Clinical trial NCT05732454
Conditions: Atopic Dermatitis Atopic Dermatitis, Unspecified Eczema Eczema, Atopic
Keywords: Systemic Failure Oral
Sponsor: Pfizer
Start date: 2023-01-18; Completion date: 2024-04-29
Enrollment: 58 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to learn about the safety and effects of the study medicine called etrasimod for the possible treatment of atopic dermatitis (AD), also called eczema, in adults who have already tried AD treatments taken by mouth or by injection that work all over the body. These adults can have moderate to severe AD.

This study is seeking participants who:

* have AD for at least 1 year
* have moderate-to-severe AD
* have tried treatments that work all over the body and saw no effects
* are willing to apply a moisturizer at least once daily during the study

This is a 2-part study that is only selecting about 60 participants for Part 1 as of now. In Part 1, half of the participants will receive etrasimod, a pill to be taken by mouth once daily. The other half will receive a placebo, a pill that looks like etrasimod but has no medicine also taken by mouth once daily. No one will know what treatment the participant is taking. The Sponsor will compare participant experiences of those taking etrasimod to those taking placebo for 16 weeks. This will help determine if the study medicine is safe and effective. After the first 16 weeks, some participants may continue the study knowing they are taking etrasimod for an additional 52 weeks.

Those participating for just the first 16-weeks, will need to visit the study clinic at least 6 times during the study (about every 4 weeks), and will have to come for 2 safety follow up visits at 2nd and 4th week after the last dose of study medicine. People who want to and can continue for an additional 52 weeks will need to visit the study clinic for at least 6 more visits making 12 total visits over 68 weeks followed by 2 safety follow up visits at the 2nd and 4th week after the last dose of study medicine.

In Part 2 of the study, around 340 more participants will be participating. Everyone will receive etrasimod pills once daily for 52 weeks. Participants will need to go to the study clinic at least 9 times after which they will have to go for 2 more safety follow up visits at the 2nd and 4th weeks after the last dose of study medicine.

At every study visit in Part 1 and Part 2, the focus will be on signs and symptoms of AD (like lesions, itch, and pain) as well as general health and overall side effects. Blood samples and vital signs will be taken at every visit. Due to the way the study medicine works, the in-study clinic visit will last at least 4 hours on Day 1 (Part 1 and Part 2) and Week 16 (Part 1).

Detailed description:

Arms: arm 1: 2 mg, oral tablet, once daily arm 2: Oral sham comparator
Interventions: intervention 1: etrasimod intervention 2: Placebo
Intervention descriptions: intervention 1: PART 1 Double Blind one 2 mg tablet once daily for up to 16 weeks PART 1 Open Label Extension one 2 mg tablet once daily for an additional 52 weeks PART 2 Open Label one 2 mg tablet once daily for up 52 weeks intervention 2: PART 1 DOUBLE BLIND Placebo - one table daily for up to 16 weeks

Protocol documents:
Prot_000.pdf: 
Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 1
Title Page
A PHASE 2/3, TWO-PART STUDY TO EVALUATE THE EFFICACY AND LONG-
TERM SAFETY WITH ORAL ETRASIMOD, 2 MG, ONCE DAILY IN ADULT 
PARTICIPANTS WITH MODERATE-TO-SEVERE ATOPIC DERMATITIS WITH 
A HISTORY OF PRIOR SYSTEMIC TREATMENT FAILURE 
Study Intervention Number:
PF-07915503 (APD334)
Study Intervention Name:
Etrasimod
US IND Number:
142182
EudraCT/CTIS Number:
2022-003361-37
ClinicalTrials.gov ID:  
NCT05732454
Pediatric Investigational Plan Number:
Not applicable
Protocol Number:
C5041005
Phase:
2/3
Sponsor Legal Address:
Pfizer Inc.
66 Hudson Boulevard East
New York, NY 10001
Brief Title: A Study of Etrasimod in Adults With Moderate-to-Severe Atopic 
Dermatitis, Who Have Tried Prior Systemic Treatments for Atopic Dermatitis 
This document and accompanying materials contain confidential information belonging 
to Pfizer. Except as otherwise agreed to in writing, by accepting or reviewing these 
documents, you agree to hold this information in confidence and not copy or disclose it 
to others (except where required by applicable law) or use it for unauthorized purposes. 
In the event of any actual or suspected breach of this obligation, Pfizer must be promptly 
notified.
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Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 2
Document History
Document 
Version Date
Amendment 2
17 May 2023
Amendment 1
07 December 2022
Original protocol
13 October 2022
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any protocol administrative change 
letter(s).
Protocol Amendment Summary of Changes Table
Amendment 2 (17 May 2023)
Overall Rationale for the Amendment: The main purposes for Protocol Amendment 2 are
to address discontinuation of study intervention for participants with certain protocol-
specified treatment-related AEs and update the approach to all-cause, i.e., irrespective of 
causality, and to update protocol statistical sections to reflect C5041005 as an estimation 
study rather than a superiority study.  Protocol Amendment 2 includes previous 
administrative changes outlined in the Protocol Administrative Change Letter (PACL, Feb 
2023).
Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s).
Discontinuation of 
study intervention 
irrespective of AE 
causality
Changes and/or 
clarification to the 
criteria for 
participant 
withdrawal 
Section 1.3. Schedule of Activities, 
Section 7.1 Discontinuation of Study 
Intervention and Participant 
Discontinuation/Withdrawal, Section 
7.1.1 Discontinuation after Part 1 DB 
(Week 16) due to a Clinically Significant 
Safety Concern, Section 7.1.3 ECG 
Changes, Section 8.4.8 Adverse Events 
of Special Interest, Section 10.10.2 
Serious Infections Monitoring, Section 
10.10.3.2 Study Treatment 
Discontinuation Related to Post Dose 
Cardiac Monitoring, Section 10.10.4 
Pulmonary Function Monitoring, Section 
10.10.5 Ophthalmic Symptom 
Monitoring
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Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
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Description of Change
Brief Rationale
Section # and Name
Updated protocol 
statistical sections to 
reflect C5041005 as an 
estimation study rather 
than a superiority study.
Change of study 
design 
classification based 
on phase of 
development 
Section 1.1 Synopsis, Section 3 
Objectives, Endpoints, and Estimands, 
Section 9.1 Statistical Hypothesis
Sponsor may conduct 
earlier unblinded 
interim analysis
To inform internal 
decision making 
regarding the 
development 
program
Section 9.4 Interim Analysis
Changed Inclusion 
Criteria #4
Expanded criteria 
for what constitutes 
acceptable prior 
systemic therapy in 
Part 1
Section 1.1 Synopsis, Section 5.1 
Inclusion Criteria
Non-substantial Modification(s)
Contraception guidance 
regarding abstinence 
and pregnancy risk
To clarify the 
meaning of being 
truly abstinent and 
to provide 
instruction on 
ongoing inquiry 
about a change in 
pregnancy risk
Section 5.3.1 Contraception, Section 
10.4 Appendix 4: Contraceptive and 
Barrier Guidance
The safety follow-up 
approach for 
participants with 
lymphocyte declines 
Clarify instruction
for the safety 
follow up to reflect 
local standard of 
care rather than a 
lab pre-specified 
cut-off value.
Section 10.10.1 Monitoring of 
Lymphocyte, Neutrophil, and White 
Blood Cell Counts
Expanded section to 
emphasize ECG values 
of potential concern at 
Screening and Day 1, 
and further detailed 
investigator 
responsibility and 
For instruction to 
clarify the ECG 
values of concern 
predose and 
process of review
and interpretation 
of ECGs, 
documentation of 
ECG data in the 
Section 8.3.3. Electrocardiograms
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Final Protocol Amendment 2, 17 May 2023
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Page 4
Description of Change
Brief Rationale
Section # and Name
process of ECG 
evaluation 
eCRF, use of local 
ECG machines in 
emergency 
situations.
Emphasized 
investigator 
responsibility for 
participant continuation 
into the OLE at Week 
16
Week 16 
assessment for 
continuation into 
the OLE is based 
on investigator
judgement (medical 
monitor may be 
consulted)
Section 1.1 Synopsis, Section 4.1 
Overall Design, Section 7.1.1. 
Discontinuation after Part 1 DB (Week 
16) due to a Clinically Significant Safety 
Concern
Removed the details of 
intercurrent events of 
the Estimands E1 and 
E2
Simplification of 
the estimand 
descriptions and 
leaving the details 
to Sections 9.1.1.1 
and 9.1.1.2 for 
Estimands E1 and 
E2 as indicated 
respectively
Section 1.1 Synopsis and Section 3 –
Objectives, Endpoints, and Estimands
Removed the detailed 
bullet of change from 
baseline in laboratory 
values for the listed 
parameters
These endpoints 
and analyses are 
already captured in 
previous bullet of 
“Incidence of 
clinically 
significant changes 
in clinical 
laboratory values, 
ECG measurements 
and vital signs” and 
this further 
consolidates the 
safety endpoints 
into one bullet and 
avoids repetition.
Section 1.1 Synopsis and Section 3 –
Objectives, Endpoints, and Estimands
Correct that the baseline 
definitions for Part 1 
OLE and Part 2 are 
different and clarified 
their definitions
Correction and 
clarification of the 
baseline definitions 
for Part 1 OLE and 
Part 2 Safety phase.
Section 1.1 Synopsis and Section 3 –
Objectives, Endpoints, and Estimands
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PFIZER CONFIDENTIAL
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Description of Change
Brief Rationale
Section # and Name
Minor administrative 
changes/clarifications to 
the protocol
Better readability, 
consistency across 
the protocol, and 
improve 
compliance
Throughout
Pfizer protocol template 
updates (14 Apr 2023) 
Section 1.1 Synopsis, Section 2.3 
Benefit Risk Assessment, Section 4.2.3 
Adjudication Committee, Section 5.3.1 
Contraception, Section 6.1 Study 
Intervention(s) Administered, Section 
6.1.1 Administration, Section 6.8 
Treatment of Overdose, Section 7.1.8. 
Potential Cases of Acute Kidney Injury, 
Section 8.4.1 Time Period and 
Frequency for Collecting AE and SAE 
Information, Section 8.4.10 Medication 
Errors, Section 10.1.6 Dissemination of 
Clinical Study Data, Section 10.1.7 Data 
Quality Assurance, Section 10.1.9 Use 
of Medical Records, Section 10.6 
Appendix 6: Kidney Safety Monitoring 
Guidelines, Section 10.13 Appendix 13: 
Protocol Amendment History
PACL 03 Feb 2023
Correction of the 
Exploratory endpoint 
statement to align with 
the SoA
POEM is not 
collected at Week 
4.
Section 1.1 Synopsis, Section 3 
Objectives, Endpoints, and Estimands
Revised prohibited 
medication list based on 
internal Pfizer standards 
The medication has 
to inhibit/induce 2 
or more of the 
enzymes explicitly 
mentioned to be 
prohibited. 
Section 6.9.2 Prior Treatments, Section 
6.9.3, Prohibited During the Study, 
Appendix 10.8.1 Prohibited 
Concomitant Medications That May 
Result in DDI
Clarified pulmonary 
function testing 
requirements and 
provided exception 
circumstance
Ensures quality of 
data and address 
regional/geographic 
differences 
regarding the lab 
Section 8.3.9 Pulmonary Function Test 
(and DLCO), Section 1.3 SoA for Part 
1 and Part 2
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Description of Change
Brief Rationale
Section # and Name
certification 
availability. 
Expanded male 
contraception verbiage. 
Requires males to 
use a male condom 
when having sexual 
intercourse with a 
pregnant or non-
pregnant WOCBP
Section 10.4.1 Male Participant 
Reproductive Inclusion Criteria
Height is only assessed 
Day 1
Correction and 
alignment with 
SoA.
Section 8.3.1 Physical Examinations
Deleted Reference 34.
In accordance with 
changes to the 
prohibited 
medication text in 
Section 6.9.2
Section 11 References
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................14
LIST OF FIGURES .................................................................................................................14
1. PROTOCOL SUMMARY...................................................................................................15
1.1. Synopsis ..................................................................................................................15
1.2. Schema ....................................................................................................................24
1.3. Schedule of Activities .............................................................................................25
1.3.1. Part 1 (DB and OLE) Screening and Treatment Period .............................25
1.3.2. Part 1 (DB and OLE) ET and Safety Follow-up.........................................40
1.3.3. Part 2 (OL Safety).......................................................................................45
2. INTRODUCTION ...............................................................................................................60
2.1. Study Rationale .......................................................................................................60
2.2. Background .............................................................................................................61
2.3. Benefit/Risk Assessment.........................................................................................61
2.3.1. Risk Assessment.........................................................................................63
2.3.2. Benefit Assessment.....................................................................................67
2.3.3. Overall Benefit/Risk Conclusion................................................................67
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS ...........................................................68
4. STUDY DESIGN.................................................................................................................70
4.1. Overall Design.........................................................................................................70
4.2. Scientific Rationale for Study Design.....................................................................72
4.2.1. Patient Input Into Design............................................................................73
4.2.2. Diversity of Study Population ....................................................................73
4.2.3. Adjudication Committee.............................................................................73
4.2.4. Choice of Contraception/Barrier Requirements .........................................73
4.3. Justification for Dose ..............................................................................................74
4.4. End of Study Definition ..........................................................................................74
5. STUDY POPULATION......................................................................................................74
5.1. Inclusion Criteria.....................................................................................................75
5.2. Exclusion Criteria....................................................................................................76
5.3. Lifestyle Considerations..........................................................................................80
5.3.1. Contraception..............................................................................................80
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5.4. Screen Failures ........................................................................................................80
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................81
6.1. Study Intervention(s) Administered........................................................................82
6.1.1. Administration............................................................................................83
6.2. Preparation, Handling, Storage, and Accountability...............................................83
6.2.1. Preparation and Dispensing........................................................................84
6.3. Assignment to Study Intervention...........................................................................84
6.4. Blinding...................................................................................................................85
6.4.1. Blinding of Participants..............................................................................85
6.4.2. Blinding of Site Personnel..........................................................................85
6.4.3. Blinding of the Sponsor..............................................................................85
6.4.4. Breaking the Blind......................................................................................85
6.5. Study Intervention Compliance...............................................................................86
6.6. Dose Modification...................................................................................................87
6.7. Continued Access to Study Intervention After the End of the Study......................87
6.8. Treatment of Overdose............................................................................................87
6.9. Prior and Concomitant Therapy..............................................................................89
6.9.1. Required Concomitant Therapy..................................................................89
6.9.2. Prior Treatments .........................................................................................89
6.9.3. Prohibited During the Study.......................................................................90
6.9.4. Rescue Medicine.........................................................................................92
6.9.5. Permitted During the Study ........................................................................92
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................93
7.1. Discontinuation of Study Intervention ....................................................................93
7.1.1. Discontinuation after Part 1 DB (Week 16) due to a Clinically 
Significant Safety Concern ..............................................................................94
7.1.2. Liver Injury.................................................................................................95
7.1.3. ECG Changes..............................................................................................95
7.1.4. Pregnancy ...................................................................................................95
7.1.5. Lack of Efficacy .........................................................................................96
7.1.6. COVID-19 ..................................................................................................96
7.1.7. Temporary Discontinuation........................................................................96
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7.1.8. Potential Cases of Acute Kidney Injury .....................................................96
7.2. Participant Discontinuation/Withdrawal From the Study.......................................99
7.2.1. Withdrawal of Consent.............................................................................100
7.3. Lost to Follow-Up .................................................................................................100
8. STUDY ASSESSMENTS AND PROCEDURES.............................................................100
8.1. Administrative Procedures ....................................................................................100
8.1.1. Baseline Procedures..................................................................................101
8.1.1.1. Demography and Other Participant Characteristics................101
8.1.1.2. Prior and Ongoing Therapies ..................................................101
8.1.1.3. Medical History/AD History...................................................102
8.1.1.4. Suicidal Ideation and Behavior Risk Screening......................102
8.1.2. Telehealth Visits.......................................................................................102
8.1.3. Home Health Visits...................................................................................103
8.2. Efficacy Assessments............................................................................................104
8.2.1. Rater Qualifications..................................................................................104
8.2.2. Clinical Assessments ................................................................................105
8.2.2.1. IGA..........................................................................................105
8.2.2.2. EASI........................................................................................106
8.2.2.3. Atopic Dermatitis BSA Involvement ......................................108
8.2.3. PROs.........................................................................................................109
8.2.3.1. PP-NRS ...................................................................................109
8.2.3.2. Skin Pain NRS.........................................................................109
8.2.3.3. POEM......................................................................................109
8.3. Safety Assessments ...............................................................................................109
8.3.1. Physical Examinations..............................................................................109
8.3.2. Vital Signs ................................................................................................110
8.3.2.1. Blood Pressure and Pulse Rate................................................110
8.3.2.2. Temperature and Respiratory Rate..........................................110
8.3.3. Electrocardiograms...................................................................................111
8.3.3.1. Alternative Facilities for Electrocardiograms .........................112
8.3.4. Chest Imaging...........................................................................................112
8.3.5. Tuberculosis Testing.................................................................................112
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8.3.6. Clinical Safety Laboratory Assessments ..................................................113
8.3.6.1. Alternative Facilities for Clinical Safety Laboratory 
Assessment ......................................................................................114
8.3.7. Hepatitis Testing.......................................................................................114
8.3.8. Pregnancy Testing ....................................................................................115
8.3.8.1. At-Home Pregnancy Testing...................................................116
8.3.9. Pulmonary Function Test (and DLCO) ....................................................116
8.3.10. Ophthalmology Exam.............................................................................117
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting ...............118
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.....118
8.4.1.1. Reporting SAEs to Pfizer Safety.............................................119
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF.................119
8.4.2. Method of Detecting AEs and SAEs ........................................................120
8.4.3. Follow-Up of AEs and SAEs....................................................................120
8.4.4. Regulatory Reporting Requirements for SAEs.........................................120
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure...................................................120
8.4.5.1. Exposure During Pregnancy....................................................121
8.4.5.2. Exposure During Breastfeeding ..............................................122
8.4.5.3. Occupational Exposure ...........................................................123
8.4.6. Cardiovascular and Death Events.............................................................123
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs............................................................................123
8.4.8. Adverse Events of Special Interest...........................................................123
8.4.8.1. Lack of Efficacy......................................................................124
8.4.9. Medical Device Deficiencies....................................................................124
8.4.10. Medication Errors...................................................................................124
8.5. Pharmacokinetics ..................................................................................................125
8.6. Genetics.................................................................................................................125
8.7. Biomarkers ............................................................................................................125
8.8. Immunogenicity Assessments...............................................................................125
8.9. Health Economics .................................................................................................126
9. STATISTICAL CONSIDERATIONS ..............................................................................126
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9.1. Statistical Hypothesis ............................................................................................126
9.1.1. Estimands..................................................................................................126
9.1.1.1. Primary Estimand....................................................................126
9.1.1.2. Secondary Estimands ..............................................................127
9.1.2. Multiplicity Adjustment............................................................................127
9.2. Analysis Sets .........................................................................................................128
9.3. Statistical Analyses ...............................................................................................128
9.3.1. General Considerations.............................................................................128
9.3.2. Primary Endpoint Analysis.......................................................................128
9.3.3. Secondary Endpoint Analysis...................................................................128
9.3.4. Tertiary/Exploratory Endpoint(s) Analysis ..............................................129
9.3.5. Safety Analyses ........................................................................................129
9.3.5.1. Electrocardiogram Analyses....................................................129
9.4. Interim Analyses ...................................................................................................130
9.5. Sample Size Determination...................................................................................130
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS........................................................................................................131
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations.............131
10.1.1. Regulatory and Ethical Considerations ..................................................131
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.......................................................................131
10.1.2. Financial Disclosure ...............................................................................132
10.1.3. Informed Consent Process ......................................................................132
10.1.4. Data Protection .......................................................................................133
10.1.5. Committees Structure .............................................................................134
10.1.5.1. Data Monitoring Committee .................................................134
10.1.6. Dissemination of Clinical Study Data ....................................................134
10.1.7. Data Quality Assurance ..........................................................................135
10.1.8. Source Documents..................................................................................136
10.1.9. Use of Medical Records..........................................................................137
10.1.10. Study and Site Start and Closure ..........................................................137
10.1.11. Publication Policy.................................................................................138
10.1.12. Sponsor’s Medically Qualified Individual............................................140
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10.2. Appendix 2: Clinical Laboratory Tests ...............................................................141
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting ...................................................................143
10.3.1. Definition of AE .....................................................................................143
10.3.2. Definition of an SAE ..............................................................................144
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period..........................................................................145
10.3.4. Reporting of SAEs..................................................................................149
10.4. Appendix 4: Contraceptive and Barrier Guidance ..............................................150
10.4.1. Male Participant Reproductive Inclusion Criteria..................................150
10.4.2. Female Participant Reproductive Inclusion Criteria...............................150
10.4.3. Woman of Childbearing Potential ..........................................................151
10.4.4. Contraception Methods...........................................................................152
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-Up Assessments .....154
10.6. Appendix 6: Kidney Safety Monitoring Guidelines ...........................................156
10.6.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury............................................................................156
10.6.2. Age-Specific Kidney Function Calculation Recommendations.............156
10.6.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations .........................................................................................156
10.6.3. Kidney Function Calculation Tools........................................................156
10.6.4. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities.................................................................................................157
10.7. Appendix 7: ECG Findings of Potential Clinical Concern .................................158
10.8. Appendix 8: Prohibited Concomitant Medications That May Result in DDI.....160
10.8.1. Prohibited Concomitant Medications That May Result in DDI.............160
10.9. Appendix 9: Country-Specific Requirements .....................................................161
10.9.1. France .....................................................................................................161
10.10. Appendix 10: Safety Monitoring Guidance ......................................................162
10.10.1. Monitoring Of Lymphocyte, Neutrophil, and White Blood Cell 
Counts ............................................................................................................163
10.10.2. Serious Infections Monitoring..............................................................164
10.10.3. First-Dose Cardiac Monitoring.............................................................165
10.10.3.1. Cardiac Monitoring Schedule After First Dose...................165
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10.10.3.2. Study Treatment Discontinuation Related to Postdose 
Cardiac Monitoring .........................................................................168
10.10.4. Pulmonary Function Monitoring ..........................................................168
10.10.5. Ophthalmic Symptom Monitoring........................................................169
10.11. Appendix 11: Guidance for the Assessment of Potential Progressive 
Multifocal Leukoencephalopathy............................................................................170
10.12. Appendix 12: Abbreviations .............................................................................171
10.13. Appendix 13: Protocol Amendment History.....................................................176
11. REFERENCES ................................................................................................................178
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LIST OF TABLES
Table 1.
Prohibited Medication or Procedure Washout Periods Prior to Day 
1 ................................................................................................................89
Table 2.
IGA of Atopic Dermatitis Score.............................................................105
Table 3.
Clinical Sign Severity Scoring Criteria for EASI...................................106
Table 4.
Handprint Determination of BSA...........................................................107
Table 5.
Eczema Area and Severity Index Score Criteria ....................................108
Table 6.
EASI Body Region Weighting ...............................................................108
Table 7.
Protocol-Required Safety Laboratory Assessments ...............................141
Table 8.
Procedures to be Performed During the First-Dose Cardiac 
Monitoring Period...................................................................................166
Table 9.
Procedures to be Performed for Extended Cardiac Monitoring on
Day 2.......................................................................................................167
LIST OF FIGURES
Figure 1:
Management of Grade 4 Lymphopenia Events ......................................163
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: 
A Phase 2/3, Two-Part Study to Evaluate the Efficacy and Long-term Safety with Oral 
Etrasimod, 2 mg, Once Daily in Adult Participants with Moderate-to-Severe Atopic 
Dermatitis with a History of Prior Systemic Treatment Failure
Brief Title: A Study of Etrasimod in Adults With Moderate-to-Severe Atopic Dermatitis, 
Who Have Tried Prior Systemic Treatments for Atopic Dermatitis. 
Regulatory Agency Identification Number(s):
US IND Number:
142182
EudraCT/CTIS Number:
2022-003361-37
ClinicalTrials.gov ID:  
NCT05732454
Pediatric Investigational Plan Number:
Not applicable
Protocol Number:
C5041005
Phase:
2/3
Rationale:
Etrasimod is a S1PRM and is being developed as an oral treatment for patients with 
moderate-to-severe AD. Part 1 of this study will evaluate efficacy of etrasimod therapy QD 
and long-term safety in participants with moderate-to-severe AD with a history of a prior 
systemic therapy failure. It will include a 16-week double-blind treatment period followed by 
an open-label extension treatment period. Part 2 of this study will evaluate the long-term 
safety of etrasimod therapy QD in participants with moderate-to-severe AD with a history of 
a prior systemic therapy failure. Enrollment into Part 2 will not begin until the IA data from 
Part 1 are reviewed, and determination made as to the favorable benefit/risk of etrasimod 
2 mg in this new target population
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Objectives, Endpoints, and Estimands:
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 

Part 1 DB: To evaluate the 
efficacy of etrasimod, 2 
mg, QD versus placebo in 
adult participants with 
moderate-to-severe AD 
and a history of a prior 
systemic therapy failure.
Proportion of participants 
achieving IGA of clear (0) or 
almost clear (1) (on a 5-point 
scale) and a reduction of ≥ 2 
points from baseline at Week 16. 

Estimand E1: The difference in 
the proportions of the binary 
endpoint between etrasimod, 2 
mg, QD and placebo in patients 
with moderate-to-severe AD and 
a history of a prior systemic 
therapy failure. More details of 
Estimand E1 are described in 
Section 9.1.1.1.

Part 1 OLE and Part 2 
(OL): To evaluate the 
long-term safety of oral 
etrasimod, 2 mg, QD in 
adult participants with 
moderate-to-severe AD 
and a history of a prior 
systemic therapy failure.

Incidence and severity of 
treatment-emergent AEs, AEs 
leading to study treatment 
discontinuation, SAEs, and 
AESIs.

Incidence of clinically 
significant changes in clinical 
laboratory values, ECG 
measurements and vital signs.  

Not Applicable.
Secondary: 
Secondary:
Secondary: 

Part 1 DB: To evaluate the 
efficacy of etrasimod, 2 
mg, QD based on 
additional measures in 
adult participants with 
moderate-to-severe AD 
and a history of a prior 
systemic therapy failure.

Proportion of participants 
achieving EASI-75 at Week 16.

Percent change from baseline in 
EASI at Week 16.

Estimand E1 described above.

Estimand E2: The mean 
difference in percent change 
from baseline in EASI between 
etrasimod, 2 mg, QD and placebo 
in patients with moderate-to-
severe AD and a history of a 
prior systemic therapy failure.  
More details of Estimand E2 are 
described in Section 9.1.1.2.
Exploratory: 
Exploratory: 
Exploratory: 

Part 1 DB: To evaluate the 
efficacy of etrasimod, 2 
mg, QD based on 
additional measures in 
adult participants with 
moderate-to-severe AD 
and a history of a prior 
systemic therapy failure.

Proportion of participants 
achieving IGA of clear (0) or 
almost clear (1) (on a 5-point 
scale) and a reduction of ≥ 2 
points from baseline at all 
timepoints except Week 16.

Proportion of participants 
achieving EASI-75 at all 
timepoints except Week 16.

Estimand E1 described above, 
for all binary endpoints.

Estimand E2 described above, 
for all continuous endpoints.
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Objectives
Endpoints
Estimands

Percent change from baseline in 
EASI at all timepoints except 
Week 16.

Proportion of participants 
achieving ≥ 4-point reduction in
PP-NRS score from baseline at 
all timepoints.

Proportion of participants 
achieving ≥ 4-point reduction in 
Skin Pain NRS score from 
baseline at all timepoints.

Proportion of participants 
achieving EASI-90 at all 
timepoints.

Proportion of participants 
achieving ≥ 4-point reduction in 
POEM from baseline at 
Week 16.

Part 1 OLE and Part 2: To 
evaluate the long-term 
efficacy of oral etrasimod, 
2 mg, QD in adult 
participants with 
moderate-to-severe AD 
and a history of a prior 
systemic therapy failure.
Baseline for Part 1 is the pre-dose 
Day 1 in Part 1. Baseline for Part 2 
is the pre-dose Day 1 in the Part 2 
OL Safety phase.

Proportion of participants 
achieving EASI-75 at all 
scheduled timepoints.

Proportion of participants 
achieving IGA of clear (0) or 
almost clear (1) (on a 5-point 
scale) at all scheduled 
timepoints.

Percent change from baseline in 
EASI at all scheduled 
timepoints.

Proportion of participants 
achieving ≥ 4-point reduction in 
PP-NRS score from baseline at 
all scheduled timepoints

Proportion of participants 
achieving ≥ 4-point reduction in 
Skin Pain NRS score from 

Not applicable.
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Objectives
Endpoints
Estimands
baseline at all scheduled 
timepoints.

Proportion of participants 
EASI-90 at all scheduled 
timepoints.

Change from baseline in POEM 
at all scheduled timepoints.
Overall Design:
This is a 2-part study with Part 1 being randomized, DB, placebo controlled, with an OLE, to 
assess efficacy and safety of 2 mg etrasimod administered orally, QD in participants with 
refractory, moderate-to-severe AD, whose disease is not adequately controlled with other 
systemic drug products, including biologics, or when use of those therapies is inadvisable (ie, 
participants with a history of a prior systemic treatment failure). The open-label Part 2 is to 
assess long-term safety of etrasimod 2 mg in participants with moderate-to-severe AD with a 
history of prior systemic therapy failure. 
Part 1: Approximately 60 participants will be randomized (1:1 ratio) in a DB manner to 
receive etrasimod 2 mg or placebo orally, QD, for 16 weeks. Randomization will be stratified 
by disease severity as measured by IGA score (3 [moderate AD], 4 [severe AD]) at Baseline. 
Following completion of the DB portion at Week 16, all participants remaining eligible with 
no clinically significant safety concerns as per investigator’s judgement (investigator may
seek medical monitor’s consideration, if needed) at Week 16, will be given the option to 
continue in the OLE portion of Part 1, whereby they will receive etrasimod 2 mg QD for 
52 weeks. The participants, investigators and sponsor study team will remain blinded to the 
treatments the participants received for the placebo-controlled period. Non responders, 
participants not achieving at least EASI-50, will be discontinued at Week 32 (ie, 16 weeks of 
treatment in the OLE period). 
An interim analysis will be conducted after all Part 1 participants have completed their 
Week 16 visit. The IA will be performed by the Sponsor and data summaries will be shared 
with the study team. The participants and investigators will remain blinded to the treatments 
the participants received for the placebo-controlled period. The study team will review the 
data in the context of the overall benefit-risk profile of etrasimod for the treatment of 
moderate-to-severe AD with prior systemic failure. The data review will include but is not 
limited to, efficacy measures of IGA and EASI-75 response and safety parameters including 
the incidence and severity of AEs, AESIs, and clinically relevant changes in ECG, and vital 
signs, and laboratory values. The efficacy and safety data will be utilized to make a go/no-go 
decision for initiating Part 2 of the study, as well as for completing the 52-week treatment for 
the Part 1 participants in the OLE. Once the decision is made it will be promptly 
communicated to the sites. 
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Part 2: If the IA results in a decision to proceed to Part 2 of the study, approximately 340 
additional participants will be enrolled to receive etrasimod 2 mg orally, once daily, for 52 
weeks in an open-label manner in order to fulfill the safety database requirements. 
Enrollment into Part 2 will not begin until the IA data from Part 1 are reviewed, and 
determination made as to the favorable benefit/risk of etrasimod 2 mg QD in the new target 
population. Non-responders, ie, participants not achieving at least EASI-50 will be 
discontinued at Week 16, Part 2.
The participant population in both Part 1 and Part 2 will include at least 40% of participants 
with moderate AD (IGA score of 3) and at least 40% of participants with severe AD (IGA 
score of 4). The application of topical emollients/moisturizers (including those containing 
ceramide, hyaluronic acid, or urea) will be required at least once daily for at least 1 week 
prior to baseline (Day 1) and throughout the treatment period without change (ie, type, 
frequency, application). TCS and other medicated topical treatments for AD must be 
discontinued at least 1 week prior to baseline (Day 1) and are not permitted in the double-
blind treatment period. Safety follow-up visits will occur at 2 and 4 weeks after the last dose 
of study treatment. Medicated and non-medicated rescue medications are not permitted 
during the Part 1 DB portion. For Part 1 OLE and Part 2 medicated and non-medicated 
topical treatments for AD will be permitted at the discretion of the investigator and in 
accordance with their usual practice.
Number of Participants:
Part 1: Approximately 60 participants will be randomized in the DB period. Participants who 
qualify based on acceptable safety and who complete the DB period will continue in the 
OLE. 
Part 2: Approximately 340 participants will be enrolled in this OL part of the study. 
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Study Population: 
Key inclusion and exclusion criteria are listed below:
Inclusion Criteria 
Participants must meet the following key inclusion criteria to be eligible for enrollment into 
the study:
1. Chronic AD (also known as atopic eczema) that was diagnosed at least 1 year prior to 
Screening and meets Hanifin and Rajka criteria at screening).1
2. Moderate-to-severe AD:
a.
IGA score ≥3 (on the 0 to 4 IGA scale, in which 3 = moderate and 4 = severe) at 
screening and baseline (Day 1)
b. BSA ≥10% of AD involvement at screening and baseline (Day 1)
c.
Eczema Area and Severity Index (EASI) ≥16 at screening and baseline (Day 1)
3. A participant who has failed a prior systemic therapy for AD, ie, refractory, moderate-
to-severe AD that is not adequately controlled with other systemic drug products, 
including biologics, or when use of those therapies is inadvisable (i.e., medical 
contraindications to systemic therapy prohibit use). 
a.
Inadequate response to ≥2 weeks of cyclosporine, azathioprine, methotrexate, 
mycophenolate, biologic, JAK inhibitors, or systemic corticosteroid (CS; defined 
as pulse of systemic CS or ≥2 weeks of continuous oral CS), or when systemic 
therapy is inadvisable.  
- In Part 1, approximately 30% of participants are permitted with a failure of a 
prior systemic corticosteroid therapy without failing another systemic treatment 
for AD.  For the remining participants, failure of a prior systemic corticosteroid 
therapy alone is not sufficient to meet the criterion of prior systemic failure, i.e., 
the participant must fail another systemic treatment for AD.  
-In Part 2, failure of systemic corticosteroids may qualify a participant for the 
study. 
b. Refractory is an insufficient clinical response defined as the inability to achieve 
and maintain remission or a low disease activity state of minimal or mild lesions 
only, within 1 year of screening, despite treatment with systemic therapy for a 
period sufficient to demonstrate efficacy as determined by the Investigator. 
c.
Acceptable documentation for these criteria includes chart notes that record 
medication prescription and treatment outcome, or Investigator documentation 
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based on communication with the patient's treating physician. For study 
purposes, document failure of prior systemic drug(s) to adequately control AD in 
the CRF.
4. Willing to apply a topical emollient/moisturizer at least once daily for ≥1 week prior to 
baseline (Day 1) and willing to maintain consistent (ie, no change in type, frequency, 
or application) daily application over the course of the study.
Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded:
1. Presence of potential confounding factors:
Skin conditions (eg, psoriasis, seborrheic dermatitis) that may interfere with evaluation of 
AD or assessment of treatment response as deemed by the Investigator.
Current significant active infection or requiring a treatment for infection that may interfere 
with the assessment of AD.
Study Arms and Duration:
Part 1 (DB period and OLE period):

Etrasimod, 2 mg (tablet) QD for 16 weeks or Placebo (tablet) QD for 16 weeks; OLE 
period: Etrasimod, 2 mg (tablet) QD for 52 weeks. 

Up to 76 weeks duration: including up to 4 weeks for screening, 16-week DB treatment 
period, 52-week OLE treatment period, and a safety follow-up at 2 and 4 weeks after 
treatment completion. 
Study Intervention(s)
Intervention Name
etrasimod
Placebo (Part 1 DB period only)
Use
experimental
placebo
IMP or NIMP/AxMP
IMP
IMP
Dose Formulation
tablet
tablet
Unit Dose Strength(s)
2 mg
Not applicable
Route of Administration
oral
oral
Study Arm(s)
Arm Title
Etrasimod
Placebo (Part 1 DB period only)
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Arm Description
Participants will receive 
etrasimod 2 mg QD 
Participants will receive placebo QD
Part 2 (OL Safety period): 

Etrasimod, 2 mg (tablet) QD for 52 weeks. 

Up to 60 weeks duration: including up to 4 weeks for screening, 52-week OL treatment 
period, and a safety follow-up at 2 and 4 weeks after treatment completion.
Intervention Name
Etrasimod
Use
experimental
IMP or NIMP/AxMP
IMP
Dose Formulation
Tablet
Unit Dose Strength(s)
2 mg
Route of Administration
Oral
Study Arm(s)
Arm Title
Etrasimod
Arm Description
Participants will receive etrasimod 2 mg QD 
Statistical Methods:
Approximately 60 participants will be randomized to etrasimod 2 mg or placebo in a ratio of 
1:1 (30 participants per treatment group) in Part 1. This is an estimation study. The primary 
objective will be to estimate the proportion (95% CI) of participants achieving IGA response 
at Week 16 in each group and the difference (95% CI) in proportions between the two 
groups. With 30 participants per group, assuming the proportions of participants achieving 
IGA response at Week 16 are 9% and 39% for placebo and etrasimod 2 mg QD, respectively: 
(1) the half-width of the 2-sided 95% CI for the proportion of participants achieving IGA 
response at Week 16 will be ≤17.5% in each treatment group using normal approximation, 
(2) the half-width of the 2-sided 95% CI for the difference in proportions between etrasimod 
2 mg QD and placebo will be 20.2% using normal approximation. The placebo response rate 
was estimated based on Phase 3 studies in literature (Simpson et al. 2016, Simpson et al. 
2020, Silverberg et al. 2020). No adjustment for multiplicity will be made. In Part 2, 
approximately 340 participants are planned and intended as a supplementary safety database 
for the etrasimod 2 mg QD program. No formal sample size calculations were performed for 
Part 2 of the study.
The primary and secondary binary efficacy endpoints for Part 1 DB, placebo-controlled 
portion will be analyzed using the Cochran-Mantel-Haenszel method adjusted for the actual
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randomization/stratification factor IGA score (3 [moderate AD], 4 [severe AD], based on 
clinical database) at Baseline using normal approximation for the difference in binomial 
proportions. For the primary endpoint, the IGA response rate difference between the 
etrasimod group and the placebo group in the proportion of participants achieving (ie, IGA of 
clear (0) or almost clear (1) (on a 5-point scale) and a reduction of ≥ 2 points from baseline at 
Week 16) along with its 95% confidence interval will be reported. 
After all Part 1 participants complete the 16-week DB treatment period, an IA will be 
conducted. Study conduct will continue while the data are prepared and analyzed for the IA. 
Based on the IA results, the study may begin to enroll participants in Part 2, or the study may 
be terminated.
All safety analyses will be performed descriptively.
Ethical Considerations:
A clinically meaningful benefit and an acceptable safety profile for 2 mg etrasimod dose was 
demonstrated in the Phase 2b study (Arena study APD334-201) in adult participants with 
moderate-to-severe AD. The potential risks of treatment include those that were noted in 
Phase 2 and/or those based on the pharmacology of S1PRMs and include cardiovascular 
events (bradycardia, AV conduction delay, hypertension), macular edema, pulmonary events 
(airflow obstruction, decreased gas exchange), infections (severe infections, opportunistic 
infections, herpes simplex and herpes zoster), liver injury, posterior reversible 
encephalopathy syndrome and malignancies. The Phase 2b data in a limited sub-population 
of systemic failure indicated a similar efficacy of etrasimod 2 mg in participants with or 
without prior systemic failure. Appropriate risk evaluation and mitigation strategies (see 
Section 2.3.1 and Section 10.10) have been incorporated into this protocol. Overall, there is a 
favorable benefit-risk profile to support the continued development of etrasimod 2 mg in the 
treatment of adult participants with moderate-to-severe AD with a prior history of systemic 
failure.
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1.2. Schema
  
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1.3. Schedule of Activities
The SoA table provides an overview of the protocol visits and procedures. Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant. 
1.3.1. Part 1 (DB and OLE) Screening and Treatment Period
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
DB Treatment Period
OLE Treatment Period
Notes
Day 1 Week 
4
Week 
8
Week 
12
Week 
16
Wee
k 20
Week 
24
Week 
32
Week 
40
Week 
52
Week 
68

Screening, and all visits during the 16 Week DB 
Treatment Period including Safety Follow up 
Visits MUST be conducted at the investigative 
study site. 

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only 
during the OLE Treatment period. See 
Section 8.1.2 and Section 8.1.3

Due to first dose cardiac monitoring Day 1 and 
Week 16 visits should be conducted in the 
morning and not on a Friday or the day before a 
site-observed holiday. See Section 10.10.3.

In preparation for the Week 16 visit, site is to 
contact participant 1-2 business days prior to 
visit to remind them they will take study 
intervention at the site. See Section 6.5. 
Study Day
-28 to -
1
1
29
57
85
113
141
169
225
281
365
477

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±7)

All screening should be done ≤ 28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
Informed consent
X

Informed consent should be obtained prior to 
undergoing any study-specific procedures. 

See Section 10.1.3 for additional information.
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Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
DB Treatment Period
OLE Treatment Period
Notes
Day 1 Week 
4
Week 
8
Week 
12
Week 
16
Wee
k 20
Week 
24
Week 
32
Week 
40
Week 
52
Week 
68

Screening, and all visits during the 16 Week DB 
Treatment Period including Safety Follow up 
Visits MUST be conducted at the investigative 
study site. 

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only 
during the OLE Treatment period. See 
Section 8.1.2 and Section 8.1.3

Due to first dose cardiac monitoring Day 1 and 
Week 16 visits should be conducted in the 
morning and not on a Friday or the day before a 
site-observed holiday. See Section 10.10.3.

In preparation for the Week 16 visit, site is to 
contact participant 1-2 business days prior to 
visit to remind them they will take study 
intervention at the site. See Section 6.5. 
Study Day
-28 to -
1
1
29
57
85
113
141
169
225
281
365
477

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±7)

All screening should be done ≤ 28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
Screen for 
inclusion/exclusion 
criteria
X
X

See Section 5.1 and Section 5.2
Demographics
X

See Section 8.1.1.1
Fitzpatrick Skin Type 
Assessment
X
See Section 8.1.1.1
Randomization
X

At randomization, the participant enrollment 
number and study intervention are assigned.
Medical History and 
Physical Examination
Medical history and AD 
history 
X
See Section 8.1.1.3
Complete Physical 
examination
X
X
Physical examinations to be completed before 
administration of study intervention.
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Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
DB Treatment Period
OLE Treatment Period
Notes
Day 1 Week 
4
Week 
8
Week 
12
Week 
16
Wee
k 20
Week 
24
Week 
32
Week 
40
Week 
52
Week 
68

Screening, and all visits during the 16 Week DB 
Treatment Period including Safety Follow up 
Visits MUST be conducted at the investigative 
study site. 

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only 
during the OLE Treatment period. See 
Section 8.1.2 and Section 8.1.3

Due to first dose cardiac monitoring Day 1 and 
Week 16 visits should be conducted in the 
morning and not on a Friday or the day before a 
site-observed holiday. See Section 10.10.3.

In preparation for the Week 16 visit, site is to 
contact participant 1-2 business days prior to 
visit to remind them they will take study 
intervention at the site. See Section 6.5. 
Study Day
-28 to -
1
1
29
57
85
113
141
169
225
281
365
477

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±7)

All screening should be done ≤ 28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
Symptom-directed (focused) examinations may 
be performed at the other study visits as described 
in Section 8.3.1.
Height
X
Weight
X
X
X

See Section 8.3.1 for additional information.
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X

To be measured prior to any blood draws that 
occur within the same collection window. 

See Section 8.3.2 for additional information.

Day 1 and Week 16 Vital signs will be collected 
pre-dose and at Hours 1, 2, 3, and 4 (± 15 
minutes) post-dose as part of the first dose, in 
clinic cardiac monitoring procedure 
Section 8.3.2.

If the first reading is abnormal for any 
parameters, they may be repeated up to 2 times 
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 28
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
DB Treatment Period
OLE Treatment Period
Notes
Day 1 Week 
4
Week 
8
Week 
12
Week 
16
Wee
k 20
Week 
24
Week 
32
Week 
40
Week 
52
Week 
68

Screening, and all visits during the 16 Week DB 
Treatment Period including Safety Follow up 
Visits MUST be conducted at the investigative 
study site. 

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only 
during the OLE Treatment period. See 
Section 8.1.2 and Section 8.1.3

Due to first dose cardiac monitoring Day 1 and 
Week 16 visits should be conducted in the 
morning and not on a Friday or the day before a 
site-observed holiday. See Section 10.10.3.

In preparation for the Week 16 visit, site is to 
contact participant 1-2 business days prior to 
visit to remind them they will take study 
intervention at the site. See Section 6.5. 
Study Day
-28 to -
1
1
29
57
85
113
141
169
225
281
365
477

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±7)

All screening should be done ≤ 28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
during a visit (only applicable to first dose 
cardiac monitoring or cardiac monitoring during 
the treatment reinitiation following the defined 
periods of treatment interruption).
12-Lead ECG 
X
X
X
X

See Section 8.3.3 for additional information.

12-lead ECGs (with participants in the supine 
position) will be performed prior to 
randomization, prior to dosing at Week 16 (prior 
to entering OLE) and at 4 (± 15 minutes) hours 
post-dose as part of the first dose, in-clinic 
cardiac monitoring procedure (Section 8.3.3). 
Pre-dose ECGs are to be collected prior to blood 
sample collection.
PML query
X
X
X
X
X
X
X
X
X
X
X

See Section 10.11
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 29
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
DB Treatment Period
OLE Treatment Period
Notes
Day 1 Week 
4
Week 
8
Week 
12
Week 
16
Wee
k 20
Week 
24
Week 
32
Week 
40
Week 
52
Week 
68

Screening, and all visits during the 16 Week DB 
Treatment Period including Safety Follow up 
Visits MUST be conducted at the investigative 
study site. 

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only 
during the OLE Treatment period. See 
Section 8.1.2 and Section 8.1.3

Due to first dose cardiac monitoring Day 1 and 
Week 16 visits should be conducted in the 
morning and not on a Friday or the day before a 
site-observed holiday. See Section 10.10.3.

In preparation for the Week 16 visit, site is to 
contact participant 1-2 business days prior to 
visit to remind them they will take study 
intervention at the site. See Section 6.5. 
Study Day
-28 to -
1
1
29
57
85
113
141
169
225
281
365
477

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±7)

All screening should be done ≤ 28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
PFT and DLCO
X
X

Visit windows for post-screening assessments are 
±10 days for performing PFT and DLCO (where 
locally available) are described in Section 8.3.9. 
Unscheduled visits should be performed, as 
clinically indicated, for participants reporting any 
respiratory symptoms (eg, dyspnea, shortness of 
breath, chest tightness, or wheezing), preferably 
on the same day (refer to Section 10.10.4). 

PFT and DLCO measurements will be performed 
at a pulmonary function laboratory or respiratory 
department per local regulations.  Exceptional 
circumstances may apply; see Section 8.3.9.

Sites where DLCO is not available should 
consult the study medical monitor.
Ophthalmology exam
X
X

Visit windows for post-screening assessments are 
±10 days for performing ophthalmology exam as 
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 30
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
DB Treatment Period
OLE Treatment Period
Notes
Day 1 Week 
4
Week 
8
Week 
12
Week 
16
Wee
k 20
Week 
24
Week 
32
Week 
40
Week 
52
Week 
68

Screening, and all visits during the 16 Week DB 
Treatment Period including Safety Follow up 
Visits MUST be conducted at the investigative 
study site. 

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only 
during the OLE Treatment period. See 
Section 8.1.2 and Section 8.1.3

Due to first dose cardiac monitoring Day 1 and 
Week 16 visits should be conducted in the 
morning and not on a Friday or the day before a 
site-observed holiday. See Section 10.10.3.

