food and Drug Administration 
(FDA) approved medications for the treatment of EoE. Therefore, long-term safe and effective 
treatments are greatly needed.
Sphingosine 1-phosphate (S1P) receptor modulators have a primary mechanism of action of 
reducing peripheral lymphocytes. Given that immune system dysregulation is a 
pathophysiological feature of many immune-mediated inflammatory disorders (IMIDs) [24,25], 
synthetic small molecule S1P receptor modulators have the potential to act across a wide range 
of such diseases. S1P receptor modulators have been shown to reduce inflammation and induce 
clinical remission in multiple sclerosis (fingolimod, ozanimod, ponesimod, siponimod) [26-28], 
psoriasis (ponesimod) [29], and ulcerative colitis (UC [ozanimod, etrasimod]) [30,31]. 
Therefore, S1P receptor modulators, such as etrasimod, may have similar effects in EoE.
1.1.2. Etrasimod
Etrasimod (APD334) is an orally administered, synthetic, selective modulator of S1P receptors 1, 
4, 5 (S1P1,4,5) that is being developed to treat IMIDs.
S1P1 is a cell surface expressed G protein-coupled receptor that has been shown to regulate 
lymphocyte migration out of lymphoid tissues. Synthetic small molecule S1P1 agonists have 
been observed to act as functional antagonists by inducing sustained receptor internalization, 
thus inhibiting lymphocyte migration out of lymphoid tissues and lowering the amount of 
peripheral blood lymphocytes available to be recruited to sites of inflammation [32]. Nonclinical 
and clinical studies with S1P receptor modulators induce the anticipated S1P1-mediated 
reduction in peripheral lymphocytes. Nonclinical studies of S1P receptor modulators have shown 
a reduction in tissue-infiltrating Th2 cells, cells expressing the pro-inflammatory cytokines IL-4, 


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IL-5, IL-13, and those cells implicated in active disease, including eosinophils [33-36]. In theory, 
a reduction in the number of circulating lymphocytes translates to reduced infiltration of 
inflammatory cells into the tissue and less release of pro-inflammatory cytokines which mediate 
tissue damage and eosinophil infiltration[32,37]. S1P receptor modulators have been shown to be 
clinically beneficial in other T cell mediated diseases including, but not limited to, inflammatory 
bowel disease, and multiple sclerosis [26,29,31,32]; etrasimod is therefore thought to be a 
potential therapeutic approach to the management of EoE.
Consistent with this hypothesis, etrasimod demonstrated positive results in a Phase 2, 
randomized, double-blind, placebo-controlled study in subjects with moderately to severely 
active UC in Study APD334-003 [38] and its open-label extension, Study APD334-005 [39]. 
Etrasimod significantly reduced circulating lymphocyte counts and demonstrated consistent and 
clinically meaningful improvements in endpoint measures reflecting cardinal symptoms of UC 
and objective findings of endoscopic colorectal mucosal healing [30,40-42]. Etrasimod 2 mg 
administered orally once daily for up to 46 weeks (per Amendment 2 of Study APD334-005 a 
subset of subjects received treatment for 52 weeks) was generally safe and well tolerated in 
subjects with UC.
A complete summary of the nonclinical and clinical data relevant to etrasimod and its study in 
human subjects is provided in the current edition of the Investigator’s Brochure (IB).
1.2. Benefit-Risk Considerations
The need for a safe, long-term, oral, efficacious non-steroid treatment for EoE is illustrated by 
the lack of FDA approved medications for the treatment of EoE, and potential negative side 
effects or compliance difficulty associated with many currently available treatments. 
The potential benefit to subjects who enroll in this study is clinical improvement in EoE 
symptoms as a result of reduced local inflammation in the esophagus through modulation of both 
T cell infiltration into the tissue and subsequent eosinophil accumulation (Section 1.1.2). As of 
08 June 2020, etrasimod has been found to be generally safe and well-tolerated in approximately 
736 adult subjects treated at various doses. The safety and tolerability of etrasimod has been 
evaluated in Phase 1 studies with healthy adult subjects at single doses up to 5 mg and repeated 
doses up to 2 mg once daily (qd) without dose-escalation and up to 4 mg qd with dose escalation. 
Etrasimod has previously demonstrated beneficial effects in another autoimmune inflammatory 
disease, UC. In a Phase 2 dose-ranging Study APD334-003, once daily treatment with 2 mg 
etrasimod for 12 weeks led to clinically meaningful and statistically significant endoscopic and 
symptomatic improvements versus placebo [38]. Sustained beneficial effects of etrasimod were 
observed for up to 46 weeks in the subsequent open-label extension Study APD334-005 (per 
Amendment 2 of Study APD334-005 a subset of subjects received treatment for 52 weeks) [39]. 
Although UC and EoE have different pathophysiology, they are Th2-driven immune-mediated 
inflammatory diseases where modulation of the S1P/S1P receptor axis is anticipated to provide 
therapeutic benefit to patients (Section 1.1.2). Therefore, it is reasonable to hypothesize that 
etrasimod may offer similar clinical benefits to EoE patients with active disease as UC patients. 
The clinical investigation proposed herein is necessary to affirm or reject this hypothesis.
While there have not been notable safety concerns with vital signs, electrocardiograms (ECGs), 
pulmonary function tests (PFTs), ophthalmoscopy, or laboratory test results with etrasimod, 
based on the mechanism of action of etrasimod and prior experience with S1P receptor 


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modulators such as fingolimod and siponimod in multiple sclerosis, monitoring for these specific 
safety parameters is planned for this study [43,44]. This monitoring includes PFTs, cardiac 
monitoring at first dose and on treatment re-initiation after a defined period of treatment 
interruption, liver function tests, and ophthalmoscopy with optical coherence tomography 
(OCT). Based on its mechanism of action, etrasimod is expected to dose-dependently reduce 
lymphocyte counts. This reduction is reversible, with lymphocyte counts returning to within 
normal limits following study drug discontinuation. Lymphocyte reduction may increase the risk 
of infections in some subjects. Thus, serial assessment of white blood cell (WBC) count and 
differential will be performed to assess the risk for serious and atypical infections and study 
subjects will be closely monitored by Investigators. Subjects with low lymphocyte count in 
circulation, or who have active infections will be excluded in this study.
S1P receptor modulators are associated with an expected, on-target, dose-dependent effect of 
reducing heart rate (HR) upon first dosing with HR recovery to predose baseline thereafter [45]. 
There have been no reported cases of symptomatic bradycardia on first dose, and rare first- or 
second-degree atrioventricular (AV) block found on ECG has been asymptomatic and transient 
(ie, spontaneous resolution) with etrasimod. An S1P1-mediated HR reduction is maximal on the 
first day of dosing with etrasimod and typically peaks approximately 3 hours postdose on Day 1 
with recovery thereafter. In Study APD334-003, the mean transient HR decrease did not exceed 
10 beats per minute (bpm) on Day 1 up to 8 hours after dosing in all treatment groups, with the 
mean nadir of HR lowering for 2 mg etrasimod occurring 3 hours after dosing [38]. Therefore, a 
dose-escalation regimen is not necessary for doses up to 2 mg.
To protect vulnerable subjects, those with certain cardiac risks or pre-existing cardiac conditions 
(eg, recent myocardial infarction, cardiac conduction delay, recurrent symptomatic bradycardia 
or syncope) will be excluded from the study. Vital signs will be monitored closely during the 
study, and direct observation will be performed after the subject receives the first dose of 
etrasimod in each treatment period (at Day 1 [Double-Blind Treatment Period] and Week 24 
[Extension Treatment Period]) or at treatment re-initiation after a defined period of treatment 
interruption (refer to Section 10.6.7.4 for additional information on Day 1 monitoring).
As additional safety measures, subjects with elevated liver enzymes, abnormal pulmonary 
function or pulmonary disease requiring hospitalization, and active retinopathy or macular edema 
will be excluded from the study.
Further description of identified risks, any potential risks, and the Reference Safety Information 
for etrasimod are provided in the current edition of the IB.
The safety profile of etrasimod coupled with a potent effect on the lymphocyte count 
demonstrate that etrasimod may be an effective oral treatment option for IMIDs such as EoE. 
Based on the favorable clinical safety and efficacy data that has been generated from etrasimod 
studies in healthy adults and subjects with UC, the precautions outlined above, and the current 
lack of safe and effective long-term oral medications for the treatment of EoE, the benefit/risk 
assessment justifies the further clinical development of etrasimod in subjects with EoE and the 
current Phase 2 study multi-center, randomized, double-blind, placebo-controlled study.


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2. OBJECTIVES
Primary:

To evaluate the effects of etrasimod on esophageal eosinophilia in adult subjects with 
active EoE

To evaluate the dose-response relationship of 2 doses of etrasimod versus placebo in 
adult subjects with active EoE

To select an etrasimod dose based on efficacy and safety for continued development
Secondary:

To evaluate the effect of etrasimod on dysphagia symptoms in adult subjects with 
active EoE
 
 
 
3. STUDY DESIGN
3.1. Overall Design
This Phase 2 randomized, double-blind, multi-center study will evaluate the efficacy, safety, and 
PK of etrasimod compared with placebo for 24 weeks in adults with active EoE.
The study will consist of a Screening Period of up to 35 days, 24 weeks of double-blind 
treatment (Double-Blind Treatment Period), 28 weeks of active extended treatment (Extension 
Treatment Period), and 4 weeks of follow-up (Safety Follow-Up Period) for a total study 
duration of up to 61 weeks.
Eligible subjects will be randomized in a double-blinded fashion (3:3:2 ratio) to etrasimod 1 mg, 
etrasimod 2 mg, or matching placebo once daily. Randomization will be stratified by baseline 
history of esophageal dilation (yes/no) and concurrent PPI therapy (yes/no).
All subjects who complete the Double-Blind Treatment Period and meet eligibility criteria for 
the Extension Treatment Period may enter the Extension Treatment Period.
Subjects who were in etrasimod 1 mg or etrasimod 2 mg groups in the Double-Blind Treatment 
Period will continue the same etrasimod dose in the Extension Treatment Period. Subjects who 
were in the placebo group during the Double-Blind Treatment Period will be re-randomized 
(1:1 ratio) to etrasimod 1 mg or etrasimod 2 mg at entry into the Extension Treatment Period. 
Subjects will have follow-up visits at 2 and 4 weeks after the last dose of study treatment after 
Week 52 or the Early Termination (ET) Visit.
A study design schematic is shown in Figure 1.
CCI


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Figure 1:
Study Design
*Esophagogastroduodenoscopy 
EoE, eosinophilic esophagitis; ETR, etrasimod; F/U, follow-up; PBO, placebo.
Numbers preceded by colons represent the randomization ratio.
3.2. Discussion and Scientific Rationale for Study Design
This Phase 2, randomized, double-blind study is designed to evaluate the safety and efficacy of 
etrasimod (1 mg and 2 mg) versus placebo for 24 weeks for the treatment of adult subjects with 
active EoE.
As previously described, EoE is a chronic, immune/antigen mediated disorder characterized 
histologically by esophageal inflammation with intraepithelial eosinophils and clinically by 
symptoms of esophageal dysfunction in adult patients (eg, dysphagia or food impaction). 
Therefore, to confirm eligibility, all subjects will undergo esophagogastroduodenoscopy (EGD) 
with biopsy and record their EoE symptoms during the Screening period. The target study 
population will comprise adult subjects with histologically active (ie, esophageal peak eosinophil 
count [PEC] ≥15 eosinophils [eos]/hpf) and sufficiently symptomatic EoE (ie, average of 
≥2 episodes of dysphagia per week over 2 weeks). Treatment options for EoE include 
medications, dietary elimination, and esophageal dilation [46]. From a clinical standpoint, the 
goal of treatment is to decrease or eliminate symptoms, improve or normalize the endoscopic 
appearance, and decrease or resolve the disease.
Treatment assignment will be blinded to minimize evaluation and reporting biases. Due to 
limited EoE treatment options, etrasimod will be compared with placebo. This will permit 
accurate characterization of the effects of investigational etrasimod relative to the placebo effect 
(ie, background effect related to fluctuations in dysphagia symptom, the natural course of EoE 
disease, regression to the mean, or response bias due to the subject’s reporting of subjective 
symptoms).
The endpoints of treatment for EoE include improvement of esophageal eosinophilic 
inflammation and clinical symptoms [47]. Therefore, several histologic primary and secondary 
efficacy endpoints will be used to characterize the effect of etrasimod on EoE including change 
(percent and absolute) in esophageal PEC and histologic response as defined by an esophageal 
PEC of < 15 or ≤6 eos/hpf. Eosinophil density is an objective, quantifiable, and highly 
reproducible measure that is also intrinsic to the disease definition. A symptom-based secondary 
efficacy endpoint (ie, change in dysphagia frequency and/or severity) will be assessed using the 
Dysphagia Symptom Questionnaire (DSQ), a validated and qualified patient-reported outcome 


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measure that has been successfully used in clinical studies investigating the efficacy and safety 
of novel treatments for EoE.
The primary efficacy endpoint is the percent change from baseline in esophageal PEC at 
Week 16. The treatment effects of 2 etrasimod doses on the reduction of esophageal tissue 
eosinophils will be characterized. The secondary endpoints include measures of histologic, 
endoscopic, and symptomatic improvement for further elucidation of the effects of etrasimod on 
EoE disease activities.
These primary and secondary endpoints will be assessed at Week 16, and treatment will be 
continued in the Double-Blind Treatment Period until Week 24. The Week 16 timepoint was 
selected for primary and secondary efficacy assessments based on meaningful clinical and 
endoscopic improvements observed in UC patients following treatment with etrasimod. Data 
from Phase 2 studies APD334-003 and APD334-005 in adult subjects with moderately to 
severely active UC demonstrated that treatment with etrasimod 2 mg once daily for up to 
46 weeks (n = 31) resulted in maximal improvements in the 2 cardinal symptoms of active UC, 
rectal bleeding and stool frequency, by Week 16, which were sustained through Week 46 
[38,39]. Although there are notable differences between EoE and UC, both are IMIDs of the 
gastrointestinal (GI) tract. Based on etrasimod’s mechanism of action and extrapolation on the 
time from etrasimod treatment initiation to observed clinical effects in patients with active UC, it 
is hypothesized that 16 weeks of etrasimod treatment will provide sufficient time to elicit the 
clinical effects of etrasimod in the treatment of patients with active EoE. Study treatment will be 
administered over 24 weeks in a double-blinded fashion and evaluation of histologic and 
patient-reported outcomes will occur at Weeks 16 and 24. Ultimately, a comparison of treatment 
effects observed at Week 16 compared to Week 24 will be performed to confirm that Week 16 is 
the timepoint at which the maximal treatment effects of etrasimod are observed in subjects with 
active EoE.
Subjects who complete the Week 24 visit will be eligible to enter the Extension Treatment 
Period, where etrasimod treatment will continue for up to an additional 28 weeks. In the 
Extension Treatment Period, subjects treated with placebo in the Double-Blind Treatment Period 
will have the opportunity to receive etrasimod, and subjects who tolerated etrasimod during the 
Double-Blind Treatment Period may continue etrasimod therapy. The maintenance or durability 
of treatment effects and longer-term safety profile of etrasimod will be characterized in the 
subset of subjects who continue etrasimod therapy over 52 weeks. Thus, the use of an Extension 
Treatment Period in this study provides study subjects with ongoing access to study treatment 
and the opportunity to evaluate the longer-term efficacy and safety profile of etrasimod.
Finally, off-treatment safety data will be collected at 2 and 4 weeks after the last dose of study 
treatment is administered.
3.3. Rationale for Dose Selection
Etrasimod doses selected for evaluation in the proposed study is based on pharmacodynamic 
(PD) and safety data from single- and multiple-ascending dose studies conducted in healthy adult 
subjects, Studies APD334-001 and APD334-002, respectively, and on safety, clinical efficacy, 
and PD data from a Phase 2 parent Study APD334-003 and extension Study APD334-005 in 
adult subjects with active UC.


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Study APD334-001 evaluated single doses of etrasimod 0.1, 0.35, 1, 3, and 5 mg. Dose-limiting 
treatment-emergent adverse events (TEAEs) of transient, asymptomatic first- or second-degree 
AV block, both with and without HR decrease, were observed in 3 subjects treated with 5 mg 
dose. No adverse events (AEs) of bradycardia or AV block were reported at doses < 5 mg. Thus, 
the 5 mg dose was discontinued in subsequent clinical studies. In Study APD334-002, etrasimod 
doses of 0.7, 1.35, and 2 mg were administered once daily for 21 days. Additionally, several dose 
escalation paradigms were evaluated in some subjects; these subjects received either 0.35 or 
0.5 mg for 7 days followed by 2 or 3 mg for 14 days, respectively. PD data from single- and 
multiple-ascending dose studies demonstrated a dose-dependent decrease in the peripheral 
lymphocyte count. Overall, etrasimod doses 0.35 to 3 mg were well-tolerated for up to 21 days.
Similarly, in Phase 2 Study APD334-003, a dose-dependent reduction in peripheral lymphocyte 
counts were observed as early as Week 1 in adult subjects with active UC treated with etrasimod 
1 mg or 2 mg, and lymphocyte counts stabilized at Week 4. Dose-dependent symptomatic and 
endoscopic improvements (ie, the Modified Mayo Score) were also observed; however, only 
favorable clinical effects of etrasimod 2 mg (and not 1 mg) demonstrated a statistically 
significant difference compared with placebo. The efficacy and safety profile of etrasimod 2 mg 
was characterized over 46 weeks across the originating Study APD334-003 and extension 
Study APD334-005. In the subset of subjects exposed to etrasimod 2 mg for up to 46 weeks, no 
clinically significant safety concerns were identified.
In summary, the PD and favorable longer-term safety profile of etrasimod 2 mg in adults with 
moderately to severely active UC suggest that it is safe to evaluate doses of etrasimod up to 2 mg 
as a chronic therapy in adult subjects with active EoE. It is hypothesized that by evaluating 
etrasimod 1 mg and 2 mg, an efficacious and safe dose for the treatment of active EoE will be 
identified for continued development.
3.4. End of Study
A subject is considered to have completed the study if he/she has completed all phases of the 
study, including the last study visit (ie, 4-Week Safety Follow-Up Visit). The end of the study is 
defined as the date of the last study visit of the last subject in the study globally.
4. STUDY POPULATION
4.1. Inclusion Criteria
Subjects must meet ALL the following inclusion criteria to be eligible for enrollment into the 
study.
1. Men or women between 18 to 65 years of age at the time of informed consent (IC)
2. Provide signed IC and willing to comply with all protocol-specified assessments and 
procedures
3. Have an EoE diagnosis prior to screening and histologically active disease with an 
esophageal PEC of ≥15 eos/hpf (~60 eos/mm2) from any level (proximal, mid, or distal) 
of the esophagus at the Screening EGD.  
4. Have dysphagia, defined as solid food going down slowly or getting stuck in the throat 
with an average frequency of ≥2 episodes per week over 2 weeks (as documented using 
the DSQ during the Screening period) 


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4.2. Exclusion Criteria
Subjects will be excluded from study if they meet any of the following exclusion criteria.
Note: A confirmed result means there have been 2 consecutive assessments showing consistent 
findings meeting exclusionary values. For criteria requiring confirmed results, the 2nd 
assessment is needed only if the first assessment result was exclusionary.
Exclusion criteria related to medications, therapies, or GI and eosinophilic disease
1. History of any of the following non-EoE conditions or procedures that may interfere with 
the evaluation of or affect the histologic, endoscopic, or symptom endpoints of the study: 
a.
Conditions that substantially contribute to esophageal eosinophilia (eg, eosinophilic 
gastritis or enteritis [ie, eosinophilic duodenitis or colitis] with esophageal 
involvement, achalasia, hypereosinophilic syndrome, CD with esophageal 
involvement, esophageal infection [fungal, viral], eosinophilic granulomatosis with 
polyangiitis (formerly known as Churg-Strauss Syndrome), pemphigus with 
esophageal involvement, pill esophagitis, graft versus host disease, Mendelian 
disorders [eg, Marfan syndrome Type II, hyper-IgE syndrome, phosphatase and 
tensin homolog (PTEN) hamartoma tumor syndrome, Netherton syndrome, severe 
atopy metabolic wasting (SAM) syndrome])
b. Conditions that interfere with the evaluation of the esophagus (eg, esophageal varices 
with risk of spontaneous bleed, high-grade esophageal stenosis where an 8- to 10-mm 
endoscope could not pass through the stricture without dilation at the time of 
Screening EGD)
c.
Conditions or procedures that substantially contribute to dysphagia (eg, histologically 
active Barrett’s esophagitis, active erosive esophagitis Los Angeles Grade B or 
above, significant hiatal hernia [≥4 cm], esophageal resection)
2. Undergone dilation of an esophageal stricture within 12 weeks prior to Screening EGD.
3. Use of corticosteroids for the treatment of EoE within 8 weeks prior to Screening EGD.
4. Discontinue, initiate, or change dosing (dosage/frequency) of the following therapies for 
EoE within 8 weeks prior to Screening EGD. Subjects on any of the following therapy 
need to stay on a stable regimen during study participation:
a.
Elemental diet
b. EoE food trigger elimination diet 
c.
PPI therapy
5. Used any immunotherapy/desensitization including oral immunotherapy (OIT) or 
sublingual immunotherapy (SLIT) within 12 months prior to the Screening EGD
Note: Stable (ie, ≥6 months prior to the Screening EGD) subcutaneous immunotherapy 
(SCIT) is permitted. Subjects on SCIT need to stay on a stable treatment during study 
participation.
6. Used any of the following immunomodulatory therapies within the timeframes prior to 
Baseline as indicated in Table 1. The Medical Monitor should be consulted with any
questions related to prior use of unlisted immunomodulatory therapies.


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Table 1:
Required Washout Period of Immunomodulatory Therapies
Time Frame
Therapies
Within 2 weeks
Antimetabolites (eg, AZA, 6-MP, MTX, 6-TG), calcineurin inhibitors (eg, 
cyclosporine, tacrolimus), MMF
Within 12 weeks (or 
5 half-lives if shorter)
Anti-IL-5 antibodies (eg, mepolizumab, reslizumab, benralizumab), anti-IL-4/13 
antibodies (eg, dupilumab), anti-IgE antibodies (eg, omalizumab), TNFα inhibitors 
(eg, infliximab), JAK inhibitors (eg, tofacitinib, oclacitinib)
Within 24 weeks 
Anti-CD20 antibodies (eg, rituximab, ocrelizumab), anti-CD52 antibodies (eg, 
alemtuzumab), other cell-depleting therapies (eg, bone marrow transplantation, total 
body irradiation)
Any time prior to 
Baseline
Sphingosine 1-phosphate receptor modulators (eg, fingolimod, siponimod, 
ozanimod), natalizumab
AZA, azacytidine; IgE, immunoglobulin E; IL-4/13, interleukin-4/13; IL-5, interleukin-5; JAK, Janus kinase; 6-MP, 
6-mercaptopurine; MMF, mycophenolate mofetil; MTX, methotrexate; 6-TG, 6-thioguanine; TNFα, tumor necrosis factor alpha
7. Use of moderate or strong inducers or inhibitors that inhibit or induce at least 2 of the 
following: cytochrome P450 (CYP) 2C8, CYP2C9, and CYP3A4 (eg, fluconazole, 
rifampin, enzalutamide) (Section 6.7.3) within 4 weeks prior to Baseline
8. Use of any investigational agent or device within 12 weeks prior Baseline
9. Have a known hypersensitivity to etrasimod or any of the excipients.
Exclusion criteria related to other medical history
10. Have any of the following conditions or risk factors:
a.
Primary or secondary immunodeficiency syndromes (eg, hereditary 
immunodeficiency syndrome, acquired immunodeficiency syndrome)
b. History of organ transplant (except corneal transplant)
c.
History of an opportunistic infection (eg, pneumocystis jirovecii pneumonia, 
cryptococcal meningitis, progressive multifocal leukoencephalopathy [PML])
d. History of disseminated herpes simplex or disseminated herpes zoster
e.
Test positive for human immunodeficiency virus (HIV [positive HIV antibody]), 
hepatitis B virus (positive hepatitis B surface antigen [HBsAg]), or active 
hepatitis C (HCV [positive hepatitis C antibody with detectable HCV RNA]) at 
Screening
Note: If the Investigator suspects false positive hepatitis serology results, such as an 
antibody pattern indicating acute hepatitis infection, but no corresponding elevated 
liver enzymes and no signs or symptoms of liver disease, an infectious disease expert 
may be consulted. If the infectious disease expert finds no evidence of acute or 
chronic hepatitis infection and considers the serology results false positive and not 
clinically relevant, the Investigator may document (in source data and in the 
electronic case report form [eCRF]) that the serology results are considered false 
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11. Have a serious infection that requires hospitalization or treatment with intravenous (IV) 
medications within 4 weeks prior to Baseline
12. Received a live-attenuated virus vaccine (except for recommended and age-appropriate 
influenza, measles/mumps/rubella, or varicella vaccine) within 4 weeks prior to Baseline
13. History of malignancy of any organ system (other than localized squamous cell or basal 
cell carcinoma of the skin that have been excised or resolved), treated or untreated, within 
the past 5 years regardless of whether there is evidence of local recurrence or metastases
14. Have active epilepsy
15. Have a history of cirrhosis
16. Have any of the following conditions or receiving treatments that may affect 
cardiovascular function:
a.
Myocardial infarction, unstable angina, stroke/transient ischemic attack, 
decompensated heart failure requiring hospitalization or Class III/IV heart failure 
within 8 weeks prior to Baseline
b. Second-degree or third-degree AV block, sick sinus syndrome without a 
functional pacemaker, or periods of asystole for > 3 seconds without an implanted 
cardiac pacemaker
c.
Recurrent symptomatic bradycardia or recurrent cardiogenic syncope
d. Confirmed Screening and Day 1 baseline vital signs (taken in the sitting position) 
with a HR < 50 bpm OR systolic blood pressure (BP) < 90 mm Hg OR diastolic 
BP < 55 mm Hg.
e.
Confirmed Screening and Day 1 baseline ECG with PR interval ≥200 ms or 
Friderica's corrected QT interval (QTcF) ≥450 ms in males or ≥470 ms in 
females. 
f.
Receiving Class Ia or Class III anti-arrhythmic drugs
g. Start, stop, or change dosage of Class Ib, II, or IV anti-arrhythmic drugs within 
1 week prior to Baseline
17. Have active diabetic retinopathy, uveitis, retinitis pigmentosum, macular edema, or had 
an intraocular surgery within 12 months prior to Baseline. Refer to Appendix 11 for 
modification in the event that coronavirus disease 2019 (COVID-19) or similar public 
health emergency (PHE)-related restrictions limit the capacity to perform non-essential 
ophthalmoscopy with OCT.
18. Have a confirmed forced expiratory volume at 1 second (FEV1) or forced vital capacity 
(FVC) of < 70% predicted (prior to the administration of a short-acting bronchodilator) 
on Screening PFTs. Refer to Appendix 11 for modification in the event that COVID-19 
or similar PHE-related restrictions limit the capacity to perform non-essential PFTs.
Exclusion criteria related to test or laboratory results (performed by central laboratory)
19. Have confirmed absolute lymphocyte count (ALC) < 0.8 × 109 cells/L at Screening
20. Have confirmed aspartate aminotransferase (AST) or alanine aminotransferase (ALT) 
> 2 × upper limit of normal (ULN) and total bilirubin > 1.5 × ULN (unless consistent with a 
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21. Have confirmed moderate or severe renal impairment (estimated glomerular filtration rate 
[eGFR] < 60 mL/min/m2)
General exclusionary criteria
22. Lactating female who is breastfeeding
23. Females who are pregnant, evidenced by a positive serum beta-human chorionic 
gonadotropin (β-hCG) pregnancy test at Screening and/or urine dipstick pregnancy test at 
Day 1, or females who do not meet criterion a or agree with criterion b below, or males 
who do not agree with criterion c below
a.
A female who is not of child-bearing potential must meet 1 of the following:

Postmenopausal, defined as no menses for 12 months without an alternative 
medical cause and confirmed by follicle-stimulating hormone (FSH) within 
postmenopausal range according to local standards

Had permanent sterilization procedure, such as hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy
b. A female who is of child-bearing potential must agree to using a highly effective 
contraception method during treatment and for 4 weeks following treatment that can 
achieve a failure rate of less than 1% per year when used consistently and correctly. 
The following are considered highly effective birth control methods: Combined 
(estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation, which may be oral, intravaginal, or transdermal; 
progestogen-only hormonal contraception associated with inhibition of ovulation, 
which may be oral, injected, or implanted; intrauterine device (IUD); intrauterine 
hormone-releasing system; bilateral tubal occlusion; vasectomized partner; sexual 
abstinence (complete sexual abstinence defined as refraining from heterosexual 
intercourse for the entire period of risk associated with study treatments). The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical study and the preferred and usual lifestyle of the subject. Periodic abstinence 
(eg, calendar, symptothermal, or post-ovulation methods) is not acceptable
c.
A male with pregnant or non-pregnant woman of child-bearing potential (WOCBP) 
partner must agree to use condoms during treatment and for 4 weeks following the 
last dose of study treatment
24. Any acute illness or medical condition including cognitive impairment and alcohol/drug 
abuse/dependence, or signs/symptoms suspicious for a serious disease that, in the 
Investigator’s opinion, could put the subject at increased risk for safety event(s), 
confound interpretation of study results, or interfere with the subject’s ability to comply 
with protocol-specified procedures or assessments. 
Testing positive for COVID-19 is NOT exclusionary on its own if other exclusion criteria (#11 
or #24) are not met. If a subject screen fails due to COVID-19, the subject may be re-screened 
for the study when their COVID-19 symptoms have improved or resolved but no sooner than 
10 days after the first date of COVID-19 symptom onset. Subjects who are asymptomatic after 
COVID-19 recovery are not required to show a negative COVID-19 viral or serology test in 
order to qualify for re-screening. 


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For subjects who have not received the COVID-19 vaccine, it is recommended that COVID-19 
vaccination is completed 14 days prior to randomization.
If a subject fails ≥1 screening laboratory criteria, the assessment(s) may be repeated once at the 
discretion of the Investigator, and the subject may be enrolled if criteria are then met, provided 
the assessments are completed within the Screening Period. Any laboratory assessments that are 
repeated beyond 1 time will need to be discussed with the Medical Monitor before proceeding.
4.3. Eligibility Criteria for the Extension Treatment Period
Inclusion Criteria:
1. Completion of the Week 24 study visit (including EGD) including subjects who 
discontinued study treatment due to lack of clinical efficacy and started rescue therapy 
between Weeks 16 and 24. Rescue therapy must be discontinued on the day etrasimod is 
initiated in the Extension Treatment Period.
2. Compliance with study procedures during the Double-Blind Treatment Period as assessed 
by the Investigator
3. No notable safety concerns during the Double-Blind Treatment Period, as determined by 
the Investigator 
4. Willing to comply with all study visits and procedures for the Extension Treatment 
Period
5. SUBJECT RESTRICTIONS
Prohibited concomitant therapies are described in Section 6.7.3. Subjects should be instructed to 
abstain from consuming herbal remedies containing St John’s wort during the study as these may 
interfere with the metabolism of etrasimod.
6. STUDY TREATMENT
6.1. Study Treatments Administered
Study treatments include the investigational medicinal product(s), defined as a pharmaceutical 
form of the active substance being tested (etrasimod) and a reference therapy (placebo). Study 
treatment is outlined in Table 2.
Table 2:
Study Treatments
Study Treatment
Dose
Mode of 
Administration
Frequency
Formulation
Etrasimod
1 mg
Oral
qd
Tablet
Etrasimod
2 mg
Oral
qd
Tablet
Placebo
NA
Oral
qd
Tablet
NA, not applicable; qd, once daily


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6.2. Identity of Study Treatments
6.2.1. Etrasimod
The active pharmaceutical ingredient in etrasimod tablets is APD334 L-arginine (the L-arginine 
salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-
tetrahydrocyclopenta[b]indol-3-yl)acetic acid), which is an off-white to light-brown solid with an 
aqueous solubility of approximately 1.38 mg/mL (pH = 8.9) at 30°C. APD334 L-arginine is 
manufactured, packaged, tested, and released in compliance with cGMP.
Etrasimod tablet drug product is a blue, round, biconvex, plain, immediate-release, film-coated 
tablet. Etrasimod tablets are composed of APD334 L-arginine active pharmaceutical ingredient 
and excipients (microcrystalline cellulose, mannitol, sodium starch glycolate, magnesium 
stearate, and Opadry® II Blue 85F90951) and is supplied in the dosage strength (based on 
etrasimod free acid content) of 1 and 2 mg. The etrasimod drug product is manufactured, 
packaged, tested, and released in compliance with cGMP. Placebo tablets are identical in 
appearance to the active drug tablets as described above.
6.2.2. Placebo
The placebo tablet formulation is composed of excipients (microcrystalline cellulose, mannitol, 
sodium starch glycolate, magnesium stearate, and Opadry® II Blue 85F90951). The placebo 
tablet is a blue, round, biconvex, plain, film-coated tablet. The placebo drug product is 
manufactured, packaged, tested, and released in compliance with cGMP.
6.3. Dosage and Administration
One tablet (etrasimod 1 mg, 2 mg, or placebo, assigned as described in Section 6.4) is to be taken 
once daily with water (either with or without food) at approximately the same time each day, 
preferably in the morning.
On study visit days with blood draws, subjects should wait to take their assigned dose after PK 
blood samples have been drawn and after all predose assessments and procedures have been 
completed. The time of PK sample collection and subsequent dosing should be documented.
6.3.1. Instructions for Missed Dose(s)
Subjects should be instructed that if they forget to take a dose, they can take the dose within 
8 hours of the normal dosing time; otherwise, they should take their next dose at the regular time 
on the following day. If the subject vomits the tablets, he/she should be instructed not to take 
additional tablets on the same day but to take the next dose at the regular time on the following 
day.
Subjects who do not take the study treatment for ≥2 consecutive days within the first week of 
either treatment period (ie, Week 1 [Double-Blind Treatment Period] or Week 24 [Extension 
Treatment Period]) or for ≥7 consecutive days after the first week of either treatment period 
must be instructed to contact the Investigator to discuss treatment re-initiation under direct 
supervision and are required to return to the study site at the time they take their next dose of 
study treatment. The subject must take the next dose of study treatment at the study site, and 
cardiac monitoring should be performed as outlined in Section 10.6.7.4.


