A PHASE 1, OPEN-LABEL, RANDOMIZED, SINGLE DOSE, CROSSOVER STUDY TO ESTIMATE THE RELATIVE BIOAVAILABILITY OF ETRASIMOD (PF-07915503) MINI TABLETS IN WATER AND 3 FOOD VEHICLES COMPARED TO THE ETRASIMOD (PF-07915503) CLINICAL IR TABLETS UNDER FASTED CONDITIONS, AND TO EVALUATE MINI TABLET PALATABILITY IN HEALTHY ADULT PARTICIPANTS
Phase: PHASE1
Conditions: Healthy Participants
Sponsor: Pfizer

Etrasimod
Protocol C5041034
Final Protocol Amendment 1, 01 Jun 2023
PFIZER CONFIDENTIAL
CT02-GSOP Clinical Pharmacology Protocol Template (14 April 2023)
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Title Page
A PHASE 1, OPEN-LABEL, RANDOMIZED, SINGLE DOSE, CROSSOVER STUDY 
TO ESTIMATE THE RELATIVE BIOAVAILABILITY OF ETRASIMOD
(PF-07915503) MINI TABLETS IN WATER AND 3 FOOD VEHICLES COMPARED
TO THE ETRASIMOD (PF-07915503) CLINICAL IR TABLETS UNDER FASTED 
CONDITIONS, AND TO EVALUATE MINI TABLET PALATABILITY IN 
HEALTHY ADULT PARTICIPANTS
Study Intervention Number:
PF-07915503
Study Intervention Name:
Etrasimod
US IND Number:
125154
EudraCT/EU CT Number:
2023-504411-32-00
ClinicalTrials.gov ID:  
Not applicable
Pediatric Investigational Plan Number:
Not applicable
Protocol Number:
C5041034
Phase:
1
Sponsor Legal Address:
Pfizer Inc.
66 Hudson Boulevard East
New York, NY 10001
Brief Title: A Study to Learn About the Study Medication Called Etrasimod Mini 
Tablets, Including Its Taste, When Mixed With Applesauce, Chocolate Pudding, Yogurt 
or Water in Healthy Participants 
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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Document History
Document
Version Date
Amendment 1
01 Jun 2023
Original protocol
03 Apr 2023
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and IRBs/ECs and any global protocol administrative 
change letter(s).
Protocol Amendment Summary of Changes Table
Amendment 1 (01 Jun 2023)
Overall Rationale for the Amendment: The protocol was amended to address queries from 
EU regulators following submission of an initial clinical trial application; the changes are 
summarized below:
Description of Change
Brief Rationale
Section # and Name
Safety laboratory 
assessments added on 
Day 2 of each period.
Added safety assessments on Day 2 
to capture safety laboratory data for 
liver enzyme assessments, bilirubin
and hematology 24 hours postdose 
(Day 2).
Section 1.3 Schedule of 
Activities
Addition of exclusion 
criteria of 
active/history of
ophthalmologic 
disorder such as 
macular edema, uveitis, 
retinopathy.
Ophthalmologic effects have been 
associated with S1P modulator 
class of drugs. Participants with 
sensitive eye issues are excluded 
from this study.
Section 1.1 Synopsis and 
Section 5.2 Exclusion 
Criteria
Additional BP and HR 
monitoring.
Added to Day 1 and Day 2: vital
signs collected hourly for the first 
6 hours, 8 hours and 24 hours
post-etrasimod dose for additional 
safety assessment to monitor for 
potential bradycardia and 
hypertension.
Added a brief rationale for the 
intense vitals monitoring.
Section 1.3 Schedule of 
Activities and Section 
8.3.2 Vital Signs
Section 4.2.2 Rationale 
for PR and BP Monitoring
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................8
1. PROTOCOL SUMMARY.....................................................................................................9
1.1. Synopsis ....................................................................................................................9
1.2. Schema ....................................................................................................................15
1.3. Schedule of Activities .............................................................................................16
2. INTRODUCTION ...............................................................................................................21
2.1. Study Rationale .......................................................................................................21
2.2. Background .............................................................................................................21
2.2.1. Nonclinical Pharmacology..........................................................................21
2.2.2. Nonclinical Pharmacokinetics and Metabolism .........................................21
2.2.3. Nonclinical Safety ......................................................................................21
2.2.4. Clinical Overview.......................................................................................22
2.2.4.1. Pharmacokinetic Overview of Etrasimod .................................23
2.2.4.2. Safety Overview of Etrasimod ..................................................23
2.3. Benefit/Risk Assessment.........................................................................................24
2.3.1. Risk Assessment.........................................................................................25
2.3.2. Benefit Assessment.....................................................................................27
2.3.3. Overall Benefit/Risk Conclusion................................................................27
3. OBJECTIVES AND ENDPOINTS.....................................................................................27
4. STUDY DESIGN.................................................................................................................28
4.1. Overall Design.........................................................................................................28
4.2. Scientific Rationale for Study Design.....................................................................29
4.2.1. Rationale for ECG Measurements..............................................................29
4.2.2. Rationale for PR and BP Monitoring..........................................................30
4.2.3. Rationale for Micro Sampling ....................................................................30
4.2.4. Choice of Contraception/Barrier Requirements .........................................30
4.3. Justification for Dose ..............................................................................................30
4.4. End of Study Definition ..........................................................................................30
5. STUDY POPULATION......................................................................................................30
5.1. Inclusion Criteria.....................................................................................................31
5.2. Exclusion Criteria....................................................................................................31
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5.3. Lifestyle Considerations..........................................................................................35
5.3.1. Contraception..............................................................................................35
5.3.2. Meals and Dietary Restrictions...................................................................36
5.3.3. Caffeine, Alcohol, and Tobacco .................................................................36
5.3.4. Activity .......................................................................................................37
5.3.5. Vaccination(s).............................................................................................37
5.4. Screen Failures ........................................................................................................37
6. STUDY INTERVENTION(S) AND CONCOMITANT THERAPY.................................38
6.1. Study Intervention(s) Administered........................................................................38
6.1.1. Administration............................................................................................39
6.2. Preparation, Handling, Storage, and Accountability...............................................40
6.2.1. Preparation and Dispensing........................................................................41
6.3. Assignment to Study Intervention...........................................................................41
6.4. Blinding...................................................................................................................41
6.5. Study Intervention Compliance...............................................................................41
6.6. Dose Modification...................................................................................................42
6.7. Continued Access to Study Intervention After the End of the Study......................42
6.8. Treatment of Overdose............................................................................................42
6.9. Prior and Concomitant Therapy ..............................................................................42
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................43
7.1. Discontinuation of Study Intervention ....................................................................43
7.1.1. Liver Injury.................................................................................................43
7.1.2. ECG Changes..............................................................................................44
7.1.3. Pregnancy ...................................................................................................44
7.1.4. COVID-19 ..................................................................................................44
7.2. Participant Discontinuation/Withdrawal From the Study.......................................45
7.2.1. Withdrawal of Consent...............................................................................45
7.3. Lost to Follow-Up ...................................................................................................46
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................46
8.1. Administrative and Baseline Procedures.................................................................46
8.1.1. Baseline Procedures....................................................................................47
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8.2. Efficacy Assessments..............................................................................................47
8.3. Safety Assessments .................................................................................................47
8.3.1. Physical Examinations................................................................................47
8.3.2. Vital Signs ..................................................................................................48
8.3.2.1. Blood Pressure and Pulse Rate..................................................48
8.3.2.2. Temperature ..............................................................................49
8.3.3. Electrocardiograms.....................................................................................49
8.3.4. Clinical Safety Laboratory Assessments ....................................................49
8.3.5. COVID-19 Specific Assessments...............................................................50
8.3.6. Pregnancy Testing ......................................................................................50
8.4. Adverse Events, Serious Adverse Events, and Other Safety Reporting .................50
8.4.1. Time Period and Frequency for Collecting AE and SAE Information.......51
8.4.1.1. Reporting SAEs to Pfizer Safety...............................................51
8.4.1.2. Recording Nonserious AEs and SAEs on the CRF...................52
8.4.2. Method of Detecting AEs and SAEs ..........................................................52
8.4.3. Follow-Up of AEs and SAEs......................................................................52
8.4.4. Regulatory Reporting Requirements for SAEs...........................................53
8.4.5. Environmental Exposure, Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure.....................................................53
8.4.5.1. Exposure During Pregnancy......................................................53
8.4.5.2. Exposure During Breastfeeding ................................................55
8.4.5.3. Occupational Exposure .............................................................55
8.4.6. Cardiovascular and Death Events...............................................................55
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................55
8.4.8. Adverse Events of Special Interest.............................................................56
8.4.8.1. Lack of Efficacy........................................................................56
8.4.9. Medical Device Deficiencies......................................................................56
8.4.10. Medication Errors.....................................................................................56
8.5. Pharmacokinetics ....................................................................................................57
8.6. Genetics...................................................................................................................58
8.6.1. Specified Genetics ......................................................................................58
8.6.2. Retained Research Samples for Genetics ...................................................58
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8.7. Biomarkers ..............................................................................................................58
8.7.1. Safety Biomarker Sample...........................................................................58
8.8. Immunogenicity Assessments.................................................................................58
8.9. Health Economics ...................................................................................................58
8.10. Palatability Assessments .......................................................................................59
9. STATISTICAL CONSIDERATIONS ................................................................................59
9.1. Statistical Hypotheses .............................................................................................59
9.2. Analysis Sets ...........................................................................................................59
9.3. Statistical Analyses .................................................................................................59
9.3.1. Efficacy Analyses .......................................................................................60
9.3.2. Safety Analyses ..........................................................................................60
9.3.3. Pharmacokinetic Analyses..........................................................................60
9.3.4. Palatability Assessment Analyses...............................................................61
9.3.5. Micro Sampling and Venous Sampling......................................................61
9.4. Interim Analyses .....................................................................................................62
9.5. Sample Size Determination.....................................................................................62
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................63
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............63
10.1.1. Regulatory and Ethical Considerations ....................................................63
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................63
10.1.2. Financial Disclosure .................................................................................64
10.1.3. Informed Consent Process ........................................................................64
10.1.4. Data Protection .........................................................................................65
10.1.5. Committees Structure ...............................................................................65
10.1.5.1. Data Monitoring Committee ...................................................65
10.1.6. Dissemination of Clinical Study Data ......................................................65
10.1.7. Data Quality Assurance ............................................................................66
10.1.8. Source Documents....................................................................................68
10.1.9. Use of Medical Records............................................................................68
10.1.10. Study and Site Start and Closure ............................................................69
10.1.11. Publication Policy...................................................................................69
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10.1.12. Sponsor’s Medically Qualified Individual..............................................70
10.2. Appendix 2: Clinical Laboratory Tests .................................................................71
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-Up, and Reporting .....................................................................72
10.3.1. Definition of AE .......................................................................................72
10.3.2. Definition of an SAE ................................................................................73
10.3.3. Recording/Reporting and Follow-Up of AEs and/or SAEs During 
the Active Collection Period............................................................................74
10.3.4. Reporting of SAEs....................................................................................78
10.4. Appendix 4: Contraceptive and Barrier Guidance ................................................79
10.4.1. Male Participant Reproductive Inclusion Criteria....................................79
10.4.2. Female Participant Reproductive Inclusion Criteria.................................79
10.4.3. Woman of Childbearing Potential ............................................................80
10.4.4. Contraception Methods.............................................................................81
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-Up Assessments .......83
10.6. Appendix 6: Kidney Safety: Monitoring Guidelines ............................................85
10.6.1. Laboratory Assessment of Change in Kidney Function and 
Detection of Kidney Injury..............................................................................85
10.6.2. Age-Specific Kidney Function Calculation Recommendations...............85
10.6.2.1. Adults (18 Years and Above)—2021 CKD-EPI 
Equations ...........................................................................................85
10.6.3. Kidney Function Calculation Tool ...........................................................86
10.6.4. Adverse Event Grading for Kidney Safety Laboratory 
Abnormalities...................................................................................................86
10.7. Appendix 7: ECG Findings of Potential Clinical Concern ...................................87
10.8. Appendix 8: Prohibited Concomitant Medications That May Result in DDI.......89
10.9. Appendix 9: Palatability Questionnaire ................................................................90
10.10. Appendix 10: Abbreviations ...............................................................................98
11. REFERENCES ................................................................................................................102
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LIST OF TABLES
Table 1.
Study Schedule of Assessment.................................................................16
Table 2.
Treatment Sequence..................................................................................28
Table 3.
Plasma Etrasimod PK Parameters Definitions .........................................60
Table 4.
Expected Width of 90% Confidence Interval for Different Possible 
Estimated Effects and Parameters of Interest...........................................62
Table 5.
Protocol-Required Laboratory Assessments.............................................71
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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Protocol Title: 
A Phase 1, Open-Label, Randomized, Single Dose, Crossover Study to Estimate the Relative 
Bioavailability of Etrasimod (PF-07915503) Mini Tablets in Water and 3 Food Vehicles
Compared to the Etrasimod (PF-07915503) Clinical IR Tablets Under Fasted Conditions, and 
to Evaluate Mini Tablet Palatability in Healthy Adult Participants
Brief Title:
A Study to Learn About the Study Medication Called Etrasimod Mini Tablets, Including Its 
Taste, When Mixed With Applesauce, Chocolate Pudding, Yogurt or Water in Healthy
Participants
Regulatory Agency Identification Number(s):
US IND Number:
125154
EudraCT/EU CT Number:
2023-504411-32-00
ClinicalTrials.gov ID:  
Not applicable
Pediatric Investigational Plan Number:
Not applicable
Protocol Number:
C5041034
Phase:
1
Rationale:
The purpose of the study is to estimate the rBA of etrasimod mini tablets 2 mg in water and 
3 food vehicles relative to etrasimod clinical IR tablets 2 mg under fasted conditions in 
healthy adult participants. The study will also assess the safety, tolerability, and palatability 
of etrasimod mini tablets 2 mg in healthy adult participants.
Objectives and Endpoints:
Objectives
Endpoints
Primary: 
Primary:
To estimate the rBA of etrasimod 2 mg mini tablets mixed 
with water compared to etrasimod 2 mg clinical IR tablets 
under fasted conditions
To estimate the rBA of the etrasimod 2 mg mini tablets
mixed with applesauce compared to the etrasimod 2 mg 
clinical IR tablets under fasted conditions
To estimate the rBA of the etrasimod 2 mg mini tablets
mixed with chocolate pudding compared to the etrasimod 
2 mg clinical IR tablets under fasted conditions
Plasma AUClast, AUCinf and Cmax of etrasimod
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Objectives
Endpoints