In preparation for the Week 16 visit, site is to 
contact participant 1-2 business days prior to 
visit to remind them they will take study 
intervention at the site. See Section 6.5. 
Study Day
-28 to -
1
1
29
57
85
113
141
169
225
281
365
477

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±7)

All screening should be done ≤ 28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
described in Section 8.3.10. Unscheduled 
assessments should be performed, as clinically 
indicated, as part of the study visit assessment 
due to complaints of decreased vision or 
identification of worsening visual acuity 
(Section 10.10.5). 
C-SSRS
X
See Section 8.1.1.4 for additional information
Contraception check
X
X
X
X
X
X
X
X
X
X
X
X
See Section 5.3.1 and Section 10.4 for additional 
information.
Laboratory
Assessments
See Section 8.3.6 for additional information.
See Appendix 2 for a list of Clinical Laboratory 
tests to be done.
For laboratory collection volumes, see the 
laboratory manual.
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 31
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
DB Treatment Period
OLE Treatment Period
Notes
Day 1 Week 
4
Week 
8
Week 
12
Week 
16
Wee
k 20
Week 
24
Week 
32
Week 
40
Week 
52
Week 
68

Screening, and all visits during the 16 Week DB 
Treatment Period including Safety Follow up 
Visits MUST be conducted at the investigative 
study site. 

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only 
during the OLE Treatment period. See 
Section 8.1.2 and Section 8.1.3

Due to first dose cardiac monitoring Day 1 and 
Week 16 visits should be conducted in the 
morning and not on a Friday or the day before a 
site-observed holiday. See Section 10.10.3.

In preparation for the Week 16 visit, site is to 
contact participant 1-2 business days prior to 
visit to remind them they will take study 
intervention at the site. See Section 6.5. 
Study Day
-28 to -
1
1
29
57
85
113
141
169
225
281
365
477

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±7)

All screening should be done ≤ 28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
Infectious Disease 
Serology
X
X
X
Infectious diseases serology include HIV, HBV, 
HCV
See Exclusion Criteria for details.
See Section 8.3.7 for hepatitis testing details. 
Week 16, Week 68, ET only for participants 
requiring HBV DNA repeat testing. 
FSH
X
FSH at Screening, only for females with no 
menses for ≥12 months to confirm 
postmenopausal status
TB Test and Chest 
imaging
X
X
TB testing will be done via an IGRA 
(preferentially QFT-G In-Tube test, however 
other IGRAs are permitted) in all participants 
except those with a history of active, latent, or 
inadequately treated infection with TB. 
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 32
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
DB Treatment Period
OLE Treatment Period
Notes
Day 1 Week 
4
Week 
8
Week 
12
Week 
16
Wee
k 20
Week 
24
Week 
32
Week 
40
Week 
52
Week 
68

Screening, and all visits during the 16 Week DB 
Treatment Period including Safety Follow up 
Visits MUST be conducted at the investigative 
study site. 

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only 
during the OLE Treatment period. See 
Section 8.1.2 and Section 8.1.3

Due to first dose cardiac monitoring Day 1 and 
Week 16 visits should be conducted in the 
morning and not on a Friday or the day before a 
site-observed holiday. See Section 10.10.3.

In preparation for the Week 16 visit, site is to 
contact participant 1-2 business days prior to 
visit to remind them they will take study 
intervention at the site. See Section 6.5. 
Study Day
-28 to -
1
1
29
57
85
113
141
169
225
281
365
477

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±7)

All screening should be done ≤ 28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
If the result of the repeat test is indeterminate, 
participants may be screened using the 
Mantoux/PPD skin test with study medical 
monitor approval. If the Mantoux PPD tuberculin 
skin test is given, the participant must return 
between 48-72 hours post-injection for induration 
evaluation.
TB testing (IGRA and PPD, if needed) will be 
conducted at a certified local laboratory unless 
unavailable in which case the Central Lab will be 
used.
Chest images (posterior anterior and lateral 
views) are required for all participants. Chest 
image or other appropriate diagnostic image (ie 
CT or MRI) may be performed up to 12 weeks 
prior to Study Day 1. Official reading must be 
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 33
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
DB Treatment Period
OLE Treatment Period
Notes
Day 1 Week 
4
Week 
8
Week 
12
Week 
16
Wee
k 20
Week 
24
Week 
32
Week 
40
Week 
52
Week 
68

Screening, and all visits during the 16 Week DB 
Treatment Period including Safety Follow up 
Visits MUST be conducted at the investigative 
study site. 

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only 
during the OLE Treatment period. See 
Section 8.1.2 and Section 8.1.3

Due to first dose cardiac monitoring Day 1 and 
Week 16 visits should be conducted in the 
morning and not on a Friday or the day before a 
site-observed holiday. See Section 10.10.3.

In preparation for the Week 16 visit, site is to 
contact participant 1-2 business days prior to 
visit to remind them they will take study 
intervention at the site. See Section 6.5. 
Study Day
-28 to -
1
1
29
57
85
113
141
169
225
281
365
477

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±7)

All screening should be done ≤ 28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
located and available in the source 
documentation.
TB test and Chest Imaging at Week 52 only for 
participants in regions which are above a low risk 
for TB.
See Section 8.3.4 and Section 8.3.5
TB questionnaire
X
X
X
X
X
X
X
X
X
X
X
X
A TB questionnaire will be administered to all 
participants at Screening. The TB questionnaire 
will be administered at designated post-baseline 
visits only for participants residing in regions 
which are above a low risk for Tuberculosis (ie, 
>10/100,000 incidence, which will be determined 
based on WHO country level data). If TB is 
suspected at any time during the study, 
participants should be screened.
See Section 8.3.5 for details
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 34
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
DB Treatment Period
OLE Treatment Period
Notes
Day 1 Week 
4
Week 
8
Week 
12
Week 
16
Wee
k 20
Week 
24
Week 
32
Week 
40
Week 
52
Week 
68

Screening, and all visits during the 16 Week DB 
Treatment Period including Safety Follow up 
Visits MUST be conducted at the investigative 
study site. 

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only 
during the OLE Treatment period. See 
Section 8.1.2 and Section 8.1.3

Due to first dose cardiac monitoring Day 1 and 
Week 16 visits should be conducted in the 
morning and not on a Friday or the day before a 
site-observed holiday. See Section 10.10.3.

In preparation for the Week 16 visit, site is to 
contact participant 1-2 business days prior to 
visit to remind them they will take study 
intervention at the site. See Section 6.5. 
Study Day
-28 to -
1
1
29
57
85
113
141
169
225
281
365
477

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±7)

All screening should be done ≤ 28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
When dosing is administered during a visit, 
samples must be collected prior to dosing.
See Section 10.2 for details.
Blood chemistry
X
X
X
X
X
X
X
X
X
X
X
X
See Section 10.2 for details.
Urinalysis
X
X
See Section 10.2 for details.
Coagulation
X
X
See Section 10.2 for details.
Pregnancy test
X
X
X
X
X
X
X
X
X
X
X
X
A serum pregnancy test for β-hCG will be 
performed on women of childbearing potential at 
Screening to determine eligibility. A urine 
pregnancy test (β hCG) will be performed at all 
other indicated visits unless a serum sample is 
required per investigator request.
On Day 1, a urine pregnancy test must be 
performed and result with a negative result prior 
to randomization. For visits that occur more than 
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 35
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
DB Treatment Period
OLE Treatment Period
Notes
Day 1 Week 
4
Week 
8
Week 
12
Week 
16
Wee
k 20
Week 
24
Week 
32
Week 
40
Week 
52
Week 
68

Screening, and all visits during the 16 Week DB 
Treatment Period including Safety Follow up 
Visits MUST be conducted at the investigative 
study site. 

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only 
during the OLE Treatment period. See 
Section 8.1.2 and Section 8.1.3

Due to first dose cardiac monitoring Day 1 and 
Week 16 visits should be conducted in the 
morning and not on a Friday or the day before a 
site-observed holiday. See Section 10.10.3.

In preparation for the Week 16 visit, site is to 
contact participant 1-2 business days prior to 
visit to remind them they will take study 
intervention at the site. See Section 6.5. 
Study Day
-28 to -
1
1
29
57
85
113
141
169
225
281
365
477

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±7)

All screening should be done ≤ 28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
4 weeks apart, participants must perform a home 
pregnancy test. Site personnel are expected to 
contact the participant every 4 weeks to confirm 
the home pregnancy test was taken, confirm 
participant continues to use contraception 
correctly, and document the pregnancy test results 
and contraception discussion in source. A home 
pregnancy test is required at W28, W36, W44, 
W48, W56, W60 and W64. If home pregnancy 
testing is not allowed per local regulations, 
pregnancy testing will be performed onsite during 
an unscheduled visit. Refer to Section 8.3.8 for 
additional guidance
TBNK panel cell counts 
X
X
X
X
X
When dosing is administered during a visit, 
TBNK samples must be collected prior to dosing.
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 36
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
DB Treatment Period
OLE Treatment Period
Notes
Day 1 Week 
4
Week 
8
Week 
12
Week 
16
Wee
k 20
Week 
24
Week 
32
Week 
40
Week 
52
Week 
68

Screening, and all visits during the 16 Week DB 
Treatment Period including Safety Follow up 
Visits MUST be conducted at the investigative 
study site. 

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only 
during the OLE Treatment period. See 
Section 8.1.2 and Section 8.1.3

Due to first dose cardiac monitoring Day 1 and 
Week 16 visits should be conducted in the 
morning and not on a Friday or the day before a 
site-observed holiday. See Section 10.10.3.

In preparation for the Week 16 visit, site is to 
contact participant 1-2 business days prior to 
visit to remind them they will take study 
intervention at the site. See Section 6.5. 
Study Day
-28 to -
1
1
29
57
85
113
141
169
225
281
365
477

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±7)

All screening should be done ≤ 28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
Study Intervention and 
Other Treatments
See Section 6 for additional information.
Dispense study 
intervention
X
X
X
X
X
X
X
X
X
X
See Section 6.1 for additional information.
Study intervention 
administration at site
X
X 

The Week 16 visit is the first dose of open label 
treatment. Sites must contact participants 1-2 
business days prior to the Week 16 visit to 
remind them not to take study intervention on the 
day of the Week 16 visit. 

All PROs and AD clinical assessments should be 
completed prior to other clinical activities and 
investigative product administration.

Extended 4-hour visit on Day 1 and Week 16 due 
to cardiac monitoring (Section 10.10.3) and also 
required on the first day of treatment re-initiation 
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 37
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
DB Treatment Period
OLE Treatment Period
Notes
Day 1 Week 
4
Week 
8
Week 
12
Week 
16
Wee
k 20
Week 
24
Week 
32
Week 
40
Week 
52
Week 
68

Screening, and all visits during the 16 Week DB 
Treatment Period including Safety Follow up 
Visits MUST be conducted at the investigative 
study site. 

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only 
during the OLE Treatment period. See 
Section 8.1.2 and Section 8.1.3

Due to first dose cardiac monitoring Day 1 and 
Week 16 visits should be conducted in the 
morning and not on a Friday or the day before a 
site-observed holiday. See Section 10.10.3.

In preparation for the Week 16 visit, site is to 
contact participant 1-2 business days prior to 
visit to remind them they will take study 
intervention at the site. See Section 6.5. 
Study Day
-28 to -
1
1
29
57
85
113
141
169
225
281
365
477

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±7)

All screening should be done ≤ 28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
after a protocol-predefined treatment interruption 
(Section 7.1.7).
Study intervention 
accountability
X
X
X
X
X
X
X
X
X
X
In the event a participant is not compliant with the 
assigned treatment regimen, the participant should 
be retrained on proper study treatment 
administration.
Prior/concomitant 
treatment(s)
X
X
X
X
X
X
X
X
X
X
X
X
See Section 6.9 for additional information
Confirm daily use of 
emollient/moisturizers
X
X
X
X
X
X
X
X
X
X
X
X
Participants must apply topical emollient or 
moisturizer at least once daily for ≥1 week prior 
to Day 1 and continue daily application over the 
course of the study without change. On visit days 
during the study, participants should not apply 
any topical emollient or moisturizer until the 
study visit has been completed.
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 38
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
DB Treatment Period
OLE Treatment Period
Notes
Day 1 Week 
4
Week 
8
Week 
12
Week 
16
Wee
k 20
Week 
24
Week 
32
Week 
40
Week 
52
Week 
68

Screening, and all visits during the 16 Week DB 
Treatment Period including Safety Follow up 
Visits MUST be conducted at the investigative 
study site. 

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only 
during the OLE Treatment period. See 
Section 8.1.2 and Section 8.1.3

Due to first dose cardiac monitoring Day 1 and 
Week 16 visits should be conducted in the 
morning and not on a Friday or the day before a 
site-observed holiday. See Section 10.10.3.

In preparation for the Week 16 visit, site is to 
contact participant 1-2 business days prior to 
visit to remind them they will take study 
intervention at the site. See Section 6.5. 
Study Day
-28 to -
1
1
29
57
85
113
141
169
225
281
365
477

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±7)

All screening should be done ≤ 28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
Assess treatment 
continuation criteria
X
X
At Week 16, to continue into the OLE portion of 
the study, participants must remain eligible with 
no clinically significant safety concerns (see 
Section 7.1.1).
At Week 32, participants who do not meet the 
pre-specified continuation criteria (EASI-50) will 
be discontinued at Week 32 and will complete ET 
visit procedures. Refer to Section 7.1.5 of the 
protocol for details.
Assessments
See Section 8 for additional information.
Efficacy
See Section 8.2 for additional information.
EASI, IGA, BSA 
affected by AD
X
X
X
X
X
X
X
X
X
X
X
X
All PROs and AD clinical assessments should be 
completed prior to other clinical activities and 
study intervention administration.
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 39
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
DB Treatment Period
OLE Treatment Period
Notes
Day 1 Week 
4
Week 
8
Week 
12
Week 
16
Wee
k 20
Week 
24
Week 
32
Week 
40
Week 
52
Week 
68

Screening, and all visits during the 16 Week DB 
Treatment Period including Safety Follow up 
Visits MUST be conducted at the investigative 
study site. 

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only 
during the OLE Treatment period. See 
Section 8.1.2 and Section 8.1.3

Due to first dose cardiac monitoring Day 1 and 
Week 16 visits should be conducted in the 
morning and not on a Friday or the day before a 
site-observed holiday. See Section 10.10.3.

In preparation for the Week 16 visit, site is to 
contact participant 1-2 business days prior to 
visit to remind them they will take study 
intervention at the site. See Section 6.5. 
Study Day
-28 to -
1
1
29
57
85
113
141
169
225
281
365
477

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±7)

All screening should be done ≤ 28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
PP-NRS, Skin Pain NRS
X
X
X
X
X
X
X
X
X
X
X
All PROs and AD clinical assessments should be 
completed prior to other clinical activities and 
study intervention administration.
POEM
X
X
X
X
All PROs and AD clinical assessments should be 
completed prior to other clinical activities and 
study intervention administration.
Safety
See Section 8.3 for additional information.
Serious and nonserious 
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.4 for additional information.
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 40
1.3.2. Part 1 (DB and OLE) ET and Safety Follow-up
Visit Identifier
Abbreviations used in this table may be 
found in Appendix 12
ET
Safety Follow-Up
Notes
Safety Follow-up 1
Week 70
Safety Follow-up 2
Week 72

If a participant ends study treatment prior to Week 68 visit, the ET 
visit assessments should be performed within 1 week of the last 
dose of study treatment, unless participant is discontinued due to 
the results of first dose cardiac monitoring when ET visit should 
occur within 3 calendar days (see Section 10.10.3). ET visit is only 
applicable to participants who end study treatment prior to EoT.

The SFU 1 and SFU 2 Visits are to be conducted 2 and 4 weeks 
(± 3 days) after last dose of study treatment, respectively, for 
participants who terminate treatment early or (for Part 1 only) who 
do not elect to participate in or are not eligible to continue in the 
OLE portion.

SFU 1 OLE visit may be a site or home health visit. SFU 1 DB 
visit (only for participants who do not continue to the Part 1 OLE) 
must occur on site due to the risk of unblinding based on WBC 
laboratory values.
Visit Window (±days)
(±3)
(±3)
Complete Physical examination
X
See Section 8.3.1 for additional information.
Weight
X

See Section 8.3.1 for additional information.
Vital signs
X
X
X

To be measured prior to any blood draws that occur within the 
same collection window. 

See Section 8.3.2 for additional information.
12-Lead ECG 
X
X

See Section 8.3.3 for additional information.

ECG is only required at SFU 2 if there are abnormal, clinically 
significant results at Week 68 (EoT)/ET or if the Week 68 
(EoT)/ET ECG is missing or if the participant does not continue to 
the OLE after completion of Week 16 DB visit and Week 16 results 
of the ECG are abnormal, clinically significant or missing 
(Section 8.3.9).
PML query
X
X
X

See Section 10.11
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 41
Visit Identifier
Abbreviations used in this table may be 
found in Appendix 12
ET
Safety Follow-Up
Notes
Safety Follow-up 1
Week 70
Safety Follow-up 2
Week 72

If a participant ends study treatment prior to Week 68 visit, the ET 
visit assessments should be performed within 1 week of the last 
dose of study treatment, unless participant is discontinued due to 
the results of first dose cardiac monitoring when ET visit should 
occur within 3 calendar days (see Section 10.10.3). ET visit is only 
applicable to participants who end study treatment prior to EoT.

The SFU 1 and SFU 2 Visits are to be conducted 2 and 4 weeks 
(± 3 days) after last dose of study treatment, respectively, for 
participants who terminate treatment early or (for Part 1 only) who 
do not elect to participate in or are not eligible to continue in the 
OLE portion.

SFU 1 OLE visit may be a site or home health visit. SFU 1 DB 
visit (only for participants who do not continue to the Part 1 OLE) 
must occur on site due to the risk of unblinding based on WBC 
laboratory values.
Visit Window (±days)
(±3)
(±3)
PFT and DLCO
X
X

Visit windows for post-screening assessments are ±10 days for 
performing PFT and DLCO (where locally available) 
(Section 8.3.9). Unscheduled visit for clinical assessment and full 
PFT should be performed, as clinically indicated, for participants 
reporting any respiratory symptoms (eg, dyspnea, shortness of 
breath, chest tightness, or wheezing), preferably on the same day 
(refer to Section 10.10.4). If PFT and DLCO were performed 
within 2 weeks of the ET Visit, repeat assessments are not required 
at the ET Visit.

PFT and DLCO measurements will be performed at a pulmonary 
function laboratory or respiratory department per local regulations. 
Exceptional circumstances may apply; see Section 8.3.9.

Sites where DLCO is not available should consult the study 
medical monitor.

Only required at SFU 2 if there are abnormal, clinically significant 
results at Week 68 (EoT)/ET or if the Week 68 (EoT)/ET PFT and 
DLCO is missing or if the participant does not continue to the OLE 
portion after completion of Week 16 DB visit and Week 16 results 
of PFT and DLCO are abnormal, clinically significant or missing 
(Section 8.3.9).
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 42
Visit Identifier
Abbreviations used in this table may be 
found in Appendix 12
ET
Safety Follow-Up
Notes
Safety Follow-up 1
Week 70
Safety Follow-up 2
Week 72

If a participant ends study treatment prior to Week 68 visit, the ET 
visit assessments should be performed within 1 week of the last 
dose of study treatment, unless participant is discontinued due to 
the results of first dose cardiac monitoring when ET visit should 
occur within 3 calendar days (see Section 10.10.3). ET visit is only 
applicable to participants who end study treatment prior to EoT.

The SFU 1 and SFU 2 Visits are to be conducted 2 and 4 weeks 
(± 3 days) after last dose of study treatment, respectively, for 
participants who terminate treatment early or (for Part 1 only) who 
do not elect to participate in or are not eligible to continue in the 
OLE portion.

SFU 1 OLE visit may be a site or home health visit. SFU 1 DB 
visit (only for participants who do not continue to the Part 1 OLE) 
must occur on site due to the risk of unblinding based on WBC 
laboratory values.
Visit Window (±days)
(±3)
(±3)
Ophthalmology exam
X
X

Visit windows are ±10 days for performing ophthalmology exam as 
described in Section 8.3.10. Unscheduled assessments should be 
performed, as clinically indicated, as part of the study visit 
assessment due to complaints of decreased vision or identification 
of worsening visual acuity (Section 10.10.5). If ophthalmoscopy 
and OCT were performed within 2 weeks of the ET Visit, repeat 
assessments are not required at the ET Visit.

Only required at SFU 2 if there are abnormal, clinically significant 
results at Week 68 (EoT)/ET or if the Week 68 (EoT)/ET 
ophthalmology exam is missing or if the participant does not 
continue to the OLE after completion of Week 16 DB visit and 
Week 16 results of the ophthalmology exam are abnormal, 
clinically significant or missing (Section 8.3.10).
Contraception check
X
X
X
See Section 5.3.1 and Section 10.4 for additional information.
Laboratory Assessments
See Section 8.3.6 for additional information.
See Appendix 2 for a list of Clinical Laboratory tests to be done.
For laboratory collection volumes, see the laboratory manual.
Infectious disease serology
X
See Section 8.3.7 for hepatitis testing details. 
Only for participants requiring HBV DNA repeat testing.
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 43
Visit Identifier
Abbreviations used in this table may be 
found in Appendix 12
ET
Safety Follow-Up
Notes
Safety Follow-up 1
Week 70
Safety Follow-up 2
Week 72

If a participant ends study treatment prior to Week 68 visit, the ET 
visit assessments should be performed within 1 week of the last 
dose of study treatment, unless participant is discontinued due to 
the results of first dose cardiac monitoring when ET visit should 
occur within 3 calendar days (see Section 10.10.3). ET visit is only 
applicable to participants who end study treatment prior to EoT.

The SFU 1 and SFU 2 Visits are to be conducted 2 and 4 weeks 
(± 3 days) after last dose of study treatment, respectively, for 
participants who terminate treatment early or (for Part 1 only) who 
do not elect to participate in or are not eligible to continue in the 
OLE portion.

SFU 1 OLE visit may be a site or home health visit. SFU 1 DB 
visit (only for participants who do not continue to the Part 1 OLE) 
must occur on site due to the risk of unblinding based on WBC 
laboratory values.
Visit Window (±days)
(±3)
(±3)
TB questionnaire
X
X
X
A TB questionnaire will be administered to all participants at 
screening. The TB questionnaire will be administered at designated 
post-baseline study visits only for participants in regions which are 
above a low risk for Tuberculosis (ie, >10/100,000 incidence, which 
will be determined based on WHO country level data),. If TB is
suspected at any time during the study, participants should be 
screened. 
See Section 8.3.5 for details
Hematology
X
X
X
See Section 10.2 for details
Blood chemistry
X
X
X
Blood chemistry is only required at SFU2 if the results at SFU1 are 
abnormal, clinically significant or missing
See Section 10.2 for details
Urinalysis
X
See Section 10.2 for details
Coagulation
X
See Section 10.2 for details
Pregnancy test
X
X
Refer to Section 8.3.8 for additional guidance.
TBNK panel cell counts 
X
X
Study Intervention and Other 
Treatments
See Section 6 for additional information.
Study intervention accountability
X
Prior/concomitant treatment(s)
X
X
X
See Section 6.9 for additional information
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 44
Visit Identifier
Abbreviations used in this table may be 
found in Appendix 12
ET
Safety Follow-Up
Notes
Safety Follow-up 1
Week 70
Safety Follow-up 2
Week 72

If a participant ends study treatment prior to Week 68 visit, the ET 
visit assessments should be performed within 1 week of the last 
dose of study treatment, unless participant is discontinued due to 
the results of first dose cardiac monitoring when ET visit should 
occur within 3 calendar days (see Section 10.10.3). ET visit is only 
applicable to participants who end study treatment prior to EoT.

The SFU 1 and SFU 2 Visits are to be conducted 2 and 4 weeks 
(± 3 days) after last dose of study treatment, respectively, for 
participants who terminate treatment early or (for Part 1 only) who 
do not elect to participate in or are not eligible to continue in the 
OLE portion.

SFU 1 OLE visit may be a site or home health visit. SFU 1 DB 
visit (only for participants who do not continue to the Part 1 OLE) 
must occur on site due to the risk of unblinding based on WBC 
laboratory values.
Visit Window (±days)
(±3)
(±3)
Confirm daily use of 
emollient/moisturizers
X
Participants must apply topical emollient or moisturizer at least 
once daily for ≥ 1 week prior to Day 1 and continue daily 
application over the course of the study without change. On visit 
days during the study, participants should not apply any topical 
emollient or moisturizer until the study visit has been completed.
Assessments
See Section 8 for additional information.
Efficacy
See Section 8.2 for additional information.
EASI, IGA, BSA affected by AD
X
X
PP-NRS, Skin Pain NRS
X
X
All PROs and AD clinical assessments should be completed prior to 
other clinical activities and investigative product administration
POEM
X
All PROs and AD clinical assessments should be completed prior to 
other clinical activities and investigative product administration
Safety
See Section 8.3 for additional information.
Serious and nonserious AE
monitoring
X
X
X
See Section 8.4 for additional information.
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 45
1.3.3. Part 2 (OL Safety)
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
Treatment Period
ET 
Safety 
Follow-up
Notes
Day 
1
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
44
Week 
52
1
Wee
k 54
2
Week 
56
If a participant ends study treatment prior to 
Week 52, the ET visit assessments should be 
performed within 1 week of the last dose of study 
treatment unless participant is discontinued due 
to the results of first dose cardiac monitoring 
when ET visit should occur within 3 calendar 
days (see Section 10.10.3).

Due to first dose cardiac monitoring, the Day 1 
visit should be conducted in the morning and not 
on a Friday or the day before a site observed 
holiday. See Section 10.10.3.

The SFU 1 and SFU 2 Visits are to be conducted 
2 and 4 weeks (± 3 days) after last dose of study 
treatment, respectively.

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only. See 
Section 8.1.2 and Section 8.1.3.
Study Day
-28 to -
1
1
29
57
113
169
253
309
365

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±3)
(±3)

All screening should be done ≤28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
Informed consent
X

Informed consent should be obtained prior to 
undergoing any study-specific procedures. 

See Section 10.1.3 for additional information.
Screen for 
inclusion/exclusion 
criteria
X
X
See Section 5.1 and Section 5.2
Demographics
X

See Section 8.1.1.1.
Fitzpatrick Skin Type 
Assessment
X

See Section 8.1.1.1.
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 46
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
Treatment Period
ET 
Safety 
Follow-up
Notes
Day 
1
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
44
Week 
52
1
Wee
k 54
2
Week 
56
If a participant ends study treatment prior to 
Week 52, the ET visit assessments should be 
performed within 1 week of the last dose of study 
treatment unless participant is discontinued due 
to the results of first dose cardiac monitoring 
when ET visit should occur within 3 calendar 
days (see Section 10.10.3).

Due to first dose cardiac monitoring, the Day 1 
visit should be conducted in the morning and not 
on a Friday or the day before a site observed 
holiday. See Section 10.10.3.

The SFU 1 and SFU 2 Visits are to be conducted 
2 and 4 weeks (± 3 days) after last dose of study 
treatment, respectively.

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only. See 
Section 8.1.2 and Section 8.1.3.
Study Day
-28 to -
1
1
29
57
113
169
253
309
365

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±3)
(±3)

All screening should be done ≤28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
Medical History and 
Physical Examination
Medical history and AD 
history 
X
See Section 8.1.1.3 for details 
Complete Physical 
examination
X
X
X
Physical examinations to be completed before 
administration of study intervention.
Symptom-directed (focused) examinations may 
be performed at the other study visits as described 
in Section 8.3.1
Height
X
Weight
X
X
X

See Section 8.3.1 for additional information.
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X

To be collected prior to any blood draws that 
occur within the same collection window. 

See Section 8.3.2 for additional information.
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 47
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
Treatment Period
ET 
Safety 
Follow-up
Notes
Day 
1
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
44
Week 
52
1
Wee
k 54
2
Week 
56
If a participant ends study treatment prior to 
Week 52, the ET visit assessments should be 
performed within 1 week of the last dose of study 
treatment unless participant is discontinued due 
to the results of first dose cardiac monitoring 
when ET visit should occur within 3 calendar 
days (see Section 10.10.3).

Due to first dose cardiac monitoring, the Day 1 
visit should be conducted in the morning and not 
on a Friday or the day before a site observed 
holiday. See Section 10.10.3.

The SFU 1 and SFU 2 Visits are to be conducted 
2 and 4 weeks (± 3 days) after last dose of study 
treatment, respectively.

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only. See 
Section 8.1.2 and Section 8.1.3.
Study Day
-28 to -
1
1
29
57
113
169
253
309
365

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±3)
(±3)

All screening should be done ≤28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.

Day 1 Vital signs will be measured pre-dose and 
at Hours 1, 2, 3, and 4 (± 15 minutes) post-dose 
as part of the first dose, in clinic cardiac 
monitoring procedure (Section 8.3.2). 

If the first reading is abnormal for any 
parameters, they may be repeated up to 2 times 
during a visit (only applicable to first dose 
cardiac monitoring or cardiac monitoring during 
the treatment reinitiation following the defined 
periods of treatment interruption).
12-Lead ECG 
X
X
X
X
X
X

See Section 8.3.3 for additional information.

12-lead ECGs (with participants in the supine 
position) will be performed prior to dosing and 4 
hours post dose (± 15 minutes) on Day 1 as part 
of the first dose, in-clinic cardiac monitoring 
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 48
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
Treatment Period
ET 
Safety 
Follow-up
Notes
Day 
1
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
44
Week 
52
1
Wee
k 54
2
Week 
56
If a participant ends study treatment prior to 
Week 52, the ET visit assessments should be 
performed within 1 week of the last dose of study 
treatment unless participant is discontinued due 
to the results of first dose cardiac monitoring 
when ET visit should occur within 3 calendar 
days (see Section 10.10.3).

Due to first dose cardiac monitoring, the Day 1 
visit should be conducted in the morning and not 
on a Friday or the day before a site observed 
holiday. See Section 10.10.3.

The SFU 1 and SFU 2 Visits are to be conducted 
2 and 4 weeks (± 3 days) after last dose of study 
treatment, respectively.

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only. See 
Section 8.1.2 and Section 8.1.3.
Study Day
-28 to -
1
1
29
57
113
169
253
309
365

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±3)
(±3)

All screening should be done ≤28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
procedure (Section 10.10.3). Pre-dose ECGs are 
to be collected prior to blood sample collection.

ECG is only required at SFU 2 if there are 
abnormal, clinically significant results at Week 
52 (EoT)/ET or if the Week 52 (EoT)/ET ECG is 
missing (Section 8.3.3).
PML query
X
X
X
X
X
X
X
X
X
X
X

See Section 10.11
PFT and DLCO
X
X
X
X

Visit windows for post-screening assessments are 
±10 days for performing PFT and DLCO (where 
locally available) are described in Section 8.3.9. 
Unscheduled visit for clinical assessment and full 
PFT should be performed, as clinically indicated, 
for participants reporting any respiratory 
symptoms (eg, dyspnea, shortness of breath, 
chest tightness, or wheezing), preferably on the 
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 49
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
Treatment Period
ET 
Safety 
Follow-up
Notes
Day 
1
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
44
Week 
52
1
Wee
k 54
2
Week 
56
If a participant ends study treatment prior to 
Week 52, the ET visit assessments should be 
performed within 1 week of the last dose of study 
treatment unless participant is discontinued due 
to the results of first dose cardiac monitoring 
when ET visit should occur within 3 calendar 
days (see Section 10.10.3).

Due to first dose cardiac monitoring, the Day 1 
visit should be conducted in the morning and not 
on a Friday or the day before a site observed 
holiday. See Section 10.10.3.

The SFU 1 and SFU 2 Visits are to be conducted 
2 and 4 weeks (± 3 days) after last dose of study 
treatment, respectively.

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only. See 
Section 8.1.2 and Section 8.1.3.
Study Day
-28 to -
1
1
29
57
113
169
253
309
365

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±3)
(±3)

All screening should be done ≤28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
same day (refer to Section 10.10.4). If PFT and 
DLCO were performed within 2 weeks of the ET 
Visit, repeat assessments are not required at the 
ET Visit.

PFT and DLCO measurements will be performed 
at a pulmonary function laboratory or respiratory 
department per local regulations. Exceptional 
circumstances may apply; see Section 8.3.9.

Sites where DLCO is not available should
consult the study medical monitor. 

Only required at SFU 2 if there are abnormal 
clinically significant results at Week 52 or ET 
visit.
Ophthalmology exam
X
X
X
X

Visit windows for post screening assessments are 
±10 days for performing ophthalmology exam as 
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 50
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
Treatment Period
ET 
Safety 
Follow-up
Notes
Day 
1
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
44
Week 
52
1
Wee
k 54
2
Week 
56
If a participant ends study treatment prior to 
Week 52, the ET visit assessments should be 
performed within 1 week of the last dose of study 
treatment unless participant is discontinued due 
to the results of first dose cardiac monitoring 
when ET visit should occur within 3 calendar 
days (see Section 10.10.3).

Due to first dose cardiac monitoring, the Day 1 
visit should be conducted in the morning and not 
on a Friday or the day before a site observed 
holiday. See Section 10.10.3.

The SFU 1 and SFU 2 Visits are to be conducted 
2 and 4 weeks (± 3 days) after last dose of study 
treatment, respectively.

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only. See 
Section 8.1.2 and Section 8.1.3.
Study Day
-28 to -
1
1
29
57
113
169
253
309
365

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±3)
(±3)

All screening should be done ≤28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
described in Section 8.3.10. Unscheduled 
ophthalmic examination may also be performed, 
as clinically indicated, as part of the study visit 
assessment due to complaints of decreased vision 
or identification of worsening visual acuity 
(Section 10.10.5). If ophthalmoscopy and OCT 
were performed within 2 weeks of the ET Visit, 
repeat assessments are not required at the ET 
Visit.

Only required at SFU 2 if there are abnormal 
clinically significant results at Week 52 or ET 
visit.
C-SSRS
X
See Section 8.1.1.4 for additional information
Contraception check
X
X
X
X
X
X
X
X
X
X
X
X
See Section 5.3.1 and Section 10.4 for additional 
information.
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 51
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
Treatment Period
ET 
Safety 
Follow-up
Notes
Day 
1
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
44
Week 
52
1
Wee
k 54
2
Week 
56
If a participant ends study treatment prior to 
Week 52, the ET visit assessments should be 
performed within 1 week of the last dose of study 
treatment unless participant is discontinued due 
to the results of first dose cardiac monitoring 
when ET visit should occur within 3 calendar 
days (see Section 10.10.3).

Due to first dose cardiac monitoring, the Day 1 
visit should be conducted in the morning and not 
on a Friday or the day before a site observed 
holiday. See Section 10.10.3.

The SFU 1 and SFU 2 Visits are to be conducted 
2 and 4 weeks (± 3 days) after last dose of study 
treatment, respectively.

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only. See 
Section 8.1.2 and Section 8.1.3.
Study Day
-28 to -
1
1
29
57
113
169
253
309
365

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±3)
(±3)

All screening should be done ≤28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
Laboratory
Assessments
See Section 8.3.6 for additional information.
See Appendix 2 for a list of Clinical Laboratory 
tests to be done.
For laboratory collection volumes, see the 
laboratory manual.
Infectious Disease 
Serology
X
X
X
X
Infectious diseases serology include HIV HBV, 
HCV.
See Exclusion Criteria for details.
Week 16, Week 52 and ET only for participants 
requiring HBV DNA repeat testing .
See Section 8.3.7 for hepatitis testing details.
FSH
X
FSH at Screening, only for females with no 
menses for ≥12 months to confirm 
postmenopausal status.
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 52
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
Treatment Period
ET 
Safety 
Follow-up
Notes
Day 
1
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
44
Week 
52
1
Wee
k 54
2
Week 
56
If a participant ends study treatment prior to 
Week 52, the ET visit assessments should be 
performed within 1 week of the last dose of study 
treatment unless participant is discontinued due 
to the results of first dose cardiac monitoring 
when ET visit should occur within 3 calendar 
days (see Section 10.10.3).

Due to first dose cardiac monitoring, the Day 1 
visit should be conducted in the morning and not 
on a Friday or the day before a site observed 
holiday. See Section 10.10.3.

The SFU 1 and SFU 2 Visits are to be conducted 
2 and 4 weeks (± 3 days) after last dose of study 
treatment, respectively.

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only. See 
Section 8.1.2 and Section 8.1.3.
Study Day
-28 to -
1
1
29
57
113
169
253
309
365

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±3)
(±3)

All screening should be done ≤28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
TB test and chest 
imaging
X
X
TB testing will be done via an IGRA 
(preferentially QFT-G In-Tube test, however 
other IGRAs are permitted) in all participants 
except those with a history of active, latent, or 
inadequately treated infection with TB.
If the result of the repeat test is indeterminate, 
participants may be screened using the 
Mantoux/PPD skin test with study medical 
monitor approval. If the Mantoux PPD tuberculin 
skin test is given, the participant must return 
between 48-72 hours post-injection for induration 
evaluation.
TB testing (IGRA and PPD, if needed) will be 
conducted at a certified local laboratory unless 
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 53
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
Treatment Period
ET 
Safety 
Follow-up
Notes
Day 
1
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
44
Week 
52
1
Wee
k 54
2
Week 
56
If a participant ends study treatment prior to 
Week 52, the ET visit assessments should be 
performed within 1 week of the last dose of study 
treatment unless participant is discontinued due 
to the results of first dose cardiac monitoring 
when ET visit should occur within 3 calendar 
days (see Section 10.10.3).

Due to first dose cardiac monitoring, the Day 1 
visit should be conducted in the morning and not 
on a Friday or the day before a site observed 
holiday. See Section 10.10.3.

The SFU 1 and SFU 2 Visits are to be conducted 
2 and 4 weeks (± 3 days) after last dose of study 
treatment, respectively.

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only. See 
Section 8.1.2 and Section 8.1.3.
Study Day
-28 to -
1
1
29
57
113
169
253
309
365

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±3)
(±3)

All screening should be done ≤28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
unavailable in which case the Central Lab will be 
used.
Chest images (posterior, anterior and lateral 
views) are required for all participants. Chest 
images or other appropriate diagnostic image (ie 
CT or MRI) may be performed up to 12 weeks 
prior to Study Day 1. Official reading must be 
located and available in the source 
documentation.
TB test and Chest Imaging at Week 52 only for 
participants in regions which are above a low risk 
for TB.
See Section 8.3.4 and Section 8.3.5
TB questionnaire
X
X
X
X
X
X
X
X
X
X
X
X
A TB questionnaire will be administered to all 
participants at screening. The TB questionnaire 
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 54
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
Treatment Period
ET 
Safety 
Follow-up
Notes
Day 
1
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
44
Week 
52
1
Wee
k 54
2
Week 
56
If a participant ends study treatment prior to 
Week 52, the ET visit assessments should be 
performed within 1 week of the last dose of study 
treatment unless participant is discontinued due 
to the results of first dose cardiac monitoring 
when ET visit should occur within 3 calendar 
days (see Section 10.10.3).

Due to first dose cardiac monitoring, the Day 1 
visit should be conducted in the morning and not 
on a Friday or the day before a site observed 
holiday. See Section 10.10.3.

The SFU 1 and SFU 2 Visits are to be conducted 
2 and 4 weeks (± 3 days) after last dose of study 
treatment, respectively.

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only. See 
Section 8.1.2 and Section 8.1.3.
Study Day
-28 to -
1
1
29
57
113
169
253
309
365

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±3)
(±3)

All screening should be done ≤28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
will be administered at designated post-baseline 
visits only for participants residing in regions 
which are above a low risk for Tuberculosis (ie, 
>10/100,000 incidence, which will be determined 
based on WHO country level data)If TB is 
suspected at any time during the study, 
participants should be screened.
See Section 8.3.5 for details
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
When dosing is administered during a visit, 
samples must be collected prior to dosing.
See Section 10.2 for details
Blood chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry is only required at SFU2 if the 
results at SFU1 are abnormal, clinically 
significant or missing.
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 55
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
Treatment Period
ET 
Safety 
Follow-up
Notes
Day 
1
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
44
Week 
52
1
Wee
k 54
2
Week 
56
If a participant ends study treatment prior to 
Week 52, the ET visit assessments should be 
performed within 1 week of the last dose of study 
treatment unless participant is discontinued due 
to the results of first dose cardiac monitoring 
when ET visit should occur within 3 calendar 
days (see Section 10.10.3).

Due to first dose cardiac monitoring, the Day 1 
visit should be conducted in the morning and not 
on a Friday or the day before a site observed 
holiday. See Section 10.10.3.

The SFU 1 and SFU 2 Visits are to be conducted 
2 and 4 weeks (± 3 days) after last dose of study 
treatment, respectively.

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only. See 
Section 8.1.2 and Section 8.1.3.
Study Day
-28 to -
1
1
29
57
113
169
253
309
365

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±3)
(±3)

All screening should be done ≤28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
See Section 10.2 for details
Urinalysis
X
X
X
See Section 10.2 for details
Coagulation
X
X
X
See Section 10.2 for details
Pregnancy test
X
X
X
X
X
X
X
X
X
X
X
A serum pregnancy test for β-hCG will be 
performed on women of childbearing potential at 
Screening to determine eligibility. A urine 
pregnancy test (β hCG) will be performed at all 
other indicated visits unless a serum sample is 
required per investigator request. On Day 1, a 
urine pregnancy test must be performed and result 
with a negative result prior to dosing. For visits 
that occur more than 4 weeks apart, participants 
must perform a home pregnancy test.  Site 
personnel are expected to contact the participant 
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 56
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
Treatment Period
ET 
Safety 
Follow-up
Notes
Day 
1
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
44
Week 
52
1
Wee
k 54
2
Week 
56
If a participant ends study treatment prior to 
Week 52, the ET visit assessments should be 
performed within 1 week of the last dose of study 
treatment unless participant is discontinued due 
to the results of first dose cardiac monitoring 
when ET visit should occur within 3 calendar 
days (see Section 10.10.3).

Due to first dose cardiac monitoring, the Day 1 
visit should be conducted in the morning and not 
on a Friday or the day before a site observed 
holiday. See Section 10.10.3.

The SFU 1 and SFU 2 Visits are to be conducted 
2 and 4 weeks (± 3 days) after last dose of study 
treatment, respectively.

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only. See 
Section 8.1.2 and Section 8.1.3.
Study Day
-28 to -
1
1
29
57
113
169
253
309
365

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±3)
(±3)

All screening should be done ≤28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
every 4 weeks to confirm the home pregnancy 
test was taken, confirm participant continues to 
use contraception correctly, and document the 
pregnancy test results and contraception 
discussion in source. A home pregnancy test is 
required at W12, W20, W28, W32, W40, W48. If 
home pregnancy testing is not allowed per local 
regulations, pregnancy testing will be performed 
onsite during an unscheduled visit.
See Section 8.3.8 for details
TBNK panel cell counts
X
X
X
X
X
X
When dosing is administered during a visit, 
TBNK samples must be collected prior to dosing.
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 57
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
Treatment Period
ET 
Safety 
Follow-up
Notes
Day 
1
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
44
Week 
52
1
Wee
k 54
2
Week 
56
If a participant ends study treatment prior to 
Week 52, the ET visit assessments should be 
performed within 1 week of the last dose of study 
treatment unless participant is discontinued due 
to the results of first dose cardiac monitoring 
when ET visit should occur within 3 calendar 
days (see Section 10.10.3).

Due to first dose cardiac monitoring, the Day 1 
visit should be conducted in the morning and not 
on a Friday or the day before a site observed 
holiday. See Section 10.10.3.

The SFU 1 and SFU 2 Visits are to be conducted 
2 and 4 weeks (± 3 days) after last dose of study 
treatment, respectively.

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only. See 
Section 8.1.2 and Section 8.1.3.
Study Day
-28 to -
1
1
29
57
113
169
253
309
365

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±3)
(±3)

All screening should be done ≤28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
Study Intervention and 
Other Treatments
See Section 6 for additional information.
Dispense study 
intervention
X
X
X
X
X
X
X
See Section 6.1 for additional information.
Study intervention 
administration at site
X

Extended 4-hour visit on Day 1 due to cardiac 
monitoring. May also required be on Day 2 
(Section 10.10.3).

Also required on the first day of treatment re-
initiation after a protocol-predefined treatment 
interruption (Section 7.1.7).
Study intervention 
accountability
X
X
X
X
X
X
X
X
In the event a participant is not compliant with 
the assigned treatment regimen, the participant 
should be retrained on proper study treatment 
administration.
090177e19d7b83d8\Approved\Approved On: 17-May-2023 17:10 (GMT)


Etrasimod
Protocol C5041005
Final Protocol Amendment 2, 17 May 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Protocol Template Phase 1 2 3 4 (01 April 2022)
Page 58
Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
Treatment Period
ET 
Safety 
Follow-up
Notes
Day 
1
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
44
Week 
52
1
Wee
k 54
2
Week 
56
If a participant ends study treatment prior to 
Week 52, the ET visit assessments should be 
performed within 1 week of the last dose of study 
treatment unless participant is discontinued due 
to the results of first dose cardiac monitoring 
when ET visit should occur within 3 calendar 
days (see Section 10.10.3).

Due to first dose cardiac monitoring, the Day 1 
visit should be conducted in the morning and not 
on a Friday or the day before a site observed 
holiday. See Section 10.10.3.

The SFU 1 and SFU 2 Visits are to be conducted 
2 and 4 weeks (± 3 days) after last dose of study 
treatment, respectively.

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only. See 
Section 8.1.2 and Section 8.1.3.
Study Day
-28 to -
1
1
29
57
113
169
253
309
365

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±3)
(±3)

All screening should be done ≤28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
Prior/concomitant 
treatment(s)
X
X
X
X
X
X
X
X
X
X
X
X
See Section 6.9 for additional information
Confirm daily use of 
emollient/moisturizers
X
X
X
X
X
X
X
X
X
Participants must apply topical emollient or 
moisturizer at least once daily for ≥1 week prior 
to Day 1 and continue daily application over the 
course of the study without change. On visit days 
during the study, participants should not apply 
any topical emollient or moisturizer until the 
study visit has been completed.
Assess treatment 
continuation criteria
X
Participants who do not meet the pre-specified 
continuation criteria (EASI-50) will be 
discontinued at Week 16 and will complete ET 
visit procedures. Refer to Section 7.1.5 of the 
protocol for details.
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Visit Identifier
Abbreviations used in this 
table may be found in 
Appendix 12
Screen
Treatment Period
ET 
Safety 
Follow-up
Notes
Day 
1
Week 
4
Week 
8
Week 
16
Week 
24
Week 
36
Week 
44
Week 
52
1
Wee
k 54
2
Week 
56
If a participant ends study treatment prior to 
Week 52, the ET visit assessments should be 
performed within 1 week of the last dose of study 
treatment unless participant is discontinued due 
to the results of first dose cardiac monitoring 
when ET visit should occur within 3 calendar 
days (see Section 10.10.3).

Due to first dose cardiac monitoring, the Day 1 
visit should be conducted in the morning and not 
on a Friday or the day before a site observed 
holiday. See Section 10.10.3.

The SFU 1 and SFU 2 Visits are to be conducted 
2 and 4 weeks (± 3 days) after last dose of study 
treatment, respectively.

Home health and/or telehealth visits may apply 
for certain extenuating circumstances only. See 
Section 8.1.2 and Section 8.1.3.
Study Day
-28 to -
1
1
29
57
113
169
253
309
365

Day relative to start of study intervention 
(Day 1).
Visit Window (±days)
NA
NA
(±5)
(±5)
(±5)
(±7)
(±7)
(±7)
(±7)
(±3)
(±3)

All screening should be done ≤28 days before 
the first dose. 