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6.3.2. Dose Interruptions
Temporary withholding of study treatment, if deemed necessary by the Investigator, is permitted 
for up to 6 days (after Week 1) without obtaining prior approval from the Medical Monitor. If 
≥7 days of study treatment interruption is required for a medical reason, the Investigator must 
contact the Medical Monitor as soon as this is anticipated.
The instruction for missed dose(s) is outlines in Section 6.3.1.
6.4. Method of Assigning Subjects to Treatment
Subjects will be centrally assigned to randomized study drug using an Interactive Web Response 
System (IWRS). Before the study is initiated, the log in information and directions for the IWRS 
will be provided to each study site.
On Day 1 of the Double-Blind Treatment Period, subjects will be randomly assigned to 
1 of 3 treatment groups (etrasimod 2 mg, etrasimod 1 mg, or placebo) in a 3:3:2 ratio. 
Randomization will be stratified by baseline history of esophageal dilation (yes/no) and ongoing 
PPI therapy at study entry (yes/no).
At the start of the Extension Treatment Period, subjects who were randomized to either 
etrasimod 1 mg or 2 mg during the Double-Blind Treatment Period will be assigned to the same 
treatment as their Double-Blind Treatment Period treatment. Subjects who were randomized to 
placebo during the Double-Blind Treatment Period will be re-randomized to etrasimod 1 mg or 
2 mg (1:1 ratio) for the Extension Treatment Period.
6.5. Blinding
The study design includes a Double-Blind Treatment Period with limited access to the 
randomization code. The etrasimod and placebo tablets and bottles are identical in physical 
appearance. The treatment each subject receives will not be disclosed to the Investigator, study 
site staff, subject, Sponsor personnel involved with the conduct of the study (with the exception 
of the clinical supply staff and designated safety staff), or study vendors. The IWRS will hold 
treatment codes for study drug.
Site staff including investigators will be blinded to the following laboratory results while subject 
is on study treatment: WBC count, WBC differential (percentage and absolute number), and 
TBNK panel (T, B, NK, CD4+ T cell, and CD8+ T cell count [absolute number and 
percentage]). The monitoring of WBC count, WBC differential, and TBNK panel during the 
study are described in Section 10.6.7.2. Additionally, post-baseline esophageal histologic 
outcomes including eosinophil counts and Eosinophilic Esophagitis Histology Scoring System 
(EoE-HSS) scores will be blinded to site staff until the end of the study.
Treatment assignments in the Double-Blind Treatment Period and Extension Treatment Period 
should remain blinded for Sponsor, site staff, and subjects until the Week 24 dose selection 
analysis, unless that knowledge is necessary to determine a subject’s emergency medical care. At 
the time of the 24-week Double-Blind Treatment Period analysis, the sponsor staff will be un-
blinded to the initial treatment assignments, but subjects, investigators and site staff will remain 
blinded. During the Extension Treatment Period, subjects, investigators, and site staff will be 


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aware that active treatment is being provided; however, they will remain blinded to the dose 
assignments.
In case of an emergency, the Investigator has the sole responsibility for determining if 
unblinding of a subject’s treatment assignment is warranted. Subject safety must always be the 
first consideration in making such a determination. The IWRS is programmed with 
blind-breaking instructions to guide the Investigator on how to obtain treatment assignment in 
the event of an emergency unblinding. The Investigator is requested to contact the Medical 
Monitor promptly in case of any treatment unblinding. If a subject’s treatment assignment is 
unblinded, the Sponsor must be notified within 24 hours after breaking the blind. The date and 
reason the blind was broken must be recorded in the source documentation and eCRF, as 
applicable.
For suspected, unexpected, serious adverse reactions, the Sponsor’s Pharmacovigilance designee 
responsible for managing serious adverse events (SAEs), will access the IWRS to obtain the 
subject’s treatment assignment for the purpose of regulatory reporting.
6.6. Treatment Compliance
The Investigator is responsible for ensuring that subjects are correctly instructed on how to take 
the study drug and that each subject is fully compliant with the assigned regimen. The study drug 
should be dispensed by the Investigator, or by a qualified individual under the Investigator’s 
supervision. An up-to-date treatment inventory/dispensing record must be maintained as 
described in Section 7.4.
Subject compliance will be based on tablet count per bottle. Tablet counts per bottle < 80% or 
> 120% of the expected value between visits should be documented as a protocol deviation.
6.7. Concomitant Therapy
Concomitant therapy refers to all medications (over the counter and prescribed) that are taken by 
subjects and all procedures that are performed from Day 1 (the date of the first dose of study 
treatment) through the safety reporting period. Concomitant therapy (medications and 
procedures) information must be recorded in the eCRF along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding concomitant 
therapy.
6.7.1. Required Concomitant Therapy
Not applicable
6.7.2. Permitted Therapy
Stable treatment, dosage and/or dosing frequency of the following therapies:

PPIs

SCIT


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
Diet therapy (eg, elimination diet, elemental diet)

Inhaled/intranasal corticosteroids for the treatment of allergic comorbidities (eg, 
asthma, allergic rhinitis)

Short course (eg, 7 days) or pulse corticosteroid therapy for exacerbation of a 
respiratory illness (eg, asthma)

COVID-19 vaccines that are not categorized as live or live-attenuated viral vaccines 
and are approved or granted emergency use authorization
The Investigator must contact the medical monitor to discuss any changes to concomitant 
medications not listed here that could impact the outcome of the study.
6.7.3. Prohibited Concomitant Therapy
The following therapies or procedures are prohibited during the study while on study treatment 
However, in the event of an emergency, any needed medications may be prescribed without prior 
approval, but the Medical Monitor must be notified of the use of any prohibited medications 
immediately.

Esophageal dilation

Systemic corticosteroids (except pulse corticosteroid therapy, refer to Section 6.7.2)

Oral or swallowed corticosteroids (for the treatment of EoE)

SLIT or OIT

Immunomodulatory agents

Examples: Antimetabolites (eg, azacytidine [AZA], 6-mercaptopurine [6-MP], 
methotrexate [MTX], 6-thioguanine [6-TG]), calcineurin inhibitors (eg, 
cyclosporine, tacrolimus), mycophenolate mofetil [MMF], S1P receptor 
modulators (eg, fingolimod, siponimod), anti-interleukin (IL)-5 antibodies (eg, 
mepolizumab, reslizumab, benralizumab), IL-4 and IL-13 antagonists 
(dupilumab), anti-IgE antibodies (omalizumab), anti-tumor necrosis factor alpha 
(TNFα) antagonists (eg, infliximab), anti-integrin antibodies (vedolizumab, 
natalizumab), Janus kinase (JAK) inhibitors (eg, tofacitinib, oclacitinib), 
anti-CD20 antibodies (rituximab, ocrelizumab), anti-CD52 antibodies 
(alemtuzumab)

Any investigational drug other than the study treatment 

Class Ia (eg, quinidine, procainamide) and Class III (eg, sotalol, amiodarone) 
anti-arrhythmic drugs

Live-attenuated virus vaccine (except for recommended and age-appropriate 
influenza, measles/mumps/rubella, or varicella vaccine) while on study treatment and 
within 4 weeks after the last dose of study treatment

Moderate/strong inhibitors or inducers that inhibit or induce at least 2 of the 
following: CYP2C8, CYP2C9, and CYP3A4 (eg, fluconazole, rifampin, 
enzalutamide); for additional information refer to United States Food and Drug 


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Administration (FDA) Drug development and drug interactions: Table of substrates, 
inhibitors and inducers [48]

Blood donations during the study and for 30 days after the last dose of study 
treatment

Sperm or oocytes donation during the study and for 30 days after the last dose of 
study treatment
6.7.4. Rescue Therapy
Any new medication or procedure used to treat new or worsened EoE symptoms is considered a 
rescue therapy. Rescue therapy should not be withheld if, in the opinion of the Investigator, 
failure to use/implement them would compromise the safety of the subject.
Subjects who discontinue between Week 16 and Week 24 due to lack of clinically meaningful 
efficacy will be provided the option to remain in the study. For these subjects, rescue therapy 
may be given until the end of the Double-Blind Treatment Period but must be discontinued upon 
entry in the Extension Treatment Period during which all subjects receive active treatment.
7. STUDY TREATMENT MATERIALS MANAGEMENT
7.1. Packaging and Labeling
Study drug will be provided in induction-sealed, high-density polyethylene bottles with 
child-resistant screw caps and desiccant canisters. Each bottle will be labeled as required per 
country requirement. Subjects will be instructed to take 1 tablet qd as described in Section 6.3.
7.2. Storage and Handling
Bottles should be stored between 15°C to 25°C (59°F to 77°F).
7.3. Preparation
No preparation by study site personnel is required.
7.4. Accountability
Subjects will be instructed to record tablet self-administration daily and to document the time of 
their last dose prior to each study visit in an electronic diary (eDiary) that will be reviewed at 
each study visit by study site staff. 
At each site visit, subjects will return all dispensed medication bottles and any remaining tablets 
to study site staff; remaining tablets will be collected and counted by the Investigator or qualified 
staff to confirm subject compliance. The number of remaining tablets in the bottle may be 
counted by visual inspection via videoconferencing for virtual assessment. In this scenario, all 
bottles and any remaining tablets must be returned at the next study site visit.
The Investigator must maintain adequate records documenting the receipt, use, loss, or other 
disposition of study treatment tablets. To ensure adequate records, all drug supplies will be 
accounted for in the drug accountability inventory and will be monitored by counting of unused 
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7.5. Retention and Disposal
All study treatment will be reconciled by the clinical monitor and then returned or destroyed 
according to applicable country regulations. On site destruction following all local regulations 
and in accordance with applicable site standard operating procedures (SOPs) is permitted. Prior 
to any action being taken with study treatment, the Investigator will contact the Sponsor (or 
contract research organization [CRO]) for approval of such action. Final reconciliation will be 
performed at study completion.
8. REMOVAL OF SUBJECTS FROM THERAPY OR ASSESSMENT
8.1. Discontinuation of Study Treatment
Study medication must be discontinued in the following instances:

Unacceptable TEAE or TEAE that, in the judgment of the Investigator, is considered 
to not be in the best interest of the subject to continue study medication, including:

Suspected drug induced liver injury as defined by the 2009 FDA Guidance for 
Industry [49] and described in Section 10.6.7.1

Sustained decrease in absolute lymphocyte count (ALC < 0.2 × 109 cells/L) with 
treatment re-initiation or re-challenge after study treatment interruption due to a 
confirmed ALC < 200 cells/µL, as described in Section 10.6.7.2

Intolerance associated with first-dose cardiac effects (Section 10.6.7.4)
Study medication may be discontinued for the following reasons:

Lack of clinical improvement or therapeutic benefit by Week 32, as determined by 
the Investigator

Loss of clinical response after initial treatment response, as determined by the 
Investigator, at any time during the Extension Treatment Period

Subject non-compliance
The Medical Monitor should be notified when a subject is discontinued from study treatment.
8.2. Reasons for Discontinuation from the Study
The reason(s) for study discontinuation must be determined by the Investigator and recorded in 
the source documents and on the eCRF. If a subject discontinues for more than 1 reason, each 
reason should be documented in the source document and the most clinically relevant reason 
should be entered on the eCRF.

AE

Withdrawal by subject

Study termination by Sponsor

Pregnancy

Non-compliance

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
Lack of efficacy

Death

Other
All patients should be encouraged to complete the study. However, a subject may elect to 
discontinue study participation at any time for any reason without prejudice to their future 
medical care by the physician or the institution. If a subject withdraws consent, no further 
evaluation should be performed, and no additional data should be collected. The Sponsor may 
retain and continue to use any data collected before such withdrawal of consent. The Investigator 
should make a reasonable attempt to document the specific reason why consent was withdrawn 
and date of last study drug intake.
Subjects who discontinue treatment prematurely, regardless of the reason, should be instructed to 
return for an Early Termination and Follow-Up Visits. Refer to Section 9.6 and Section 9.5 for 
description of ET and follow-up procedures, respectively.
8.3. Lost to Follow-Up
A subject will be considered lost to follow-up if the subject repeatedly fails to return for 
scheduled visits and cannot be contacted by the study site.
The following actions must be taken if a subject fails to return to the study site for a required 
study visit:

The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study

Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and 
if necessary, a certified letter to the subject’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s
eCRF
Should the subject continue to be unreachable, he/she will be considered to have withdrawn from 
the study.
8.4. Premature Termination of the Study or a Study Site
The Sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include, but are not limited to, the following:

The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects

Subject enrollment is unsatisfactory

Upon request of Health Authorities
The Sponsor will notify the Investigator if the study is placed on hold or if the Sponsor decides 
to discontinue the study. Health authorities and Independent Ethics Committees 


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(IECs)/Institutional Review Boards (IRBs) will be informed about the termination of the study in 
accordance with applicable regulations.
The Sponsor has the right to replace a study site at any time. Reasons for replacing a study site 
may include, but are not limited to:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the ICH guideline for GCP
9. STUDY PERIODS
9.1. General Instructions
Study procedures and their timing are summarized in the Schedules of Assessments 
(Appendix 1; Table 7 and Table 8). Protocol waivers or exemptions are not allowed unless 
specified otherwise.

Results of all protocol required procedures must be recorded in the eCRF.

Immediate safety concerns should be discussed with the Medical Monitor 
immediately upon occurrence or awareness to determine if the subject should 
continue or discontinue study treatment.

Adherence to the study design requirements, including those specified in the 
Schedules of Assessments, is essential and required for study conduct.

Study visits should be scheduled in the morning, whenever possible.

All laboratory assessments required by the protocol will be performed by a central 
laboratory unless otherwise stated.

On study day visits with blood draws, subjects should take their study treatment after 
predose assessments and procedures (eg, PK sample collection) have been completed.
The Investigator will maintain a screening log and enrollment log to record details of all subjects 
screened and to confirm eligibility or record reasons for screening failure, as applicable.
9.2. Screening
Subjects must sign the informed consent form (ICF) and meet study eligibility criteria before any 
study-specific procedure can be performed (Section 12.2).
All screening evaluations should be completed and reviewed within 35 days prior to Day 1 to 
confirm subject eligibility. In some cases, the screening visit window for a given subject may be 
extended by 2 business days beyond the date the Investigator receives the screening 
histopathology report to confirm subject eligibility. Note that only extension of the screening 
visit window due to a legitimate delay in the reporting of screening histopathology report will be 
approved by the Medical Monitor and will not be considered a protocol deviation.   
Refer to Appendix 11 for modification in the event that COVID-19 or similar PHE-related 
restrictions limit the capacity to perform certain Screening assessments. 


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The Medical Monitor should be consulted to see whether repeat testing is needed if the subject is 
planned to be enrolled > 35 days from the signing of the ICF.
The Screening EGD should be performed early in the screening period (preferably within the 
first 7 days of the screening period) to allow sufficient time for central reading to confirm 
eligibility by histology.
During Screening, subjects will record daily presence of dysphagia to solid food in their eDiary, 
according to the question-answer format of the DSQ. Subjects will begin daily eDiary entries 
starting on the first day of Screening after the eDiary training is completed. eDiary device and 
training should be provided at Screening to ensure capturing of entries within the required 
14-day period. Study site staff will monitor the eDiary compliance. At least 8 DSQ daily entries 
in the last 2 weeks prior to Day 1 visit as well as completion of Patient Global Impression of 
Severity (PGIS) are needed for randomization.
9.3. Double-Blind Treatment Period
9.3.1. Day 1 Pre-Randomization and Predose
The day of administration of the first dose is defined as Day 1.
The following procedures/assessments must be performed and assessed again on Day 1 to 
confirm eligibility before randomization:

HR and BP, followed by 12-lead ECG

Pregnancy test for all WOCBP
If the subject remains eligible based on HR, BP, and 12-lead ECG parameters, and has a negative 
pregnancy test result (WOCBP only), then blood samples for laboratory and PK assessments will 
be collected, after the 12-lead ECG assessment is completed.
Subjects will also complete selected questionnaires to assess baseline status.
9.3.2. Day 1 Randomization and Postdose
After the eligibility criteria have been confirmed and the Day 1 predose assessments 
(Section 9.3.1) are completed, subjects will be enrolled and randomly assigned to treatment.
First dosing of study treatment will be given, and cardiac monitoring will take place under direct 
observation for at least 4 hours. HR and ECG measurements will be performed according to 
Table 5 and the subject will be assessed for discharge at 4 hours postdose. Refer to 
Section 10.6.7.4 for detailed guidance on first-dose cardiac monitoring and subject discharge 
criteria postdose.
Additional blood sample for PK assessment will be taken 4 hours (± 15 minutes) postdose after 
the Hour 4 ECG.
9.4. Extension Treatment Period
9.4.1. Week 24 Visit
The Week 24 visit will be used to assess eligibility for the Extension Treatment Period and is 
considered the beginning of the Extension Treatment Period. During this visit, eligibility for 


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entry into the Extension Treatment Period will be confirmed (ie, meets eligibility criteria; 
Section 4.3).
At the Week 24 visit, vital signs should be measured first, followed by ECG, predose PK sample 
collection, study drug dosing at the study site, and first-dose cardiac monitoring (direct 
observation) for at least 4 hours in all subjects continuing in the Extension Treatment Period. 
Cardiac monitoring is required because there is a subset of subjects who will transition from 
placebo in the Double-Blind Treatment Period to an etrasimod dose in the Extension Treatment 
Period. Refer to Section 10.6.7.4 for detailed guidance on first-dose cardiac monitoring and 
subject discharge criteria postdose.
9.5. Follow-Up/End of Study
All subjects will have follow-up visits for safety assessment at 2 and 4 weeks after the last dose 
of study treatment. All AEs should be recorded for 30 days after last dose of study medication 
(Section 10.6.8.1.9). Refer to Section 10.6.7.2 for details on the post-treatment follow up 
assessments and procedures for subjects who experience an ongoing AE of decreased 
lymphocyte count or infection.
In the event that a subject fails to attend any follow-up visits, all reasonable efforts will be made 
to contact the subject to ensure that he/she is in satisfactory health. All contacts and contact 
attempts must be documented in the subject’s medical record.
9.6. Early Termination
Subjects who discontinue the study prior to the end of the 24-week Double-Blind Treatment 
Period or the 28-week Extension Treatment Period (Week 52) will return to the study site for an 
ET Visit. The ET Visit should occur within 7 days of last dose and before initiation of any new 
treatments.
Site staff will work with subjects who withdraw early to obtain as much follow-up data as 
possible, including an EGD, if not done within 4 weeks, and PFTs and ophthalmic and OCT 
testing. If a subject discontinues due to pregnancy, they may not be required to complete the 
EGD and biopsy.
9.7. Telehealth and Hybrid Visits
Study visits may be conducted as a Telehealth Visit, Home Health Visit or a Hybrid Visit. Refer 
to Section 10.1 for details on virtual and in-person assessments and procedures. These types of 
study visit will reduce direct human-to-human contact time, an important public health strategy 
to reduce COVID-19 transmission.
Study visits that may be conducted as a Telehealth Visit are designated in the Schedules of 
Assessments (Appendix 1; Table 7 and Table 8). All other study visits may be conducted as a 
Hybrid Visit.
9.7.1. Telehealth Visits
A Telehealth Visit refers to a visit consisting only of virtual assessments. 
Telehealth visits may be used to assess subject safety and collect data points. Telehealth includes 
the exchange of healthcare information and services via telecommunication technologies (eg, 
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communicate on aspects of clinical care, including medical advice, reminders, education, and 
safety monitoring. The following assessments must be performed during a telehealth visit (see 
the SoA):

Review and record study drug(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 10.6.8.  

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing. Confirm that 
the subject is adhering to the contraception method(s) required in the protocol. Refer to 
Section 4.2. 
Study subjects must be reminded to promptly notify site staff about any change in their health 
status.
9.7.2. Home Health Visits 
A home health care service may be utilized to facilitate scheduled visits. Home health visits 
include a healthcare provider conducting selected in-person study assessments at the subject’s 
location, rather than an in-person study visit at the site. The following may be performed during 
a home health visit (see the SoA):  

Review and record study drug (s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 10.6.8.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method and results of pregnancy testing. Confirm that 
the subject is adhering to the contraception method(s) required in the protocol. Refer to 
Section 4.2. 
9.7.3. Hybrid Visits
A Hybrid visit refers to a visit consisting of both virtual assessments and in-person assessments 
that may be performed on different days within the study visit window.
10. STUDY ASSESSMENTS AND PROCEDURES
10.1. Virtual and In-Person Assessments
Virtual assessment refers to an assessment conducted by phone or video-conferencing where the 
study site staff (including the Investigator) and subject are not physically present with each other. 
In-person assessment refers to assessments that require physical presence of both the subject and 
Investigator or delegated study staff. For in-person assessments, subjects may visit the study site 


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or the Investigator or delegated study staff may arrange to visit the subject (ie, Home Health 
Visit).
Assessments or procedures that may be conducted virtually include the following: The informed 
consent process including obtaining written informed consent, medical history and concomitant 
medication query to assess eligibility criteria, review of demographic information, social and 
family history, AE query, review of concomitant medications, eDiary training and compliance 
review/monitoring including study drug administration and questionnaires, and the urine 
pregnancy testing (for WOCBP). 

AE Assessment: During the virtual assessment, a subject may report an AE that 
requires a follow-up symptom-focused physical exam or diagnostic testing, as 
determined by the Investigator. In this scenario, the Investigator may have the subject 
return to the study site for an unscheduled study visit to perform the assessment.

Pregnancy Test: Pregnancy test results (for WOCBP) should be visually inspected, 
when possible, via video conferencing when it is a virtual assessment.

Study Drug Dispensation: Study drug may be dispensed by secure mail per 
country-specific guidance prior to the Telehealth Visit. Alternatively, a future supply 
of study medications may be dispensed to the subject at a site visit to cover study 
medications to be dispensed at the Telehealth Visit. In-person dispensation of study 
drug is preferred. 

Study Drug Accountability: Medication bottle(s) and remaining tablets may be 
visually inspected and counted on video conferencing. Subjects must return dispensed 
bottle(s) and any remaining tablets to the study site at the next site visit.
Subjects will visit the study site or a specialist (eg, ophthalmologist) for the following in-person 
assessments: EGD, full or focused physical exam, first-dose cardiac monitoring, and ophthalmic 
exam with OCT. Other in-person assessments (eg, vital signs, blood collections for serum 
pregnancy test, clinical laboratory tests, and PK sampling) may be performed by delegated study 
staff deployed to visit the subject.
Guidance on mitigating challenges that may occur as a result of COVID-19-related limitations, 
restrictions, or local/national public health official mandates is provided in Appendix 11.
10.2. Subject Informed Consent
The Investigator, or a person designated by the Investigator, will obtain written IC [50] from 
each subject before any study specific activity is performed (refer to Section 12.2 for additional 
details). A digital IC document may be used to provide information usually contained in a 
physical IC document, and the electronic signature may be used to document the subject’s signed 
informed consent. The IC process may take place at the study site with both the Investigator and 
subject physically in the same location, or it may take place over the phone or by video 
conferencing, where the Investigator and subject are in different locations. The Investigator or 
the person designated by the Investigator will administered the IC process and answer the 
subject’s questions in the same manner, whether the process is done in person, by phone or using 
other telehealth communication technology. The virtual process may be used where permitted by 
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10.3. Screening and Eligibility
10.3.1. Demography and Other Subject Characteristics
Demographics including year of birth, sex at birth, Hispanic ethnicity, and race as described by 
the subject will be collected at Screening.
10.3.2. Social and Family History
A history of current tobacco and/or alcohol use at Screening will be recorded.
Family history of eosinophilic, atopic (eg, eczema, asthma, and rhinoconjunctivitis), and other 
GI diseases will also be collected at Screening.
10.3.3. Prior Therapies
Prior or current use of the following therapies, if applicable, will be recorded in the eCRF. 

Elemental diet (specify name, year start and stop, reason for discontinuation of 
elemental diet, if applicable).

Trigger food elimination diet (name of EoE food triggers, year start and stop, reason 
for discontinuation of elimination diet, if applicable).

EoE medical therapies (eg, PPIs, swallowed topical steroids, investigational EoE 
therapies accessed through a clinical trial): name of medication, dosage, dosing 
frequency, route of administration, side effects or intolerance, start and stop dates 
(month and year), the reason(s) for treatment discontinuation (eg, initial inadequate 
response, initial response followed by loss of response, or intolerance). Record the 
Investigator’s characterization of the subject’s responsiveness to PPIs and/or 
swallowed topical steroid therapy as responsive, refractory, or not applicable.

Esophageal dilation (month and year of first procedure and most recent procedure). If 
more than 1 dilation has been performed, record the duration of time (in months) 
between the last 2 dilation procedures and the impact of dilation on EoE symptoms 
(eg, complete or partial resolution of dysphagia to solid food). 

Any history of immunotherapies for allergies (eg, OIT, SLIT, SCIT): Type of 
immunotherapy, name of specific food or aeroallergen, start and stop date (month and 
year) of immunotherapy, if applicable.
All medications (eg, prescribed medications, over-the-counter medications, vitamins, and herbal 
supplements) received within 30 days prior to the Baseline visit (Day 1) will be recorded in the 
eCRF as follows: Name of medication, dosage, dosing frequency, indication, and start and stop 
date (month and year), if applicable. The name of any live-attenuated vaccines received within 
30 days prior to the Baseline visit will also be recorded.
10.3.4. Medical History
The following EoE medical history will be recorded in the eCRF: Year of EoE diagnosis, known 
food triggers of EoE disease, last known esophageal PEC and location (proximal, mid, and or 
distal esophagus), known endoscopic findings (eg, fixed rings, exudates, furrows, edema, 
strictures), dominant EoE symptoms (eg, dysphagia, food impaction, and/or specific food 


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avoidance), and EoE histopathologic phenotype (eg, inflammatory, fibrostenosis with or without 
strictures).
If a subject has a history of esophageal dilation, any prior complications related to dilation 
procedure should be noted.
History of atopic comorbidities (eg, allergic rhinitis, bronchial asthma, atopic dermatitis, 
IgE-mediated food allergies, other eosinophilic diseases), exclusionary comorbidities (refer to 
Section 4.2), and all prior hospitalizations and surgeries (reason and year) will also be recorded.
10.3.5. Pregnancy Testing
The following instructions on pregnancy testing apply to all WOCBP. Women who are 
surgically sterile or who are postmenopausal are not considered to be of child-bearing potential. 
Postmenopausal is defined as 12 consecutive months with no menses without an alternative 
medical cause and confirmed by an FSH level in the postmenopausal range. In the absence of 
12 months of amenorrhea, a single FSH measurement is insufficient to confirm postmenopausal 
state.
At Screening a serum pregnancy test for β-hCG will be performed to determine eligibility. On 
Day 1, urine pregnancy test must be performed and negative pregnancy must be documented 
prior to dosing.
After Day 1, urine pregnancy tests (β-hCG) should be performed monthly either at home per 
country-specific guideline or at the study site and documented in the eDairy or eCRF. Monthly 
home urine pregnancy tests will be supplied to subjects as needed. Negative pregnancy test 
results for the respective month must be verified prior to in-person dosing for Hybrid Visits. 
Visual inspection of the pregnancy test result via videoconferencing is recommended for virtual 
assessments and it should be documented. Subjects should be instructed to immediately report 
any positive result to the study site, and the subject will have study treatment interrupted and a 
serum sample will be submitted to the central laboratory for β-hCG testing. If the serum test 
confirms positive, the subject will be discontinued from the study treatment and all the necessary 
follow-up will be conducted as per Section 10.6.9. If the serum test is negative, the subject may 
resume study treatment.
10.3.6. Esophagogastroduodenoscopy
Planned timepoints for the EGD with biopsy collection are provided in the Schedules of 
Assessments (Appendix 1; Table 7 and Table 8).
To ensure quality data and standardization, the same trained endoscopist at each site should be 
used throughout the study wherever possible.
Endoscopic findings will be assessed by the trained personnel performing the EGD using the 
Eosinophilic Esophagitis Endoscopic Reference Score (EREFS; Section 10.4.2.1).
Biopsy collection (Section 10.3.6.1) and histopathology assessments by central reading will 
include eosinophil count (Section 10.4.1.1) and histologic characterization using the EoE-HSS 
(Section 10.4.1.2).


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10.3.6.1. Biopsy Collection
Biopsies will be obtained at each endoscopy to support assessment of the histopathology and, 
where permitted, for the assessment of
.
At the Screening EGD (Baseline), biopsies from 3 levels of esophagus as well as the gastrum and 
duodenum will be obtained for all subjects to determine eligibility criteria. If any of these 
assessments are missing, the subject will not be eligible. If the Screening EGD identifies 
eosinophilia in the stomach and/or duodenum, the subject will be excluded from the study. At 
each subsequent EGD, only esophageal biopsies will be taken.

For esophageal biopsy collection, approximately 4 specimens will be collected from 
each esophageal level (proximal, mid and distal) targeting areas of apparent 
inflammation, when possible, to increase the diagnostic yield [6]

For gastric biopsy collection, approximately 2 specimens will be collected from 
antrum and from fundus or body of the stomach each

For duodenal biopsy collection, approximately 4 specimens will be collected from the 
second (descending) portion of the duodenum
Detailed instructions for endoscopic biopsies (eg, number of biopsies, anatomic site, normal or 
inflamed mucosa) will be provided in the Histopathology Manual.
All esophageal biopsy samples will be processed by a central laboratory. Biopsy specimen 
transfer, processing, slide preparation, and digitization procedures will be detailed in a 
Histopathology Manual.
10.3.7. Rescreening
If a subject fails Screening, 1 rescreening attempt during a new Screening Period may be made at 
the Investigator’s discretion. Additional screening attempts beyond the first should be approved 
by the Medical Monitor prior to rescreening. Each subject must be reconsented prior to each 
screening attempt.
The results from the Screening EGD, ophthalmoscopy with OCT or PFTs from the first 
Screening Period may be used to confirm eligibility for rescreening if the results were obtained 
within 90 days prior to Day 1 (Baseline).
10.4. Efficacy Assessments
The efficacy assessments (esophageal PEC, EoE Histology Scoring System [HSS], DSQ, Food 
Avoidance Question [FAQ], EREFS, Adult Eosinophilic Esophagitis Quality of Life 
[EoE-QOL-A], Patient Global Impression of Change [PGIC] and Patient Global Impression of 
Severity [PGIS]) will be performed according to the Schedules of Assessments (Appendix 1; 
Table 7 and Table 8).
10.4.1. Histology
Details on biopsy collection are provided in Section 10.3.6.1.
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10.4.1.1. Esophageal Peak Eosinophil Count
Eosinophils will be counted in the areas of greatest eosinophil density. Counts will be reported as 
the number of eos/hpf and multiple hpfs will be analyzed until the PEC is clearly identified after 
taking into account all biopsies from all esophageal levels.
The esophageal PEC will be determined by a central reader who is blinded to the identity of 
treatment assignment and EGD collection timepoints (except for the Screening EGD). Eligibility 
based on PEC will be made available to the study sites.
A subject with a PEC of ≥15 eos/hpf at any levels (proximal, mid, or distal) of the esophagus 
will be eligible to enroll in the study. Change from baseline (percentage and absolute) in PEC 
and histologic response (yes/no) based on pre-defined PEC timepoints will be used to 
characterize histologic efficacy as described in Section 11.5.
10.4.1.2. Eosinophilic Esophagitis Histology Scoring System
The EoE-HSS is a method to objectively assess histologic changes in the esophageal mucosa 
beyond eosinophil number. It describes changes in 8 histologic features of the esophageal 
mucosa: eosinophil density, basal zone hyperplasia, eosinophil abscesses, eosinophil surface 
layering, dilated intercellular spaces, surface epithelial alteration, dyskeratotic epithelial cells, 
and lamina propria fibrosis [51]. The severity (grade) and extent (stage) of abnormalities are 
scored using a 4-point scale (0 normal; 3 maximum change).
The EoE-HSS will be used to characterize the baseline esophageal histopathologic severity of 
EoE disease and changes with treatment intervention. Histopathologic scoring by EoE-HSS will 
be performed by a central reader who is blinded to treatment allocation and EGD collection 
timepoints. The EoE-HSS is further defined in Appendix 2.
10.4.2. Endoscopy
10.4.2.1. Eosinophilic Esophagitis Endoscopic Reference Score
The EREFS will be used to characterize the baseline endoscopic severity of EoE and changes 
with treatment.
The presence and severity of esophageal endoscopic features (eg, edema, rings, exudates, 
furrows, and strictures) will be characterized using the EREFS [52]. Endoscopic scoring by 
EREFS will be performed by the local endoscopist, who is blinded to the subject’s treatment 
assignment. Grading severity and respective description of each endoscopic feature is detailed in 
Appendix 3.
10.4.3. Clinical Outcome Assessments
Completion of the following questionnaires will be monitored by site staff.
10.4.3.1. Dysphagia Symptom Questionnaire
The DSQ is a validated patient-reported outcome questionnaire that captures the presence and 
severity of dysphagia to solid food in patients with EoE. Subjects record whether they have eaten 
solid food since waking up, any dysphagia to solid food on that day, dysphagia severity based on 
relief strategies utilized during the dysphagia episode and the severity of the worst daily pain 
related to swallowing, if there is any [47,53]. The DSQ will be used to characterize baseline 
dysphagia severity and changes with treatment intervention.


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Questions 1 and 2 of the DSQ from the subject’s daily eDiary entries will be used to determine 
the eligibility regarding active dysphagia during the Screening Period. One episode of dysphagia 
is counted when a subject responds “yes” to questions 1 and 2 of the DSQ. Subjects must have at 
least an average of 2 episodes of dysphagia per week over 2 weeks during the Screening Period.
During the study, the DSQ will be completed daily in the evening after the last meal of the day.
The DSQ will be scored over a 14-day period, and a minimum of 8 DSQ daily eDiary entries out 
of the 14-day period preceding the date of scoring are required to calculate DSQ score. The DSQ 
total score range is 0 to 84.
Daily dysphagia symptom diary questions are provided in Appendix 4.
10.4.3.2. Food Avoidance Question
The FAQ assesses the reason(s) why a subject did not try to eat solid food in a given day: 
1) Because of EoE, or 2) Because of other reasons. The FAQ will be administered daily via the 
eDiary, after the subject completes the DSQ diary questions. Only the subjects who did not eat 
solid food on the respective day will complete the FAQ.
The FAQ is provided in Appendix 5.
10.4.3.3. EoE-QOL-A
The EoE-QOL-A questionnaire is a disease-specific measure of health-related quality of life 
(QOL) in adults with EoE [54]. It measures 5 domains: eating⁄dietary impact, social impact, 
emotional impact, disease anxiety and choking anxiety. Subjects will complete the questionnaire, 
if available, via the eDiary on Day 1 (Baseline) and at Weeks 16, 24, 32, and 52.
10.4.3.4. Patient Global Impression of Severity
The PGIS is a current-state, 4-point Likert scale that captures the subject’s overall impression of 
EoE symptom severity over the past week. The PGIS will be administered via eDiary on Day 8 
and Day 1 of the Screening Period which will serve as the baseline and at Weeks 15, 16, 23, 24, 
31, 32, 51, and 52.
The PGIS is provided in Appendix 6.
10.4.3.5. Patient Global Impression of Change
The PGIC is a 5-point Likert scale that captures the subject’s overall impression of change in 
EoE symptoms from Baseline. The recall period is 16 to 52 weeks. The PGIC will be 
administered via eDiary at Weeks 16, 24, 32, and 52.
The PGIC is provided in Appendix 7.
10.5. Pharmacokinetic Assessments
Blood samples for plasma analysis of etrasimod will be collected at the following timepoints 
from all subjects who received ≥1 dose of study drug (etrasimod or placebo):

Predose and at 4 hours (± 15 minutes) postdose (after ECG) on Day 1

Predose (trough; within 60 minutes prior to dosing) at Weeks 4, 8, 16, 24, 28, 32, 46, 
and 52 or at the ET Visit, if applicable


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
At the 4-Week Safety Follow-Up Visit (28 days [± 3 days] after the last dose of study 
drug)

If possible, at the time of an AE leading to study drug discontinuation or when there 
is a significant AE such as a severe or atypical infection (including but not limited to 
systemic infections like sepsis) and severe drug induced liver injury that meets Hy’s 
criteria [49]. The time of the last study treatment dose should be documented.
Subjects should be instructed to document the time of their last dose prior to the study visit 
(Section 7.4) and the time must be recorded in the eCRF. The time of PK sample obtained 
predose and when study drug is administered during the study visit must also be recorded in the 
source.
Blood samples will be processed for collection of plasma fractions for determination of the 
concentrations of etrasimod and, if warranted, metabolites of interest. Blood samples collected 
for PK analyses may also be used for profiling of drug-binding proteins, bioanalytical method 
validation purposes, stability assessments, metabolite assessments, or to assess other actions of 
etrasimod with plasma constituents.
No urine samples will be collected for PK analysis.
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
Planned timepoints for all PK assessments are provided in the Schedules of Assessments 
(Appendix 1; Table 7 and Table 8).
10.6. Safety Assessments
Planned timepoints for all safety assessments are provided in the Schedules of Assessments 
(Appendix 1; Table 7 and Table 8).
10.6.1. Vital Signs
Resting vital signs measurements will be made in the seated position and include HR, BP, body 
temperature, and respiratory rate. Vital signs will be measured prior to any blood draws that 
occur at the same study visit or overlapping timepoint.
10.6.2. Physical Examinations
Full physical examination includes the following assessments:

General inspection, including height (Day 1 only) and weight

Head/ears/eyes/nose/throat examination 

Cardiac examination

Auscultation of lungs

Abdominal examination (liver, spleen)

Neurological assessment

Musculoskeletal assessment 

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Full physical examinations will be performed on Day 1 and Week 52 or at the ET Visit. For 
visits where a full physical examination is not required, symptom-directed physical examination 
should assess clinically significant changes from prior study visits including the baseline 
physical examination or any new signs or symptoms. Symptom-directed physical examination 
may be performed at the Investigator’s discretion at any time during the study.
10.6.3. Electrocardiography
All ECGs will be recorded from a 12-lead ECG machine. Every attempt should be made to 
ensure the subject ECG readings are obtained using the same machine throughout the study.
All ECGs will be recorded with subjects in supine position.
Intervals to be provided on the confirmed read for each safety ECG are RR, PR, QRS, QT, QTcB 
(Bazett’s corrected QT interval), and QTcF.
The Investigator or designee will be responsible for review and interpretation of ECGs on site 
and assessing if the ECG is normal, abnormal clinically insignificant, or abnormal clinically 
significant. Findings will be documented in the eCRF.
Specific guidance on cardiac monitoring including ECG assessment following the first dose of 
study treatment is provided in Section 10.6.7.4.
10.6.4. Clinical Laboratory Assessments
Details regarding clinical laboratory sample collection, preparation, and shipment are provided in 
the laboratory manual by the central laboratory. All laboratory assessments required by the 
protocol will be performed by a central laboratory unless otherwise stated or warranted due to 
special circumstances (eg, inability to ship to central laboratory due to COVID-19 restrictions, 
Appendix 11). Refer to Table 3 for the list of clinical laboratory tests to be performed.
Clinical safety laboratory tests should be completed predose. The Investigator must review the 
laboratory report, document the review, and record any clinically relevant changes in the AE 
section of the eCRF (results of the white blood cell differential including ALC will be reviewed 
and monitored as described in Section 10.6.7.2). The laboratory reports must be filed with the 
source documents.
All laboratory tests with values considered clinically significantly abnormal (ie, those that are 
AEs) during participation in the study or within 30 days after the last dose of study treatment 
should be repeated until the values return to normal range, have stabilized, or are no longer 
considered clinically significant by the Investigator. If such values do not return to normal or 
stabilized, or otherwise resolve to a non-clinically significant value within a reasonable period of 
time, as judged by the Investigator, the etiology should be identified, and the Medical Monitor 
should be notified. In cases when laboratory values from non-protocol-specified assessments are 
performed at the institution’s local laboratory and result in a change in subject management or 
are considered clinically significant by the Investigator (eg, AE), then the results must be 
recorded in the eCRF.
Information on the grading and management of laboratory abnormalities according to assessed 
severity is provided in Appendix 8 and Appendix 9. See Appendix 12 for suggested actions and 
follow-up assessments in the event of potential DILI.