To estimate the rBA of the etrasimod 2 mg mini tablets
mixed with yogurt compared to the etrasimod 2 mg clinical
IR tablets under fasted conditions
Secondary: 
Secondary:
To evaluate the safety and tolerability of etrasimod in 
healthy participants
To assess the palatability of etrasimod mini tablets mixed 
with water/applesauce/chocolate pudding/yogurt
Assessment of first dose HR reduction, TEAEs, 
clinical laboratory abnormalities, vital signs, PEs, and 
12-lead ECGs
Assessment of palatability via questionnaire: mouth 
feel, bitterness, tongue/mouth burns, throat burn, and 
overall liking
Overall Design:
This is a Phase 1, open-label, single-dose, randomized 4-crossover periods and 1-fixed period 
design in a single cohort of approximately 16 healthy male or female participants. 
The study will consist of 5 treatments. Participants will be randomly assigned to 1 of the 
4 sequences in which participants are randomized in crossover design to receive 
Treatments A to D in Periods 1 to 4 with Treatment E being fixed in Period 5.
Treatment sequence
(n=4 per sequence)
Period 1
Period 2
Period 3
Period 4
Period 5
(fixed)
1
A
B
C
D
E
2
B
D
A
C
E
3
C
A
D
B
E
4
D
C
B
A
E
Treatment A: Single oral dose of etrasimod 2 mg clinical IR tablets under fasted conditions (Reference)
Treatment B: Single oral dose of etrasimod 2 mg mini tablets mixed with applesauce under fasted conditions (Test 1)
Treatment C: Single oral dose of etrasimod 2 mg mini tablets mixed with chocolate pudding under fasted conditions 
(Test 2)
Treatment D: Single oral dose of etrasimod 2 mg mini tablets mixed with water under fasted conditions (Test 3)
Treatment E: Single oral dose of etrasimod 2 mg mini tablets mixed with yogurt under fasted conditions (Test 4)
Participants will be discharged on Day 9 of Period 5, following completion of all 
assessments. Each treatment is 9 days that includes dosing, PK sampling and an extra day to 
minimize any residual etrasimod concentrations prior to start of the next treatment. The total 
planned duration of participation from the screening visit to the last follow-up phone call, is 
approximately 14 weeks.
Number of Participants:
A total of 16 participants will be randomly assigned to study intervention such that 
4 participants will be enrolled to each of the 4 sequences. 
Participants who withdraw from the study or whose PK samples are determined to be 
non-analyzable may be replaced at the discretion of the investigator upon consultation with 
the sponsor.
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Note: “Enrolled” means a participant’s agreement to participate in a clinical study following 
completion of the informed consent process and randomization to study intervention. 
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.
Male and female participants aged 18 years or older (or the minimum age of consent 
in accordance with local regulations) at screening who are overtly healthy as 
determined by medical evaluation including a detailed medical history, full physical 
exam, which includes BP and pulse rate measurement, clinical laboratory tests, 
temperature, and 12-lead ECG.
2.
BMI of 16 to 32 kg/m2; and a total body weight >50 kg (110 lb).
3.
Participants who are willing and able to comply with all scheduled visits, treatment
plan, laboratory tests, lifestyle considerations, and other study procedures.
4.
Capable of giving signed informed consent.
Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded:
1.
Evidence or history of clinically significant hematological, renal, endocrine,
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, 
anaphylactic, ophthalmologic disorder (such as macular edema, uveitis, retinopathy), 
or allergic disease.
2.
Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).
3.
Known immunodeficiency disorder, including positive serology for HIV, or a first
degree relative with a hereditary immunodeficiency.
4.
Infection with hepatitis B or hepatitis C viruses according to protocol specific testing
algorithm history.
5.
Participants with any of the specified acute or chronic infections or infection history.
6.
History of febrile illness within 5 days prior to the first dose of study intervention.
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7.
History of any lymphoproliferative disorder such as EBV related lymphoproliferative
disorder, history of lymphoma, history of leukemia, or signs or symptoms suggestive
of current lymphatic or lymphoid disease.
8.
Known present or a history of malignancy other than a successfully treated or excised
nonmetastatic basal cell or squamous cell cancer of the skin or cervical carcinoma in
situ.
9.
Evidence of untreated or inadequately treated active or latent Mycobacterium TB
infection.
Study Arms and Duration:
Participants will receive a single dose of etrasimod on Day 1 of each period. The total 
planned duration of participation from the screening visit to the last follow-up phone call, is 
approximately 14 weeks.
Study Intervention(s)
Intervention Name
Etrasimod clinical IR tablets, 2 mg
Reference product
Etrasimod mini tablets, 0.125 mg
Test product
Use
Experimental
Experimental
IMP or NIMP/AxMP
IMP
IMP
Dose Formulation
Coated tablets containing 2 mg 
etrasimod each
Coated mini tablets containing 
0.125 mg etrasimod each
Unit Dose Strength(s)
2 mg/tablet
0.125 mg/tablet
Route of 
Administration
Oral
Oral
Study Arm(s)
Arm Title
Period 1
Period 2
Period 3
Period 4
Period 5
Arm Description
Participants will receive a single dose of etrasimod on Day 1 of each period. 
Participants will be randomly assigned to 1 of the 4 sequences in which participants 
are randomized in crossover design to receive Treatments A to D in Periods 1 to 4 
with Treatment E being fixed in Period 5.
Administration of etrasimod will be etrasimod 2 mg clinical IR tablet with 240 mL 
water or 16 × 0.125 mg mini tablets (2 mg total) in 5 mL of water (followed by an 
additional 5 mL water rinse of dosing vehicle) or on soft foods (applesauce, 
chocolate pudding, or yogurt) in suitable container as per dosing instructions, 
followed by 235 mL water for soft food or 230 mL water for dispersion in water.
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Etrasimod will be supplied as clinical IR tablet and mini tablet to the CRU in bulk in HDPE 
bottles. 
Statistical Methods:
Sample Size Estimation
A sample size of 16 participants will provide adequate precision to estimate the rBA of 
etrasimod. These estimates are based on the assumption that within-participant standard 
deviations are 0.064 and 0.0933 for lnAUCinf and lnCmax, respectively, as obtained from 
studies APD334-007 and APD334-114. 
Primary Endpoints
PK parameters will be summarized descriptively by treatment, in accordance with Pfizer data 
standards. Plasma concentrations will be listed and summarized descriptively by nominal PK 
sampling time and treatment. Individual participant and median profiles of the plasma 
concentration-time data will be plotted by treatment using actual and nominal times, 
respectively. Median profiles will be presented on both linear-linear and log-linear scales.
Natural log transformed AUCinf, AUClast and Cmax will be analyzed using a mixed effect 
model with sequence, period and treatment as fixed effects and participant within the 
sequence as a random effect. Estimates of the adjusted mean differences (Test-Reference) 
and corresponding 90% CIs will be obtained from the model. The adjusted mean differences 
and 90% CIs for the differences will be exponentiated to provide estimates of the ratio of 
adjusted geometric means (Test/Reference) and 90% CI for the ratios. Treatment A 
(etrasimod 2 mg clinical IR tablets under fasted conditions) will be the Reference treatment 
while Treatment B (etrasimod 2 mg mini tablets mixed with applesauce under fasted 
conditions), Treatment C (etrasimod 2 mg mini tablets mixed with chocolate pudding under 
fasted conditions), and Treatment D (etrasimod 2 mg mini tablets mixed with water under 
fasted conditions) will be the Test treatments.
Natural log transformed AUCinf, AUClast and Cmax will be analyzed using a mixed effect 
model with sequence and treatment as fixed effects and participant within the sequence as a 
random effect. Treatment A (etrasimod 2 mg clinical IR tablets under fasted conditions) will 
be the Reference treatment while Treatment E (etrasimod 2 mg mini tablets mixed with 
yogurt under fasted conditions) will be the Test treatment.
Secondary Endpoints
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the study to evaluate the safety of participants. Any clinical 
laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern will be 
described. Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
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The data used in the palatability assessment analysis will be transcribed and rescaled to a 
score from 0 to 100 from the raw measurements on the palatability questionnaire. The 
sensory attributes (mouth feel, bitterness, tongue/mouth burn, throat burn, and overall liking) 
from the palatability assessment questionnaire for each treatment will be listed and 
descriptively summarized by collection time. Radar plots for each time point, summarizing 
all attributes, will be generated.
Ethical Considerations:
Etrasimod, an investigational, oral, and once daily S1P receptor modulator, is not expected to 
provide any clinical benefit to healthy participants. In this study, etrasimod will be 
administered as a single dose of 2 mg in each period of the study. This study is designed 
primarily to generate safety, tolerability, pharmacokinetic, and palatability data for the 
etrasimod mini tablets to support future pediatric studies. 
Etrasimod was determined to be well tolerated and to have an acceptable safety profile in 
both healthy participant and diseased clinical studies.
Participants will be expected to commit time and may experience some discomfort while 
undergoing study assessments. In addition, participants of childbearing potential must agree 
to use appropriate contraception methods. Participants should avoid vaccination with live 
attenuated replication-competent vaccines. It is recommended that participants keep their diet 
habits constant throughout the study.
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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.
Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations used in this table may be 
found in Appendix 10
Screen
Period 1
Check 
In
Periods 1-5
F/U
Telephone 
Contact
ET
Notes
Days Relative to Day 1 in Each Period
Day -28 
to 
Day -2
Day
-1
Day
1
Days
2-8
Day
9