See Section 8.4.3 for follow-up AE and SAE 
assessments.
Assessments
See Section 8 for additional information.
Efficacy
See Section 8.2 for additional information.
EASI, IGA, BSA 
affected by AD
X
X
X
X
X
X
X
X
X
X
X
PP-NRS, Skin pain NRS
X
X
X
X
X
X
X
X
X
X
All PROs and AD clinical assessments should be 
completed prior to other clinical activities and 
investigative product administration.
POEM
X
X
X
X
All PROs and AD clinical assessments should be 
completed prior to other clinical activities and 
investigative product administration
Safety
See Section 8.3 for additional information.
Serious and nonserious 
AE monitoring
X
X
X
X
X
X
X
X
X
X
X
X
See Section 8.4 for additional information.
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2. INTRODUCTION
Etrasimod (also known as APD334) is a synthetic, next generation, selective modulator of 
S1P1,4,5 in development as a once daily oral treatment for immune mediated inflammatory 
disorders.
S1P1 is a cell surface expressed G protein coupled receptor shown to regulate lymphocyte 
egress from lymphoid tissues. Upon binding to S1P1, synthetic receptor modulators, such as 
etrasimod, have been observed to act as functional antagonists by inducing sustained receptor 
internalization. Loss of cell surface expressed S1P1 prevents cells from migrating along S1P 
gradients and results in lymphocyte retention within lymphoid tissue, thus lowering the 
amount of peripheral blood lymphocytes available for recruitment to sites of inflammation.2
This reduction in infiltrating lymphocytes may result in decreases in the release of 
proinflammatory cytokines, signaling proteins known to mediate tissue inflammation.3
Modulation of the S1P/S1P receptor axis offers a potential therapeutic approach to the 
management of a variety of immune mediated disorders. Consistent with this hypothesis, S1P 
receptor modulators have been shown to be clinically beneficial in multiple T cell mediated 
diseases including, but not limited to, inflammatory bowel disease, multiple sclerosis, and 
plaque psoriasis. 2,4-7 Etrasimod may therefore provide therapeutic benefit to patients with 
AD.
Dendritic cells and T cells play critical roles in driving AD immunopathology. 8,9 In AD, skin 
resident dendritic cells readily engulf foreign antigens and allergens that have penetrated the 
perturbed dermal barrier, and traffic to the lymph nodes, where they activate and polarize 
naïve T cells.10 Once activated, T cells exit lymphoid organs, migrate to the skin, and secrete 
inflammatory cytokines and chemokines. Activated T cells can directly drive skin 
inflammation, or recruit other immune cells, including eosinophils and mast cells, that further 
contribute to the inflammatory processes.
Trafficking of dendritic cells, T cells, and eosinophils have all been shown to be modulated 
in part by functional antagonism of S1P1. In addition to the effect of reducing circulating 
lymphocytes described above, S1P1 has been shown to modulate the trafficking of dendritic 
cells towards draining lymph nodes 11,12and the egress of eosinophils from the bone 
marrow.13 The role of S1P1 functional antagonism in the immune cells implicated in AD 
pathogenesis, and therefore the potential to reduce skin inflammation, supports the 
development of etrasimod as a potential therapeutic for AD.
A complete summary of the nonclinical and clinical data relevant to etrasimod and its study 
in human participants is provided in the current edition of the etrasimod IB.
2.1. Study Rationale 
Etrasimod is a S1PRM and is being developed as an oral treatment for patients with 
moderate-to-severe AD. Part 1 of this study will evaluate efficacy of etrasimod therapy QD 
and long-term safety in participants with moderate-to-severe AD with a history of a prior 
systemic therapy failure. Part 2 of this study will evaluate the long-term safety of etrasimod 
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therapy QD in participants with moderate-to-severe AD with a history of a prior systemic 
therapy failure.
2.2. Background 
AD, also known as atopic eczema, is the most common chronic relapsing, inflammatory skin 
disease. 9,14 The lifetime prevalence of AD is 10 to 20% in developed nations with a 2- to 3-
fold increase in prevalence during the past decades in industrialized countries.15 AD is 
characterized by chronic cutaneous inflammation and perturbed epidermal-barrier function 
resulting in dry, red skin and intense itch. 8,14,16,17 Essential features for diagnosis of AD are 
pruritus, eczematous dermatitis, and a chronic or relapsing history of disease. 8,14 The 
pathogenesis of AD is thought to stem from the mutually reinforcing interaction between a 
disrupted epidermal barrier and an inappropriate immune response in the skin. 14,18 Epidermal 
barrier disruption facilitates allergen penetration, IgE sensitization, and bacterial colonization 
(particularly Staphylococcus aureus), all of which induce persistent type 2 helper T cell 
responses. Although an individual’s predisposition to AD is not fully understood, it is likely 
determined by a combination of genetic, environmental, and immunologic factors. 19,20
AD is a major cause of skin-related disability globally21 with a substantial burden of disease 
on the patient.22 Patients with AD are more likely to have other allergic or atopic conditions. 
In a 2016 study of 380 adults with moderate-to-severe AD, 51.3% had allergic rhinitis, 
40.3% had asthma, 24.2% had allergic conjunctivitis, and 60.5% had other allergies.23 Recent 
research also shows AD is associated with a significantly increased risk of anxiety and 
depression.24 The disease burden of those with AD significantly impacts quality of life and 
patients report that their condition affects social and leisure activities (43.9%), work or 
studying (41.8%), and clothing choice (57.9%).23 AD is difficult to treat due to its chronic, 
heterogeneous and relapsing-remitting nature, and it often requires the polypharmacy 
approach to effectively manage signs and symptoms long term.25 The goals of treatment are 
to reduce AD signs (eg, lesions, erythema) and symptoms (pruritus and pain). 
Currently, the available systemic treatments in the US and European countries include 
conventional immunosuppressants (eg, oral corticosteroid, cyclosporine, azathioprine, 
mycophenolate mofetil, methotrexate), biologics (eg, dupilumab) and JAK inhibitors (eg, 
baricitinib, abrocitinib and upadacitinib).26-28 Overall, these systemic agents show varying 
degrees of efficacy and safety and there is no single systemic option that is widely accepted 
as standard of care for AD. Many of the currently available therapies for moderate-to-severe 
AD are limited to short-term or intermittent use due to inconvenience (phototherapy) or 
patient nonadherence due to factors including side effect intolerance. 29,30 In consideration of 
the current gaps in the AD treatment paradigm, there remains a significant unmet need for 
effective and safe treatments for AD.
2.3. Benefit/Risk Assessment
Etrasimod, an investigational, oral, and once daily S1P receptor modulator, offers an 
alternative treatment option for patients with moderate-to severe AD. The use of S1P 
receptor modulation for AD is supported by literature indicating association of S1P with a 
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variety of chronic itchy and inflammatory skin dermatoses including AD, allergic contact 
dermatitis, psoriasis, scleroderma as well as neuropathic pain.31
The safety and tolerability of etrasimod have been evaluated in Phase 1 studies with healthy 
adult participants at single doses up to 5 mg and repeat doses up to 4 mg once daily. 
Etrasimod 2 mg has been/is being evaluated in multiple indications including AD, AA, UC, 
CD and EoE. 
Study APD334-201 was a Phase 2, multicenter, randomized, double-blinded, 
placebo-controlled study designed to assess the safety and efficacy of once daily etrasimod in 
participants with moderate-to-severe AD that could not be adequately controlled with topical 
medications. Participants were randomized 1:1:1 to etrasimod 1 mg, etrasimod 2 mg, or 
placebo taken orally once daily during a 12-week double-blind treatment period with a 
4-week safety follow-up period following the last dose of study treatment. After the 4 week 
safety follow-up period, eligible participants could enter an OLE treatment period to receive 
etrasimod 2 mg once daily for 52 weeks. Compared with placebo, treatment with etrasimod 2 
mg resulted in a greater percentage of participants achieving clear or almost clear skin per 
vIGA assessment at Week 12. The overall safety profile of etrasimod 2 mg was consistent 
with the safety demonstrated in healthy participants. The most common AEs for participants 
of >5% and greater than placebo were lymphocyte count decreased, UTI, nausea, 
constipation, back pain and dizziness. Maintenance of effect was observed in the 52-week 
OLE with no new clinically relevant safety signals. In the OLE, the most common AEs for 
>5% of participants were lymphocyte count decreased, headache, SARS-CoV-2 test positive 
and dermatitis atopic.
A clinically meaningful benefit and an acceptable safety profile for 2 mg etrasimod dose was 
demonstrated in the Phase 2b study (Arena study APD334-201) in adult participants with 
moderate-to-severe AD.
In conclusion, based on the overall exposure data to date, the safety profile of etrasimod 2 mg 
remains favorable and supports further development in participants with AD and the current 
Phase 2/3 study. The Phase 2/3 AD program is designed to exclude participants at high risk 
for S1P-related adverse events, proactively monitor and assess safety parameters, and 
includes predefined stopping criteria to manage patient safety as described in Section 7. The 
newly defined population for this study is adults with refractory, moderate-to-severe AD 
whose disease is not adequately controlled with other systemic drug products, including 
biologics, or when use of those therapies is inadvisable, for whom the benefit/risk ratio may 
be favorable based on the etrasimod MOA and totality of etrasimod 2 mg data.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of etrasimod may be found in the IB, which is the SRSD for this study. Refer 
to the Study Intervention table in Section 6.1 for a complete description of SRSDs.
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2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk.
Mitigation Strategy
Study Intervention(s) Etrasimod
S1P receptor modulator-related effects (class effect 
of AEs observed with S1P receptor modulators) 
may be observed.
Limited long-term safety data of S1P receptor 
modulators is available in the AD population as 
there are no approved drugs in this class for 
dermatologic conditions.
Adverse events associated with S1P receptor 
modulators are well characterized in the adult MS 
and UC population. 
AESIs associated with S1P receptor modulators 
(class labeling) include cardiovascular events (eg, 
bradycardia, atrioventricular conduction delay and 
hypertension), infections (severe infections, 
opportunistic infections, Herpes simples and 
Herpes zoster), macular edema, pulmonary events 
(airflow obstruction or decreased gas exchange), 
liver injury, malignancies, and PRES. 
The totality of clinical data up to date in several 
dermatological and non-dermatological 
inflammatory indications indicate that 2 mg 
etrasimod is well-tolerated with no clinically 
significant safety signals.
The proposed Phase 2/3 Study includes the 
following risk mitigation methods: 

Exclusion criteria for participants with elevated 
risk factors for adverse events associated with 
S1P receptor modulators 

Extensive safety monitoring measures for 
potential S1P receptor modulator drug 
reactions, including first dose reactions and 
active query for signs and symptoms of PML

Unscheduled assessments, as clinically 
indicated, for participants reporting any 
respiratory symptoms (eg, dyspnea, shortness 
of breath, chest tightness or wheezing) and 
due to complaints of decreased vision or 
identification of worsening visual acuity 

Clearly defined stopping criteria for clinical 
findings associated with S1P receptor 
modulators. 

An E-DMC will be used throughout the study 
(Part 1 and Part 2) to review safety data.
S1P receptor modulator-specific lymphocyte level 
decreases.
Dose-dependent reductions in peripheral 
lymphocyte counts is an expected PD effect of 
etrasimod. A clinically significant reduction in 
peripheral lymphocyte count, especially CTCAE 
Grade 4, may increase the risk of infections in 
some participants.
The PD effect (lymphocyte lowering) of etrasimod 
is reversible following treatment discontinuation. 
In Arena Study APD334-201 treatment with 
etrasimod resulted in a dose-dependent decrease in 
lymphocyte count and quick reversal (within 2 – 4 
Participants with conditions or risk factors related 
to infection or immune function will be excluded 
from the study.
Participants will be assessed for safety including 
infections at regular intervals throughout the study 
to identify and mitigate the potential risks.
In the completed Phase 2 study APD334-201, 
including a 12-week DB treatment period and a 
52-week OLE, there were no clinically relevant 
safety signals related to infections.
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk.
Mitigation Strategy
weeks) to normal levels following cessation of 
drug treatment, which is consistent with etrasimod 
clinical studies in other inflammatory conditions. 
Serial assessments of white blood cell count and 
differential will be performed in this study to 
assess the risk for serious and atypical infections.
Pre-defined stopping/drug interruption criteria are 
included in the design of this Study for CTCAE 
Grade 4 lymphopenia (ALC < 0.2 × 109 cells/L).
First dose cardiac effect. 
The S1P receptor modulator class of drugs is 
associated with an expected, on-target effect of 
reducing HR when first dosed.
The totality of clinical data up to date in several 
inflammatory indications indicate that 2 mg 
etrasimod is well-tolerated with modest HR
reduction that is maximal on the first day of dosing 
without major clinically relevant cardiac safety 
events.
Participants with elevated cardiac risk factors will 
be excluded from participation in the study. 
4-hour first dose cardiac monitoring is included in 
Part 1 (Day 1 and Week 16) and Part 2 (Day 1), 
including for participants with etrasimod re-
initiation after a temporary interruption/re-
initiation.
Participants with cardiac effects associated with 
first dose will be required to permanently 
discontinue study intervention.
Reproductive and developmental toxicity.
The effects of etrasimod on human fertility and 
embryonic development are unknown. Nonclinical 
reproductive and developmental toxicity studies of 
etrasimod combined with data and knowledge on 
the role of S1P1 in vascular embryogenesis 
demonstrate embryo fetal toxicity of etrasimod if 
used during pregnancy. Etrasimod is potentially 
teratogenic in humans with a low genotoxic 
potential. 
There is no margin of safety for these findings 
compared to therapeutic exposure range. 
Etrasimod should not be given to women who are 
pregnant, lactating, or breast-feeding.
WONCBP or WOCBP status will be determined at 
screening. WOCBP who are pregnant, lactating, or 
breast-feeding will be excluded from this study.
WOCBP will be eligible only if she and her 
partner(s) agree(s) with the contraceptive method 
as described in Section 5.3.1 and Section 10.4
throughout the study period and for at least 
28 days after the last dose of etrasimod. 
Males with female partners of childbearing 
potential must agree to use contraception 
throughout the study period and for at least 
28 days after the last dose of etrasimod.
Pregnancy will be monitored monthly, including 
follow-up visit. 
Exposure during pregnancy and breastfeeding 
should be reported to Pfizer Safety. Participants 
who become pregnant will be permanently 
discontinued from study intervention.
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk.
Mitigation Strategy
Potential risk of etrasimod on vaccine effect
Use of live attenuated vaccines while taking an 
S1P receptor modulator carries a theoretical risk of 
infection and should therefore be avoided during 
treatment and for a defined period of time after 
stopping treatment.
Currently, there are no data on the effect of 
etrasimod treatment on vaccine efficacy and safety 
including severe acute respiratory system 
coronavirus 2 (SARs CoV 2) vaccines to protect 
against COVID-19.
Live attenuated vaccines are prohibited during 
study treatment, 6 weeks prior to baseline (Day 1) 
and for 4 weeks after the last dose of study 
treatment.
It is recommended that participants receive a 
vaccination against COVID-19 to decrease the risk 
of contracting SARs-CoV-2.
Interactions with other medicinal products and 
other forms of interaction
Based on data from CYP-mediated clinical drug 
interaction studies, moderate increases in exposure 
of etrasimod were observed when multiple CYPs 
were inhibited (fluconazole) or decreased when 
multiple CYPs were induced (rifampin). Thus, the 
use of moderate or strong inhibitors or inducers 
that inhibit or induce at least 2 of the following is 
not recommended: cytochrome P450 CYP2C8, 
CYP2C9, and CYP3A4. 
Caution should be used during concomitant 
administration of immunomodulatory or 
immunosuppressive therapies with etrasimod due 
to the risk of additive immune effects during such 
therapy and in the weeks following administration.
To minimize potential DDI, drugs known to inhibit 
or induce the following cytochrome P450 
enzymes, CYP2C8, CYP2C9, and CYP3A4 are 
prohibited within 4 weeks prior to baseline 
(Day 1):
•
Moderate to strong inducers/inhibitors of two 
or more of the CYP enzymes above (eg, 
fluconazole)
To minimize the risk of additive immune effects 
during the study, mandatory washout periods for 
immune-modulating and immunosuppressive 
therapies will be implemented as described in 
Section 6.9.2.
Study Procedures 
Worsening of AD
Participants discontinuing their AD treatment 
during the washout period may experience the 
worsening of their AD symptoms.
A worsening of AD may occur during the 
treatment period and follow-up period.
Participants may discontinue treatment or 
withdraw from the study at any time for any 
reason.
Participants meeting withdrawal/discontinuation 
criteria (Section 7.2) may be able to use alternative 
treatments after withdrawal from the study.
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk.
Mitigation Strategy
Participants will be assessed for safety at regular 
intervals throughout the study to identify and 
mitigate the risks the potential risks.
Other 
The COVID-19 pandemic/regional emergency 
situations may pose risks to study participation 
Participants may be at increased safety risk by 
attending a clinic visit.
Use of telehealth and/or home health visits will be 
utilized in the study to minimize potential 
exposure of trial participants to emergency 
situations (Section 8.1.2 and Section 8.1.3). 
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2.3.2. Benefit Assessment
Oral administration of etrasimod is anticipated to provide a therapeutic benefit in the 
treatment of AD by targeting the signaling of cytokines in Th2 response through the 
reduction of dendritic cell trafficking to lymph nodes, sequestration of lymphocytes and 
reduction of levels of circulating T cells. In a Phase 2b clinical Study (Arena study 
APD334-201), efficacy for 2 mg etrasimod was shown in participants with moderate-to-
severe AD with a history of a topical treatment failure. In the DB study portion statistically 
significant improvements were reported at Week 12 for the number of participants with 
vIGA of 0 or 1 and a 2-point improvement from baseline (29.8% vs 13.0% P=0<0.05), 
≥4-point change in DLQI (69.8% vs 55.6% P<0.05) and ≥4-point change in POEM (56.7% 
vs 37.0% P<0.05). Further improvement and maintenance of response was observed in the 
52-week OLE period of the study for the key endpoints of number of participants with vIGA 
of 0 or 1 and a 2-point improvement from baseline, EASI-75 and ≥4-point improvement in 
PP-NRS. Other S1P receptor modulators are being currently studied in other dermatological 
conditions including AD,32 and an S1P receptor modulator ponesimod has demonstrated 
efficacy in the treatment of psoriasis.33
Similar clinical response was shown for etrasimod in participants with moderate-to-severe 
AD with a history of a prior systemic treatment failure vs without a history of a prior 
systemic treatment failure. Participants in this study, ie participants with moderate-to-severe 
AD with a history of a prior systemic therapy failure, may, therefore, receive a beneficial 
effect, in addition to regular intensive clinical trial assessment to support management of 
their AD.
2.3.3. Overall Benefit/Risk Conclusion
A clinically meaningful benefit for 2 mg QD dose of etrasimod was demonstrated in the 
Phase 2b clinical Study (Arena Study APD334-201) in adult participants with moderate-to-
severe AD. Compared with placebo, treatment with 2 mg QD dose of etrasimod resulted in a 
greater percentage of participants achieving clear or almost clear skin per vIGA assessment 
at Week 12. Maintenance of effect and continuous efficacy was observed in the 52-Week 
OLE with no new clinically relevant safety signals. The potential risks of treatment include 
those that were noted in Phase 2b and/or those based on the pharmacology of S1P receptor 
modulators and include cardiovascular events (bradycardia, AV conduction delay, 
hypertension), macular edema, pulmonary disorders (airflow obstruction, decreased gas 
exchange), infections (severe infections, opportunistic infections, herpes simplex and herpes 
zoster), liver injury (liver transaminase elevation, bilirubin elevation), PRES and 
malignancies. Considering the measures to minimize risk to study participants, the potential 
risks identified in association with 2 mg QD dose of etrasimod are justified by the anticipated 
benefits that may be afforded to participants with AD.
The Benefit/Risk balance of etrasimod is considered favorable and supported by:

The favorable safety profile for etrasimod to date based on non-clinical studies and Arena 
clinical Study APD334-201 in AD.
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
The totality of safety data for etrasimod to date including the long-term safety data based 
on an ongoing clinical study in AA (Arena Study APD334-205) with etrasimod 2 mg and 
3 mg. 

The totality of safety and efficacy data from the Phase 3 UC Program.

The expected efficacy of etrasimod for the treatment of AD based on pre-clinical and 
translational data generated with etrasimod and efficacy in Arena clinical Study 
APD334201

The expected efficacy of etrasimod for the treatment of moderate-to-severe AD with a 
history of a prior systemic therapy failure based on the post hoc efficacy analysis of data 
from Arena clinical Study APD334-201 
C5041005 study includes the appropriate safety monitoring and risk management measures 
including the exclusion of participants with increased risk, ongoing safety monitoring by the 
investigator and the sponsor during the study (e-DMC), and prespecified stopping criteria for 
participants with potential safety risks. In conclusion, Pfizer considers that the clinical 
experience to date with 2 mg QD dose of etrasimod support the continued development of 
etrasimod for the treatment of AD and the initiation of the Phase 2/3 Study C5041005. 
Additional background information on etrasimod can be found in the current version of the 
IB, especially the Summary of Data and Guidance for the Investigator (Section 6 of the 
Arena IB).
Taking into account the measures to minimize risk to study participants, the potential risks 
identified in association with etrasimod are justified by the anticipated benefits that may be 
afforded to participants with AD.
3. OBJECTIVES, ENDPOINTS, AND ESTIMANDS
Objectives
Endpoints
Estimands
Primary: 
Primary:
Primary: 
Part 1 DB: To evaluate the 
efficacy of etrasimod, 2 mg, 
QD versus placebo in adult 
participants with moderate-to-
severe AD and a history of a 
prior systemic therapy failure.
Proportion of participants 
achieving IGA of clear (0) or 
almost clear (1) (on a 5-point 
scale) and a reduction of ≥ 2 
points from baseline at 
Week 16. 
Estimand E1 (binary 
endpoints): The difference in 
the proportions of the binary 
endpoint between etrasimod, 2 
mg, QD and placebo in 
patients with moderate-to-
severe AD and a history of a 
prior systemic therapy failure. 
More details of Estimand E1 
are described in Section 
9.1.1.1.
Part 1 OLE and Part 2: To 
evaluate the long-term safety 
of oral etrasimod, 2 mg, QD in 
adult participants with 

Incidence and severity of 
treatment-emergent AEs, AEs 
leading to study treatment 
Not applicable.
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Objectives
Endpoints
Estimands
moderate-to-severe AD and a 
history of a prior systemic 
therapy failure.
discontinuation, SAEs, and 
AESIs.

Incidence of clinically 
significant changes in clinical 
laboratory values, ECG 
measurements and vital signs.
Secondary: 
Secondary:
Secondary: 
Part 1 DB: To evaluate the 
efficacy of etrasimod, 2 mg, 
QD based on additional 
measures in adult participants 
with moderate-to-severe AD 
and a history of a prior 
systemic therapy failure.

Proportion of participants 
achieving a EASI-75 at 
Week 16.

Percent change from baseline in 
EASI at Week 16.
Estimand E1 described above.
Estimand E2: The mean 
difference in percent change 
from baseline in EASI between 
etrasimod, 2 mg, QD and 
placebo in patients with 
moderate-to-severe AD and a 
history of a prior systemic 
therapy failure. More details of 
Estimand E2 are described in 
Section 9.1.1.2.
Exploratory: 
Exploratory: 
Exploratory: 
Part 1 DB: To evaluate the 
efficacy of etrasimod, 2 mg, 
QD based on additional 
measures in adult participants 
with moderate-to-severe AD 
and a history of a prior 
systemic therapy failure.

Proportion of participants 
achieving IGA of clear (0) or 
almost clear (1) (on a 5-point 
scale) and a reduction of ≥ 2 
points from baseline at all 
timepoints except Week 16.

Proportion of participants 
achieving a EASI-75 at all 
timepoints except Week 16.

Percent change from baseline in 
EASI at all timepoints except 
Week 16.

Proportion of participants 
achieving ≥ 4-point reduction in 
PP-NRS score from baseline at 
all timepoints.

Proportion of participants 
achieving ≥ 4-point reduction in 
Skin Pain NRS score from 
baseline at all timepoints.
Estimand E1 described above, 
for all binary endpoints.
Estimand E2: described above, 
for all continuous endpoints.
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Objectives
Endpoints
Estimands

Proportion of participants 
EASI-90 at all timepoints.

Proportion of participants 
achieving ≥ 4-point reduction in 
POEM from baseline at 
Week 16.
Part 1 OLE and Part 2: To 
evaluate the long-term efficacy 
of oral etrasimod, 2 mg, QD in 
adult participants with 
moderate-to-severe AD and a 
history of a prior systemic 
therapy failure.
Baseline for Part 1 is the pre-dose 
Day 1 in Part 1. Baseline for Part 2 
is the pre-dose Day 1 in the Part 2 
OL Safety phase.

Proportion of participants 
achieving EASI-75 at all 
scheduled timepoints.

Proportion of participants 
achieving IGA of clear (0) or 
almost clear (1) (on a 5-point 
scale) at all scheduled 
timepoints.

Percent change from baseline in 
EASI at all scheduled 
timepoints.

Proportion of participants 
achieving ≥ 4-point reduction in 
PP-NRS score from baseline at 
all scheduled timepoints.

Proportion of participants 
achieving ≥ 4-point reduction in 
Skin Pain NRS score from 
baseline at all scheduled 
timepoints.

Proportion of participants 
EASI-90 at all scheduled 
timepoints.
Change from baseline in POEM 
at all scheduled timepoints.
Not applicable.
4. STUDY DESIGN
4.1. Overall Design
This is a two-part study with Part 1 being 16 week, randomized, DB, placebo controlled, with 
an OLE, to assess efficacy and safety of 2 mg etrasimod administered orally, QD in 
participants with refractory, moderate-to-severe AD, whose disease is not adequately 
controlled with other systemic drug products, including biologics, or when use of those 
therapies is inadvisable (ie, participants with a history of a prior systemic treatment failure). 
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The open-label Part 2 is to assess long-term safety of etrasimod 2 mg QD in participants with 
moderate-to-severe AD with a history of prior systemic therapy failure. 
Part 1: Approximately 60 participants with moderate-to-severe AD with a history of prior 
systemic treatment failure will be randomized (1:1 ratio) in a double-blind manner to receive 
etrasimod 2 mg QD or placebo orally, once daily, for 16 weeks. Randomization will be 
stratified by disease severity as measured by IGA score (3 [moderate AD], 4 [severe AD]) at 
baseline. 
Following completion of the double-blind, placebo-controlled period, all participants with no 
clinically significant safety concerns as per investigator’s judgement (investigator may seek 
medical monitor’s consideration, if needed) at Week 16 will be given the option to continue 
in an OLE whereby they will receive etrasimod 2 mg (tablet) QD for 52 weeks. The 
participants, investigators and sponsor study team will remain blinded to the treatments the 
participants received for the placebo-controlled period. Non-responders, participants not 
achieving EASI-50, will be discontinued at Week 32 (ie, 16 weeks of treatment in the OLE 
period). 
An interim analysis will be conducted after all Part 1 participants have completed the 16-
week DB treatment period. The IA will be performed by the Sponsor and data summaries 
will be shared with the study team. The participants and investigators will remain blinded to 
the treatments the participants received for the placebo-controlled period. The study team 
will review the data in the context of the overall benefit-risk profile of etrasimod for the 
treatment of moderate-to-severe AD with prior systemic failure. The data review will include 
but is not limited to, efficacy measures of IGA and EASI-75 response and safety parameters 
including the incidence and severity of AEs, AESIs, and clinically relevant changes in ECG, 
and vital signs, and laboratory values. The efficacy and safety data will be utilized to make a 
go/no-go decision for initiating Part 2 of the study, as well as for completing the 52-week 
treatment for the Part 1 participants in the OLE. Once the decision is made it will be 
promptly communicated to the sites. 
Part 2: If the IA results in a decision to proceed to Part 2 of the study, approximately 340 
additional participants will be enrolled to receive etrasimod 2 mg orally, once daily, for 52 
weeks in an open-label manner in order to fulfill the safety database requirements. 
Enrollment into Part 2 will not begin until the IA data from Part 1 are reviewed, and 
determination made as to the favorable benefit/risk of etrasimod 2 mg QD in this new target 
population. Non-responders, ie, participants not achieving at least EASI-50 will be 
discontinued at Week 16, Part 2.
The participant population in both Part 1 and Part 2 will include at least 40% of participants 
with moderate AD (IGA score of 3) and at least 40% of participants with severe AD (IGA 
score of 4). The application of topical emollients/moisturizers (including those containing 
ceramide, hyaluronic acid, or urea) will be required at least once daily for at least 1 week 
prior to baseline (Day 1) and throughout the treatment period without change (ie, type, 
frequency, application). TCS and other medicated topical treatments for AD must be 
discontinued at least 1 week prior to baseline (Day 1) and are not permitted in the 
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double-blind treatment period. Safety follow-up visits will occur at 2 and 4 weeks after the 
last dose of study treatment. Medicated and non-medicated rescue medications are not 
permitted during the Part 1 DB portion. For Part 1 OLE and Part 2 medicated and 
non-medicated topical treatments for AD will be permitted at the discretion of the 
investigator and in accordance with their usual practice.
4.2. Scientific Rationale for Study Design
This is a Phase 2/3 study designed to evaluate the efficacy and safety of etrasimod in 
participants 18 to 80 years of age with refractory, moderate-to-severe AD (IGA ≥3, EASI 
≥16, BSA ≥10%) whose disease is not adequately controlled with other systemic drug 
products, including biologics, or when use of those therapies is inadvisable, ie, participants 
with a history of a prior systemic treatment failure. 
Part 1 will assess etrasimod 2 mg QD monotherapy compared to placebo. The choice of 
placebo as a control is appropriate for the objectives of this study as it will provide the most 
robust assessment of the efficacy and safety of etrasimod. The 16-week treatment duration 
for the DB portion was selected based on the Phase 2 Arena study APD334-201 to ensure 
that etrasimod could approach maximal efficacy while minimizing the time that a participant 
may be on placebo treatment. 
The duration of study participation is up to 76 weeks, which includes a ≤ 4-week screening 
period, a 16-week DB treatment period, a 52-week OLE, and a 4-week follow-up period. The 
2- and 4-week safety follow-up visits will provide off-treatment safety information for 
participants who terminate treatment early or who do not elect to participate in or are not 
eligible to continue to the OLE Part 1 portion. Participants with no clinically significant 
safety concerns as defined in Section 7.1.1 who complete the treatment period will have the 
option to continue to OLE study to further assess the 52-week, long term safety and efficacy 
of etrasimod 2 mg QD as a chronic therapy.
Efficacy will be primarily measured by evaluating changes in AD severity using IGA and 
EASI. To determine the potential efficacy of etrasimod, the primary endpoint will be the 
proportion of participants with an IGA score of 0 or 1 (on a 5-point scale) and a reduction of 
≥ 2 points from baseline at Week 16. 
Additionally, the study design includes the assessment of disease symptoms as secondary 
endpoints, ie, pruritus via PP-NRS and pain via Skin Pain NRS. Clinician-reported outcomes 
and broader quality of life measures will be collected to gather supportive information on 
participant perspectives on aspects of disease conditions and overall health status.
Part 2 will assess the long-term safety and efficacy of etrasimod 2 mg QD monotherapy. The 
duration of study participation is up to 60 weeks, which includes a ≤ 4-week screening 
period, a 52-week OL treatment period, and a 4-week follow-up period. Part 2 is intended as 
a supplementary safety database for the etrasimod 2 mg program. 
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4.2.1. Patient Input Into Design 
No input was obtained specifically for this study, however input for other similar studies in 
moderate-to-severe AD has been obtained and incorporated into this protocol.
4.2.2. Diversity of Study Population 
Reasonable attempts will be made to enroll participants that are representative of the patient 
population that will be treated with etrasimod in clinical practice after approval. The team 
will follow best practices for diverse study population enrollment and retention which 
include tactical diversity questioning in early site engagement and providing diversity 
materials to support the sites’ patient engagements.
Decentralized elements of patient documentation, safety assessments, and testing will result 
in less burdensome procedures for patients and thus possibly enhancing enrollment for
underrepresented populations.
4.2.3. Adjudication Committee 
This protocol will use an independent endpoint adjudication committee to determine whether 
certain investigator-reported events meet the definition of disease-related safety endpoints, 
using predefined endpoint criteria. Further information about this endpoint adjudication 
committee is provided in a charter, including a description of the scope of the committee’s 
responsibilities, the process and definitions to be utilized by the committee for adjudication, 
and communication plan including timelines.
Within the etrasimod program potential cases of PML will be adjudicated. The safety event 
adjudication committee will be blinded to treatment assignment in order to allow for 
unbiased assessments.
Events requiring review may be identified by the Pfizer study team or designee during the 
blinded review of participant data listings or monitors during routine monitoring of 
participants’ study records. The Pfizer study team or designee will notify relevant 
investigators of any events identified. Investigators will be responsible for obtaining and 
submitting the documentation to be reviewed by the safety event adjudication committee.
Additional safety event adjudication committees may be established during the study to 
standardize additional safety event assessments. As described above, individual committee 
charters will provide specific descriptions of the scope of responsibilities and the processes 
and definitions used to assess specific safety events.
4.2.4. Choice of Contraception/Barrier Requirements
Etrasimod is known to cause risk for severe manifestations of developmental toxicity in 
humans or suspected on the basis of the intended pharmacology. Therefore, the use of a 
highly effective method of contraception is required (see Appendix 4).
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4.3. Justification for Dose
The study investigates a dose regimen (2 mg, once daily) equivalent to the planned to be 
marketed dose regimen. The etrasimod 2 mg, once daily dose regimen has been selected 
based on the safety, efficacy, and PK data generated in Study APD3334-201 in participants 
with moderate-to-severe AD, which evaluated 2 doses of etrasimod (etrasimod 1 mg and 2 
mg, once daily) versus placebo. Overall, the 2 mg etrasimod dose demonstrated higher 
efficacy than the 1 mg dose, in particular, 2 mg dose showed statistically significant 
improvement for the key endpoint of vIGA, whereas 1 mg etrasimod was non-significant. 
The etrasimod 2 mg dose selection was further supported by safety and PK data from Phase 2 
and Phase 3 UC studies. The safety and efficacy data of the Phase 2 AD study (Study 
APD334-201) are summarized as follows:

Etrasimod 2 mg demonstrated efficacy and superiority over placebo in the key clinical 
efficacy outcome measures including vIGA success as well as PRO measures, DLQI and 
POEM during the Double-Blind Treatment Period

Etrasimod 2 mg showed continuous improvement and maintenance of response on the 
key efficacy measures of vIGA success, EASI-75, and pruritus improvement during the 
52-week OLE Period of the study

In post hoc analysis, the efficacy and safety profile of etrasimod 2 mg were not notably 
different for participants with prior systemic therapy failure as compared to participants 
without prior systemic therapy failure

Treatment with etrasimod resulted in a dose-dependent decrease in lymphocyte count and 
quick reversal to normal levels following cessation of drug treatment

Etrasimod 2 mg was generally safe and well-tolerated with no clinically relevant safety 
signals resulting from longer exposure (up to 52 consecutive weeks of treatment) in the 
moderate-to-severe AD population
In conclusion, the AD data to date show a clinical benefit in the absence of clinically 
significant safety signals and supports further evaluation of etrasimod 2 mg in this clinical 
trial.
4.4. End of Study Definition
The end of the study is defined as the date of the last visit of the last participant in the study 
or last scheduled procedure shown in the SoA for the last participant in the trial globally.
A participant is considered to have completed the study if they have completed all periods of 
the study, including the last visit or the last scheduled procedure shown in the SoA.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled, including 
participants across diverse and representative racial and ethnic backgrounds. If a 
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prescreening tool is utilized for study recruitment purposes, it will include collection of 
information that reflects the enrollment of a diverse participant population including, where 
permitted under local regulations, age, sex, race, and ethnicity. The following eligibility 
criteria are designed to select participants for whom participation in the study is considered 
appropriate. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular participant is suitable for this protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Participants aged 18 (or the minimum age of consent in accordance with local 
regulations) to 80 years of age at screening.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Disease Characteristics:
2. Chronic AD (also known as atopic eczema) that was diagnosed at least 1 year prior to 
Screening and meets Hanifin and Rajka criteria at screening.1
3. Moderate-to-severe AD:
a) IGA score ≥3 (on the 0 to 4 IGA scale, in which 3 = moderate and 4 = severe) at 
screening and baseline (Day 1).
b) BSA ≥10% of AD involvement at screening and baseline (Day 1).
c) EASI ≥16 at screening and baseline (Day 1).
4. A participant who has failed a prior systemic therapy for AD, ie refractory, moderate-
to-severe AD that is not adequately controlled with other systemic drug products, 
including biologics, or when use of those therapies is inadvisable (i.e., medical 
contraindications to systemic therapy prohibit use).   
a.
Inadequate response to ≥2 weeks of cyclosporine, azathioprine, methotrexate, 
mycophenolate, biologic, JAK inhibitors, or systemic corticosteroid (CS; defined 
as pulse of systemic CS or ≥2 weeks of continuous oral CS), or when systemic 
therapy is inadvisable.  
- In Part 1, approximately 30% of participants are permitted with a failure of a 
prior systemic corticosteroid therapy without failing another systemic treatment 
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for AD.  For the remining participants in Part 1, failure of a prior systemic 
corticosteroid therapy alone is not sufficient to meet the criterion for prior 
systemic failure, i.e., the participant must fail another systemic treatment for AD.  
- In Part 2, failure of systemic corticosteroids may qualify a participant for the 
study.
b. Refractory is an insufficient clinical response, defined as the inability to achieve 
and maintain remission or a low disease activity state of minimal or mild lesions 
only, within 1 year of screening, despite treatment with systemic therapy for a 
period sufficient to demonstrate efficacy as determined by the Investigator. 
c.
Acceptable documentation for these criteria includes chart notes that record 
medication prescription and treatment outcome, or Investigator documentation 
based on communication with the patient's treating physician. For study purposes, 
document failure of prior systemic drug(s) to adequately control AD in the CRF.
5. Willing to apply a topical emollient/moisturizer at least once daily for ≥1 week prior 
to baseline (Day 1) and willing to maintain consistent daily application over the 
course of the study
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Presence of confounding factors:

Skin conditions (eg, psoriasis, seborrheic dermatitis) that may interfere with 
evaluation of AD or assessment of treatment response as deemed by the investigator.

Current significant active infection or requiring a treatment for infection that may 
interfere with the assessment of AD.
2. Hypersensitivity to etrasimod or any of the excipients.
3.Other medical or psychiatric condition including recent (within the past year) or active 
suicidal ideation/behavior or laboratory abnormality that may increase the risk of 
study participation or, in the investigator’s judgment, make the participant 
inappropriate for the study.

Suicidal ideation associated with actual intent and a method or plan in the past year: 
“Yes” answers on items 4 or 5 of the Columbia suicide severity rating scale (C-
SSRS);

“Yes” answer to any of the suicidal behavior items of the C-SSRS in the past 5 years;
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
Participants who answer “Yes” on items 4 or 5 of the C-SSRS or suicidal 
behavior may still be included in the study if a mental health professional judges 
the potential benefits of the participant inclusion outweigh the risk (see 
Section 8.1.1.4).

Have undergone significant trauma or major surgery within 4 weeks prior to Day 1.
4. Active or past history of macular edema, any type of retinopathy (including diabetic) 
or uveitis.
5. Have any malignancies or have a history of malignancies with the exception of 
adequately treated or excised nonmetastatic basal cell or squamous cell cancer of the 
skin or cervical carcinoma in situ.
Prior/Concomitant Therapy:
6. Current use of any prohibited concomitant medication(s) or participants 
unwilling/unable to use required concomitant medication(s). Refer to Section 6.9 
Prior and Concomitant Therapy. 
Prior/Concurrent Clinical Study Experience:
7. Prior treatment with etrasimod or prior participation in an etrasimod clinical study.
Diagnostic Assessments:
8. Renal impairment as defined by an eGFR of <30 mL/min/1.73m2 confirmed by 1 
repeat measurement at screening. Based upon participant age at screening, eGFR or 
eCrCl is calculated using the recommended formulas in Section 10.6.2.1 to determine 
eligibility and to provide a baseline to quantify any subsequent kidney safety events. 
For eligibility assessment based upon estimated renal function, the higher of the 
screening and baseline eGFR values may be used. 
9. Hepatic dysfunction defined as:

Total bilirubin ≥1.5 × ULN (except for Gilbert’s syndrome)

AST ≥2 × ULN

ALT ≥2 × ULN
10. Hematologic abnormalities defined as:

WBC <3500/mm3 (<3.5 x 109 cells/L)

ANC <1200/mm3 (<1.2 x 109 cells/L)
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
ALC <1000/mm3 (<1.0 x 109 cells/L)
11. Have any of the following conditions or risk factors related to infection or immune 
function:

Participants with active, uncontrolled bacterial, fungal, or viral infection, 
including (but not limited to) COVID-19/SARS-CoV-2, HBV, HCV, and HIV or 
AIDS related illness. Comments regarding specific circumstances follow. 

Hepatitis B: This criterion excludes participants with a positive HBsAg (ie, 
either acute or chronic active hepatitis). Participants who are HBsAg negative, 
HBcAb positive, and HBsAb positive at Screening will have reflex testing for 
HBV DNA. For more details, refer to Section 8.3.7.

Hepatitis C: Positive HCV Ab is indicative of infection but may not 
necessarily render a potential candidate ineligible, depending on clinical 
circumstances. If exposure to HCV is recent, HCV Ab may not have yet 
turned positive. In these circumstances test for HCV RNA. If HCV RNA is 
detected the patient is not eligible. Refer to CDC website for further details 
(https://www.cdc.gov/hepatitis/hbv/pdfs/SerologicChartv8.pdf).

COVID-19/SARS-CoV-2: While SARS-CoV-2 testing is not mandated for 
entry into this study, testing should follow local clinical practice standards. If 
a participant has a positive test result for SARS-CoV-2 infection, is known to 
have asymptomatic infection or is suspected of having SARS-CoV-2, the 
participant is excluded until a negative antigen test and resolution of 
symptoms if applicable.

History of organ transplant (except corneal transplant). 

History of an opportunistic infection (eg, cryptococcal meningitis, PML).

History (single episode) of disseminated herpes zoster or disseminated herpes 
simplex, or a recurrent (more than one episode of) localized, dermatomal herpes 
zoster.

Have evidence of active or latent or inadequately treated infection with TB as 
defined by the following:

A positive QFT-G In-Tube test (preferred) performed at or within the 12 
weeks prior to Day 1. NOTE: The QFT-G (or an alternative IGRA) for 
screening may be repeated once if the investigator deems this to be necessary. 
If the result of the repeat test is indeterminate, participants may be screened 
using the Mantoux/PPD skin test with study medical monitor approval. 
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
Chest radiograph (or chest computed tomography scan, or magnetic resonance 
imaging [MRI], if available) taken at screening with changes suggestive of 
active TB infection as determined by a qualified radiologist. A chest image or 
other appropriate imaging is required, unless previously performed and 
documented within 12 weeks prior to Study Day 1. 

A history of either untreated or inadequately treated latent or active TB 
infection;

If a participant has previously received an adequate course of therapy for 
either latent (eg, 9 months of isoniazid in a locale where rates of primary 
multi-drug TB resistance are <5% or an acceptable alternative regimen) or 
active (acceptable multi-drug regimen) TB infection, neither a QFT-G test, 
nor a Mantoux/PPD tuberculin skin test is needed, but a chest imaging is 
required if not performed within 12 weeks prior to Day 1. To be considered 
eligible for the study, chest imaging must be negative for active tuberculosis 
infection as determined by a qualified radiologist. Documentation of adequate 
treatment for TB and negative chest imaging results must be obtained prior to 
Day 1. If the current incidence rates of multi-drug resistant TB infection in the 
locale are unavailable, an adequate treatment regimen should be defined as the 
regimen recommended by the health ministry or expert panel in the locale; 

It is recommended that participants with a history of BCG vaccination be 
tested with the QFT-G test since the Mantoux/PPD tuberculin skin test may be 
positive due to vaccination. See Section 8.3.5 for requirements for 
Mantoux/PPD tuberculin skin testing.

A participant who is currently being treated for active TB infection is to be 
excluded.
12. FEV1 or FVC < 70% of predicted values at screening.
13. 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 Screening
b. History of second degree or third-degree atrioventricular block, sick sinus 
syndrome or periods of asystole for > 3 seconds without a functional pacemaker
c.
History of recurrent symptomatic bradycardia or recurrent cardiogenic syncope
d. Screening or Day 1 predose 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. Abnormal vital signs should be confirmed by 1 repeat measurement. 
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Abnormal results that are confirmed on a repeat assessment are considered 
exclusionary.
e.
Screening or Day 1 predose electrocardiogram (ECG) with PR interval ≥200 ms 
or QTcF ≥450 ms in males or ≥470 ms in females
f.
Start, stop, change dosage of any Class I to IV anti-arrhythmic drugs within 1 
week before Day 1
Other Exclusion Criteria:
14. Investigator site staff directly involved in the conduct of the study and their family 
members, site staff otherwise supervised by the investigator, and sponsor and sponsor 
delegate employees directly involved in the conduct of the study and their family 
members.
5.3. Lifestyle Considerations
5.3.1. Contraception
The investigator or their designee, in consultation with the participant, will confirm that the 
participant is utilizing an appropriate method of contraception for the individual participant 
and their partner(s) from the permitted list of contraception methods (see Appendix 4,
Section 10.4.4) and will confirm that the participant has been instructed in its consistent and 
correct use. The investigator or designee will advise the participant to seek advice about the 
donation and cryopreservation of germ cells prior to the start of study intervention, if 
applicable.
At time points indicated in the SoA, the investigator or designee will inform the participant 
of the need to use highly effective contraception consistently and correctly and document the 
conversation and the participant’s affirmation in the participant’s chart. Participants need to 
affirm their consistent and correct use of at least 1 of the selected methods of contraception, 
considering that their risk for pregnancy may have changed since the last visit. The 
investigator or designee should inquire of both WOCBP and male participants if a change in 
the risk of becoming pregnant or getting someone pregnant has occurred.
In addition, the investigator or designee will instruct the participant to call immediately if the 
selected contraception method is discontinued and document the requirement to use an 
alternate protocol-specified method, including if the participant will no longer be truly 
abstinent as the selected contraception method, or if pregnancy is known or suspected in the 
participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
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publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once at the Investigator’s discretion. 
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY
Study interventions are all prespecified investigational and noninvestigational medicinal 
products, medical devices, and other interventions (eg, surgical and behavioral) intended to 
be administered to the study participants during the study conduct.
For the purposes of this protocol, study intervention refers to etrasimod and placebo.
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6.1. Study Intervention(s) Administered
Study Intervention(s)
Intervention Name
etrasimod
placebo (Part 1 DB period only)
Type
drug
drug
Use
experimental
placebo
Dose Formulation
tablet
tablet
Unit Dose Strength(s)
2 mg
Not applicable
Dosage Level(s)
one tablet once daily
one tablet once daily
Route of 
Administration
oral
oral
IMP or NIMP/AxMP
IMP 
IMP 
Sourcing
Provided centrally by the sponsor.
Provided centrally by the sponsor.
Packaging and 
Labeling
Study intervention will be provided in 
bottles. Each bottle will be labeled as 
required per country requirement.
Study intervention will be provided in 
bottles. Each bottle will be labeled as 
required per country requirement.
SRSD
IB
Not applicable
Current/Former 
Name or Alias
APD334, PF-07915503
Not applicable
Study Arm(s)
Arm Title
Etrasimod
Placebo (Part 1 DB period only)
Arm Description
Participants will receive 
etrasimod 2 mg QD 
Participants will receive placebo QD
Study intervention may be shipped by courier to study participants if permitted by local 
regulations and in accordance with storage and transportation requirements for study 
intervention. Pfizer does not permit the shipment of study intervention by mail. The tracking 
record of shipments, including temperature monitoring data, and the chain of custody 
of study intervention must be kept in the participant’s source documents/medical records.
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6.1.1. Administration
Participants will self-administer one tablet of study treatment each day by mouth (with water 
either with or without food) at approximately the same time each day, preferably in the 
morning. Participants will swallow the study intervention whole and will not manipulate or 
chew the study intervention prior to swallowing.