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Table 3:
Clinical Laboratory Tests
Infectious Disease
HIV-1 and -2 antibody, HBsAg, total anti-HBc, HCV 
antibody (if positive, reflex to HCV RNA 
quantification)
Coagulation
International normalized ratio (INR)
Activated partial thromboplastin time
Pregnancy and Postmenopausal Status Testing
Serum pregnancy test for β-hCG (Screening or if 
positive urine pregnancy test; WOCBP only)
Urine pregnancy test for β-hCG (Day 1 and monthly 
post-Day 1; WOCBP only)
FSH (Screening; postmenopausal women only)
CBC with Differentials
Hematocrit
Hemoglobin
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin concentration
Mean corpuscular volume
Platelet count
Red blood cell count
WBCa count
WBC differential count (absolute and %): lymphocytes, neutrophils, eosinophils, monocytes, basophils  
TBNK Panela
T, B, NK, CD4+ T cell and CD8+ T cell count (absolute number and percentage)
Serum Chemistry
Albumin
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Bicarbonate
Blood urea nitrogen
Calcium
Chloride
Creatinine
Glucose
Potassium
Sodium
Total bilirubin
Total protein
a WBC count, WBC differential count, and TBNK panel will be assessed by an independent Medical Monitor during treatment 
(ie, after Day 1) until completion of the Double Blind Treatment Period dose selection analysis at Week 24 or subject 
discontinues study treatment (whichever occurs first) while the Investigators will assess the results of these lab parameters during 
Screening, on Day 1, and during the post treatment follow-up (refer to Section 10.6.7.2).
β-hCG, beta-human chorionic gonadotropin; CBC, complete blood count; FSH, follicle-stimulating hormone; HBsAg, hepatitis B 
surface antigen; anti-HBc, hepatitis B core antibody; HCV, hepatitis C virus; HIV, human immunodeficiency virus; 
INR, international normalized ratio; TBNK, T, B, NK, CD4+ T cell, and CD8+ T cell count (absolute number and percentage); 
WBC, white blood cell; WOCBP, woman of child-bearing potential
CCI


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10.6.5. Pulmonary Function Test
PFTs will be performed according to the Schedules of Assessments (Appendix 1; Table 7 and 
Table 8). Where locally available, diffusing capacity of the lungs for carbon monoxide (DLCO) 
measurements will also be performed (sites where DLCO is not available should consult the 
Sponsor or Sponsor’s delegate). Because carbon monoxide binds readily to hemoglobin, the 
diffusion capacity needs to be corrected for hemoglobin in order to reflect an altered lung gas 
transport rather than altered hemoglobin. All DLCO values will be corrected for hemoglobin 
concentration (ie, hemoglobin-adjusted diffusion capacity) in the study.
PFTs and DLCO (or other acceptable pulmonary function methods) will be conducted in all 
subjects in a manner consistent with the American Thoracic Society/European Respiratory 
Society guidelines for standardization of spirometry and single breath determination of carbon 
monoxide uptake in the lung [55-57]. Concern has been raised that pulmonary function testing 
could represent a potential avenue for COVID-19 transmission due to the congregation of 
patients with lung disease and because of the potential for coughing and droplet formation 
surrounding pulmonary function testing procedures. Refer to Appendix 11 for modifications in 
the event that COVID-19 or similar PHE-related restrictions limit the capacity to perform 
non-essential PFTs.
Patient respiratory history will be collected at the Screening Visit, and any condition that might 
affect the outcome of PFT, including infection, respiratory symptoms, occupational exposures 
(including asbestos) and cigarette smoking, will be collected before every PFT and recorded in 
the eCRF. Furthermore, any issues with patient effort or compliance with the test procedure 
should be explicitly recorded in the eCRF. This information is important to determine whether 
PFT abnormalities may be the result of poor effort or compliance with test procedure. Smoking 
status (including ecigarettes) will be collected and recorded in the eCRF each time a PFT 
assessment is conducted.
Subjects reporting any respiratory symptoms (eg, dyspnea, shortness of breath, chest tightness, or 
wheezing) should be seen at an unscheduled visit for clinical assessment and full PFT 
assessment, preferably on the same day.
Additional guidance on clinical monitoring of pulmonary function is provided in 
Section 10.6.7.5.
10.6.6. Ophthalmoscopy and Optical Coherence Tomography
A complete ophthalmoscopy and OCT assessment will be performed according to the Schedules 
of Assessments (Appendix 1; Table 7 and Table 8) and all ophthalmic findings should be 
recorded in eCRF.
The OCT machine used should preferably not be changed during the study to allow for 
comparison of central foveal thickness measurements within each subject across timepoints.
The ophthalmologist should be provided with a study referral letter explaining the reason for the 
referral along with information about the study, the investigational drug, and the ophthalmic 
clinical data to be collected for the study.
At the Screening and Post-Screening Visits, eye examination performed by an ophthalmologist 
will include:


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
Ophthalmologic history

Best corrected visual acuity measurement (autorefraction, using Snellen chart 
internationally)

Ophthalmoscopy

May include contact lens biomicroscopy to examine the macula and optic disc

A dilated fundus exam should be performed in all subjects at the Screening Visit 
and as needed at subsequent visits in subjects with significant abnormalities 
identified on the screening exam. Subjects should be advised to wear sunglasses 
after pupil dilation and arrange for a driver to transport them after the exam

Retinal photographs (only if evidence of clinically significant abnormalities)

OCT for the measurement of central foveal thickness (recorded in micrometers)

Fluorescein angiogram (FA) (at the discretion of the ophthalmologist) if there is a 
suspicion of macular edema by ophthalmoscopy and increased central foveal 
thickness by OCT
Subjects experiencing unexpected ophthalmic symptoms without a known suspected etiology or 
experiencing a relevant ophthalmic AE may need to have repeat ophthalmoscopy and OCT 
testing performed.
Additional guidance on clinical monitoring of ophthalmic symptoms is provided in 
Section 10.6.7.6.
10.6.7. Safety Monitoring Guidance
10.6.7.1. Drug-Induced Liver Injury
There is no published consensus on exactly when to stop a drug in the face of laboratory 
abnormalities and the decision may be affected by the clinical status of the patient and many 
other factors. The following can be considered a basic guide. When there is no alternative 
etiology for persistently elevated liver enzymes, discontinuation of study treatment should be 
considered, consistent with the United States FDA guidance [49], if: 

ALT or AST > 8 × ULN

ALT or AST > 5 × ULN for more than 2 weeks

ALT or AST > 3 × ULN and (total bilirubin > 2 × ULN or INR > 1.5) 

ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)
See Appendix 12 for suggested actions and follow-up assessments in the event of potential DILI. 
Information on the grading and management of laboratory abnormalities according to assessed 
severity is provided in Appendix 8 and Appendix 9. 


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10.6.7.2. Guidance on Management of Lymphocyte, Neutrophil, and White Blood Cell 
Counts, and Monitoring for Infections
Etrasimod prevents lymphocyte egress from lymphoid tissues, resulting in a reduction in 
peripheral lymphocyte count and lymphocyte availability for recruitment to sites of 
inflammation. Site staff including investigators will be blinded to the WBC count, WBC 
differential (percentage and absolute number), and the TBNK panel cell count while subjects are 
on study treatment. During this time, WBC count, WBC differential, and the TBNK panel results 
will be assessed by an independent Medical Monitor (not involved in any other aspects of study 
conduct or data analysis) and will direct Investigators on specific actions to take. Blinded values 
may be released to treating physicians and Investigators as deemed medically necessary to 
monitor the risk of infection and/or aid in diagnostic work-up as clinically indicated, and/or as a 
tool to assess the effectiveness of therapeutic interventions for an infection.
ALC
The independent Medical Monitor will notify Investigators when the subject has an absolute 
lymphocyte count (ALC) < 0.2 × 109 cells/L. In this scenario, the Investigator will be asked to 
have the subject return for a repeat CBC with differential within 7 days to confirm the ALC.  If 
the ALC is confirmed to be below 0.2 × 109 cells/L, study treatment should be interrupted. While 
study treatment is interrupted, the Investigator will repeat the CBC with differentials weekly 
until ALC is > 0.5 × 109 cells/L. Re-initiation of the study treatment can be considered when 
ALC is > 0.5 × 109 cells/L. ALC recovery is expected to occur within 7 to 10 days after study 
treatment interruption. 
When there is a sustained decreased in ALC < 0.2 × 109 cells/L, defined as having a second 
confirmed ALC < 0.2 × 109 cells/L with treatment rechallenge (after the initial study treatment 
interruption due to a low ALC), study treatment must be permanently discontinued. 
Subjects with an ongoing AE of decreased lymphocyte count or infection at the post-treatment 
4 Week Follow-Up Visit will continue to have weekly CBC with differential until ALC recovery 
is achieved (defined as ALC return to within the normal range or to at least 80% of the 
pre-treatment value). 
ANC and WBC 
In addition, the independent Medical Monitor will notify Investigators when there is at least 
1 measurement of ANC < 1.0 × 109 cells/L or WBC count > 20 × 109 cells/L. 
Investigators will repeat the CBC with differentials weekly until ANC > 1.0 × 109 cells/L or the 
increased WBC count trends downward (on 2 separate days), respectively. 
Refer to Section 10.6.7.3 for information on monitoring for signs and symptoms of infections 
and diagnostic work-up and treatment of infections.
10.6.7.3. Guidance on Monitoring Subjects for Infections
Low lymphocyte counts with the use of other S1P receptor modulators in patients with multiple 
sclerosis have been associated with serious and atypical infections [43,44]. To date, there have 
been no reports of PML with the use of etrasimod in clinical studies. Nevertheless, Investigators 
should remain vigilant in monitoring for signs and symptoms of serious and atypical infections 


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during the study and after discontinuation of study treatment (ie, the 28-day posttreatment 
period).
If a subject exhibits signs and symptoms suspicious for PML, study drug must be interrupted and 
cannot be restarted until diagnostic evaluation is completed and PML has been excluded. The 
Medical Monitor should be informed of any suspected cases of PML. Refer to Appendix 10 for 
PML signs and symptoms and case evaluation algorithm. In the evaluation and management of 
treatment-emergent infections, Investigator may consult with infectious disease or relevant 
experts, as needed.
All radiologic images (eg, magnetic resonance imaging, computer tomography, X-rays) and 
diagnostic laboratory test results performed by local laboratories/facilities should be retained as 
source documents by study sites and made available upon request by the Sponsor for central 
adjudication as needed. All infections that develop during the study will be reported as AEs on 
the respective eCRF pages.
10.6.7.4. Guidance for Cardiac Monitoring Following Treatment Initiation or Re-Initiation
Cardiac monitoring following treatment initiation applies to the first dose administered in the 
Double-Blind Treatment Period (Day 1) and in the Extension Treatment Period (Week 24). The 
lowest predose HR measurement (by vital signs) will be used for comparison to the postdose 
measurement (by vital signs). Subjects should receive the first dose of study treatment before 
12:00 PM (noon).
First-Dose Heart Rate Monitoring
Cardiac monitoring of at least 4 hours following the first dose (Day 1 and Week 24) will include 
the following (Table 4):

Full baseline vital signs (HR, BP, body temperature, and respiratory rate) and 12-lead 
ECG will be assessed predose (ie, Baseline)

After the first dose of study treatment (Day 1 and Week 24), subjects must remain 
under direct observation at the study site for at least 4 hours.

At Hours 1, 2, and 3 (± 15 minutes) postdose, the HR and BP will be assessed with 
the subject in the seated position, with the time recorded. If the subject has an 
HR < 50 bpm evaluate cardiac rhythm by 12-lead ECG to identify any clinically 
relevant ECG changes.

At the Hour 4 (± 15 minutes) discharge assessment, HR and BP will be assessed with 
the subject in the seated position and a 12-lead ECG in the supine position will also 
be performed. Subjects may be discharged from the study site after the Hour 4 
assessment if they meet the discharge criteria described in Table 5. Subjects not 
meeting the discharge criteria will require extended monitoring as described below.

Subjects experiencing a treatment-related symptomatic event (eg, chest pain, 
dizziness, palpitations, lightheadedness, shortness of breath, or syncope) associated 
with reduction of the HR together with clinically relevant 12-lead ECG changes at 
any time during the 4-hour monitoring period should be discontinued from study 
treatment.


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Table 4:
Procedures to Be Performed During the Cardiac Monitoring Period
Procedure
Predose
Hours 1, 2, and 3
Postdosea      
Hour 4
Postdosea
Blood pressure and heart rateb      
X
X
X
12-lead ECG
X
X
Assess discharge criteria
X
a Measurements may be taken ± 15 minutes of the scheduled time.
b Heart rate is based on vital signs.
ECG, electrocardiogram


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Table 5:
Discharge Criteria After Cardiac Monitoring
Subjects will be released from the study site after dosing on Day 1 or Week 24 (but no sooner than 4 hours 
postdose) when they fulfill all of the following discharge criteria:

Heart rate ≥50 bpm or no more than 10 bpm lower than the predose value

Heart rate is not the lowest value measured during the observation period

No evidence of second-degree AV block or higher

No cardiac symptoms (eg, chest pain, dizziness, palpitations, lightheadedness, shortness of breath, or 
syncope)a      
a Subjects experiencing a symptomatic event (eg, chest pain, dizziness, palpitations, lightheadedness, shortness of breath, and/or 
syncope) at any time during the 4-hour monitoring period that is not associated with either a reduction in HR or clinically 
relevant change in 12-lead ECG, may be discharged provided they meet the other discharge criteria, and deemed appropriate by 
the Investigator.
Note: Subjects should have written instructions on when to return to the study site and a 24-hour contact phone number to call in 
the event of any new or worsened cardiovascular symptoms.
AV, atrioventricular; bpm, beats per minute; ECG, electrocardiogram; HR, heart rate
Extended Cardiac Monitoring
Subjects who do not meet discharge criteria at 4 hours postdose will require extended cardiac 
monitoring:

Vital signs (BP and HR) will be assessed hourly and a 12-lead ECG may be 
performed, as clinically indicated, until the subject meets the discharge criteria 
(Table 5)

The Medical Monitor should be contacted if the subject does not meet the discharge 
criteria after ≥4 hours of extended cardiac monitoring
If an ECG shows a new onset QTcF interval above 500 ms (CTCAE Grade 3), a repeat ECG is 
warranted, and, if this abnormal finding is confirmed and is considered related to study 
treatment, then study treatment must be interrupted. Effective diagnostic and therapeutic 
strategies should be employed.
Reversible causes of prolonged QTcF interval (eg, electrolyte abnormalities like hypokalemia 
and hypomagnesemia), should be corrected as clinically indicated. When evaluating a subject 
with new onset QTcF interval above 500 ms, referral to a physician experienced in treating 
cardiac conduction disorders should be considered. If treatment is interrupted, re-initiation of 
study treatment can only be considered if the QTcF interval is < 450 ms (males) or < 470 ms 
(females), the prolonged QTcF interval is not considered related to study treatment, the 
individual risk benefit is favorable (as determined by the Investigator, in agreement with the 
cardiologist), and after discussion with the Medical Monitor. If, after re-initiation, the QTcF 
interval is again prolonged above 500 ms, then study drug must be discontinued.
Cardiac Monitoring Upon Treatment Re-Initiation Following Dose Interruption
The procedure for first-dose cardiac monitoring as outlined above should be performed any time 
a subject misses study treatment for:


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
≥2 consecutive days within the first week of treatment during the Double-Blind 
Treatment Period or during Week 24 of the Extension Treatment Period or

≥7 consecutive days after the first week of treatment during the Double-Blind 
Treatment Period or after Week 24 of the Extension Treatment Period.
Subjects are not to re-initiate therapy until they return to the study site for dosing with cardiac 
monitoring.
10.6.7.5. Pulmonary Function Monitoring
Based on changes in pulmonary function observed with the use of S1P receptor modulators such 
as fingolimod and siponimod, approved for relapsing multiple sclerosis [43,44], pulmonary 
function will be assessed in this study. PFTs will be performed at the start and conclusion of the 
study.
Subjects experiencing clinically significant dyspnea or other respiratory AEs, may need to have 
additional PFT testing as clinically indicated. Severity of respiratory AEs should be categorized 
using the CTCAE scale described in Appendix 8. Investigators should consider interruption of 
study treatment when there is a clinically significant respiratory AE considered related to study 
drug that leads to limitations in instrumental or self-care activities of daily living (ADL). The 
decision to interrupt study treatment should be discussed with the Medical Monitor. Subjects 
should be promptly referred to a pulmonologist for further evaluation and treatment. The 
pulmonologist should be provided with a standard referral letter explaining the reason for the 
referral along with information about the investigational drug. Clinically significant respiratory 
AEs should be followed until there is stability, improvement, or resolution.
Re-initiation of study treatment can only be considered if the respiratory AE has improved, 
stabilized, and/or resolved, and is not considered related to study treatment; the individual 
risk-benefit is favorable (as determined by the Investigator, in agreement with the 
pulmonologist); and after discussion with the Medical Monitor.
10.6.7.6. Ophthalmic Symptom Monitoring
Subjects experiencing unexpected ophthalmic symptoms, including blurred vision, decreased 
visual acuity, or other clinically significant ocular AEs, without a known/suspected etiology may 
need to have repeat ophthalmoscopy and OCT testing performed. 
If, during the study, there are complaints of decreased vision or identification of worsening 
visual acuity (equal to or more than 2 lines on a standard eye chart using best corrected vision) 
then an unscheduled ophthalmic examination should be performed: 

Best corrected visual acuity measurement

Ophthalmoscopy (may include contact lens biomicroscopy to examine the macula and 
optic disc)

OCT for all subjects to investigate a suspected diagnosis of macular edema
Note: For both scheduled and unscheduled visits, in case of suspected macular edema based on 
the ophthalmoscopy or a relevant increase of central foveal thickness, then FA may be 
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If there is evidence of new onset macular edema considered related to study treatment, then study 
treatment should be interrupted as appropriate and the subject should be monitored closely with 
the appropriate diagnostic and clinical work-up.
Subjects with a diagnosis of macular edema considered related to study treatment during the 
study must interrupt the study drug. These subjects must be followed up monthly with 
ophthalmologic evaluations until such time as resolution is confirmed or no further improvement 
is expected by the ophthalmologist (based on a follow-up period of no less than 3 months). 
These evaluations will include repeat best corrected- visual acuity, fundus examination, and 
OCT. FA may also be performed at the discretion of the ophthalmologist. If the subject does not 
show definite signs of improvement on examination by specialist testing (eg, OCT, FA) 
6 to 8 weeks after interruption of study drug, then therapy for macular edema in conjunction with 
an ophthalmologist experienced in the management of this condition should be initiated.
For subjects diagnosed with macular edema, copies of the colored OCT and FA images (if 
conducted) should be kept by the investigative site as source documents. These documents may 
need to be submitted for review by an independent panel.
10.6.8. Adverse Events
10.6.8.1. Definitions
10.6.8.1.1. Adverse Event
An AE is any untoward medical occurrence that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or 
disease temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
AEs can include, but are not limited to, any of the following:

Unfavorable changes in general condition

Subjective or objective signs/symptoms

Concomitant disease or accidents

Clinically relevant adverse changes in laboratory parameters over the course of the 
study

Pre-existing conditions that worsen in severity, increase in frequency, or have new 
signs/symptoms
Additional guidance on the management of AEs according to assessed severity is provided in 
Appendix 9.
10.6.8.1.2. Serious Adverse Event
An AE should be classified as an SAE if it meets one of the following criteria:
Fatal:
The AE resulted in death.
Life-threatening:
The AE placed the subject at immediate risk of death. This 
classification does not apply to an AE that hypothetically might cause 
death if it were more severe.


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Hospitalization:
The AE required or prolonged an existing inpatient hospitalization. 
Hospitalizations for elective medical or surgical procedures or 
treatments planned before the signing of informed consent in the study 
or routine check-ups are not SAEs by this definition.
Disabling/ 
incapacitating:
The AE resulted in a persistent or significant incapacity or substantial 
disruption of the subject’s ability to conduct normal life functions.
Congenital anomaly 
or birth defect:
An adverse outcome in a child or fetus of a subject exposed to the 
study treatment before conception or during pregnancy.
Medically significant:
The AE did not meet any of the above criteria but could have 
jeopardized the subject and might have required medical or surgical 
intervention to prevent one of the outcomes listed above or involves 
suspected transmission via a medicinal product of an infectious agent.
Additionally, in this study, any diagnosis of PML will be considered an SAE.
10.6.8.1.3. Adverse Drug Reaction
An adverse drug reaction (ADR) in the pre-approval clinical experience with a new medicinal 
product or its new usages, particularly as the therapeutic dose(s) may not be established, is any 
noxious and unintended response to a medicinal product related to any dose. The phrase 
“responses to a medicinal product” means that a causal relationship between a medicinal product 
and an AE is at least a reasonable possibility (ie, the relationship cannot be ruled out).
10.6.8.1.4. Adverse Events of Special Interest
Based on the mechanism of action of etrasimod and prior experience with other agents acting via 
a similar mechanism, potential adverse events of special interest (AESIs) will be identified. In 
addition to appropriate reporting of these events as an AE or SAE, supplementary detailed 
information may be collected. 
Potential AESI for etrasimod include but are not limited to:

Cardiovascular events (eg, bradycardia, AV conduction delay, and hypertension)

Macular edema 

Pulmonary events (airflow obstruction or altered gas exchange)

Infections (severe infections, opportunistic infections, Herpes simplex, and Herpes 
zoster)

Liver injury

PRES

Malignancies
10.6.8.1.5. Severity
The severity of each AE will be assessed at the onset by medically qualified personnel in 
accordance with the local or regional requirements in participating countries. When recording 
the outcome of the AE the maximum severity of the AE experienced will also be recorded. The 
severity of each AE will be graded according to the CTCAE:


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Grade 1:
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.
Grade 2:
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL).
Grade 3:
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care activities of daily living (ADL) (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing 
money).
Grade 4:
Life-threatening consequences, urgent intervention indicated.
Grade 5:
Death related to AE.
Additional information on CTCAE grading of AEs is provided in Appendix 8.
10.6.8.1.6. Relationship
The Investigator is obligated to assess the relationship (causal relationship) between the study 
treatment and each occurrence of each AE. The AE relationship (causal relationship) to study 
treatment must be characterized as one of the following categories:
Not Related:
The AE does not follow a reasonable temporal sequence from 
administration of the drug, does not abate upon discontinuation of the 
drug, does not follow a known or hypothesized cause-effect relationship, 
and (if applicable) does not reappear when the drug is reintroduced, 
furthermore, there may exist a clear alternative medical explanation (eg, 
underlying disease state) or association with study procedure or study 
conduct.
Unlikely Related:
The temporal association between the AE and the drug is such that the 
drug is not likely to have any reasonable association with the AE.
Probably Related:
The AE follows a reasonable temporal sequence from administration of 
the drug and cannot be reasonably explained by the known 
characteristics of the subject’s clinical state, environmental, or toxic 
factors, or other modes of therapy administered to the subject.
Related:
The AE follows a reasonable temporal sequence from administration of 
the drug, abates upon discontinuation of the drug, follows a known or 
hypothesized cause-effect relationship, and (if appropriate) reappears 
when the drug is reintroduced.
The Investigator will use clinical judgment to determine the relationship (causal relationship). 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to the study treatment administration should be 
considered and investigated. The Investigator should consult the IB and the Product Information 
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must document in the medical notes that he/she has reviewed the AE and has provided an 
assessment of causality. There may be situations in which an SAE has occurred, and the 
Investigator has minimal information to include in the initial report to the Sponsor; however, the 
Investigator should always make an initial assessment of causality for every event before the 
initial transmission of the SAE to the Sponsor. The Investigator may change his/her opinion of 
causality based on subsequent receipt of information and send an SAE follow-up report with the 
updated causality assessment. The causality assessment is one of the criteria used when 
determining regulatory reporting requirements.
10.6.8.1.7. Eliciting, Recording, and Reporting Adverse Events
10.6.8.1.8. Eliciting Adverse Events
Subjects will be instructed that they may report AEs at any time. An open-ended or nondirected 
method of questioning should be used at each study visit to elicit the reporting of AEs.
10.6.8.1.9. Recording Adverse Events
The AE reporting period for safety surveillance begins when the subject is initially included in 
the study (date of first signature of informed consent) and continues up to 30 days after the last 
study treatment administration. If an AE is not resolved or stabilized by this time, the Sponsor in 
consultation with the Investigator will decide whether to continue to monitor the AE or closeout 
the event in the database if no further follow-up is necessary. 
Investigators are not obligated to actively seek information on AEs or SAEs after the subject has 
concluded study participation. Any SAE suspected to be related to the study treatment must be 
reported whenever it occurs, irrespective of the time elapsed since the last administration.
Investigator and study personnel will record all AEs and SAEs whether received through an 
unsolicited report by a subject, elicited during subject questioning, discovered during physical 
examination, laboratory testing, and/or other means by recording them on the eCRF and SAE 
Report Form, as appropriate. The following information should be recorded on the AE eCRF:

Description including onset and resolution dates

Whether it met SAE criteria

Severity

Relationship to study treatment or other causality

Outcome
For SAEs, events occurring secondary to the primary event should be described on the SAE 
Report Form in the narrative description field.
The following should be considered when recording SAEs:

Death is an outcome of an event. The event that resulted in the death should be 
recorded and reported on the SAE Report Form and eCRF.

For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself. The procedure should be captured in the narrative as part of the action taken in 
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10.6.8.1.10. Diagnosis Versus Signs or Symptoms
In general, the use of a unifying diagnosis is preferred to the listing out of individual symptoms. 
Grouping of symptoms into a diagnosis should only be done if each component sign and/or 
symptom is a medically confirmed component of a diagnosis as evidenced by standard medical 
textbooks. If any aspect of a sign or symptom does not fit into a classic pattern of the diagnosis, 
report the individual symptom as a separate AE.
10.6.8.1.11. Reporting Serious Adverse Events
All SAEs are subject to reporting requirements.
10.6.8.1.12. Serious Adverse Events
All SAEs, whether or not considered related to study drug, must be immediately reported to 
Pfizer Safety on the CT SAE Report Form upon awareness and under no circumstances should 
the time to report exceed 24 hours of becoming aware of the event.
If additional follow-up information is required or becomes available for a previously reported 
SAE, entry into eCRF of the new or updated information should be completed and reported to 
Pfizer Safety on a new CT SAE Report Form within 24 hours of awareness.
Elective hospitalization and/or surgery for clearly preexisting conditions (eg, a surgery that has 
been scheduled prior to the subject’s entry into the study) will not be reported as an SAE.
Any SAE that is ongoing when the subject completes the study or discontinues the study will be 
followed by the Investigator until the event resolves, stabilizes or returns to baseline status.
10.6.8.1.13. Serious, Unexpected Adverse Drug Reactions
All ADRs that are both serious and unexpected are subject to expedited reporting to regulatory 
agencies and will be reported in accordance with Directive 2001/20/EC or as per national 
regulatory requirements in participating countries. An unexpected ADR is one for which the 
nature or severity is not consistent with information in the relevant source documents.
The following documents or circumstances will be used to determine whether an AE/ADR is 
expected:
5. For a medicinal product not yet approved for marketing in a country, the reference safety 
information section of a company’s IB will serve as the source document in that country
6. Reports that add significant information on specificity or severity of a known, already 
documented serious ADR constitute unexpected events. For example, an event more 
specific or more severe than described in the reference safety information in the IB would 
be considered “unexpected.”
10.6.9. Pregnancy and Lactation
Pregnancy
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Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of study treatment and until 30 days after the last dose.
Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an AE; however, to fulfill regulatory requirements, any pregnancy and/or pregnancy outcome 
should be reported to Pfizer Safety via the CT SAE Report Form and the EDP Supplemental 
Form within 24 hours of awareness.

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and should be reported as 
such (following the SAE reporting process) even if outside the SAE reporting period. 
Examples of environmental exposure may include oral ingestion of, inhalation of, or skin 
contact with a tablet that is broken/crushed. 
Any such exposures to the study drug under study are reportable to Pfizer Safety within 24 hours 
of investigator awareness irrespective of whether an AE has occurred.
10.6.9.1. Exposure During Pregnancy
An environmental EDP occurs if:   

A female nonsubject is found to be pregnant while being exposed or having been exposed 
to study treatment because of environmental exposure.

A male nonsubject who has been exposed to the study drug then inseminates his female 
partner prior to or around the time of exposure.
10.6.9.2. Exposure During Breastfeeding
An environmental EDB occurs if:  

A female nonsubject is found to be breastfeeding while being exposed or having been 
exposed to study drug.
When EDB occurs in the setting of environmental exposure, the exposure information does not 
pertain to the subject enrolled in the study, so the information is not recorded on a CRF. 
However, a copy of the completed CT SAE Report Form is maintained in the investigator site 
file.
10.6.9.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 24 
hours of the investigator’s awareness using the CT SAE Report Form, regardless of whether 
there is an associated SAE. Since the information about the occupational exposure does not 
pertain to a subject enrolled in the study, the information is not recorded on a CRF; however, a 
copy of the completed CT SAE Report Form must be maintained in the investigator site file.
10.6.10. Lack of Efficacy
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of 
efficacy. Lack of efficacy or failure of expected pharmacological action is reportable to Pfizer 
Safety only if associated with an SAE.


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10.6.11. Medication Errors
Medication errors may result from the administration or consumption of the study drug by the 
wrong subject, or at the wrong time, or at the wrong dosage strength. Medication errors not 
associated with an AE/SAE should be recorded as a protocol deviation.
A medication error with a potentially associated AE/SAE is recorded in the CRF. Medication 
errors associated with an SAE (per the Investigator’s assessment) should be reported to Pfizer 
Safety within 24 hours on the CT SAE Report Form. SAEs must be reported to the designated 
Sponsor Contact via established reporting mechanism within 24 hours of awareness.
In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report Form 
only when associated with an SAE.
10.7. Procedures for Overdose
The current edition of the IB should be referenced for overdose procedures.
There is no established overdose threshold for this clinical study, nor is there any recommended 
specific treatment for an overdose but to provide supportive care if clinically indicated.
In the event of a suspected overdose, the Investigator and/or treating physician should:

Closely monitor the subject for any AE/SAE and laboratory abnormalities and follow 
AE reporting process, including contacting the Medical Monitor

Obtain a plasma sample for PK analysis within 7 days from the date of the last dose 
of study treatment, if possible, and if requested by the Medical Monitor

Document the total quantity of the excess dose, taking into consideration the duration 
of the overdose in the eCRF and the time frame
Subjects who overdose will be counseled on correct dosing and administration of study 
treatment. Decisions regarding study discontinuation, dose interruptions, or dose modifications 
will be made by the Investigator in consultation with the Medical Monitor based on the clinical 
evaluation of the subject.
10.8. Genetic Testing
Genetics may be evaluated in this study to assess genetic variation that may impact response to 
treatment, metabolism, and mechanism of action of etrasimod and for consideration of risks of 
the disease state.
A blood sample for DNA isolation will be collected from subjects who have consented to 
participate in the genetic analysis component of the study. Participation is optional. Subjects who 
do not wish to participate in the genetic research may still participate in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the subject. An additional ICF may be provided to subjects for genetic analyses. Signed 
informed consent will be required to obtain a replacement sample unless it was included in the 
original consent.


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Details on processes for collection and shipment and destruction of these samples are provided in 
the Laboratory Manual.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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10.10. Qualitative Interview
Qualitative interviews may be conducted with a subset of subjects who have consented to 
participate in the Qualitative Interview component of the study. Participation is optional. 
Subjects who do not wish to participate in the Qualitative Interview may still participate in the 
study.
The Qualitative Interview will gather insights about subjects’ symptom experience during the 
study and identify any additional aspects of change that might be important to assess for future 
studies. Other factors driving subject satisfaction with treatment and perceptions on meaningful 
change will be asked.
The Qualitative Interview will be conducted via telephone by a trained qualitative research 
interviewer using a semi-structured interview guide. All interviews will be conducted in the 
participant’s native language and will be audio recorded in accordance with applicable laws of 
the jurisdictions where the subjects are located. The audio recording will be transcribed for 
analysis and will be destroyed after evaluation. Interviews will be conducted within 14 days after 
the Week 24 visit. Failure to complete the optional interview that a subject has consented to will 
not constitute a protocol deviation. If a potential adverse event is discovered during the interview 
process, the information will be shared by the interviewer with the Investigator.
11. PLANNED STATISTICAL METHODS
11.1. General Considerations
Details regarding the statistical analyses will be provided in the Statistical Analysis Plan (SAP), 
which will be finalized prior to database lock and unblinding.
Continuous variables will be summarized using the number of observations, mean, standard 
deviation (SD), median, minimum, and maximum. Categorical variables will be summarized 
using frequency counts and percentages. 
For Double Blinded Treatment Period, hypotheses tests will be performed for efficacy endpoints 
for the comparison of etrasimod dose versus the placebo group. However, these hypotheses tests 
will not be controlled for type-I error rate. Un-adjusted p-values will be reported.
For the Extension Treatment Period, no hypothesis tests between treatment groups will be 
performed; only descriptive statistics will be provided. 
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The SAP will describe an overall plan to address the alignment between the target of efficacy 
estimation (ie, trial objective, or estimand of interest), the analysis set, the method of estimation, 
and primary method to handle intercurrent events; along with a plan of sensitivity analysis to 
evaluate the robustness of findings that can sustain limitations in missing data and intercurrent 
events of non-adherence to protocol.
Efficacy data will be analyzed by randomized treatment, while safety data will be analyzed by 
actual treatment.
 