Participants will be screened within 28 days of 
the first dose of study intervention.

Follow-up contact will occur by telephone and 
must occur at least 28 to 35 days after the last 
administration of etrasimod (Day 1 of Period 5 
if dosing completed).
Period 1 Study Days
-28 to -2
-1
1
2-8
9
Period 2 Study Days
10
11-17
18
Period 3 Study Days
19
20-26
27
Period 4 Study Days
28
29-35
36
Period 5 Study Days
37
38-44
45
65-72

Participants will be discharged on Day 9 of 
Period 5.
Informed consent
X
Inclusion/exclusion criteria
X
X

Inclusion/exclusion criteria should be updated 
on Day -1.
CRU confinement
X


X
Demography
X

Including measurement of height and weight
Medical/medication history, drug, tobacco, 
and alcohol history
X
X

Include history of alcohol abuse, 
tobacco/nicotine containing products, licit and 
illicit drug use or dependence within 6 months 
of screening. 

For Day -1, records should be reviewed or 
updated only.
Physical exam
X
X

See Section 8.3.1

Must be conducted at screening or upon 
admission on Day -1 only.
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Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations used in this table may be 
found in Appendix 10
Screen
Period 1
Check 
In
Periods 1-5
F/U
Telephone 
Contact
ET
Notes
Days Relative to Day 1 in Each Period
Day -28 
to 
Day -2
Day
-1
Day
1
Days
2-8
Day
9

Participants will be screened within 28 days of 
the first dose of study intervention.

Follow-up contact will occur by telephone and 
must occur at least 28 to 35 days after the last 
administration of etrasimod (Day 1 of Period 5 
if dosing completed).
Period 1 Study Days
-28 to -2
-1
1
2-8
9
Period 2 Study Days
10
11-17
18
Period 3 Study Days
19
20-26
27
Period 4 Study Days
28
29-35
36
Period 5 Study Days
37
38-44
45
65-72

Participants will be discharged on Day 9 of 
Period 5.
Safety laboratory
X
X
X*
X
X

Safety laboratory screening testing must be 
collected, reported, and reviewed within 28 
days prior to first administration of study 
intervention.  

Safety laboratory assessments including 
urinalysis, hematology, and chemistry will be 
performed. Participants should fast for at least 
4 hours prior to any safety blood collection. 
Additional laboratory assessments may be 
performed if deemed necessary by the 
investigator. 

*Safety laboratory assessment will be only 
performed on Day 2 of each period.

If labs are not within normal range on Day 9 of 
Period 5, unscheduled follow-up visits will 
occur per protocol.