Participants will be observed for at least 4 hours following administration of study 
intervention on Study Day 1 of Part 1 and Part 2, Week 16 of Part 1, and whenever 
participants interrupt study intervention for ≥ 2 consecutive days within the first week 
of treatment or Week 16 of Part 1, or for ≥ 7 consecutive days after the first week of 
treatment (excluding Week 16 of Part 1 where missing 2 doses applies) (See Section 
10.10.3). Observation will be performed by an appropriately qualified and trained 
member of the study staff. Appropriate medication and other supportive measures for 
management of a medical emergency will be available in accordance with local 
guidelines and institutional guidelines.
Participants 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 participant vomits the tablet, 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. 
In the event a participant is not compliant with the assigned treatment regimen, the 
participant should be retrained on proper study treatment administration. Participants should 
be instructed to contact the Investigator if they miss 2 or more consecutive doses within the 
first week of treatment or Week 16 of Part 1, or if they miss 7 or more consecutive doses 
after the first week of treatment (excluding Week 16 of Part 1 where missing 2 doses 
applies). Participants must contact the Investigator to discuss treatment reinitiation if 
consecutive days of study treatment are missed as described in Section 7.1.7.
6.2. Preparation, Handling, Storage, and Accountability
1. The investigator or designee must confirm that appropriate conditions (eg, temperature) 
have been maintained during transit for all study interventions received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply, prepare, and/or administer study intervention. 
3. All study interventions must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled storage 
conditions with access limited to the investigator and authorized site staff. At a minimum, 
daily minimum and maximum temperatures for all site storage locations must be 
documented and available upon request. Data for nonworking days must indicate the 
minimum and maximum temperatures since previously documented upon return to 
business.
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4. Any excursions from the study intervention label storage conditions should be reported to 
Pfizer upon discovery along with actions taken. The site should actively pursue options 
for returning the study intervention to labeled storage conditions, as soon as possible. 
Once an excursion is identified, the study intervention must be quarantined and not used 
until Pfizer provides permission to use the study intervention. Specific details regarding 
the excursion definition and information to report for each excursion will be provided to 
the site in the IPM.
5. Any storage conditions stated in the SRSD will be superseded by the storage conditions 
stated on the label. Site staff will instruct participants on the proper storage requirements 
for take home study intervention.
6. Study interventions should be stored in their original containers.
7. The investigator, institution, head of the medical institution (where applicable), or 
authorized site staff is responsible for study intervention accountability, reconciliation, 
and record maintenance (ie, receipt, reconciliation, and final disposition records), such as 
the IPAL or sponsor-approved equivalent. All study interventions will be accounted for 
using a study intervention accountability form/record. All study intervention that is taken 
home by the participant, both used and unused, must be returned to the investigator by 
the participant. Returned study intervention must not be redispensed to the 
participants.
8. Further guidance and information for the final disposition of unused study interventions 
are provided in the IPM. All destruction must be adequately documented. If destruction is 
authorized to take place at the investigator site, the investigator must ensure that the 
materials are destroyed in compliance with applicable environmental regulations, 
institutional policy, and any special instructions provided by Pfizer.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IPM.
6.2.1. Preparation and Dispensing
A qualified staff member will dispense the study intervention using unique container 
numbers via an IRT system in the bottles provided, in quantities appropriate according to the 
SoA. A second staff member will verify the dispensing. The participant should be instructed 
to maintain the product in the bottle throughout the course of dosing and return the bottle to 
the site at the next study visit.
6.3. Assignment to Study Intervention
Allocation of participants to treatment groups will proceed through the use of an IRT system. 
The site personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s ID and password, the protocol number, 
and the participant number. The site personnel will then be provided with a randomization 
number corresponding to the assigned treatment group, and DU or container number(s) when 
study intervention is being supplied via the IRT system. The IRT system will provide a 
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confirmation report containing the participant number, randomization number, and DU or 
container number assigned. The confirmation report must be stored in the site’s files. 
Study intervention will be dispensed at the study visits summarized in the SoA. 
The study-specific IRT reference manual and IPM will provide the contact information and 
further details on the use of the IRT system.
6.4. Blinding
This is a double-blind study with OLE (Part 1) and OL study (Part 2). 
6.4.1. Blinding of Participants
In Part 1, participants will be blinded to their DB treatment assignment for the entire portion 
of Part 1, i.e., participants will remain blinded to their DB treatment assignment until the 
completion of Part 1 DB and OLE periods of the study.
6.4.2. Blinding of Site Personnel
Investigators and other site staff will remain blinded during the OLE to participants’ assigned 
study intervention received in the DB portion until the completion of Part 1 DB and OLE 
periods of the study. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study intervention records at the site(s) to verify that randomization/dispensing has been done 
accurately.
6.4.3. Blinding of the Sponsor
Sponsor staff will be blinded to participants’ assigned study intervention during the DB 
treatment period in Part 1 of the study, until all applicable participants had completed their 
Week 16 visit.  The Sponsor study team will be unblinded to treatment assignment for the 
first 16 weeks of Part 1 (DB period) once treatment assignments are released for the IA. 
6.4.4. Breaking the Blind
The IRT will be programmed with blind-breaking instructions. In case of an emergency, the 
investigator has the sole responsibility for determining if unblinding of a participant’s 
treatment assignment is warranted. Participant safety must always be the first consideration 
in making such a determination. If the investigator decides that unblinding is warranted, the 
investigator should make every effort to contact the study medical monitor prior to 
unblinding a participant’s treatment assignment unless this could delay further management 
of the participant. If a participant’s treatment assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind. The date and reason that the blind was 
broken must be recorded in the source documentation and CRF/DCT.
The study-specific IRT reference manual and IPM will provide the contact information and 
further details on the use of the IRT system.
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6.5. Study Intervention Compliance
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit through a combination of the accounting of unused 
study intervention returned by the participant at the study visits and discussion (direct 
questioning) with the participant which will be documented in the source documents and 
CRF. Deviation(s) from the prescribed dosage regimen should be recorded in the CRF.
A record of the number of tablets dispensed to and taken by each participant must be 
maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates, including dates for intervention delays, will also be recorded in the CRF.
Part 1: The Week 16 visit is the first dose of open label (etrasimod) treatment. Sites 
must contact participants 1-2 business days prior to the Week 16 visit to remind them 
not to take study intervention on the day of the Week 16 visit. Should the participant 
come to the site having already taken study intervention, all Week 16 procedures will be 
completed, except for administering open label treatment and first-dose cardiac 
monitoring procedures for which an unplanned visit is required as soon as possible 
(within 3 days). The unplanned visit should be scheduled in the morning and not on a 
Friday or day before a site-observed holiday. The participant will continue taking 
blinded study intervention up to 1 day prior to the unplanned visit. Again, sites must 
contact the participants 1-2 business days prior to the unplanned visit to remind them 
not to take study intervention the day of the visit. The unplanned visit will be the start 
of the OLE period. See Section 10.10.3 for details of first-dose cardiac monitoring 
procedures.
The following non-compliance cases will be considered medication errors and will be 
discussed with the sponsor for possible withdrawal from the study:
1. Participants interrupting study intervention for ≥ 2 consecutive days within the first 
week of treatment or Week 16 of Part 1, or for ≥ 7 consecutive days after the first 
week of treatment (excluding Week 16 of Part 1 where missing 2 doses applies).
NOTE The first-dose cardiac monitoring outlined in Section 10.10.3 must be 
performed any time a participant reinitiates study treatment following dose 
interruptions as described above and the participant must take the next dose of study 
treatment at the study site.
2. Participants who have an overall compliance of <80% or >120% between visits.
3. Participants who have taken >5 mg meeting the definition of overdose (see 
Section 6.8).
4. When participants take the Week 16 dose prior to the visit it will be considered a 
medication error (wrong drug administered). 
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Any deviation from protocol specified dosing should be recorded as a protocol deviation and 
the investigator or designee is to counsel the participant, legally acceptable representative/ 
legal guardian (if applicable) and ensure steps are taken to improve compliance. In addition, 
if the compliance deviation reaches the thresholds defined above it should also be recorded as 
a medication error (see Section 8.4.10).
Note: temporary interruption to dosing per investigator judgement, as described in 
Section 10.10, will not be considered a protocol deviation or medication error.
6.6. Dose Modification 
Dose modification is not permitted in this study.
6.7. Continued Access to Study Intervention After the End of the Study
No study intervention will be provided to participants at the end of their study participation. 
It is expected that participants will be treated as required with standard-of-care treatments, as 
advised by their usual care physician.
6.8. Treatment of Overdose
The following scenarios are considered overdose:

Consuming >3 mg on Day 1, on Week 16 visit day in Part 1, or on a day of treatment 
re-initiation after protocol defined treatment interruptions.

Consuming >5 mg any day after Day 1 or starting a day after Week 16 visit in Part 1 
except on a day of treatment re-initiation, as specified above. 
There is no specific treatment recommended for an overdose but to provide supportive care if 
clinically indicated. AV conduction delays and bradycardia were observed on Day 1 in 
several participants who received 5 mg etrasimod in Phase 1 single-ascending dose Study 
(Arena Study APD334-001); this dose was not used in subsequent clinical studies. Etrasimod 
has not been evaluated for drug abuse or dependence. Participants with suspected overdose 
will be counseled on correct dosing and administration of study treatment.
In the event of an overdose, the investigator should:
1. Contact the study medical monitor within 24 hours.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities as 
medically appropriate and follow up until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
4. Overdose is reportable to Pfizer Safety only when associated with an SAE.
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Decisions regarding dose interruptions or permanent discontinuation will be made by the 
investigator in consultation with the study medical monitor as needed based on the clinical 
evaluation of the participant.
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6.9. Prior and Concomitant Therapy
Any medication (including over-the-counter or prescription medicines, vitamins, and/or 
herbal supplements) or vaccine that a participant receives and all procedures that are 
performed during the screening period and during the study through the safety reporting 
period 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 study medical monitor should be contacted if there are any questions regarding 
concomitant therapy.
6.9.1. Required Concomitant Therapy
Participants are required to apply topical emollients/moisturizers (including those containing 
ceramide, hyaluronic acid, or urea) at least once daily for at least 1 week prior to baseline 
(Day 1) and throughout the study without change (ie, type, frequency, application). All 
topical emollients/moisturizers are generally permitted, except for new prescription 
emollients/moisturizers or emollients/moisturizers containing additives (including ceramide, 
hyaluronic acid, or urea) during the study. On visit days during the study, participants should 
not apply any topical emollient or moisturizer until the study visit has been completed.
6.9.2. Prior Treatments
Table 1.
Prohibited Medication or Procedure Washout Periods Prior to Day 1
Time Frame
Therapies
Any time prior to 
Randomization
S1P receptor modulators (eg, fingolimod, siponimod, ozanimod), α4β1 
integrin receptor antagonist (eg, natalizumab)
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)
Within 8 weeks (or 5 
half-lives if shorter)
Any biologic treatment other than already listed, eg, anti-IL4/13 
antibodies (eg, dupilumab), anti-IL13 antibodies (eg, tralokinumab, 
lebrikizumab), anti-IL-17 antibodies (eg, secukinumab), anti-IL-12/23 
antibodies (eg, ustekinumab), anti-IL-31 antibodies (eg, nemolizumab), 
anti-IL-23 antibodies (eg, risankizumab) 
Within 6 weeks
Live-attenuated replication-competent vaccines are prohibited 
Within 4 weeks (or 
5 half-lives if shorter)
Any investigational therapy other than the study treatment, unless therapy 
belongs to a drug category described above which requires a longer 
washout period, in which case the longer washout period should be used. 
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Table 1.
Prohibited Medication or Procedure Washout Periods Prior to Day 1
Time Frame
Therapies
Within 4 weeks
Any other systemic treatment intended for AD (eg, azathioprine, 
methotrexate, cyclosporine, mycophenolate, PDE-4 inhibitors, and 
systemic glucocorticoids)
Note: corticosteroid intranasal sprays and/or corticosteroid inhalers are 
allowed for participants with stable asthma. Ophthalmic and ear drop 
corticosteroids are also allowed.
Topical and systemic JAK inhibitors (eg, baricitinib, abrocitinib, 
upadacitinib, ruxolitinib, delgocitinib, tofacitinib)
Any IV medications taken in response to serious infection that required 
hospitalization or treatment
Moderate or strong inhibitors or inducers that inhibit or induce at least 2 
of the following: cytochrome P450 (CYP)2C8, CYP2C9, and CYP3A4 
(e.g., fluconazole, rifampin, enzalutamide) 
Phototherapy for AD or artificial tanning (beds, booths, or lamps), 
including psoralen and ultraviolet A, ultraviolet B, tanning booth, and 
excimer laser
Within 1 week
Topical treatments that could affect AD disease and/or evaluation of AD 
(eg, crisaborole, corticosteroids, calcineurin inhibitors [eg, tacrolimus, 
pimecrolimus], tars, antibiotic creams, topical antihistamines).
Sedating, systemic antihistamines (eg, diphenhydramine, hydroxyzine, 
promethazine) (non-sedating systemic antihistamines are allowed)
6.9.3. Prohibited During the Study
In the event of an emergency, any needed medications may be prescribed without prior 
approval, but the study medical monitor must be notified of the use of any prohibited 
medications immediately.
Prohibited Medications Not Requiring Interruption or Discontinuation of Study Treatment

The following therapies are prohibited during the study until completion of study 
treatment. Participants receiving any of the following must discontinue such use 
immediately without interruption or discontinuation of study treatment:

Low-to-moderate potency TCS (Class VII-IV), calcineurin inhibitors (eg, tacrolimus and 
pimecrolimus), or crisaborole or high potency TCS (Class III-I) administered for 
<7 consecutive days. TCS classes (VII-IV) are based on WHO classification of topical 
corticosteroids34,35). See CRF guidelines.

Topical antihistamines, tars, topical anesthetics, or antibiotic creams 
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
Sedating, systemic antihistamines (eg, diphenhydramine, hydroxyzine, promethazine) 
(nonsedating systemic antihistamines are allowed)

Initiation of any new (ie, during the screening and treatment period) 
emollients/moisturizers containing additives such as ceramide, hyaluronic acid, urea, 
antipruritic or antiseptic agents during the screening and treatment period (patients may 
continue using stable doses of such emollients/moisturizers if initiated before the 
screening visit)
Prohibited Medications Requiring Permanent Discontinuation of Study Treatment
Use of the following therapies during the study until completion of study treatment will 
require permanent discontinuation of study treatment and withdrawal from the study except 
when specified otherwise below:

High- to ultra-high potency TCS (Class III-I) administered for ≥7 consecutive days. TCS 
Classes III-I are based on WHO classification of topical corticosteroids34,35. See CRF 
guidelines.

Systemic corticosteroids (intranasal sprays, corticosteroid inhalers, ophthalmic and ear 
drop corticosteroids are allowed) (requires permanent discontinuation of study treatment 
but participants are not required to withdraw from the study).

S1P receptor modulators (eg, fingolimod, ozanimod).

α4β1 integrin receptor antagonist (eg, natalizumab).

Anti-CD20 antibodies (eg, rituximab, ocrelizumab), anti-CD52 antibodies (eg, 
alemtuzumab), other cell depleting therapies (eg, bone marrow transplantation, total body 
irradiation).

Systemic immunosuppressive/immunomodulating drugs (eg, cyclosporine, azathioprine, 
methotrexate), including topical or oral JAK inhibitors (requires permanent 
discontinuation of study treatment but participants are not required to withdraw from the 
study).

Any biologic treatment, anti-IL4/13 antibodies (eg, dupilumab), anti-IL13 antibodies (eg, 
tralokinumab, lebrikizumab), anti-IL17A antibodies (eg, secukinumab), anti-IL12/23 
antibodies (eg, ustekinumab), anti-IL31 antibodies (eg, nemolizumab), anti-IL23 
antibodies (eg, risankizumab) requires permanent discontinuation of study treatment, but 
participants are not required to withdraw from the study.

Any IV medications taken in response to serious infection that required hospitalization or 
treatment.
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
Moderate/strong inhibitors or inducers that inhibit or induce at least 2 of the following: 
cytochrome P450 (CYP)2C8, CYP2C9, and CYP3A4 (e.g., fluconazole, rifampin, 
enzalutamide, Section 10.8.1).

Live-attenuated replication-competent vaccines starting 6 weeks prior to baseline (Day 
1), during study treatment and for 4 weeks after the last dose of study treatment.

Start, stop, or change in dosage of any anti-arrhythmic drugs (Class I to IV) within 
1 week before or after treatment initiation or reinitiation following dose interruption of a 
duration requiring in-clinic cardiac monitoring (Section 6.1.1).

Any investigational drug other than the study treatment.
Participants who complete the treatment period no longer need to abstain from the 
medications that were prohibited during the treatment periods, unless noted otherwise (eg, 
live attenuated vaccines for 4 weeks after the last dose of study treatment).
For prohibited concomitant procedures:

Participants may not undergo phototherapy for AD or artificial tanning (beds, booths, or 
lamps), including psoralen and ultraviolet A, ultraviolet B, tanning booth, and excimer 
laser.

Participants should not take bleach baths.

Participants should not undergo cell depleting therapies (eg, bone marrow transplantation, 
total body irradiation).

Participants should not undergo major elective surgery while on study treatment.

Participants may not donate blood during the study and for 30 days after the last dose of 
study treatment.

Participants may not donate sperm, or oocytes during the study and for 28 days after the 
last dose of study treatment.
6.9.4. Rescue Medicine
Medicated and non-medicated rescue medications are not permitted during the Part 1 DB 
portion. For Part 1 OLE and Part 2 medicated and non-medicated topical treatments for AD 
will be permitted at the discretion of the investigator and in accordance with their usual 
practice.
6.9.5. Permitted During the Study
Vaccinations are permitted as clinically indicated except for live-attenuated replication-
competent vaccines. At this time, there are no data on the effect of etrasimod treatment on 
vaccine efficacy and safety including severe acute respiratory system 
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coronavirus 2 (SARs-CoV-2) vaccines to protect against COVID-19. It is recommended that 
participants receive a vaccination against COVID-19 to decrease the risk of contracting 
SARs-CoV-2. 
The American Academy of Dermatology has published recommendations that advise patients 
on immunomodulating drugs to be vaccinated as “The CDC does not consider COVID-19 
vaccine to be contraindicated in persons taking biologic or traditional immunosuppressive 
medications, hedgehog pathway inhibitors, and PD-1 inhibitors”. 
If a participant receives a vaccination, the vaccination date and type (eg, SARS-CoV-2) 
should be captured in the Concomitant Medication log/eCRF. The vaccine brand, 
manufacturer, and lot number (if available) should be captured in the source documentation.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4) and should be captured on the Concomitant 
Medication log/eCRF.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue study intervention. Reasons 
for permanent discontinuation of study intervention include the following:

Adverse events noted below (participants with AEs listed below, irrespective of 
causality, will be discontinued from the study intervention) NOTE: Sub bullets below 
are examples and are not intended to be an all-inclusive list.
o
Second episode of confirmed Grade 4 lymphopenia in the same participant 
(Protocol Sections 10.10.1, 10.10.2)  
o
Repeated episode of a serious infection for the same participant (Protocol Section 
10.10.2)
o
Diagnosis of PML (Protocol Section 10.11)
o
Diagnosis of PRES (Protocol Section 8.4.8)
o
ECG changes (Protocol Section 7.1.3)
o
Suspected intolerance associated with first dose cardiac effects (Protocol 
Section 10.10.3.2)
o
Malignancy (Protocol Section 8.4.8) 
o
HBV DNA above LLQ (Protocol Section 8.3.7)
o
Active, latent, or inadequately treated TB infection (Protocol Section 8.3.5)
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o
Clinically significant respiratory AE and or a decline in confirmed PFT values 
(FEV1 and/or FVC below 50% of the predicted values; Protocol Section 10.10.4)
o
Confirmed macular edema (Protocol Section 10.10.5)
o
Drug-induced liver injury confirmed cases after all results of reasonable 
investigations have been received as per Protocol Section 10.5, and alternative 
etiology have been excluded (Protocol Section 10.10.5)
o
Clinically significant safety concern as per investigator’s judgement at Week 16 
(Protocol Section 7.1.1) 

Death

Lost to follow up

Physician decision

Pregnancy 

Protocol deviation

Study terminated by Sponsor

Withdrawal by participant

Lack of Efficacy
Discontinuation of study intervention does not represent withdrawal from the study. If study 
intervention is permanently discontinued, the participant should remain in the study to be 
evaluated for safety. See the SoA for data to be collected at the time of discontinuation of 
study intervention and follow-up for any further evaluations that need to be completed.
In the event of discontinuation of study intervention, it must be documented on the 
appropriate CRF/in the medical records whether the participant is discontinuing further 
receipt of study intervention or also from study procedures, further study follow-up, and/or 
future collection of additional information.
7.1.1. Discontinuation after Part 1 DB (Week 16) due to a Clinically Significant Safety 
Concern 
Per investigator’s judgement, participants must permanently discontinue study intervention at 
the Part 1 Week 16 visit if they experienced an AE and/or SAE during the DB study portion 
that was a clinically significant safety concern for study continuation which may or may not 
have resulted in study treatment interruption. The investigator may seek medical monitor’s 
consideration, if needed, to determine participant continuation.  
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7.1.2. Liver Injury
Participants must permanently discontinue study intervention if drug-induced liver injury 
(Section 10.5).
7.1.3. ECG Changes
Participants must permanently discontinue study intervention if suspected intolerance 
associated with first dose cardiac effects (Section 10.10.3.2).
If an ECG shows a new onset QTc interval above 500 ms during the treatment period, a 
repeat ECG is warranted. If this abnormal finding is confirmed, study intervention must be 
interrupted. Effective diagnostic and therapeutic strategies should be employed.
Reversible causes of prolonged QTc interval (eg, electrolyte abnormalities or 
hypomagnesemia), should be corrected as clinically indicated. When evaluating a participant 
with new onset QTc interval above 500 ms, referral to a cardiologist experienced in treating 
cardiac conduction disorders should be considered. Re-initiation of study treatment (refer to 
Section 10.10.3) can only be considered after all of the following have occurred: 
-
The QTcF interval is <450 ms (males) or <470 ms (females), 
-
The QTc prolongation is considered by the Investigator and confirmed by the 
cardiologist as not related to study intervention and likely caused by other factors, 
-
Individual risk-benefit is favorable (as determined by the Investigator, in agreement 
with the cardiologist), and 
-
After discussion with the Sponsor Medical Monitor.
If, after re-initiation, the QTc interval is again prolonged above 500 ms, then study 
intervention must be permanently discontinued.
If a clinically significant finding is identified (including, but not limited to, changes from 
baseline in QTcF after enrollment), the investigator or qualified designee will determine if 
the participant can continue in the study and if any change in participant management is 
needed. This review of the ECG printed at the time of collection must be documented. Any 
new clinically relevant finding should be reported as an AE.
7.1.4. Pregnancy
Female participants who have missed a menstrual period, suspect a pregnancy, or who show 
an indeterminate or positive result on the urine test may not progress in the study until 
pregnancy is ruled out using further diagnostic testing (eg, a negative quantitative serum 
pregnancy test conducted at a certified laboratory). Study intervention should be interrupted 
immediately until pregnancy status is confirmed. See Section 7.1.7 for details.
In the case of a confirmed positive pregnancy, the participant will be permanently withdrawn 
from administration of study intervention but may remain in the study until completion of the 
4 week follow-up period. See Section 8.4.1 for details.
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7.1.5. Lack of Efficacy 
Lack of efficacy will result in permanent discontinuation of study intervention only for the 
reason below:

Participants who do not meet EASI-50 criteria at Week 32 in Part 1 (Week 16 of OLE) or 
at Week 16 of Part 2. In the case of lack of efficacy, the participant will be permanently 
withdrawn from administration of study intervention, complete Early Termination 
procedures, and then complete the 2- week (SFU 1) and 4-week (SFU 2) follow-up visits. 
7.1.6. COVID-19
If a participant has COVID-19 during the study, this should be reported as an AE or SAE (as 
appropriate) and appropriate medical intervention provided. Temporary discontinuation of 
the study intervention may be medically appropriate until the participant has recovered from 
COVID-19 (Section 7.1.7). 
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor. 
7.1.7. Temporary Discontinuation
Dose interruptions are defined as the following consecutive days of missed study treatment:

≥2 consecutive days within the first week of treatment or during Week 16 of Part 1, or

≥7 consecutive days after the first week of treatment (excluding Week 16 of Part 1 where 
missing 2 doses applies)
If the Investigator deems it necessary to withhold study treatment due to an adverse event, 
temporary withholding is permitted for up to 6 days (after the first week of treatment) 
without obtaining prior approval from the study medical monitor. Planned dose interruptions 
during the first week of treatment requires consultation with the study medical monitor. If 
study treatment interruption ≥ 7 days is required for a medical reason at any time in the 
study, the Investigator must contact the study medical monitor for further instruction as soon 
as this is anticipated. Any time a participant reinitiates study treatment following 
protocol-defined dose interruptions, the first dose cardiac monitoring outlined in 
Section 10.10.3 must be performed and the participant must take the next dose of study 
treatment at the study site.
Doses not taken due to an adverse event per investigator’s request do not constitute protocol 
deviations or medication errors and should not be considered dosing errors but should be 
noted in the dosing log with the reason for reduced drug consumption clearly described.
7.1.8. Potential Cases of Acute Kidney Injury
Participants exposed to IMP demonstrating transient or sustained increase in Screat (with 
decrease in Screat-based eGFR or eCrCL require expedited evaluation to differentiate AKI 
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from DICI. DICI is defined as transporter-mediated effect related to altered renal tubular 
creatinine handling without histological injury. 
AKI may be due to one or more types of injury, including DIKI. Differentiation of DIKI 
from other causes of AKI and from DICI may require clinical, radiographic, histopathologic, 
and laboratory assessments, as well as nephrology consultation.
Follow-Up Assessments
The participant should return to the site for evaluation as soon as possible, preferably within 
48 hours of awareness of the abnormal results. 
Evaluation should include physical examination, laboratory tests, detailed medical and 
surgical history, review of all medications (including recreational drugs and supplements 
[herbal]), family history, sexual history, travel history, blood transfusion, and potential 
occupational exposure to chemicals.
Laboratory assessments should include simultaneous serum cystatin C (Scys) and serum 
creatinine (Screat) tests. Estimates of eGFR, eCrCl and Screat-based eGFR and combined 
Screat-Scys-based eGFR should also be derived using the appropriate equation described in 
Appendix 6.
Assessments of urine albumin-to-creatinine ratio or urine volume may also be performed as 
appropriate.
Differentiating Acute Kidney Injury from DICI 
A confirmed Screat increase is defined as:
(i) ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours OR 
(ii) confirmed Screat increase ≥1.5 times baseline (known or suspected to have occurred 
within the prior 7 days). 
Based on the assessments performed, suspected AKI (including DIKI) may be differentiated 
from DICI as follows.
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Adult Participants
AKI (including DIKI)
Any one of the below
DICI
Scys & Screat
Simultaneous, confirmed serum 
cystatin C (Scys) increase and 
confirmed Screat increase 
Confirmed Screat increase 
without confirmed increase in 
reflex Scys 
AND 
Confirmed Screat-based eGFR 
decrease without confirmed 
combined Screat-Scys-based 
eGFR decrease.
eGFR
Decrease in Screat-based eGFR 
and combined Screat-Scys-based 
eGFR (when available)
Albuminuria or proteinuria
Confirmed albuminuria increase 
(see Appendix 6 for Grades A1 to 
A3 quantitation)
Urine volume
Urine volume <0.5 mL/kg/h for 6 
consecutive hours
Regardless of the presence or absence of increase in Screat, DIKI and other causes of AKI 
may be suspected if either (i) new-onset or worsening albuminuria or proteinuria are detected 
or (ii) urine volume (if measured) is <0.5 mL/kg/h for 6 consecutive hours.
All confirmed cases of clinically relevant decrease in kidney function should be considered 
potential cases of DIKI if no other reason for the kidney function abnormalities has been 
found.
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7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at their own request. Reasons for 
discontinuation from include the following: 

Adverse event

Death

Lost to follow up

Physician decision

Pregnancy

Protocol deviation

Study terminated by Sponsor

Withdrawal by participant

Lack of efficacy

Other
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted. See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed.
The early discontinuation visit applies only to participants who are enrolled/randomized and 
then are prematurely withdrawn from the study. Participants should be questioned regarding 
their reason for withdrawal. 
The participant will be permanently discontinued from the study intervention and the study at 
that time.
If a participant withdraws from the study, they may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
for disclosure of future information, no further evaluations will be performed and no 
additional data will be collected. The sponsor may retain and continue to use any data 
collected before such withdrawal of consent.
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7.2.1. Withdrawal of Consent 
Participants who request to discontinue receipt of study intervention will remain in the study 
and must continue to be followed for protocol-specified follow-up procedures. The only 
exception to this is when a participant specifically withdraws consent for any further contact 
with them or persons previously authorized by the participant to provide this information. 
Participants should notify the investigator in writing of the decision to withdraw consent 
from future follow-up, whenever possible. The withdrawal of consent should be explained in 
detail in the medical records by the investigator, as to whether the withdrawal is only from 
further receipt of study intervention or also from study procedures and/or posttreatment study 
follow-up, and entered on the appropriate CRF page. In the event that vital status (whether 
the participant is alive or dead) is being measured, publicly available information should be 
used to determine vital status only as appropriately directed in accordance with local law.
7.3. Lost to Follow-Up 
A participant will be considered lost to follow-up if the participant repeatedly fails to return 
for scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to attend a required study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible. Counsel the participant on the importance of maintaining the assigned visit 
schedule, and ascertain whether the participant wishes to and/or should continue in the 
study;

Before a participant is deemed lost to followup, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record;

Should the participant continue to be unreachable, the participant will be considered to 
have withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
8.1. Administrative Procedures
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures. 
Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
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All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Chest imaging conducted as part of the participant’s routine clinical management ( and 
obtained (within 12 weeks of Day 1) before signing of the ICD may be utilized for screening 
or baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that make it unfeasible to perform the 
test. In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant. When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that they have taken to ensure that required processes are adhered to as soon as 
possible. The study team must be informed of these incidents in a timely manner.
Laboratory results that have been collected for the purposes of this study and could unblind 
the study will not be reported to investigative sites or other blinded personnel.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
165 mL. The actual collection times of blood sampling may change. Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 56 consecutive 
days. 
8.1.1. Baseline Procedures 
8.1.1.1. Demography and Other Participant Characteristics
Demographics including year of birth, sex at birth, Hispanic ethnicity, and race as described 
by the participant will be collected at screening. As part of baseline characteristics, a skin 
type assessment will be done at the Screening visit using the Fitzpatrick Skin Type 
assessment. This assessment classifies a person’s skin type by their response to sun exposure 
(ie, burning or tanning).
8.1.1.2. Prior and Ongoing Therapies
Any use of S1P receptor modulators (eg, fingolimod, siponimod, ozanimod), α4β1 integrin 
receptor antagonist (eg, natalizumab), or vaccines for COVID-19 at any time prior to 
enrollment must be recorded. All AD therapy attempts, both systemic and topical, within 
1 year prior to screening will be recorded. Use of any other medication or therapy listed in 
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Table 1 within 24 weeks of screening will be recorded to confirm last known dose/treatment 
meets washout requirements. All other medications and procedures conducted within 30 days 
prior to screening will be recorded at screening. For prior AD therapies, documentation 
should include history of inadequate response to and/or intolerance to prior treatment. 
Updates to medications or procedures prior to dosing at the Day 1 visit should be made as 
needed.
8.1.1.3. Medical History/AD History
A complete medical history of each participant will be collected and documented during 
screening to determine participant eligibility. The history should include illnesses, 
hospitalizations, procedures, and participation in other investigational drug studies.
The diagnosis of AD by Hanifin and Rajka criteria1, and the duration of AD will be recorded.
8.1.1.4. Suicidal Ideation and Behavior Risk Screening
Any psychiatric condition including recent (within the past year) or active suicidal 
ideation/behavior that, in the investigator’s judgement, may increase the risk of study 
participation and make the participant inappropriate for the study. 
The C-SSRS is a validated tool for investigative staff to use to evaluate suicidal ideation and 
behavior.36 At the screening visit, if there are “yes” answers on items 4 or 5 in the past year, 
or if there is a “yes” answer to any of the suicidal behavior items of the C-SSRS in the past 5 
years, the participant will not be included in the study as deemed by the investigator unless a 
mental health professional judges the potential benefits of the participant’s inclusion 
outweigh the risks, and this is documented in the source. Trained site staff is to administer 
the C-SSRS to all participants at screening and immediately score to assess the participant’s 
eligibility based on the answers. 
For participants meeting screening exclusionary results on the C-SSRS, the participant 
should be referred for follow up with a mental health professional practice.
8.1.2. Telehealth Visits
The following visits may be conducted via Telehealth only due to pandemic/regional 
emergency situations:

In Part 1 OLE only due to the risk of unblinding: Visits 7, 9 (Week 24, 40) and SFU1 but 
not SFU1 after DB portion (if applicable) 

In Part 2: Visits 3, 5, 7 (Weeks 8, 24, 44) and SFU1
In the event that in-clinic study visit cannot be conducted, every effort should be made to 
follow up on safety of study participants at scheduled visits per the SoA or unscheduled 
visits. 
Telehealth visits may be used to assess participant safety and collect data points. Telehealth 
includes the exchange of healthcare information and services via telecommunication 
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technologies (eg, audio, video, videoconferencing software) remotely, allowing the 
participant and the investigator to 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 intervention(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 8.4.

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 participant is adhering to the contraception method(s) required in the protocol. Refer 
to Appendix 4. 

The substitution of the in-clinic visit by a telehealth visit for efficacy assessments can 
increase data variability and require changes to the planned SAP, therefore Clinician 
Reported Outcomes (IGA, EASI) should not to be performed at a telehealth visit.

Unless clinically urgent, blood work collection for WBC and TBNK are not permitted at 
a local laboratory during the Part 1 DB portion due to risk of unblinding; however, blood 
work may be collected at a certified local laboratory if permitted by local regulations 
during Part 1 OLE and during Part 2.
Study participants must be reminded to promptly notify site staff about any change in their 
health status.
8.1.3. Home Health Visits 
The following visits may be conducted via Home Health only due to pandemic/regional 
emergency situations and only by site investigators who are qualified raters:

In Part 1 OLE only due to the risk of unblinding: Visits 7, 9 (Week 24, 40) and SFU1 but 
not SFU1 after DB portion (if applicable) 

In Part 2: Visits 3, 5, 7 (Weeks 8, 24, 44) and SFU1
Home health visits will be only conducted by site investigators who are qualified raters. 
In the event that in-clinic study visit cannot be conducted, every effort should be made to 
follow up on safety of study participants at scheduled visits per the SoA or unscheduled 
visits. 
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A home health care service may be utilized to facilitate scheduled visits. Home health visits 
include a healthcare provider conducting an in-person study visit at the participant’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 intervention(s), including compliance and missed doses.

Review and record any AEs and SAEs since the last contact. Refer to Section 8.4.

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 participant is adhering to the contraception method(s) required in the protocol. Refer 
to Appendix 4. 

Unless clinically urgent, blood work collection for WBC and TBNK are not permitted at 
a local laboratory during the Part 1 DB portion due to risk of unblinding; however, blood 
work may be collected at a certified local laboratory if permitted by local regulations 
during Part 1 OLE and during Part 2.

Clinical laboratory assessments vital signs, ECGs, physical examination.
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor.
8.2. Efficacy Assessments
Clinician Reported Outcomes include IGA, EASI, and BSA assessments and will be 
conducted only if a qualified rater is available. Rater qualifications are defined in Section
8.2.1. Patient Reported Outcomes (PROs) include PP-NRS, Skin Pain NRS, and POEM.
8.2.1. Rater Qualifications 
For specific rating assessments, only qualified raters will be allowed to evaluate and/or rate 
participants in this study. The minimum qualifications a rater must meet for each study rating 
assessment will be outlined in the Rater Qualification Plan provided to each participating 
site. The level of experience with the target population (or equivalent), specific scale 
experience (or equivalent), and certification required (if applicable) will be listed and used to 
determine whether a rater is approved for a given assessment. The rater must become 
certified to perform selected study assessments before they can participate in the conduct of 
the study. For specifically defined assessments, rater training and standardization exercises 
may be conducted, and written documentation will be provided by the site for each rater’s 
certification. In return, each site will be provided written documentation outlining each 
rater’s certification for specific study assessments. Recertification may be required at 
periodic intervals during the study. The raters who administer specific study assessments will 
be documented in a centralized location and all site staff who administer ratings will be 
verified in the site study documentation during the conduct of the study.
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Clinical evaluations of atopic dermatitis will be performed by an experienced and qualified 
dermatologist (board certified or equivalent) or an experienced and qualified nondermatology 
physician. Alternatively, an experienced and qualified medical professional with experience 
in the conduct of dermatology clinical trials may be permitted to perform the clinical 
evaluations of atopic dermatitis when designated by the primary site Investigator. The 
evaluator must receive and document protocol specific and applicable efficacy assessment 
scales training prior to performing these evaluations. To ensure consistency and reduce 
variability, the same evaluator must assess all dermatological clinical evaluations for any 
individual participant throughout the study whenever possible; a backup experienced and 
qualified, protocol trained evaluator will only be allowed and documented in case of 
emergency or special situations when the designated evaluator is unable to perform the 
evaluation.
8.2.2. Clinical Assessments
All PROs and AD clinical assessments should be completed prior to other clinical activities 
and study intervention administration. Results of clinical assessment of AD should not be
shared with the participant until they have completed their PROs.
8.2.2.1. IGA
The Investigator’s Global Assessment of atopic dermatitis is scored on a 5-point scale (0-4), 
reflecting a global consideration of the erythema, induration and scaling. The clinical 
evaluator of atopic dermatitis will perform an assessment of the overall severity of atopic 
dermatitis and assign an IGA score and category as described in Table 2. The assessment will 
be a static evaluation without regard to the score at a previous visit.
The IGA will be performed at time points specified in the Schedule of Assessments SoA.
Table 2.
IGA of Atopic Dermatitis Score
Score
Category
Description
0
Clear
Atopic dermatitis is cleared, except for any residual discoloration 
(post-inflammatory hyperpigmentation and/or hypopigmentation).
1
Almost Clear
Overall, the atopic dermatitis is not entirely cleared and remaining 
lesions are light pink (not including post inflammatory 
hyperpigmentation) and/or; have barely palpable hard thickened skin 
and/or papules and/or; have barely perceptible lichenification; 
excoriation and oozing/crusting are absent.
2
Mild
Overall, the atopic dermatitis consists of lesions that are light red; with 
slight, but definite hard thickened skin and/or papules; with slight, but 
definite linear or picked scratch marks or penetrating surface injury; 
with slight, but definite thickened skin, fine skin markings, and 
lichenoid scale; oozing/crusting is absent.
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Table 2.
IGA of Atopic Dermatitis Score
Score
Category
Description
3
Moderate
Overall, the atopic dermatitis consists of lesions that are red; with easily 
palpable moderate hard thickened skin and/or papules; with moderate 
linear or picked scratch marks or penetrating surface injury; with 
moderate thickened skin, coarse skin markings, and coarse lichenoid 
scale; with slight oozing/crusting.
4
Severe
Overall, the atopic dermatitis consists of lesions that are deep, dark red; 
with severe hard thickened skin and/or papules; with severe linear or 
picked scratch marks or penetrating surface injury; with severe 
thickened skin with very coarse skin markings and lichenoid scale; with 
moderate-to-severe oozing/crusting.
8.2.2.2. EASI
The EASI quantifies the severity of a participant’s atopic dermatitis based on both severity of 
lesion clinical signs and the percent of BSA affected. EASI is a composite scoring by the 
atopic dermatitis clinical evaluator of the degree of erythema, induration/papulation, 
excoriation, and lichenification (each scored separately) for each of four body regions, with 
adjustment for the percent of BSA involved for each body region and for the proportion of 
the body region to the whole body.
Lesion Severity by Clinical Signs: The basic characteristics of atopic dermatitis 
lesions-erythema, induration/papulation, excoriation, and lichenification-provide a means for 
assessing the severity of lesions. Assessment of these four main clinical signs is performed 
separately for four body regions: head and neck, upper limbs, trunk (including axillae and 
groin) and lower limbs (including buttocks). Average erythema, induration/papulation, 
excoriation, and lichenification are scored for each body region according to a 4-point scale: 
0 = absent; 1 = mild; 2 = moderate; 3 = severe. Morphologic descriptors for each clinical sign 
severity score are shown in Table 3. 
Table 3.
Clinical Sign Severity Scoring Criteria for EASI
Score
Description
Erythema (E)
0
Absent
None; may have residual discoloration (post-inflammatory 
hyperpigmentation and/or hypopigmentation).
1
Mild
Light pink to light red
2
Moderate
Red
3
Severe
Deep, dark red
Induration/Papulation (I)
0
Absent
None
1
Mild
Barely palpable to slight, but definite hard thickened skin and/or 
papules
2
Moderate
Easily palpable moderate hard thickened skin and/or papules
3
Severe
Severe hard thickened skin and/or papules
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Table 3.
Clinical Sign Severity Scoring Criteria for EASI
Score
Description
Excoriation (Ex)
0
Absent
None
1
Mild
Slight, but definite linear or picked scratch marks or penetrating 
surface injury
2
Moderate
Moderate linear or picked scratch marks or penetrating surface 
injury
3
Severe
Severe linear or picked scratch marks or penetrating surface 
injury
Lichenification (L)
0
Absent
None
1
Mild
Barely perceptible to slight, but definite thickened skin, fine skin 
markings, and lichenoid scale
2
Moderate
Moderate thickened skin, coarse skin markings, and coarse 
lichenoid scale
3
Severe
Severe thickened skin with very coarse skin markings and 
lichenoid scale
Percent BSA with Atopic Dermatitis: The number of handprints of skin afflicted with 
atopic dermatitis in a body region can be used to determine the extent (%) to which a body 
region is involved with atopic dermatitis (Table 4). When measuring, the handprint unit 
refers to the size of each individual participant’s hand with fingers in a closed position.
Table 4.
Handprint Determination of BSA
Body Region
Total Number of 
Handprints in Body 
Region*
Surface Area of Body 
Region Equivalent of One 
Handprint*
Head and Neck
10
10%
Upper Limbs
20
5%
Trunk (including axillae and 
groin/genitals)
30
3.33%
Lower Limbs (including 
buttocks)
40
2.5%
*Handprint refers to the hand size of each individual participant.
The extent (%) to which each of the four body regions is involved with atopic dermatitis is 
categorized to a numerical Area Score using a non-linear scaling method according to the 
following BSA scoring criteria (Table 5).
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Table 5.
Eczema Area and Severity Index Score Criteria
Percent BSA with Atopic Dermatitis in a Body Region
Area Score
0%
0
>0 - <10%
1
10 - <30%
2
30 - <50%
3
50 - <70%
4
70 - <90%
5
90 - 100%
6
Body Region Weighting: Each body region is weighted according to its approximate 
percentage of the whole body (Table 6).
Table 6.
EASI Body Region Weighting
Body Region
Body Region Weighting
Head and Neck
0.1
Upper Limbs
0.2
Trunk (including axillae and groin/genitals)
0.3
Lower Limbs (including buttocks)
0.4
In each body region, the sum of the Clinical Signs Severity Scores for erythema, 
induration/papulation, excoriation, and lichenification is multiplied by the Area Score and by 
the Body Region Weighting to provide a body region value, which is then summed across all 
four body regions resulting in an EASI score as described in Equation 3.
Equation 3:
EASI = 0.1Ah(Eh+Ih+Exh+Lh) + 0.2Au(Eu+Iu+Exu+Lu) + 
0.3At(Et+It+Ext+Lt) + 0.4Al(El+Il+Exl+Ll)
A = Area Score; E = erythema; I = induration/papulation; Ex = excoriation; 
L = lichenification; h = head and neck; u = upper limbs; t = trunk; l = lower limbs
The EASI score can vary in increments of 0.1 and range from 0.0 to 72.0, with higher scores 
representing greater severity of atopic dermatitis.
8.2.2.3. Atopic Dermatitis BSA Involvement 
BSA affected by AD will be determined by the participant’s handprint method, where the full 
hand of the participant (ie, the participant’s fully extended palm, fingers and thumb together 
in a closed position) represents approximately 1% of total BSA. The BSA AD involvement 
ranges from 0 to 100%, with higher values representing greater severity of AD. The BSA is 
performed separately for 4 regions of the body: Region 1 – head and neck; Region 2 – trunk 
(including genital area); Region 3 – upper limbs; and Region 4 – lower limbs (including 
buttocks) (Table 4). BSA Efficacy will be derived from the sum of the BSA in handprints 
across 4 body regions assessed as part of the EASI assessment.
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The BSA assessment will be performed at timepoints specified in the SoA.
8.2.3. PROs
All PROs and AD clinical assessments should be completed prior to other clinical activities 
and investigative product administration. Results of clinical assessment of AD should not be 
shared with the participant until they have completed their PROs. The PROs should be 
checked for completeness by the study site staff before proceeding with other steps of the 
clinical visit procedures. 
8.2.3.1. PP-NRS
The PP-NRS is a single-item measuring a 0 (no itch) to 10 (worst itch imaginable) NRS 
rating scale to assess itch at the worst moment during the previous 24 hours. Participants will 
complete the PP-NRS at study visits specified in the SoA.
8.2.3.2. Skin Pain NRS
The Skin Pain NRS is a single-item score using a 0 (no skin pain) to 10 (worst skin pain 
imaginable) NRS rating scale to assess the skin pain at its worst over the previous 24 hours. 
Participants will complete the Skin Pain NRS at study visits specified in the SoA.
8.2.3.3. POEM
The POEM is a 7-item measure used for monitoring symptom severity of atopic eczema. 37,38
To address severity, the POEM measures 7 aspects of the experiences of participants with 
eczema including skin itch, sleep disturbance, skin bleeding, weeping/oozing of the skin, 
cracked skin, flaking skin, and skin dryness/roughness. Participants are asked to answer 
based on the number of days they experienced each on a 5-point scale (0: No days, 1: 1 to 2 
days, 2: 3 to 4 days, 3: 5 to 6 days, and 4: everyday) over the past week based on recall. The 
scores from the 7 questions are accumulated to provide an overall POEM score with a range 
of 0 to 28. An overall POEM score is as follows: 0 to 2 = ‘clear/almost clear’; 3 to 7 = 
‘mild’; 8 to 16 = ‘moderate’; 17 to 24 = ‘severe’; and 25 to 28 = ‘very severe’ atopic eczema.
The POEM will be assessed at timepoints specified in the SoA.
8.3. Safety Assessments
Planned time points for all safety assessments are provided in the SoA. Unscheduled safety 
measurements may be obtained at any time during the study to assess any perceived safety 
issues.
8.3.1. Physical Examinations
A complete physical examination will include, at a minimum, assessments of the general 
inspection, head/ears/eyes/nose/throat examination, neck and thyroid, lymph nodes, cardiac 
examination, auscultation of lungs, skin, abdominal examination (liver, spleen, and lower 
abdomen), neurological assessment, musculoskeletal assessment to include lower extremity 
edema evaluation systems. Height (at Day 1 only) and weight will also be measured and 
recorded.
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Symptom-directed (focused) physical examinations may be performed at the Investigator’s 
discretion at any time during the study and should include, at a minimum, a physical 
examination that assesses any new signs or symptoms. Investigators should pay special 
attention to clinical signs related to previous serious illnesses. 
Physical examination findings collected during the study will be considered source data and 
will not be required to be reported, unless otherwise noted. Any untoward physical 
examination findings that are identified during the active collection period and meet the 
definition of an AE or SAE (Appendix 3) must be reported according to the processes in 
Sections 8.4.1 to 8.4.3.
8.3.2. Vital Signs
Resting vital signs measurements will be made in the seated position and include pulse rate, 
blood pressure, body temperature, and respiratory rate. Pulse rate will be collected as part of 
vital signs and heart rate will be collected as part of the ECG. Vital signs will be measured 
prior to any blood draws that occur within the same collection window. Vital signs will be 
collected at timepoints specified in the SoA. See Section 10.10.3.1.2 for first dose cardiac 
monitoring details. If the first reading is abnormal for any parameters, they may be repeated 
up to 2 times during a visit (only applicable to first dose cardiac monitoring or cardiac 
monitoring during the treatment reinitiation following the defined periods of treatment 
interruption).
Any untoward vital sign findings that are identified during the active collection period and 
meet the definition of an AE or SAE (Appendix 3) must be reported according to the 
processes in Sections 8.4.1 to 8.4.3. 
8.3.2.1. Blood Pressure and Pulse Rate
BP and PR measurements will be assessed in the seated position with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available.
BP and PR measurements should be preceded by at least 5 minutes of rest with the 
participant in a sitting position, in a quiet setting without distractions.
Vital signs will be taken before blood collection for laboratory tests and consist of a single 
measurement of PR and 3 BP measurements (3 consecutive BP readings will be recorded at 
intervals of at least 1 minute apart). The average of the 3 BP readings will be recorded on the 
CRF. See Section 10.10.3 for first dose cardiac monitoring details. 
8.3.2.2. Temperature and Respiratory Rate
Temperature, and respiratory rate, will be assessed.
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Temperature and respiratory rate findings collected during the study will be considered 
source record and will not be required to be reported, unless they meet the definition of AE 
or SAE (see Section 8.2.2).
8.3.3. Electrocardiograms
Every attempt should be made to ensure the participant ECG readings are obtained using the 
same machine throughout the study. ECGs recordings will be transferred to and interpreted 
by a central reader. Parameters to be provided on the confirmed read for each safety ECG are 
HR and the following intervals: RR, PR, QRS, QT, QTc, and QTcF. 
ECG values of potential concern and are exclusionary at Screening and Day 1 predose are 
noted below.  A complete review of conditions or treatments that may affect cardiovascular 
function are seen in Protocol Section 5.2 Exclusion Criterion #13.