 
 
 
 
11.3. Analysis Sets
For purposes of analysis, the following analysis sets are defined for each treatment period as 
shown in Table 6.
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Table 6:
Analysis Sets
Analysis Set
Description
Full Analysis Set (FAS); 
(Double-Blind Treatment Period)
The FAS will include all randomized subjects in the Double-Blind 
Treatment Period, who receive at least 1 dose of study treatment. Subjects 
will be summarized by treatment to which they were randomized, regardless 
of treatment actually received.
Modified Full Analysis Set 
(mFAS); 
(Double-Blind Treatment Period)
The mFAS will include all randomized subjects who receive at least one 
dose of study medication and have a baseline measurement and have at least 
1 post-randomization measurement. The mFAS is endpoint specific, 
therefore subjects included in the analysis set for one endpoint may differ 
from another endpoint, based on the baseline and post-baseline data.
Per Protocol Set; 
(Double-Blind Treatment Period)
The Per Protocol will include all subjects from the FAS without major 
protocol violations that might affect the evaluation of the effect of study 
treatment on the primary endpoint. The Per Protocol will be used in 
sensitivity analyses of the primary and secondary endpoints to evaluate the 
influence of major protocol violators and protocol deviators on the main 
efficacy results. Subjects may be excluded from this population if they 
violate the eligibility criteria or significantly deviate from the study plan. 
Specific reasons for warranting exclusion from this population will be 
documented prior to database lock and may include, but are not limited to, 
study treatment noncompliance, receiving incorrect study treatment, and 
missing more than a defined number of visits while still on study. The 
statistical analysis plan, which will be finalized prior to database lock, will 
be the final documentation for the Per Protocol Set definition.
Pharmacokinetic Set; 
(Double-Blind Treatment Period)
The Pharmacokinetic Set will include all subjects in the FAS with at least 
1 postdose PK measurement.
Safety Set; (Double Blind 
Treatment Period and Extension 
Treatment Period)
The Safety Set will include all randomized subjects who received at least 
one dose of study treatment during the specified treatment period.
Efficacy Evaluable Set: 
(Extension Treatment Period)
The Efficacy Evaluable Set will include subjects who receive at least one 
dose of etrasimod and have at least one efficacy measurement in the 
Extension Treatment Period (endpoint specific)
Baseline for the Extension Treatment Period is defined as the last measurement prior to the first 
etrasimod dose started at Week 24.
11.4. Missing Data
11.4.1. Primary Methods of Handling Missing Data and Rescue Medication/Rescue 
Procedure Usage
In order to analyze efficacy endpoints at Week 16 and Week 24 in the Full Analysis Set (FAS), 
handling missing data and rescue mediation uses are specified as following. For the endpoint of 
the percent change from Baseline in esophageal PEC at Week 16 and Week 24, PEC after rescue 
medication/rescue procedure use will be set to missing. All missing PEC at scheduled visits up to 
Week 24 will be imputed using a multiple imputation (MI) procedure with a fully conditional 
specification (FCS) method and predictive mean matching for PEC [64-66]. The use of rescue 
medication/rescue procedure, reasons for early discontinuation (eg, AE), and duration of study 
treatment prior to early discontinuation will be captured to address and characterize the nature of 


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missing data in the MI procedure with an FCS method. Detailed MI model descriptions and 
analysis procedures will be specified in the SAP.
For analysis of dichotomous endpoints (eg, proportion of subjects with esophageal PEC of 
< 15 and ≤6 eos/hpf at Week 16 and Week 24), all subjects in the FAS will be included in the 
analyses. Subjects in any of the following cases will be considered as a “non-responder” or 
“failure”:

Use of rescue medications/rescue procedures during the Double-Blind Treatment 
Period;

Prematurely discontinue from study due to any reason prior to Week 16 and Week 24; 
or 

With missing data at Week 16 and Week 24 for any reason
11.4.2. Sensitivity Analyses
In addition to the primary method for handling missing data and rescue medication/rescue 
procedure use in the FAS described in Section 11.4.1, the following sensitivity analyses will be 
performed for primary, secondary, and selected 
 using alternative methods 
to handle missing data and/or in alternative analysis populations:

MI usually assumes that the data are missing at random (MAR) but MAR cannot be 
verified using the observed data. Therefore, the sensitivity of inferences to departures 
from the MAR assumption will be examined. For the MI analysis of the primary 
endpoint of percent change from Baseline in esophageal PEC at Week 16 and Week 
24, data MAR within each treatment group will be investigated using tipping point 
analyses method and results will be described using Rubin’s rule [1]

Percent change in esophageal PEC from Baseline to Week 16 and Week 24 will be 
analyzed in the modified Full Analysis Set (mFAS), data will be set to missing after 
rescue medication/rescue procedure uses

Proportion of subjects with esophageal PEC of < 15 and ≤6 eos/hpf at Week 16 and 
Week 24 will be analyzed in the FAS using PEC imputed by the MI method 
discussed in Section 11.4.1

Proportion of subjects with esophageal PEC of < 15 and ≤6 eos/hpf at Week 16 and 
Week 24 will be analyzed in the mFAS using PEC imputed by the MI method 
discussed in Section 11.4.1

Observed data analyses in mFAS, regardless of rescue medication/rescue procedure
use and without missing data imputation:

For longitudinal continuous variables, a linear mixed effects model  will be 
performed and results will be reported by visit.

For longitudinal dichotomous measures, logistic regression analysis may be 
performed by visit

Completers analyses (also known as complete case) of primary and secondary 
endpoints for subjects who complete 16 and 24 weeks of study treatment
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
Per Protocol Set analyses in subjects who meet the criteria of Per Protocol definition 
approved prior to database lock
Detailed sensitivity analysis methods will be described in the SAP.
11.5. Efficacy Analyses
For the Double-Blind Treatment Period, the primary and secondary endpoints will be analyzed 
using the FAS. Other important statistical considerations, such as handling rescue 
medication/rescue procedure uses during study treatment, missing data imputation strategies, 
sensitivity analyses, and subgroup analyses will be described in the SAP.
The endpoints of percentage change in esophageal PEC from Baseline to Week 16 and Week 24 
will be analyzed using analysis of covariance (ANCOVA) model based on rank scores due to the 
skewed distribution of the data and possible outliers. The ANCOVA model will include 
treatment group and randomization stratification factors as factors and Baseline eosinophil PEC 
as a covariate. PEC after rescue medication/rescue procedure uses will be set to missing; all 
missing data will be imputed in the FAS using MI procedure as appropriate. Multiple results of 
ANCOVA (least square [LS] mean rank scores and LS mean rank score difference from placebo) 
for each MI dataset will be analyzed and reported along with  final p-value  using Rubin’s 
method [1]. In addition, a descriptive summary of percentage change in esophageal PEC from 
baseline as well as the difference between treatment groups will be presented by treatment group. 
When applying the same ANCOVA model to key secondary continuous variables, norank 
transformation will be used.
For the efficacy endpoints of the percentage change in esophageal PEC from Baseline at 
Week 16 and Week 24, in the FAS, subjects who have experienced intercurrent events, such as 
rescue medication/rescue procedure use, early discontinuation of study treatment, etc., will be 
included in the analysis and their missing data at Week 16 and Week 24 will be imputed using a 
MI model. The MI model will take into consideration the reason and nature of intercurrent event 
leading to missing data. A detailed plan for constructing and analyzing the primary estimand will 
be described in the SAP.
Proportion-based secondary endpoints (eg, histologic responders or symptomatic responders) at 
Week 16 will be analyzed in the FAS; subjects who use rescue medication or have a rescue 
procedure, or with missing data for any reason will be considered a “non-responder” or “failure.” 
The analyses will be performed using the Cochran-Mantel-Haenszel (CMH) method adjusted for 
randomization stratification factors. The number and percentage of subjects achieving the goal 
and the difference in proportion between treatment groups achieving the goal, along with p-value 
and the 95% CIs will be reported.
Longitudinal continuous endpoints (Section 11.5.1.2) will also be analyzed up to Week 24 using 
a linear mixed effects model. The model will include treatment group, visit, interaction of 
treatment-by-visit, and randomization stratification factors as factors, and Baseline measure as 
covariates. An unstructured covariance matrix will be specified for the within-subject 
measurements. LS means and LS mean differences between treatment group with unadjusted 
p-values and corresponding 95% CIs will be reported at each scheduled visit. This method will 
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Endpoints measured during the Extension Treatment Period after Week 24 up to Week 52 will be 
summarized using descriptive statistics without inferential comparison. Dichotomous remission 
or response outcomes derived from specific scores will be assessed. Continuous variables will be 
summarized by visit using the number of observations, mean, SD, median, minimum, and 
maximum; and categorical variables will be summarized by visit using frequency counts and 
percentages, with following considerations:

Four treatment sequence (as listed below) in the Extension Treatment Period will be 
analyzed, if applicable

etrasimod 1 mg-1 mg

etrasimod 2 mg-2 mg

placebo - etrasimod 1 mg

placebo - etrasimod 2 mg

Change from baseline in continuous variables will be analyzed on change from 
Baseline in the Double-Blind Treatment Period and change from Baseline in the 
Extension Treatment Period
In addition to between group analyses on the primary and secondary endpoints, dose-response  
relationship will be investigated using exposure-response modeling and the details will be 
described in the PK/PD analysis document.   The PK/PD modeling will be written as a 
standalone document.
11.5.1. Efficacy Endpoints
11.5.1.1. Primary Endpoint

Percent change from Baseline in esophageal PEC at Week 16
11.5.1.2. Secondary Endpoints

Absolute change from Baseline in DSQ score at Week 16

Absolute change from Baseline in esophageal PEC at Week 16

Proportion of subjects with esophageal PEC < 15 eos/hpf at Week 16

Proportion of subjects with esophageal PEC ≤6 eos/hpf at Week 16
CCI
CCI


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11.6. Subgroup Analyses
Subgroup analyses will be performed in primary and secondary endpoints and selected 
 for the following baseline demographics and disease characteristics:

Sex (male, female)

Race (white, non-white)

Age (≤ or > median)

History of dilation (yes or no)

Duration of disease (≤ or > median)

Concurrent PPI therapy (yes or no)

Concurrent atopic comorbidities (yes or no)

Concurrent elimination diet (yes or no)
CCI
CCI


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
Baseline esophageal PEC (≤ or > median) 

Baseline DSQ score (≤ or > median) 

Baseline EREFS (≤ or > median)

Baseline swallowed topical steroid treatment refractory status (yes or no)
11.7. Testing Strategy
  For Double Blinded Treatment Period, hypotheses tests will be performed for efficacy 
endpoints for the comparison of etrasimod dose versus the placebo group. However, these 
hypotheses tests will not be controlled for type-I error rate. Un-adjusted p-values will be 
reported. The associated 95% confidence intervals will be reported.
For the Extension Treatment Period, no hypothesis tests between treatment groups will be 
performed; only descriptive statistics will be provided.
11.8. Interim Analysis
No formal interim analyses for efficacy are planned. 
11.9. Safety Analyses
All safety data will be listed and summarized by treatment group. All TEAEs will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) and tabulated by System Organ 
Class and Preferred Term. Incidence of AEs, SAEs, AESIs, and AEs leading to study treatment 
discontinuation will be summarized and presented in descending order of frequency. In addition, 
details regarding risk-based safety analyses (eg, risk difference or hazard ratio) and exposure 
adjusted incidence rates could be described in the SAP if deemed appropriate. Laboratory 
parameters will be summarized by treatment group at each scheduled assessment timepoint using 
descriptive statistics. Associated laboratory parameters such as hepatic enzymes, renal function, 
and hematology values will be grouped and presented together. Individual subject values will be 
listed and values outside of the standard reference range will be noted. Shift tables and analyses 
of changes from Baseline will be produced. The change from Baseline for each of the vital signs 
and ECG parameters will be summarized. Incidence of abnormal vital signs parameters and 
outlier ECG results will be tabulated. 
Safety analyses for the Extension Treatment Period will follow the general considerations used 
for the Double-Blind Treatment Period with the following exceptions:

Four treatment sequences (as mentioned in Section 11.5) in the Extension Treatment 
Period will be analyzed

Change from Baseline will be analyzed based on change from the Double Blind 
Treatment Period Baseline and change from Extension Treatment Period Baseline
A detailed description of all safety analyses will be provided in the SAP.
11.9.1. Safety Endpoints

Incidence and severity of AEs


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
Incidence and severity of laboratory abnormalities, and change from baseline in 
laboratory values (to include hematology, serum chemistry, and coagulation)

Incidence of clinically significant vital sign abnormalities and changes from baseline
11.9.2. Adverse Events
AEs will be coded using the MedDRA.
For each treatment group, the proportion of subjects with TEAEs will be summarized overall, by 
severity, and by relationship to study treatment. SAEs and AEs leading to study treatment 
discontinuation will also be summarized by treatment group. AE summaries by System Organ 
Class and Preferred Term will be presented in descending order of frequency. A TEAE is defined 
as:

An AE that occurs after initiation of study treatment that was not present at the time 
of treatment start.

An AE that increases in severity after the initiation of medication, if the event was 
present at the time of treatment start.
AEs occurring before the first dose of study treatment will be summarized separately.
11.9.3. Extent of Exposure
The duration of time on study and time on study treatment will be summarized for each treatment 
using descriptive statistics. The number of subjects on treatment for certain time intervals will 
also be summarized. The total subject -years on study will also be included in this summary.
11.9.4. Clinical Laboratory Parameters
Laboratory parameters will be summarized by treatment group at each scheduled assessment 
timepoint using descriptive statistics. Associated laboratory parameters such as hepatic enzymes, 
renal function, and hematology values will be grouped and presented together. Individual subject 
values will be listed and values outside of the standard reference range will be noted. Shift tables 
and analyses of changes from Baseline will be produced.
11.9.5. Electrocardiograms
ECG rhythms and intervals will be listed by visit and summarized using descriptive statistics. 
Intervals to be provided for each ECG are RR, PR, QRS, QT, QTcB, and QTcF. Post-baseline 
ECGs for each subject will be compared with the baseline ECG. Any clinically significant 
change from baseline may be recorded as an AE if deemed appropriate by the Investigator. 
Outlier analysis will be performed on all subjects with QTcF values greater than 500 ms or 
change from baseline > 60 ms in the absence of baseline ECG abnormalities that preclude 
accurate surface ECG assessment of ventricular repolarization (eg, bundle branch block).
11.9.6. Vital Signs
Descriptive statistics for vital signs (BP, HR, body temperature, and respiratory rate) will be 
presented by treatment group. Incidence of abnormal vital signs parameters will be summarized. 
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11.9.7. Physical Examination
Clinically significant physical examination abnormalities will be included in medical history or 
recorded and summarized as an AE.
11.10. Pharmacokinetic Analyses
Plasma concentrations of etrasimod and if warranted metabolites of interest will be determined 
from samples collected prior to dosing and 4 hours (± 15 minutes) postdose (after ECG) on 
Day 1.
Plasma concentrations of etrasimod will be determined from samples collected prior to dosing 
(trough) at other post-baseline (Day 1) visits.
11.10.1. Pharmacokinetic Endpoint

To determine the plasma concentration of etrasimod in subjects with EoE
A descriptive summary of observed plasma concentration will be displayed by time and by 
treatment group. The Pharmacokinetic Set will be used to analyze plasma levels. Full details of
PK analysis will be provided in the SAP.
11.11. Clinical Outcome Assessments
The clinical outcome measures based on questionnaires (DSQ, FAQ, EoE-QOL-A, PGIC, and 
PGIS) will be summarized by treatment and visit using descriptive statistics.
12. REGULATORY AND ETHICAL CONSIDERATIONS
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC by the 
investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study subjects.
Protocols and any substantial amendments to the protocol will require health authority approval 
prior to initiation except for changes necessary to eliminate an immediate hazard to study 
subjects.
The investigator will be responsible for the following:


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
Providing written summaries of the status of the study to the IRB/EC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by IRB/EC 
procedures;

Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 536/2014 for clinical 
studies, European Medical Device Regulation 2017/745 for clinical device research, and 
all other applicable local regulations.
12.1. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the study drug, Pfizer 
should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures taken 
by the investigator to protect the study subjects against any immediate hazard, and of any serious 
breaches of this protocol or of the ICH GCP guidelines that the investigator becomes aware of.
12.2. Informed Consent and Assent
The Investigator will fully inform the subject of all pertinent aspects of the study, including the 
approval of the study by the IRB/IEC. Before informed consent/assent (parent or legal guardian 
must provide consent for a minor subject according to local regulations who has assented to 
participate in the study) may be obtained, the Investigator should provide the subject ample time 
and opportunity to inquire about details of the study and to decide whether to participate.
Prior to a subject’s participation in the study, the IRB/IEC-approved ICF must be signed and 
personally dated by the subject and by the person who conducted the informed consent 
discussion. If a subject is unable to read, an impartial witness will be present during the entire 
informed consent discussion.
The written ICF and any other written information to be provided to subjects should be revised 
whenever important new information becomes available that may be relevant to the subject’s 
consent. Any revised written ICF or study materials to be available and/or supplied to subjects 
should receive the IRB/IEC’s approval in advance of use. The subject will be informed in a 
timely manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study. The communication of this information should 
be documented.
12.3. Confidentiality
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is provided from the Sponsor.


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Prior to study participation, the Investigator shall inform the subject that the monitor(s), 
auditor(s), IRB/IEC, and the regulatory authorities will be granted direct access to the subject’s 
original medical records for verification of clinical study procedures and/or data, and that, by 
signing a written ICF, the subject is authorizing such access.
In addition, prior to study participation, the subject must be informed that the records identifying 
the subject will not be made publicly available; if the results of the study are published, the 
subject’s identity will remain confidential.
12.4. Protocol Compliance
The Investigator/institution will conduct the study in compliance with the protocol agreed to by 
the Sponsor and regulatory authorities (if applicable) and that was approved by the IRB/IEC. The 
Investigator/institution and the Sponsor should sign the protocol, or an alternative contract, to 
confirm agreement.
The Investigator should not implement any deviation from, or changes to, the protocol without 
agreement by the Sponsor and prior review and documented approval from the IRB/IEC of an 
amendment, except where necessary to eliminate immediate hazard(s) to study subjects or when 
the change involves only logistical or administrative aspects of the study (eg, change in monitor, 
change of telephone number).
When an important deviation from the protocol is deemed necessary for an individual subject, 
the Investigator must contact the Medical Monitor for the study. Such contact must be made as 
soon as possible to permit a review by the Sponsor to determine the impact of the deviation on 
the subject’s participation and/or the assessment of safety or efficacy in the study. Any 
significant protocol deviations affecting subject eligibility and/or safety must be reported by 
Investigator or site delegate to the IRB/IEC and regulatory authorities, as applicable, prior to 
implementation.
The Investigator should document and explain any deviation from the approved protocol.
13. QUALITY CONTROL AND QUALITY ASSURANCE
Quality assurance and quality control systems shall be implemented and maintained with written 
SOPs to ensure that the study is conducted, and data are generated, documented (recorded), and 
reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s). 
Quality control shall be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.
An agreement must be secured from all involved parties to ensure direct access to all 
study-related sites, source documents, and reports for the purpose of monitoring and auditing by 
the Sponsor and inspection by regulatory authorities.
13.1. Training of Study Site Personnel
Prior to study activities being initiated at the study site, the Sponsor or designee will train study 
site personnel on the protocol and applicable procedures. Training should be documented.
Note: If new study site personnel are assigned to the study after the initial training, study sites 
should contact the study monitor to coordinate training. Qualified study personnel may conduct 
training, as appropriate. Training of new study personnel should also be documented.


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13.2. Monitoring
Study site monitoring is conducted to ensure the study is progressing as expected, the rights and 
well-being of human subjects are protected, the reported study data are accurate, complete, and 
verifiable, and the conduct of the study is in compliance with the currently approved protocol, 
with GCP and with applicable regulatory requirements. Protocol deviations identified will be 
documented.
Details of study site monitoring are documented in the study Clinical Monitoring Plan (CMP) or 
similar document. The CMP describes in detail who will conduct the monitoring, at what 
frequency monitoring will be done, at what level of detail monitoring will be performed (eg, 
targeted and/or risk based), and the distribution of monitoring reports. Monitoring may include a 
study site selection visit, which may be conducted in person or via communication media (eg, 
teleconference, online meeting) or may be waived in accordance with policy and procedures 
being followed for the study, if appropriate. Monitoring will include a study site initiation visit, 
interim monitoring visit(s), and a study site closeout visit. An interim monitoring visit may be 
combined with a closeout visit, if applicable.
13.3. Audit
An audit of one or more participating study sites may be performed independently of, and 
separately from, routine monitoring to evaluate clinical study conduct and compliance with the 
protocol, SOPs, GCP, and the applicable regulatory requirements.
14. DATA HANDLING AND RECORD KEEPING
14.1. Data Management
14.1.1. Case Report Forms
An eCRF must be completed for each subject screened/enrolled in this study. These forms will 
be used to transmit information collected during the study to the Sponsor and regulatory 
authorities, as applicable.
The documentation related to the validation of the eCRFs will be maintained in the Trial Master 
File. The Trial Master File will be maintained by the CRO and the Sponsor.
The Investigator will document subject data in his/her own subject files. These subject files will 
serve as source data for the study. All eCRF data required by this protocol will be recorded by 
study site personnel. All data entered into the eCRF will be supported by source documentation.
The Investigator or an authorized member of the Investigator’s staff will make any necessary 
corrections to the eCRF. All changed information, including the date and person performing the 
corrections, will be available via the audit trail, which will be part of the electronic data capture 
system. For any correction, a reason for the alteration will be provided. The eCRFs will be 
reviewed periodically for completeness and acceptability by Sponsor personnel (or their 
representatives). The Sponsor’s representatives will also be allowed access to all source 
documents pertinent to the study in order to verify eCRF entries. The Investigator will review the 
eCRFs for completeness and accuracy and provide his or her electronic signature and date to the 
eCRFs as evidence thereof.


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14.1.2. Source Documents
Per regulatory requirements, the Investigator or designee will maintain accurate and up-to-date 
study documentation, including source documentation for each study subject. Source documents 
are defined as original documents, data, and records. These may include, but are not limited to, 
hospital records, clinical and office charts, endoscopy reports, laboratory data/information, 
subject eDiaries or evaluation checklists, pharmacy dispensing and other records, recorded data 
from automated instruments, ECGs, X-rays, ultrasounds. Data collected during this study must 
be recorded on the appropriate source documents.
The Investigator(s)/institution(s) will permit study-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) and will provide direct access to the source data.
14.2. Study Documentation and Records Retention
The Investigator and study staff have the responsibility of maintaining a comprehensive and 
centralized filing system containing all study-related documentation. These files must be 
available for inspection by the Sponsor, representatives of the Sponsor, the IRB/IEC, and 
regulatory authorities (ie, FDA or international regulatory authorities) at any time, and should 
consist of the following elements:

Subject files: Containing the completed eCRFs (if applicable), supporting source 
documentation including medical records, laboratory data, and signed ICFs.

Regulatory files: Containing the protocol with all amendments and Investigator 
signature pages, copies of all other regulatory documentation, all correspondence 
between the study site and the IRB/IEC and Sponsor, and drug accountability files, 
including a complete account of the receipt and disposition of the study treatment.
Records will be available for 2 years after marketing application approval, or if the application is 
not approved or never submitted, 2 years after the appropriate regulatory authorities have been 
notified of the discontinuation of clinical development of the investigational product, but may be 
retained for a longer period of time if required by the applicable regulatory requirements. The 
Sponsor will provide written notification when it is appropriate for the Investigator to discard the 
study-specific documents referenced above.
During the record retention period, the Investigator or designee must inform the Sponsor or 
designee (eg, CRO), of the following: 

Location of study documentation

If the custody of documentation will be transferred or moved to another location

If the Investigator is unable to retain documentation for the specified period
14.3. Clinical Study Report
Whether the study is completed or prematurely terminated, a clinical study report will be 
prepared and provided to the regulatory agencies according to applicable regulatory 
requirement(s).


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14.4. Disclosure of Study Results
The Sponsor will post the results of the study in a publicly accessible database in accordance 
with the applicable laws and regulations.
15. RESPONSIBILITIES
15.1. Investigator Responsibilities
The Investigator must comply with this protocol and the conduct of all study procedures. The 
Investigator will disclose to the Sponsor sufficient, accurate, financial information to allow the 
Sponsor to submit accurate disclosure statements to the FDA per 21 Code of Federal Regulations 
(CFR) Part 54 (Financial Disclosure by Clinical Investigators). The Investigator is responsible 
for compliance with applicable sections of 21 CFR Part 312, Subpart D (Responsibilities of 
Investigators), and other ICH GCP requirements, federal, and local laws, applicable to 
conducting drug studies.
The Investigator is responsible for ensuring an investigation is conducted according to the signed 
Investigator statement, the investigational plan, and applicable regulations; for protecting the 
rights, safety, and welfare of subjects under the Investigator’s care; and for the control of drugs 
under investigation. An Investigator shall, in accordance with the provisions of 21 CFR Part 50, 
obtain the IC of each human subject to whom the drug is administered.
15.2. Sponsor’s Medically Qualified Individual
The contact information for the sponsor's MQI for the study is documented in the study contact 
list located in the supporting study documentation. 
To facilitate access to their investigator and the sponsor’s MQI for study related medical 
questions or problems, subjects are provided with an Emergency Contact Card (ECC) at the time 
of informed consent. The ECC contains, at a minimum, (a) protocol and study drug identifiers, 
(b) subject’s study identification number, (c) site emergency phone number active 24 hours/day, 
7 days per week, and (d) Pfizer Call Center number.
The ECC is intended to augment, not replace, the established communication pathways between 
the subject and their investigator and site staff, and between the investigator and sponsor study 
team. The ECC is only to be used by healthcare professionals not involved in the research study, 
as a means of reaching the investigator or site staff related to the care of a subject. The Pfizer 
Call Center number is to be used when the investigator and site staff are unavailable. The Pfizer 
Call Center number is not for use by the subject directly; if a subject calls that number directly, 
they will be directed back to the investigator site.
15.3. Sponsor Responsibilities
The Sponsor is responsible for compliance with applicable sections of 21 CFR Part 312, 
Subpart D (Responsibilities of Sponsors). The Sponsor is responsible for selecting qualified 
Investigators, providing them with the information they need to conduct an investigation 
properly, ensuring proper monitoring of the investigation(s), ensuring the investigation(s) is 
conducted in accordance with the general investigational plan and protocols contained in the 
Investigational New Drug (IND) application, maintaining an effective IND with respect to the 
investigations, and ensuring the FDA and all participating Investigators are promptly informed of 
significant new adverse effects or risks with respect to the drug.


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a randomized, placebo-controlled, Phase 2 study of etrasimod in patients with moderately to 
severely active ulcerative colitis. Gastroenterology. 2019;156(6):S-217.
41. Sandborn WJ, Peyrin-Biroulet L, Trokan L, et al. A randomized, double-blind, placebo-
controlled trial of a selective, oral sphingosine 1-phosphate (S1P) receptor modulator, etrasimod 
(APD334), in moderate to severe ulcerative colitis (UC): Results from the OASIS study. Am J 
Gastroenterol. 2018;113(Suppl):S327-S28.
42. Vermeire S, Panes J, Chiorean M, et al. Long-term efficacy and safety of etrasimod for 
ulcerative colitis: Results from the open-label extension of the OASIS study [abstract].  United 
European Gastroenterology Week (UEGW); October 19-23; Barcelona, Spain2019.
43. GILENYA. (2019).  Fingolimod capsules, for oral use [Package Insert]. Novartis 
Pharmaceuticals Corporation. 


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44. MAYZENT. (2019).  Siponimod tablets, for oral use [Package Insert]. Novartis 
Pharmaceuticals Corporation. Accessed on: April.
45. Camm J, Hla T, Bakshi R, et al. Cardiac and vascular effects of fingolimod: Mechanistic 
basis and clinical implications. Am Heart J. 2014;168(5):632-44.
46. Dellon ES, Liacouras CA. Advances in clinical management of eosinophilic esophagitis.
Gastroenterology. 2014;147(6):1238-54.
47. Dellon ES, Irani AM, Hill MR, et al. Development and field testing of a novel patient-
reported outcome measure of dysphagia in patients with eosinophilic esophagitis. Aliment 
Pharmacol Ther. 2013;38(6):634-42.
48. FDA. (2019).  Drug development and drug interactions: Table of substrates, inhibitors and 
inducers. U.S. Department of Health and Human Services, Food and Drug Administration, Silver 
Spring, MD. 
49. FDA. (2009).  Drug-induced liver injury: Premarketing clinical evaluation. U.S. Department 
of Health and Human Services, Food and Drug Administration, Silver Spring, MD. 
50. FDA. (2016).  Use of electronic informed consent form, questions and answers. U.S. 
Department of Health and Human Services, Food and Drug Administration, Silver Spring, MD. 
51. Collins MH, Martin LJ, Alexander ES, et al. Newly developed and validated eosinophilic 
esophagitis histology scoring system and evidence that it outperforms peak eosinophil count for 
disease diagnosis and monitoring. Dis Esophagus. 2017;30(3):1-8.
52. Hirano I, Moy N, Heckman MG, et al. Endoscopic assessment of the oesophageal features of 
eosinophilic oesophagitis: Validation of a novel classification and grading system. Gut. 
2013;62(4):489-95.
53. Hudgens S, Evans C, Phillips E, et al. Psychometric validation of the Dysphagia Symptom 
Questionnaire in patients with eosinophilic esophagitis treated with budesonide oral suspension. 
J Patient Rep Outcomes. 2017;1(1):3.
54. Taft TH, Kern E, Kwiatek MA, et al. The adult eosinophilic oesophagitis quality of life 
questionnaire: A new measure of health-related quality of life. Aliment Pharmacol Ther. 
2011;34(7):790-8.
55. MacIntyre N, Crapo RO, Viegi G, et al. Standardisation of the single-breath determination of 
carbon monoxide uptake in the lung. Eur Respir J. 2005;26(4):720-35.
56. Miller MR, Crapo R, Hankinson J, et al. General considerations for lung function testing. Eur 
Respir J. 2005;26(1):153-61.
57. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 
2005;26(2):319-38.


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58. Baron U, Werner J, Schildknecht K, et al. Epigenetic immune cell counting in human blood 
samples for immunodiagnostics. Sci Transl Med. 2018;10(452):eaan3508.
59. Dellon ES, Katzka DA, Collins MH, et al. Budesonide oral suspension improves 
symptomatic, endoscopic, and histologic parameters compared with placebo in patients with 
eosinophilic esophagitis. Gastroenterology. 2017;152(4):776-86.
60. Dellon ES, Woosley JT, Arrington A, et al. Efficacy of budesonide vs fluticasone for initial 
treatment of eosinophilic esophagitis in a randomized controlled trial. Gastroenterology. 
2019;157(1):65-73.
61. Hirano I, Collins MH, Assouline-Dayan Y, et al. RPC4046, a monoclonal antibody against 
IL13, reduces histologic and endoscopic activity in patients with eosinophilic esophagitis. 
Gastroenterology. 2019;156(3):592-603.
62. Hirano I, Dellon ES, Hamilton JD, et al. Efficacy of dupilumab in a Phase 2 randomized trial 
of adults with active eosinophilic esophagitis. Gastroenterology. 2020;158(1):111-22.
63. Lucendo AJ, Miehlke S, Schlag C, et al. Efficacy of budesonide orodispersible tablets as 
induction therapy for eosinophilic esophagitis in a randomized placebo-controlled trial. 
Gastroenterology. 2019;157(1):74-86.
64. Brand JPL. Development, implementation and evaluation of multiple imputation strategies 
for the statistical analysis of incomplete data sets.  Edited by.  Rotterdam, Netherlands: 1999. p. 
1-212.
65. Heitjan DF, Little RJA. Multiple imputation for the fatal accident reporting system. Appl 
Statist. 1991;40(1):13-29.
66. van Buuren S. Multiple imputation of discrete and continuous data by fully conditional 
specification. Stat Methods Med Res. 2007;16(3):219-42.
67. Collins MH, Capocelli K, Yang GY. Eosinophilic gastrointestinal disorders pathology. Front 
Med. 2018;4:261.
68. FDA. (2020).  FDA guidance on conduct of clinical trials of medical products during 
COVID-19 public health emergency. U.S. Department of Health and Human Services, Food and 
Drug Administration, Silver Spring, MD. 
69. EMA. (2020).  Guidance on the management of clinical trials during the COVID-19 
(coronavirus) pandemic (Version 4). European Medicines Agency, Amsterdam, The 
Netherlands. 
70. Lim S, MacRae KD, Seed WA, et al. The value of forced expiratory volume in 1 s in 
screening subjects with stable COPD for PaO2 < 7.3 kPa qualifying for long-term oxygen 
therapy. Respir Med. 1998;92(9):1122-6.


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71. Kelly AM, McAlpine R, Kyle E. How accurate are pulse oximeters in patients with acute 
exacerbations of chronic obstructive airways disease? Respir Med. 2001;95(5):336-40.


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APPENDIX 1:
SCHEDULES OF ASSESSMENTS
Table 7:
Schedule of Assessments – Screening, Double-Blind Treatment Period, and Safety Follow-Up Period
Evaluation
Screening 
Period
24-Week Double-Blind Treatment Period
Safety Follow-Up 
Period
D 35 to 
D 1
W0/D1
W2/
D15
(± 3)
W4/
D29
(± 3)
W8/
D57
(± 5)
W12/
D85
(± 5)
W16/
D113/
(± 5)
W20/
D141
(± 5)
W24/
D169a
(± 5)      
ETb
2-Week
F-U
Visit
(± 3)
4-Week
F-U
Visit
(± 3)
[Tele-
health]
[Tele-
health]
[Tele-
health]
[Tele-
health]
Informed consent
X
Inclusion/
exclusion criteria
X
X
X
Demographics, social and 
family history
X
Medical historyc      
X
X
Prior and concomitant therapies
X
X
X
X
X
X
X
X
X
X
X
X
Virology screen (HIV, HBV, 
HBsAg, HCV)
X
Randomization/ 
re-randomization
X
X
eDiary trainingd      
X
eDiary monitoringe      
X
X
X
X
X
X
X
X
X
X
Adverse event assessment
X
X
X
X
X
X
X
X
X
X
X
X
Vital signsf      
Xf
Xf
X
X
X
X
X
X
12-lead ECGg      
X
X
X
X
Physical examinationh      
X
X
Pulmonary function testi      
X
X
X
X


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Evaluation
Screening 
Period
24-Week Double-Blind Treatment Period
Safety Follow-Up 
Period
D 35 to 
D 1
W0/D1
W2/
D15
(± 3)
W4/
D29
(± 3)
W8/
D57
(± 5)
W12/
D85
(± 5)
W16/
D113/
(± 5)
W20/
D141
(± 5)
W24/
D169a
(± 5)      
ETb
2-Week
F-U
Visit
(± 3)
4-Week
F-U
Visit
(± 3)
[Tele-
health]
[Tele-
health]
[Tele-
health]
[Tele-
health]
Ophthalmoscopy with OCTj      
X
X
X
X
Pregnancy testk      
X
X
X
X
X
X
X
X
X
X
TBNK panel
X
X
X
X
X
X
X
X
Laboratory testsl      
X
X
X
X
X
X
X
X
EGD and biopsiesm      
X
X
X
X
PK assessmentsn      
X
X
X
X
X
X
X
      
Study drug dispensationp      
X
X
X
Xq
Study drug accountabilityr      
X
X
X
X
X
X
X
X
In-person study drug dosings      
X
X
X
X
X
Qualitative interview (optional)t  
X
a For subjects who complete Week 24 and are eligible to enter the Extension Treatment Period, the Week 24 visit will be used to assess eligibility for the extension and may also 
serve as the Day 1 visit of the Extension Treatment Period. Subjects on placebo during the 24-Week Treatment Period will be re-randomized to study drug for the Extension 
Treatment Period (Section 6.4).
b Subjects discontinuing prior to Week 24 should have an ET visit within 7 days of the last study treatment administration and before initiation of any new treatments. Note that 
safety evaluations (eg, AE query, review of concomitant medications, symptom-directed and focused physical exams as needed and relevant laboratory assessments) will be 
performed as described in Section 10.6.
c Medical history will be collected during Screening and should be updated for any new conditions or medications as needed prior to dosing at the Week 0/Day 1 visit 
(Section 10.3.4).
d eDiary device and training should be provided at Screening to ensure capturing of entries within the required 14-day period.
e Study site staff will monitor subject eDiary compliance. During Screening, the completion of the following eDiary questionnaires should be monitored: DSQ (daily), FAQ 
(daily), PGIS (Day 8 and Day 1). At least 8 DSQ daily entries in the last 2 weeks prior to Week 0/Day 1 (Baseline) visit as well as completion of PGIS are needed for 
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randomization. During the Treatment Period, the completion of the following eDiary questionnaires should be monitored: DSQ (daily), FAQ (daily), PGIS (Weeks 15, 16, 23, 
and 24), PGIC (Weeks 16 and 24), EoE-QOL-A (Week 0/Day 1 and Weeks 16 and 24).
f Safety vital signs (resting HR and systolic and diastolic BP, body temperature, and respiratory rate) taken with subjects in the sitting position will be performed at Screening and 
prior to randomization on Week 0/Day 1 (Baseline). Vital signs may be repeated up to 2 times during a visit to confirm abnormal readings (no need for second reading if the first 
reading is normal). Inclusion and exclusion criteria related to vital signs and ECG must be reviewed and reassessed to confirm eligibility. Vital signs including HR and BP must 
be measured first, followed by 12-lead ECG. The 12-lead ECGs should be obtained prior to predose blood sample collection. The first-dose cardiac monitoring procedure 
(Section 10.6.7.4) should be repeated if a subject has a dose interruption of: 1) ≥2 consecutive days within the first week of treatment during the Double-Blind Treatment Period 
or during Week 24; or 2) ≥7 consecutive days after the first week of treatment during the Double-Blind Treatment Period or after Week 24.
g Safety 12-lead ECGs will be performed with the subject in the supine position prior to blood sample collection and after vital signs are measured at Screening and prior to 
randomization on Week 0/Day 1 (Baseline), and 4 hours (± 15 minutes) after dosing on Week 0/Day 1. At the Week 24 visit, vital signs should be measured first, followed by 
ECGs, predose PK sample collection, study drug dosing at the study site, and first-dose cardiac monitoring for subjects continuing in the Extension Treatment Period.
h Complete physical examination (including assessments of the skin, head, eyes, ears, nose, throat, thyroid, lungs, heart, abdomen, back, lymph nodes, extremities, body weight, 
and height [height collected at Week 0/Day 1 Visit only]) should be performed at Week 0/Day 1 and the ET visit.
i PFTs include FEV1 and FVC measurements. Where locally available, DLCO measurements will also be performed (sites where DLCO is not available should consult the 
Sponsor or Sponsor’s delegate). If Week 24 or ET result is abnormal, then testing should be repeated as soon as able. Post-screening PFTs may be performed within7 days of the 
study visit. Details regarding additional PFTs are provided in Section 10.6.5.
j Scheduled non-screening ophthalmoscopy with OCT may be performed within 7 days of the study visit. Screening ophthalmoscopy with OCT is to be conducted with subjects’ 
pupils dilated (Section 10.6.6).
k Only for women of child-bearing potential. Serum β-hCG test required at screening. On Day 1, urine pregnancy test must be performed and negative test result verified prior to 
dosing. Monthly urine pregnancy test either at home or at the study site at all other visits. Visual inspection of the test result via videoconferencing for virtual assessment is 
recommended. If at any point there is a positive urine β-hCG test, the subject will have study treatment interrupted and a serum sample submitted to the central laboratory for 
β-hCG testing (Section 10.6.9).
l Clinical laboratory tests will include serum chemistry, CBC with differentials, and coagulation. Screening samples should be obtained, and results must be available and 
reviewed prior to the first dose of study treatment. On other study visits, samples should be obtained prior to the daily dosing. Refer to Section 10.6.4.
m Screening EGD (Section 10.3.6) and biopsies (Section 10.3.6.1) should be performed preferably within the first 7 days of the screening period visit to allow sufficient time to 
confirm histology eligibility. The eosinophil counts from the central reader must be available for confirmation of eligibility. The EREFS will be scored by personnel performing 
the EGD. If the ET visit is within 4 weeks of the last EGD and biopsy, these procedures do not need to be repeated.
n PK blood samples are to be collected predose (for trough level, within 60-minute period prior to dosing) and 4 hours (± 15 minutes) postdose on Week 0/Day 1 (after 12-lead 
ECG), and predose on all other indicated days. A PK sample should be taken, if possible, at the time of any SAE or AE leading to study treatment discontinuation. For all PK 
blood draws, the time of the last dose should be documented.
p Study drug may be dispensed by secure mail per country specific guidance. Alternatively, a future supply of study medications may be dispensed to the subject at a site visit to 
cover study medications to be dispensed at the Telehealth Visit.
q Study treatment should be dispensed at Week 24 if the subject continues treatment in the Extension Treatment Period. Additionally, subjects who continue on study but do not 
enter the Extension Treatment Period on the same day as the Week 24 visit may also be dispensed bridging study treatment.
r At each site visit, previously dispensed medication bottles and any remaining tablets will be collected and counted by the Investigator or qualified staff. The number of remaining 
tablets in the bottle may be counted by visual inspection via videoconferencing for virtual assessment. The bottle(s) and any remaining tablets must be returned to the site at the 
next site visit.
s On study visit days with blood draws, subjects should take their dose of study treatment after predose assessments and procedures have been completed.
t The visit window is 14 days following Week 24 visit.
AE, adverse event; β-hCG, beta-human chorionic gonadotropin; BP, blood pressure; CBC, complete blood count; D, day; DLCO, diffusing capacity of the lungs for carbon 
monoxide; DSQ, Dysphagia Symptom Questionnaire; ECG, electrocardiogram; eDiary, electronic diary; EGD, esophagogastroduodenoscopy; EoE-QOL-A, Adult Eosinophilic 
Esophagitis Quality of Life; EREFS, Eosinophilic Esophagitis Endoscopic Reference Score; ET, Early Termination; FAQ, Food Avoidance Question; FEV1, forced expiratory 
volume at 1 second; F-U, follow-up; FVC, forced vital capacity; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human 
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immunodeficiency virus; HR, heart rate; OCT, optical coherence tomography assessment; PFT, pulmonary function test; PGIC, Patient Global Impression of Change; PGIS, 
Patient Global Impression of Severity; PK, pharmacokinetics; SAE, serious AE; TBNK, T, B, NK, CD4+ T cell, and CD8+ T cell count (absolute number and percentage); W, 
week