Refer to Table 5 for full list of assessments
Urine drug testing
X
X
Pregnancy test (WOCBP only)
X
X

Given that the participant will be confined in 
CRU for the entire study, if tested negative on 
Day -1, no further test is needed unless 
otherwise specified.

See Table 5 for more details.
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Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations used in this table may be 
found in Appendix 10
Screen
Period 1
Check 
In
Periods 1-5
F/U
Telephone 
Contact
ET
Notes
Days Relative to Day 1 in Each Period
Day -28 
to 
Day -2
Day
-1
Day
1
Days
2-8
Day
9

Participants will be screened within 28 days of 
the first dose of study intervention.

Follow-up contact will occur by telephone and 
must occur at least 28 to 35 days after the last 
administration of etrasimod (Day 1 of Period 5 
if dosing completed).
Period 1 Study Days
-28 to -2
-1
1
2-8
9
Period 2 Study Days
10
11-17
18
Period 3 Study Days
19
20-26
27
Period 4 Study Days
28
29-35
36
Period 5 Study Days
37
38-44
45
65-72

Participants will be discharged on Day 9 of 
Period 5.
Contraception check
X
X
X
X
X

The contraception check is to confirm that 
contraception, if applicable, is used consistently 
and correctly.

Day 9 only for Period 5
12-Lead ECG
X
X
X
X
X

On Day 1 of each period perform ECGs 
pre-etrasimod dose and every hour up to 
6 hours, and at 8 and 24 hours post-etrasimod 
dose. The pre-etrasimod- dose 12-lead ECGs 
will be done in triplicate. 

Day 9 only for Period 5

Refer to Section 8.3.3 for additional details
Blood pressure, pulse rate, temperature 
X
X
X
X
X

On Day 1 of each period pulse rate and blood 
pressure will be performed at predose (baseline) 
and every hour up to 6 hours, and at 8 and 
24 hours post-etrasimod dose.

On Day 1 temperature will only be performed 
predose.

ECG will be taken first followed by vital signs.

Day 9 only for Period 5
HIV, HbsAg, HbcAb, HbsAb, HCVAb
X

If HbsAg is negative and HbcAb is positive, 
HbsAb should be evaluated.
COVID-19 related procedures
X

Performed per local procedures
TB (QuantiFERON® Gold Test)
X
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Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations used in this table may be 
found in Appendix 10
Screen
Period 1
Check 
In
Periods 1-5
F/U
Telephone 
Contact
ET
Notes
Days Relative to Day 1 in Each Period
Day -28 
to 
Day -2
Day
-1
Day
1
Days
2-8
Day
9

Participants will be screened within 28 days of 
the first dose of study intervention.

Follow-up contact will occur by telephone and 
must occur at least 28 to 35 days after the last 
administration of etrasimod (Day 1 of Period 5 
if dosing completed).
Period 1 Study Days
-28 to -2
-1
1
2-8
9
Period 2 Study Days
10
11-17
18
Period 3 Study Days
19
20-26
27
Period 4 Study Days
28
29-35
36
Period 5 Study Days
37
38-44
45
65-72

Participants will be discharged on Day 9 of 
Period 5.
Study intervention administration
X

Participants assigned to receive study 
intervention under fasted must be fasted for at 
least 10 hours predosing and 4 hours 
postdosing.

See Section 6.1.1 for additional details
Palatability assessment 
X

Review palatability assessment questionnaire 
and instructions with participants prior to 
dosing in each period, Day 1 for Treatments B, 
C, D and E. 

Each participant will record the sensory 
attributes at time intervals within 1 minute
(immediately after dosing), 5, 10 and 20 
minutes after administration using a palatability
assessment questionnaire (see Appendix 9).
PK blood sampling
X
X
X

PK sample collection will be on the day of 
dosing at the following timepoints: predose and 
at 1, 2, 4, 6, 8, 12, 24, 48, 72, 96, 120, 144, and 
168 hours postdose.
PK micro sampling
X
X

Micro sampling PK sample collection will be 
on the day of dosing at the following 
timepoints: predose and at 1, 2, 4, 6, 8, 12, and 
24 hours postdose for only Treatment A 
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Table 1.
Study Schedule of Assessment
Visit Identifier
Abbreviations used in this table may be 
found in Appendix 10
Screen
Period 1
Check 
In
Periods 1-5
F/U
Telephone 
Contact
ET
Notes
Days Relative to Day 1 in Each Period
Day -28 
to 
Day -2
Day
-1
Day
1
Days
2-8
Day
9

Participants will be screened within 28 days of 
the first dose of study intervention.

Follow-up contact will occur by telephone and 
must occur at least 28 to 35 days after the last 
administration of etrasimod (Day 1 of Period 5 
if dosing completed).
Period 1 Study Days
-28 to -2
-1
1
2-8
9
Period 2 Study Days
10
11-17
18
Period 3 Study Days
19
20-26
27
Period 4 Study Days
28
29-35
36
Period 5 Study Days
37
38-44
45
65-72

Participants will be discharged on Day 9 of 
Period 5.
group. Micro PK sampling occurs after PK 
blood sampling and taken from the other arm. 
Safety Biomarker Samples (Prep B2)
X

Period 1 Day 1 only

See Section 8.7.1
CRU discharge 
X

The participants will be discharged on Day 9 of 
Period 5.
Serious and nonserious AE monitoring
X