Screening or Day 1 predose ECG with PR interval ≥200 ms or QTcF ≥450 ms 
in males or ≥470 ms in females are exclusionary.
ECG values of potential concern for all other visits are listed in Protocol Sections 7.1.3 and
10.7.
Use ECG machine provided to the site; local ECG machine can be used only if provided 
ECG machine is not functional. Qualified study site personnel must order, receive, and 
review results.
Standard 12-lead ECGs utilizing limb leads (with a 10-second rhythm strip) should be 
collected at times specified in the SoA section of this protocol using an ECG machine that 
automatically calculates the HR and measures PR interval, QT interval, QTcF, and QRS 
complex. Alternative lead placement methodology using torso leads (eg, Mason-Likar) 
should not be used given the potential risk of discrepancies with ECGs acquired using 
standard limb lead placement. All scheduled ECGs should be performed after the participant 
has rested quietly for at least 5 minutes in a supine position. If a meal or snack is scheduled at 
the same time as an ECG, the ECG measurement must be performed prior to the meal or 
snack.
ECGs will be interpreted by a central reader. Clinically significant or exclusionary ECG 
findings at the screening visit will result in screen failure. The final ECG report from the 
central laboratory should be maintained in the participant’s source documentation and be the 
final interpretation of the ECG recording. Any clinically significant changes from the 
baseline/Day 1 ECG may potentially be AEs (Section 10.3) and should be evaluated further, 
as clinically warranted. 
The Investigator will be responsible for review and interpretation of ECGs on site and 
assessing whether the ECG is normal, abnormal clinically insignificant, or abnormal 
clinically significant. Abnormal clinically significant findings will be documented in the 
eCRF. All ECGs performed should be available for collection upon request. 
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In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead 
placement as contributing to the ECG abnormality. It is important that leads be placed in the 
same positions each time in order to achieve precise ECG recordings. If a machine-read QTc 
value is prolonged, as defined above, repeat measurements may not be necessary if a 
qualified medical provider’s interpretation determines that the QTcF values are in the 
acceptable range. Please refer to Section 7.1.3. ECG Changes for guidance on QTcF changes 
management.
Specific guidance on cardiac monitoring including ECG assessment following the first dose 
is provided in Section 10.10.3
ECGs will be performed at timepoints specified in the Schedule of Assessments SoA and if 
clinically indicated at any time during the treatment period at the Investigator’s discretion
8.3.3.1. Alternative Facilities for Electrocardiograms 
If the participant is unable to visit the study site for ECGs, the participant may visit an 
alternative certified facility to have the ECGs performed. Use of alternative facilities for 
ECGs is not permitted on Day 1 (and Day 2, if applicable), Week 16 of Part 1 (and a day 
after, if extended cardiac monitoring is applicable), or for cardiac monitoring during 
treatment re-initiation after protocol pre-defined treatment interruptions (see Section 7.1.6).
Qualified study site personnel must order, receive, and review results.
8.3.4. Chest Imaging
Chest X-ray or other appropriate diagnostic image (ie, computerized tomography or magnetic 
resonance imaging) to aid in TB status determination may be performed up to 12 weeks prior 
to Day 1. Chest images (posterior/anterior and lateral views) are required of all participants. 
Official reading must be located and available in the source documentation. Having a 
negative chest image alone does not rule out latent TB, and is thus not sufficient to qualify 
for the study. Likewise, having a negative chest image but a positive IGRA or PPD/Mantoux 
does not qualify the participants to participate in the study.
8.3.5. Tuberculosis Testing
At the time of screening, all participants will undergo TB testing unless performed within 12 
weeks of Day 1. QFT-G in-Tube Test is the preferred testing method, however an alternative 
IGRA is permitted if QFT-G in-Tube is not available. The IGRA may be repeated once if the 
investigator deems this to be necessary. 
TB testing (IGRA and PPD, if needed) will be conducted at a certified local laboratory unless 
unavailable in which case the Central Lab will be used.
If the results of IGRA (eg, QFT-G In-Tube test) cannot be determined by the reference 
laboratory to be either positive or negative, then participants may retest with the IGRA or be 
screened using the PPD Tuberculin Skin Test (Mantoux method) with approval of the study 
medical monitor. Participants must have the PPD test administered and evaluated by a health 
care professional 48 to 72 hours later in order to be eligible for the study, unless performed 
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and documented within the last 3 months. The test should be performed according to local 
standards with induration of <5 mm required for inclusion.
In addition to TB testing as specified in this clinical protocol, a chest image will be 
performed to aid in TB status determination. Following one year of total exposure to study 
intervention since the last TB test, all participants will undergo tuberculosis re-testing 
(including chest imaging) in regions which are above a low risk for Tuberculosis (ie, 
>10/100,000 incidence; as determined based on WHO country level data at the site below
https://worldhealthorg.shinyapps.io//tb_profiles/?_inputs_&entity_type="country"&lan="
EN"&iso2="AF"). 
QFT-G In-Tube is an in vitro diagnostic test using a peptide cocktail simulating ESAT6, 
CFP10 and TB 7.7 proteins to stimulate cells in heparinized whole blood. Detection of 
interferon gamma by ELISA is used to identify in vitro responses to these peptide antigens 
that are associated with Mycobacterium tuberculosis infection. QFT-G Gold In-Tube is an 
indirect test for M. tuberculosis infection (including disease) and is intended for use in 
conjunction with risk assessment, radiography, and other medical and diagnostic evaluations.
A blood sample (approximately 3 mL) will be collected at screening for IGRA testing (eg, 
QFT-G InTube test) at a certified local laboratory.
During Screening, a TB questionnaire will be completed by the Investigator for all 
participants. 
TB questionnaire will be completed at designated post-baseline study visits (per protocol 
schedule of assessments) for participants with suspected TB during the study and for 
participants who reside in regions which are above a low risk for TB (ie, >10/100,000 
incidence) as identified by WHO.
TB questionnaire findings collected during the study will be considered source record and 
will not be required to be reported, unless they meet the definition of an AE or SAE.
8.3.6. Clinical Safety Laboratory Assessments 
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in 
Appendix 2, must be conducted in accordance with the laboratory manual and the SoA. 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.
The investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the CRF.
Clinically significant abnormal laboratory test findings are those that are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
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All laboratory tests with values considered clinically significant and abnormal during 
participation in the study or within 28 days after the last dose of study intervention should be 
repeated until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or study medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Section 10.5 for suggested actions and follow-up assessments in the event of potential 
DILI.
See Section 10.6 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities.
For laboratory collection volumes, see the laboratory manual.
8.3.6.1. Alternative Facilities for Clinical Safety Laboratory Assessment
During Part 1 DB portion, all attempts should be made to collect bloodwork at the 
study site in order to use Central Lab analysis and maintain the blinding. If a study 
participant is unable to visit the site for protocol-specified safety laboratory evaluations, 
testing may be conducted at a certified local laboratory if permitted by local regulations in 
Part 1 OLE and Part 2. The local laboratory may be a standalone institution or within a 
hospital. Unless clinically urgent, blood work collection for WBC and TBNK are not 
permitted at a local laboratory during the Part 1 DB portion (including the SFU for 
participants who do not continue to Part 1 OLE) due to risk of unblinding; however, blood 
work may be collected at a certified local laboratory if permitted by local regulations during 
Part 1 OLE and during Part 2. If there is a question or safety concern, contact the unblinded 
independent medical monitor for guidance. Refer to Section 10.10.1.
If a local laboratory is used, qualified study site personnel must order, receive, and review 
results. Site staff must collect the local laboratory reference ranges and certifications/
accreditations for filing at the site. Laboratory test results are to be provided to the site staff 
as soon as possible. The local laboratory reports should be filed in the participant’s source 
documents/medical records. Relevant data from the local laboratory report should 
be recorded on the CRF.
8.3.7. Hepatitis Testing
Hepatitis B testing: HB surface antigen (HBsAg), HB core antibody (HBcAb), HB surface 
antibody (HBsAb).
Interpretation of Hepatitis B Testing Results: 

HBsAg negative and HBcAb negative: Participant is eligible for the study;

HBsAg positive and HBcAb negative: Participant is excluded from study participation;
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
HBsAg negative and HBcAb positive and HBsAb positive: Participant is eligible for 
study if HBV DNA is negative or below LLQ;
o
Participants who are HBsAg negative, HBcAb positive, and HBsAb positive at 
Screening will have reflex testing for HBV DNA. Participants who have HBV DNA 
at or above the LLQ will be excluded. Participants who are HBV DNA negative or 
below LLQ may enroll but will have HBV DNA testing repeated at Weeks 16, 68 or 
ET in Part 1 and Week 16, Week 52 or ET in Part 2. 

HBsAg negative and HBcAb positive and HBsAb negative: participant is excluded from 
study participation.
A single positive HBV DNA test result above the LLQ for a participant requires immediate 
and permanent discontinuation from treatment, and the study medical monitor (or designee) 
must be notified. The participant must be scheduled for an End of Treatment visit/Early 
Termination visit, enters the end of treatment follow up period, and must be scheduled for an 
End of Study visit. No further scheduled HBV DNA tests will be required for a participant 
once a result above the LLQ is established for that participant during any study in the 
program. 
Hepatitis C testing: Hepatitis C Antibody (HCV Ab), Hepatitis C Viral RNA (HCV RNA for 
confirmation of positive HCV Ab result). 
Interpretation of Hepatitis C Testing Results: 

HCV Ab positive and HCV RNA positive: participant is excluded from study 
participation.
8.3.8. Pregnancy Testing 
A serum pregnancy test is required at screening. Following screening, pregnancy tests may 
be urine or serum tests, and must have a sensitivity of at least 25 mIU/mL. Pregnancy tests 
will be performed in WOCBP at the times listed in the SoA. Following a negative pregnancy 
test result at screening, appropriate contraception must be commenced and a second negative 
pregnancy test result will be required at the baseline visit prior to the participant’s receiving 
the study intervention. Pregnancy tests will also be done whenever 1 menstrual cycle is 
missed during the active treatment period (or when potential pregnancy is otherwise 
suspected) and at the end of the study. Pregnancy tests may also be repeated if requested by 
IRBs/ECs or if required by local regulations. If a urine test cannot be confirmed as negative 
(eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant 
must be excluded if the serum pregnancy result is positive.
For visits that occur more than 4 weeks apart, participants must perform a home pregnancy 
test. Site personnel are expected to contact the participant every 4 weeks to confirm the home 
pregnancy test was taken, confirm participant continues to use contraception correctly, and 
document the pregnancy test results and contraception discussion in source. If home 
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pregnancy testing is not allowed per local regulations, pregnancy testing will be performed 
onsite during an unscheduled visit.
8.3.8.1. At-Home Pregnancy Testing
If a participant requiring pregnancy testing cannot visit a local laboratory, a home urine 
pregnancy testing kit with a sensitivity of at least 25 mIU/mL may be used by the participant 
to perform the test at home, if compliant with local regulatory requirements. The pregnancy 
test outcome should be documented in the participant’s source documents/medical records 
and relevant data recorded on the CRF. Confirm that the participant is adhering to the 
contraception method(s) required in the protocol.
8.3.9. Pulmonary Function Test (and DLCO)
Pulmonary function testing will include FEV1 and FVC measurements.  In addition, DLCO 
measurements will be performed, where locally available.  Pulmonary function testing will 
be performed in a pulmonary function laboratory or respiratory department per local 
regulations.  In exceptional cases, pulmonary function will be performed at the clinical trial 
site or qualified physician’s office by a qualified pulmonary technician/professional and 
results interpreted by a pulmonologist or other qualified physician, as per local standard 
practice.  This exception requires Sponsor’s approval. 
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). PFTs and DLCO assessments must be completed 
during the Screening Period (ie, prior to randomization). The window to perform PFTs and 
DLCO is ±10 days for all post-screening visits. Sites where DLCO is not available should 
consult the study medical monitor. PFTs and DLCO  will be conducted 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.39-41 Spirometers must be compliant with ATS/ERS guidelines for the 
standardization of spirometry, including calibration and record keeping. Records must be 
available to confirm compliance.
Participants who demonstrate a ≥ 20% decline in PFT values (FEV1 and/or FVC) from 
baseline after enrollment should have the PFT repeated for confirmation. Any issues with 
participant effort or compliance with the test procedure should be explicitly recorded. This 
information is important to determine whether PFT abnormalities may be the result of poor 
effort or compliance with test procedure. Smoking status (including e cigarettes) will be 
collected and recorded in the source record each time a PFT assessment is conducted. 
Participants 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 10.10.4.
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PFTs will be performed at timepoints specified in the SoA.
8.3.10. Ophthalmology Exam 
A complete ophthalmoscopy and OCT assessment will be performed at timepoints specified 
in the SoA and all clinically significant ophthalmic findings should be recorded in eCRF. 
Ophthalmoscopy and OCT assessment must be completed during the screening period (ie, 
prior to randomization) and the window is ± 10 days for all post-screening visits.
The OCT machine used should preferably not be changed during the study to allow for 
comparison of center point thickness measurements within each participant across 
timepoints.
The ophthalmologist/optometrist (where permitted) will 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.
Eye examination performed by an ophthalmologist will include:

Ophthalmologic history

Best corrected visual acuity measurement (autorefraction, using Snellen chart 
internationally)

Ophthalmoscopy

Intraocular pressure

May include contact lens biomicroscopy to examine the macula and optic disc

A dilated fundus exam should be performed in all participants at the Screening Visit and 
as needed at subsequent visits in participants with significant abnormalities identified on 
the screening exam. Participants 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 center point thickness (recorded in microns) 

FA (at the discretion of the ophthalmologist) if there is a suspicion of macular edema by 
ophthalmoscopy and increased center point thickness by OCT.
In the event that restrictions imposed by governments or regional health authorities, or safety 
recommendations issued by professional societies limit the capacity to perform OCT (eg, 
COVID 19 or similar public emergency situations), the 28-day screening period may be 
extended on a case-by-case basis to accommodate reasonable delays in OCT. The study 
medical monitor should be consulted on each case.
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When ophthalmoscopy with OCT cannot be performed, exclusion criterion 4 may be 
modified as shown by the following text to identify and exclude participants with potential 
macular edema at Screening: “History of macular edema or retinopathy 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 pandemic/regional emergency situations).” 
Under the scenario above, the missed ophthalmoscopy with OCT exam must be performed 
no later than 10 days after restrictions are lifted and the ophthalmology consultant’s office is 
opened for nonurgent ophthalmic evaluations. 
Participants 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 10.10.5.
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting
The definitions of an AE and an SAE can be found in Appendix 3.
AEs may arise from symptoms or other complaints reported to the investigator by the 
participant (or, when appropriate, by a caregiver, surrogate, or the participant's legally 
authorized representative), or they may arise from clinical findings of the investigator or 
other healthcare providers (clinical signs, test results, etc).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
During the active collection period as described in Section 8.4.1, each participant/legally 
authorized representative will be questioned about the occurrence of AEs in a nonleading 
manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.4.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before undergoing any study-related procedure and/or receiving study 
intervention, through and including a minimum of 4 weeks after the last administration of the 
study intervention. 
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Follow-up by the investigator continues throughout the active collection period and until the 
AE or SAE or its sequelae resolve or stabilize at a level acceptable to the investigator.
When a clinically important AE remains ongoing at the end of the active collection period, 
follow-up by the investigator continues until the AE or SAE or its sequelae resolve or 
stabilize at a level acceptable to the investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant permanently discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form. 
Investigators are not obligated to actively seek information on AEs or SAEs after the 
participant has concluded study participation. However, if the investigator learns of any SAE, 
including a death, at any time after a participant has concluded study participation, and they 
consider the event to be reasonably related to the study intervention, the investigator must 
promptly report the SAE to Pfizer using the CT SAE Report Form.
8.4.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period as described in
Section 8.4.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3. The investigator will submit any updated SAE data to the sponsor within 
24 hours of its being available.
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period, 
which begins after obtaining informed consent as described in Section 8.4.1, will be recorded 
on the AE section of the CRF. 
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE. To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study.
Reporting of AEs and SAEs for participants who fail screening are subject to the CRF 
requirements as described in Section 5.4.
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8.4.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.4.3. Follow-Up of AEs and SAEs
After the initial AE or SAE report, the investigator is required to proactively follow each 
participant/legally authorized representative at subsequent visits/contacts. For each event, the 
investigator must pursue and obtain adequate information until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in 
Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided. In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is provided in Appendix 3.
8.4.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/EC, if appropriate according to local requirements.
8.4.5. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure occurs when a person not enrolled in the study as a participant 
receives unplanned direct contact with or exposure to the study intervention. Such exposure 
may or may not lead to the occurrence of an AE or SAE. Persons at risk for environmental 
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exposure include healthcare providers, family members, and others who may be exposed. An 
environmental exposure may include EDP, EDB, and occupational exposure.
Any such exposures to the study intervention under study are reportable to Pfizer Safety 
within 24 hours of investigator awareness.
8.4.5.1. Exposure During Pregnancy
An EDP occurs if:

A female participant is found to be pregnant while receiving or after discontinuing 
study intervention. 

A male participant who is receiving or has discontinued study intervention 
inseminates a female partner. 

A female nonparticipant is found to be pregnant while being exposed or having been 
exposed to study intervention because of environmental exposure. Below are 
examples of environmental EDP: 
A female family member or healthcare provider reports that she is pregnant after having been 
exposed to the study intervention by ingestion, inhalation, or skin contact.

A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion, inhalation, or skin contact then inseminates his female 
partner prior to or around the time of conception.
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant/participant’s partner, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP Supplemental 
Form, regardless of whether an SAE has occurred. Details of the pregnancy will be 
collected after the start of study intervention and until pregnancy completion or 
termination. 

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form. Since the exposure information does not pertain to the participant enrolled in 
the study, the information is not recorded on a CRF; however, a copy of the 
completed report is maintained in the investigator site file.
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
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follow-up to the initial report. In the case of a live birth, the structural integrity of the neonate 
can be assessed at the time of birth. In the event of a termination, the reason(s) for 
termination should be specified and, if clinically possible, the structural integrity of the 
terminated fetus should be assessed by gross visual inspection (unless preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
Abnormal pregnancy outcomes are considered SAEs. If the outcome of the pregnancy meets 
the criteria for an SAE (ie, ectopic pregnancy, spontaneous abortion, intrauterine fetal 
demise, neonatal death, or congenital anomaly in a live-born baby, a terminated fetus, an 
intrauterine fetal demise, or a neonatal death), the investigator should follow the procedures 
for reporting SAEs. Additional information about pregnancy outcomes that are reported to 
Pfizer Safety as SAEs follows: 

Spontaneous abortion including miscarriage and missed abortion should be reported 
as an SAE;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the study intervention. 
Additional information regarding the EDP may be requested by the sponsor. Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the participant with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.
8.4.5.2. Exposure During Breastfeeding
An EDB occurs if:

A female participant is found to be breastfeeding while receiving or after 
discontinuing study intervention. 

A female nonparticipant is found to be breastfeeding while being exposed or having 
been exposed to study intervention (ie, environmental exposure). An example of 
environmental EDB is a female family member or healthcare provider who reports 
that she is breastfeeding after having been exposed to the study intervention by 
ingestion, inhalation, or skin contact. 
The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The information must be reported 
using the CT SAE Report Form. When EDB occurs in the setting of environmental exposure, 
the exposure information does not pertain to the participant enrolled in the study, so the 
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information is not recorded on a CRF. However, a copy of the completed report is maintained 
in the investigator site file.
An EDB report is not created when a Pfizer drug specifically approved for use in 
breastfeeding women (eg, vitamins) is administered in accordance with authorized use. 
However, if the infant experiences an SAE associated with such a drug, the SAE is reported 
together with the EDB.
8.4.5.3. 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 participant enrolled in the study, the information is not recorded on a CRF; 
however, a copy of the completed report is maintained in the investigator site file.
8.4.6. Cardiovascular and Death Events
Based on the mechanism of action of etrasimod and prior experience with etrasimod and 
other agents acting via a similar mechanism, certain AESIs have been identified as they may 
be associated with exposure to etrasimod. In addition to appropriate reporting of these events 
as an adverse event or SAE, supplementary detailed information may be collected, and close 
monitoring may be required. 
Cardiovascular AESIs associated with S1P receptor modulators, such as etrasimod, include 
HR reduction and/or transient atrioventricular conduction delays after the initial dose. For 
participants who experience a cardiovascular symptomatic event (eg, chest pain, dizziness, 
palpitations, lightheadedness, shortness of breath, and/or syncope) at any time during the 
first-dose cardiac monitoring, the Investigator should determine whether or not this event is 
associated with a HR reduction or clinically relevant change in 12 lead ECG.
Cardiac monitoring is described in Section 10.10.3.
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
8.4.8. Adverse Events of Special Interest
AESIs are examined as part of routine safety data review procedures throughout the clinical 
trial and as part of signal detection processes. They require close monitoring and are assessed 
as close to real time as possible, and they are promptly reported to the study monitor even if 
the event is not considered an SAE according to the criteria in Section 10.3.2. Should an 
aggregate analysis indicate that these prespecified events occur more frequently than 
expected, eg, based on epidemiological data, literature, or other data, then this will be 
submitted and reported in accordance with Pfizer’s safety reporting requirements. Aggregate 
analyses of safety data will be performed on a regular basis per internal SOPs. 
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All AESIs must be reported as an AE or SAE following the procedures described in 
Sections 8.4.1 through 8.4.4. An AESI is to be recorded as an AE or SAE on the CRF. In 
addition, an AESI that is also an SAE must be reported using the CT SAE Report Form or via 
PSSA.
AESI for etrasimod are:

Cardiovascular events (eg, bradycardia, AV conduction delay and hypertension),

Macular edema* (Section 10.10.5), 

Pulmonary events (airflow obstruction or decreased gas exchange; Section 10.10.4),

Infections (severe infections, opportunistic infections, Herpes simplex and Herpes zoster, 
PML*; Section 10.10.2 and Section 10.11),

Liver injury (liver transaminase elevation and bilirubin elevation; Section 10.5),

PRES*,

Malignancies*
* A diagnosis of this event requires permanent discontinuation of study intervention. See 
Section 7.1 for additional AEs requiring discontinuation. 
8.4.8.1. 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. 
8.4.9. Medical Device Deficiencies
Not applicable.
8.4.10. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.
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Medication errors are recorded and reported as follows:
Recorded on the 
Medication Error Page 
of the CRF
Recorded on the 
Adverse Event Page 
of the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
All (regardless of whether 
associated with an AE)
Any AE or SAE associated 
with the medication error
Only if associated with an 
SAE
Medication errors include:

Medication errors involving participant exposure to the study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.

Refer to Section 6.5 for examples of medication error related to compliance with 
study intervention.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, such medication errors occurring to a study participant are recorded on the 
medication error page of the CRF, which is a specific version of the AE page and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on the AE page of the 
CRF.
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 or via PSSA only when associated with an SAE.
8.5. Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
8.6. Genetics
Genetic analyses will not be collected in this study.
8.7. Biomarkers
Biomarkers are not evaluated in this study.
8.8. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
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8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in the SAP, which will be maintained by the sponsor. 
The SAP may modify what is outlined in the protocol where appropriate; however, any major 
modifications of the primary endpoint definitions will also be reflected in a protocol 
amendment. Data from Part 1 and Part 2 of the study will not be pooled.
9.1. Statistical Hypothesis
Part 1 of this study is an estimation study with the objective to estimate the IGA response 
rates of the treatment groups (Etrasimod 2 mg QD and Placebo) as well as the IGA response 
rate difference between the treatment groups at Week 16. There are no statistical hypotheses 
in this study. The sample size calculation considers only the precision of the estimation of 
IGA response rates and the treatment difference in response rate (Section 9.5). 
9.1.1. Estimands
9.1.1.1. Primary Estimand
The primary estimand (E1) is defined by the following attributes:
1. Treatment condition: received study intervention of etrasimod 2 mg QD or placebo.
2. Population: Participants with moderate-to-severe AD as defined by the inclusion and 
exclusion criteria.
3. Variables: Proportion of participants achieving IGA score of clear (0) or almost clear 
(1) and a reduction from baseline of ≥2 points at Week 16. A participant who 
experiences an intercurrent event of initiation of prohibited medications or 
discontinuation of study treatment due to any reason (whichever is earlier), will be 
considered an IGA non-responder (ie, treatment failure) at Week 16.
4. Intercurrent Events: 
A) Initiation of prohibited medications – a participant who receives prohibited 
medication post-randomization prior to the Week 16 visit will be considered an IGA 
non-responder (ie, treatment failure) at Week 16. 
B) Discontinuation of study intervention due to any reason prior to the Week 16 visit 
– a participant who discontinues study intervention due to any reason will be 
considered an IGA non-responder (ie, treatment failure) at Week 16. 
5. Population level summary: The difference in IGA response rates at Week 16 between 
etrasimod 2 mg QD and placebo.
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Estimand E1 will be similarly applied to the binary secondary endpoint (ie, EASI-75 at Week 
16) as well as the binary exploratory endpoints (eg, ≥4-point reduction from baseline in PP-
NRS score at Week 16) with the endpoint substituted appropriately. 
9.1.1.2. Secondary Estimands
Estimand (E2) strategy is defined for a continuous secondary endpoint at a visit (eg, percent 
change from baseline in EASI score at Week 16). The secondary estimand (E2) for 
continuous endpoints is defined by the following attributes:
1. Treatment condition: received study intervention of etrasimod 2 mg QD or placebo.
2. Population: Participants with moderate-to-severe AD as defined by inclusion and 
exclusion criteria.
3. Variables: Percent change from baseline in EASI total score at Week 16. If a 
participant in the etrasimod 2 mg QD group experiences the intercurrent event of 
initiation of prohibited medications or discontinuation of study treatment due to any 
reason (whichever is earlier), the endpoint data after the intercurrent event will be 
treated as missing and then imputed via multiple imputations as if they are in placebo 
group (ie, no treatment benefit).
4. Intercurrent events: 
A) Initiation of prohibited medications – a participant who receives prohibited 
medications post-randomization prior to Week 16, the endpoint data after the 
intercurrent event will be treated as missing and then imputed via multiple imputation 
as if they are in placebo group (ie, no treatment benefit). 
B) Discontinuation of study intervention due to any reason prior to the Week 16 visit
- a participant who discontinues study treatment due to any reason, the endpoint data 
after the intercurrent event will be treated as missing and then imputed via multiple 
imputation as if they are in placebo group (ie, no treatment benefit).  
5. Population-level summary: The mean difference in percent change from baseline in 
EASI score at Week 16 between etrasimod 2 mg QD and placebo.
Estimand E2 will also be applied to percent change from baseline in EASI score at visits 
prior to Week 16.
9.1.2. Multiplicity Adjustment
No multiplicity adjustment will be made in the study.
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9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Full analysis set 
All participants randomly assigned to study intervention, 
irrespective of whether they received any dose of study 
intervention. Participants will be analyzed in the treatment 
groups as they are randomized.
Safety analysis set
All participants randomly assigned to study intervention and 
who take at least 1 dose of study intervention. Participants 
will be analyzed according to the product they actually 
received.
9.3. Statistical Analyses
The SAP will be developed and finalized before any analyses are performed and will 
describe the analyses and procedures for accounting for missing, unused, and spurious data. 
This section is a summary of the planned statistical analyses of the primary and secondary 
endpoints.
9.3.1. General Considerations
The efficacy and safety data will be summarized by treatment group in Part 1. The Part 2 will 
be summarized separately. The efficacy endpoints will be summarized using descriptive 
statistics: the number and percent of participants for response-type endpoints, and with the 
number of participants, mean, standard deviation, median, minimum, and maximum for 
continuous endpoints.
9.3.2. Primary Endpoint Analysis
A landmark analysis of the IGA response endpoint at Week 16, defined in Section 9.1.1.1, 
will be performed in the FAS (among participants with baseline IGA ≥2) using the Cochran-
Mantel-Haenszel method adjusted for the actual randomization/stratification factor IGA 
score (3 [moderate AD], 4 [severe AD] based on clinical database) at Baseline using normal 
approximation for the difference in binomial proportions. The IGA response rate difference 
between the etrasimod group and the placebo group in the proportion of participants 
achieving (ie, IGA of clear (0) or almost clear (1) (on a 5-point scale) and a reduction of ≥ 2 
points from baseline at Week 16) along with its 95% confidence interval will be reported. 
Estimand E1 defined in Section 9.1.1.1 will be used. Any missing values after accounting for 
the intercurrent events will be considered as an IGA non-responder (ie, treatment failure). 
9.3.3. Secondary Endpoint Analysis
Binary secondary endpoints will be analyzed similarly to the primary endpoint.
A landmark analysis of continuous endpoints including percent change from baseline in 
EASI at Week 16, defined in Section 9.1.1.2. will be performed by the Jump-to-Control 
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(JTC) method. An MMRM that includes fixed effects of treatment group, visit, treatment 
group-by-visit interaction, actual randomization/stratification factor (baseline IGA of 3 or 4 
based on clinical database), actual-stratification-factor-by-visit interaction, EASI baseline 
value, and EASI-baseline-value-by-visit interaction will be used to analyze the endpoint’s 
data across all visits after accounting for intercurrent events as the imputation model. 
MMRM parameters will be estimated using Bayesian framework. Multiple imputation will 
be performed from multivariate conditional Normal distribution constructed from the 
sampled posterior parameter values. Participants in the etrasimod group with missing data at 
a visit will be imputed using mean estimated for the placebo group for the same visit (ie, JTC 
implementation). This will result in multiple imputed datasets for this visit. An ANCOVA 
model will include treatment group, EASI baseline value and actual 
randomization/stratification factor (IGA of 3 or 4 based on clinical database) as covariates 
and it will be applied to the multiple complete imputed datasets. Results of the multiple 
ANCOVA analyses will be combined using Rubin’s rules (Rubin 1987) to generate the 
combined LSM (SE) for each treatment group and LSM treatment difference estimate and its 
SE, 95% CI, and 2-sided p-value for the visit of interest. The EASI baseline value will be 
obtained on Day 1 or prior in the double-blind phase. Estimand E2 defined in Section 9.1.1.2
will be used. 
9.3.4. Tertiary/Exploratory Endpoint(s) Analysis
Exploratory endpoints will be analyzed descriptively. Any additional analyses will be
described in the SAP.
9.3.5. Safety Analyses
The safety data will be summarized in accordance with CDISC and Pfizer Standards (CaPS). 
All safety analyses will be performed on the safety population. Safety endpoints include 
Incidence of treatment emergent AEs and SAEs, clinically significant changes in laboratory 
tests and ECG. All safety analyses will be performed descriptively.
9.3.5.1. Electrocardiogram Analyses
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS complex will be summarized by treatment group and time.
Changes from baseline for the ECG parameters HR, QTcF, PR interval, and QRS complex 
will be summarized by treatment group and time. The frequency of uncorrected QT values 
above 500 ms will be tabulated.
The number (%) of participants with maximum postdose QTcF values and maximum 
increases from baseline in the following categories will be tabulated by treatment group: 
Safety QTcF Assessment
Degree of Prolongation
Mild (ms)
Moderate (ms)
Severe (ms)
Absolute value
>450-480
>480-500
>500
Increase from baseline
30-60
>60
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9.4. Interim Analyses
An interim analysis will be conducted to assess efficacy and safety after all Part 1 
participants complete the 16-week DB treatment period. The interim analysis results will be 
used for decisions regarding stopping for futility and internal program development. Study 
conduct, including Part 1 participant continuation in OLE, will continue while the data are 
prepared and analyzed for the IA. The Part 2 enrollment will not be triggered until after the 
IA shows an acceptable safety and efficacy of etrasimod 2 mg QD in the target population. 
Based on the IA results, the study may continue to enroll participants, or the study may be 
early terminated. Details on the IA will be provided in the SAP. The IA will be conducted by 
the Sponsor (refer to Section 4.1). Prior to this formal Part 1 DB IA, Sponsor may perform 
earlier unblinded interim analyses to inform internal decision-making regarding the 
development program. These earlier interim analyses will be conducted and reviewed by a 
limited number of team members independent of the study team.  Details on these earlier 
unblinded interim analyses will be described in an unblinding operational plan.
9.5. Sample Size Determination
Part 1: Approximately 60 participants will be randomized to etrasimod 2 mg QD or placebo 
in a ratio of 1:1 (30 participants per treatment group). This is an estimation study. The 
primary objective will be to estimate the proportion (95% CI) of participants achieving IGA 
response at Week 16 in each treatment group and the difference (95% CI) in proportions 
between the two groups.
With 30 participants per group, assuming the proportions of participants achieving IGA 
response at Week 16 are 9% and 39% for placebo and etrasimod 2 mg QD, respectively:

the half-width of the 2-sided 95% CI for the proportion of participants achieving IGA 
response at Week 16 will be ≤17.5% in each treatment group using normal 
approximation.

the half-width of the 2-sided 95% CI for the difference in proportions between 
etrasimod 2 mg QD and placebo will be 20.2% using normal approximation. 
The placebo response rate was estimated based on Phase 3 studies in literature.42-44
No adjustment for multiplicity will be made.
Part 2: Approximately 340 participants are planned in order to fulfill the safety database 
requirements. No formal sample size calculations are performed.
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. 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 participants.
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 participants.
The investigator will be responsible for the following:

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.
10.1.1.1. 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 
intervention, Pfizer should be informed immediately. 
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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of the ICH GCP guidelines that the investigator 
becomes aware of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process 
The investigator or the investigator’s representative will explain the nature of the study, 
including the risks and benefits, to the participant or their legally authorized representative
and answer all questions regarding the study. The participant or their legally authorized 
representative should be given sufficient time and opportunity to ask questions and to decide 
whether or not to participate in the trial.
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative (if allowed by local regulations) will be required to sign a statement 
of informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, privacy and data protection requirements, where applicable, and the IRB/EC or 
study center.
The investigator must ensure that each participant or their legally authorized representative is 
fully informed about the nature and objectives of the study, the sharing of data related to the 
study, and possible risks associated with participation, including the risks associated with the 
processing of the participant’s personal data. 
The participant or their legally authorized representative must be informed that their personal 
study-related data will be used by the sponsor in accordance with local data protection law. 
The level of disclosure must also be explained to the participant or their legally authorized 
representative.
The participant or their legally authorized representative must be informed that their medical 
records may be examined by Clinical Quality Assurance auditors or other authorized 
personnel appointed by the sponsor, by appropriate IRB/EC members, and by inspectors 
from regulatory authorities.
The investigator further must ensure that each study participant or their legally authorized 
representative is fully informed about their right to access and correct their personal data and 
to withdraw consent for the processing of their personal data.
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The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date on which the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICD.
Participants or their legally authorized representative must be reconsented to the most current 
version of the IRB/EC-approved ICD(s) during their participation in the study as required per 
local regulations.
A copy of the ICD(s) must be provided to the participant or their legally authorized 
representative (if allowed by local regulations).
Participants who are rescreened are required to sign a new ICD.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room to ensure that only 
authorized study staff have access. The study site will implement appropriate technical and 
organizational measures to ensure that the personal data can be recovered in the event of 
disaster. In the event of a potential personal data breach, the study site will be responsible for 
determining whether a personal data breach has in fact occurred and, if so, providing breach 
notifications as required by law.
To protect the rights and freedoms of participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The sponsor maintains standard operating procedures on how to respond in the event of 
unauthorized access, use, or disclosure of sponsor information or systems.
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10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will use an E-DMC. The E-DMC is independent of the study team and includes 
only external members. The E-DMC charter describes the role of the E-DMC in more detail.
The E-DMC will be responsible for ongoing monitoring of the safety of participants in the 
study according to the charter. The recommendations made by the E-DMC will be forwarded 
to the appropriate authorized Pfizer personnel for review and final decision. Pfizer will 
communicate such decisions, which may include summaries of aggregate analyses of 
endpoint events and of safety data that are not endpoints, to regulatory authorities and 
investigators, as appropriate. 
Members of the E-DMC and an independent statistician responsible for interacting with the 
E-DMC will have access to unblinded study data. The E-DMC recommendations to the study 
team will be communicated in a blinded fashion (ie, treatment assignment for individual 
participants will not be shared). To ensure the scientific integrity of the study, members of 
the E-DMC will not be directly involved in the ongoing management of the study.
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT/CTIS
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer-sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
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are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 
18 months after study completion. Participant-level data will be anonymized in accordance 
with applicable privacy laws and regulations. CSRs will have personally identifiable 
information anonymized.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
10.1.7. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
QTLs are predefined parameters that are monitored during the study. Important deviations 
from the QTLs and any remedial actions taken will be summarized in the CSR.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source records and documents. 
This verification may also occur after study completion. It is important that the 
investigator(s) and their relevant personnel are available during the monitoring visits and 
possible audits or inspections and that sufficient time is devoted to the process.
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Monitoring details describing strategy, including definition of study-critical data items and 
processes (eg, risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, virtual, or on-site monitoring), are provided in the data management plan and 
monitoring plan maintained and utilized by the sponsor or designee. 
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study. Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection. The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant’s medical records. The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent. Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.8. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
In this study, the CRF will serve as the source document. A document must be available at 
the investigative site that identifies those data that will be recorded on the CRF and for which 
the CRF will be the source document.
Definition of what constitutes source data and its origin can be found in the Source 
Document Locator, which is maintained by the sponsor.
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Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the sponsor.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The sponsor or designee will perform monitoring to confirm that data entered into the CRF 
by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of participants are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP guidelines, and all applicable regulatory requirements.
10.1.9. Use of Medical Records
In certain situations, sponsor review of redacted copies of participant medical records for 
certain cases may be performed, where ethically and scientifically justified and permitted by 
local regulations, to ensure participant safety. 
Due to the potential for a participant to be re-identified from their medical records, the 
following actions must be taken when medical records are sent to the sponsor or sponsor 
designee:

The investigator or site staff must redact personal information from the medical record. 
The personal information includes, but is not limited to, the following: participant names 
or initials, participant dates (eg, birth date, date of hospital admission/discharge, date of 
death), participant identification numbers (eg, Social Security number, health insurance 
number, medical record number, hospital/institution identifier), participant location 
information (eg, street address, city, country, postal code, IP address), participant contact 
information (eg, telephone/fax number, email address).

Each medical record must be transmitted to the sponsor or sponsor designee using 
systems with technical and organizational security measures to ensure the protection of 
personal data (eg, Florence is the preferred system if available). 

There may be unplanned situations where the sponsor may request medical records (eg, 
sharing medical records so that the sponsor can provide study-related advice to the 
investigator). The medical records should be submitted according to the procedure 
described above.
10.1.10. Study and Site Start and Closure
The study start date is the date of the first participant’s first visit. The sponsor designee 
reserves the right to close the study site or terminate the study at any time for any reason at 
the sole discretion of the sponsor, including (but not limited to) regulatory authority decision, 
change in opinion of the IRB/EC, or change in benefit-risk assessment. Study sites will be 
closed upon study completion. A study site is considered closed when all required documents 
and study supplies have been collected and a study-site closure visit has been performed.
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The investigator may initiate study-site closure at any time upon notification to the sponsor if 
requested to do so by the responsible IRB/EC or if such termination is required to protect the 
health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/EC 
or local health authorities, the sponsor’s procedures, or the ICH GCP guidelines;

Inadequate recruitment of participants by the investigator; 

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement. If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.11. Publication Policy
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study.
Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, participant to the 
other requirements described in this section.
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. If any patent action is required to protect intellectual property rights, the 
investigator agrees to delay the disclosure for a period not to exceed an additional 60 days 
upon request from Pfizer. This allows Pfizer to protect proprietary information and to provide 
comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study-intervention or Pfizer-related 
information necessary for the appropriate scientific presentation or understanding of the 
study results. For joint publications, should there be disagreement regarding interpretation 
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and/or presentation of specific analysis results, resolution of, and responsibility for, such 
disagreements will be the collective responsibility of all authors of the publication.
For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication.
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10.1.12. 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 from non-study healthcare professionals, participants are provided 
with an ECC at the time of informed consent. The ECC contains, at a minimum, (a) protocol 
and study intervention identifiers, (b) participant’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 participant 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 
participant. 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 participant directly; if a 
participant calls that number directly, they will be directed back to the investigator site.
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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed at times defined in the SoA section of 
this protocol. Additional laboratory results may be reported on these samples as a result of 
the method of analysis or the type of analyzer used by the clinical laboratory, or as derived 
from calculated values. These additional tests would not require additional collection of 
blood. Unscheduled clinical laboratory measurements may be obtained at any time during the 
study to assess any perceived safety issues.
Table 7.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Reflex Tests
CBC with 
differentialsa
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count: Full 
differential
including %
Total neutrophils 
(Abs and %)
Eosinophils (Abs 
and %)
Monocytes (Abs 
and %)
Basophils (Abs 
and %)
Lymphocytes 
(Abs and %)
TBNK Panela
Total T-Cells 
(CD3+), B cells 
(CD3-CD19+), 
NK cells (CD3-
CD16+CD56+), 
CD4+ Tcells 
(CD3+CD4+) and
CD8+ Tcells 
(CD3+CD8+) 
count (Abs and %)
Coagulation Panel
aPTT
INR
PT
Urea and 
creatinine, 
Cystatin C (at 
baseline)
Sodium
Potassium
AST, ALT
Total bilirubin
Alkaline 
phosphatase
Albumin
Total protein
GFRb
Local 
dipstick:
Protein (qual)
Blood (qual)
Nitrites
Leukocyte 
esterase
Laboratory:
Microscopy 
and culturec
At screening:

FSHd

Pregnancy test 
(β-hCG)e

TBf

HBsAg (if 
equivocal, reflex 
to HBV DNA 
quantification)

HBcAbg

HBsAbg

HCVAb (if 
positive, reflex 
to HCV RNA 
quantification)

HIV serology
Required Tests:
For suspected DILI:
AST/ALT 
T bili, direct and indirect 
bili 
Total bile acids, GGT 
Total protein, albumin 
CK 
PT, INR 
Acetaminophen/paracetamol 
or 
protein adduct levels 
Hepatitis serology (even if 
screening negative) 
For suspected DICI/DIKI: 
Creatinine (Scr) 
Cystatin C (Scys) 
eGFR (Scr only and 
combined Scr+Scys) 
Spot (dipstick) UACR
a.
Site staff, including Investigators, will be blinded to the WBC count, WBC differential (percentage and 
absolute number), and TBNK panel cell counts; results will be assessed by an unblinded Independent 
medical monitor who will notify Investigators when participants experience events of Grade 4 
lymphopenia (ALC < 0.2 × 109 cells/L) and will direct Investigators on specific actions to take. Refer to 
Section 10.10.1
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Table 7.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Reflex Tests
b.
GFR will be calculated with the CKD-EPI algorithm.
c.
Only if UTI is suspected and urine dipstick is positive for nitrites or leukocyte esterase or both.
d.
For confirmation of postmenopausal status only.
e.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or IRB/EC. Serum or urine hCG for female participants of childbearing potential.
f.
In addition to a chest imaging (ie, CT or MI), TB screening will be done via an IGRA (QFT-G In-Tube 
test (preferred)) in all participants except those with a history of active, latent, or inadequately treated 
infection with TB. If the result of the repeat test is indeterminate, participants may be screened using the 
Mantoux/PPD skin test with study medical monitor approval. If a participant has previously received an 
adequate course of therapy for either latent (eg, 9 months of isoniazid in a locale where rates of primary 
multi-drug TB resistance are <5% or an acceptable alternative regimen) or active (acceptable multi-drug 
regimen) TB infection, neither a QFT-G test, nor a Mantoux/PPD tuberculin skin test is needed, but a 
chest imaging is required if not performed within 12 weeks prior to Day 1. If the current incidence rates 
of multi-drug resistant TB infection in the locale are unavailable, an adequate treatment regimen should 
be defined as the regimen recommended by the health ministry or expert panel in the locale. 
Tuberculosis testing is required at Week 52 in Part 1 and Part 2 of the study for all participants in regions 
which are above a low‑risk for tuberculosis (ie, >10/100,000 incidence) which will be determined based 
on World Health Organization (WHO) country‑level data, and a negative test result for TB will be 
required for ongoing eligibility for study participation.
g.
Reflex testing for HBV DNA only if HBsAg negative, HBcAb positive and HBsAb positive at 
screening. Participants who are HBsAg negative, HBsAb negative and HBcAb positive are excluded 
from the study (Section 8.3.7)
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. 
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention.

Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator. Any abnormal test results that 
meet any of the conditions below must be recorded as an AE:

Is associated with accompanying symptoms.

Requires additional diagnostic testing or medical/surgical intervention.

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional 
concomitant drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition, including an 
increase in either frequency and/or intensity of the condition.

New condition detected or diagnosed after study intervention administration, even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. Overdose per se will not be reported as 
an AE or SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae.
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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2. Definition of an SAE
An SAE is defined as any untoward medical occurrence that, at any dose, meets one 
or more of the criteria listed below:
a. Results in death
b. Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an AE.
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d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance, such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle), that may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Is a suspected transmission via a Pfizer product of an infectious agent, pathogenic 
or nonpathogenic 
The event may be suspected from clinical symptoms or laboratory findings indicating 
an infection in a participant exposed to a Pfizer product. The terms “suspected 
transmission” and “transmission” are considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by pharmacovigilance 
personnel. Such cases are also considered for reporting as product defects, if 
appropriate.
g. Other situations:

Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations, such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent one of the other outcomes listed in the above 
definition. These events should usually be considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse.
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During the Active 
Collection Period 
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs using the CT SAE Report Form or via PSSA to Pfizer Safety throughout 
the active collection period. These requirements are delineated for 3 types of events: (1) 
SAEs; (2) nonserious AEs; and (3) exposure to the study intervention under study during 
pregnancy or breastfeeding, and occupational exposure. 
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It should be noted that the CT SAE Report Form/PSSA for reporting of SAE information 
is not the same as the AE page of the CRF. When the same data are collected, the forms 
must be completed in a consistent manner. AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form/PSSA for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form/PSSA to 
Pfizer Safety Within 24 
Hours of Awareness
SAE
All
All
Nonserious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding 
All AEs or SAEs associated 
with EDP or EDB
Note: Instances of EDP or 
EDB not associated with an 
AE or SAE are not captured 
in the CRF
All instances of EDP are 
reported (whether or not 
there is an associated 
SAE)*
All instances of EDB are 
reported (whether or not 
there is an associated 
SAE)**
Environmental or 
occupational exposure to 
the product under study to 
a nonparticipant (not 
involving EDP or EDB)
None. Exposure to a study 
nonparticipant is not 
collected on the CRF
The exposure (whether or 
not there is an associated 
AE or SAE) must be 
reported***
*
EDP (with or without an associated AE or SAE)is reported to Pfizer Safety using the CT SAE 
Report Form and EDP Supplemental Form or via PSSA.
** EDB is reported to Pfizer Safety using the CT SAE Report Form or via PSSA, which would also 
include details of any SAE that might be associated with the EDB. 
*** Environmental or occupational exposure: AEs or SAEs associated with occupational exposure 
are reported to Pfizer Safety using the CT SAE Report Form or via PSSA. 

When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE or SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE or SAE CRF page.
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
There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety. Refer to Section 10.1.9 for actions that 
must be taken when medical records are sent to the sponsor or sponsor designee.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE or SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with 
usual ADL.

Moderate: A type of AE that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual ADL, causing discomfort, 
but poses no significant or permanent risk of harm to the research participant. 

Severe: A type of AE that interrupts usual ADL, or significantly affects clinical 
status, or may require intensive therapeutic intervention.
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. The investigator will use clinical 
judgment to determine the relationship.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated.
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
The investigator will also consult the IB and/or product information, for marketed 
products, in their assessment.

For each AE or SAE, the investigator must document in the medical notes that they 
have reviewed the AE or SAE and have 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, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change their opinion of causality in light of follow-up 
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.