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Table 8:
Schedule of Assessments – Extension Treatment Period and Safety Follow-Up Period
Evaluation
28-Week Extension Treatment Period
Safety Follow-Up Period
W28/D197
± 7 Days
W32/D225
± 7 Days
W46/D323
± 7 Days
W52/D365
± 7 Days
Early
Terminationa     
2-Week
Follow-Up
Visit
± 3 Days
4-Week
Follow-Up
Visit
± 3 Days
[Telehealth]
EGD and biopsiesb      
X
X
X
eDiary monitoringc      
X
X
X
X
X
Concomitant therapyd      
X
X
X
X
X
X
X
Adverse event assessment
X
X
X
X
X
X
X
Vital signse      
X
X
X
X
X
X
12-lead ECGf      
X
X
Physical examinationg      
X
X
Pulmonary function testh      
X
X
X
Ophthalmoscopy with OCTi      
X
X
X
Pregnancy testj      
X
X
X
X
X
X
TBNK panel
X
X
X
X
X
X
Laboratory testsk      
X
X
X
X
X
X
PK assessmentsl      
X
X
X
X
X
X
      
Study drug dispensationn      
X
X
Study drug accountabilityo      
X
X
X
X
X
In-person study drug dosingp      
X
X
X
X
a Subjects discontinuing the study prior to Week 52/Day 365 should have an ET visit within 7 days of the last study treatment administration and before initiation of any new 
treatments. 
b The EREFS will be scored by the personnel performing the EGD. If the ET visit is within 4 weeks of the last EGD and biopsy, these procedures do not need to be repeated.
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c The completion of the following eDiary questionnaires should be monitored: DSQ (daily), FAQ (daily), PGIS (Weeks 31, 32, 51, and 52), PGIC (Weeks 32 and 52), and 
EoE-QOL-A (Weeks 32 and 52).
d All concomitant medications and procedures should be collected through the safety reporting period (Section 6.7).
e Vital signs including HR and BP must be measured first, followed by 12-lead ECG. 
f Safety 12-lead ECGs will be performed with the subject in the supine position prior to predose blood sample collection and after vital signs are measured.
g At the Week 52 or ET visit, a complete physical examination (including assessments of the skin, head, eyes, ears, nose, throat, neck, thyroid, lungs, heart, abdomen, back, lymph 
nodes, extremities, and body weight) should be performed. 
h PFTs include FEV1 and FVC measurements. Where locally available, DLCO measurements will also be performed (sites where DLCO is not available should consult the 
Sponsor or Sponsor’s delegate). If Week 52 or ET result is abnormal, then testing should be repeated as soon as able. Post-screening PFTs may be performed within 7 days of the 
study visit. Details regarding additional PFTs are provided in Section 10.6.5.
i Details regarding ophthalmoscopy and OCT assessments and instruction following abnormal results are provided in Section 10.6.6.
j Urine pregnancy test only for women of child-bearing potential. Monthly urine pregnancy test should be performed either at home or at the study site. At Weeks 32 and 46, 
sufficient urine pregnancy test kits should be provided to female subjects for monthly testing until the next study site visit. Visual inspection of the test result via 
videoconferencing for virtual assessment is recommended. If at any point there is a positive urine β-hCG test, the subject will have study treatment interrupted and a serum 
sample submitted to the central laboratory for β-hCG testing (Section 10.6.9).
k Clinical laboratory tests will include serum chemistry, CBC with differentials and coagulation and should be obtained prior to the daily dosing. Refer to Section 10.6.4.
l PK blood samples are to be collected predose (within 60-minutes prior to dosing). A PK sample should be taken, if possible, at the time of any SAE or AE leading to study 
treatment discontinuation. For all PK blood draws, the time of the last dose should be documented.
n Study drug may be dispensed by secure mail per country specific guidance. Alternatively, a future supply of study medications may be dispensed to the subject at a site visit to 
cover study medications to be dispensed at the Telehealth Visit. 
o At each site visit, previously dispensed medication bottles and any remaining tablets will be collected and counted by the Investigator or qualified staff. The number of remaining 
tablets in the bottle may be counted by visual inspection via videoconferencing for virtual assessment. The bottle(s) and any remaining tablets must be returned to the site at the 
next site visit.
p On study visit days with blood draws, subjects should take their dose of study treatment after all predose assessments and procedures have been completed.
AE, adverse event; β-hCG, beta-human chorionic gonadotropin; BP, blood pressure; CBC, complete blood count; D, day; DLCO, diffusing capacity of the lungs for carbon 
monoxide; DSQ, Dysphagia Symptom Questionnaire; eDiary, electronic diary; ECG, electrocardiogram; EGD, esophagogastroduodenoscopy; EoE-QOL-A, Adult Eosinophilic 
Esophagitis Quality of Life; EREFS, Eosinophilic Esophagitis Endoscopic Reference Score; ET, Early Termination; FAQ, Food Avoidance Question; FEV1, forced expiratory 
volume at 1 second; FVC, forced vital capacity; HR, heart rate; OCT, optical coherence tomography; PFT, pulmonary function test; PGIC, Patient Global Impression of Change; 
PGIS, Patient Global Impression of Severity; PK, pharmacokinetics; SAE, serious AE; TBNK, T, B, NK, CD4+ T cell, and CD8+ T cell count (absolute number and percentage); 
W, week
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APPENDIX 2:
EOSINOPHILIC ESOPHAGITIS HISTOLOGY SCORING 
SYSTEM
Table 9:
Eosinophilic Esophagitis Histology Scoring System Definitions
Each feature will be scored separately for grade (severity) or stage (extent) of abnormality using 
a 4-point scale (0 = normal; 3 = most severe or extensive).
Features
Definition
Eosinophilic inflammation
Based on peak eosinophil count
Basal zone hyperplasia
Basal zone occupies more than 15% of total epithelial thickness
Eosinophil abscess
Eosinophil aggregate that disrupts the underlying epithelial architecture
Eosinophil surface layering
Eosinophils align in one or more rows in the upper third of the 
epithelium
Dilated intercellular spaces
Intercellular bridges are visible in paracellular spaces
Surface epithelial alteration
Surface epithelial cells stain more darkly than normal and eosinophils 
that may be present among the altered epithelial cells
Dyskeratotic epithelial cells
Epithelial cells with deeply staining cytoplasm and shrunken 
hyperchromatic nuclei that generally occur singly and may be found 
anywhere in the epithelium
Lamina propria fibrosis
Coalesced fibrils form fibers of varying diameter
Source: [67].


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APPENDIX 3:
EOSINOPHILIC ESOPHAGITIS ENDOSCOPIC REFERENCE 
SCORE
Major features
-
Fixed rings (also referred to as concentric rings, corrugated esophagus, corrugated rings, 
ringed esophagus, trachealisation)
–
Grade 0: none
–
Grade 1: mild (subtle circumferential ridges)
–
Grade 2: moderate (distinct rings that do not impair passage of a standard 
diagnostic adult endoscope (outer diameter 8-9.5 mm))
–
Grade 3: severe (distinct rings that do not permit passage of a diagnostic 
endoscope)
-
Exudates (also referred to as white spots, plaques)
–
Grade 0: none
–
Grade 1: mild (lesions involving < 10% of the esophageal surface area)
–
Grade 2: severe (lesions involving > 10% of the esophageal surface area)
-
Furrows (also referred to as vertical lines, longitudinal furrows)
–
Grade 0: absent
–
Grade 1: present
-
Edema (also referred to as decreased vascular markings, mucosal pallor)
–
Grade 0: absent (distinct vascularity present)
–
Grade 1: loss of clarity or absence of vascular markings
-
Stricture
–
Grade 0: absent
–
Grade 1: present
Minor features
-
Crepe paper esophagus (mucosal fragility or laceration upon passage of diagnostic 
endoscope but not after esophageal dilation)
–
Grade 0: absent
–
Grade 1: present
Source: [52].


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APPENDIX 4:
DYSPHAGIA SYMPTOM QUESTIONNAIRE
1. Since you woke up this morning, did you eat solid food? 
Possible responses:

Yes

No
2. Since you woke up this morning, has food gone down slowly or been stuck in your 
throat?
Possible responses:

Yes (2)

No (0)
3. For the most difficult time you had while swallowing food today, did you have to do 
anything to make the food go down or to get relief?
Possible responses:

No, it got better or cleared up on its own (0)

Yes, I had to drink liquid to get relief (1)

Yes, I had to cough and/or gag to get relief (2)

Yes, I had to vomit to get relief (3)

Yes, I had to seek medical attention to get relief (4)
4. The following question concerns the amount of pain you have experienced when 
swallowing food. What was the worst pain you had while swallowing food today?
Possible responses:

None, I had no pain (0)

Mild (1)

Moderate (2)

Severe (3)

Very Severe (4)
The Dysphagia Symptom Questionnaire questions above will be administered via the electronic 
diary (eDiary), which will be completed daily in the evening after subjects have their last meal of 
the day.


Clinical Study Protocol
APD334-206
Etrasimod Versus Placebo in Subjects with Eosinophilic Esophagitis
Amendment 3.0
Arena Pharmaceuticals, Inc.
Confidential
Page 100 of 111
APPENDIX 5:
FOOD AVOIDANCE QUESTION
If you did not try to eat solid food today, what is the primary reason for this? 
Mark 
in applicable box(es).
   
Not applicable because I ate solid food today
Because of eosinophilic esophagitis symptoms 
Because of other reasons
The Food Avoidance Question will be administered via the electronic diary (eDiary), after 
subject completes the Dysphagia Symptom Questionnaire diary questions.


Clinical Study Protocol
APD334-206
Etrasimod Versus Placebo in Subjects with Eosinophilic Esophagitis
Amendment 3.0
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APPENDIX 6:
PATIENT GLOBAL IMPRESSION OF SEVERITY
Please choose the response below that best describes the severity of your eosinophilic esophagitis symptoms 
over the past 7 days.
Mark 
in one box below.
None 
Mild
Moderate 
Severe


Clinical Study Protocol
APD334-206
Etrasimod Versus Placebo in Subjects with Eosinophilic Esophagitis
Amendment 3.0
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Page 102 of 111
APPENDIX 7:
PATIENT GLOBAL IMPRESSION OF CHANGE
Please choose the response below that best describes the overall change in your eosinophilic esophagitis 
symptoms since you started taking the study medication.
Mark 
in one box below.
Much better 
A little better
No change
A little worse 
Much worse
If you had a change, was it meaningful to you?
Yes 
No


Clinical Study Protocol
APD334-206
Etrasimod Versus Placebo in Subjects with Eosinophilic Esophagitis
Amendment 3.0
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APPENDIX 8:
GRADING OF CLINICAL AND LABORATORY 
ADVERSE EVENTS
All clinical and clinically significant laboratory abnormalities will be graded according to the 
Common Terminology Criteria for Adverse Events (CTCAE) Scale for Severity of Adverse 
Events and Laboratory Abnormalities.
Examples of CTCAE terms and grading are provided for clinical adverse events in Table 10 and 
for laboratory abnormalities in Table 11.
Table 10: Example of CTCAE Terms and Grading for Clinical Adverse Events
Respiratory, thoracic and mediastinal disorders
CTCAE Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Cough
Mild symptoms; 
nonprescription 
intervention indicated
Moderate symptoms; 
medical intervention 
indicated; limiting 
instrumental ADL
Severe symptoms; 
limiting self-care 
ADL


Definition: A disorder characterized by sudden, often repetitive, spasmodic contraction of the thoracic cavity, resulting in 
violent release of air from the lungs and usually accompanied by a distinctive sound.
Dyspnea
Shortness of breath 
with moderate 
exertion
Shortness of breath 
with minimal 
exertion; limiting 
instrumental ADL
Shortness of breath at 
rest; limiting self-care 
ADL
Life-threatening 
consequences; 
urgent intervention 
indicated
Death
Definition: A disorder characterized by an uncomfortable sensation of difficulty breathing.
Wheezing
Detectable airway 
noise with minimal 
symptoms
Moderate symptoms; 
medical intervention 
indicated; limiting 
instrumental ADL
Severe respiratory 
symptoms limiting 
self-care ADL; 
oxygen therapy or 
hospitalization 
indicated
Life-threatening 
consequences; 
urgent intervention 
indicated
Death
Definition: A disorder characterized by a high-pitched, whistling sound during breathing. It results from the narrowing or 
obstruction of the respiratory airways.
Dizziness
Mild unsteadiness or 
sensation of 
movement
Moderate 
unsteadiness or 
sensation of 
movement; limiting 
instrumental ADL
Severe unsteadiness 
or sensation of 
movement; limiting 
self-care ADL


Definition: A disorder characterized by a disturbing sensation of lightheadedness, unsteadiness, giddiness, spinning or rocking.
Blurred vision
Intervention not 
indicated
Symptomatic; 
moderate decrease in 
visual acuity (best 
corrected visual 
acuity 20/40 and 
better or 3 lines or 
less decreased vision 
from known 
baseline); limiting 
instrumental ADL
Symptomatic with 
marked decrease in 
visual acuity (best 
corrected visual acuity 
worse than 20/40 or 
more than 3 lines of 
decreased vision from 
known baseline, up to 
20/200); limiting 
self-care ADL
Best corrected 
visual acuity of 
20/200 or worse in 
the affected eye

Definition: A disorder characterized by visual perception of unclear or fuzzy images.
Blood and lymphatic system disorders
Anemia
Hgb < LLN–
10.0 g/dL; < LLN-6.2 
mmol/L; < LLN-100 
g/L
Hgb < 10.0-
8.0 g/dL; < 6.2-4.9 
mmol/L; < 100-80 
g/L
Hgb < 8.0 g/dL; < 4.9 
mmol/L; < 80 g/L; 
transfusion indicated
Life-threatening 
consequences; 
urgent intervention 
indicated
Definition: A disorder characterized by a reduction in the amount of hemoglobin in 100 ml of blood. Signs and symptoms of 
anemia may include pallor of the skin and mucous membranes, shortness of breath, palpitations of the heart, soft systolic 
murmurs, lethargy, and fatigability.
ADL, activities of daily living; CTCAE, Common Terminology Criteria for Adverse Events; Hgb, hemoglobin


Clinical Study Protocol
APD334-206
Etrasimod Versus Placebo in Subjects with Eosinophilic Esophagitis
Amendment 3.0
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Table 11: Example of CTCAE Terms and Grading for Laboratory Abnormalities and 
Pulmonary Functions Tests
Investigations
CTCAE Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Alanine 
aminotransferase 
increased
> ULN-3.0 × ULN if 
baseline was normal; 
1.5-3.0 × baseline if 
baseline was abnormal
> 3.0-5.0 × ULN if 
baseline was normal; 
> 3.0-5.0 × baseline if 
baseline was 
abnormal
> 5.0-20.0 × ULN if 
baseline was normal;
> 5.0-20.0 × baseline 
if baseline was 
abnormal
> 20.0 × ULN if 
baseline was 
normal; > 20.0 × 
baseline if baseline 
was abnormal

Definition: A finding based on laboratory test results that indicate an increase in the level of alanine aminotransferase (ALT or 
SGPT) in the blood specimen.
Navigational Note: Also consider Hepatobiliary disorders: Hepatic failure
Aspartate 
aminotransferase 
increased
> ULN-3.0 × ULN if 
baseline was normal; 
1.5-3.0 × baseline if 
baseline was abnormal
> 3.0-5.0 × ULN if 
baseline was normal; 
> 3.0-5.0 × baseline if 
baseline was 
abnormal
> 5.0-20.0 × ULN if 
baseline was normal; 
> 5.0-20.0 × baseline 
if baseline was 
abnormal
> 20.0 × ULN if 
baseline was 
normal; > 20.0 × 
baseline if baseline 
was abnormal

Definition: A finding based on laboratory test results that indicate an increase in the level of aspartate aminotransferase (AST or 
SGOT) in a blood specimen.
Navigational Note: Also consider Hepatobiliary disorders: Hepatic failure
Platelet count 
decreased
< LLN-75,000/mm3; 
< LLN-75.0 × 109/L
< 75,000 –
50,000/mm3; 
< 75.0-50.0 × 109/L
< 50,000-
25,000/mm3; 
< 50.0-25.0 × 109/L
< 25,000/mm3; 
< 25.0 × 109/L

Definition: A finding based on laboratory test results that indicate a decrease in number of platelets in a blood specimen.
Forced expiratory 
volume decreased
FEV1% (percentages 
of observed FEV1 and 
FVC related to their 
respective predicted 
values) 99-70% 
predicted
FEV1 60%-69%
50%-59%
≤49%

Definition: A finding based on test results that indicate a relative decrease in the fraction of the forced vital capacity that is 
exhaled in a specific number of seconds.
Navigational Note: Also consider Respiratory, thoracic and mediastinal disorders: Respiratory failure or Dyspnea
Vital capacity 
abnormal
90%-75% of predicted 
value
< 75%-50% of 
predicted value; 
limiting instrumental 
ADL
< 50% of predicted 
value; limiting 
self-care ADL


Definition: A finding based on pulmonary function test results that indicate an abnormal vital capacity (amount of exhaled after 
a maximum inhalation) when compared to the predicted value.
Navigational Note: Also consider Investigations: Forced Expiratory Volume; Respiratory, thoracic and mediastinal disorders: 
Respiratory failure or Dyspnea
Carbon monoxide 
diffusing capacity 
decreased
3-5 units below LLN; 
for follow-up, a 
decrease of 3-5 units 
(mL/min/mm Hg) 
below the baseline 
value; asymptomatic 
and intervention not 
indicated
6-8 units below LLN; 
for follow-up, an 
asymptomatic 
decrease of 
> 5-8 units 
(mL/min/mm Hg) 
below the baseline 
value; symptomatic 
and intervention not 
indicated
Asymptomatic 
decrease of > 8 units 
drop; > 5 units drop 
along with the 
presence of 
pulmonary symptoms 
(eg, > Grade 2 
hypoxia or > Grade 2 
dyspnea); intervention 
indicated


ADL, activities of daily living; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; FEV1, forced expiratory volume at 1 second; 
FVC, forced vital capacity; LLN, lower limit of normal; SGOT, serum glutamic-oxaloacetic transaminase; SGPT, serum glutamic-pyruvic 
transaminase; ULN, upper limit of normal


Clinical Study Protocol
APD334-206
Etrasimod Versus Placebo in Subjects with Eosinophilic Esophagitis
Amendment 3.0
Arena Pharmaceuticals, Inc.
Confidential
Page 105 of 111
APPENDIX 9:
GUIDANCE FOR THE MANAGEMENT OF CLINICAL 
AND LABORATORY ADVERSE EVENTS
Clinical adverse events (AEs) and abnormal results of laboratory tests and safety assessments 
considered to be an AE by the Investigator should be graded according to the severity scale of 
the Common Terminology Criteria for Adverse Events. 
Uniform guidance for the management of AEs is provided in Figure 2.
Grade 3 and 4 clinically significant laboratory abnormalities should be confirmed by repeat 
testing within 3 calendar days of receipt of results and before investigational product 
discontinuation, unless such a delay is not consistent with good medical practice.
A clinically significant Grade 4 laboratory abnormality that is not confirmed by repeat testing 
should be managed according to the algorithm for the new AE grade.
Investigational product may be continued without dose interruption for a clinically non-
significant Grade 4 laboratory abnormality (eg, Grade 4 creatinine kinase after strenuous 
exercise, or triglyceride elevation that is non-fasting or that can be medically managed) or a 
clinical event considered unrelated to investigational product.
Any questions regarding adverse event management should be directed to the Medical Monitor.
Figure 2:
Algorithm for the Management of Clinical and Safety Assessment-Related 
Adverse Events
Grade 1
Grade 2
May continue dosing at the  
discretion of the investigator
Grade 3
Grade 4
If related to IP:  
Interrupt IP dosing until ≤ Grade 2, then 
restart IP after discussion with the Medical Monitor
If unrelated to IP:
Continue IP dosing 
at the discretion of the investigator
If recurrence of confirmed Grade 3 or 4 & is related to IP: 
Discontinue IP dosing permanently 
and manage according to local practice.b
If recurrence of confirmed Grade 3 or 4, but is unrelated to IP: 
Continue IP at the discretion of the investigator; 
discuss with the Medical Monitor
If related to IP: 
Discontinue IP dosing 
permanently and 
manage according to 
local practice.b
AE, adverse event; ECG, electrocardiogram; IP, investigational product; PFT, pulmonary function test. 
a Repeat lab tests, ECG, or PFT to confirm AE grade. Clinical adverse event(s) may require additional assessment, therapeutic intervention, and/or consultation 
with relevant expert.  
b Laboratory and/or clinical AEs should be followed until there is stability, improvement or resolution.
Refer to footnote a
Refer to footnote a


Clinical Study Protocol
APD334-206
Etrasimod Versus Placebo in Subjects with Eosinophilic Esophagitis
Amendment 3.0
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APPENDIX 10:
GUIDANCE FOR THE ASSESSMENT OF POTENTIAL 
PROGRESSIVE MULTIFOCAL 
LEUKOENCEPHALOPATHY
To date, there have been no reports of progressive multifocal leukoencephalopathy (PML) with 
the use of etrasimod in clinical studies. Nevertheless, investigators should remain vigilant in 
monitoring for signs and symptoms of serious and atypical infections during the study and after 
discontinuation of study treatment (ie, the 28-day Safety Follow-Up Period).
If a subject exhibits signs and symptoms suspicious for PML, the Investigator must interrupt 
study treatment and perform a targeted neurologic examination to assess for signs of PML, 
which are diverse, progress over days to weeks, and may include progressive weakness on one 
side of the body or clumsiness of limbs or difficulty with walking or writing or fine motor skills, 
disturbance of vision, changes in thinking, memory and orientation leading to confusion and 
personality changes, paresthesia/anesthesia (of any domain: peripheral to central), dysarthria 
(expressive aphasia), and/or agnosia (receptive aphasia). In the evaluation of suspected PML 
cases, investigators may consult with a local neurologist or relevant experts, as needed. If PML 
cannot be ruled out, an Independent Adjudication Committee (IAC) of PML medical experts 
may be consulted.
The Medical Monitor should be informed of any suspected cases of PML and, if needed, will 
facilitate investigator/local neurologist consultation with PML medical experts on the IAC. 
Based on the results of investigator/neurologist examination and IAC input, subject may need 
additional diagnostic tests to exclude or confirm the diagnosis of PML (eg, magnetic resonance 
imaging of the brain, spinal tap).
Study treatment may resume, and no further evaluation is needed if the investigator assessment 
reveals no objective signs of PML, the neurologist confirms that the patient does not have PML, 
or the IAC’s review of the evidence concludes that PML is ruled out.


Clinical Study Protocol
APD334-206
Etrasimod Versus Placebo in Subjects with Eosinophilic Esophagitis
Amendment 3.0
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APPENDIX 11:
GUIDANCE ON CLINICAL TRIAL CONDUCT DURING 
THE COVID-19 PANDEMIC
With a public health emergency (PHE) such as the coronavirus disease 2019 (COVID-19) 
pandemic, it is recognized that the conduct of clinical trials of medical products may be greatly 
impacted. However, the investigator will remain responsible for assuring the safety of trial 
participants, maintaining compliance with Good Clinical Practice, and minimizing risks to trial 
integrity. Additionally, it is expected that every effort will be made to avoid protocol deviation 
while abiding with national and local health official mandates related to the control and 
management of COVID-19.
Consistent with guidance provided by the Food and Drug Administration [68] and European 
Medicines Agency [69], the following general considerations are provided to illustrate 
appropriate action(s) that may be implemented should ongoing COVID-19 or similar 
PHE-related challenges lead to difficulties in adhering to protocol-specified study visits, 
assessments and/or procedures.
Screening
1. The 35-day Screening Period may be extended on a case-by-case basis to accommodate 
reasonable delays in specific screening assessments (eg, pulmonary function tests [PFTs], 
optical coherence tomography [OCT]). The Medical Monitor should be consulted on each 
case. 
2. If significant delay is expected in getting the histology results back, Screening esophageal 
biopsy specimens may be read locally to determine peak eosinophil count for eligibility 
verification. The local histology read may be confirmed by a central read at a later 
timepoint. The Sponsor will determine when it is appropriate to proceed by this 
alternative route. 
3. Depending on local institutional practices or country-specific guidelines, the Investigator 
may consider having the subject obtain COVID-19 diagnostic testing 5 to 7 days prior to 
a scheduled esophagogastroduodenoscopy (EGD) (performed by any qualified healthcare 
provider) and use the result to inform the vigilance of infection control measures to be 
carried on the day of EGD. COVID-19 testing for this trial that is not covered by the 
subject’s health insurance plan may be invoiced to the Sponsor. Consult your clinical 
research associate (CRA) on this matter.
Safety Assessments
1. When required in-person safety assessments (eg, clinical safety laboratory tests) can only 
be performed outside of a study visit window, the investigator should consider whether 
the safety of the trial participant can be assured with the delayed evaluation. 

It is recommended that in-person safety assessments (eg, clinical safety laboratory 
tests) and efficacy assessments (eg, EGD) be performed no later than the 
timepoint that is halfway between two consecutive study visits. 
2. When the subject cannot return to the study site or delegated study staff cannot be 
deployed to visit the subject for in-person safety assessments (eg, clinical safety 
laboratory tests) for submission to the central lab, the clinical safety laboratory tests may 


Clinical Study Protocol
APD334-206
Etrasimod Versus Placebo in Subjects with Eosinophilic Esophagitis
Amendment 3.0
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Page 108 of 111
be processed and analyzed by a local lab. This option will require prior agreement by the 
Sponsor.
3. Due to the risk of COVID-19 transmission from dispersion of respiratory droplets, 
medical societies or local/national public health officials may recommend that pulmonary 
function testing and DLCO be limited to tests that are essential for immediate treatment 
decisions. 

When PFTs cannot be performed, the Sponsor may recommend other methods of 
monitoring respiratory health including measurement of arterial oxygen saturation 
(SpO2) by pulse oximeter at Screening and post-baseline visits. It has been shown 
that the SpO2 in patients with chronic obstructive pulmonary disease (COPD) 
correlates with the forced expiratory volume in 1 second (FEV1) [70]. A pulse 
oximeter SpO2 of ≤92% on room air is 100% sensitivity and 86% specificity for 
detecting hypoxemia [71].

When Screening PFTs cannot be performed, Exclusion Criterion 18 may be 
modified as shown by the text in italicized font to identify and exclude subjects 
with underlying pulmonary disease at Screening: Have an FEV1 or forced vital 
capacity (FVC) of < 70% predicted (prior to the administration of a short-acting 
bronchodilator) on Screening PFTs; or a Screening pulse oximeter SpO2 of ≤92% 
on room air when Screening PFTs are not available due to COVID-19-related 
restrictions or a history of pulmonary disease requiring hospitalization 
≤6 months prior to Baseline. 

Under the scenario above, the missed PFTs and DLCO must be performed no 
later than 10 days after COVID-19 restrictions are lifted and the PFT lab re-opens.
4. Due to risk of COVID-19 transmission from prolonged contact time between patients and 
medical staff, medical societies may recommend limiting ophthalmic evaluations to tests 
that are essential for immediate treatment decisions. 

When ophthalmoscopy with OCT cannot be performed, Exclusion Criterion 17 
may be modified as shown by the text in italicized font to identify and exclude 
subjects with potential macular edema at Screening: “Have active diabetic 
retinopathy, uveitis, retinitis pigmentosum, history of intraocular surgery 
≤12 months prior to Baseline, macular edema or symptoms of blurry or wavy 
central vision, report colors appearing washed out or different, or have difficulty 
reading ≤6 months prior to Baseline (when Screening ophthalmoscopy with OCT 
cannot be performed due to COVID-19-related restrictions).” 

Under the scenario above, the missed ophthalmoscopy with OCT exam must be 
performed no later than 10 days after COVID-19 restrictions are lifted and the 
ophthalmology consultant’s office is opened for non-urgent ophthalmic 
evaluations. 
Documentation Guidance 
When COVID-19-related restrictions/mandates lead to protocol deviations, the following 
COVID-19-related reasons should be documented for each deviation and each subject.


Clinical Study Protocol
APD334-206
Etrasimod Versus Placebo in Subjects with Eosinophilic Esophagitis
Amendment 3.0
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
Specific local restrictions (eg, mandated quarantines, mandated travel limitations) 
and/or

Site-specific circumstances (eg, limitation on the number of patients that can be 
seen in at a clinic/investigative site at any one time due to social distancing 
parameters) and/or

Patient-specific circumstances (eg, patient with COVID-19) 
Valid COVID-19-related reasons will be taken into considerations when determining the 
corrective action for the protocol deviation. 
Ask your CRA and/or the Medical Monitor for guidance on any alternative safety monitoring 
approaches that are not described above.


Clinical Study Protocol
APD334-206
Etrasimod Versus Placebo in Subjects with Eosinophilic Esophagitis
Amendment 3.0
Arena Pharmaceuticals, Inc.
Confidential
Page 110 of 111
APPENDIX 12:
Liver Safety: Suggested Actions and Follow-Up 
Assessments 
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt are 
termed “adaptors.” In some subjects, transaminase elevations are a harbinger of a more serious 
potential outcome. These subjects fail to adapt and therefore are “susceptible” to progressive and 
serious liver injury, commonly referred to as DILI. Subjects who experience a transaminase 
elevation above 3 × ULN should be monitored more frequently to determine if they are 
“adaptors” or are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations (>2 × 
ULN) by several days or weeks. The increase in T bili typically occurs while AST/ALT is/are 
still elevated above 3 × ULN (ie, AST/ALT and T bili values will be elevated within the same 
laboratory sample). In rare instances, by the time T bili elevations are detected, AST/ALT values 
might have decreased. This occurrence is still regarded as a potential DILI. Therefore, abnormal 
elevations in either AST OR ALT in addition to T bili that meet the criteria outlined below are 
considered potential DILI (assessed per Hy’s law criteria) cases and should always be considered 
important medical events, even before all other possible causes of liver injury have been 
excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the subject’s 
individual baseline values and underlying conditions. Subjects who present with the following 
laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) cases to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST/ALT and T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value ≥2 × ULN 
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not 
available.

For subjects with baseline AST OR ALT OR T bili values above the ULN, the following 
threshold values are used in the definition mentioned above, as needed, depending on 
which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT values 
≥2 times the baseline values AND ≥3 × ULN; or ≥8 × ULN (whichever is smaller).

Preexisting values of T bili above the normal range: T bili level increased from 
baseline value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN 
(whichever is smaller).
Rises in AST/ALT and T bili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.


Clinical Study Protocol
APD334-206
Etrasimod Versus Placebo in Subjects with Eosinophilic Esophagitis
Amendment 3.0
Arena Pharmaceuticals, Inc.
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Page 111 of 111
The subject should return to the investigator site and be evaluated as soon as possible, preferably 
within 48 hours from awareness of the abnormal results. This evaluation should include 
laboratory tests, detailed history, and physical assessment.
In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law cases, 
additional laboratory tests should include albumin, CK, direct and indirect bilirubin, GGT, 
PT/INR, total bile acids, and alkaline phosphatase. Consideration should also be given to 
drawing a separate tube of clotted blood and an anticoagulated tube of blood for further testing, 
as needed, for further contemporaneous analyses at the time of the recognized initial 
abnormalities to determine etiology. A detailed history, including relevant information, such as 
review of ethanol, acetaminophen/paracetamol (either by itself or as a coformulated product in 
prescription or over-the-counter medications), recreational drug, or supplement (herbal) use and 
consumption, family history, sexual history, travel history, history of contact with a jaundiced 
person, surgery, blood transfusion, history of liver or allergic disease, and potential occupational 
exposure to chemicals, should be collected. Further testing for acute hepatitis A, B, C, D, and E 
infection, liver imaging (eg, biliary tract), and collection of serum samples for 
acetaminophen/paracetamol drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and T bili 
elevation defined above should be considered potential DILI (Hy’s law) cases if no other reason 
for the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) cases are to be 
reported as SAEs, irrespective of availability of all the results of the investigations 
performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of reasonable 
investigations have been received and have excluded an alternative etiology.


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SAP_001.pdf: 
 
PROTOCOL APD334-206 
Statistical Analysis Plan 
Page 1 of 70
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
APD334-206 (C5041009) 
 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of Etrasimod in 
Adult Subjects with Eosinophilic Esophagitis 
 
 
 
 
AUTHOR: 
 
VERSION NUMBER AND DATE: V 1.0, 12Jan2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document
:
Author:
Version Number:
1.0
Version Date: 
12Jan2023
 
Reference:  
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are 
confidential and proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or 
reproduction is strictly prohibited. 
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PROTOCOL APD334-206 
Statistical Analysis Plan 
Page 2 of 70
 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V1.0 (Dated 12 Jan. 2023) for Protocol APD334-206. 
 
 
Name 
Signature 
Date (DDMMYYYY) 
Approved By: 
 
Refer to eSignature 
 
Position: 
 
Company: 
IQVIA 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date (DDMMYYYY) 
Approved By: 
 
 
 
Position: 
 
Company: 
IQVIA 
 
 
Name 
Signature 
Date (DDMMYYYY) 
Approved By: 
 
 
 
Position: 
 
Company: 
Pfizer, Inc. 
 