X
X

See Section 8.4.3 for follow up AE and SAE 
assessments.
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2. INTRODUCTION
Etrasimod is an orally administered, selective, synthetic S1P1,4,5 modulator that is being 
developed to treat immune-mediated inflammatory disorders, including UC, AA, AD, and 
EoE. The S1P1 is a cell surface expressed protein that has been shown to regulate lymphocyte 
migration out of lymphoid tissues. Synthetic small molecule S1P1 agonists have been 
observed to act as functional antagonists by inducing sustained receptor internalization, thus 
inhibiting lymphocyte migration out of lymphoid tissues and lowering the amount of 
peripheral blood lymphocytes available to be recruited to sites of inflammation. Modulation 
of the S1P/S1P receptor axis is thought to be a potential therapeutic approach to the 
management of immune-mediated inflammatory disorders.
2.1. Study Rationale 
The purpose of the study is to estimate the rBA of etrasimod mini tablets 2 mg in water and
3 food vehicles relative to etrasimod clinical IR tablet 2 mg under fasting conditions in 
healthy adult participants. The study will also assess the safety, tolerability, and palatability 
of etrasimod mini tablets (total dose of 2 mg) in healthy adult participants. The etrasimod 
mini tablets are intended for dosing in pediatric population 2 years old to <12 years old.
2.2. Background 
The pharmacology, safety pharmacology, PK, metabolism, toxicology and clinical 
dose-ranging efficacy and safety of etrasimod oral administration had been comprehensively 
studied. A summary of relevant, currently available data is provided in this protocol. 
Additional details and further information for this compound could be found in the current 
IB.
2.2.1. Nonclinical Pharmacology
A summary of the nonclinical investigational programs can be found in the current IB.
2.2.2. Nonclinical Pharmacokinetics and Metabolism
Etrasimod is eliminated primarily hepatically by extensive metabolism involving oxidation of 
etrasimod, along with dehydrogenation and conjugation, and showed no human specific 
metabolite(s) compared to those observed in the toxicology species. The main CYP enzymes 
involved in the oxidative metabolism of etrasimod are CYP2C8 (38%), CYP2C9 (37%), and 
CYP3A4 (22%), and with CYP2C19 and CYP2J2 being minor contributors (1% each). There 
are no major circulating metabolites and etrasimod is the primary circulating drug entity.
Additional information of the nonclinical PK and metabolism of etrasimod is available in the 
current IB.
2.2.3. Nonclinical Safety
Etrasimod was well tolerated across the general toxicity program conducted in CD-1 mice,
Sprague Dawley rats, and beagle dogs, with no etrasimod-induced mortality following repeat
administration up to 91-days, 6-months, and 9-months at 20, 150, and 15 mg/kg/day in mice,
rats, and dogs, respectively.  Most etrasimod-related findings were considered nonadverse,
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reversible upon cessation of treatment, and/or readily monitorable in the clinic. One of the 
most common adverse effects across species was decreased body weight and/or body weight 
gain, with associated decreases in food consumption. The primary target organs identified 
across all species were lymphoid tissues, lung, and liver. In addition, the heart was identified 
as a target organ in the dog. When administered at doses within and above the therapeutic 
range (up to 858 × in rats and 380 × in dogs over the total Cmax exposure at the proposed 
human dose for the treatment of UC) in safety pharmacology studies, etrasimod showed no 
effect on CNS, respiratory, or cardiovascular function.
The potential effects of etrasimod on the cardiovascular system were investigated in a series 
of in vitro and in vivo studies. In vitro, etrasimod increased hERG currents by 31.4% at 1 
mm and 58.9% at 3 mm. These concentrations are approximately 193 × and 578 × over the 
free Cmax exposure at the proposed human dose for the treatment of UC. An IC50 for hERG
current inhibition could not be established for etrasimod since only increases in hERG
channel current, rather than inhibition, were observed.  Based on the G protein receptor 
signaling associated with the primary PD activity, etrasimod was observed to activate GIRK 
currents in vitro. GIRK1 and GIRK4 are the 2 homologous subunits of IκACh that interact with 
Gβγ to mediate the activation of the potassium channel.1 G-protein signaling via GIRK IκACh 
channel activation in cardiac cells is considered to be responsible for the transient 
cardiovascular effects seen with first dose of S1P receptor modulators.2, 3, 4 At IκACh in 
primary human atrial cardiomyocytes, etrasimod exhibited an EC50 of 29.9 nM and there was 
no difference between S1P and etrasimod in the time course of IκACh activation. The maximal 
current induced by etrasimod, however, was 90% of that observed with carbachol and was 
10 × lower (based on EC50) than S1P itself.
Etrasimod was not mutagenic or clastogenic in in vitro genetic toxicity studies and is not 
considered genotoxic in rats or to pose a genotoxic risk to humans. There were no etrasimod-
related effects on spermatogenesis or fertility in males at any dose level evaluated. In the 
embryo-fetal development studies in rats and rabbits, administration of etrasimod during the 
period of organogenesis resulted in increased post implantation loss and decreased mean 
litter numbers and proportions of viable fetuses in both species. The embryo lethality and 
fetal malformations noted with etrasimod in the rat and rabbit embryo-fetal development 
studies are consistent with similar findings observed with approved S1P modulators5, 6, 7, 8
and are believed to be a result of the important role of S1P1 in embryogenesis, including 
vascular and neural development.9
Further details of the nonclinical safety program are provided in the current IB.
2.2.4. Clinical Overview
Safety, tolerability and PK of etrasimod were evaluated in 15 Phase 1 studies in healthy adult
participants. Efficacy and safety of etrasimod was evaluated in 3 completed Phase 2, 6
ongoing Phase 2, 3 completed Phase 3 and 2 ongoing Phase 3 studies across several disease 
indications. Clinical pharmacology data established the PK properties of etrasimod with or 
without food and in specified participant subpopulations (eg, participants with renal or 
hepatic impairment), and included comprehensive drug interaction studies to inform dosing 
recommendations.
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A complete summary of the clinical data relevant to etrasimod and its study in human 
participants is provided in the current edition of the IB.
2.2.4.1. Pharmacokinetic Overview of Etrasimod
Etrasimod is absorbed with a median Tmax of 4 hours after administration as an etrasimod 
2 mg IR tablet in the fasted state, and up to 6 hours in the fed state. Food did not affect 
etrasimod exposure measures (Cmax and AUC). Plasma Cmax and AUC values of etrasimod 
are dose proportional following a single dose of 0.1 to 5 mg. For multiple-doses of etrasimod 
over a range of 0.7 to 2 mg once daily, steady-state Cmax increased dose proportionally and 
steady-state AUC0-24 increased slightly greater than dose proportionally. Apparent dose
proportional increases were also observed for mean steady-state Cmax and AUC0-24 values 
from 2 to 4 mg once daily dosing in healthy participants. The time to reach approximate 
steady-state for etrasimod exposure measures (Cmax, AUC0-24, Ctrough) is within 7 days of the 
first dose. Mean Rac for etrasimod exposure measures are <3-fold with once daily dosing. 
These observations are consistent with etrasimod’s elimination (effective) half-life of 
approximately 30 hours. The mean oral Vz/F of etrasimod ranged from 50 to 103 L in healthy 
participants across evaluated single and multiple-dose levels and Phase 1 studies, indicating 
extravascular distribution. The mean oral plasma CL/F of etrasimod following single and 
multiple-dose administration of etrasimod was low and ranged from 1.13 to 1.43 L/h and 
0.97 to 1.70 L/h, respectively, in healthy participants across evaluated dose levels
in the Phase 1 studies.
The human mass balance study identified 2 oxidative metabolites, AR503641 (M3) and
AR504344 (M6) present in systemic circulation, though minor as they are each <10% of total
radioactivity. The oxidation of etrasimod occurs by 3 CYPs (CYP2C8, CYP2C9 and 
CYP3A4). Etrasimod is primarily eliminated in feces, with no parent drug detected in the 
urine. 
2.2.4.2. Safety Overview of Etrasimod
As of 30 Aug 2022, a total of 2119 participants (419 healthy participants and 1700 
participants with disease) have been exposed to etrasimod in clinical development programs.  
Clinical evidence in participants of healthy status, UC, CD, AD, AA or EoE to date have 
demonstrated that etrasimod is well tolerated in humans. 
Across all clinical studies (Phase 1 to Phase 3), etrasimod caused expected mild, transient, 
and generally asymptomatic reduction in HR at first dose and very few participants with HR 
< 50 bpm. These reductions were greatest following first dose and lessened upon repeat 
dosing due to development of tolerance, allowing HR to return to baseline. The HR effects 
are related to S1P1 localized on atrial myocytes that activate GIRK channels, which are 
transient and not clinically adverse or associated with safety findings.
Etrasimod 2 mg administered once daily demonstrated an acceptable safety profile up to
52 weeks in controlled studies and up to 104 weeks in uncontrolled studies. There was a low
incidence of SDEIs such as infections, including severe (ie, Grade ≥3) infections, 
opportunistic infections, and herpes infections (herpes zoster and herpes simplex), cardiac 
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safety events (bradycardia, AV conduction delays, and hypertension), malignancies, liver 
injury (liver transaminase elevation and bilirubin elevation), macular oedema, and pulmonary 
disorders (airflow obstruction and decreased gas exchange) in participants who were treated 
with etrasimod 2 mg.
2.3. Benefit/Risk Assessment
Etrasimod, an investigational, oral, and once daily S1P receptor modulator, is not expected to 
provide any clinical benefit to healthy participants. In this study, etrasimod will be 
administered at single doses of 2 mg. This study is designed primarily to generate safety, 
tolerability, pharmacokinetic, and palatability data for the etrasimod mini tablets to support 
future pediatric studies. 
Etrasimod was determined to be well tolerated and to have an acceptable safety profile in 
both healthy participant and diseased clinical studies. 
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(s) 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.

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 
altered gas exchange)

liver injury

malignancy
Clinical experience with other S1P receptor 
modulators for the treatment of MS and UC.  