If the investigator does not know whether or not the study intervention caused the 
event, then the event will be handled as “related to study intervention” for reporting 
purposes, as defined by the sponsor. In addition, if the investigator determines that 
an SAE is associated with study procedures, the investigator must record this 
causal relationship in the source documents and CRF, and report such an 
assessment in the dedicated section of the CT SAE Report Form/PSSA and in 
accordance with the SAE reporting requirements.
Follow-Up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations, as medically indicated or as requested by the 
sponsor, to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare providers.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings, including histopathology.

New or updated information will be recorded in the originally submitted 
documents.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
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10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic DCT

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic DCT (eg, eSAE or PSSA).

If the electronic system is unavailable, then the site will use the paper SAE report 
form (see next section) to report the event within 24 hours.

The site will enter the SAE data into the electronic DCT (eg, eSAE or PSSA) or 
paper form (as applicable) as soon as the data become available.

After the study is completed at a given site, the electronic DCT will be taken 
off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic DCT has been taken off-line, 
then the site can report this information on a paper SAE form (see next section) or 
to Pfizer Safety by telephone.
SAE Reporting to Pfizer Safety via the CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is one of the preferred methods
to transmit this information to Pfizer Safety.

Facsimile transmission of the CT SAE Report Form is the back-up method to 
transmit this information to Pfizer Safety in case PSSA is unavailable for more than 
24 hours.

In circumstances when the facsimile is not working, an alternative method should 
be used, eg, secured (Transport Layer Security) or password-protected email. If 
none of these methods can be used, notification by telephone is acceptable with a 
copy of the CT SAE Report Form sent by overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.
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10.4. Appendix 4: Contraceptive and Barrier Guidance 
At time points indicated in the SoA, the investigator or designee should inquire of both 
WOCBP and male participants if a change in the risk of becoming pregnant or getting 
someone pregnant has occurred, and they will inform the participant of the need to use highly 
effective contraception consistently and correctly. Refer to details in Section 5.3.1.
10.4.1. Male Participant Reproductive Inclusion Criteria
Male participants are eligible to participate if they agree to the following requirements during 
the intervention period and for at least 28 days after the last dose of study intervention, which 
corresponds to the time needed to eliminate reproductive safety risk of the study 
intervention(s):

Refrain from donating sperm.
PLUS either:

Be truly abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent. 
OR

Must agree to use contraception/barrier as detailed below:

Agree to use a male condom when having sexual intercourse with a pregnant or non-
pregnant WOCBP.
10.4.2. Female Participant Reproductive Inclusion Criteria
The criteria below are part of Inclusion Criterion 1 (Age and Sex; Section 5.1) and specify 
the reproductive requirements for including female participants. Refer to Section 10.4.4 for a 
complete list of contraceptive methods permitted in the study. 

A female participant is eligible to participate if she (a) is not pregnant or breastfeeding; 
(b) agrees to not donate eggs (ova, oocytes) for the purpose of reproduction for at least 28 
days after the last dose of study intervention; and (c) at least 1 of the following conditions 
applies:

Is not a WOCBP (see definition in Section 10.4.3).
OR

Is a WOCBP who agrees to use a highly effective contraceptive method (failure rate of 
<1% per year) with low user dependency during the intervention period and for at least 
28 days after the last dose of study intervention, which corresponds to the time needed to 
eliminate any reproductive safety risk of the study intervention(s). The investigator 
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should evaluate the effectiveness of the contraceptive method in relationship to the first 
dose of study intervention.
OR

Is a WOCBP and agrees to use a highly effective (failure rate of <1% per year) user-
dependent method of contraception during the intervention period and for at least 28 days 
after the last dose of study intervention, which corresponds to the time needed to 
eliminate any reproductive safety risk of the study intervention(s). In addition to her use 
of the highly effective method above, she agrees to concurrently use an effective barrier 
method. The investigator should evaluate the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention.
The investigator is responsible for reviewing the woman’s medical history, menstrual history, 
and recent sexual activity in order to decrease the risk of enrolling a woman with an early, 
undetected pregnancy. 
10.4.3. Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following: 

Documented hysterectomy;

Documented bilateral salpingectomy;

Documented bilateral oophorectomy.
For individuals with permanent infertility due to a medical cause other than the above (eg, 
mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry.
Note: Documentation for any of the above categories can come from the site personnel’s 
review of the participant’s medical records, medical examination, or medical history 
interview. The method of documentation should be recorded in the participant’s medical 
record for the study.
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2. Postmenopausal female:

A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. In addition:
A high FSH level in the postmenopausal range must be used to confirm a 
postmenopausal state in women under 60 years of age and not using hormonal 
contraception or HRT. 
A female on HRT and whose menopausal status is in doubt will be required to use 
one of the highly effective nonestrogen hormonal contraception methods if she 
wishes to continue her HRT during the study. Otherwise, she must discontinue HRT 
to allow confirmation of postmenopausal status before study enrollment.
10.4.4. Contraception Methods
Contraceptive use by men or women should be consistent with local availability/regulations 
regarding the use of contraceptive methods for those participating in clinical trials.
The following contraceptive methods are appropriate for this study:
Highly Effective Methods That Have Low User Dependency 
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device.
3. Intrauterine hormone-releasing system.
4. Bilateral tubal occlusion.
5. Vasectomized partner.

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the WOCBP and the absence of sperm has 
been confirmed. If not, an additional highly effective method of contraception 
should be used. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent 
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:

Oral + barrier*

Intravaginal + barrier*
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
Transdermal + barrier*
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

Oral + barrier*

Injectable + barrier*
* Acceptable barrier methods to be used concomitantly with options 6 or 7 for the study 
include any of the following:

Male or female condom with or without spermicide;

Cervical cap, diaphragm, or sponge with spermicide;

A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods).
8. Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study intervention.  The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study and the preferred and usual lifestyle of the 
participant. Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method are not acceptable methods of contraception for female participants. Male 
condom and female condom should not be used together (due to risk of failure with 
friction).
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10.5. Appendix 5: 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 participants, transaminase elevations are a harbinger of a 
more serious potential outcome. These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as DILI. 
Participants 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 
participant’s individual baseline values and underlying conditions. Participants 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:

Participants 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 participants 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).
o
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.
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The participant 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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10.6. Appendix 6: Kidney Safety Monitoring Guidelines
10.6.1. Laboratory Assessment of Change in Kidney Function and Detection of Kidney 
Injury
Standard kidney safety monitoring requires assessment of baseline and postbaseline Screat
measurement to estimate kidney function [Screat-based eGFR] or creatinine clearance 
[eCrCl]). Baseline and postbaseline Scys makes it feasible to distinguish AKI from other 
causes of Screat increase. If Screat increase is confirmed after baseline, then reflex 
measurement of Scys is indicated.
Currently, 2021 CKD-EPI eGFR equations (Screat only-based and combined Screat plus 
Scys-based) are valid for use in adults only. At baseline Screat and Scys values are needed to 
calculate 2021 CKD-EPI eGFR by Screat only-based equation (see Table 10.6.2.1.) and by 
combined Screat plus Scys-based equation. When post-baseline Screat increase ≥0.3 mg/dL 
is confirmed, then reflex Scys measurement is needed to enable post-baseline comparison of 
eGFR changes (Screat only-based eGFR and combined Screat plus Scys eGFR).
Regardless of whether kidney function monitoring tests are required as a routine safety 
monitoring procedure in the study, if the investigator or sponsor deems it necessary to further 
assess kidney safety and quantify kidney function, then these test results should be managed 
and followed per standard of care.
10.6.2. Age-Specific Kidney Function Calculation Recommendations
10.6.2.1. Adults (18 Years and Above)—2021 CKD-EPI Equations
2021 CKD-
EPI            
Scr Only
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤ 0.7
N/A
eGFR = 143 × (Scr/0.7)-0.241  ×  (0.9938)Age
Female
if 0.7
N/A
eGFR = 143 × (Scr/0.7)-1.200  ×  (0.9938)Age
Male
if ≤ 0.9
N/A
eGFR = 142 × (Scr/0.9)-0.302  ×  (0.9938)Age
Male
if 0.9
N/A
eGFR = 142 × (Scr/0.9)-1.200  ×  (0.9938)Age
2021 CKD-
EPI           
Scr-Scys 
Combined
Scr
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤ 0.7
if ≤ 0.8
eGFR = 130 × (Scr/0.7)-0.219  × (Scys/0.8)-0.323  × (0.9961)Age
Female
if ≤ 0.7
if 0.8
eGFR = 130 × (Scr/0.7)-0.219  × (Scys/0.8)-0.778  × (0.9961)Age
Female
if 0.7
if ≤ 0.8
eGFR = 130 × (Scr/0.7)-0.544  × (Scys/0.8)-0.323  × (0.9961)Age
Female
if 0.7
if 0.8
eGFR = 130 × (Scr/0.7)-0.544  × (Scys/0.8)-0.778  × (0.9961)Age
Male
if ≤ 0.9
if ≤ 0.8
eGFR = 135 × (Scr/0.9)-0.144  × (Scys/0.8)-0.323  × (0.9961)Age
Male
if ≤ 0.9
if 0.8
eGFR = 135 × (Scr/0.9)-0.144  × (Scys/0.8)-0.778  × (0.9961)Age
Male
if 0.9
if ≤ 0.8
eGFR = 135 × (Scr/0.9)-0.544  ×  (Scys/0.8)-0.323  × (0.9961)Age
Male
if 0.9
if 0.8
eGFR = 135 × (Scr/0.9)-0.544  ×  (Scys/0.8)-0.778  × (0.9961)Age
Inker LA et al. N Engl J Med. 2021;385:1737-49.45
10.6.3. Kidney Function Calculation Tools
The sponsor has provided the following resources to investigational sites when required to 
calculate age-specific kidney function at Screening, Baseline, and post-Baseline visits. Site 
calculations of kidney function can be performed manually, using the age appropriate 
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formulae (see Section 10.6.2) and can use recommended online kidney function calculators 
to reduce the likelihood of a calculation error. 
The United States National Kidney Foundation Online Calculators. 
Adults (18 years and above) - 2021 CKD-EPI Creatinine Online Calculator (eGFR): 
https://www.kidney.org/professionals/KDOQI/gfr_calculator
Investigational sites are responsible to ensure that the accurate age-specific equation is 
selected and that the correct units for serum creatinine (mg/dL only), serum cystatin C (mg/L 
only), total body weight (kg only), and age (years). Investigators are expected to (i) review 
and confirm correctness of the kidney function calculation results and (ii) evaluate the 
calculated value within the context of historical information available to them in the 
participant’s medical record. Investigators are responsible for the clinical oversight of the 
participant eligibility process, kidney function calculation, and dose selection and 
adjustments per study protocol. Investigators are encouraged to direct questions or 
uncertainties regarding kidney function and dosing to the Pfizer Clinical Team and Medical 
Monitor, if needed.
10.6.4. Adverse Event Grading for Kidney Safety Laboratory Abnormalities
AE grading for decline in kidney function (ie, eGFR or eCrCl) will be according to KDIGO 
criteria.
KDIGO 
criteria
Study 
Population
G1
G2
G3
G4
G5
Decreased 
Kidney 
Function due 
to either 
Acute or 
Chronic 
Kidney 
Injury 
Adult 
participants
eGFR
(mL/min/1.7
3m2)
≥90 
≥60 to 89
30 to 59 
15 to 29
<15
KDIGO albuminuria 
(A) criteria
A1
A2
A3
Albumin-to-creatinine 
ratio (ACR)
<30 mg/g
OR     
<3 mg/mmol 
30 to 300 mg/g
OR 
3 to 30 mg/mmol
>300 mg/g 
OR 
>30 mg/mmol
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10.7. Appendix 7: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as AEs

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 ms.

New prolongation of QTcF to >480 ms (absolute) or by ≥60 ms from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ 
duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 ms.

New ST-T changes suggestive of myocardial ischemia.

New-onset LBBB (QRS complex >120 ms).

New-onset right bundle branch block (QRS complex >120 ms).

Symptomatic bradycardia. 

Asystole:

In awake, symptom-free participants in sinus rhythm, with documented periods 
of asystole ≥3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node; 

In awake, symptom-free participants with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer; 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).
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
Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (HR 
<40 bpm), accelerated idioventricular rhythm (HR 40 bpm to <100 bpm), and 
monomorphic/polymorphic ventricular tachycardia (HR >100 bpm [such as 
torsades de pointes]).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as SAEs

Change in pattern suggestive of new myocardial infarction. 

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all-inclusive of what to be reported as AEs/SAEs.
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10.8. Appendix 8: Prohibited Concomitant Medications That May Result in DDI 
10.8.1. Prohibited Concomitant Medications That May Result in DDI 
Moderate or strong inhibitors or inducers that inhibit or induce at least 2 of the following are 
prohibited: Cytochrome P450 (CYP)2C8, CYP2C9, and CYP3A4.  Examples include 
fluconazole, rifampin, and enzalutamide.
The Pfizer study team is to be notified of any prohibited medications taken during the study. 
After consulting with the sponsor, the investigator will make a judgment on the ongoing 
participation of any participant with prohibited medication use during the study.
This list of drugs prohibited for potential DDI concerns with the IMP may be revised during 
the course of the study with written notification from sponsor, to include or exclude specific 
drugs or drug categories for various reasons (eg, emerging DDI results for the IMP, 
availability of new information in literature on the DDI potential of other drugs). 
Investigators should consult the product label for any other medication used during the study 
for information regarding medication that is prohibited for concomitant use. 
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10.9. Appendix 9: Country-Specific Requirements
This appendix is only applicable to Part 2.
10.9.1. France 
Contrat Unique
1. GCP Training 
Before enrolling any participants, the investigator and any subinvestigators will 
complete the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP 
Training”) or training deemed equivalent by Pfizer. Any investigators who later join 
the study will do the same before performing study-related duties. For studies of 
applicable duration, the investigator and subinvestigators will complete Pfizer GCP
Training or equivalent every 3 years during the term of the study, or more often if 
there are significant changes to the ICH GCP guidelines or course materials. 
2. Study Intervention 
No participants or third-party payers will be charged for study intervention.
3. Urgent Safety Measures 
In addition, the investigator will inform Pfizer immediately of any urgent safety 
measures taken by the investigator to protect the study participants against any 
immediate hazard, and of any serious breaches of this protocol or of ICH GCP that 
the investigator becomes aware of.
4. Termination Rights 
Pfizer retains the right to discontinue development of etrasimod at any time.
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10.10. Appendix 10: Safety Monitoring Guidance
This study will utilize 2 medical monitors: 
The unblinded independent medical monitor 

is a clinician independent from and not a member of the study team

monitors unblinded WBCs and TBNK values while remaining blinded to study treatment

will notify investigators when participant has Grade 4 lymphopenia (ALC < 0.2 × 109 
cells/L) and will direct investigators on specific actions to take (outlined in Protocol 
Section 10.10.1)

will notify investigators when there is at least 1 measurement of ANC < 1.0 × 109 cells/L 
or WBC count > 20 × 109 cells/L (outlined in Protocol Section 10.10.1)
The blinded study medical monitor: 

is a Pfizer clinician and a blinded member of the C5041005 study team

should be contacted for questions on the protocol, eligibility (including roll-over to the 
OLE) and continuation criteria based on EASI-50 

Should be contacted if participant does not meet discharge criteria after 4 hours of cardiac 
monitoring (outlined in Protocol Section 10.10.3)

Should be contacted when referenced as the “study medical monitor” in the protocol, in 
cases of overdose, protocol predefined study intervention interruption and re initiation, 
suspected cases of PML (outlined in Protocol Section 10.11), and for all other safety 
concerns.
Temporary Interruption to Dosing 
Dose interruptions are defined as the following consecutive days of missed study treatment:

≥2 consecutive days within the first week of treatment and Week 16 of Part 1, or

≥7 consecutive days after the first week of treatment (excluding Week 16 of Part 1 where 
missing 2 doses applies)
If the Investigator deems it necessary to withhold study treatment due to an adverse event, 
temporary withholding is permitted for up to 6 days (after the first week of treatment) 
without obtaining prior approval from the study medical monitor. Planned dose interruptions 
during the first week of treatment requires consultation with the study medical monitor. If 
study treatment interruption ≥ 7 days is required for a medical reason at any time in the 
study, the Investigator must contact the study medical monitor for further instruction as soon 
as this is anticipated. 
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Any time a participant reinitiates study treatment following protocol-defined dose 
interruption, the first dose cardiac monitoring outlined in Section 10.10.3 must be 
performed and the participant must take the next dose of study treatment at the study 
site. 
Doses not taken due to an adverse event per investigator’s request do not constitute protocol 
deviations or medication errors and should not be considered dosing errors but should be 
noted in the dosing log with the reason for reduced drug consumption clearly described.
10.10.1. Monitoring Of Lymphocyte, Neutrophil, and White Blood Cell Counts
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 TBNK panel cell counts. WBC count, 
WBC differential, and TBNK panel results will be assessed by the unblinded independent 
medical monitor who is not involved in any other aspects of study conduct or data analysis 
and who is blinded to study treatment. The unblinded independent medical monitor will 
notify Investigators when participants experience events of Grade 4 lymphopenia (ALC 
< 0.2 × 109 cells/L) and will direct Investigators on specific actions to take as described in 
Figure 1. Participants must permanently discontinue study treatment in the event of sustained 
Grade 4 lymphopenia, defined as a second confirmed Grade 4 measurement with treatment 
rechallenge after study treatment interruption.
Figure 1:
Management of Grade 4 Lymphopenia Events
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*If repeat assessment does not confirm Grade 4 lymphopenia, continue study treatment. If 
study intervention has been interrupted ≥2 consecutive days during Week 1 or Week 16 
of Part 1 or ≥7 consecutive days after Week 1 (excluding Week 16 of part 1 where 2
doses applies), First Dose Cardiac Monitoring must be conducted when study 
intervention is re-initiated (see Section 10.10.3).
In addition, the unblinded 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. 
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 workup as clinically 
indicated, and/or as a tool to assess the effectiveness of therapeutic interventions for an 
infection. Investigators will repeat CBC with differentials weekly until ANC 
> 1.0 × 109 cells/L or the increased WBC count trends downward (on 2 separate days), 
respectively.
Participants with an ongoing AE of decreased lymphocyte count or infection at the 4-Week 
Follow Up Visit should return for CBC with differential according to local standard of care 
(captured as subsequent Follow-Up Visit or unscheduled visit).
10.10.2. Serious Infections Monitoring
Low lymphocyte counts observed with the use of other S1P receptor modulators in patients 
with multiple sclerosis have been associated with serious and atypical infections. 4,5,46
Investigators should remain vigilant in monitoring for signs and symptoms of serious and 
atypical infections during the study and after discontinuation of study treatment. Serious 
infection monitoring (refer to definition for Serious Adverse Events in Section 10.3.2) 
requires a temporary interruption of study intervention. Study intervention cannot be 
restarted until the serious infection has resolved per investigator judgement (investigator may 
discuss restarting study intervention with the medical monitor, if needed). If the participant 
cannot be restarted on study intervention, then the participant must be permanently 
discontinued. 
Participants will be queried for signs and symptoms of PML. If a participant exhibits signs 
and symptoms suspicious for PML, study treatment must be interrupted and cannot be 
restarted until diagnostic evaluation is completed and PML has been excluded. The study 
medical monitor should be informed of any suspected cases of PML. Refer to Section 10.11
for signs and symptoms of PML and a PML case evaluation algorithm. In the evaluation and 
management of treatment emergent infections, the 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 AE eCRF page. 
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10.10.3. First-Dose Cardiac Monitoring
Cardiac monitoring following treatment initiation applies to the first dose administered in the 
Treatment Period (Day 1). Day 1 predose (ie, Baseline) vital signs (resting HR, BP, body 
temperature, and respiratory rate) will be used as the baseline measurements. The lowest 
predose HR measurement (by vital signs) will be used for comparison to the postdose 
measurement. It should be noted that in this section heart rate refers to pulse rate. Pulse rate 
will be collected as part of vital signs and heart rate will be collected as part of the ECG. 
Cardiac monitoring is required at the Day 1 (first blinded dose) of Part 1 and Part 2 and 
Week 16 (first open label etrasimod dose) of Part 1 and will also be necessary to reinitiate 
study treatment if consecutive days of study treatment are missed as described in 
Section 7.1.7. These visits for cardiac monitoring should be conducted in the morning and 
not on a Friday or the day before a site-observed holiday. In the following sections describing 
first-dose cardiac monitoring, Day 1 refers to the first day of treatment in the Treatment 
Period, but the same procedures will also be used at the Week 16 visit in Part 1 (first open 
label dose) and the first day of treatment re-initiation following the defined periods of 
treatment interruption noted above. Day 2 refers to the subsequent dosing day.
10.10.3.1. Cardiac Monitoring Schedule After First Dose
After the first dose of study treatment on Day 1 of Part 1 and Part 2, participants will be 
observed up to 8 hours. Cardiac monitoring on the first 4 hours (0H, 1H, 2H, 3H and 4H) is 
required for all participants. The second 4 hours (5H, 6H, 7H, and 8H) are not required and 
will only be performed for participants who do not meet discharge criteria at hour 4 of 
cardiac monitoring. The in-clinic cardiac monitoring on Day 1 will include assessments at the 
timepoints specified in Table 8. These criteria will also be used at the Part 1 Week 16 visit, 
the first day of treatment re-initiation following the defined periods of treatment interruption, 
and for Day 1 Part 2 of the study.
Participants who do not meet discharge criteria at 4 hours postdose on Day 1 will require 
extended cardiac monitoring on Day 1 (Table 8) and on Day 2, as described in 
Section 10.10.3.1.2.
For participants who experience a cardiovascular symptomatic event (eg, chest pain, 
dizziness, palpitations, lightheadedness, shortness of breath, and/or syncope) at any time 
during the first 4-hours postdose (ie, on Day 1), the Investigator should determine whether or 
not this event is associated with a HR reduction or clinically relevant change in 12-lead ECG. 
Participants who experience a symptomatic event associated with HR reduction or clinically 
relevant 12-lead ECG should be discontinued from study treatment if they meet the criteria 
described in Section 10.10.3.2. Participants who experience a symptomatic event that is not 
associated with HR reduction or clinically relevant 12-lead ECG may be discharged on Day 1 
at Hour 4 postdose (at the Investigator’s discretion and provided they meet the discharge 
criteria (Section 10.10.3.1.1), but must return to the clinic on Day 2 for extended cardiac 
monitoring as described in Section 10.10.3.2.
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Table 8.
Procedures to be Performed During the First-Dose Cardiac Monitoring 
Period
Procedure
Predose
Hours 1, 2, and 
3
Postdosea       
Hour 4
Postdosea
Day 1 Extended 
Cardiac Monitoringb
Blood pressure and HR 
derived from vital signs 
(seated position)
Xe
Xc
Xc
Xc
12-lead ECG (supine 
position)d       
X
–
X
X
Assess discharge criteria
–
–
X
X
a
Measurements may be taken within ± 15 minutes of the scheduled time. Record time of assessment.
b
Only for participants not meeting discharge criteria (Section 10.10.3.1.1) at Hour 4. Assessments should 
be repeated hourly (± 15 minutes of the scheduled time) until the participant meets the discharge criteria; the 
blinded study medical monitor should be contacted if the participant does not meet the discharge criteria after 
4 hours of extended cardiac monitoring on Day 1. Record time of assessment.
c
If the participant has a vital sign HR of < 50 bpm or if cardiovascular symptoms develop (eg, chest pain, 
dizziness, palpitations, and/or syncope associated with reduction of HR), conduct 12-lead ECGs as clinically 
indicated. Include body temperature and respiratory rate.
d
Additional 12-lead ECGs may be conducted as clinically indicated.
e
Include body temperature and respiratory rate.
10.10.3.1.1. Discharge Criteria After First-Dose Cardiac Monitoring
These criteria will also be used on Day 1 Part 1, at the Week 16 visit of Part 1, first day of 
treatment re-initiation following the defined periods of treatment interruption, and for Day 1 
Part 2 of the study. 
Participants will be released from the clinical site after dosing (but no sooner than 4 hours 
postdose) when they fulfill the following discharge criteria:
1. Vital sign HR ≥ 50 bpm 

If vital sign HR < 50 bpm, then the decrease from baseline must be < 10 bpm

If participant is meeting the protocol pre-specified discharge criteria at Hour 4, the
participant can only be discharged if the lowest HR recorded is not at Hour 4. If 
Hour 4 HR has the lowest value, the participant needs to be further monitored 
following extended cardiac monitoring on Day 1 procedures until it is confirmed the 
HR is on the upward trend before participant is discharged from the site. The full 4 
hours of extended cardiac monitoring is not required to establish the upward trend, 
and participant is not required to return for additional cardiac monitoring on Day 2.
2.
No evidence from ECG of second-degree AV block or higher
3. No participant-reported cardiac symptoms (eg, chest pain, dizziness, palpitations, 
lightheadedness, shortness of breath, or syncope)
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For participants not meeting discharge criteria on Day 1: 

The blinded study medical monitor should be contacted if the participant does not meet 
the discharge criteria after 4 hours of extended cardiac monitoring on Day 1 (after 8 hour 
post dose).

PI and the blinded study medical monitor should come to agreement on how to proceed 
and if it is appropriate to discharge the participant.

Participants should have written instructions on when to return to the clinic on Day 2 and 
a 24-hour contact phone number to call in the event of any new or worsened 
cardiovascular symptoms.
Additional cardiac-monitoring data collected post Hour 4 needs to be captured on the CRFs.
Medically qualified personnel as per local clinical practice standards, experienced in 
interpreting ECGs may perform local ECG reads. If the machine-read is normal, not 
clinically significant, and the participant meets all other protocol pre-specified discharge 
criteria, the medically qualified site personnel can choose to discharge the participant based 
on the local ECG read. If, however, there is any clinical uncertainty, the site should wait 
for the interpretation by the Central reader prior to discharging the participant.
10.10.3.1.2. Cardiac Monitoring on Day 2 for Participants Not Meeting Discharge 
Criteria on Day 1 (and Week 16 + 1 day in Part 1)
Table 9 describes extended cardiac monitoring on Day 2 for participants not meeting 
discharge criteria at 4 hours on Day 1 (Section 10.10.3.1.1) or for participants who 
experienced a cardiovascular symptomatic event associated with HR reduction or clinically 
relevant 12-lead ECG during the 4-hour monitoring period on Day 1.
Table 9.
Procedures to be Performed for Extended Cardiac Monitoring on Day 2
Procedure
Predose
Hours 1, 2, 3 Postdosea   
Hour 4 Postdosea
Blood pressure and HR 
derived from vital signs 
(seated position)
Xb
Xc
Xc
12-lead ECG (supine 
position)d           
X
–
X
Assess discharge criteria
–
–
X
a
Measurements may be taken within ± 15 minutes of the scheduled time. Record time of assessment.
b
Include body temperature and respiratory rate.
c
If the participant has a vital sign HR of < 50 bpm or if cardiovascular symptoms develop (eg, chest pain, 
dizziness, palpitations, and/or syncope associated with reduction of HR), the participant should continue to 
be closely monitored, including 12-lead ECGs as clinically indicated, until the Hour 4 discharge assessment. 
Include body temperature and respiratory rate.
d
Additional ECGs may be performed as clinically indicated.
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10.10.3.2. Study Treatment Discontinuation Related to Postdose Cardiac Monitoring
Study treatment discontinuation specific to postdose cardiac monitoring will occur in 
the following scenarios:

Suspected intolerance associated with first dose cardiac effects – Symptomatic 
cardiovascular events associated with first dose cardiac monitoring (e.g., chest pain, 
dizziness, palpitations, lightheadedness, shortness of breath, and/or syncope) associated 
with HR reduction or associated with clinically relevant 12-lead ECG changes at any 
time during the cardiac monitoring period on Day 1 or the extended cardiac monitoring 
on Day 2, if extended cardiac monitoring is  applicable; participants with such AEs, 
irrespective of causality will be discontinued from the study intervention.

Participants who have not met the discharge criteria by 4 hours postdose during the 
extended cardiac monitoring on Day 2 will be discontinued from the study treatment.
Participants who discontinue treatment due to first dose cardiac monitoring should return to 
site within 3 calendar days for ET visit that includes an ECG (in accordance with the SoA). 
The study medical monitor should be contacted before discontinuing a participant from study 
treatment. 
10.10.4. Pulmonary Function Monitoring 
Based on changes in pulmonary function observed with the use of S1P receptor modulators 
for relapsing multiple sclerosis4,5, pulmonary function will be assessed in this study. 
Participants 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. Investigators should consider interruption of study 
treatment when there is a clinically significant respiratory AE that leads to limitations in self-
care activities of daily living and is associated with PFT decrease. Participants experiencing a 
confirmed decline in PFT values (FEV1 and/or FVC) below 50% of the predicted values 
must be discontinued from study treatment and scheduled for a follow-up visit. The decision 
to interrupt study treatment should be discussed with the blinded Pfizer medical monitor. 
Participants 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.
Reinitiation of study treatment can only be considered if the respiratory AE has improved, 
stabilized, and/or resolved; the individual risk benefit is favorable (as determined by the 
Investigator, in agreement with the pulmonologist); and after discussion with the blinded 
Pfizer medical monitor. The investigator is to ensure first dose cardiac monitoring 
(Section 10.10.3) is implemented upon drug reinitiation if consecutive days of study 
treatment are missed as described in Section 7.1.7.
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Information regarding the collection of PFTs is provided in Section 8.3.9. PFTs will be 
performed at timepoints specified in the SoA.
10.10.5. Ophthalmic Symptom Monitoring
Participants 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 to include: 

Best corrected visual acuity measurement

Ophthalmoscopy (may include contact lens biomicroscopy to examine the macula and 
optic disc)

Intraocular pressure

OCT for all participants 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 center point thickness, then FA may be 
performed.
If there is evidence of confirmed macular edema, then study treatment should be permanently 
discontinued, and the participant should be monitored closely with the appropriate diagnostic 
and clinical work-up. 
These participants 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/optometrist (where 
permitted). If the participant does not show definite signs of improvement on examination by 
specialist testing (eg, OCT, FA) 6 to 8 weeks after interruption of study treatment, then 
therapy for macular edema in conjunction with an ophthalmologist/optometrist (where 
permitted) experienced in the management of this condition should be initiated.
For participants diagnosed with macular edema, copies of the 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.
Information regarding ophthalmoscopy and OCT is provided in Section 8.3.10. 
Ophthalmoscopy and OCT will be performed at timepoints specified in the SoA.
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10.11. Appendix 11: Guidance for the Assessment of Potential Progressive Multifocal 
Leukoencephalopathy
Planned time points are provided in the SoA. If a participant exhibits signs and/or 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, writing, 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). Consultation with a local neurologist may be warranted, 
as presented in the PML case evaluation algorithm in the figure below. 
All suspected cases of PML will be adjudicated by an independent adjudication committee 
(refer to Section 4.2.3). The study 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 independent adjudication committee.
Progressive Multifocal Leukoencephalopathy Case Evaluation Algorithm
*Note: Study treatment administration may resume, and no further evaluation is needed if the 
Investigator assessment reveals no objective signs of PML, the local neurologist confirms 
that the participant does not have PML, or the IAC’s review of the evidence concludes that 
PML is ruled out.
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10.12. Appendix 12: Abbreviations
The following is a list of abbreviations that may be used in the protocol. 
Abbreviation
Term
Abs
absolute
AA
alopecia areata
AD
atopic dermatitis
ADL
activity/activities of daily living
AE
adverse event
AESI
adverse event of special interest
AIDS
acquired immunodeficiency syndrome
AKI
acute kidney injury
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANCOVA
analysis of covariance
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATS
American Thoracic Society 
AV
atrioventricular
AxMP
auxiliary medicinal product
BCG
Bacillus Calmette-Guérin
-hCG
-human chorionic gonadotropin
BP
blood pressure
bpm
beats per minute
BSA
body surface area
CaPS
CDISC and Pfizer Standards
CBC 
complete blood count
CD
cluster of differentiation
CD4
CD4 T lymphocytes
CDC
Centers for Disease Control
CDISC
Clinical Data Interchange Standards Consortium
CE
contrast-enhanced
CFP10
10-kDa culture filtrate protein
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CKD-EPI
chronic kidney disease epidemiology 
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
contract research organization
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Abbreviation
Term
CS
corticosteroid
CSF
cerebral spinal fluid
CSR
Clinical Study Report
C-SSRS
Columbia suicide severity rating scale
CT
computed tomography/clinical trial
CTCAE
Common Terminology Criteria for Adverse Events
CT SAE
clinical trial serious adverse event 
CTIS
Clinical Trial Information System
CYP
cytochrome P450
DB
double-blind
DCT
data collection tool
DDI
drug-drug interaction 
DICI
drug-induced creatinine increase
DIKI
drug-induced kidney injury
DILI
drug-induced liver injury
DLCO
diffusing capacity of lung for carbon monoxide
DLQI
Dermatology Life Quality Index
DNA
Deoxyribonucleic acid
DU
dispensable unit
EASI
Eczema Area and Severity Index
EASI-50
≥50% reduction from Baseline in Eczema Area and Severity 
Index
EASI-75
≥75% reduction from Baseline in Eczema Area and Severity 
Index
EASI-90
≥90% reduction from Baseline in Eczema Area and Severity 
Index
EC
ethics committee
ECC
emergency contact card
ECG
electrocardiogram or electrocardiography
eCrCl
estimated creatinine clearance
eCRF
electronic case report form
EDB
exposure during breastfeeding
E-DMC
External Data Monitoring Committee
EDP
exposure during pregnancy
eGFR
estimated glomerular filtration rate
E1
estimand 1
E2
estimand 2
ELISA
Enzyme Linked Immunosorbent Assay
EoE
eosinophilic esophagitis
EOS
end of study
EOT
end of treatment
ERS
European Respiratory Society
eSAE
electronic serious adverse event
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Abbreviation
Term
ESAT6
Early Secreted Antigenic Target 6 kDa
ET
early termination
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
FA
fluorescein angiogram
FDA
Food and Drug Administration
FEV1
forced expiratory volume in 1 second
FVC
forced vital capacity
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GFR
glomerular filtration rate
GGT
gamma-glutamyl transferase
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HCV ab
hepatitis C antibody
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IA
interim analysis
IAC
independent adjudication committee
IB
Investigator’s Brochure
ICD
informed consent document
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ID
identification
IGA
Investigator’s Global Assessment
IGRA
Interferon-Gamma Release Assays
IL
interleukin
IMP
investigational medicinal product
IND
Investigational New Drug
INR
international normalized ratio
IP
Internet Protocol
IPAL
Investigational Product Accountability Log
IPM
investigational product manual
IRB
Institutional Review Board
IRT
Interactive Response Technology
JAK
janus kinase
JCV
John Cunningham Virus
JTC
Jump-to-Control
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Abbreviation
Term
KDIGO
Kidney Disease: Improving Global Outcomes
LBBB
left bundle branch block
LFT
liver function test
LLQ
lower limit of quantification
LSM
Least squares mean
MDR
multi-drug resistance 
MOA
mechanism of action
MMRM
mixed model repeated measures
MQI
medically qualified individual
MRI
magnetic resonance imaging
MS
multiple sclerosis
ms
millisecond
NCT
National Clinical Trials identifier
NIMP
noninvestigational medicinal product
NRS
numerical rating scale
OCT
optical coherence tomography
OL
open label
OLE
open label extension
PACL
Protocol Administrative Change Letter
PCP
primary care physician
PCR
polymerase chain reaction
PD
pharmacodynamic(s)
PDE-4
phosphodiesterase 4
PFT
pulmonary function test
PI
principal investigator
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
POEM
Patient-Oriented Eczema Measure
PPD
Purified Protein Derivative
PP-NRS
Peak Pruritus Numerical Rating Scale
PR
pulse rate
PRES
posterior reversible encephalopathy syndrome
PRO
patient reported outcome
PSSA
Pfizer's Serious Adverse Event Submission Assistant
PT
prothrombin time
PVC
premature ventricular contraction
QD
once daily
QFT-G
QuantiFERON -TB Gold
QTc
corrected QT interval
QTcF
QTc corrected using Fridericia’s formula
QTL
quality tolerance limit
qual
qualitative
RBC
red blood cell
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Abbreviation
Term
RR
respiration rate
S1P
sphingosine 1-phosphate
S1P1,4,5
S1P receptors 1, 4, and 5
S1PRM
sphingosine 1-phosphate receptor modulator
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
Scr/Screat
serum creatinine
Scys
serum cystatin C
SE
standard error
SFU
safety follow-up
SoA
schedule of activities
SOP
standard operating procedure
SRSD
Single Reference Safety Document
SUSAR
Suspected Unexpected Serious Adverse Reaction
TB
tuberculosis 
TBNK
T and B lymphocyte and natural killer cell
T bili
total bilirubin
TCS
topical corticosteroids
Th2
type 2 helper cells
TOC
table of contents
UACR
urine albumin-to-creatinine ratio
ULN
upper limit of normal
US
United States
UTI
urinary tract infection
vIGA
validated investigator’s global assessment
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of non-childbearing potential
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10.13. Appendix 13: Protocol Amendment History
The protocol amendment summary of changes table for the current amendment is located 
directly before the TOC. The protocol amendment summary of changes tables for past 
amendment(s) can be found below:
Amendment 1 (07 December 2022)
Overall Rationale for the Amendment: Removal of inclusion of participants with a known 
history of HIV based on new clinical data of relevance for the investigator; clarifications for 
documentation and minor administrative changes.
Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
5.2 Exclusion 
Criteria
Removal of inclusion 
of participants with a 
known history of HIV 
Based on new clinical 
data of relevance for 
the investigator.
Substantial 
1.3.1, 1.3.2, 
1.3.3 Schedule 
of Activities
10.2 Table 7 
Clinical 
Laboratory 
Tests
Removal of testing 
specific for 
participants with a 
known history of HIV
Based on new clinical 
data of relevance for 
the investigator.
Substantial
5.2 Exclusion 
Criteria
Added exclusion of 
active diabetic 
retinopathy, macular 
edema or uveitis
Based on new clinical 
data of relevance for 
the investigator.
Substantial:
8.3.2 Blood 
Pressure and 
Pulse Rate 
10.10.3. First-
Dose Cardiac 
Monitoring
Clarification that 
pulse rate is collected 
as part of vital signs, 
and heart rate is 
collected as part of 
ECG.
Required for proper 
documentation.
Nonsubstantial
10.10.3.1 
Cardiac 
Monitoring 
Schedule After 
First Dose
Clarification of 
required monitoring 
timepoints.
Required for proper 
documentation.
Nonsubstantial
6.9.2 Prior 
Treatments;
6.9.3 
Prohibited 
Clarification that live-
attenuated replication-
competent vaccines 
are prohibited.
Clarification of 
prohibited vaccines
Nonsubstantial
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Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
During the 
Study;
6.9.5 
Permitted 
During the 
Study
6.1.1 
Administration
Included missed doses 
during Week 16
Week 16 is the first 
Open Label dose of 
etrasimod
Nonsubstantial
6.5 Study 
Intervention 
Compliance
Removal of the 
possibility of dose 
reductions
Clarification since 
dose reduction is not 
allowed.
Nonsubstantial
Synopsis
4.1 Overall 
Design 
9.4 Interim 
Analysis
Clarification that 
Sponsor conducts 
Interim Analysis and 
removed specific 
timing for the decision 
to start Part 2
For consistency 
between Sections 4.1 
and 9.4
Nonsubstantial
8.2.1 Rater 
Qualifications
Clarification.
Administrative
Nonsubstantial
1.3.1, 1.3.3 
Schedule of 
Activities
Study Day correction
Administrative
Nonsubstantial
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Cohen JA, Comi G, Selmaj KW, et al. Safety and efficacy of ozanimod versus 
interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, 
randomised, 24-month, phase 3 trial. Lancet Neurol. 2019;18(11):1021-33.
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SAP_001.pdf: 
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Protocol C5041005
A PHASE 2/3, TWO-PART STUDY TO EVALUATE THE EFFICACY AND LONG-
TERM SAFETY WITH ORAL ETRASIMOD, 2 MG, ONCE DAILY IN ADULT 
PARTICIPANTS WITH MODERATE-TO-SEVERE ATOPIC DERMATITIS WITH 
A HISTORY OF PRIOR SYSTEMIC TREATMENT FAILURE
Statistical Analysis Plan 
(SAP)
Version:
2
Date:
28 Jul 2023  
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
LIST OF FIGURES ...................................................................................................................4
APPENDICES ...........................................................................................................................5
1. VERSION HISTORY............................................................................................................6
2. INTRODUCTION .................................................................................................................8
2.1. Modifications to the Analysis Plan Described in the Protocol..................................8
2.2. Study Objectives, Endpoints, and Estimand .............................................................9
2.2.1. Primary Estimand .......................................................................................12
2.2.2. Secondary Estimands..................................................................................13
2.2.3. Additional Estimand...................................................................................14
2.3. Study Design ...........................................................................................................16
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ................................................................................................................18
3.1. Primary Endpoints...................................................................................................18
3.2. Secondary Endpoints...............................................................................................18
3.3. Exploratory Endpoints.............................................................................................18
3.4. Baseline Variables...................................................................................................19
3.4.1. Stratification Factor ....................................................................................20
3.5. Safety Endpoints .....................................................................................................20
3.5.1. Adverse Events (Including Laboratory Data).............................................20
3.5.2. Adverse Events of Special Interest.............................................................20
3.5.3. Study Treatment Compliance .....................................................................21
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................21
4.1. Full Analysis Sets....................................................................................................21
4.2. Safety Analysis Set..................................................................................................22
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................23
5.1. Hypotheses and Decision Rules ..............................................................................23
5.2. General Methods .....................................................................................................23
5.2.1. Analyses for Binary Endpoints...................................................................25
5.2.1.1. Cochran-Mantel Haenszel (CMH) Approach............................25
5.2.2. Analyses for Continuous Endpoints ...........................................................26
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5.2.2.1. Analyses for Continuous Data (Repeated Measures Under 
Estimand E2) .....................................................................................26
5.2.2.2. Analyses for Continuous Data (Repeated Measures With 
No Estimand).....................................................................................27
5.3. Methods to Manage Missing Data ..........................................................................27
6. ANALYSES AND SUMMARIES ......................................................................................28
6.1. Primary Endpoint ....................................................................................................28
6.1.1. Primary Analysis ........................................................................................28
6.1.2. Supportive Analysis....................................................................................29
6.2. Secondary and Exploratory Endpoints....................................................................30
6.2.1. Secondary Binary Endpoints ......................................................................30
6.2.2. Exploratory Binary Endpoints ....................................................................31
6.2.3. Secondary Continuous Endpoint (Repeated Visits) ...................................31
6.2.4. Other Exploratory Binary Endpoints..........................................................32
6.2.5. Other Exploratory Continuous Endpoints (Repeated Visits)......................32
6.3. Subset (Subgroup) Analyses ...................................................................................33
6.4. Baseline and Other Summaries and Analyses.........................................................34
6.4.1. Baseline Summaries....................................................................................34
6.4.2. Study Conduct and Participant Disposition................................................36
6.4.3. Study Treatment Duration ..........................................................................36
6.4.4. Prior and Concomitant Medications and Nondrug Treatments ..................37
6.5. Safety Summaries and Analyses .............................................................................37
6.5.1. Adverse Events...........................................................................................37
6.5.2. Laboratory Data..........................................................................................37
6.5.3. Vital Signs ..................................................................................................38
6.5.4. Electrocardiograms.....................................................................................38
6.5.5. Physical Examination .................................................................................38
6.5.6. Protocol Deviations and COVID-19 Related Reporting ............................38
7. INTERIM ANALYSES.......................................................................................................39
8. REFERENCES ....................................................................................................................40
9. APPENDICES .....................................................................................................................41
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LIST OF TABLES
Table 1.
Summary of Changes..................................................................................6
Table 2.
Clarification and Modification to Statistical Concepts or Methods 
Outlined in Protocol Amendment 1, 07 Dec 2022 .....................................9
Table 3.
Objectives, Endpoints, and Estimands........................................................9
Table 4.
IGA Response at Week 16 and Intercurrent Events .................................30
Table 5.
Reporting Categories for Study Treatment Duration (in Day) .................36
Table 6.
Safety QTcF Assessment..........................................................................38
Table 7.
Table of Efficacy Analyses.......................................................................41
Table 8.
Analysis Visit Windows for Part 1 ...........................................................44
Table 9.
Analysis Visit Windows for Part 2 ...........................................................45
Table 10.
Handprint Determination of BSA.............................................................46
Table 11.
Mapping of Body Region BSA Percentage to Area Score.......................47
Table 12.
Symbols Denoting Lesion Clinical Signs by Body Region......................47
Table 13.
Numerical Characteristics of Select Continuous Scores and Derived 
Effiacy Endpoints .....................................................................................49
Table 14.
Efficacy Data Set Differentiation by Estimand in Part 1 DB Phase.........50
Table 15.
Table of Abbreviations .............................................................................51
LIST OF FIGURES
Figure 1.
Study Schematic .......................................................................................17
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APPENDICES
Appendix 1. Summary of Efficacy Analyses...........................................................................41
Appendix 2. Data Derivation Details.......................................................................................44
Appendix 2.1. Definition and Use of Analysis Visit Windows in Reporting..........................44
Appendix 2.2. Endpoint Derivations .......................................................................................45
Appendix 2.2.1. Investigator’s Global Assessment (IGA) ......................................................45
Appendix 2.2.2. Body Surface Area (BSA).............................................................................46
Appendix 2.2.3. Eczema Area and Severity Index (EASI)......................................................47
Appendix 2.2.4. Peak Pruritus Numerical Rating Scale (PP-NRS).........................................48
Appendix 2.2.5. Skin Pain Numerical Rating Scale (Skin Pain NRS) ....................................48
Appendix 2.2.6. Patient-Oriented Eczema Measure (POEM) .................................................49
Appendix 2.2.7. Range of Values for Continuous Efficacy Endpoints ...................................49
Appendix 3. Efficacy Data Set Descriptions For Part 1 Double-Blind Phase.........................50
Appendix 4. Initiation of Prohibited Medications ...................................................................50
Appendix 5. List of Abbreviations...........................................................................................51
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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
1
15 Mar 2023
Amendment 1
07 Dec 2022
First version
NA
2
28 Jul 2023
Amendment 2
17 May 2023
1) Adjusted study 
objective considering
inputs from US FDA.
2) Aligned with updates in 
the most recent protocol 
amendment 2.
3) Corrected 
typographical errors.
1) The change is:
Modified study objective
from superiority 
hypothesis testing to 
estimation in section 5.1
and section 6.
2) The changes are:
Updated label of Part 2 as 
“Part 2 OL Safety” in 
various sections;
Updated Table 3 in section 
2.2 to remove details of 
intercurrent events and to 
consolidate descriptions 
of safety endpoints;
Updated definitions of 
estimands E1 and E2, not 
to consider 
discontinuation of study 
treatment due to COVID-
19/regional emergency 
siutations as a separate 
reason from other reasons
in section 2.2;
Removed estimand E1b as 
it is captured in new 
definition of E1 in section 
2.2 and removed E1b 
related descriptions in 
various sections;
Added provision on how to 
handle a subject enrolled 
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Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
with baseline IGA < 3 as 
protocol deviation in 
stratification factor ub 
Section 3.4;
Removed “Physical 
Examination” as this CRF 
is not included in data 
collection, in Section 
3.5.1;
Updated details of AESI to 
align with protocol 
amendment 2 in section 
3.5.2;
Clarified how participants 
with multiple enrollments 
are handled in Section 4;
Clarified the definition of 
Day 1 (baseline) for 
participants who are 
randomized but not 
treated in section 4.1;
Updated JTC methodology 
under E2 in section 
5.2.2.1 to reflect new 
estimand E2 definition;
Added one subgroup 
variable corresonding to 
expanded inclusion of 
participants with prior 
systemic corticosteriod 
failure only in Section 
6.3;
Added description of 
unblinded interim 
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Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
analyses prior to formal 
IA in section 7;
Updated efficacy data set 
descriptions for Part 1 DB 
according to new 
estimand definitions in 
Appendix 3.
3) Corrected typographical 
errors in relevant sections
including Table 5.
2. INTRODUCTION
Etrasimod is a S1PRM and is being developed as an oral treatment for patients with 
moderate-to-severe AD. C5041005 is a two-part study with Part 1 being 16-week, 
randomized, DB, placebo controlled, with an OLE, to assess efficacy and safety of 2 mg 
etrasimod administered orally, QD in participants with refractory, moderate-to-severe AD, 
whose disease is not adequately controlled with other systemic drug products, including 
biologics, or when use of those therapies is inadvisable (ie, participants with a history of a 
prior systemic treatment failure). The OL Part 2 is to assess long-term safety of etrasimod 2 
mg QD in participants with moderate-to-severe AD with a history of prior systemic therapy 
failure. This statistical analysis plan (SAP) provides the detailed methodology for summary 
and statistical analyses of the data collected in Study C5041005.  In this SAP, in order to 
differentiate the different phases of this study, the label “Part 1 DB” is used to refer to the 
DB phase of Part 1, “Part 1 OLE” to the OLE phase of Part 1, and “Part 2 OL Safety” to the 
Part 2 of this study.
2.1. Modifications to the Analysis Plan Described in the Protocol
There are no modifications in this SAP (Version 2, 28 Jul 2023) to the analysis plan 
described in the protocol amendment 2 (17 May 2023).
The previous SAP version (Version 1, 15 Mar 2023) was written based on the most recent 
approved protocol (protocol amendment 1, 07 Dec 2022) and other protocol-related 
documents (eg, PACL) preceding this SAP (Section 1). This SAP was intended to provide 
more details on statistical methodology and analyses in accordance to the study objectives 
(Section 2.2). This SAP also further clarified or modified what was outlined in the protocol 
version where appropriate. These clarification or modification are provided in the table 
below.
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Table 2.
Clarification and Modification to Statistical Concepts or Methods 
Outlined in Protocol Amendment 1, 07 Dec 2022
Section of 
Protocol
Protocol Description
Clarification or Modification
Section 1:
Protocol 
Summary, 
Section 3:
Estimands
The intercurrent events for Estimand E1 and 
E2 are “the benefit of additional prohibited 
medications and regardless of treatment 
compliance.”
The intercurrent events for Estimand E1 and 
E2 are updated to “initiation of prohibited 
medications or discontinuation of study 
treatment” (whichever is earlier) to reflect 
the intention to objectively account for these 
two post-randomization events for these two 
estimand strategies. These changes are 
detailed in Section 2.2 and Appendix 3.
Section 1:
Protocol 
Summary, 
Section 3:
Estimands
Under Exploratory Objectives for Part 1 
OLE and Part 2, “Baseline, for efficacy 
endpoints, is defined as pre-dose Day 1 in 
the double-blind phase.”
The definitions of baseline for Part 1 and 
Part 2 are different. The baseline described in 
protocol is for Part 1 only, since Part 2 is a 
separate part of the study with de novo
participant enrollment. Baseline for Part 2 is 
the pre-dose Day 1 in the Part 2 OL phase. 
These changes are detailed in Section 2.2 and 
Section 3.4.
2.2. Study Objectives, Endpoints, and Estimand
Table 3.
Objectives, Endpoints, and Estimands
Type
Objective
Endpoint
Estimand
Primary
Efficacy

Part 1 DB: To evaluate 
the efficacy of etrasimod 
2 mg QD versus placebo 
in adult participants with 
moderate-to-severe AD 
and a history of a prior 
systemic therapy failure.