 
 
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PROTOCOL APD334-206 
Statistical Analysis Plan 
Page 3 of 70
 
MODIFICATION HISTORY 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
0.1 
19FEB2021 
 
Not Applicable – First Version 
0.2 
21Jul2021 
 
 
Updated based on Legacy Arena draft 1 
comments and alignment with other ongoing 
etrasimod studies, including APD334-301 and 
APD334-302. 
0.3 
01Mar2022 
 
Update based on Legacy Arena draft 2 
comments and alignment with Version 1 SAPs 
for APD334-301 and APD334-302. The 
analysis visit window (study day) ranges are 
updated to be “212 to 274” for Week 32, and 
“275 to 344” for Week 46. 
 
Baseline eosinophil PEC (eos/hpf) is removed 
from section 8.2 as it is not a randomization 
stratification factor. 
0.4 
23Aug2022 
 
“Additionally, a listing of retinal photograph 
and eye pressure assessments will be provided 
for subjects who experienced an AE related to 
eye disorders.” is removed from 17.7.3. Kye 
from Pfizer confirmed the removal on 
23Aug2022. 
1.0 
Dec2022 
 
Mainly updates are as follows:  
Added the Identification of Rescue Therapy 
guidance in Appendix to document/align with 
the Rescue Therapy identification process  
 
Updated the DSQ total score calculation 
 
Updated the visit window language 
 
PPD
PPD
PPD
PPD
PPD


 
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Updated the model for primary endpoint by 
using rank score per protocol amendment v3.0 
(04Jan2023). 
 
Added/updated the safety analyses in extension 
period per protocol amendment v3.0 
(04Jan2023). 
 
 


 
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TABLE OF CONTENTS 
 
1. 
INTRODUCTION............................................................................................................. 13 
2. 
STUDY OBJECTIVES AND ESTIMANDS .................................................................. 13 
2.1. 
Primary Objective ......................................................................................................................................... 13 
2.2. 
Secondary Objectives .................................................................................................................................... 13 
 
 
2.4. 
Estimands ....................................................................................................................................................... 14 
3. 
STUDY DESIGN ............................................................................................................... 16 
3.1. 
General Description ....................................................................................................................................... 16 
3.2. 
Schedule of Events ......................................................................................................................................... 17 
3.3. 
Changes to Analysis from Protocol .............................................................................................................. 17 
4. 
PLANNED ANALYSES ................................................................................................... 17 
4.1. 
Main Analysis ................................................................................................................................................. 17 
4.2. 
Final Analysis ................................................................................................................................................. 18 
5. 
ANALYSIS SETS.............................................................................................................. 19 
5.1. 
Process for Analysis Set Assignment ............................................................................................................ 19 
5.2. 
Screened Set ................................................................................................................................................... 19 
5.3. 
Randomized Set ............................................................................................................................................. 19 
5.4. 
Full Analysis Set ............................................................................................................................................. 20 
5.5. 
Per Protocol Set.............................................................................................................................................. 20 
5.6. 
Modified Full Analysis Set ............................................................................................................................ 20 
5.7. 
Safety Set ........................................................................................................................................................ 21 
5.8. 
Pharmacokinetic Set ...................................................................................................................................... 21 
5.9. 
Completers Sets .............................................................................................................................................. 21 
5.10. Efficacy evaluable Set .................................................................................................................................... 21 
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6. 
GENERAL CONSIDERATIONS ................................................................................... 21 
6.1. 
Reference Start Date and Study Day ........................................................................................................... 21 
6.2. 
Baseline ........................................................................................................................................................... 22 
6.3. 
Retests, Unscheduled Visits, and Early Termination Data ........................................................................ 22 
6.4. 
Windowing Conventions ............................................................................................................................... 22 
6.5. 
Statistical Tests .............................................................................................................................................. 24 
6.6. 
Common Calculations ................................................................................................................................... 24 
6.7. 
General Study Information ........................................................................................................................... 25 
 
 
8. 
STATISTICAL CONSIDERATIONS ............................................................................ 25 
8.1. 
Adjustments for Covariates and Factors to be Included in Analyses ....................................................... 25 
8.2. 
Multicenter Studies ........................................................................................................................................ 25 
8.3. 
Missing data ................................................................................................................................................... 26 
8.4. 
Multiple Comparisons/ Multiplicity ............................................................................................................. 26 
8.5. 
Subgroup Analyses ........................................................................................................................................ 26 
9. 
OUTPUT PRESENTATIONS ......................................................................................... 27 
10. 
DISPOSITION AND PROTOCOL DEVIATIONS ...................................................... 27 
11. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 29 
12. 
DERIVATIONS ................................................................................................................ 30 
13. 
MEDICAL HISTORY ...................................................................................................... 30 
14. 
MEDICATIONS ............................................................................................................... 31 
15. 
STUDY MEDICATION EXPOSURE ............................................................................ 31 
15.1. Derivations ..................................................................................................................................................... 32 
16. 
STUDY MEDICATION COMPLIANCE ...................................................................... 32 
16.1. Derivations ..................................................................................................................................................... 32 
17. 
EFFICACY OUTCOMES................................................................................................ 33 
17.1. Primary Efficacy ............................................................................................................................................ 33 
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17.1.1. 
Primary Efficacy Variable & Derivation ................................................................................................. 33 
17.1.2. 
Missing Data Methods for Primary Efficacy Variable ............................................................................ 33 
17.1.3. 
Multiple Imputation Under MAR ............................................................................................................ 34 
17.1.4. 
Primary Analysis of Primary Efficacy Variable(s) .................................................................................. 35 
17.1.5. 
Supplementary Analysis of Primary Efficacy Variable(s) ....................................................................... 35 
17.1.6. 
Sensitivity Analysis of Primary Efficacy Variable(s) .............................................................................. 36 
17.1.6.1. 
Tipping Point Analysis .................................................................................................................... 36 
17.1.6.2. 
Observed Data Only ......................................................................................................................... 37 
17.2. Secondary Efficacy ........................................................................................................................................ 38 
17.2.1. 
Secondary Efficacy Variables & Derivations .......................................................................................... 38 
17.2.2. 
Missing Data Methods for Secondary Efficacy Variable(s) .................................................................... 42 
17.2.3. 
Primary Analysis of Secondary Efficacy Variables ................................................................................. 42 
17.2.3.1. 
Change from Baseline in DSQ total score and Esophageal PEC at Week 16 .................................. 42 
17.2.3.2. 
Proportion of Subjects with Esophageal PEC < 15 and ≤ 6 eos/hpf at Week 16 ............................. 42 
17.2.4. 
Supplementary Analysis of Secondary Efficacy Variables ..................................................................... 43 
17.2.5. 
Sensitivity Analysis of Secondary Efficacy Variables ............................................................................. 43 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18. 
SAFETY OUTCOMES .................................................................................................... 47 
18.1. Adverse Events ............................................................................................................................................... 47 
18.2. All TEAEs ....................................................................................................................................................... 47 
18.2.1. 
Severity .................................................................................................................................................... 47 
18.2.2. 
Relationship to Study Treatment ............................................................................................................. 48 
18.2.3. 
TEAEs Leading to Discontinuation of Study Treatment ......................................................................... 48 
18.2.4. 
Serious Adverse Events ........................................................................................................................... 48 
18.2.5. 
TEAEs Leading to Death ......................................................................................................................... 48 
18.2.6. 
TEAEs of Special Interest ........................................................................................................................ 49 
18.2.7. 
Overall Summary of Adverse Events ...................................................................................................... 51 
18.3. Deaths ............................................................................................................................................................. 51 
18.4. Laboratory Evaluations ................................................................................................................................ 52 
18.4.1. 
Safety Laboratory Evaluations ................................................................................................................. 52 
18.4.2. 
Pregnancy Tests ....................................................................................................................................... 53 
18.4.3. 
Other Screening Laboratory Assessments ............................................................................................... 53 
18.5. ECG Evaluations ........................................................................................................................................... 53 
18.5.1. 
ECG Markedly Abnormal Criteria........................................................................................................... 54 
18.6. Vital Signs ....................................................................................................................................................... 54 
18.6.1. 
Vital Signs Specific Derivations .............................................................................................................. 55 
18.6.2. 
Vital Signs Markedly Abnormal Criteria ................................................................................................. 56 
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18.7. Physical Examination .................................................................................................................................... 56 
18.8. Other Safety Assessments ............................................................................................................................. 56 
18.8.1. 
Pulmonary Function Tests ....................................................................................................................... 56 
18.8.2. 
PFT Markedly Abnormal Criteria ............................................................................................................ 57 
18.8.3. 
Ophthalmoscopy and Optical Coherence Tomography (OCT)................................................................ 57 
19. 
PHARMACOKINETICS ................................................................................................. 57 
20. 
DATA NOT SUMMARIZED OR PRESENTED .......................................................... 60 
21. 
REFERENCES .................................................................................................................. 61 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS .............................. 62 
APPENDIX 2. PARTIAL DATE CONVENTIONS ............................................................. 64 
APPENDIX 3. QUESTIONNAIRE SCORING INFORMATION ...................................... 67 
APPENDIX 4.   IDENTIFICATION OF RESCUE THERAPY ............................................ 68 
 
LIST OF FIGURES AND TABLES 
 
LIST OF ESTIMANDS .............................................................................................................. 14 
FIGURE 1:  STUDY DESIGN ................................................................................................... 17 
VISIT WINDOWS FOR EFFICACY AND SAFETY ANALYSES ...................................... 23 
PLANNED ANALYSES BY ENDPOINT ................................................................................ 41 
 
 
APPENDIX 1. 
Programming Conventions for Outputs ..................................................................................... 62 
APPENDIX 2. 
Partial Date Conventions ............................................................................................................. 64 
APPENDIX 3. 
Questionnaire Scoring Information ............................................................................................ 67 
APPENDIX 4.   Identification of Rescue Therapy .................................................................................................. 68 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Explanation               
ADL 
activities of daily living            
ADR 
adverse drug reaction             
AE 
adverse event              
AESI 
adverse event of special interest           
ALC 
absolute lymphocyte count             
ALT 
alanine aminotransferase              
ANCOVA 
analysis of covariance             
AST 
aspartate aminotransferase              
AV 
atrioventricular               
AZA 
azacytidine               
β-hCG 
beta-human chorionic gonadotropin             
BP 
blood pressure              
bpm 
beats per minute             
CBC 
complete blood count             
CD 
Crohn’s disease              
CFR 
Code of Federal Regulations            
cGMP 
current Good Manufacturing Practices            
CI 
confidence interval              
CMH 
Cochran-Mantel-Haenszel               
CMP 
Clinical Monitoring Plan             
COPD 
chronic obstructive pulmonary disease            
COVID-19 
coronavirus disease 2019             
CRA 
clinical research associate             
CRO 
contract research organization             
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events          
CYP 
cytochrome P450              
DLCO 
diffusing capacity of the lungs for carbon monoxide        
DNA 
deoxyribonucleic acid              
DSQ 
Dysphagia Symptom Questionnaire             
ECG 
electrocardiogram               
eCRF 
electronic case report form            


 
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Abbreviation 
Explanation               
eDiary 
electronic diary              
EEn 
eosinophilic enteritis              
EG 
eosinophilic gastritis              
EGD 
esophagogastroduodenoscopy               
eGFR 
estimated glomerular filtration rate            
EGID 
eosinophilic gastrointestinal disease             
EoE 
eosinophilic esophagitis              
EoE-HSS 
Eosinophilic Esophagitis Histology Scoring System           
EoE-QOL-A 
Adult Eosinophilic Esophagitis Quality of Life          
eos 
eosinophils               
EREFS 
Eosinophilic Esophagitis Endoscopic Reference Score           
ET 
Early Termination              
FA 
fluorescein angiogram              
FAQ 
Food Avoidance Question             
FCS 
fully conditional specification             
FDA 
Food and Drug Administration            
FEV 1 
forced expiratory volume at 1 second          
FAS 
Full Analysis Set             
FSH 
follicle-stimulating hormone              
FVC 
forced vital capacity             
GCP 
Good Clinical Practice             
GERD 
gastroesophageal reflux disease             
GI 
gastrointestinal               
GWAS 
genome-wide association studies             
HBsAg 
hepatitis B surface antigen            
HBV 
hepatitis B virus             
HCV 
hepatitis C virus             
HIV 
human immunodeficiency virus             
hpf 
high power field             
HR 
heart rate              
HSS 
Histology Scoring System             
IAC 
independent adjudication committee             
IB 
Investigator’s Brochure              


 
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Abbreviation 
Explanation               
IC 
informed consent              
ICF 
informed consent form             
ICH 
International Council for Harmonization            
IEC 
Independent Ethics Committee             
IgE 
immunoglobulin E              
IL 
interleukin               
IMID 
immune-mediated inflammatory disorder             
IND 
Investigational New Drug             
INR 
international normalized ratio             
IRB 
Institutional Review Board             
IUD 
intrauterine device              
IV 
intravenous               
IWRS 
Interactive Web Response System            
JAK 
Janus kinase              
LS 
least square              
6-MP 
6-mercaptopurine               
MAR 
missing at random             
MedDRA 
Medical Dictionary for Regulatory Activities           
MH 
Mantel-Haenszel 
mFAS 
modified Full Analysis Set            
MI 
multiple imputation              
MMF 
mycophenolate mofetil              
MTX 
methotrexate               
NASH 
nonalcoholic steatohepatitis              
OCT 
optical coherence tomography             
OIT 
oral immunotherapy              
PD 
pharmacodynamic(s)          
PDMP 
 Protocol Deviation Management Plan  
PEC 
peak eosinophil count             
PFT 
pulmonary function test             
PGIC 
Patient Global Impression of Change           
PGIS 
Patient Global Impression of Severity           
PHE 
public health emergency             


 
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Abbreviation 
Explanation               
PK 
pharmacokinetic(s)  
PML 
progressive multifocal leukoencephalopathy             
PPI 
proton pump inhibitor             
PPI-REE 
proton pump inhibitor-responsive esophageal eosinophilia           
PTEN 
phosphatase and tensin homolog            
qd 
once daily              
QOL 
quality of life             
QTcB 
Bazett’s corrected QT interval            
QTcF 
Fridericia’s corrected QT interval            
RNA 
ribonucleic acid              
S1P 
sphingosine 1-phosphate              
S1P1,4,5 
sphingosine 1-phosphate receptors "1," "4," 5          
SAE 
serious adverse event             
SAM 
severe atopy metabolic wasting            
SAP 
Statistical Analysis Plan             
SCIT 
subcutaneous immunotherapy              
SD 
standard deviation              
SLIT 
sublingual immunotherapy              
SOP 
standard operating procedure             
SpO2 
arterial oxygen saturation             
6-TG 
6-thioguanine               
TBNK 
"T," "B," "NK," CD4+ T cell and CD8+ T cell count (absolute number and percentage) 
TEAE 
treatment-emergent adverse event             
TGF-β 
transforming growth factor-beta             
Th2 
type 2 helper T            
TNFα 
tumor necrosis factor alpha            
TSLP 
thymic stromal lymphopoietin             
UC 
ulcerative colitis              
ULN 
upper limit of normal            
WBC 
white blood cell             
WOCBP 
woman of child-bearing potential            
 
 


 
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1. INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the statistical rationale, methods, rules, and conventions to be used in 
the presentation and analysis of efficacy, safety, pharmacokinetic (PK), 
 for 
Clinical Study Protocol APD334-206. It describes the data to be summarized and analyzed, including specifics of 
the statistical analyses to be performed (ICH 1998). This SAP is based on the Clinical Study Protocol APD334-206 
Amendment 3.0, dated XX January 2023 and will cover the whole study period (i.e., Double-Blind Treatment Period 
and Extension Treatment Period). 
 
 
 
The table, figure, and listing (TFL) shells are prepared in a separate file based on this analysis plan. Upon approval 
of the SAP, some updates (including, but not limited to titles, footnotes, headings and re-numbering of tables) on 
TFL shells are allowed without SAP amendment if the updates within TFL shells do not conflict with the contents of 
the SAP. 
2. STUDY OBJECTIVES AND ESTIMANDS 
2.1. 
PRIMARY OBJECTIVE 
The primary objectives are: 
 
To evaluate the effects of etrasimod on esophageal eosinophilia in adult subjects with active 
eosinophilic esophagitis (EoE) 
 
To evaluate the dose-response relationship of 2 doses of etrasimod versus placebo in adult subjects 
with active EoE 
 
To select an etrasimod dose based on efficacy and safety for continued development 
2.2. 
SECONDARY OBJECTIVES 
The secondary objective is: 
 
To evaluate the effect of etrasimod on dysphagia symptoms in adult subjects with active EoE 
 
 
 
 
 
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2.4. 
ESTIMANDS 
The primary and secondary estimands to support regulatory decisions are described in Table 1 below. 
Supplementary analyses for the primary and secondary estimands will be performed in the Modified Full Analysis 
Set (mFAS), Completers, and Per Protocol Set, respectively. 
List of Estimands 
Estimand 
Definition 
Attributes 
Population 
Variable/ 
Endpoint 
Intercurrent event 
handling strategy 
Population-level 
summary measure 
Primary  
Estimand 
Efficacy of 
etrasimod on 
esophageal 
peak 
eosinophil 
count (PEC) at 
Week 16 
Full 
Analysis 
Set 
Percentage 
change from 
Baseline in 
esophageal 
PEC at 
Week 16 
Subjects with missing 
data for any reason 
(including early 
discontinuation) or who 
initiated rescue 
medication and/or 
rescue procedure before 
the primary efficacy 
assessments prior to 
Week 16 will have 
subsequent PEC data 
set to missing from that 
point forward through 
Week 24. The missing 
data at Week 16 will be 
imputed using a 
multiple imputation 
(MI) method.  
Differences between 
etrasimod (2 mg, 1 mg 
and any dose) and 
placebo in percent 
change from Baseline 
in esophageal PEC at 
Week 16  
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Key 
Secondary 
Estimand 1 
Efficacy of 
etrasimod on 
Dysphagia 
Symptom 
Questionnaire 
(DSQ) at 
Week 16 
Full 
Analysis 
Set 
Change 
from 
Baseline in 
DSQ at 
Week 16 
Same as the intercurrent 
event handling strategy 
for the primary 
estimand 
Differences between 
etrasimod (2 mg, 1 mg 
and any dose) and 
placebo in change from 
Baseline in DSQ at 
Week 16 
Key  
Secondary 
Estimand 2 
Efficacy of 
etrasimod on 
esophageal 
PEC at Week 
16 
Full 
Analysis 
Set 
Change 
from 
Baseline in 
esophageal 
PEC at 
Week 16 
Same as the intercurrent 
event handling strategy 
for the primary 
estimand 
Difference between 
etrasimod (2 mg, 1 mg 
and any dose) and 
placebo in change from 
Baseline in esophageal 
PEC at Week 16 
Key  
Secondary 
Estimand 3 
Efficacy of 
etrasimod on 
esophageal 
PEC at Week 
16 
Full 
Analysis 
Set 
Proportion 
of subjects 
with 
esophageal 
PEC < 15 
eos/hpf at 
Week 16 
Subjects in any of the 
following cases will be 
treated as 
nonresponders: use of 
rescue medication 
and/or rescue procedure 
prior to Week 16; 
premature 
discontinuation for 
study due to any reason 
prior to Week 16; or 
with missing data at 
Week 16 for any 
reason. If subject had 
rescue medication 
and/or rescue procedure 
after Week 16, any 
assessment after the 
rescue medication 
and/or rescue procedure 
time will be set to 
missing. 
Difference between 
etrasimod (2 mg, 1 mg 
and any dose) and 
placebo in the 
proportion of 
responders at Week 16 


 
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Key  
Secondary 
Estimand 4 
Efficacy of 
etrasimod on 
esophageal 
PEC at Week 
16 
Full 
Analysis 
Set 
Proportion 
of subjects 
with 
esophageal 
PEC ≤ 6 
eos/hpf at 
Week 16 
Same as intercurrent 
event handling strategy 
for key secondary 
estimand 3 
Difference between 
etrasimod (2 mg, 1 mg 
and any dose) and 
placebo in the 
proportion of 
responders at Week 16 
a Intercurrent events include: 1) initiate a rescue medication and/or rescue procedure for EoE, 2) have a rescue non-
drug treatment before the efficacy assessment.  
ES, endoscopic score; RB, rectal bleeding, SF, stool frequency; UC, ulcerative colitis. 
 
3. STUDY DESIGN 
3.1. 
GENERAL DESCRIPTION 
This Phase 2 randomized, double-blind, multi-center study will evaluate the efficacy, safety, and PK of etrasimod 
compared with placebo for 24 weeks in adults with active EoE. 
 
The study will consist of a Screening Period of up to 35 days, 24 weeks of double-blind treatment (Double-Blind 
Treatment Period), 28 weeks of active extended treatment (Extension Treatment Period), and 4 weeks of follow-up 
(Safety Follow-Up Period) for a total study duration of up to 61 weeks. Approximately 96 subjects were planned to 
be enrolled. 
 
Eligible subjects will be randomized in a double-blinded fashion (3:3:2 ratio) to etrasimod 1 mg, etrasimod 2 mg, or 
matching placebo once daily. Randomization will be stratified by baseline history of esophageal dilation (yes/no) 
and concurrent proton pump inhibitor (PPI) therapy (yes/no). 
 
All subjects who complete the Double-Blind Treatment Period and meet eligibility criteria for the Extension 
Treatment Period may enter the Extension Treatment Period. Subjects who were in the etrasimod 1 mg or etrasimod 
2 mg groups in the Double-Blind Treatment Period will continue the same etrasimod dose in the Extension 
Treatment Period. Subjects who were in the placebo group during the Double-Blind Treatment Period will be re-
randomized (1:1 ratio) to etrasimod 1 mg or etrasimod 2 mg at entry into the Extension Treatment Period.  
 
Subjects will have follow-up visits at 2 and 4 weeks after the last dose of study treatment after Week 52 or the Early 
Termination (ET) visit. 


 
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Figure 1:  Study Design 
 
*Esophagogastroduodenoscopy  
EoE, eosinophilic esophagitis; ETR, etrasimod; F/U, follow-up; PBO, placebo. 
Numbers preceded by colons represent the randomization ratio.
 
3.2. 
SCHEDULE OF EVENTS 
Schedule of events can be found in Appendix 1 of the protocol. 
3.3. 
CHANGES TO ANALYSIS FROM PROTOCOL 
 
Not applicable. 
4. PLANNED ANALYSES 
The following analyses will be performed for this study: 
 
Main Analysis  
 
Final Analysis  
4.1. 
MAIN ANALYSIS 
A Main Analysis will take place for this study at the end of the Double-Blind Treatment Period when all subjects 
have completed Week 24 visit or discontinued from the study prior to Week 24. The results of which will be based 
on the unblinded treatment groups. All planned Main Study Analyses identified in this SAP will be performed by 
IQVIA Biostatistics following Pfizer Pharmaceutical Sponsor Authorization of this SAP, database unblinding, and 
Analysis Sets.  


 
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Derivations and definitions for the Main Analysis will be based on those required for the final analysis contained in 
this SAP, unless deviations are stated within the text. The list of outputs provided with the full set of output 
templates (planned for the final analysis) will highlight which of these outputs will also be provided for the Main 
Analysis.  
 
After all subjects have completed the Double-Blind Treatment Period or discontinued from the study prior to Week 
24, outstanding data queries have been resolved/closed, and the data have been cleaned and finalized, the sponsor 
will authorize breaking of the study blind for Double Blind Treatment Period and the Main Analysis of the data will 
be performed. No treatment assignment unblinded, or analyses completed until this SAP has been approved.  
 
At the time of the main analysis, the sponsor staff will be unblinded to the initial treatment assignments at the 
beginning of Double-Blind Treatment Period, but participants, investigators and site staff will remain blinded. 
During the Extension Treatment Period, participants, investigators, and site staff will be aware that active treatment 
is being provided; however, they will remain blinded to the dose assignments. An unblinded team at IQVIA will 
receive the Double-Blind Treatment assignments and perform the Main Analysis  
 
4.2. 
FINAL ANALYSIS  
The Final Analysis will occur when all subjects have completed the Extension Treatment Period or discontinued 
from the study. All final, planned analyses identified in SAP will be performed by IQVIA Biostatistics following 
Pfizer Sponsor Authorization of this SAP, database unblinding, and Analysis Sets.  
 
After all subjects have completed the study, outstanding data queries have been resolved/closed, and the data have 
been cleaned and finalized, the sponsor will authorize locking the database, unblinding for the second randomization 
schedule used for subjects receiving placebo in the Double Blind Treatment  period and entering into the extension 
periodand the final analysis of the data will be performed. No database may be unblinded or analyses completed 
until this SAP has been approved. 
 
Any, post-hoc, 
 completed to support planned study analyses, which were not identified in this 
SAP, will be documented and reported in the clinical study report. Any results from these unplanned analyses will 
also be clearly identified in the text of the clinical study report. 
 
 
 
Unless specified otherwise, the following treatment (treatment sequence) will be used for Double-blind Treatment 
Period and Extension Treatment Period, respectively: 
 
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List of treatments/treatment sequences 
Study Period 
Treatment / Treatment Sequence 
Double-Blind Treatment 
Period 
 
etrasimod 1 mg  
 
etrasimod  2mg  
 
etrasimod any dose 
 
Placebo  
Extension Treatment Period 
 
etrasimod 1 mg – 1 mg 
 
etrasimod  2mg – 2 mg 
 
Placebo – etrasimod 1 mg 
 
Placebo – etrasimod 2 mg  
5. ANALYSIS SETS 
Agreement and authorization of subjects included/excluded from each analysis set will be conducted prior to the 
unblinding of the study for the Main Analysis and Final Analysis.  
5.1. 
PROCESS FOR ANALYSIS SET ASSIGNMENT 
Before the database is unblinding for the Main Analysis and Final Analysis, the subjects excluded from each 
analysis set and the reason for exclusion will be sent to Pfizer for blinded review. The Clinical Protocol Deviation 
log file will be needed to define the Per Protocol Set for each analysis. This file will be incorporated into the 
analysis datasets and used, along with programmable deviations, to determine which subjects to include in the Per 
Protocol Set. Any changes to the analysis sets will occur before the database is unblinded.  Pfizer will approve the 
final analysis sets which will be used for analyses prior to database unblinding. Once the analysis sets are approved, 
the subjects will be unblinded. Any additional analysis set assignments after database unblinding will also need to be 
approved. 
5.2. 
SCREENED SET 
The Screened Set will contain all subjects who provide informed consent for this study. 
 
5.3. 
RANDOMIZED SET 
The Randomized Set will contain all subjects who are randomized to study treatment. 


 
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5.4. 
FULL ANALYSIS SET  
The Full Analysis Set (FAS) will consist of all randomized subjects in the Double-Blind Treatment Period who 
receive at least 1 dose of study treatment. Subjects will be summarized by treatment to which they were randomized, 
regardless of treatment actually received. 
5.5. 
PER PROTOCOL SET  
The Per Protocol Set will consist of all subjects in the FAS without major protocol violations on or before Week 16 
that might affect the evaluation of the effect of study treatment on the primary endpoint. This set will be used in 
sensitivity analyses of the primary and secondary endpoints to evaluate the influences of major protocol violators 
and deviators on the primary results. Subjects will be excluded from the Per Protocol Set if they violate the 
eligibility criteria or significantly deviate from the study plan, including: 
 
Study treatment non-compliance (< 80 or > 120%) 
 
Received incorrect study treatment for > 7 days in total 
 
Used rescue medication or undergo rescue medical procedure that may affect primary efficacy 
endpoint at Week 16 
 
Missed Week 16 esophageal PEC in pre-specified analysis window per Section 6.4 for reasons other 
than discontinuing due to lack of efficacy  
 
All protocol deviations will be reviewed in addition to the programmable deviations listed above (e.g., study 
treatment non-compliance) to determine if any deviation is significant enough to exclude a subject from the Per 
Protocol Set. All exclusion flags will be finalized before study unblinding. Subjects excluded from the Per Protocol 
Set will be listed along with the reason category above. Subjects will be summarized by treatment to which they 
were randomized, regardless of treatment actually received.  
5.6. 
MODIFIED FULL ANALYSIS SET  
The modified FAS (mFAS) will consist of all randomized subjects who receive at least 1 dose of study treatment in 
the Double-Blind Treatment Period and have a Baseline and at least 1 post-randomization measurement, In addition, 
subjects with baseline DSQ total score <8 will be excluded from mFAS for DSQ based endpoint analyses. Subjects 
will be summarized by treatment to which they were randomized, regardless of treatment actually received. Note 
that the mFAS can vary with endpoints since some subjects may have the needed data for inclusion in the mFAS for 
some endpoints, but not for other endpoints. 
 
 


 
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5.7. 
SAFETY SET  
The Safety Set will be derived for both the Double-Blind Treatment Period and the Extension Treatment Period, 
respectively and includes all randomized subjects who receive at least 1 dose of study treatment during the specified 
treatment period. In Double-Blind Treatment Period, subjects will be analyzed according to treatment received In 
Extension Treatment Period, subjects will be analyzed according to the treatment sequence received, regardless of 
randomization. The Safety Set will be used for all safety analyses.  
5.8. 
PHARMACOKINETIC SET 
The Pharmacokinetic Set will include all subjects in the Safety Set with at least 1 quantifiable postdose PK 
measurement of etrasimod which is not impacted by protocol violations or events with potential to affect the PK 
concentration. 
5.9. 
COMPLETERS SETS 
The Completers Set (Week 16) will consist of all subjects in the FAS who complete Week 16 visit during the 
Double-Blind Treatment Period. Subjects will be summarized by treatment to which they were randomized. 
The Completers Set (Week 24) will consist of all subjects in the FAS who complete Week 24 visit during the 
Double-Blind Treatment Period. Subjects will be summarized by treatment to which they were randomized. 
5.10. 
EFFICACY EVALUABLE SET  
The Efficacy Evaluable Set will be derived for the Extension Treatment Period only and includes all randomized 
subjects who receive at least 1 dose of study treatment and have at least one efficacy measurement in the Extension 
Treatment Period. Subjects will be analyzed according to treatment received in the Double-Blind Treatment Period 
and Extension Treatment Period (see treatments/treatment sequences in Section 4.2 for more details).   
 Note that the Efficacy Evaluable Set can vary with endpoints since some subjects may have the needed data for 
inclusion in the Efficacy Evaluable Set for some endpoints, but not for other endpoints.  
6. GENERAL CONSIDERATIONS 
6.1. 
REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date and will be used to show start/stop day of assessments and 
events.  Unless specified otherwise, reference start date is defined as the date of first dose (Day 1) and will appear in 
every listing where an assessment date or event date appears.  


 
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If the date of the event is on or after the reference date then:  
                  Study Day = (date of event – reference date) + 1 
If the date of the event is prior to the reference date then:  
                  Study Day = (date of event – reference date) 
In the situation where the event date is partial or missing, Study Day, and any corresponding durations will appear 
missing in the listings. 
6.2. 
BASELINE 
Unless otherwise specified, Baseline for the Double-Blind Treatment Period is defined as the last non-missing 
measurement taken prior to the first dose (including unscheduled assessments), and Baseline for the Extension 
Treatment Period is defined as the last non-missing measurement taken prior to the date of first dose in Extension 
Treatment Period at Week 24. If measurements include time (except for Quality of Life assessments (QoL)), the 
date/time will be used to define Baseline. Otherwise, only dates will be compared. QoL baseline is measured on Day 
1 prior to the first dose. In the case where the last non-missing measurement and the date of first dose coincide and 
time is not collected, if the measurement was planned in the protocol to be done prior to the date of first dose, that 
measurement will be considered in defining Baseline. 
 
6.3. 
RETESTS, UNSCHEDULED VISITS, AND EARLY 
TERMINATION DATA 
For by-visit analyses and summaries, efficacy, safety, health-related quality of life, and 
 (including 
scheduled, retests, unscheduled, and early termination) will be assigned to visits after the application of the 
windowing conventions described in Section 6.4. All measurements will be considered in summaries of 
abnormalities or worst-case values post-Baseline. 
 
The visit windowing will be applied before missing data are imputed. 
 
Listings will include scheduled, unscheduled, retest, and early discontinuation data. 
6.4. 
WINDOWING CONVENTIONS  
All scheduled study visits are defined relative to Study Day 1, the date of first dose. Scheduled visit windows are 
defined in Appendix 1 of the protocol. A windowing convention will be used to determine the analysis visit value 
for a given measurement and will be applicable for all by-visit summaries and analyses for efficacy and safety data. 
See Table 3 below for specific visit windows. 
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Visit Windows for Efficacy and Safety Analyses 
For all efficacy (except for DSQ total score ), 
 health-related quality of life, safety 
labs and vital signs. 
Scheduled Study Visit  
(Protocol Scheduled Day) 
Analysis Visit Window  
(Study Day) 
 
Baseline (Double-Blind Treatment Period)  
≤ 1, in addition to Study Day ≤ 1 , a measurement also needs to 
fulfill the baseline criteria identified in Section 6.2 in order to be 
considered as baseline measurement    
Week 0 (Day 1) 
1 
Week 2 (Day 15 ± 3) 
2 to 22 
Week 4 (Day 29 ± 3) 
23 to 43 
Week 8 (Day 57 ± 5) 
44 to 71  
Week 12 (Day 85 ± 5) 
72 to 99 
Week 16 (Day 113 ± 5) 
100 to 127 
Week 20 (Day 141 ± 5) 
128 to 155 
Week 24 (Day 169 ± 5) 
156 to 183 
Week 28 (Day 197 ± 7) 
184 to 211 
Week 32 (Day 225 ± 7) 
212 to 274 
Week 46 (Day 323 ± 7) 
275 to 344 
Week 52 (Day 365 ± 7) 
> 344 
 DSQ total score will be calculated every 2 weeks (week 0, 2, 4, 6, 8, 10, etc.) based on the scheduled study day 
starting on Day 1 For example, DSQ total score for Week 2, 4 and 6 will be calculated on Day 15, 29 and 43, 
respectively. . 
 
For ECGs, OCT, and PFT. 
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Scheduled Study Visit  
(Protocol Scheduled Day) 
Analysis Visit Window  
(Study Day) 
Baseline (Double-Blind Treatment Period) 
≤1 
Week 0 (Day 1) 
1 
Week 24 (Day 169 ± 5) 
71 to 267 
Week 52 (Day 365 ± 7) 
> 267 
 
 
 
 
Windowing will be applied prior to any missing data calculations. The measurement that meets the Baseline criteria 
described in Section 6.2 will be labeled as “Baseline”. Unscheduled or Screening visits that occurred before the 
Baseline visit will not be assigned an analysis visit. The early discontinuation visit will be eligible for allocation to 
an analysis visit. The 2- and 4-Week Follow-Up visits will not be included in the visit windows and will be 
summarized separately without any window applied. 
 
 
If one or more results for a variable are assigned to the same analysis visit, the result with the date closest to the 
protocol scheduled day will be used in the analysis. If two measurements in the same analysis visit window are 
equidistant from the protocol scheduled study day, the earlier measurement will be used in the analysis. If multiple 
assessments are available on the same day, then the average of the assessment will be used in the analysis, except for 
laboratory and ECG data where the assessment at the earliest time of the same day will be used. If both central and 
local assessments of the same lab test are available on the same day, the central result will take precedence over the 
local result. If both central and local assessments of the same ECG test are available on the same day, the assessment 
of clinical significance by local reader will take precedence over the determination by a central reader. 
6.5. 
STATISTICAL TESTS 
The default significance level will be 0.05, confidence intervals will be 95%, and all tests will be 2-sided, unless 
otherwise specified in the description of the analyses. 
6.6. 
COMMON CALCULATIONS 
For quantitative measurements, change from baseline and proportions will be calculated as: 
 
 
Change from Baseline = Test Value at Visit X – Baseline Value 


 
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 
Percent Change from Baseline = ((Test Value at Visit X – Baseline Value) / Baseline Value) * 100 
 
Proportion at Visit X = Number of subjects satisfying criteria at Visit X / Total number of subjects at 
Visit X 
6.7. 
GENERAL STUDY INFORMATION 
A general table with summary of study information will be generated, including date of first subject signed informed 
consent form (ICF), last subject visit date and database lock date. All analyses will be conducted using SAS® 
(version 9.4, SAS Institute Inc., Cary, NC). 
 
 
 
 
 
 
 
8. STATISTICAL CONSIDERATIONS 
8.1. 
ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE 
INCLUDED IN ANALYSES 
The following covariates and factors, and/or endpoint Baseline measure are used in the analyses. For details of their 
inclusion in the models, see the specific analysis section. 
 