The totality of etrasimod clinical studies 
(Phase 1, 2 and 3 studies) have shown that 
2 mg etrasimod is well-tolerated with no 
clinically significant safety signals.
Exclusion of participants at risk. Short duration of 
treatment. Safety labs at screening and baseline
and when deemed necessary by the investigator
throughout the study. AE monitoring throughout 
the study.
S1P receptor modulator-specific lymphocyte level 
decreases.
Dose-dependent reductions in peripheral
lymphocyte counts are an expected PD effect of 
etrasimod.
The totality of clinical studies following single 
dose administration of study intervention is 
well-tolerated with a return to normal range by 
Day 7.
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.
First dose cardiac effect
S1P receptor modulators 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 across Phase 
1 to 3 studies across several indications indicate 
that etrasimod 2 mg is well-tolerated with modest 
HR reduction that is maximal on the first day of 
Participants with elevated cardiac risk factors will 
be excluded from participation in the study.
Hourly HR monitoring for the first 6-hours post 
first dose will be conducted for all dose periods.
Participants with cardiac effects associated with
first dose will be required to permanently
discontinue study intervention.
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Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
dosing without major clinically relevant cardiac 
safety events.
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 breastfeeding.
WOCBP who are pregnant, lactating, or 
breastfeeding 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 10.4.4 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.
Study Procedures Blood Collection for PK
Extravasation, bruising, local discomfort
Collection of 14 PK plasma samples per period per 
sequence
Collection of 8 PK micro samples collected
for Treatment A.
Use of highly qualified nurses, with venipuncture 
experience. 
Use of alternating arms for adjacent time points 
can provide more resting and healing time for 
each arm between samplings.
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2.3.2. Benefit Assessment
Etrasimod is not expected to provide any clinical benefit to healthy participants. This study is 
designed primarily to generate safety, tolerability, and PK data for further clinical 
development of etrasimod mini tablets. In this study, etrasimod will be administered at single 
doses of 2 mg.
2.3.3. Overall Benefit/Risk Conclusion
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 UC.
3. OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary: 
Primary: 
To estimate the rBA of etrasimod 2 mg mini tablets
mixed with water compared to etrasimod 2 mg 
clinical IR tablets under fasted conditions
To estimate the rBA of the etrasimod 2 mg mini
tablets mixed with applesauce compared to the 
etrasimod 2 mg clinical IR tablets under fasted 
conditions
To estimate the rBA of the etrasimod 2 mg mini
tablets mixed with chocolate pudding compared to 
the etrasimod 2 mg clinical IR tablets under fasted 
conditions
To estimate the rBA of the etrasimod 2 mg mini
tablets mixed with yogurt compared to the etrasimod 
2 mg clinical IR tablets under fasted conditions
Plasma AUClast, AUCinf and Cmax of etrasimod
Secondary:
Secondary: 
To evaluate the safety and tolerability of etrasimod 
in healthy participants
To assess the palatability of etrasimod mini tablets
mixed with water/applesauce/chocolate 
pudding/yogurt
Assessment of first dose HR reduction, 
TEAEs, clinical laboratory abnormalities, vital 
signs, PEs, and 12-lead ECGs
Assessment of palatability via questionnaire: 
mouth feel, bitterness, tongue/mouth burns, 
throat burn, and overall liking
Tertiary/Exploratory: 
Tertiary/Exploratory: 
To characterize the PK parameters of etrasimod 2 mg 
mini tablets mixed with water or soft foods 
(applesauce, chocolate pudding, or yogurt) compared 
to etrasimod 2 mg clinical IR tablet
To validate the PK measurement of etrasimod in 
capillary blood sample collected using micro
sampling device against the PK measurement of 
etrasimod in venous blood samples. 
Plasma etrasimod: t½, CL/F, Vz/F and Tmax of 
etrasimod
Plasma concentration of etrasimod obtained 
via micro sampling compared to venous 
sampling
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4. STUDY DESIGN
4.1. Overall Design
This is a Phase 1, open-label, single-dose, randomized 4-crossover periods and 1-fixed period 
design in a single cohort of approximately 16 healthy male or female participants . 
The study will consist of 5 treatments as shown below: 
1. Treatment A: Single oral dose of etrasimod 2 mg clinical IR tablet under fasted 
conditions (Reference)
2. Treatment B: Single oral dose of etrasimod 2 mg mini tablets mixed with applesauce 
under fasted conditions (Test 1)
3. Treatment C: Single oral dose of etrasimod 2 mg mini tablets mixed with chocolate 
pudding under fasted conditions (Test 2)
4. Treatment D: Single oral dose of etrasimod 2 mg mini tablets mixed with water under 
fasted conditions (Test 3)
5. Treatment E: Single oral dose of etrasimod 2 mg mini tablets mixed with yogurt
under fasted conditions (Test 4)
Sixteen participants will be enrolled in Period 1 for a total of 12 evaluable participants to 
complete study.  Participants will be randomly assigned to 1 of the 4 sequences shown in
Table 2 in which participants are randomized in crossover design to receive Treatments A to 
D in Periods 1 to 4 with Treatment E being fixed in Period 5. Participants will be discharged 
on Day 9 of Period 5, following completion of all assessments. Each treatment is 9 days that 
includes dosing, PK sampling and an extra day to minimize any residual etrasimod 
concentrations prior to start of the next treatment. The total planned duration of participation 
from the screening visit to the last follow-up phone call, is approximately 14 weeks.
Table 2.
Treatment Sequence
Treatment sequence
(n=4 per sequence)
Period 1
Period 2
Period 3
Period 4
Period 5
(fixed)
1
A
B
C
D
E
2
B
D
A
C
E
3
C
A
D
B
E
4
D
C
B
A
E
Since etrasimod has a half-life approximately 30 hours, there will be a 9-day washout
between each dose.
Blood samples for PK analysis will be collected predose and at 1, 2, 4, 6, 8, 12, 24, 48, 72, 
96, 120, 144 and 168 hours postdose (SoA). Capillary blood samples (using micro sampling 
Tasso device) will be collected at predose and at 1, 2, 4, 6, 8, 12 and 24 hours postdose (SoA)
for PK assessments (Treatment A). Micro PK sampling occurs after PK blood sampling, and 
taken from the other arm.
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A palatability assessment will be conducted during which a palatability assessment 
questionnaire will be completed for the sprinkled mini tablets in every period, with 1 minute 
(immediately after dosing), before administered the water up to a total volume of 240 mL, 
and at 5 minutes, 10 minutes, 20 minutes after dosing is fully completed. Additionally, 
participants will be asked to not verbalize their responses and not discuss palatability with 
other participants until after they have filled out the responses in the questionnaire.
Participants will participate in the study up to approximately 3.5 months, with the inclusion
of the screening and follow-up period. Participants will be screened within 28 days of the
first dose of study intervention and if all entry criteria are fulfilled, the participants will report
to the CRU on the day prior to Day 1 dosing (Day -1). On Day 1 of each period, participants
will receive a single dose of study intervention. Administration of etrasimod will be oral via 
dosing of clinical IR tablet 2 mg or mini tablets 2 mg (as 16 × 0.125 mg) with water or on 
soft foods as per dosing instructions. Participants will be fasted for at least 10 hours 
predosing and 4 hours postdosing.
Participants will be confined in the CRU for a total of at least 45 days and discharged at the
discretion of the investigator. A follow-up phone call will be made at least 28 calendar days
and up to 35 calendar days after the last administration of the study intervention to capture
any potential AEs and confirm appropriate contraceptive usage.
Tolerability and safety will be assessed for all treatments by monitoring AEs. Participants 
who withdraw from the study or whose PK samples are determined to be non-analyzable may 
be replaced at the discretion of the of the investigator upon consultation with the sponsor.
4.2. Scientific Rationale for Study Design
Etrasimod mini tablet is an alternative formulation suitable for pediatric patients who are not 
able to swallow etrasimod 2 mg clinical IR tablets. The mini tablets are formulated in 
strength of 0.125 mg that can be sprinkled on soft foods for administration to pediatric UC 
patients. Study C5041034 will be conducted in healthy adult participants to evaluate the PK
of etrasimod mini tablets 2 mg (as 16 × 0.125 mg) dissolved in water or soft foods 
(applesauce, chocolate pudding and yogurt [Test]) in comparison to etrasimod clinical IR 
tablet (Reference) in fasted state. Furthermore, a palatability assessment will be conducted 
with the mini tablets in soft foods. 
4.2.1. Rationale for ECG Measurements
In the heart, S1P1 is expressed on atrial myocytes and is associated with the regulation of 
heart rate. S1P1 agonism activates both G alpha i (Gi) and β-arrestin signaling pathways. 
β-arrestin activation leads to receptor internalization, while Gi coupled signaling activates 
GIRK channels that regulate potassium efflux and membrane potential. As a result, there is a 
transient, first dose associated, chronotropic (slowing of HR) and dromotropic (slowing of 
AV nodal conduction) effects associated with etrasimod (a class effect). For all Phase 1 
studies, intensive ECG have been taken for the first 6-hours post first dose. For this study, 
this practice should be in place until the NDA is approved.
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4.2.2. Rationale for PR and BP Monitoring
In addition to the transient, first dose associated, chronotropic effect associated with 
etrasimod, hypertension has been observed with S1P receptor modulators and AEs of 
hypertension have been reported. For all phase 1 studies, intensive BP and PR monitoring 
post dose has been undertaken and this will continue for this study.
4.2.3. Rationale for Micro Sampling
Etrasimod will be evaluated in children as young as 2 years old in a future pediatric study 
(C5041018) in which IV blood draw may be challenging. This is designed to validate 
etrasimod PK concentrations in capillary blood collected using the Tasso device against PK 
samples collected from traditional venous blood samples. Findings from the validation will 
enable patient-centric blood sampling using this innovative device in future etrasimod 
pediatric clinical studies.
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 for both female and male participants
(see Appendix 4).
4.3. Justification for Dose
The dose of etrasimod 2 mg once daily has been shown to be efficacious and safe in 
moderate to severely active adult UC patients.  
This study is designed to evaluate rBA of etrasimod 2 mg mini tablets (as 16 × 0.125 mg)
with water or 3 food vehicles compared to etrasimod 2 mg clinical IR tablet formulation in 
healthy adult participants. The projected doses in pediatric study utilizing mini tablets range 
from 0.5 mg to 1.5 mg.  The dose selected for pediatric participants based on age and body 
weight is intended to generate exposures (AUC) to match adult exposures following 
etrasimod 2 mg.
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 and the investigator has reviewed the final 
safety data and determined that no additional evaluation is required.
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 
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 
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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.
Male and female participants aged 18 years or older (or the minimum age of 
consent in accordance with local regulations) at screening who are overtly healthy 
as determined by medical evaluation including a detailed medical history, full
physical exam, which includes BP and pulse rate measurement, clinical laboratory 
tests, temperature, and 12-lead ECG.

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and 
female (Section 10.4.2) participants.
Other Inclusion Criteria:
2.
BMI of 16 to 32 kg/m2; and a total body weight > 50 kg (110 lb).
3.
Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
4.
Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the ICD and in 
this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Evidence or history of clinically significant hematological, renal, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, neurological, 
anaphylactic, ophthalmologic disorders (such as macular edema, uveitis, retinopathy), 
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or allergic disease (including drug allergies, but excluding untreated, asymptomatic, 
seasonal allergies at the time of dosing).