Proportion of participants 
achieving IGA of clear 
(0) or almost clear (1) (on 
a 5-point scale) and a 
reduction of ≥2 points 
from baseline at Week 
16.

Estimand E1 (Primary 
Estimand): The 
difference in the 
proportions of the binary 
endpoint between 
etrasimod 2 mg QD and 
placebo in patients with 
moderate-to-severe AD 
and a history of a prior 
systemic therapy failure. 
More details of Estimand 
E1 (Primary Estimand)
are described in Section 
2.2.1.
Safety
(depending 
on Part 1 
DB IA 
results)

Part 1 OLE and Part 2 
OL Safety: To evaluate 
the long-term safety of 
oral etrasimod 2 mg QD 
in adult participants with 
moderate-to-severe AD 
and a history of a prior
systemic therapy failure.

Incidence and severity of 
treatment-emergent AEs, 
AEs leading to study 
treatment 
discontinuation, SAEs, 
and AESIs.

Incidence of clinically 
significant changes in 
clinical laboratory values, 

Not applicable.
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Table 3.
Objectives, Endpoints, and Estimands
Type
Objective
Endpoint
Estimand
ECG measurements and 
vital signs.
Note: Baseline for Part 1 is 
the pre-dose Day 1 in Part 1. 
Baseline for Part 2 is the pre-
dose Day 1 in the Part 2 OL
Safety phase.
Secondary
Efficacy

Part 1 DB: To evaluate 
the efficacy of etrasimod 
2 mg QD versus placebo 
in adult participants with 
moderate-to-severe AD 
and a history of a prior 
systemic therapy failure.

Proportion of participants 
achieving EASI-75 at 
Week 16.

Estimand E1: described 
above. More details of 
Estimand E1 are 
described in Section 
2.2.2.

Percent change from 
baseline in EASI score at
Week 16.

Estimand E2: The mean 
difference in percent 
change from baseline in 
EASI score between 
etrasimod 2 mg QD and 
placebo in patients with 
moderate-to-severe AD 
and a history of a prior 
systemic therapy failure. 
More details are 
described in Section 
2.2.2.
Exploratory
Efficacy

Part 1 DB: To evaluate 
the efficacy of etrasimod 
2 mg QD versus placebo 
based on additional 
measures in adult 
participants with 
moderate-to-severe AD 
and a history of a prior 
systemic therapy failure.

Proportion of participants 
achieving IGA of clear 
(0) or almost clear (1) (on 
a 5-point scale) and a 
reduction of ≥2 points 
from baseline at all 
timepoints except Week 
16.

Proportion of participants 
achieving EASI-75 at all 
timepoints except Week 
16.

Percent change from 
baseline in EASI score at 
all timepoints except 
Week 16.

Estimand E1 described 
above for all binary 
endpoints.

Estimand E2 described 
above for all continuous 
endpoints.
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Table 3.
Objectives, Endpoints, and Estimands
Type
Objective
Endpoint
Estimand

Proportion of participants 
achieving ≥4-point 
reduction in PP-NRS 
score from baseline at all 
timepoints.

Proportion of participants 
achieving ≥4-point 
reduction in Skin Pain 
NRS score from baseline 
at all timepoints.

Proportion of participants 
achieving EASI-90 at all 
timepoints.

Proportion of participants 
achieving ≥4-point 
reduction in POEM from 
baseline at Week 16.
Efficacy
(depending 
on Part 1 
DB IA 
results)

Part 1 OLE and Part 2: 
To evaluate the long-term 
efficacy of oral etrasimod 
2 mg QD in adult  
participants with 
moderate-to-severe AD 
and a history of a prior 
systemic therapy failure.

Proportion of participants 
achieving EASI-75 at all 
scheduled timepoints.

Proportion of participants 
achieving IGA of clear 
(0) or almost clear (1) (on 
a 5-point scale) at all
scheduled timepoints.

Percent change from 
baseline in EASI score at 
all scheduled timepoints.

Proportion of participants 
achieving ≥4-point 
reduction in PP-NRS 
score from baseline at all 
scheduled timepoints.

Proportion of participants 
achieving ≥4-point 
reduction in Skin Pain 
NRS score from baseline 
at all scheduled 
timepoints.

Proportion of participants 
achieving EASI-90 at all 
scheduled timepoints.

Not applicable.
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Table 3.
Objectives, Endpoints, and Estimands
Type
Objective
Endpoint
Estimand

Change from baseline in 
POEM at all scheduled 
timepoints.
Note:  Baseline for Part 1 is 
pre-dose Day 1 in Part 1. 
Baseline for Part 2 is the pre-
dose Day 1 in the Part 2 OL
Safety phase.
2.2.1. Primary Estimand
There are two intercurrent events considered for Part 1 DB phase of this study, (1) the 
initiation of prohibited medications, and (2) the discontinuation of the study treatment
(etrasimod or placebo) due to any reason.  Estimand E1 is an estimand strategy for a binary 
endpoint at a visit, when applied to the primary endpoint of IGA response at Week 16, it is
known as the primary estimand. Estimand E1 is illustrated using the primary endpoint below.
Estimand E1 for a binary endpoint at a visit:
Estimand E1 uses a composite strategy and estimates the treatment effect at a visit 
considering a participant as non-responder after experiencing the intercurrent event of 
initiation of prohibited medications or discontinuation of study treatment.  The primary 
estimand is Estimand E1 applied to the primary endpoint of IGA response at Week 16, and is 
defined according to the primary objective.  The primary estimand is defined by the 
following five attributes: 
1. Treatment condition: received study intervention of etrasimod 2 mg QD or placebo.
2. Population: Participants with moderate-to-severe AD as defined by the inclusion and
exclusion criteria.
3. Variable: IGA response at Week 16 is score of clear (0) or almost clear (1) and a 
reduction from baseline of ≥2 points. A participant who experiences the intercurrent 
event of initiation of prohibited medications or discontinuation of study treatment due 
to any reason (whichever is earlier), will be considered an IGA non-responder (ie, 
treatment failure) at Week 16.
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4. Intercurrent events:

Initiation of prohibited medications – a participant who receives prohibited 
medications post-randomization prior to the Week 16 visit will be considered an 
IGA non-responder (ie, treatment failure) at Week 16.

Discontinuation of study intervention due to any reason prior to the Week 16 visit
– a participant who discontinues study treatment due to any reason will be 
considered an IGA non-responder (ie, treatment failure) at Week 16. 
5. Population-level summary: The difference in IGA response rates at Week 16 between 
etrasimod 2 mg QD and placebo.
2.2.2. Secondary Estimands
Estimand E1 will be similarly applied to the binary secondary endpoint (ie, EASI-75 at Week 
16) as well as the binary exploratory endpoints (eg, ≥4-point reduction from baseline in PP-
NRS score at Week 16) with the endpoint substituted appropriately.  
Estimand E2 strategy is defined for a continuous secondary endpoint at a visit (eg, percent 
change from baseline in EASI score at Week 16).
Estimand E2 for a continuous endpoint at a visit:
Estimand E2 uses a composite strategy and estimates the treatment effect at a visit 
considering a participant as having no treatment benefit after experiencing the intercurrent 
event of initiation of prohibited medications or discontinuation of study treatment. Estimand 
E2 is applied to the secondary endpoint of percent change from baseline in EASI score at 
Week 16, and is defined according to the secondary objective.  This Estimand E2 is defined 
by the following five attributes:
1. Treatment condition: received study intervention of etrasimod 2 mg QD or placebo.
2. Population: Participants with moderate-to-severe AD as defined by the inclusion and 
exclusion criteria.
3. Variable: Percent change from baseline in EASI score at Week 16. If a participant in 
the etrasimod 2 mg QD group experiences the intercurrent events of initiation of 
prohibited medications or discontinuation of study treatment due to any reason 
(whichever is earlier), the endpoint data after the intercurrent event (Appendix 3, 
Post-intercurrent-event data) will be treated as missing and then imputed via multiple 
imputations as if they are in placebo group (ie, no treatment benefit).
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4. Intercurrent events:

Initiation of prohibited medications – a participant who receives prohibited
medications post-randomization prior to Week 16, the endpoint data after the 
intercurrent event (Appendix 3, Post-intercurrent-event data) will be treated as 
missing and then imputed via multiple imputation as if they are in placebo group 
(ie, no treatment benefit).

Discontinuation of study intervention due to any reason prior to the Week 16 visit 
– a participant who discontinues study treatment due to any reason, the endpoint 
data after the intercurrent event (Appendix 3, Post-intercurrent-event data) will be 
treated as missing and then imputed via multiple imputation as if they are in 
placebo group (ie, no treatment benefit). 
5. Population-level summary: The mean difference in percent change from baseline in 
EASI score at Week 16 between etrasimod 2 mg QD and placebo.
Estimand E2 will also be applied to percent change from baseline in EASI score at visits
prior to Week 16.
2.2.3. Additional Estimand
One supportive estimand is defined to support the Estimand E1 (primary estimand) of the 
primary endpoint (IGA response at Week 16) as well as Estimand E1 of IGA response at all 
visits prior to Week 16. It is Estimand E1a, detailed below.
Estimand E1a for IGA response at Week 16:
Estimand E1a uses a treatment policy strategy and estimates the treatment effect at a visit 
regardless of initiation of prohibited medications or discontinuation of study treatment.  This
supportive estimand is defined by the following five attributes: 
1. Treatment condition: received study intervention of etrasimod 2 mg QD or placebo.
2. Population: Participants with moderate-to-severe AD as defined by the inclusion and 
exclusion criteria.
3. Variable: IGA response at Week 16 is score of clear (0) or almost clear (1) and a 
reduction from baseline of ≥2 points. The intercurrent events of initiation of 
prohibited medications or discontinuation of study treatment due to any reason will 
not be considered here. All IGA data collected including those collected after the 
intercurrent events are also included to derive the IGA response at Week 16.
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4. Intercurrent events:

Initiation of prohibited medications is not considered for data exclusion.

Discontinuation of study intervention due to any reason is not considered for data 
exclusion.
5. Population-level summary: The difference in IGA response rates at Week 16 between 
etrasimod 2 mg QD and placebo.
The difference between Estimand E1 and E1a is that Estimand E1a disregards intercurrent 
events and includes all data collected regardless of intercurrent events.
One supportive estimand is defined to support the Estimand E2 of the continuous secondary 
endpoint at a visit (eg, percent change from baseline in EASI score at Week 16). It is 
Estimand E2a, detailed below.
Estimand E2a for percent change from baseline in EASI score at Week 16:
Estimand E2a uses a treatment policy strategy and estimates the treatment effect at a visit 
regardless of initiation of prohibited medications or discontinuation of study treatment. 
Estimand E2a is applied to the secondary endpoint of percent change from baseline in EASI 
score at Week 16. This Estimand E2a is defined by the following five attributes:
1. Treatment condition: received study intervention of etrasimod 2 mg QD or placebo.
2. Population: Participants with moderate-to-severe AD as defined by the inclusion and 
exclusion criteria.
3. Variable: Percent change from baseline in EASI score at Week 16. The intercurrent 
events of initiation of prohibited medications or discontinuation of study treatment 
will not be considered here. All data collected including those collected after the 
intercurrent events are also included in statistical analysis at Week 16.
4. Intercurrent events:

Initiation of prohibited medications is not considered for data exclusion.

Discontinuation of study intervention due to any reasons is not considered for data 
exclusion.
5. Population-level summary: The mean difference in percent change from baseline in 
EASI score at Week 16 between etrasimod 2 mg QD and placebo.
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Estimand E2a will also be applied to percent change from baseline in EASI score at visits 
prior to Week 16.
It can be noted that Estimand E1a for binary efficacy endpoint and Estimand E2a for 
continuous efficacy endpoint use the same treatment-policy strategy in estimand definition.
No estimands will be defined for efficacy endpoints in Part 1 OLE and Part 2 OL Safety
phases, and all safety endpoints in this study, so all data collected in these phases will be 
used in analyses.
2.3. Study Design
This is a 2-part study with Part 1 being 16-week, randomized, DB, placebo controlled, with
an OLE, to assess efficacy and safety of 2 mg etrasimod administered orally, QD in
participants with refractory, moderate-to-severe AD, whose disease is not adequately
controlled with other systemic drug products, including biologics, or when use of those
therapies is inadvisable (ie, participants with a history of a prior systemic treatment failure).
The OL Part 2 is to assess long-term safety of etrasimod 2 mg QD in participants with
moderate-to-severe AD with a history of prior systemic therapy failure.
Part 1: Approximately 60 participants with moderate-to-severe AD with a history of prior
systemic treatment failure will be randomized (1:1 ratio) in a double-blind manner to receive
etrasimod 2 mg QD or placebo orally, once daily, for 16 weeks. Randomization will be 
stratified by disease severity as measured by IGA score (3 [moderate AD], 4 [severe AD]) at 
baseline. Following completion of the double-blind, placebo-controlled period, all 
participants with no clinically significant treatment-related safety concerns will be given the 
option to continue in an OLE whereby they will receive etrasimod 2 mg (tablet) QD for 52 
weeks. Non-responders, participants not achieving EASI-50, will be discontinued at Week 32 
(ie, 16 weeks of treatment in the OLE period).
Part 2: An interim analysis will be conducted after all applicable Part 1 participants have 
completed the 16-week DB treatment period. The IA will be performed by the Sponsor and 
data summaries will be shared with the study team. The study team will review the data in 
the context of the overall benefit-risk profile of etrasimod for the treatment of moderate-to-
severe AD with prior systemic failure. The data review will include but is not limited to, 
efficacy measures of IGA and EASI-75 response and safety parameters including the 
incidence and severity of AEs, AESIs, and clinically relevant changes in ECG, and vital 
signs, and laboratory values. The efficacy and safety data will be utilized to make a go/no-go 
decision for initiating Part 2 of the study, as well as for completing the 52-week treatment for 
the Part 1 participants in the OLE. Once the decision is made it will be promptly 
communicated to the sites.
If the IA results in a decision to proceed to Part 2 of the study, approximately 340 additional
(de novo) participants will be enrolled to receive etrasimod 2 mg orally, once daily, for 52 
weeks in an open-label manner in order to fulfill the safety database requirements. 
Enrollment into Part 2 will not begin until the IA data from Part 1 DB are reviewed, and 
determination made as to the favorable benefit/risk of etrasimod 2 mg QD in this new target 
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population. Non-responders, ie, participants not achieving at least EASI-50 will be 
discontinued at Week 16, Part 2. The participant population in both Part 1 and Part 2 will 
include at least 40% of participants with moderate AD (IGA score of 3) and at least 40% of 
participants with severe AD (IGA score of 4). Figure 1 below provides a schematic of this 
study design.
The application of topical emollients/moisturizers (including those containing ceramide, 
hyaluronic acid, or urea) will be required at least once daily for at least 1 week prior to 
baseline (Day 1) and throughout the treatment period without change (ie, type, frequency, 
application). TCS and other medicated topical treatments for AD must be discontinued at 
least 1 week prior to baseline (Day 1) and are not permitted in the double-blind treatment 
period. Safety follow-up visits will occur at 2 and 4 weeks after the last dose of study 
treatment. Medicated and non-medicated rescue medications are not permitted during the 
Part 1 DB portion. For Part 1 OLE and Part 2 medicated and non-medicated topical 
treatments for AD will be permitted at the discretion of the investigator and in accordance 
with their usual practice.
Figure 1.
Study Schematic
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3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoints
For Part 1 DB,

IGA response at Week 16.
IGA response is defined as clear (0) or almost clear (1) on a 5-point scale and a 
reduction of ≥2 points from baseline (Appendix 2.2.1). Only participants with 
baseline IGA ≥2 in the FAS are included in all analyses of IGA response. 
For Part 1 OLE and Part 2,

Incidence and severity of treatment-emergent AEs, AEs leading to study treatment 
discontinuation, SAEs, and AESIs.

Incidence of clinically significant changes in clinical laboratory values, ECG 
measurements and vital signs.
3.2. Secondary Endpoints
For Part 1 DB,

EASI-75 at Week 16.
EASI-75 response is defined as ≥75% reduction in EASI from baseline
(Appendix 2.2.3).

Percent change from baseline in EASI score at Week 16 (Appendix 2.2.3).
3.3. Exploratory Endpoints
For Part 1 DB,

IGA response at at all timepoints except Week 16.

EASI-75 at all timepoints except Week 16.

Percent change from baseline in EASI score at all timepoints except Week 16.

≥4-point reduction in PP-NRS score from baseline at all timepoints (Appendix 2.2.4).
Only participants with baseline PP-NRS ≥4 in the FAS are included in all analyses of 
this endpoint.

≥4-point reduction in Skin Pain NRS score from baseline at all timepoints
(Appendix 2.2.5). Only participants with baseline Skin Pain NRS ≥4 in the FAS are 
included in all analyses of this endpoint.
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
EASI-90 at all timepoints.
EASI-90 response is defined as ≥90% reduction in EASI from baseline
(Appendix 2.2.3).

≥4-point reduction in POEM from baseline at Week 16 (Appendix 2.2.6). Only 
participants with baseline POEM ≥4 in the FAS are included in all analyses of this 
endpoint.
For Part 1 OLE and Part 2,

EASI-75 at all scheduled timepoints.

IGA of clear (0) or almost clear (1) on a 5-point scale at all scheduled timepoints. 
It is important to note that this is different from IGA response, in that this is without 
the ≥2-point reduction component.

Percent change from baseline in EASI score at all scheduled timepoints.

≥4-point reduction in PP-NRS score from baseline at all scheduled timepoints. Only 
participants with baseline PP-NRS ≥4 are included in all analyses of this endpoint.

≥4-point reduction in Skin Pain NRS score from baseline at all scheduled timepoints.
Only participants with baseline Skin Pain NRS ≥4 are included in all analyses of this 
endpoint.

EASI-90 at all scheduled timepoints.

Change from baseline in POEM at all scheduled timepoints.
3.4. Baseline Variables
For Part 1 DB and OLE, baseline value for efficacy and safety endpoints is defined as pre-
dose value obtained on Day 1 (ie, baseline visit) or prior (if the Day 1 value is not available) 
in the Part 1 double-blind phase in the analyses. For Part 2, baseline value is defined as pre-
dose value obtained on Day 1 (ie, baseline visit) or prior (if the Day 1 value is not available) 
in the Part 2 open-label phase in the analyses.
A participant’s baseline IGA score value (3 [moderate AD], 4 [severe AD]) recorded in the 
clinical database will be used as the actual IGA stratification factor for both Part 1 and Part 2. 
If a participant is randomized but the actual baseline IGA is less than 3 (ie, protocol 
deviation), this participant will be grouped in the actual stratum of baseline IGA score of 3, 
in order to keep the participant in analyses. This is described in more detail below.
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3.4.1. Stratification Factor
Participants will be stratified by disease severity as measured by baseline IGA score (3 
[moderate AD], 4 [severe AD]).  The stratum derived from data collected on IGA score at 
baseline will be used for all analyses requiring this stratification variable (Section 5.2). This 
stratification is called the actual IGA stratification variable. The stratum of IGA score
reported to the randomization system is called the reported IGA stratification. 
For the primary endpoint of IGA response at Week 16 in Part 1 DB phase, a sensitivity 
analysis will be performed using the reported IGA stratification if there are discrepancies 
between the actual IGA stratification and the reported IGA stratification. A participant listing 
will be provided comparing the reported IGA stratification variable (to the randomization 
system) and actual IGA stratification variable (derived using the clinical database).
3.5. Safety Endpoints
All the safety data will be summarized descriptively through appropriate data tabulations, 
descriptive statistics, and graphical presentations.  Treatment-emergent AEs including SAEs 
and AE leading to discontinuation of study treatment, vital signs, 12-lead ECG parameters, 
and laboratory tests, etc. will be summarized according to the Clinical Data Interchange 
Standards Consortium (CDISC) and Pfizer Standards (CaPS). Treatment-emergent AE is 
defined as an AE that started on or after the first dose of study treatment (ie, baseline, 
without regard to baseline severity). The MedDRA version for AE coding at the time of 
database release will be adopted and the version used will be displayed in all relevant safety 
data tabulations. All safety analyses will be performed on the SAS (Section 4.2). 
3.5.1. Adverse Events (Including Laboratory Data)
In this study, the safety endpoints included in safety data summaries are listed in, although 
not limited to, the following:

Incidence and severity of treatment-emergent AEs, AE leading to study treatment 
discontinuation, SAEs, and AESI, etc.

Incidence of clinically significant changes in clinical laboratory values, 12-lead ECG 
measurements, and vital signs, etc.

Change from baseline in laboratory values (hematology, serum chemistry, 
coagulation, and urinalysis), 12-lead ECG measurement, vital signs, and other 
objective safety measures.
These safety endpoints are considered as primary endpoints for the Part 1 OLE and Part 2 OL
Safety phases. Definitions of baseline for Part 1 and Part 2 are previously provided (Section 
3.4). 
3.5.2. Adverse Events of Special Interest
Treatment-emergent AESIs are identified per study protocol and require close monitoring. 
All AESIs must be reported as an AE or SAE following the reporting procedures described in 
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the protocol. An AESI that is also an SAE must also be reported using the CT SAE Report 
Form. The following are AESI identified for etrasimod (except for PML, the MedDRA 
search terms for AESI are recorded in a separate charter for the etrasimod clinical program):

Cardiovascular events (eg, bradycardia, AV conduction delay, and hypertension);

Macular oedema*;

Pulmonary events (airflow obstruction or altered gas exchange);

Infections (severe infections, opportunistic infections including PML*, herpes 
simplex and herpes zoster);

Liver injury (liver transaminase elevation and bilirubin elevation);

PRES*; and

Malignancies*.
* A diagnosis of this event requires permanent discontinuation of study intervention.
3.5.3. Study Treatment Compliance
In addition to safety endpoints, the study treatment compliance (%) will be derived from the 
total number of doses actually taken divided by the total number of doses expected to take 
between two scheduled visits using dosing data collected in the Treatment Dosing CRF page.
Compliance is expressed in percentage.  Both the randomized treatments (ie, etrasimod 2 mg 
QD and placebo) will be taken into account. Participants who have study treatment 
compliance of <80% or >120% between two scheduled visits will be identified in a listing. 
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis set (population) prior to unblinding, releasing the database for 
analyses. Classification of participants to analysis sets will be documented per standard 
operating procedures. For participants with multiple enrollments, only the participant 
identifier and data under initial enrollment will be included and summarized. Data collected 
for other enrollments with be included only in listings and narratives.
Participants who are screened but do not meet inclusion criteria or meet exclusion criteria to 
enter the study (ie, screen failure), they will be counted as a single group and this is how far 
they are summarized (Section 6.4.2). Below are descriptions of the analysis sets defined for 
this study. 
4.1. Full Analysis Sets
The full analysis set (FAS) will include all participants who are randomized to the study 
irrespective of whether they receive any dose of study intervention (ie, etrasimod or placebo).  
Participants will be analyzed in the treatment groups as they are randomized.  If a participant
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is treated but not randomized, then this participant will be excluded from the FAS.  A 
narrative will be provided for this participant in the clinical study report (CSR). For a 
participant who is randomized but not treated, for Part 1 DB and OLE, baseline value for 
efficacy and safety endpoints is defined as the value obtained on the date of randomization as 
Day 1 or prior (if the Day 1 value is not available) in the Part 1 DB phase in the analyses.
In general, the analysis population for analzying all efficacy endpoints in this study is defined 
by the complete FAS. However, there are some exceptions: some efficacy endpoints, defined 
by specific point reduction from baseline, require the inclusion of only participants who meet 
a baseline threshold in the analysis set to allow them the potential to respond in these efficacy
endpoints. The details of these exceptions are provided below. Therefore, when considering 
analyzing an efficacy endpoint under an estimand, it is important to consider these 
exceptions.
FAS for Specific Efficacy Endpoints 
The following four binary efficacy endpoints will only be analyzed including participants 
who meet the specific baseline threshold. This is to ensure that only participants with the 
potential to respond at a post-baseline visit are included in the analyses.

IGA response defined as clear (0) or almost clear (1) on a 5-point scale and a 
reduction of ≥2 points from baseline (Appendix 2.2.1): Only participants with 
baseline IGA ≥2 in the FAS are included in all analyses of IGA response, knowing 
that only participants with baseline IGA ≥3 are eligible to enroll in this study.

≥4-point reduction in PP-NRS score from baseline (Appendix 2.2.4): Only 
participants with baseline PP-NRS ≥4 in the FAS are included in all analyses of this 
endpoint. 

≥4-point reduction in Skin Pain NRS score from baseline (Appendix 2.2.5): Only 
participants with baseline Skin Pain NRS ≥4 in the FAS are included in all analyses 
of this endpoint.

≥4-point reduction in POEM from baseline (Appendix 2.2.6): Only participants with 
baseline POEM ≥4 in the FAS are included in all analyses of this endpoint.
For all other efficacy endpoints, the general rule of including the complete FAS still applies.
4.2. Safety Analysis Set
The safety analysis set (SAS) will include all participants who are randomized and receive at 
least one dose of the study treatment (ie, etrasimod or placebo).  Participants will be analyzed 
in the treatment groups as they receive.  If a participant is treated but not randomized, then 
the participant will be excluded from SAS.  A narrative will be provided for this participant
in the CSR. The SAS will be the analysis set for safety analyses in all phases of the study.
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5. GENERAL METHODOLOGY AND CONVENTIONS
For Part 1, there will be a total of 2 planned analyses. The first (interim) analysis (IA) for 
Part 1 will be conducted when all applicable participants have completed or discontinued 
from study prior to their Part 1 DB Week 16 visit. The IA will be performed by the Sponsor 
and it will include all efficacy and safety data through Week 16. Data summaries from the IA
will be shared with the study team. The study team will review the data in the context of the 
overall benefit-risk profile of etrasimod for the treatment of moderate-to-severe AD with 
prior systemic failure. The efficacy and safety data up to Week 16 will be utilized to assess 
the primary efficacy endpoint, secondary efficacy endpoints, and safety endpoints (Section
2.2, Section 5.1) and to make a go/no-go decision for initiating Part 2 of the study, as well as 
for completing the 52-week treatment for the Part 1 participants in the OLE. The IA efficacy 
results through Week 16 for Part 1 DB phase is not final and definitive.   
The second (final) analysis for Part 1 will be conducted when all applicable participants have 
completed or discontinued from study prior to their Week 68 visit (including safety follow-
up visits at Weeks 70 and 72) if Part 1 OLE is planned for completion by the sponsor.
Otherwise, if Part 1 OLE is decided to be terminated by the sponsor, the final analysis will 
only be conducted based on data collected up to the date of study termination. The final 
analysis will contain final safety and efficacy data, as Part 1 final database, to assess the 
primary endpoints, secondary endpoints as well as exploratory efficacy endpoints (Section 
2.2). This will also include efficacy analyses for Part 1 DB phase repeated based on this final 
data, and this final analysis is considered final and definitive.
For Part 2, there will only be one final analysis when all applicable participants have 
completed their Part 2 OL Safety phase Week 52 visit (including safety follow-up visits at 
Weeks 54 and 56) if Part 2 OL Safety phase is planned by the sponsor based on the Part 1 
DB IA result. The final analysis will contain final safety data to assess the primary safety 
endpoints, and final efficacy data to assess exploratory efficacy endpoints (Section 2.2).
5.1. Hypotheses and Decision Rules
This protocol is designed to estimate the treatment difference in response rates of etrasimod 2 
mg QD versus placebo, as well as their individual response rates (Section 5.2.1.1), for the 
treatment of moderate-to-severe AD based on the primary endpoint of IGA response rate at 
Week 16 in Part 1 DB (based on Estimand E1 as primary estimand) among adult participants
(with baseline IGA ≥2) with a history of a prior systemic therapy failure. There are no 
statistical hypotheses in this study, therefore no multiplicity adjustment will be made in this 
study.
5.2. General Methods
In Part 1 DB, as all participants randomized to treatment groups of etrasimod 2 mg QD and 
placebo will switch to open-label treatment of etrasimod 2 mg QD at Week 16, the treatment 
labels used for reporting DB visits up to Week 16 will be “Etrasimod 2 mg QD” and
“Placebo” respectively. At the end of Part 1 OLE, when reporting OLE visits from Week 20
through Week 68, the treatment labels used will be “Etrasimod 2 mg QD” and “Placebo → 
Etrasimod 2 mg QD” respectively to differentiate these two treatment groups.
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For Part 1 DB analyses up to Week 16, the following treatment comparison will be made at 
each timepoint, where applicable:

Etrasimod 2 mg QD vs. Placebo.
The primary efficacy comparison for the primary endpoint of IGA response at Week 16 will 
be between etrasimod 2 mg QD and placebo. For analyses after Week 16 from Week 20 
through Week 68 (Part 1 OLE phase), the following treatment comparison will be made at 
each timepoint,

Etrasimod 2 mg QD vs. Placebo → Etrasimod 2 mg QD.
For Part 2 OL Safety phase, there will only be one treatment group of etrasimod 2 mg QD, 
the label will be “Etrasimod 2 mg QD”. There is no treatment comparison in Part 2. There 
will be no pooling of efficacy and safety data of Part 1 and Part 2 in this study.
Descriptive Summaries
In general, the data for all continuous endpoints will be summarized by treatment group and 
by timepoint in tables containing descriptive statistics (N as the number of participants 
evaluable for the endpoint at the timepoint, mean, standard deviation, standard error of the 
mean, minimum, 1st, 2nd (ie, median) and 3rd quartiles and maximum) for actual and change 
from baseline (or percent change from baseline) values for those endpoints measured at 
baseline.  In case when N=1 (ie, only one particpant is available/evaluable for summary), 
standard deviation and standard error will be reported as “NA” (not applicable) while the 
remaining statistical parameters will have the same value as the mean.  The data for all 
response-type binary endpoints will be summarized by treatment group and by timepoint in 
tables showing descriptive statistics: N, n (ie, number of responders), response rate, standard 
error (SE) of the response rate, and 95% confidence interval (CI) based on normal 
approximation, all expressed in %.  If ̂ is the estimated response rate, then the 95% CI is 
calculated as: 
̂ ± .
 = ̂ ± .
̂(1 −̂)

where z0.975 is the 97.5th percentile of the standard normal distribution and N is the number of 
participants evaluable for the endpoint at the timepoint.  If the lower bound is calculated to 
be negative, it will be set to 0%; if the upper bound is calculated to be larger than 100%, it 
will be set to 100%.  In case when response rate is 0 or 100%, standard error will be reported 
as “NA” and the 95% CI bounds will be the same as the response rate.  The displays 
described above for continuous and response-type binary endpoints will only use available 
data with no imputation.  Therefore, the calculation of response rates will use the number of 
evaluable participants as denominators. 
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5.2.1. Analyses for Binary Endpoints
5.2.1.1. Cochran-Mantel Haenszel (CMH) Approach
At a single timepoint (eg, IGA response at Week 16 in Part 1 DB), difference in response rate
between etrasimod 2 mg QD and placebo groups will be estimated using the Cochran-Mantel 
Haenszel (CMH) approach adjusting for the stratification factor of IGA score (3 [moderate 
AD], 4 [severe AD]) at baseline) (Cochran, 1954; Mantel and Haenszel, 1959). Large sample 
approximation will be used for testing the superiority of etrasimod 2 mg to placebo at Part 1 
Week 16 and for forming 95% CI and calculating p-value. This approach will be referred to 
as CMH. This method is also applicable for all other timepoints in Part 1.
Explicitly, let 
and 
represent the estimated response rates for etrasimod 2 mg (A) and 
placebo (B), respectively, of the th stratum.  Using the CMH weights, the weighted 
difference in rates between etrasimod 2 mg QD and placebo groups, d, is expressed by:
where 




i
Bi
Ai
Bi
Ai
Bi
Ai
Bi
Ai
i
n
n
n
n
n
n
n
n
w
)
/(
)
(
)
/(
)
(
, is the CMH weight for the th stratum, with 
and 
equal the numbers of participants in the etrasimod and placebo groups, respectively, per 
stratum.  The weights are normalized such that the sum across strata adds up to 1.
Two-sided 95% CI will be estimated using the normal approximation to the binomial 
distribution via the following method, 
 ± / !()"
where the variance of d is
with
Bi
Bi
Bi
Ai
Ai
Ai
Bi
Ai
n
p
p
n
p
p
p
p
)
ˆ
1(
ˆ
)
ˆ
1(
ˆ
)
ˆ
ˆ
var(





.
Two-sided p-value for the test of the 0 difference between etrasimod 2 mg QD and placebo 
groups will be calculated as:
 = 2(1 −$(|&|)),
where $(.) is the Gaussian cumulative density function and 
is the Normal Z
test statistic.
If there is no (ie, 0%) response or 100% response rate in any one or both of the two treatment 
groups for the comparison in a stratum, eg, etrasimod vs. placebo, when calculating the 
proportions above, 0.5 will be added to the number of responses (ie, numerator) and 1 will be 
Ai
pˆ
Bi
pˆ
)
ˆ
ˆ
(
d
Bi
Ai
i
i
p
p
w


Ai
n
Bi
n
)
ˆ
ˆ
var(
var(d)
2
Bi
Ai
i
i
p
p
w


)
var(d
d
Z 
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added to the denominator in each treatment in that stratum only corresponding to the pair of 
comparison for calculating the treatment difference, standard error (ie,  !()), 95% CI 
and 2-sided p-value (Agresti, 2002).
When response rate of 0% or 100% is observed in both treatments in comparison and in both 
strata, no formal comparison will be performed.  Estimated response rate of 0% or 100% will
be reported as observed.  Standard error will be reported as 0. The final results will be 
expressed in percentages, ie, (proportions x 100)%.
5.2.2. Analyses for Continuous Endpoints
5.2.2.1. Analyses for Continuous Data (Repeated Measures Under Estimand E2)
For a continuous efficacy endpoint analyzed under the Estimand E2 and measured at multiple 
post-baseline visits (ie, percent change from baseline in EASI score at Week 16), this 
endpoint will be analyzed using the Jump-to-Control (JTC) method (Carpenter, Roger and 
Kenward 2013). This JTC method is implemented in the following steps.
1. A mixed model for repeated measures (MMRM) that includes fixed effects of
treatment group, visit, treatment group-by-visit interaction, actual stratification factor 
(ie, baseline IGA of 3 or 4 from clinical database), actual-stratification-factor-by-visit 
interaction, baseline value, and baseline-value-by-visit interaction, will be used to 
analyze the endpoint’s data across all visits (ie, all visits up to Week 16 for Part 1 DB 
phase). This MMRM will include all relevant observed values across all visits in the 
pre-intercurrent-event-data without imputation of missing values on the FAS for 
Estimand E2 (Section 4.1, Appendix 3). The data after intercurrent events of 
initiation of prohibited medications or discontinuation of study treatment due to any 
reason will be set to missing (see Appendix 3 for more details on data inclusion). A 
common unstructured variance-covariance matrix will be used. Estimation of model 
parameters is performed under the Bayesian framework using MCMC method with 
non-informative prior densities for the model parameters. This is known as the 
estimation model.
2. Multiple imputation allows for uncertainty of the imputed values. Using the 
estimated model specified in step 1, missing percent change from baseline value at a 
particular visit of interest (eg, Week 16) for a participant can be imputed multiple 
times using multivariate conditional Normal distribution as the imputation model 
constructed from the parameter values sampled from their posterior densities (using 
MCMC) conditional on participant’s observed values at prior visits, if any. 
3. In order to apply the JTC concept, for a participant in the etrasimod 2 mg QD group
with monotone missing values, the means of the multivariate conditional Normal 
distribution for those visits with monotone missing values will be equal to those 
means estimated for the placebo group for the same visits. The visit of interest will 
be subject to multiple imputation based on this distribution. This will result in 
multiple imputed datasets at this visit of interest. Intermittent missing values will be 
imputed under MAR. Participants in the placebo group with missing values at this 
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visit of interest will be imputed based on the MAR assumption. The number of 
imputation (R) can be specified as 100 here.
4. For each of the R completed imputed dataset for a visit of interest, an analysis of 
covariance (ANCOVA) model which includes fixed effects of treatment group, actual 
stratification factor (ie, baseline IGA of 3 or 4 from clinical database), and baseline 
value, will be used to analyze the data (observed and imputed) at the visit of interest. 
This will generate LSM (SE) for each treatment group and LSM treatment difference 
estimate as well as standard error of this estimate. This will produce R sets of 
estimates and standard errors. These R sets of results will be combined using the 
Rubin’s rules (Rubin 1987) to generate the combined LSM (SE) for each treatment 
group and LSM treatment difference estimate and its standard error, 95% CI and 2-
sided p-value, for this visit of interest.
The implementation of this JTC method for continuous endpoint measured at multiple post-
baseline visits under the Estimand E2 will provide analysis result for each visit of interest. 
The implementation may be using the Statistical Analysis System (SAS) macro developed by 
Carpenter, Roger and Kenward, 2013. Further programming details of JTC method will be 
laid out in the programming plan.
5.2.2.2. Analyses for Continuous Data (Repeated Measures With No Estimand)
When Estimand E2a or no estimand is defined for a continuous efficacy endpoint, repeated 
measures data for continuous endpoints will be analyzed as change or percent change from 
baseline as appropriate with a MMRM that includes fixed effects of treatment group, visit,
treatment group-by-visit interaction, actual stratification factor (ie, baseline IGA of 3 or 4
from clinical database), actual-stratification-factor-by-visit interaction, baseline value, and 
baseline-value-by-visit interaction. This MMRM is similar to the estimation model used in 
JTC method (Section 5.2.2.1). MMRM will include observed values without imputation of 
missing values. A common unstructured variance-covariance matrix will be used, provided 
the model converges, otherwise alternative covariance structures will be attempted in this 
order depending on model convergence and feasibility: heterogeneous compound symmetry 
(CSH) then compound symmetry (CS). The Kenward-Roger degrees of 
freedom approximation will be used. Comparison of treatment groups (providing LSM of the 
treatments, LSM of the treatment difference, 2-sided p-value and 95% CI) at each included 
timepoint will be generated using this MMRM.  MMRM can only include participants with 
observed baseline value and at least one observed post-baseline value. If the baseline value is 
missing or if there are no post-baseline measurements, this participant will not be included 
this analysis (Section 4.1).Therefore, when reporting the result of MMRM, the number of
participants by treatment group in the FAS (N), the number of participants by treatment 
group included in the MMRM (N1) and the number of participants by treatment group 
evaluable at each of the timpoints (N2) are to be reported.  
5.3. Methods to Manage Missing Data
In Part 1 DB phase, after accounting for relevant intercurrent events in the data sets (Section 
2.2, Appendix 3) and visit windowing (Appendix 2.1) in the data, if a binary efficacy 
endpoint at a visit has missing value, it will be handled by setting the missing binary efficacy 
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endpoint to non-response. This method of handling missing binary efficacy endpoint is 
known as missing response as non-response (MR=NR). In general, if a continuous efficacy 
endpoint at a visit has missing value, it will remain missing and no imputation of this missing 
value will be performed in the datasets. 
Under Estimand E1 (eg, IGA response at Week 16), after accounting for the occurrence of 
relevant intercurrent events in the dataset and in the FAS, missing binary efficacy endpoint at 
a visit will be set to non-response (ie, treatment failure). If intercurrent events have not 
occurred before a visit, and the binary efficacy endpoint at this visit has missing value, it will 
be set to non-response due to MR=NR. Under the Estimand E1a, since intercurrent events are 
not considered, if the binary efficacy endpoint at a visit has missing value, it will be set to 
non-response due to MR=NR.
For continuous efficacy endpoint analyzed under Estimand E2 (eg, percent change from 
baseline in EASI score at a visit), after accounting for the occurrence of relevant intercurrent 
events, the post-intercurrent-event data will be treated as missing, only pre-intercurrent event 
data will be included in the JTC method via multiple imputations (Section 5.2.2.1).
In Part 1 OLE phase, since no estimands are defined for (binary or continuous) efficacy 
endpoints, all observed data collected/assessed regardless of any prior intercurrent events will 
be included in deriving the efficacy endpoints at a visit. If the binary efficacy endpoint at any 
visit has missing value, it will be handled by setting the binary efficacy endpoint to non-
response. This method of handling missing binary efficacy endpoint is known as missing 
response as non-response (MR=NR), which is similar to using Estimand E1a (treatment 
policy estimand). If the continuous efficacy endpoint at any visit has missing, it will remain 
as missing, without imputation of missing value at this visit, which is similar to using 
Estimand E2a (treatment policy estimand). The same approach of including all observed data 
collected/assessed regardless of any prior intercurrent events will also be applicable to Part 2 
OL Safety phase. Missing binary efficacy endpoints in Part 2 OL Safety phase will not be 
imputed as non-response, only observed values will be summarized.  
In general, missing values in any (binary or continuous) efficacy endpoint will not be
imputed when summarizing these endpoints using descriptive statistics. In addition, missing 
values for safety endpoints will not be imputed.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint
6.1.1. Primary Analysis
The IGA response at Week 16 is the primary efficacy endpoint in Part 1 DB phase. The 
analysis of the primary endpoint will be based on Estimand E1 accounting for the 
intercurrent events using the FAS analyzed for participants with baseline IGA ≥2 (Section 
4.1, Appendix 3). This corresponds to the primary estimand including only the pre-
intercurrent-event data (Appendix 3). For the primary analysis, the normal approximation for 
the difference in binomial proportions adjusting for the actual stratification factor of baseline 
IGA (3 vs 4) via the CMH approach (Section 5.2.1.1) will be used. The baseline IGA from 
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the clinical database will be used as the actual stratification factor (Section 3.4.1). This CMH 
approach will be used to estimate the treatment difference in response rates of etrasimod 2 
mg QD versus placebo and to generate 95% CI for the IGA response rate difference at Week 
16 along with the 2-sided p-value (Section 5.2.1.1). Missing values will be handled by setting 
the IGA response value to non-response, MR=NR (Section 5.3). This is the primary analysis 
for IGA response at Week 16. 
Analysis of IGA response at other visits prior to Week 16 (ie, exploratory endpoints) will 
also be analyzed using the same method based on the Estimand E1 including only the pre-
intercurrent-event data on the FAS analyzed for participants with baseline IGA ≥2.
6.1.2. Supportive Analysis
A supportive analysis will be conducted for the primary efficacy endpoint of IGA response at 
Week 16 based on Estimand E1a without regard to intercurrent events using the FAS 
analyzed for participants with baseline IGA ≥2 (Section 2.2.3, Appendix 3). This corresponds 
to the supportive estimand including all data (Appendix 3). For this supportive analysis, the 
same normal approximation for the difference in binomial proportions adjusting for the 
actual stratification factor of baseline IGA (3 vs 4) via the CMH approach (Section 5.2.1.1) 
will be used. The baseline IGA from the clinical database will be used as the actual 
stratification factor (Section 3.4.1). This CMH approach will be used to support the primary 
analysis of estimating the treatment difference in response rates of etrasimod 2 mg QD versus 
placebo and to generate 95% CI for the IGA response rate difference at Week 16 along with 
the 2-sided p-value. Missing values will be handled by setting the IGA response value to 
non-response, MR=NR (Section 5.3). This is the first supportive analysis for IGA response at 
Week 16. 
Supportive analysis of IGA response at other visits prior to Week 16 will also be performed
using the same method based on the Estimand E1a including all data on the FAS, all 
analyzing participants with baseline IGA ≥2.
When there are discrepancies between actual stratification factor (baseline IGA of 3 vs 4) 
versus reported stratification factor from the randomization system, a sensitivity analysis for 
the IGA response at Week 16 and visits prior to Week 16 will be conducted using the normal 
approximation for the difference in binomial proportions adjusting for the reported (instead 
of actual) stratification factor of baseline IGA of 3 vs 4 via the CMH approach (Section 
5.2.1.1). This includes the pre-intercurrent-event data under Estimand E1 on the FAS 
analyzed for participants with baseline IGA ≥2 (Section 3.4.1, Section 4.1, Appendix 3).
In addition, for the primary endpoint of IGA response at Week 16 under Estimand E1, a 
summary similar to the following will also be generated to assess the impact of intercurrent 
events on the estimates.
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Table 4.
IGA Response at Week 16 and Intercurrent Events
IGA Response at Week 16 – Estimand E1, FAS with Baseline IGA ≥2 for Estimand E1, MR=NR
n (%)
Etrasimod 2 mg QD 
(FAS N=xxx) [1]
Placebo 
(FAS N=xxx) [1]
IGA Responders 
xx (xx.xx)
xx (xx.xx)
IGA Non-Responders
xx (xx.xx)
xx (xx.xx)
1) Week 16 Completers with Observed Non-Response
xx (xx.xx)
xx (xx.xx)
2) Week 16 Completers with Missing Response Set as 
Non-Response
xx (xx.xx)
xx (xx.xx)
3) Initiation of Prohibited Medications Prior to Week 16 
Visit (Earlier) 
xx (xx.xx)
xx (xx.xx)
4) Discontinued Study Treatment Due to Any Reason 
Prior to Week 16 Visit (Earlier)
xx (xx.xx)
xx (xx.xx)
Reasons for Discontinuation of Study Treatment [2]
             Lack of Efficacy
xx (xx.xx)
xx (xx.xx)
             Adverse Event
xx (xx.xx)
xx (xx.xx)
             Death
xx (xx.xx)
xx (xx.xx)
             Lost to Follow-up
xx (xx.xx)
xx (xx.xx)
             Withdrawal by Subject
xx (xx.xx)
xx (xx.xx)
             Non-Compliance with Study Drug
xx (xx.xx)
xx (xx.xx)
             Protocol Deviation
xx (xx.xx)
xx (xx.xx)
             Pregnancy
xx (xx.xx)
xx (xx.xx)
             Physician Decision
xx (xx.xx)
xx (xx.xx)
             Medication Error without Associated Adverse 
            Event
xx (xx.xx)
xx (xx.xx)
             Study Terminated by Sponsor
xx (xx.xx)
xx (xx.xx)
             Other
xx (xx.xx)
xx (xx.xx)
[1] N = number of participants in the FAS with Baseline IGA ≥2. IGA response rates are calculated based on 
this as denominator.
[2] Only reasons with at least one participant in any group will be summarized.
6.2. Secondary and Exploratory Endpoints
6.2.1. Secondary Binary Endpoints
The EASI-75 response at Week 16 is the binary secondary efficacy endpoint in Part 1 DB 
phase. The analysis of the binary secondary endpoint will be based on Estimand E1 
accounting for the intercurrent events using the FAS (Section 2.2.2, Appendix 3). This 
corresponds to the Estimand E1 including only the pre-intercurrent-event data (Appendix 3). 
For the secondary analysis, the normal approximation for the difference in binomial 
proportions adjusting for the actual stratification factor of baseline IGA (3 vs 4) via the CMH 
approach (Section 5.2.1.1) will be used. The baseline IGA is from the clinical database will 
be used as the actual stratification factor (Section 3.4.1). This CMH approach will be used to 
estimate the treatment difference in response rates of etrasimod 2 mg QD versus placebo and 
to generate 95% CI for the EASI-75 response rate difference at Week 16 along with the 2-
sided p-value (Section 5.2.1.1). Missing values will be handled by setting the EASI-75
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response value to non-response, MR=NR (Section 5.3). This is the secondary analysis for 
EASI-75 response at Week 16. 
Analysis of EASI-75 response at other visits prior to Week 16 (ie, exploratory endpoints)
will also be analyzed using the same CMH method based on the Estimand E1 including pre-
intercurrent-event data on the FAS.
Supportive analyses for EASI-75 for visits up to Week 16 will also be performed under the 
Estimand E1a using FAS (including all data). The same CMH approach adjusting to actual 
stratification factor (Section 3.4.1) will also be used. These analyses are to support the 
secondary analysis of estimating the treatment difference in response rates of etrasimod 2 mg 
QD versus placebo for EASI-75 at Week 16.
6.2.2. Exploratory Binary Endpoints
Analysis of other exploratory endpoints for Part 1 DB phase: ≥4-point reduction from 
baseline in PP-NRS at all visits up to Week 16 (analyzed only for participants with baseline 
PP-NRS ≥4), ≥4-point reduction from baseline in Skin Pain NRS at all visits up to Week 16
(analyzed only for participants with baseline Skin Pain NRS ≥4), EASI-90 response at all 
visits up to Week 16, and ≥4-point reduction from baseline in POEM at Week 16 (analyzed 
only for participants with baseline POEM ≥4), will also be analyzed using the same CMH 
method based on the Estimand E1 including pre-intercurrent-event data on the FAS. No 
supportive analyses are performed for these exploratory endpoints.
6.2.3. Secondary Continuous Endpoint (Repeated Visits)
The percent change from baseline in EASI at Week 16 is the continuous secondary efficacy 
endpoint in Part 1 DB phase. The analysis of the continuous secondary endpoint will be 
based on Estimand E2 accounting for the intercurrent events using the FAS (Section 2.2.2, 
Appendix 3). This corresponds to the Estimand E2 including only the pre-intercurrent-event 
data (Appendix 3). For this secondary analysis, the JTC method will be used to analyze 
percent change from baseline in EASI score at Week 16 (Section 5.2.2.1 for details on how 
to handle intercurrent events). This analysis will provide the LSM of the treatment group, the 
LSM of the treatment difference (Etrasimod 2 mg QD versus Placebo) in percent change 
from baseline in EASI score at Week 16, 95% CI and the 2-sided p-value from the Rubin’s 
rules to estimate the treatment difference of etrasimod 2 mg QD versus placebo of this 
continuous secondary endpoint (Section 5.2.2.1). 
Analysis results of percent change from baseline in EASI score at other visits prior to Week 
16 (ie, exploratory endpoints) will also be obtained from the same JTC method performed 
above under the same Estimand E2 using the FAS.
A supportive analysis will be performed for percent change from baseline in EASI score at 
visits up to Week 16 under the Estimand E2a regardless of intercurrent events using the FAS 
(Section 2.2.3, Appendix 3). The MMRM model including all available data up to Week 16 
will be used (Section 5.2.2.2). This analysis is to support the secondary analysis of estimating 
the treatment difference of etrasimod 2 mg QD versus placebo for percent change from 
baseline in EASI at Week 16.
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6.2.4. Other Exploratory Binary Endpoints
For Part 1 OLE, binary exploratory endpoints at all visits from Week 20 up to Week 68 (eg, 
EASI-75 response), will be analyzed at each visit, including all available data on the FAS
(since intercurrent events are not considered in this Part 1 OLE phase), using the normal 
approximation for the difference in binomial proportions adjusting for the actual stratification 
factor of baseline IGA (3 vs 4) via the CMH approach (Section 5.2.1.1). The baseline IGA 
from the clinical database will be used as the actual stratification factor (Section 3.4.1). This 
CMH approach will provide treatment comparison of Etrasimod 2 mg QD versus Placebo →  
Etrasimod 2 mg QD and generate 95% CI for the EASI-75 response rate difference at this 
visit along with the 2-sided p-value (Section 5.2.1.1). Missing values will be handled by 
setting the EASI-75 response value to non-response, MR=NR (Section 5.3). 
This CMH approach will also be applied to IGA of clear (0) or almost clear (1) response, ≥4-
point reduction from baseline in PP-NRS score (analyzed only for participants with baseline 
PP-NRS ≥4), ≥4-point reduction from baseline in Skin Pain NRS score (analyzed only for 
participants with baseline Skin Pain NRS ≥4), and EASI-90 response, at all visits from Week 
20 up to Week 68.
For Part 2 OL Safety, binary exploratory endpoints at all visits will only be descriptively 
summarized for the single treatment group of Etrasimod 2 mg QD using only observed 
values on the FAS (since intercurrent events are not considered in this Part 2 OL Safety
phase). Therefore, missing responses will not be imputed using the MR=NR in this Part 2 OL
Safety phase (Section 5.3). This approach is applicable to EASI-75 response, IGA of clear 
(0) or almost clear (1) response, ≥4-point reduction from baseline in PP-NRS score (analyzed 
only for participants with baseline PP-NRS ≥4), ≥4-point reduction from baseline in Skin 
Pain NRS score (analyzed only for participants with baseline Skin Pain NRS ≥4), and EASI-
90 response, at all visits from Week 4 to Week 52. The baseline is the pre-dose Day 1 of Part 
2 OL Safety phase (Section 3.4).
6.2.5. Other Exploratory Continuous Endpoints (Repeated Visits)
For Part 1, continuous exploratory endpoints will be descriptively summarized by treatment 
group and by visits for percentage change from baseline in EASI score and change from 
baseline in POEM.  
For Part 1 OLE, continuous exploratory endpoints at all visits from Week 20 up to Week 68
(eg, percent change from baseline in EASI score), will be analyzed using a single MMRM 
without imputation for missing data (Section 5.2.2.2).  The model will include all data from 
Part 1 DB Week 4 up to Part 1 OLE Week 68 on the FAS (Appendix 3). The actual 
stratification factor (ie, baseline IGA of 3 or 4) from clinical database will be used in the 
MMRM analysis. This analysis will provide the LSM of the treatment groups by visit, the LSM 
of the treatment difference by visit (Etrasimod 2 mg QD versus Placebo →  Etrasimod 2 mg 
QD from Week 20 to Week 68; results from Week 4 to Week 16 will not be displayed from 
this analysis since they will come from a repeated analysis of the Part 1 DB phase for this 
endpoint) in percent change from baseline in EASI score, 95% CI and the 2-sided p-value by 
visit (Section 5.2.2.2). This approach is also similary applied to change from baseline in 
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POEM including all data at Part 1 DB Week 16 (Etrasimod 2 mg QD versus Placebo), Part 1
OLE Weeks 32 and 68 (Etrasimod 2 mg QD versus Placebo →  Etrasimod 2 mg QD) on the 
FAS. Results from all visits will be displayed.
For Part 2 OL Safety phase, continuous exploratory endpoints at all visits will only be 
descriptively summarized for the single treatment group of Etrasimod 2 mg QD using only 
observed values on the FAS (since intercurrent events are not considered in this Part 2 OL
Safety phase). Therefore, missing values will not be imputed in this Part 2 OL Safety phase. 
This approach is applicable to percent change from baseline in EASI score and change from 
baseline in POEM score, at all visits from Week 4 to Week 52. The baseline is the pre-dose 
Day 1 of Part 2 OL Safety phase (Section 3.4).
6.3. Subset (Subgroup) Analyses
For Part 1 DB, subgroup analyses are only performed for the primary endpoint of IGA 
response at Week 16 under the primary estimand (ie, Estimand E1) including only the pre-
intercurrent-event data on the FAS analyzed for participants with baseline IGA ≥2. The 
treatment comparison of Etrasimod 2 mg QD vs. Placebo for the primary endpoint at Week 
16 will be assessed at each level of the subgroup variables.
The following subgroup variables will be considered:

Baseline IGA score – 2 levels (3, 4), based on actual clinical data.

Sex – 2 levels (Female, Male).

Age at baseline  – 2 levels (18 - <50 years, ≥50 years).

Race – 2 levels (White, Non-White).

BMI at baseline – 2 levels (<30, ≥30 kg/m2).

AD disease duration since diagnosis by Hanifin and Rajka criteria (Hanifin and 
Rajka, 1980) – 2 levels (<5, ≥5 years).

Prior systemic corticosteroid failure only – 2 levels (Yes, No).
Estimates of the treatment difference between etrasimod 2 mg QD and placebo for the 
primary endpoint (primary estimand) along with the 95% CI without p-value, will be 
presented for each level of a subgroup variable.  The normal approximation using CMH 
approach adjusting for actual stratification factor of IGA score (Section 3.4.1) will be used 
for each level of a subgroup variable, except for the subgroup of baseline IGA score. 
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For the subgroup of baseline IGA score (2 levels of 3 or 4), the normal approximation 
approach to the difference in binomial proportions on the FAS will be used.  For each level
of baseline IGA score (3 or 4), the 95% CI of the treatment difference is calculated as:
(̂' −̂() ± .
̂'(1 −̂')
)'
+ ̂((1 −̂()
)(
where ̂' and ̂( represent the estimated response rates for etrasimod 2 mg QD and placebo 
respectively, and )' and )( are their respective sample sizes. .
 is the 97.5th percentile of 
the standard normal distribution.  No p-value will be produced for subgroup analyses.  The 
method of handling 0 or 100% response rate in either or both treatment groups can be found 
in Section 5.2.1.1.
The primary purpose of subgroup analyses is to check for consistency of the primary 
endpoint results across subgroup levels, ie, making sure overall results are not driven by 
some subset of participants (ie, particular level of a subgroup variable).  Graphical display 
(eg, forest plot) of the treatment differences in IGA response at Week 16 (primary estimand) 
between etrasimod 2 mg QD and placebo by subgroups will be presented.  There is no 
intention to have any specific inference within subgroup variables, therefore only 95% CI’s 
are produced without corresponding p-values.
6.4. Baseline and Other Summaries and Analyses
6.4.1. Baseline Summaries
For Part 1 and Part 2 of this study, similar demographics and baseline characteristics will be 
included but may not be limited to the ones listed below. These characteristics will be 
summarized descriptively.  For continuous variables, the summary will include N (which is 
the number of participants evaluable for the baseline characteristics), mean, median, SD and 
range (ie, minimum and maximum). For binary and categorical variables, the summary will 
include frequencies and percentages. A missing category will be included for those 
participants with missing value.  Some ordinal variables may also be summarized as 
continuous variables.  In addition to displays by treatment group, the summaries will also be 
provided for all the treatment groups combined. 
Demographic characteristics:

Baseline age (continuous in years);

Baseline age categories (≥16 to <18, ≥18 to <50, ≥50 to <70, ≥70 years);

Gender (Female, Male);

Race (categories as reported in Demographics CRF);
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
Ethnicity (Hispanic/Latino or Spanish origin, Not Hispanic/Latino or Spanish 
original, Not Reported);

Baseline body weight (continuous in kg);

Baseline body weight categories (<60, ≥60 to ≤100, >100 kg);

Baseline height (continuous in cm);

Baseline BMI (continuous kg/m2);

Baseline BMI categories (<18.5, ≥18.5 to <25, ≥25 to <30, ≥30 to <40, and 40 
kg/m2).
Baseline disease characteristics: 

AD disease duration since diagnosis by Hanifin and Rajka criteria (continuous in 
years);

AD disease duration since diagnosis categories by Hanifan and Rajka criteria (<5, ≥5 
years);

Baseline IGA (3, 4) – Actual in Database (note that baseline IGA of values ≤2 will 
also be summarized if recorded, as they are protocol deviations);

Baseline IGA (3, 4) – Reported in Randomization;

Baseline EASI score (continuous);

Baseline Total BSA (continuous in %);

Baseline PP-NRS (continuous);

Baseline PP-NRS categories (<4, ≥4);

Baseline Skin Pain NRS (continuous);

Baseline Skin Pain NRS categories (<4, ≥4);

Baseline POEM (continuous);

Baseline POEM categories (<4, ≥4);

Prior Systemic Therapies (Biologics, JAK inhibitors, conventional systemic 
therapies).
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6.4.2. Study Conduct and Participant Disposition
Study conduct and participant disposition is summarized by frequency and percentages for 
the following sets by treatment group for Part 1 and Part 2.

Total number of participants screened;

Number of participants who failed screening;

Number of participants randomized;

Number of participants randomized and treated;

Number of participants in the FAS;

Number of participants in the FAS who discontinued from the study due to any 
reason (for Part 1 DB phase, this will be DB phase);

Number of participants in the FAS who completed the study (for Part 1 DB phase, 
this will be DB phase);

Number of participants in the SAS.
Participants who are treated but are not randomized will also be summarized if at least one 
participant falls into this category.
6.4.3. Study Treatment Duration
Within any study phases (Part 1 DB, Part 1 DB+OLE, or Part 2 OL Safety), study treatment 
duration (in day) is defined as the time from the day of first dose (ie, Day 1) to the day of last 
dose of the study treatment. Besides descriptive summaries of the study treatment duration, 
the number of participants (%) will also be summarized by the following categories (where 
the upper limits correspond to the target day of the visit windows, Appendix 2.1), and ≥
categories, which are aligned with the protocol’s study visits.
Table 5.
Reporting Categories for Study Treatment Duration (in Day)
Part 1 DB
Part 1 DB + OLE
Part 2 OL Safety
Categories 
(day)
≥Categories 
(day)
Categories
(day)
≥Categories 
(day)
Categories 
(day)
≥Categories 
(day)
1
≥ 1
1
≥ 1
1
≥ 1
2 – 29 
≥ 2
2 – 29
≥ 2
2 – 29
≥ 2
30 – 57
≥ 30
30 – 57
≥ 30
30 – 57
≥ 30
58 – 85
≥ 58
58 – 85
≥ 58
58 – 113
≥ 58
86 - 113
≥ 86
86 – 113
≥ 86
114 – 169
≥ 114
≥ 114
≥ 114
114 – 141
≥ 114
170 – 253 
≥ 170
142 – 169
≥ 142
254 – 309 
≥ 254
170 – 225 
≥ 170
310 – 365
≥ 310
226 – 281
≥ 226
≥ 366
≥ 366
282 – 365 
≥ 282
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Table 5.
Reporting Categories for Study Treatment Duration (in Day)
Part 1 DB
Part 1 DB + OLE
Part 2 OL Safety
Categories 
(day)
≥Categories 
(day)
Categories
(day)
≥Categories 
(day)
Categories 
(day)
≥Categories 
(day)
366 – 477
≥ 366
≥ 478
≥ 478
The upper limit of period category corresponds to visit window’s target day (target week x 7 days + 1 day).
6.4.4. Prior and Concomitant Medications and Nondrug Treatments
Prior medications and non-drug treatments which start prior to baseline (ie, Day 1) will be 
summarized by treatment group and study phases. Concomitant medications and non-drug 
treatments which were taken any time during the study treatment period will also be 
summarized by treatment group and study phases. In addition, Concomitant (Day 1) 
medication and non-drug treatments may also be summarized for those medications and non-
drug treatments taken at baseline (ie, Day 1). All summaries will be coded to the WHODrug
version at the time of database release and this version will be noted in the summaries.
6.5. Safety Summaries and Analyses
All the safety data will be summarized descriptively through appropriate data tabulations, 
descriptive statistics, and graphical presentations.  Treatment-emergent AEs including SAEs 
and AE leading to discontinuation of study treatment, vital signs, 12-lead ECG parameters, 
and laboratory tests, etc. will be summarized according to the Clinical Data Interchange 
Standards Consortium (CDISC) and Pfizer Standards (CaPS). All safety analyses will be 
performed on the SAS (Section 4.2). 
6.5.1. Adverse Events
The MedDRA version for AE coding at the time of database release will be adopted and the 
version used will be displayed in all relevant safety data tabulations. TEAEs will be 
displayed by these 3 phases: (1) Part 1 DB (up to Week 16), (2) Part 1 DB+OLE (up to Week 
68), (3) Part 2 (up to Week 52), using the same treatment group labels (Section 5.2). Safety 
data from follow-up visits will also be be included for summaries.
In general, all treatment-emergent AE are tabulated in standard safety displays. AESIs will 
be summarized descriptively only (Section 3.5.2). The number and percent of participants 
reporting specific past and present medical histories at screening or baseline will be 
summarized by medical history reporting term (MedDRA) and treatment group following 
CaPS. 
6.5.2. Laboratory Data
All relevant laboratory tests will be summarized. These summaries include categorical tables 
(eg, normal, high, low), and descriptive statistics for change or percent change from baseline 
by treatment group and visit. These laboratory tests may include the following but are not 
limited to this list: hematology (including TBNK and coagulation Panel), blood chemistry, 
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urinalysis, liver function assessment, etc. Participants who meet clinically significant 
categories or defined abnormal ranges as defined by laboratory will also be summarizd. 
6.5.3. Vital Signs
Absolute values and changes from baseline in systolic and diastolic BP and pulse rate will be 
summarized by treatment group and time post-dose in accordance with the CaPS. The 
number and percent of participants with clinically significant change from baseline will be 
tabulated by treatment group.
6.5.4. Electrocardiograms
Changes from baseline for the ECG parameters QT interval, heart rate, QTc interval, PR 
interval, and QRS complex will be summarized by treatment and time.
Changes from baseline for the ECG parameters HR, QTcF, PR interval, and QRS complex
will be summarized by treatment and time. The frequency of uncorrected QT values above
500 ms will be tabulated.
The number (%) of participants with maximum post-dose QTcF values and maximum
increases from baseline in the following categories will be tabulated by treatment.
Table 6.
Safety QTcF Assessment
Degree of Prolongation
Mild (ms)
Moderate (ms)
Severe (ms)
Absolute value
>450 – 480
>480 – 500
>500
Increase from baseline
30-60
>60
6.5.5. Physical Examination
This is not applicable as physcial examination is not collected in the study database. 
6.5.6. Protocol Deviations and COVID-19 Related Reporting
In order to describe the impact of COVID-19, participants who discontinue from the study 
due to COVID-19 as the primary reason will be summarized in the disposition table (Section 
6.4.2). The specific reasons for participants who discontinue from the study due to COVID-
19, if collected in detail, such as participant decision, participant self-isolation, non-
compliance with protocol, transportation issue, site restrictions, physician decision, site 
closed, lack of drug at site, sponsor decision, and severity of COVID-19 infection will be 
presented in the disposition listing.
The number and percentage of participants with at least one important PD and with at least 
one PD associated with COVID-19 will be summarized for the Part 1 DB phase by treatment 
group, deviation category, and deviation sub-category using the FAS. Important PDs and 
PDs related to COVID-19 will be summarized similarly overall using the FAS. This is also 
performed similarly for Part 1 OLE phase and Part 2 OL Safety phase.
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A listing of all PDs will be provided. Important PDs and COVID-19 related PDs will be 
flagged in this listing for the Part 1 DB phase, Part 1 OLE phase, and Part 2 OL Safety phase.
7. INTERIM ANALYSES
An interim analysis (IA) will be conducted by the Sponsor in an unblinded manner to assess 
efficacy and safety after all applicable Part 1 participants complete or discontinue from study 
prior to the 16-week DB treatment period. The IA results will be used for decisions regarding 
stopping for futility and internal program development. Study conduct, including Part 1 
participant continuation in OLE, will continue while the data are prepared and analyzed for 
the IA. The Part 2 enrollment will not be triggered until after IA shows an acceptable safety 
and efficacy of etrasimod 2 mg QD in the target population. Based on the IA results, the 
study may continue, or the study may be terminated early. 
Specifically, the scope of this IA includes the following. When all applicable Part 1 
participants have completed the 16-week DB treatment phase, an interim datacut will be 
performed that will include all efficacy and safety data up to Week 16 visit. After data 
cleaning is performed, unblinding of Part 1 DB treatment assignments will take place, and 
interim database will be released for the IA to be performed by the Sponsor and the study 
team. Investigators and other site staff will remain blinded during the OLE to participants’ 
treatment assignment received in the Part 1 DB phase until the end of Part 1 OLE. Efficacy 
data summary will include the assessment of primary efficacy endpoint, secondary efficacy 
endpoints, and exploratory efficacy endpoints for Part 1 DB (Section 2.2) using the pre-
specified statistical methodologies (Section 5) to perform all relevant analyses described for 
Part 1 DB including subgroup analysis (Section 6.3). Safety data summary will include the 
assessment of all relevant safety endpoints (Section 3.5) descriptively summarized up to end 
of Part 1 DB phase.
Prior to this formal Part 1 DB IA, Sponsor may perform earlier unblinded interim analyses to 
inform internal decision-making regarding the development program. These earlier interim 
analyses will be conducted and reviewed by a limited number of team members independent 
of the study team. Details on these earlier unblinded interim analyses will be described in an 
unblinding operational plan.
When Part 1 OLE treatment phase is completed, the final analysis will be performed based 
on the final released official database for Part 1 of this study. This final analysis of Part 1 will 
include repeating the IA for Part 1 DB phase using this final data, as well as cumulative 
analyses including the final data from the Part 1 OLE phase. There will be no IA planned for 
Part 2 OL Safety phase of this study. When Part 2 OL Safety treatment phase is completed, 
the final analysis will be performed based on the final released official database for Part 2 of 
this study.
The e-DMC will be responsible for ongoing monitoring of the safety of participants in the 
study according to the charter.  The recommendations made by the e-DMC to alter the 
conduct of the study will be forwarded to Pfizer for final decision.  Information about the e-
DMC can be found in the e-DMC Charter, which outlines the operating procedures of the 
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committee, including specific description of the scope of their responsibilities, including a 
plan where communication timelines are defined.  
8. REFERENCES
1.
Cochran WG. (1954). Some methods of strengthening the common X2 tests. Biometrics. 
10: 417-451.
2.
Mantel N, Haenszel, W. (1959). Statistical aspects of the analysis of data from 
retrospective studies of disease. J. Natl. Cancer Inst. 22:719-748.
3.
Agresti A. (2002). Categorical Data Analysis, 2nd Edition, New York: John Wiley & 
Sons.
4.
Miettinen O, Nurminen M. (1985). Comparative analysis of two rates. Statistics in 
Medicine. 4: 213-226. 
5.
Hanifin, JM, Rajka, G. (1980). Diagnostic features of atopic dermatitis. Acta 
Dermatovener (Stockholm). Suppl 92:44-47.
6.
Carpenter JR, Roger JH, Kenward MG. (2013). Analysis of longitudinal trials with 
protocol deviation: a framework for relevant, accessible assumptions, and inference via
multiple imputation. Journal of Pharmaceutical Statistics. 23: 1352-1371.
7.
Rubin DB. (1987). Multiple imputation for nonresponse in surveys. New York: Wiley.
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9. APPENDICES
Appendix 1. Summary of Efficacy Analyses
Table 7.
Table of Efficacy Analyses
Endpoint 
Type
Estimand
FAS
Part 1 DB Phase
Part 1 DB + OLE Phase
Part 2 OL Safety
Binary Endpoints
Estimand E1 (Pre-Intercurrent Event Data)
FAS for Estimand E1
Method: CMH method adjusting 
to actual stratification factor of 
IGA score (3 or 4), MR=NR

IGA Response at Week 16 
(Primary Endpoint), 
participants with baseline 
IGA ≥2

EASI-75 Response at Week 
16 (Secondary Endpoint)

IGA Response at all 
timepoints except Week 16, 
participants with baseline 
IGA ≥2

EASI-75 Response at all 
timepoints except Week 16

≥4-point reduction from 
baseline in PP-NRS at all 
timepoint, participants with 
baseline PP-NRS ≥4 

≥4-point reduction from 
baseline in Skin Pain NRS 
at all timepoints, 
participants with baseline 
Skin Pain NRS ≥4

EASI-90 Repsonse at all 
timepoints

≥4-point reduction from 
baseline in POEM at Week 
16, participants with 
baseline POEM ≥4
The analyses for Part 1 DB 
Phase will be repeated using 
Part 1 final database.
None
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Table 7.
Table of Efficacy Analyses
Endpoint 
Type
Estimand
FAS
Part 1 DB Phase
Part 1 DB + OLE Phase
Part 2 OL Safety
Estimand E1a (All Data)
FAS for Estimand E1a
Method: CMH method adjusting 
to actual stratification factor of 
IGA score (3 or 4), MR=NR

IGA Response at Week 16 
(Primary Endpoint), 
participants with baseline 
IGA ≥2

IGA Response at all 
timepoints except Week 16, 
participants with baseline 
IGA ≥2

EASI-75 Response at Week 
16 (Secondary Endpoint)

EASI-75 Response at all 
timepoints except Week 16
The analyses for Part 1 DB 
Phase will be repeated using 
Part 1 final database.
None
No Estimand (All data)
FAS
None
Method: CMH method 
adjusting to actual 
stratification factor of IGA 
score (3 or 4), MR=NR

EASI-75 Response at 
all timepoints

IGA of clear (0) or 
almost clear (1) based 
on 5-point scale at all 
timepoints

≥4-point reduction from 
baseline in PP-NRS at 
all timepoints, 
participants with 
baseline PP-NRS ≥4

≥4-point reduction from 
baseline in Skin Pain 
NRS at all timepoints, 
participants with 
baseline Skin Pain NRS 
≥4

EASI-90 Repsonse at 
all timepoints
Method: Descriptive 
summary using observed 
data

EASI-75 Response at 
all timepoints

IGA of clear (0) or 
almost clear (1) based 
on 5-point scale at all 
timepoints

≥4-point reduction from 
baseline in PP-NRS at 
all timepoints. 
participants with 
baseline PP-NRS ≥4

≥4-point reduction from 
baseline in Skin Pain 
NRS at all timepoints, 
participants with 
baseline Skin Pain NRS 
≥4

EASI-90 Repsonse at 
all timepoints
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Table 7.
Table of Efficacy Analyses
Endpoint 
Type
Estimand
FAS
Part 1 DB Phase
Part 1 DB + OLE Phase
Part 2 OL Safety
Continuous Endpoints
Estimand E2 (Pre-Intercurrent Event 
Data)
FAS for Estimand E2
Method: JTC method via 
multiple imputations of missing 
data including data up to Week 
16

Percent change from 
baseline in EASI score at 
Week 16 (Secondary 
Endpoint)

Percent change from 
baseline in EASI score at 
all timepoints except Week 
16
The analyses for Part 1 DB 
Phase will be repeated using 
Part 1 final database.
None
Estimand E2a (All Data)
FAS for Estimand E2a
Method: MMRM without 
imputation of missing data
including data up to Week 16

Percent change from 
baseline in EASI score at 
Week 16 (Secondary 
Endpoint)

Percent change from 
baseline in EASI score at 
all timepoints except Week 
16
The analyses for Part 1 DB 
Phase will be repeated using 
Part 1 final database.
No Estimand (All data)
FAS
None
Method: MMRM without 
imputation of missing data 
including data at all 
timepoints (Report only OLE 
visits for Percent change 
from baseline in EASI score, 
report all visits for Change 
from baseline in POEM)

Percent change from 
baseline in EASI score 
at all timepoints

Change from baseline in 
POEM at Weeks 16, 32 
and 68
Method: Descriptive 
summaries using observed 
data

Percent change from 
baseline in EASI score 
at all timepoints

Change from baseline 
in POEM at Weeks 24 
and 52
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Appendix 2. Data Derivation Details
Appendix 2.1. Definition and Use of Analysis Visit Windows in Reporting
There are two sets of analysis visit windows, one set for Part 1 (both DB and OLE phases) 
and another set for Part 2 (OL). For reporting purposes, the analysis visit windows will be 
used for efficacy and safety display that show by scheduled visits. Observations from all 
visits including scheduled, unscheduled and early termination visits will all be eligible for 
allocation to an analysis visit. If two or more observations fall into the same visit window, 
the observation closest to the target day will be used in the analysis. If there is a tie, the later 
observation will be used. However, for a participant who discontinues from the study early 
prior to Week 68 visit window in Part 1 (similarly to Week 52 visit window in Part 2), if two 
or more observations fall in the same visit window prior to Week 68 in Part 1 (similarly to 
Week 52 in Part 2), then the latest observation (rather than the observation closest to the 
target day) within this visit window will be used in the analysis for that visit window.
The analysis visit windowing will be applied after intercurrent events (initation of prohibited 
medications or discontinuation of study treatment, whichever is earlier) have been accounted 
for, that is, to the pre-intercurrent-event data and to all data separately (Appendix 3).
Table 8.
Analysis Visit Windows for Part 1
Visit Label
Target Daya
Window Definition 
Baseline
Day 1
Last non-missing assessment on or before Day 1 and prior to first 
dose of investigational product (ie, etrasimod or placebo) 
Week 4
Day 29
Day 2 to Day 42 
Week 8
Day 57
Day 43 to Day 70
Week 12
Day 85
Day 71 to Day 98
Week 16b
Day 113
Day 99 to [Treatment Switch Dayc or Day 126, whichever is smaller]
Week 20
Day 141
[Treatment Switch Dayc+1 or Day 127, whichever is smaller] to 
Day 154
Week 24 
Day 169
Day 155 to Day 196
Week 32 
Day 225
Day 197 to Day 252
Week 40 
Day 281
Day 253 to Day 322
Week 52
Day 365
Day 323 to Day 420
Week 68
Day 477
≥ Day 421
a.
Target day is equal to the target week×7 days + 1 day.
b.
All data collected on Week 16 visit, first open-label dose day (treatment switch day), will be included in ≤ Week 
16 except for AE data, which will be included in ≥ Week 20.  Any new treatment-emergent AE occurred on the 
day of first open-label dose (treatment switch day) will be included in ≥ Week 20.
c.
Day of first open-label dose at Week 16 = Treatment switch day (ie, treatment switch day = treatment switch date 
– date of the first dose +1), where treatment switch date is taken from the Treatment Dosing CRF, as the start date 
in the first entry of the Treatment Dosing log for the period of Week 16 to Week 20. 
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Note that the upper limit of the Week 16 visit window and the lower limit of the 
Week 20 visit window are defined uniquely for each of the participants in the study 
regardless of which treatment group the participants are randomized to.  
If treatment switch day (ie, day of first open-label etrasimod dose) falls between Day 99 and 
Day 126, then the upper limit of the Week 16 visit window is the smaller of treatment switch 
day or Day 126, and the lower limit of the Week 20 visit window is the smaller of treatment 
switch day+1 or Day 127.
In the unlikely case if treatment switch day < Day 99, > Day126, or missing (eg, 
discontinuation of study treatment or study prior to Week 16), then the upper limit of the 
Week 16 visit window will be set to Day 126 and the lower limit of the Week 20 visit 
window will be set to Day 127.
Table 9.
Analysis Visit Windows for Part 2
Visit Label
Target Daya
Window Definition 
Baseline
Day 1
Last non-missing assessment on or before Day 1 and prior to first 
dose of etrasimod
Week 4
Day 29
Day 2 to Day 42 
Week 8
Day 57
Day 43 to Day 84
Week 16
Day 113
Day 85 to Day 140
Week 24 
Day 169
Day 141 to Day 210
Week 36
Day 253
Day 211 to Day 280
Week 44
Day 309
Day 281 to Day 336
Week 52
Day 365
≥ Day 337
a. Target day is equal to the target week×7 days + 1 day.
For safety data collected for participants who complete the 2-week and 4-week follow-up 
visits (Weeks 70 and 72 in Part 1 OLE, Weeks 54 and 56 in Part 2 OL Safety phase), 
available safety data will be summarized for these nominal visits.
For 12-Lead ECG collected on Day 1 during first-dose cardiac monitoring, the labels for 
timepoints can be “Day 1 Predose”, “Day 1 1HR Postdose” to “Day 1 4HR Postdose”.
Appendix 2.2. Endpoint Derivations
Appendix 2.2.1. Investigator’s Global Assessment (IGA)
IGA of AD is scored on a 5-point scale (0-4), reflecting a global consideration of the 
erythema, induration, and scaling. The clinical evaluator of AD will perform an assessment 
of the overall severity of AD and assign an IGA score: 0=clear, 1=almost clear, 2=mild, 
3=moderate, or 4=severe. The assessment will be a static evaluation without regard to the 
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score at a previous visit. According to protocol’s inclusion criteria, only participants with 
IGA score ≥3 at screening and baseline (Day 1) are included in this study. The following 
binary efficacy endpoints will be derived based on IGA score at a visit.

IGA response: IGA score of clear (0) or almost clear (1) on a 5-point scale and a 
reduction from of ≥2 from baseline. Only participants with baseline IGA ≥2 are 
included in all analyses of this endpoint.

IGA score of clear (0) or almost clear (1) on a 5-point scale.
Appendix 2.2.2. Body Surface Area (BSA)
BSA affected by AD will be determined by the participant’s handprint method, where the full 
hand of the participant (ie, the participant’s fully extended palm, fingers, and thumb together
in a closed position) represents approximate 1% of the total BSA. The BSA AD involvement
ranges from 0% to 100%, with higher values representing greater severity of AD. The BSA is 
performed separately for 4 regions of the body: Region 1 – head and neck; Region 2 – trunk 
(including genital area); Region 3 – upper limbs; and Region 4 – lower limbs (including
buttocks). The total number of handprints in each body region is given in the following table. 
The total number of handprints summed up across the 4 body regions is 100, which is used as 
the denominator for total BSA. Total BSA efficacy (%) will be derived from the sum of the 
BSA in handprints across 4 body regions (out of total of 100), and it is assessed as part of the 
EASI assessment (Appendix 2.2.3). According to protocol’s inclusion criteria, only 
participants with BSA ≥10% of AD involvement at screening and baseline (Day 1) are 
included in this study.
Table 10.
Handprint Determination of BSA
Body Region
Total Number of Handprints 
in Body Region*
Surface Area of Body Region 
Equivalent of One Handprint*
Head and Neck (h)
10
10%
Upper Limbs (u)
20
5%
Trunk (including axillae and 
groin/genitals) (t)
30
3.33%
Lower Limbs (including buttocks) (l)
40
2.5%
*Handprint refers to the hand size of each individual participant.
Further, the extent (%) of each of the four body region (h, u, t, and l) will be determined by 
dividing the number of BSA handprints by the total (maximum) number of handprints for 
that body region (range: 0% to 100%). For example, if there are 3 BSA handprints for Head 
and Neck region, the extent (%) of the Head and Neck region is (3/10) x 100% = 30%. This
extent (%) to which each of the four body regions (h, u, t, and l) is involved with atopic 
dermatitis is categorized (ie, mapped) to a numerical Area Score (Ah, Au, At, and Al, 
respectively) using a non-linear scaling method according to the following BSA scoring 
criteria. Using the same previous example, Ah is 3.
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Table 11.
Mapping of Body Region BSA Percentage to Area Score
Percent BSA with AD in a body region (h, u, t, and l)
Area Score (Ah, Au, At, and Al)
0%
0
>0 - <10%
1
10 - <30%
2
30 - <50%
3
50 - <70%
4
70 - <90%
5
90 - 100%
6
These Area Scores (Ah, Au, At, and Al) of the four body regions will be used to derive the 
EASI score (Appendix 2.2.3). If any one of the four body regions has missing number of 
BSA handprints, the extent (%) of BSA in this body region will be missing and so will the 
Area Score for this body region. The total BSA (%) will also be missing. 
Appendix 2.2.3. Eczema Area and Severity Index (EASI)
The EASI quantifies the severity of a participant’s AD based on both severity of lesion 
clinical signs and the percent of BSA affected. EASI is a composite scoring by the atopic 
dermatitis clinical evaluator of the degree of erythema, induration/papulation, excoriation, 
and lichenification (each scored separately) for each of four body regions, with adjustment 
for the percent of BSA involved for each body region and for the proportion of the body 
region to the whole body.
There are 4 lesion clinical signs for each of the 4 body regions (Appendix 2.2.2): erythema 
(E), induration/papulation (I), excoriation (Ex) and lichenification (L). For each of the lesion 
clinical signs, severity is scored on a 4-point scale: 0=absent, 1=mild, 2=moderate, and 
3=severe. These 16 scores (0-3) are denoted as follows. Morphologic descriptors for each 
clinical sign severity score can be found in the study protocol.
Table 12.
Symbols Denoting Lesion Clinical Signs by Body Region
Body Regions 
(row)/Clinical Signs 
(column)
Erythema
(E)
Induration/Papulation 
(I)
Excoriation 
(Ex)
Lichenification 
(L)
Head and Neck (h)
Eh
Ih
Exh
Lh
Upper Limbs (u)
Eu
Iu
Exu
Lu
Trunk (including axillae 
and groin/genitals) (t)
Et
It
Ext
Lt
Lower Limbs (including 
buttocks) (l)
El
Il
Exl
Ll
In EASI scoring, each body region carries different body region weighting, the sum of these 
weightings is equal to 1: Head and Neck (0.1), Upper Limbs (0.2), Trunk (including axillae 
and groin/genitals) (0.3) and Lower Limbs (including buttocks) (0.4). 
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In each body region, the sum of the Clinical Signs Severity Scores for erythema, 
induration/papulation, excoriation, and lichenification is multiplied by the Area Score
(Appendix 2.2.2) and by the body region weighting to provide a body region value (ie, body 
region subscore), which is then summed across all four body regions resulting in an EASI 
score as described in the following equation.
EASI = 0.1 Ah (Eh + Ih + Exh + Lh) + 0.2 Au (Eu + Iu + Exu + Lu) + 0.3 At (Et + It + Ext + 
Lt) + 0.4 Al (El + Il + Exl + Ll)
The EASI score can vary in increments of 0.1 and range from 0.0 to 72.0, with higher scores 
representing greater severity of AD. According to protocol’s inclusion criteria, only 
participants with EASI ≥16 at screening and baseline (Day 1) are included in this study. The 
following efficacy endpoints will be derived based on the EASI scores assessed at baseline 
and at post-baseline visits:

Percent change from baseline in EASI score, defined as the change from baseline in 
EASI score divided by baseline EASI score, scaled to %. 

EASI-50, defined as a response if ≥50% reduction from baseline in EASI score (as a 
pre-specified discontinuation criterion rather than an efficacy endpoint). 

EASI-75, defined as a response if ≥75% reduction from baseline in EASI score.

EASI-90, defined as a response if ≥90% reduction from baseline in EASI score.
If any component score (BSA Area Score or lesion clinical sign severity score) in the 
equation is missing at a visit, the EASI will be missing at that visit. The derived endpoints 
will also be missing at that visit.
Appendix 2.2.4. Peak Pruritus Numerical Rating Scale (PP-NRS)
PP-NRS is a single-item on the scale from 0 (no itch) to 10 (worst itch imaginable), NRS 
rating scale, to assess itch at the worst moment during the previous 24 hours. The following 
binary efficacy endpoint will be derived: ≥4-point reduction from baseline in PP-NRS. Only 
participants with baseline PP-NRS ≥4 are included in all analyses of this endpoint. If PP-
NRS score is missing for a visit, the derived endpoint will also be missing at that visit.
Appendix 2.2.5. Skin Pain Numerical Rating Scale (Skin Pain NRS)
The Skin Pain NRS is a single-item on the scale from 0 (no skin pain) to 10 (worst skin pain 
imaginable), NRS rating scale, to assess the skin pain at its worst over the previous 24 ours.
The following binary efficacy endpoint will be derived: ≥4-point reduction from baseline in 
Skin Pain NRS. Only participants with baseline Skin Pain NRS ≥4 are included in all 
analyses of this endpoint. If Skin Pain NRS score is missing for a visit, the derived endpoint 
will also be missing at that visit.
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Appendix 2.2.6. Patient-Oriented Eczema Measure (POEM)
POEM is a 7-item measurement used for monitoring symptom severity of atopic eczema. To 
address severity, the POEM measures 7 aspects of the experiences of participants with 
eczema including skin itch, sleep disturbance, skin bleeding, weeping/oozing of the skin,
cracked skin, flaking skin, and skin dryness/roughness. Participants are asked to answer 
based on the number of days they experienced each on a 5-point scale (0=No days, 1=1 to 2 
days, 2=3 to 4 days, 3=5 to 6 days, and 4=everyday) over the past week based on recall. The 
scores from the 7 questions are accumulated to provide an overall POEM score with a range 
of 0 to 28. An overall POEM score is as follows: 0 to 2 = ‘clear/almost clear’; 3 to 7 =‘mild’; 
8 to 16 = ‘moderate’; 17 to 24 = ‘severe’; and 25 to 28 = ‘very severe’ atopic eczema.
POEM is measured at baseline, Weeks 16, 32, and 68 in Part 1; baseline, Weeks 24 and 52 in 
Part 2. The following efficacy endpoints will be derived using POEM:

Change from baseline in POEM.

≥4-point reduction from baseline in POEM. Only participants with baseline POEM 
≥4 are included in all analyses of this endpoint.
If POEM score is missing at a visit, the derived endpoints will also be missing at that visit.
Appendix 2.2.7. Range of Values for Continuous Efficacy Endpoints
The following table displays the unit, theoretical range of values, and the direction of 
improvement for each of select continuous efficacy endpoints.
Table 13.
Numerical Characteristics of Select Continuous Scores and Derived 
Effiacy Endpoints
Endpoint
Unit
Theoretical Range of 
Values
Direction of 
Improvement from 
Baseline
IGA
None
0-4
Decrease from 
Baseline 
Total BSA
%
0-100
Decrease from 
Baseline 
EASI
None
0-72
Decrease from 
Baseline 
PP-NRS
None
0-10 (NRS)
Decrease from 
Baseline 
Skin Pain NRS
None
0-10 (NRS)
Decrease from 
Baseline 
POEM
None
0-28
Decrease from 
Baseline 
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Appendix 3. Efficacy Data Set Descriptions For Part 1 Double-Blind Phase
There are two intercurrent events considered for Part 1 DB phase of this study, (1) the 
initiation of prohibited medications, and (2) the discontinuation of the study treatment 
(etrasimod 2 mg QD or placebo) due to any reason.  
During the Part 1 DB phase, if a participant initiates prohibited medications (intercurrent 
event 1 above) and/or discontinues study treatment due to any reason (intercurrent event 2 
above), the date of the earlier intercurrent event is noted (as recorded on relevant CRF page)
and is used to differentiate and to define the data up to Week 16 into “Pre-intercurrent-event 
data”, “Post-intercurrent-event data”, and “All data” (ie, both Pre- and Post-intercurrent-
event data together), as laid out in the table below. Only efficacy data are in scope for this 
data differentiation.
Table 14.
Efficacy Data Set Differentiation by Estimand in Part 1 DB Phase
Estimand
Participants who initiate prohibited medications and/or 
discontinue study treatment due to any reason prior to 
Week 16
Participants who do not experience any 
intercurrent events 
E1
For this participant, the date/day of the earlier intercurrent 
event is flagged and noted (eg, Day X relative to baseline 
Day 1). Only data collected/assessed on or before Day X+2 
(ie, allowing up to 2 additional days after date of earlier 
intercurrent event), as pre-intercurrent-event data, are 
included in this dataset. Any data collected/assessed after 
Day X+2, as post-intercurrent-event data, are excluded in 
this dataset. Visit windowing is performed after this data 
differentiation on the Pre-intercurrent-event data.
All data (unaffected due to no intercurrent 
events) of these participants will be included.
E1a
All data of these participants will be included regardless of 
the intercurrent events.
Same as E1 above.
E2
Same as E1 above.
Same as E1 above.
E2a
Same as E1a above.
Same as E1a/E1 above.
No 
Estimand
All data of these participants and available data will be included regardless of the intercurrent events.
All efficacy data collected in Part 1 OLE phase and Part 2 OL Safety phase will include all 
data collected/assessed regardless of these intercurrent events (ie, no estimand defined). All 
safety data will be analyzed regardless of these intercurrent events.
Appendix 4. Initiation of Prohibited Medications
The intercurrent event of initiation of prohibited medications will be identified using the final 
reconciliated PIPD dataset. The PD category of “concomitatnt medications” and the 
subcategory of “took prohibited concomitant medication/vaccine – meeting intercurrent 
event” will be used to identify this protocol deviation as the intercurrent event. This protocol 
deviation has to be verified using participant’s entries of concomitant medications via clinical 
review. Once verified, the analysis population exclusion (APE) status will be checked “Yes”
and this protocol deviation is deemed to be the intercurrent event of initiation of prohibited 
medications. The onset date of the protocol deviation as recorded on the PIPD dataset will 
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serve as the date of initiation of prohibited medications. This is applicable to the Part 1 DB 
phase only. 
Appendix 5. List of Abbreviations
The following table provides a comprehensive list of abbreviations. Mathematical symbols 
are not included on this list.
Table 15.
Table of Abbreviations
Abbreviation
Term
AD
atopic dermatitis
AE
adverse event
AESI
adverse event of special interest
ANCOVA
analysis of covariance
APE
analysis population exclusion
AV
atrioventricular
BMI
body mass index
BP
blood pressure
CaPS
Clinical Data Interchange Standards Consortium and Pfizer 
Standards 
CDISC
Clinical Data Interchange Standards Consortium 
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus Disease 2019
CRF
case report form
CS
compound symmetry
CSH
heterogeneous compound symmetry
CSR
clinical study report
CT SAE
clinical trial serious adverse event
DB
Double-Blind
e-DMC
external data monitoring committee
E1
Estimand E1 strategy
E1a
Estimand E1a strategy
E2
Estimand E2 strategy
E2a
Estimand E2a strategy
EASI
Eczema Area and Severity Index
EASI-50
≥50% reduction from baseline in EASI score
EASI-75
≥75% reduction from baseline in EASI score
EASI-90
≥90% reduction from baseline in EASI score
ECG
electrocardiogram
FAS
Full Analysis Set
HR
heart rate
IA
interim analysis
IGA
Investigator’s Global Assessment
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Table 15.
Table of Abbreviations
Abbreviation
Term
JTC
Jump-to-Control
LSM
least-squares mean
MAR
missing at random
MCMC
Markov Chain Monte Carlo
MedDRA
Medical Dictionary for Regulatory Activities
mg
milligram
MMRM
mixed-effects model with repeated measures
MR=NR
missing response as non-response
ms
millisecond
NA
Not Applicable
NRS
Numerical Rating Scale
OL
Open-Label
OLE
Open-Label Extension
PACL
Protocol Administrative Change Letter
PD
Protocol Deviation
PIPD
Potentially Important Protocol Deviation
PML
Progressive multifocal leukoencephalopathy
POEM
Patient-Oriented Eczema Measure
PP-NRS
Peak Pruritus Numerical Rating Scale
PRES
posterior reversible encephalopathy syndrome
PR 
pulse rate
QD
once daily
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
S1PRM
Sphingosine-1-phosphate receptor modulators
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Safety Analysis Set / Statistical Analysis System
SD
standard deviation
SE
standard error
TBNK
T-lymphocyte, B-Lymphocyte, and Natural Killer cell
TCS
topical corticosteroids
WHODrug
World Health Organization Drug Dictionary
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