Baseline history of esophageal dilation (Yes/No)  
 
Concurrent PPI therapy (Yes/No) 
If a subject was assigned the wrong stratum at randomization, their reported stratum based on the randomization 
system will be used for the statistical analyses. Analyses may be repeated using actual stratum based on eCRF as 
sensitivity analysis if randomization based on mis-stratification occurs in more than 10% of randomized subjects. 
8.2. 
MULTICENTER STUDIES 
 
This study will be conducted by multiple investigators at multiple centers internationally.  
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Data from all sites will be pooled and statistical analyses will not be adjusted for investigational site, country, or 
geographic region. 
8.3. 
MISSING DATA 
Missing adverse event (AE) relationship to study drug and AE seriousness will be imputed as described in Section 
17.1.1.2 and 17.1.3, respectively. Partial or missing AE start dates, Concomitant Medication (CM) start dates, and 
hospitalization dates will also be imputed as described in Appendix 2. No other missing safety data will be imputed. 
 
Missing efficacy data will be handled as described in Sections 16.1.2, 16.2.2, and 16.3.2. In the primary analysis of 
the primary endpoint, PEC after rescue medication and/or rescue procedure uses will be set to missing; all missing 
data will then be imputed in the FAS using multiple imputation. In the main analyses of all binary responder-type 
endpoints, all subjects with missing data, regardless of reason for missingness, will be considered as nonresponders. 
In the main analysis of continuous or score endpoints, subjects with missing data will be handled using observed 
cases only, multiple imputation, or a linear mixed effect model. 
8.4. 
MULTIPLE COMPARISONS/ MULTIPLICITY 
  
For Double Blinded Treatment Period, hypotheses tests will be performed for efficacy endpoints for the comparison 
of etrasimod dose versus the placebo group. However, these hypothesis tests will not be controlled for type-I error 
rate. Un-adjusted p-values will be reported. The associated 95% confidence intervals will be reported. 
 
For the Extension Treatment Period, no hypothesis tests between treatment groups will be performed; only 
descriptive statistics will be provided.  
 
8.5. 
SUBGROUP ANALYSES 
The following subgroups will be assessed for the primary, secondary, and 
 endpoints: 
 
Sex (Female, Male) 
 
Race (white, non-white) 
 
Age (≤ Median, > Median) 
 
History of Dilation (Yes, No) 
 
Duration of Disease (≤ Median, > Median) 
 
Concurrent PPI Therapy (Yes, No) 
 
Concurrent Atopic Comorbidities (Yes, No) 
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 
Concurrent Elimination Diet (Yes, No) 
 
Baseline Esophageal PEC (≤ Median, > Median) 
 
Baseline DSQ Score (≤ Median, > Median) 
 
Baseline Eosinophilic Esophagitis Endoscopic Reference Score (EREFS) (≤ Median, > Median) 
 
Baseline Swallowed Topical Steroid Treatment Refractory Status (Yes, No) 
Additional subgroups may be assessed, if deemed necessary. The medians will be derived based on the FAS for all 
subgroups cut at the median. It should be noted that the study was not designed to detect treatment differences with 
high statistical power within subgroups. If any subgroup includes < 5% of all subjects, no inferential statistics will 
be generated. 
 
The actual stratum at Baseline will be used for all subgroup analyses.  
  
9. OUTPUT PRESENTATIONS 
0 shows conventions for presentation of data in outputs.  
10. DISPOSITION AND PROTOCOL DEVIATIONS 
All subjects who provide informed consent will be accounted for in this study. Inclusion criteria not met and 
exclusion criteria met will be listed. 
 
Among the randomized subjects, the number and percent of subjects who completed/discontinued treatment, reasons 
off treatment, the number and percent of subjects who completed/discontinued the study, and reasons off study will 
be summarized in all randomized subjects. This summary will also be provided by region and country. The number 
and percent of subjects in each analysis set will be summarized in all randomized subjects. An additional summary 
of the number of subjects screened, the number of screen failed subjects, and reason for screen failure will be 
presented for all screened subjects. A listing of subjects whose blind was broken will be provided. The number of 
subjects whose visit was impacted by the COVID-19 pandemic per CRF will also be summarized by nominal visit. 
 
During site monitoring, protocol deviations will be graded as Critical, Major, or Minor. According to ICH E3 and 
ICH E3(R1), important protocol deviations are a subset of protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a subject's rights, safety, 
or well-being (ICH 1995, ICH 2012). For example, important protocol deviations might include enrolling subjects in 
violation of key eligibility criteria designed to ensure a specific subject population or failing to collect data 
necessary to interpret primary endpoints, as this may compromise the scientific value of the study.  
 


 
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During the review of all reported deviations, important deviations related to study inclusion or exclusion criteria, 
conduct of the study, patient management, or patient assessment will be identified. Where relevant the importance of 
a potentially important protocol deviations will be assessed in the context of the study’s estimands to evaluate 
potential impact. All important protocol deviations will be summarized for the FAS in the following categories in 
descending frequency by study treatment group.  
 
All protocol deviations will be listed, including whether a deviation was impacted by the COVID-19 pandemic (Yes 
or No). Protocol deviation categories include but are not limited to the following: 
 
Informed Consent and Process 
 
Inclusion Criteria 
 
Exclusion Criteria 
 
Concomitant Medication Criteria 
 
Laboratory Assessment Criteria 
 
Study Procedures Criteria  
 
Blinding 
 
Patient Report Outcomes 
 
Safety 
 
Visit Schedule criteria 
 
Investigational Product Condition 
 
Subject Investigational Product Compliance 
 
Investigation Product (IP) Administration  
 
Efficacy Criteria 
 
Source Document Criteria  
 
Subject Discontinuation  
Note, all protocol deviation categories above are based on the final PDMP that is completed after May 2022 except 
for Source Document Criteria, which is based on old PDMP prior to May 2022. 
 
Important protocol deviations will also be summarized by whether they were impacted by COVID-19 pandemic 
(Yes or No). Additionally, a summary of missing endoscopy regardless of reason and missing endoscopy due to visit 
impacted by the COVID-19 pandemic will be presented by visit. The summary of important protocol deviations will 
be provided for Double-blinded Treatment period and Extension Treatment period, respectively.  
 
The protocol deviation categories above are based on the latest version of PDMP and associated protocol deviation 


 
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categories prior to the unblinding of Double-blind Treatment period. If there is any update for these 2 documents 
regarding the protocol deviation categories after the unblinding of Double-blind Treatment period, the summary and 
listings regarding protocol deviation could be subject to be updated if deemed needed. 
11. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
The following demographic data and Baseline characteristics will be summarized for the FAS: 
 
Age on consent (years)  
 
Sex 
 
Race  
 
Ethnicity 
 
Woman of childbearing potential (Yes or No) 
 
Height (cm) 
 
Weight (kg) 
 
Body mass index (BMI) (kg/m2) 
 
Alcohol consumption (Yes or No) 
 
Tobacco use (Yes or No)  
 
This summary will be repeated for age, sex, race, ethnicity, or woman of childbearing potential for 
subjects who fail screening.  
The following Baseline characteristics related to EoE will be summarized for the FAS: 
 
Primary EoE Symptom experienced (Dysphagia, Food Impaction, Specific food avoidance, other) 
 
Duration of EoE (years) 
 
History of Esophageal Dilation (Yes or No) 
o 
Subjects with more than 1 esophageal dilation (Yes or No) 
o 
Duration of Time Between the Last 2 Esophageal dilation procedures (months) 
o 
Impact of Dilation on EoE symptoms  
o 
Complications Related to Dilation Procedure (Yes or No) 
 
EoE Histopathologic Phenotype  
 
Biopsy of the esophagus previously assessed for PEC (Yes or No) 
 
Esophageal Level assessed for PEC: Proximal, Mild , Distal  
 
Endoscopic Findings  
 
Comorbid Conditions  
 
Type of Dietary Therapy 
 
Food Groups Eliminated from Food Elimination Diet  
 
Reason for Discontinuation of Diet  


 
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 
Family History of EoE (Yes or No) 
o 
Relation  
o 
Type  
 
Baseline history of esophageal dilation (Yes or No) – Reported (used for stratification at 
randomization) 
 
Baseline history of esophageal dilation (Yes or No) – Actual (reported on the eCRF) 
 
Baseline history of esophageal dilation – Difference 
 
Concurrent PPI therapy (Yes or No) – Reported (used for stratification at randomization) 
 
Concurrent PPI therapy (Yes or No) – Actual (reported on the eCRF). The reference start date used to 
identify the Concurrent PPI therapy status is the date of randomization 
 
Concurrent PPI therapy – Difference 
 
Baseline PEC (eos/hpf)  
 
Prior EoE Treatment (Yes or No)  
 
Reason for Prior EoE Treatment Discontinuation  
 
 
Prior treatment for EoE will be summarized, including category of treatment, reason for 
discontinuation, and estimated duration (weeks) of treatment over the last 12 months. 
 
12. DERIVATIONS 
 
Duration of EoE (years) = (Informed consent date – Date of diagnosis + 1) / 365.25 
 
Weight (kg) = Weight (lb) × 0.4536  
 
Height (cm) = Height (in) × 2.54 
 
Height (m) = Height (in) × 0.0254 = Height (cm) × 0.01 
 
BMI (kg/m2) = Weight (kg) / Height (m)2 
13. MEDICAL HISTORY 
Medical history will be collected on the medical history eCRF and coded using Medical Dictionary for Regulatory 
Activities (MedDRA, version 25.1 or higher). The version used to code medical history will be displayed in the 
outputs. All medical history will be summarized for the Safety Set by system organ class (SOC) and preferred term 
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14. MEDICATIONS 
Medications will be captured on the Concomitant Medications eCRF and coded using the WHO Drug dictionary 
(WHODD01SEP2021 or later version). Refer to APPENDIX 2 for handling of partial dates for medications. In the 
case where it is not possible to define a medication as prior or concomitant, the medication will be classified by the 
worst case (i.e. concomitant).  
 
‘Prior’ medications are medications which started and stopped prior to the first dose of study treatment. 
 
‘Concomitant’ medications for the Double-Blind Treatment Period are medications which started prior 
to, on or after the first dose of study treatment AND ended on or after the date of first dose of study 
treatment or were ongoing at the end of the study. 
 
‘Concomitant’ medications for the Extension Period are medications which started prior to, on or after 
the first dose of study treatment in the Extension Period AND ended on or after the date of first dose of 
study treatment in the Extension Period or were ongoing. 
Concomitant medications will be summarized by Anatomical-Therapeutic-Chemical (ATC) Level 2 and Preferred 
Drug name for the Safety Set. Concomitant medications used for ongoing EoE will be flagged as such on the 
Concomitant Medications eCRF and summarized by ATC Level 2 and Preferred Drug name for the Safety Set. 
Concomitant medication summaries will be prepared for the End of Double-Blind Treatment Period and End of 
Extension Period, respectively. 
 
Prior therapies for EoE, which will be captured on EoE Prior Therapies eCRF, will also be summarized by ATC 
Level 2 and Preferred Drug name for the Safety Set. 
15. STUDY MEDICATION EXPOSURE 
Exposure to study treatment in weeks will be summarized for the Safety Set for the End of Double-Blind Period, 
Extension Period, and overall, respectively. For overall exposure to study treatment in the Double-Blind Treatment 
Period, the date of first and last study treatment administration will be taken from the Dosing Administration for 
Double-Blind Period eCRF. For the overall exposure to study treatment in the Extension Period, the date of first and 
last study treatment will be taken from the Dosing Administration for Extension Period eCRF. Exposure for the 
entire study may also be summarized, in which case, the earliest study treatment date from both periods will be used 
for the first date and the latest study treatment date in both periods will be used for the last date. Interruptions, 
compliance, and dose changes are not taken into account for duration of exposure. Total subject-years on study will 
also be summarized. 
 
Dose interruptions will be recorded on the Dosing Administration for Double-Blind Period and Dosing 
Administration for Extension Period eCRFs. Overdoses will be recorded on the Overdose eCRF. The frequency and 
percentage of subjects who had at least one dose interruption, who had at least one dose interruption of >7 days, who 


 
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had at least one dose interruption of >14 days, who had one overdose, and who had >1 overdose will be summarized 
for the Safety Set. 
 
15.1. 
DERIVATIONS 
Duration of exposure (weeks) = (date of last study treatment administration – date of first study treatment 
administration + 1) / 7. For subjects with missing study treatment end dates collected on the Dosing Administration 
eCRFs, their date of last study treatment administration will be imputed by the last date of all dosing administration 
start/stop dates recorded. 
16. STUDY MEDICATION COMPLIANCE  
Total number of tablets expected, total number of tablets taken, total number of tablets missed, overall compliance 
to study treatment, frequency and percentage of subjects with overall compliance of <80% or >120% are based on 
Dosing Administration in the EDC. They will be summarized for the Safety Set for both the Double-Blind Period 
and Extension Period. 
16.1. 
DERIVATIONS 
Compliance to study treatment is based on the Drug Accountability eCRF and will be calculated as the number of 
tablets taken (total dispensed – total returned) divided by the prescribed number of tablets expected during the 
treatment period, expressed as a percentage, see calculations below.  
The total number of tablets expected is defined as the number of tablets that a subject is expected to have taken 
between their first and last study treatment administration and is numerically identical to the subject’s overall study 
treatment exposure, since the medication is to be taken once daily. On any site visit day, the medication is to be held 
and taken at the site, after all predose assessments have been completed. For example, if a subject took their last 
dose of study treatment on Day 60 and returned to the site on Day 78 to return the study treatment bottle, then the 
total number of tablets expected would be 60, not 77. 
 
Overall Compliance to study treatment will be calculated as follows: 
([୘୭୲ୟ୪ ୒ ୭୤ ୲ୟୠ୪ୣ୲ୱ ୢ୧ୱ୮ୣ୬ୱୣୢ ୧୬ ୲୦ୣ ୱ୲୳ୢ୷] ି [୘୭୲ୟ୪ ୒ ୭୤ ୲ୟୠ୪ୣ୲ୱ ୰ୣ୲୳୰୬ୣୢ ୧୬ ୲୦ୣ ୱ୲୳ୢ୷])
[ୈୟ୲ୣ ୭୤ ୪ୟୱ୲ ୢ୭ୱୣ] ି [ୈୟ୲ୣ ୭୤ ୤୧୰ୱ୲ ୢ୭ୱୣ] ା ଵ
  x 100 
If a bottle is not returned, all dispensed tablets will be assumed to be taken. For each subject, if a high percentage (> 
25%) of bottles were not returned by a subject, additional analyses may be done where bottles not returned are 
excluded from the overall compliance calculation for the subject. In such analysis, the date of last dose or the date of 
last bottle return, whichever is earlier, will be used as the “date of last dose” in the calculation above.  
Both scheduled and unscheduled study treatment dispensations will be used in the compliance calculation. Overall 


 
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compliance calculations will be performed for the Double-Blind Treatment Period and the entire study and will be 
used in determining inclusion/exclusion of subjects in the Per Protocol Set. For subjects discontinued prior to Week 
16, their overall compliance for the 16 Week Treatment Period and the entire study will be identical. For subjects 
who remained in the study beyond Week 16, the 16 Week total tablets expected will be defined as Date of Week 16 
visit – Date of first dose, since their last dose in the 16 Week Treatment Period should have been taken on the day 
before Week 16 visit. 
17. EFFICACY OUTCOMES  
17.1. 
PRIMARY EFFICACY 
17.1.1. PRIMARY EFFICACY VARIABLE & DERIVATION 
The primary efficacy variable is percent change from Baseline in esophageal PEC at Week 16. Esophageal PEC will 
be based on the central esophagogastroduodenoscopy (EGD) results. A decrease in esophageal PEC indicates 
improvement in disease. 
17.1.2. MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE  
Subjects who 1) discontinue the study for worsening of disease, lack of efficacy, or adverse event related to EoE, 2) 
use a rescue medication for EoE, or 3) have rescue medical procedure during the study as confirmed after blinded 
review by clinical and medical team members before study unblinding will be considered to have a missing outcome 
in the analysis of all efficacy endpoints at any subsequent timepoints, including the primary endpoint. The rescue 
medications/rescue medical procedure will be identified by the Pfizer clinical team during blinded data review. The 
detailed information regarding the identification of rescue therapy is provided in Appendix 4. In scenarios 2 and 3 
above, if a subject has an efficacy measurement collected after the initiation of rescue medication/rescue medical 
procedure, the observed data will be censored at the time of initiation and they will be considered as having a 
missing outcome. Subjects in all 3 scenarios above may still be included in the respective Per Protocol Set, provided 
they do not violate other criteria for Per Protocol Set. For example, they will be excluded from the respective Per 
Protocol Set if they initiate a prohibited medication before the Week 16 efficacy assessment that can affect efficacy 
of the study treatment and the indication is unrelated to EoE.  
 
Analysis visits will be mapped as per Section 6.4 before any missing data imputation method is applied. 
 
Subjects who initiate rescue medication will have PEC results after the start of rescue medication/rescue medical 
procedure set to missing. All missing PEC at Week 16 and Week 24 will then be imputed using multiple imputation 
under missing at random (MAR) procedure with a fully conditional specification (FCS) and predictive mean 


 
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matching for PEC as the primary missing data method. There are two different types of missing data patterns: non-
monotone and monotone. A subject with missing data at any post-Baseline visit, and a non-missing data point after 
that visit is said to have intermittent missing data (non-monotone). A subject with missing data at any post-Baseline 
visit and at all subsequent visits is said to have monotone missing data. 
17.1.3. MULTIPLE IMPUTATION UNDER MAR 
Any missing PEC at the planned assessments will be imputed using multiple imputation under MAR. MAR assumes 
the missing value is independent of unobserved outcomes given observed data (i.e., subjects with missing PEC can 
be modeled based on subjects with observed PEC values) (Rubin 1987).  
 
The following steps will be implemented: 
 
Step 1: 
Regardless of the arbitrary missing data pattern (i.e. monotone or non-monotone), a fully conditional specification 
(FCS) method with predictive mean matching for continuous variables will be used to impute the missing PEC data. 
The FCS method allows for separate conditional distributions for each imputed variable. The predictive mean 
matching approach creates a regression model using parameters sampled from the posterior distribution and then a 
predicted value for each missing value is computed. The missing value is replaced by randomly selecting an 
observation from a set of ‘k’ values that are the closest predicted values to the missing predicted value. Missing data 
imputation will be performed using the SAS PROC MI procedure. The number of imputations will be 40. A separate 
imputation model will be used for each treatment group. The stratification variables will be included in the 
imputation models.  
 
Step 2: 
Percent change from Baseline in PEC will be re-computed at Week 16 for each of the 40 imputed datasets.  
 
Step 3: 
The analysis of covariance (ANCOVA) model based on rank scores including treatment group, reported 
randomization stratification factors of Baseline history of esophageal dilation (Yes/No) and concurrent PPI therapy 
(Yes/No) as factors and Baseline eosinophil PEC as a covariate will be run for each of the 40 datasets to obtain 40 
estimators of interest. 
 
Step 4: 
Use SAS PROC MIANALYZE to produce an overall pooled estimate (mean of 40 estimates) with its associated 
standard error, confidence interval, and pooled p-value. 
 
There could be certain adjustments to the multiple imputation model due to unexpected data issues after unblinding 


 
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treatment. All post-unblinding modifications to the multiple imputation model or approaches to address missing data 
will be described in the Clinical Study Report (CSR).  
 
Additionally, missing data will be imputed using the following missing data methods: Tipping point analysis and 
observed data only. More details are provided in Section 16.1.5.  
17.1.4. PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
The following hypotheses (H01 and H02) for the primary endpoint will be tested: 
 
H01: The percentage change from Baseline in esophageal PEC at Week 16 is the same between etrasimod 2mg and 
placebo. 
H11: The percentage change from Baseline in esophageal PEC at Week 16 is different between etrasimod 2mg and 
placebo.  
H02: The percentage change from Baseline in esophageal PEC at Week 16 is the same between etrasimod 1mg and 
placebo. 
H12: The percentage change from Baseline in esophageal PEC at Week 16 is different between etrasimod 1mg and 
placebo. 
All hypotheses will be tested at the 2 sided α level, 0.05.  
The primary efficacy analysis will be performed for the FAS. Percent change from baseline in esophageal PEC will 
be summarized using the number of observations, mean, standard deviation (SD), median, minimum, and maximum.  
An analysis of covariance (ANCOVA) model based on rank scores due to the skewed distribution of the data and 
possible outliers will be used. The ANCOVA model will include treatment group and randomization stratification 
factors of Baseline history of esophageal dilation (Yes/No) and concurrent PPI therapy (Yes/No) as factors and 
Baseline eosinophil PEC as a covariate. Multiple results of the ANCOVA model will be expressed as least square 
(LS) means rank scores, LS mean rank scores difference from placebo, 95% confidence interval (CI) and p-value. 
For the treatment comparisons of etrasimod 1 mg vs. placebo and etrasimod 2 mg vs placebo, the treatment group 
factor in the ANCOVA model will include placebo, etrasimod 1 mg and etrasimod 2 mg. For the comparison of 
etrasimod any dose vs placebo, a separate ANCOVA model based on rank scores will be used, where treatment 
group factor will only include placebo and etrasimod any dose treatment. For the Extension Treatment Period, no 
pair-wise comparison will be performed; only descriptive statistics will be provided. In addition, descriptive 
summary of percentage change in esophageal PEC from baseline as well as difference between treatment groups 
will be presented by treatment group. 
 
17.1.5. SUPPLEMENTARY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
The primary model as described in Section 16.1.3 will be repeated using the Completers Set and Per Protocol Set as 


 
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supplementary analyses. Subgroup analyses will also be performed for the primary model.  
17.1.6. SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
Sensitivity analyses will be implemented to explore different types of missing data approaches. 
17.1.6.1. 
Tipping Point Analysis 
A tipping point approach based on multiple imputation of values through Week 16 will be used with a specified 
adjustment (referred to as delta adjustment or shift) applied to values imputed under a MNAR-based imputation 
model. To find a tipping point, a series of imputations will be performed with increasing values of delta.   
The goal is to evaluate the plausibility of the assumed expected values for missing outcomes on each treatment 
group under which the conclusions change, ie, under which values of delta there are no longer evidence of 
significant treatment difference. 
The following steps will be implemented: 
Step 1:  
Same as Step 1 described in 16.1.2 above.  
 
Step 2: 
Apply a shift (i.e. additive delta adjustment) to the imputed PEC at each visit in both treatment groups. Percent 
change from Baseline in PEC will be re-computed at Week 16 for each of the 40 imputed datasets.  
 
Step 3: 
Same as Step 3 described in 16.1.2 above.  
 
Step 4: 
Same as Step 4 described in 16.1.2 above.  
 
Note, imputations with delta adjustment will be performed with progressively increasing delta values until a tipping 
point is reached based on the significance of the ANCOVA test based on rank scores. A tipping point will 
correspond to the smallest value of delta for which the primary hypothesis is no longer rejected. The shift parameter 
(delta) for the active treatment group will take increasing values from 0 with increments of 40 (maximum PEC of 
X), representing adjustments in towards worse outcomes (i.e., after dropout, on average, subjects on treatment will 
have PEC worsen). For placebo arm, delta adjustments will decrease with increments of 40, representing 
adjustments in the direction of better outcomes. The adjustments in each treatment group will be continued until the 
ANCOVA test based on rank scores for the primary hypotheses are no longer significant at the 2sided α level, 0.05. 
The corresponding shift parameters in both treatment groups at the tipping point will be reported along with the LS 
means rank scores, LS mean rank scores difference from placebo, 95% CI, and p-values from each ANCOVA test 
based on rank scores.  


 
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Results will be plotted as a heat map on a two-dimensional plot with axes corresponding to the delta values used in 
each treatment group respectively, and different colors will be used to represent the magnitude of the 2-sided p-
values corresponding to analysis with each combination of delta values.  The clinical interpretation about the 
plausibility of the assumptions underlying the tipping point will be provided in the CSR.  
17.1.6.2. 
Observed Data Only 
 
This analysis will be performed using the mFAS. No imputation for missing data will be performed.  
 
 


 
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17.2. 
SECONDARY EFFICACY 
The secondary efficacy analyses will be performed for the FAS.  
17.2.1. SECONDARY EFFICACY VARIABLES & DERIVATIONS 
The secondary efficacy analyses will be performed for the FAS. The secondary efficacy endpoints are: 
 
Change from Baseline in DSQ total score at Week 16 
 
Change from Baseline in Esophageal PEC at Week 16. 
 
Proportion of Subjects with Esophageal PEC < 15 eos/hpf at Week 16 
 
Proportion of Subjects with Esophageal PEC ≤ 6 eos/hpf at Week 16 
Change from Baseline in DSQ total score at Week 16 will be based on daily DSQ score from subject daily Diary 
data. The DSQ total score and daily DSQ score calculations are provided below. An increase in DSQ total score 
indicates worsening of dysphagia symptoms. 
 
Calculation 
Approach 
DSQ Total Score 
Daily DSQ Score 
14-day period 
approacha 
DSQ total Score = (Sum of daily DSQ score with 14-day 
period preceding the scheduled visit day) ×14 / (Number of 
days with diaries reported with nonmissing data within 14-
day period).  
 
Shifting rule when calculating DSQ total score at each visit 
based on the number of reported diary entries within the 14-
day period prior to the visit:  
 
Baseline visit : 
If there are less than 8 reported diaries that are available 
within the 14-day period prior to baseline, then the most 
recent 8 reported diaries in a consecutive 14-day period 
would be used to calculate the DSQ total core. In order to 
determine the most recent 14-day period with the minimum 
number of reported diaries, it may be necessary to make 
adjustments in some cases by shifting to earlier diary 
entries. Such 14-day periods cannot be shifted for more 
than 7 days (not including the study visit day).  After 
shifting 7 days, if there are still less than 8 reported diaries 
Daily DSQ Score= sum of 
answers to Questions 2 and 3 
in the daily DSQ questionnaire 
 
Daily DSQ Score is set to 
missing if the diary is not 
reported or if the diary is 
reported but the answer to 
Question 1 is “No” in daily 
DSQ questionnaire. In this 
case the diary is considered as 
missing 
 
Daily DSQ Score is set to zero 
if the answer to Question 2 is 
“No” in daily DSQ 
questionnaire 


 
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within the 14-day period, then the DSQ total score for 
baseline visit will be set to missing. 
 
Week 2 visit: 
If there are less than 8 reported post-baseline diaries are 
available within the 14-day period prior to week 2 visit, 
then DSQ total score will be set to missing without any 
shift rule applied. 
 
All other post baseline visits after Week 2: 
If there are less than 8 reported diaries that are available 
within the 14-day period prior to baseline, then the most 
recent 8 reported diaries in a consecutive 14-day period 
would be used to calculate the DSQ total core. In order to 
determine the most recent 14-day period with the minimum 
number of reported diaries, it may be necessary to make 
adjustments in some cases by shifting to earlier diary 
entries. Such 14-day periods cannot be shifted for more 
than 14 days (not including the study visit day).  After 
shifting 14 days, if there are still less than 8 reported diaries 
within the 14-day period, then the DSQ total score for 
baseline visit will be set to missing.  
The DSQ total score range is 0 to 84 
14-day period: 
worst case 
scenario 
approachb 
DSQ total score calculation: same as 14-day period 
approach  
 
Shifting rule: same as as 14-day period approach 
 
The DSQ total score range is 0 to 84 
Daily DSQ Score= sum of 
answers to Questions 2 and 3 
in the daily DSQ questionnaire 
 
Missing Daily DSQ Score 
handling approach is the same 
as 14-day approach except 
that:  
Daily DSQ Score is set to 
(maximum value of ) 6 if the 
answer to Question 1 is “No”  
in daily DSQ questionnaire 
and the answer for Food 
Avoidance Question (FAQ) is 
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a Primary approach to calculate DSQ total score 
s Sensitivity approach to calculate DSQ total score 
 
 
 
 
 
esophagitis symptoms” 
 
Daily DSQ Score is set to zero 
if the answer to Question 2 is 
“No” in daily DSQ 
questionnaire 
7-day period 
approachb 
DSQ total Score = (Sum of daily DSQ score with 7-day 
period preceding the scheduled visit day) ×7 / (Number of 
days with diaries reported with nonmissing* data within 7-
day period).  
 
Shifting rule when calculating DSQ total score at each visit 
based on the number of reported diary entries within the 7-
day period prior to the visit:  
 
Baseline visit and each post baseline visit: 
If there are less than 4 reported diary entries that are 
available within the 7-day period prior to the visit, then the 
most recent 4 reported diary entries in a consecutive 7-day 
period would be used to calculate the DSQ total core. In 
order to determine the most recent 7-day period with the 
minimum number of reported diaries, it may be necessary 
to make adjustments in some cases by shifting to earlier 
diary entries. Such 7-day periods cannot be shifted for more 
than 7 days (not including the study visit day).  After 
shifting 7 days, if there are still less than 4 reported diary 
entries within the 7-day period, then the DSQ total score for 
baseline visit will be set to missing. 
 
The DSQ total score range is 0 to 42 
Same as 14-day period 
approach 


 
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Change from Baseline in esophageal PEC at Week 16 will based on the central EGD results.  
 
Proportion of subjects with esophageal PEC < 15 eos/hpf and ≤ 6 eos/hpf at Week 16, will be based on central 
reading of the EGD results. Subjects who achieve esophageal PEC < 15 eos/hpf and ≤ 6 eos/hpf will be referred to 
as responders, respectively. Subjects who do not achieve esophageal PEC < 15 eos/hpf and ≤ 6 eos/hpf will be 
referred to as nonresponders, respectively. 
 
Planned Analyses by Endpoint 
Endpoint (at Week 16) 
ANCOVAa/ 
Weighted 
MH  
Sensitivity 
Analyses: 
MI 
Sensitivity 
Analyses: 
Tipping Point 
Analysis 
Completer 
Sets and Per 
Protocol Set 
Linear 
mixed 
effects 
model 
Key primary endpoints 
 
 
 
 
 
Percent Change from baseline in 
esophageal PEC 
Xc 
Xe 
Xc 
Xc 
 
Key secondary endpoints 
 
 
 
 
 
Change from baseline in DSQ total 
score 
Xe, f 
Xe, f 
Xe, f 
Xb, f, g 
Change from baseline in esophageal 
PEC 
Xc 
Xe 
Xc 
Xc 
 
Proportion esophageal PEC < 15 
eos/hpf 
Xd 
Xe 
 
Xd 
 
Proportion esophageal PEC <=6 
eos/hpf 
Xd 
Xe 
 
Xd 
 
a No rank transformation will be applied 
b No missing data methods will be implemented since missing data will be handled in the linear mixed effect model. 
c Subjects who initiate rescue medication/rescue procedure will have assessments collected after the rescue 
medication/rescue procedure is initiated set to missing. 
d Subjects who initiate rescue medication/rescue procedure will have assessments collected after the rescue 
medication/rescue procedure is initiated set to missing. Missing data for any reason will be considered as 
nonresponder. Adjusted difference and p-values are based on the estimated common risk difference using the MH 
weights 
e Subjects who initiate rescue medication/rescue procedure will have assessments collected after the rescue 
medication is initiated set to missing. Missing data will be imputed using multiple imputation. 
f primary approach (14-day period approach) will be used to calculate DSQ total score 
g sensitivity approaches (14-day period: worst case scenario approach and 7-day period approach) will be used to 
calculate DSQ total score. 
 


 
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In addition, some of the additional analyses above will be conducted as follows: 
Percent change from baseline in esophageal PEC at Week 16 above will be repeated at week 24  
using the same ANCOVA model. 
Change from baseline in DSQ total score at Week 16 above will be repeated for week 2, 4, 6, 8, 10, 12, 14, 20 and 
24 in Double-Blind Treatment Period, using the same linear mixed effects model for change from baseline in DSQ 
total score at Week 16. 
 
17.2.2. MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLE(S) 
The same missing data methods used for the primary endpoint described in Section 16.1.2 will be used for the 
continuous secondary efficacy endpoints. For proportion-based secondary endpoints, subjects with missing data for 
any reason or took rescue medication and/or rescue procedure will be considered a nonresponder.  
17.2.3. PRIMARY ANALYSIS OF SECONDARY EFFICACY VARIABLES 
17.2.3.1. 
Change from Baseline in DSQ total score and Esophageal PEC at Week 16 
Analysis of the secondary efficacy variables change from Baseline in DSQ total core at Week 16 will use a linear 
mixed effect model. The linear mixed effect model will include treatment group, visit, interaction of treatment-by-
visit, Baseline history of esophageal dilation (Yes or No), and concurrent PPI therapy (Yes or No) as factors and 
Baseline DSQ total score as a covariate using an unstructured covariance matrix. If there is a convergence issue in 
fitting the unstructured covariance, a compound symmetry covariance structure will be used. The Kenward-Rogers 
method will be used to estimate the denominator degrees of freedom. Change from Baseline in Esophageal PEC at 
Week 16 will use an ANCOVA model including treatment group and randomization stratification factors as factors 
and Baseline eosinophil PEC as a covariate. Eosinophil PEC assessments after rescue medication and/or rescue 
procedure use will be set to missing. LS means at visit and LS mean differences between treatment groups (i.e. 
etrasimod 1 mg vs placebo, etrasimod 2 mg vs placebo, and etrasimod pooled vs placebo) with p-values and 
corresponding 95% CIs will be reported. For the individual etrasimod summaries, treatment group will include 
placebo, etrasimod 1 mg and etrasimod 2 mg. For the pooled etrasimod summary, treatment group will include 
placebo and pooled etrasimod.  
17.2.3.2. 
Proportion of Subjects with Esophageal PEC < 15 and ≤ 6 eos/hpf at Week 16 
Analysis of the secondary efficacy variables proportion subjects with esophageal PEC < 15 eos/hpf at Week 16 and 
proportion of subjects with esophageal PEC ≤ 6 eos/hpf at Week 16 will be performed  for randomization 
stratification factors of baseline history of esophageal dilation (Yes or No) and concurrent PPI therapy (Yes or No). 
Subjects who use rescue medication or have a rescue dilation, or with missing data at Week 16 for any reason will 
be considered nonresponders. The stratified analyses will be performed for randomization stratification factors. 
Results will be expressed as the number and percentage of subjects who achieved the goal, risk difference in 


 
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proportion between treatment groups achieving the goal using Mantel-Haenszel weights, the associated 95% CI and 
p-value. If there are zero responders in both treatment groups in any stratum, the difference in proportions and 
associated inferences can still be made.  
17.2.4. SUPPLEMENTARY ANALYSIS OF SECONDARY EFFICACY VARIABLES 
The primary analysis of the secondary efficacy variables as described in Section 16.2.3 will be repeated using the 
Completers Set and Per Protocol Set as supplementary analyses. Subgroup analyses will also be performed. 
17.2.5. SENSITIVITY ANALYSIS OF SECONDARY EFFICACY VARIABLES 
The same sensitivity analyses for the primary endpoint described in 16.1.5 will be performed for the continuous 
secondary efficacy endpoints.  
 
For proportion-based secondary endpoints, a sensitivity analysis using the primary endpoint multiple imputation 
method described in 16.1.2 will be performed for the FAS. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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18. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the Safety Set. There will be no statistical comparisons between the 
treatment groups for safety data, unless otherwise specified. Subjects will be analyzed according to treatment 
received in the Double-Blind Treatment Period and Extension Treatment Period.  Unless otherwise specified, the 
safety analyses will be conducted for Double-Blind Treatment period and Extension Treatment period, respectively, 
when its applicable. 
18.1. 
ADVERSE EVENTS 
Adverse Events (AEs) will be coded using MedDRA (version 25.1 or higher). Treatment-emergent adverse events 
(TEAEs) are defined as follows for Double-Blind Treatment period and Extension Treatment period, respectively:  
 
Double-Blind Treatment period: TEAE is defined as AEs that started or worsened in severity on or 
after the first dose of study treatment (etrasimod 1 mg, 2 mg or placebo) in Double-Blind Treatment 
period.  
 
Extension Treatment period: TEAE is defined as AEs that started or worsened in severity on or after 
the first dose of study treatment (etrasimod 1 mg or 2 mg) in Extension Treatment period. 
 
 
See APPENDIX 2 for handling of partial dates for AEs for the purpose of assigning treatment-emergent flags. In the 
case where it is not possible to define an AE as treatment-emergent or not, the AE will be classified as treatment-
emergent. 
 
An overall summary of number of subjects within each of the categories described in the sub-section below, will be 
provided as specified in the templates.  Listings will include TEAEs and Non-TEAEs. 
18.2. 
ALL TEAES 
All TEAEs will be summarized by SOC and PT. This summary table and all other TEAE summaries by SOC and PT 
will be presented by descending frequency in the etrasimod pooled (1 mg and 2 mg) group. All AEs, regardless of 
treatment emergent status, will be included in an AE listing. Additionally, a listing of other AE details as collected 
on the CRF will be presented. 
18.2.1. SEVERITY 
Severity is classified as Grade 1: Mild, Grade 2: Moderate, Grade 3: Severe, Grade 4: Life-Threatening, Grade 5: 
Death Related to AE, using the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0). 
 