Myocardial infarction, unstable angina, stroke/transient ischemic attack, 
decompensated heart failure requiring hospitalization, or Class III/IV heart 
failure ≤8 weeks prior to study treatment

Second- or third-degree AV block, sick sinus syndrome without a functional 
pacemaker, or periods of asystole for 3 seconds without an implanted cardiac 
defibrillator

Recurrent symptomatic bradycardia or recurrent cardiogenic syncope

History of congenital long QT syndrome

Other medical or psychiatric condition including recent (within the past year) 
or active suicidal ideation/behavior, laboratory abnormality or other conditions 
that may increase the risk of study participation or, in the investigator’s 
judgment, make the participant inappropriate for the study
2. Any condition possibly affecting drug absorption (eg, gastrectomy, cholecystectomy).
3. Known immunodeficiency disorder, including positive serology for HIV, or a first 
degree relative with a hereditary immunodeficiency.
4. Infection with hepatitis B or hepatitis C viruses according to protocol specific testing 
algorithm history.

For hepatitis B, all participants will undergo testing for HbsAg and HbcAb.

If HbsAg is positive, the participant must be excluded from participation in the 
study.

If HbsAg and HbcAb are both negative, the participant is eligible for study 
inclusion.

If HbsAg is negative and HbcAb is positive, HbsAb should be evaluated:

If HbsAb is negative, the participant must be excluded from participation in 
the study;

If HbsAb is positive, the participant is eligible for study inclusion.

For hepatitis C, all participants will undergo testing for HCVAb. Only
participants who are HCVAb negative are eligible.
5. Participants with any of the following acute or chronic infections or infection history:

Any infection requiring treatment within 2 weeks prior to dosing.
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
Any infection requiring hospitalization or parenteral antimicrobial therapy 
within 60 days of the first dose of study intervention.

Any infection judged to be an opportunistic infection or clinically significant 
by the investigator, within the past 6 months of the first dose of study 
intervention.

Known active or history of recurrent bacterial, viral, fungal, mycobacterial or 
other infections.

History of recurrent (more than one episode of) localized dermatomal herpes 
zoster, or history of disseminated (single episode) herpes simplex or 
disseminated herpes zoster.

History of febrile illness within 5 days prior to the first dose of study 
intervention.
6. History of any lymphoproliferative disorder such as EBV related lymphoproliferative 
disorder, history of lymphoma, history of leukemia, or signs or symptoms suggestive 
of current lymphatic or lymphoid disease. Known present or a history of malignancy 
other than a successfully treated or excised nonmetastatic basal cell or squamous cell 
cancer of the skin or cervical carcinoma in situ.
7. Evidence of untreated or inadequately treated active or latent Mycobacterium TB 
infection as evidenced by the following:

A positive QFT-G test performed within the 12 weeks prior to screening. If the 
laboratory reports the test as indeterminate, the test should be repeated. If the 
result of the repeat test is indeterminate, a PPD test may be substituted for the 
QFT-G test only with approval from the Pfizer Medical Monitor on a case-by-
case basis.

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 (9 months of isoniazid in a locale where rates of primary multi-drug 
resistant TB infection are <5% or an acceptable alternative regimen) or active 
(acceptable multi-drug regimen) TB infection, neither a QFT-G test nor a PPD 
test need be obtained. Details of the previous course of therapy (eg, 
medication(s) used, dose, duration of therapy) should be documented in the 
source documentation.

A participant who is currently being treated for active or latent TB infection 
must be excluded from the study.
8. Participants with ANY of the following abnormalities in clinical laboratory tests at 
screening or Day -1, as assessed by the study-specific laboratory and confirmed by a 
single repeat test, if deemed necessary: 

WBC <3500/mm3 (<3.5 × 109 cells/L)
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
ANC <1500/mm3 (<1.5 × 109 cells/L)

ALC <800/mm3 (<0.8 × 109 cells/L)

Platelet count <100/mm3 (<100 × 109 cells/L)

Hemoglobin <10 g/dL

AST or ALT level > ULN;

Total bilirubin level > ULN; participants with a history of Gilbert’s syndrome 
may have direct bilirubin measured and would be eligible for this study 
provided the direct bilirubin level is ≤ULN;

eGFR <60 mL/min/1.73 m2 based on the CKD-EPI equation. Based upon 
participant age at screening, eGFR or eCrCl is calculated using the 
recommended formulas in Section 10.6.2 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. 

In the opinion of the investigator or Pfizer (or designee), have any clinically 
significant laboratory abnormality that could affect interpretation of study data 
or the participant’s participation in the study.
Prior/Concomitant Therapy:
9. Use of prescription or nonprescription drugs and dietary and herbal supplements 
within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
intervention. (Refer to Section 6.9 Prior and Concomitant Therapy for additional 
details).
Prior/Concurrent Clinical Study Experience:
10. Previous administration with an investigational product (drug or live or attenuated
vaccine) within 30 days (or as determined by the local requirement) or 5 half-lives 
preceding the first dose of study intervention used in this study (whichever is longer). 
Diagnostic Assessments:
11. A positive urine drug test.
12. A positive pregnancy test.
13. Screening or Day 1 prerandomization vital signs (taken in the supine position) with 
a HR <50 bpm OR systolic BP <90 mm Hg or ≥140 mm Hg OR diastolic BP 
<50 mm Hg or ≥90 mm Hg. Abnormal vital signs should be confirmed by 2 repeat 
measurements. Abnormal results that are confirmed on a repeat assessment are 
considered exclusionary.
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14. Standard 12-lead ECG that demonstrates clinically relevant abnormalities that may 
affect participant safety or interpretation of study results (eg, QTcF >450 ms,
complete LBBB, signs of an acute or indeterminate- age myocardial infarction, 
ST-T interval changes suggestive of myocardial ischemia, second- or third- degree
AV block, or serious bradyarrhythmias or tachyarrhythmias). If QTcF exceeds 
450 ms, or QRS exceeds 120 ms, the ECG should be repeated twice and the 
average of the 3 QTcF or QRS values used to determine the participant’s 
eligibility. Computer-interpreted ECGs should be overread by a physician 
experienced in reading ECGs before excluding a participant.
Other Exclusion Criteria:
15. History of alcohol abuse or binge drinking and/or any other illicit drug use or 
dependence within 6 months of Screening. Binge drinking is defined as a pattern of 
5 (male) and 4 (female) or more alcoholic drinks in about 2 hours. As a general 
rule, alcohol intake should not exceed 14 units per week (1 unit = 8 ounces 
(240 mL) beer, 1 ounce (30 mL) of 40% spirit, or 3 ounces (90 mL) of wine).
16. Use of tobacco/nicotine containing products in excess of 5 cigarettes/day.
17. Blood donation (excluding plasma donations) of approximately 1 pint (500 mL) or 
more within 60 days prior to dosing.
18. WOCBP who are unwilling or unable to use an acceptable method of contraception 
as outlined in Section 10.4 during the intervention period and for at least 28 days 
after the last dose of study intervention.
19. History of severe allergic or anaphylactic reactions.
20. Unwilling or unable to comply with the criteria in the Lifestyle Considerations
section of this protocol.
21. 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
The following guidelines are provided:
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 
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donation and cryopreservation of germ cells prior to the start of study intervention, if 
applicable.
At time points indicated in 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. 
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 use abstinence 
as the selected contraception method, or if pregnancy is known or suspected in the participant 
or partner.
5.3.2. Meals and Dietary Restrictions

Participants must abstain from all food and drink (except water) at least 4 hours prior 
to any safety laboratory evaluations and 10 hours prior to the collection of the predose 
PK sample.

Water is permitted until 1 hour prior to study intervention administration. Water may 
be consumed without restriction beginning 1 hour after dosing. Noncaffeinated drinks
(except grapefruit or grapefruit-related citrus fruit juices—see below) may be 
consumed with meals and the evening snack.

Lunch will be provided approximately 4 hours after dosing.

Dinner will be provided approximately 9 to 10 hours after dosing.

An evening snack may be permitted.

Participants will refrain from consuming red wine, grapefruit, or grapefruit-related 
citrus fruits (eg, Seville oranges, pomelos, fruit juices) from 7 days prior to the first 
dose of study intervention until collection of the final PK blood sample.  

While participants are confined, their total daily nutritional composition should be 
approximately 55% carbohydrate, 30% fat, and 15% protein. The daily caloric intake 
per participant should not exceed approximately 3200 kcal.
5.3.3. Caffeine, Alcohol, and Tobacco
Participants will abstain from caffeine-containing products for 24 hours prior to the start of 
dosing until collection of the final PK sample of each study period. 

Participants will abstain from alcohol for 24 hours prior (or as specified above for red 
wine) to admission to the CRU and continue abstaining from alcohol until collection 
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of the final PK sample of each study period. Participants may undergo an alcohol 
breath test or blood alcohol test at the discretion of the investigator.