 
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All TEAEs will be summarized by SOC, PT, and maximum severity, with SOC and PT presented by descending 
frequency. If a subject reports a TEAE more than once within a SOC/PT, the AE with the worst-case severity will be 
used in this summary. 
18.2.2. RELATIONSHIP TO STUDY TREATMENT 
Relationship is classified as “not related”, “unlikely related”, “probably related”, or “related” by the Investigator.  
 
All related TEAEs will be summarized by SOC and PT. A “related TEAE” for the purpose of this summaries is 
defined as a TEAE with relationship to study drug of “probably related” or “related”.  
 
All TEAEs will be summarized by SOC, PT, and highest relationship (as reported on the eCRF, not grouped), with 
SOC and PT presented by descending frequency. If a subject reports a TEAE more than once within a SOC/PT, the 
AE with the worst-case relationship to study treatment will be used in this summary. TEAEs with a missing 
relationship to study treatment will be regarded as “Related” to study treatment for summary tabulation purpose 
only. 
18.2.3. TEAES LEADING TO DISCONTINUATION OF STUDY TREATMENT 
TEAEs leading to permanent discontinuation of study treatment will be identified by action taken being recorded as 
“Drug withdrawal” on the Adverse events eCRF.   
 
All TEAEs leading to discontinuation of study treatment will be summarized by SOC and PT. A listing of all 
TEAEs leading to discontinuation of study treatment will also be presented. 
 
18.2.4. SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Event eCRF.  
 
All serious TEAEs will be summarized by SOC and PT. If the seriousness is missing, the AE will be considered as 
“Serious”. A serious TEAE listing will also be presented. All non-serious TEAEs will also be summarized by SOC 
and PT. 
18.2.5. TEAES LEADING TO DEATH 
TEAEs leading to Death are those events which are recorded with an outcome as “Fatal” on the Adverse Events 
eCRF. All TEAEs leading to death will be listed. 


 
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18.2.6. TEAES OF SPECIAL INTEREST 
Categories of Targeted Medical Events (TMEs) and a list of preferred terms associated with these TME categories 
were developed based on the mechanism of action of etrasimod, prior experience with other agents acting via a 
similar mechanism, and disease-specific clinical judgment. In addition, where standard testing has been 
implemented to screen for potential AEs(eg, electrocardiograms, spirometry, serum transaminases, etc.), the relevant 
data will be reviewed to identify potential cases of AESI that investigators may not have identified and to provide 
quantitative data for AESIs. The proposed candidate terms will be reviewed to identify which events reflect AESI. 
 
TEAEs of special interest will be summarized by category, subcategory, and PT by descending frequency by 
treatment group. Categories and subcategories of TEAEs of special interest are the following: 
 
Cardiovascular Events  
- Bradycardia 
- AV conduction delay 
- Hypertension 
 
Infections 
- Severe infections 
- Opportunistic infections (Narrow) 
- Herpes simplex and herpes zoster 
 
Macular Edema 
 
Pulmonary Disorders 
- 
Airflow obstruction (forced expiratory volume in 1 second [FEV1], forced vital capacity 
[FVC]) 
- 
Decrease gas exchange (diffusing capacity of the lungs for carbon monoxide [DLCO]) 
 
Liver Injury 
- 
Liver transaminases elevation 
- 
Bilirubin elevation 
- 
Elevated BP 
 
Posterior reversible encephalopathy syndrome (PRES) 
 
Malignancies 
 
For the TEAE of special interest, the Exposure-adjusted incidence rate (EAIR) will also be provided for the 
following group based on the subject in Safety Set in Double-Blinded Treatment Period  


 
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Group 1: Subjects who take etrasimod 2 mg anytime during the course of study. This includes the subjects who  
 
receive the etrasimod 2 mg in Double-Blind Treatment period and continue 
receiving Etrasimod 2 mg in Extension Treatment period, or  
 
receive the etrasimod 2 mg in Double-Blind Treatment period and discontinue 
early without entering Extension Treatment period, or  
 
receive the placebo in Double-Blind Treatment period and receive etrasimod 2 mg 
in Extension Treatment period 
Group 2: Subjects who take etrasimod 1 mg anytime during the course of study. This includes the subjects who 
 
 
Subjects who take etrasimod 1 mg anytime during the course of study. This 
includes the subjects who  
 
receive the etrasimod 1 mg in Double-Blind Treatment period and continue 
receiving etrasimod 1 mg in Extension Treatment period, or  
 
receive the etrasimod 1 mg in Double-Blind Treatment period and discontinue 
early without entering Extension Treatment period, or  
 
receive the placebo in Double-Blind Treatment period and receive etrasimod 1 
mg in Extension Treatment period 
 
Group 3: Subjects who take placebo in Double-Blind Treatment period   
 
The EAIR for a given TEAE of special interest is calculated as the number of subjects with the TEAE of special 
interest divided by the total exposure in subject-years. The 95% confidence interval (CI) of the EAIR will be 
provided along with EAIR. Some notes for the exposure and AE used in EAIR calculation are  provided as follows 
 
Group 
Note for Exposure used in EAIR calculation 
Note for TEAE of special interest used in 
EAIR calculation 
1) 
sum of either time (year) from first dose of etrasimod 
2 mg to the onset of first such event for those who 
experienced the TEAE of interest, or time (year) from 
first dose of etrasimod 2 mg to last participation for 
those who did not experience the TEAE of special 
interest. 
For a placebo subject who receive 2 mg in 
Extension Treatment period, only the AE 
that started or worsened in severity on or 
after the first dose of etrasimod 2 mg in 
Extension Treatment period will be included 
in the EAIR for the subject 
2) 
sum of either time (year) from first dose of etrasimod 
1 mg to the onset of first such event for those who 
experienced the TEAE of interest, or time (year) from 
For a placebo subject who receive 1 mg in 
Extension Treatment period, only the AE 
that started or worsened in severity on or 


 
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first dose of etrasimod 1 mg to last participation for 
those who did not experience the TEAE of special 
interest. 
after the first dose of etrasimod 1 mg in 
Extension Treatment period will be included 
in the EAIR for the subject 
3) 
sum of either time (year) from first dose of placebo to 
the onset of first such event for those who experienced 
the TEAE of interest during Double-Blind Treatment 
period, or time (year) from first dose of placebo to last 
participation for those who did not experience the 
TEAE of special interest. during Double-Blind 
Treatment period 
For a placebo subject in Double Blind 
Treatment period, only the AE that started or 
worsened in severity on or after the first dose 
of placebo in Double Blind Treatment period 
will be included in the EAIR for the subject 
 
18.2.7. OVERALL SUMMARY OF ADVERSE EVENTS 
In addition to the summaries above, an overview of TEAEs will be summarized (not broken down by SOC or PT) by 
number and frequency of subjects and by number of AEs: 
 
Any TEAEs 
- 
Any related TEAEs* 
 
Any serious TEAEs 
- 
Any related serious TEAEs* 
 
TEAEs leading to death 
 
TEAEs leading to study drug discontinuation 
- 
Related TEAEs leading to study drug discontinuation 
 
TEAEs leading to study drug interruption 
- 
Related TEAEs leading to study drug interruption* 
 
TEAEs by maximum severity 
- 
Related TEAEs by maximum severity* 
 
TEAEs by relationship to study drug 
* “Related TEAEs” refers to TEAEs related or probably related to study drug or are missing relationship. 
 
18.3. 
DEATHS 
Information collected about deaths (e.g., date of death, primary cause of death) will be presented in a data listing, as 
described in Section 18.2.5. 


 
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18.4. 
LABORATORY EVALUATIONS 
No local laboratory assessments will be used in any summaries except for lipid panel and thyroid panel tests. No 
local laboratory assessments will be used to derive maximum/minimum/worst value. Local laboratory assessments 
will be listed. 
18.4.1. SAFETY LABORATORY EVALUATIONS 
Hematology, serum chemistry, and coagulation are analyzed and reported by central laboratory and sometimes by 
local laboratory. Results out of reference range are flagged by the performing laboratory (e.g., low, high). A full list 
of laboratory assessments to be included in the outputs is included in Table 3 of protocol amendment v3.0 
(04Jan2023).  
 
Presentations will use SI Units. Quantitative laboratory measurements reported as “< X” or “> X”, where X may be 
the lower limit of quantification (LLQ) or the upper limit of quantification (ULQ), respectively, will be converted to 
X for the purpose of quantitative summaries, but will be presented as recorded, i.e. as “< X” or “> X” in the listings. 
For urinalysis, only pH and specific gravity are considered as quantitative tests. If local and central laboratory 
assessments are available from the same day, central laboratory assessments will be used in the summary as per 
Section 6.4. 
   
The following summaries will be provided for laboratory data: 
 
Value and change from Baseline by visit (for hematology, TBNK panel, serum chemistry, 
quantitative urinalysis [pH and specific gravity], and coagulation) 
 
Incidence of abnormal values according to laboratory reference ranges by visit 
 
Incidence of lymphocytes <0.2 x 109/L, 0.5 x 109/L, or neutrophils < 0.5 x 109/L, 1 x 109/L at end 
of treatment and anytime in the study  
 
Change and Percent Change from Baseline in Absolute Lymphocyte Count (ALC) at Weeks 16, 
24, 32, and 52  
 
Shift from Baseline to end of treatment according to laboratory reference range (for quantitative 
measurements and categorical measurements) 
 
eDISH plots for the following laboratory assessments: 
 
Maximum Alkaline Phosphatase vs. Same-Day Total Bilirubin  
 
Maximum Alkaline Phosphatase vs. Same-Day Total Bilirubin Adjusted for Elevated Baseline 
 
Maximum Alanine Aminotransferase vs. Same-Day Total Bilirubin 
 
Maximum Alanine Aminotransferase vs. Same-Day Total Bilirubin Adjusted for Elevated 
Baseline 
 
Maximum Aspartate Aminotransferase vs. Same-Day Total Bilirubin 
 
Maximum Aspartate Aminotransferase vs. Same-Day Total Bilirubin Adjusted for Elevated 


 
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Baseline 
If both central and local assessments of total bilirubin are available on the same day, the central result will take 
precedence over the local result in the eDISH plot. If the maximum AST/ALT/GGT assessment occurs at two 
different dates, the assessment with the higher accompanying Bilirubin value will be used. Two versions of the 
eDISH plots will be presented, with one showing values as multiples of upper limit of normal, and the other one 
showing values as multiples of upper limit of normal, or subject’s baseline, whichever is higher.  
Only laboratory tests completed by 50 or more subjects in the SAF will be presented in the summaries. All 
laboratory tests will be listed.   
Subject’s laboratory assessments at all timepoints will be listed in chronological order. Values outside of the 
laboratory reference range will be flagged. Values obtained from local laboratory will be flagged. Listing of 
lymphocytes and neutrophils over time in subjects ever with lymphocytes <0.5 x 109/L or neutrophils < 1 x 109/L 
will also be provided. 
18.4.2. PREGNANCY TESTS 
Urine beta-human chorionic gonadotropin (β-hCG) and/or serum β-hCG pregnancy tests are performed in female 
subjects of childbearing potential. All pregnancy test results will be listed in chronological order. 
18.4.3. OTHER SCREENING LABORATORY ASSESSMENTS 
Laboratory assessments for virology, T, B, NK, CD4+ T cell and CD8+ T cell counts (TBNK) and Urine drug 
screening will be listed. Analyses of genetics and 
 data based on samples 
collected in subjects who provided consent will be described in a separate plan. 
18.5. 
ECG EVALUATIONS 
ECGs are recorded on a 12-lead ECG machine and read locally and centrally. The following ECG parameters will 
be reported for this study: 
 
HR (bpm) 
PR Interval (ms) 
RR Interval (ms) 
QRS Interval (ms) 
QT Interval (ms) 
QTcF Interval (ms)  
Overall interpretation of ECG (Investigator’s judgment): 
o 
Normal 
o 
Abnormal, Not Clinically Significant (Abnormal NCS) 
CCI


 
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o 
Abnormal, Clinically Significant (Abnormal CS) 
Overall interpretation of ECG (central reader): 
o 
Normal 
o 
Abnormal, Not Clinically Significant (Abnormal NCS) 
o 
Abnormal, Clinically Significant (Abnormal CS) 
The following summaries will be provided for ECG data: 
 
Value and change from Baseline by visit (for quantitative measurements)  
 
Incidence of markedly abnormal values (defined in Section 17.4.1) by visit  
 
Shift in normal/abnormal NCS/abnormal CS in the overall interpretation (by investigator) from Baseline to 
end of treatment and to the worst-case post-Baseline  
 
Shift in markedly abnormal categories from Baseline to post-Baseline by visit  
 
All ECG results, including first dose cardiac monitoring, will be listed. Discharge criteria for first dose cardiac 
monitoring will also be listed.  
 
A listing of all ECG assessments over time in subjects meeting markedly abnormal criteria will also be provided. 
For each subject, only ECG parameters ever meeting markedly abnormal criteria will be included. 
18.5.1. ECG MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal quantitative ECG measurements will be identified in accordance with the following predefined 
markedly abnormal criteria: 
 
Absolute values in QT and QTcF: 
 
≥ 450 ms (male) or ≥ 470 msec (female) in QTcF 
 
> 500 ms in QT 
 
Change from Baseline in QT and QTcF: 
 
> 30 ms increase from Baseline 
 
> 60 ms increase from Baseline 
In shift tables, subjects will be classified according to the binary category for each parameter and the predefined 
markedly abnormal criterion (i.e., Markedly abnormal vs. Not markedly abnormal, with markedly abnormal defined 
in the footnote). 
18.6. 
VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 


 
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o 
Systolic Blood Pressure (mmHg) 
o 
Diastolic Blood Pressure (mmHg) 
o 
Heart Rate (bpm) 
o 
Respiratory Rate (resp/min) 
o 
Temperature (⁰C) 
o 
Weight (kg) 
o 
Height (cm) [Screening only] 
 
The following summaries will be provided for vital signs data: 
 
Value and change from Baseline by visit  
 
Value and change from predose on Day 1 and Week 24 (as reported on the eCRF) by timepoint  
o 
For heart rate only, also include value and change from predose to minimum postdose heart 
rate on Day 1 in the same table 
 
Incidence of markedly abnormal values (defined in section 17.5.2) by visit 
 
Listing of subjects meeting markedly abnormal criteria  
 
Incidence of minimum heart rate on Day 1 by postdose timepoint (1, 2, 3, 4, and > 4 
hours postdose, and Day 1 overall) and heart rate interval (≥ 65, 60 to 64, 55 to 59, 
50 to 54, 45 to 49, 40 to 44, < 40 bpm) 
- If minimum heart rate is attained at multiple postdose timepoints, only the earliest 
timepoint will be counted in this incidence summary 
 
Time to minimum heart rate on Day 1 by planned hourly timepoint (if minimum heart rate is attained 
at multiple postdose timepoints, only the earliest timepoint will be counted). Actual time elapsed from 
first dose to minimum heart rate on Day 1 will also be summarized using descriptive statistics (n, 
mean, SD, median, minimum, and maximum) in the same table. 
 
All vital signs, including first dose cardiac monitoring, will be listed. Discharge criteria first dose cardiac monitoring 
will also be listed. A listing of all vital signs assessments over time in subjects meeting markedly abnormal criteria 
will also be provided. For each subject, only vital sign parameters ever meeting markedly abnormal criteria will be 
included.  
 
For subjects with extended monitoring, systolic blood pressure, diastolic blood pressure and heart rate values and 
change from predose on Day 1 will be listed. 
18.6.1. VITAL SIGNS SPECIFIC DERIVATIONS  
 
Temperature (⁰C) = (5/9) (Temperature (⁰F) – 32) 


 
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18.6.2. VITAL SIGNS MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal quantitative Vital Signs measurements will be identified in accordance with the following 
predefined markedly abnormal criteria: 
Table 5:  Markedly Abnormal Criteria for Vital Signs 
Variable 
Unit 
Low 
High 
SBP 
mmHg 
≤ 90 mmHg  
 
 > 150 mmHg 
DBP 
mmHg 
≤ 50 mmHg 
 
 > 90 mmHg 
Heart rate 
bpm 
< 40 bpm 
< 50 bpm 
< 50 bpm and decrease from predose 
(Baseline) of > 10 bpm at 4 hours on 
Day 1 or remonitoring visit 
>100 bpm  
 
18.7. 
PHYSICAL EXAMINATION  
A listing of all physical examination assessments in subjects who had at least 1 abnormal physical examination 
finding will be provided. 
18.8. 
OTHER SAFETY ASSESSMENTS 
18.8.1. PULMONARY FUNCTION TESTS 
The following pulmonary function test (PFT) measurements (actual and % Predicted) will be reported for this study: 
 
Forced Expiratory Volume at 1 second (FEV1) 
 
Forced Vital Capacity (FVC) 
 
Total Lung Capacity (TLC) 
 
FEV1/FVC 
 
Forced Expiratory Flow (FEF) 25-75 
 
Diffusing Capacity of the Lungs for Carbon Monoxide (DLCO) (if available) 
The following summaries will be provided for PFT data:  
 
Value and change from Baseline by visit 
 
Incidence of markedly abnormal values by visit 


 
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All PFT data will be listed. A listing in subjects who ever reported an abnormality in PFT will also be provided, 
including a flag for whether markedly abnormal criterion is also met. 
18.8.2. PFT MARKEDLY ABNORMAL CRITERIA 
Markedly abnormal quantitative PFT measurements will be identified in accordance with the following predefined 
markedly abnormal criteria: 
 
% Predicted FEV1 < 50% 
 
% Predicted FVC < 50% 
 
% Predicted FEV1/FVC ratio < 50% 
Potentially important PFT measurements will also be identified using the criteria below: 
 
Decrease from Baseline > 20% in FEV1, ie, percent change from Baseline < -20% 
 
Decrease from Baseline > 20% in FVC, ie, percent change from Baseline < -20% 
 
Decrease from Baseline > 20% in DLCO, ie, percent change from Baseline < -20% 
18.8.3. OPHTHALMOSCOPY AND OPTICAL COHERENCE TOMOGRAPHY (OCT) 
The following summaries will be provided for ophthalmoscopy and OCT data: 
 
Values and change from Baseline in central foveal thickness by visit 
 
Categorical result in ophthalmoscopy with OCT parameters by visit (the categories are listed on 
the eCRF) 
 
Only PFT and OCT assessments completed by 50 or more subjects in the SAF will be presented 
in the summaries. 
A listing of all ophthalmoscopy and OCT assessments will be provided. A listing of subjects who ever reported an 
abnormality in OCT will also be provided.  
19. PHARMACOKINETICS 
Plasma concentrations of etrasimod, and if warranted M3 (AR503641) and M6 (AR504344), will be assessed from 
samples collected prior to dosing and 4 hours (± 15 minutes) post-dose (after ECG) on Week 0/Day 1, samples 
collected prior to dosing (trough) at Weeks 4, 8, 16, 24 of the double-blind period, and Weeks 28, 32, 46, 52 or the 
ET visit, if applicable, of the extension period. Additionally, a 4-Week Safety Follow-up visit sample is being 
collected. Concentrations below the limit of quantification (BLQ) will be assigned a numerical value of zero for the 
calculation of descriptive statistics in concentrations (except for geometric mean and geometric %CV) and plotting 
of concentrations. For geometric mean and geometric %CV, the zero values will be excluded. 


 
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The pharmacokineticist will determine the strategy for dealing with data affected by protocol deviations or events 
which may impact the quality of PK concentration data on a case-by-case basis with input from the Pfizer study 
physician and Pfizer clinical pharmacologist, as needed. Examples for protocol deviations or events include, but 
may not be limited to, vomiting on the day prior to trough sample collection, sample processing errors that lead to 
inaccurate bioanalytical results, and/or inaccurate dosing prior to PK sampling. In the case of an important protocol 
deviation or event, the affected PK data collected may be excluded from the summaries, calculation of the average 
steady state trough plasma concentration (Ctrough) based on Week 4 to Week 24 trough concentrations 
(Ctrough,ss,W4W24), exposure-response analysis, and/or population PK analysis, but will still be reported in the study 
result listings.   
 
Unless otherwise specified, PK summaries will use the Pharmacokinetic Set. Exposure-response analysis will use 
the Safety Set. 
 
Individual subject etrasimod plasma concentrations (and etrasimod metabolites, if applicable) will be presented in 
the data listings, including subject ID, treatment received, sex, age, weight, nominal timepoint, actual blood 
collection date/time, concentration, and time since last dose, and also summarized using descriptive statistics (n, 
mean, SD, %CV, geometric mean, geometric % CV, median, minimum, and maximum) by nominal timepoint and 
treatment. 
 
All subjects are expected to achieve steady-state plasma concentration by Week 2. For each subject, the average 
steady state trough (pre-dose) plasma concentration (Ctrough) based on Week 4 to Week 24 trough concentrations 
(Ctrough,ss,W4-W24) per subject will also be calculated and presented in a data listing and summarized using descriptive 
statistics by treatment.  
 
Mean (±SD) etrasimod concentration versus nominal time will be plotted by treatment on linear scale for the double-
blind period and the extension period separately. Additionally, a mean (±SD) concentration-time plot with etrasimod 
and metabolites overlaid on linear scale will be generated for each treatment for the induction period and the 
extension period separately. 
 
Box plots of etrasimod, M3, and M6 concentrations at Day 1, 4 hour post-dose timepoint (C4hr) and steady-state 
Ctrough (Weeks 2 through 24 [Ctrough,ss,W4-W24]) will be plotted versus nominal timepoint on ordinal scale, separately by 
treatment. Similarly, box plots of etrasimod, M3, and M6 concentrations will be presented for the extension phase 
by treatment.  
 
Individual subject plasma concentrations versus actual time will be plotted since start of treatment on linear scale for 
the induction period (Weeks 0 to 24) and the extension period (Weeks 28 to 52) separately. Individual subject plots 
with etrasimod and metabolite concentration data will be overlaid on the same plot.  


 
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Scatter plots of individual subject average steady-state Ctrough ss,W4-W24 versus Baseline body weight and versus 
Baseline age as continuous variables will be generated by treatment for the Pharmacokinetic Set, which will also 
include the Spearman's rank correlation coefficient, p-value, and LOESS trend line. 
 
To explore potential etrasimod plasma exposure-response relationships, the following scatter plots will be generated 
in the Safety Set, including data from placebo subjects (plotted at ‘zero’ concentration). Any contributing data from 
the placebo subjects will be annotated with a different color or symbol. All scatter plots will include the Spearman's 
rank correlation coefficient, p-value, and LOESS trend line (based on subjects that received active treatment only). 
 
Individual subject percentage change in esophageal PEC versus etrasimod steady-state Ctrough at 
Week 16  
 
Individual subject lymphocytes versus etrasimod steady-state Ctrough by visit (Weeks 4 through 24) 
 
Individual subject absolute changes from Baseline in lymphocytes versus etrasimod steady-state 
Ctrough by visit (Weeks 4 through 24) 
 
Individual subject percent changes from Baseline in lymphocytes versus etrasimod steady-state 
Ctrough by visit (Weeks 4 through 24)   
 
Individual subject heart rate versus etrasimod concentration at matching visit/timepoint (Day 1 
through Week 24): two-panel plot with Day 1 on the left and Weeks 4 through 24 on the right 
 
Individual subject absolute changes from Day 1 Pre-dose in heart rate versus etrasimod 
concentration at matching visit/timepoint (Day 1 through Week 24): two-panel plot with Day 1 on 
the left and Weeks 4 through 24 on the right 
Furthermore, the following overlay plots will be generated in the Pharmacokinetic Set within the etrasimod group 
only: 
 
Mean (SD) absolute change from Baseline in lymphocytes and mean (SD) etrasimod concentration 
versus nominal timepoint (Weeks 0-24) 
 
Mean (SD) percent change from Baseline in lymphocytes and mean (SD) etrasimod concentration 
versus nominal timepoint (Weeks 0-24) 
 
Mean (SD) heart rate and mean (SD) etrasimod concentration versus nominal timepoint (Weeks 0-24) 
 
Mean (SD) absolute change from Baseline in heart rate and mean (SD) etrasimod concentration versus 
nominal timepoint (Weeks 0-24)  
All summary figures, with the exception of the etrasimod and metabolite overlay plots, scatter plots of individual 
subject Ctrough,ss,W4-W24 values versus Baseline body weight and versus Baseline age, scatter plots of individual 
subject heart rate versus etrasimod concentration at matching visit/timepoint (Day 1 through Week 24), and scatter 
plots of individual subject absolute changes from Day 1 Pre-dose in heart rate versus etrasimod concentration at 
matching visit/timepoint will be repeated by: 


 
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 
Sex 
 
Weight (≤ Median or > Median) 
 
Age at consent  
 
Tobacco use (Yes/No) 
The plasma concentrations over time will be used in a population PK analysis, which will be described in a separate 
plan. 
20. DATA NOT SUMMARIZED OR PRESENTED 
The other variables and/or domains not summarized or presented are: 
 
Comments 
These domains and/or variables will not be summarized or presented, but will be available in the clinical study 
database, SDTM and/or ADaM datasets. 


 
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21. REFERENCES  
ICH E3. Structure and Content of Clinical Study Reports. Dated 30 November 1995. Available at: 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_Guideline.pdf (accessed 
14 August 2018). 
 
ICH E9. Statistical Principles For Clinical Trials. Dated 5 February 1995. Available at: 
https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/E9_Guideline.pdf 
(accessed 14 August 2018).   
 
ICH E9 R(1). Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the Guideline on Statistical 
Principles for Clinical Trials. Dated 20 November 2019. Available at: https://database.ich.org/sites/default/files/E9-
R1_Step4_Guideline_2019_1203.pdf. 
 
Rubin, D.B. (1987).  Multiple Imputations for Nonresponse in Surveys. Wiley. 
FDA. Statistical Considerations for Clinical Trials During the COVID 19 Public Health Emergency: Guidance for 
Industry. Center for Drug Evaluation and Research, Food and Drug Administration. 
https://www.fda.gov/media/139145/download. Published 2020. Accessed February 22, 2021. 
 
 
 


 
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APPENDICES 
APPENDIX 1. 
PROGRAMMING CONVENTIONS FOR OUTPUTS 
Output Conventions 
Outputs will be presented as shown in the Output shells. 
 
Decimals, Percentages, and P-Values 
 
If the original data has N decimal places, then the summary statistics should have the following 
decimal places: 
 
Minimum and maximum: N 
 
Mean (and LS Means), median (and Q1, Q3): N + 1 
 
SD or SE: N + 2 
 
Percentages will be reported to one decimal place. Where counts are zero, percentages will not appear 
in the output.  
 
P-values will be reported to four decimal places, except values <1.000 but >0.999 will be presented as 
‘>0.999’ (e.g., 0.9998 is presented as >0.999); and 
 
values <0.0001 will be presented as ‘<0.0001’ (e.g., 0.00009 is presented as <0.0001). Rounding will 
be applied after the <0.0001 and >0.999 rule. 
Dates & Times 
Depending on data available, dates and times will take the form DDMMMYYYY or DDMMMYYYY:hh:mm. 
 
Spelling Format 
English US.  
 
Presentation of Treatment Groups 
For outputs, treatment groups will be represented as follows and in that order: 
Treatment Group 
For Tables and/or Graphs 
For Listings 
etrasimod 2 mg 
etrasimod 2 mg 
etrasimod 2 mg 
etrasimod 1mg 
etrasimod 1 mg 
etrasimod 1 mg 
etrasimod any dose* 
etrasimod any dose 
Placebo 
Placebo 
Placebo 
Screen Failure 
Screen Failure 
Screen Failure 
 


 
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Treatment Group 
For Tables and/or Graphs 
For Listings 
Not Treated** 
Not Treated 
Placebo 
* To be used for tables and/or graphs only. 
** To be used for subjects in safety listings who are randomized but do not receive study drug. 
 
Presentation of Visits 
For outputs, visits will be represented as follows and in that order when applicable: 
Visit Name*  
Study Period  
Screening 
Screening 
Baseline, Day 1, Week 2, Week 4, Week 8, Week 16, 
Week 20, Week 24 
Double-Blind Treatment 
Week 28, Week 32, Week 46, Week 52 
Extension Treatment 
2-Week Follow-Up, 4-Week Follow-Up 
Safety Follow-Up 
 
*If a visit is not available for a certain analysis, it won’t be displayed 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
 
Randomized treatment group (or treatment received if it’s a safety output), first by Etrasimod 2 mg, 
Etrasimod 1 mg, then Placebo, then Screen Failure and then No Treatment (only in safety listings if 
there are any randomized subjects who did not receive study drug) 
 
Subject number (which is expected to incorporate study site/center),  
 
Date (where applicable) 
 
 


 
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APPENDIX 2. 
PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
AE START DATE 
AE STOP 
DATE 
ACTION 
Known 
Known, Partial 
or Missing 
If AE start date < study drug first dose date, then not TEAE 
If AE start date ≥ study drug first dose date, then TEAE 
 
 
 
Partial, but known 
components show that 
it cannot be on or after 
date of first dose of 
study drug 
Known, Partial 
or Missing 
Not TEAE 
 
 
 
Partial, could be on or 
after date of first dose 
of study drug 
Known 
If AE stop date < study drug first dose date, then not TEAE 
If AE stop date ≥ study drug first dose date, then TEAE 
 
Partial 
Impute AE stop date as latest possible date (i.e. last day of month if 
day unknown or 31st December if day and month are unknown), 
then: 
If AE stop date < study drug first dose date, then not TEAE 
If AE stop date ≥ study drug first dose date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
Missing 
Known 
If AE stop date < study drug first dose date, then not TEAE 
If AE stop date ≥ study drug first dose date, then TEAE 
 
Partial 
Impute AE stop date as latest possible date (i.e. last day of month if 
day unknown or 31st December if day and month are unknown), 
then: 
If AE stop date < study drug first dose date, then not TEAE 
If AE stop date ≥ study drug first dose date, then TEAE 


 
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AE START DATE 
AE STOP 
DATE 
ACTION 
 
Missing 
Assumed TEAE 
 
ALGORITHM FOR PRIOR AND CONCOMITANT MEDICATIONS: 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If medication stop date < study med first dose date, assign as prior  
If medication stop date >= study med first dose date, assign as concomitant  
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If medication stop date < study med first dose date, assign as prior 
If medication stop date ≥ study med first dose date, assign as concomitant 
 
Missing 
If medication stop date is missing could never be assumed a prior 
medication, assign as concomitant 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If medication stop date < study med first dose date, assign as prior 
If medication stop date ≥ study med first dose date, assign as concomitant 
 
Partial 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown) and impute stop 
date as latest possible date (i.e. last day of month if day unknown or 31st 
December if day and month are unknown), then: 
If medication stop date < study med first dose date, assign as prior 
If medication stop date ≥ study med first dose date, assign as concomitant 
 
Missing 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If medication stop date is missing could never be assumed a prior 
medication, assign as concomitant 
 
 
 


 
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START DATE 
STOP DATE 
ACTION 
Missing 
Known 
If medication stop date < study med first dose date, assign as prior 
Else assign as concomitant 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If medication stop date < study med first dose date, assign as prior 
If medication stop date ≥ study med first dose date, assign as concomitant 
 
Missing 
Assign as concomitant 
 
 


 
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APPENDIX 3. QUESTIONNAIRE SCORING INFORMATION 
DSQ  
The DSQ is a validated patient-reported outcome questionnaire that will be used to characterize baseline dysphagia 
severity and changes with treatment intervention. Questions 1 and 2 of the DSQ will be used to determine the 
eligibility regarding active dysphagia during the Screening Period. One episode of dysphagia is counted when a 
subject responds “yes” to questions 1 and 2. Subjects must have at least an average of 2 episodes of dysphagia per 
week over 2 weeks during the Screening Period. 
 
The DSQ will be scored over a 14-day period, and a minimum of 8 DSQ daily subject eDiary entries out of the 14-
day period preceding the date of scoring are required to calculate DSQ score. The DSQ total score range is 0 to 84. 
 
PGIC  
The PGIC is a 1-item questionnaire using a 5-point Likert scale to capture the subject’s overall impression of change 
in EoE symptoms from Baseline. The recall period is 16 to 52 weeks. The PGIC score range is 1 to 5. 
 
PGIS  
The PGIS is a current-state, 1-item questionnaire using a 4-point Likert scale to capture the subject’s overall 
impression of EoE symptom severity over the past 7 days.  The PGIS score range is 1 to 4. 
EoE-HSS  
The EoE-HSS objectively assesses histologic changes in esophageal mucosa beyond eosinophil number. It describes 
changes in 8 histologic features and assesses severity (grade) and extent (stage) of abnormalities that are scored 
using a 4-point scale (0 = normal; 3 = most severe or extensive). The 8 features include: 
 
1. Eosinophilic inflammation 
2. Basal zone hyperplasia 
3. Eosinophil abscess 
4. Eosinophil surface layering 
5. Dilated intercellular spaces 
6. Surface epithelial alteration 
7. Dyskeratotic epithelial cells 
8. Lamina propria fibrosis 
EREFS  
The EREFS will be used to characterize the baseline endoscopic severity of EoE and changes with treatment. 
Presence and severity of 6 esophageal endoscopic features are scored by the local endoscopist. The endoscopic 
features include: 


 
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1. Fixed Rings 
2. Exudates 
3. Furrows 
4. Edema 
5. Stricture 
6. Crepe paper esophagus 
EoE-QOL-A  
The EoE-QOL-A 37-item questionnaire is a disease-specific measure of health-related QOL in adults with EoE. It is 
scored using a 5-point scale and measures 5 domains:  
 
1. Eating/Dietary Impact 
2. Social Impact 
3. Emotional Impact 
4. Disease Anxiety 
5. Choking Anxiety 
 
APPENDIX 4.   IDENTIFICATION OF RESCUE THERAPY 
 
This appendix outlines the process the Pfizer clinical team/medical reviewers will use to determine rescue therapy 
for EoE in the APD334-206 study.  
 
The objective of rescue therapy identification is to establish 1) intercurrent events for the efficacy estimands, and 2) 
exclusion of subjects from the Per Protocol Set(s).  
 
Per protocol, rescue therapy is defined as any new therapy (ie, medication or procedure) or change in existing EoE 
therapy used to treat new or worsened EoE symptoms. In addition, use of certain medications/procedures that do not 
meet the definition of rescue therapy but are deemed to have significant impact on the efficacy assessment will be 
reviewed and may be considered as rescue therapy. 
 
Only therapies reported on the electronic case report forms (eCRFs) will be assessed for rescue therapy 
determination. Use of rescue therapy during the follow-up period (beginning on or after the date of last study 
treatment administration) will not be considered as a rescue therapy. 
 
The list of all rescue therapy uses in the study will be identified and finalized prior to study unblinding.  


 
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Medical procedure 
- 
Esophagogastroduodenoscopy (EGD)  
o Rule:  
 
When dilation was done during EGD, any after first dose 
 
When dilation was not done during EGD, any EGD with food bolus 
removal after first dose 
Medications 
- 
Proton Pump Inhibitors 
o Examples of Medications 
 
Omeprazole (Prilosec) 
 
Lansoprazole (Prevacid) 
 
Dexlansoprazole (Dexilant) 
 
Esomeprazole (Nexium) 
 
Pantoprazole (Protonix) 
 
Rabeprazole (Aciphex) 
o Rules 
 
When used for EoE: any new initiation or change in dose after Day 1 
 
When used for other disease (eg, GERD): New initiation or change in 
dose after Day 1 AND 
 
Use > 4 weeks at the time of EGD OR 
 
Use > 8 weeks with the end of treatment date falling within 4 
weeks of EGD 
- 
Corticosteroids 
o Applicable route of administration: swallowed, oral, IM, SC, IV 
o Examples of Medications 
 
Fluticasone (Flovent) 
 
Budesonide (Pulmicort, Flexhaler) 
 
Betamethasone 
 
Cortisone 
 
Deflazacort 
 
Dexamethasone 
 
Fludrocortisone 
 
Hydrocortisone 
 
Methylprednisolone 
 
Predinisone 
 
Prednisolone 


 
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 
Triamcinolone 
o Rules 
 
When used for EoE: any new initiation after Day 1 
 
When used for other diseases: any new initiation after Day 1 AND  
 
Use > 7 days at the time of EGD OR 
 
Use > 14 days with the end of treatment date falling within 8 
weeks of EGD 
- 
Drugs that have been or are being investigated in clinical trials for the treatment of EoE 
o Examples of medications 
 
Anti-interleukin (IL)-5 antibodies (eg, mepolizumab, reslizumab, 
benralizumab) 
 
IL-4 and IL-13 antagonists (dupilumab) 
 
Anti-IgE antibodies (omalizumab) 
o Rule 
 
Any new initiation after Day 1  
- 
Other protocol-prohibited immunomodulatory agents 
o Examples of medications: please refer to the protocol section 6.7.3. Prohibited 
Concomitant Therapy 
o Rule 
 
Any new initiation after Day 1  
 


Statistical Analysis Plan - SAP-APD334-206 - 13-Jan-2023
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