Participants will abstain from the use of tobacco- or nicotine-containing products for 
24 hours prior to dosing and during confinement in the CRU.
5.3.4. Activity

Participants will abstain from strenuous exercise (eg, heavy lifting, weight training, 
calisthenics, aerobics) for at least 48 hours prior to each blood collection for clinical 
laboratory tests. Walking at a normal pace will be permitted;

In order to standardize the conditions on PK sampling days, participants will be 
required to refrain from lying down (except ECG measurements), eating, and 
drinking beverages other than water during the first 4 hours after dosing.
5.3.5. Vaccination(s)
Vaccination with live attenuated replication-competent vaccines is prohibited within the 
4 weeks prior the first dose of study intervention, while receiving study intervention, and for 
4 weeks after the last dose of study intervention. Similarly, current routine household contact 
with individuals who have been vaccinated with live attenuated, replication-competent 
vaccines should be avoided while receiving study intervention and for 4 weeks after the last 
dose of study intervention. Following vaccination with a live attenuated 
replication-competent vaccine, the virus may be shed in bodily fluids, including stool, and 
there is a potential risk that the virus may be transmitted.
Such vaccines include, but are not limited to: Flu Mist® (intranasal influenza vaccine), 
attenuated rotavirus vaccine, varicella (chickenpox) vaccine, attenuated typhoid fever 
vaccine, oral polio vaccine, MMR vaccine, vaccinia (smallpox) vaccine, and Zostavax® 
(zoster vaccine live). 
Live attenuated vaccines that are known not to be replication-competent in humans are 
permitted. Such vaccines include but are not limited to the Modified Vaccinia Ankara 
Bavarian Nordic (Jynneos®, Imvamune®, Imvanex®) smallpox and monkeypox vaccine. By 
contrast, the ACAM2000 smallpox and monkeypox vaccine is prohibited because it is live 
and replicates in humans.
Vaccines (including COVID-19 vaccines) that are not live attenuated are permitted.
Individuals receiving immunosuppressive therapy may have a diminished response to 
vaccination.
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. Screen failure data are collected and remain as 
source and are not reported on the CRF.
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Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. 
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.
6.1. Study Intervention(s) Administered
Study interventions will be administered orally and according to the conditions described in 
the SoA and Meals and Dietary Restrictions of this protocol.
Study Intervention(s)
Intervention Name
Etrasimod clinical IR tablets, 2 mg
Reference product
Etrasimod mini tablets, 0.125 mg
Test product
Type
drug
drug
Use
Experimental
Experimental
IMP or NIMP/AxMP
IMP
IMP
Dose Formulation
Coated tablets containing 2 mg 
etrasimod each
Coated mini tablets containing 
0.125 mg etrasimod each
Unit Dose Strength(s)
2 mg/tablet
0.125 mg/tablet
Dosage Level(s)
2 mg per Period
2 mg per Period
Route of Administration
Oral
Oral
Sourcing
Etrasimod provided centrally by the 
sponsor.
See IPM for more information.
Etrasimod provided centrally by the 
sponsor.
See IPM for more information.
Packaging and Labeling
Study intervention will be provided 
in HDPE bottle. 
Each bottle will be labeled as 
required per country requirement.
Study intervention will be provided 
in HDPE bottle. 
Each bottle will be labeled as 
required per country requirement.
SRSD
IB
IB
Current/Former Name(s) 
or Alias(es)
Etrasimod/PF-07915503, APD334
Etrasimod/PF-07915503, APD334
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Study Arm(s)
Arm Title
Period 1
Period 2
Period 3
Period 4
Period 5
Arm Description
Participants will receive a single dose of etrasimod on Day 1 of each period. 
Participants will be randomly assigned to 1 of the 4 sequences in which participants 
are randomized in crossover design to receive Treatments A to D in Periods 1 to 4 
with Treatment E being fixed in Period 5.
Administration of etrasimod will be etrasimod 2 mg clinical IR tablet with 240 mL 
water or 16 × 0.125 mg mini tablets (2 mg total) in 5 mL of water (followed by an 
additional 5 mL water rinse of dosing vehicle) or on soft foods (applesauce, chocolate 
pudding, or yogurt) in suitable container as per dosing instructions, followed by 
235 mL water for soft food or 230 mL water for dispersion in water.
Etrasimod will be supplied as clinical IR tablet and mini tablet to the CRU in bulk in HDPE 
bottles. Etrasimod will be provided as 1) a clinical IR tablet in the strength of 2 mg provided 
in the individual dosing container, 2) mini tablets of 0.125 mg etrasimod of which 16 mini 
tablets equivalent to 2 mg dose will be presented to the participants mixed with soft
foods/water in a suitable dosing container.
6.1.1. Administration
On Day 1 of each period,following an overnight fast of at least 10 hours, participants will 
receive study intervention at approximately 0800 hours (plus or minus 2 hours). Investigator 
site personnel will administer study intervention during each period.
Etrasimod clinical IR tablets will be administered with ambient temperature water to a total 
volume of approximately 240 mL.
Etrasimod mini tablets will be administered mixed with 5 mL of either applesauce, chocolate 
pudding, yogurt or water followed by approximately 235 mL of ambient temperature water 
or by 5 ml rinsing if dispersion in water followed by 230 ml water. See IPM for detailed 
instructions on preparation and administration of study intervention. 
Participants will swallow the clinical IR tablets whole and mini tablets mixed with 
applesauce, chocolate pudding, yogurt, or water, and will not manipulate or chew the study 
intervention prior to swallowing.
In order to standardize the conditions on PK sampling days, all participants will be required 
to refrain from lying down (except when required for ECG measurements), eating, and 
drinking beverages other than water during the first 4 hours after dosing.
Administration of study intervention(s) will be performed by an appropriately qualified and 
trained member of the study staff as allowed by local, state, and institutional guidance.
Following administration of study intervention(s), participants will be observed for the
complete period/study by an appropriately qualified and trained member of the study staff. 
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Appropriate medication and other supportive measures for management of a medical 
emergency will be available in accordance with local guidelines and institutional guidelines.
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.
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 the 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. See the IPM for storage conditions of the study intervention once 
reconstituted.
6.
Study interventions should be stored in their original containers and in accordance with 
the labels. Refer to DAI/IPM for cap mini tablets mixed with 
applesauce/yogurt/chocolate pudding/water.
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.
8.
Further guidance and information for the final disposition of unused study interventions 
are provided in the PCRU’s local/site procedures. 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.
9.
Upon identification of a product complaint, notify the sponsor within 1 business day of 
discovery as described in the IPM.
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6.2.1. Preparation and Dispensing
Within this protocol, preparation refers to the investigator site activities performed to make 
the study intervention ready for administration or dispensing to the participant by qualified 
staff. Dispensing is defined as the provision of study intervention, concomitant treatments, 
and accompanying information by qualified staff member(s) to a healthcare provider, 
participant, in accordance with this protocol. Local health authority regulations or 
investigator site guidelines may use alternative terms for these activities.
Etrasimod clinical IR tablets and mini tablets will be prepared at the CRU in the individual 
dosing containers by 2 operators, 1 of whom is an appropriately qualified pharmacist. 
Prepared doses will be provided in unit dose containers and labeled in accordance with Pfizer 
regulations and the clinical site’s labeling requirements. 
Study intervention with soft foods should be prepared by 2 operators, 1 of whom is a 
pharmacist. Detailed instructions on the dose preparation for administration will be provided 
in a separate IPM. Prepared doses will be provided in unit dose containers and labeled in 
accordance with Pfizer regulations and investigator site’s labelling requirement.
Dispensing will be performed in CRU by an appropriately qualified and experienced member 
of the study staff (eg, physician, nurse, physician’s assistant, nurse practitioner, pharmacy 
assistant/technician, or pharmacist) as allowed by local, state, and institutional guidance.
Only qualified personnel who are familiar with procedures that minimize undue exposure to 
themselves and to the environment should undertake the preparation, handling, and safe 
disposal of study interventions.
6.3. Assignment to Study Intervention
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled.
The investigator will assign participant numbers to the participants as they are screened for 
the study. Pfizer will provide a randomization schedule to the investigator and, in accordance 
with the randomization numbers, the participant will receive the study treatment regimen 
assigned to the corresponding randomization number.
6.4. Blinding
This is an open-label study. 
6.5. Study Intervention Compliance
When the individual dose for a participant is prepared from a bulk supply, the preparation of 
the dose will be confirmed by a second qualified member of the study site staff.
When participants are dosed, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered will be recorded in the source documents and recorded in the CRF. The dose of 
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study intervention and study participant identification will be confirmed at the time of dosing 
by a member of the study site staff. Study site personnel will examine each participant’s 
mouth to ensure that the study intervention was ingested.
A record of the number of clinical IR tablets and mini 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.
6.6. Dose Modification
Not applicable.
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.
6.8. Treatment of Overdose
For this study, any dose of etrasimod greater than 2 mg within a 24-hour time period will be 
considered an overdose.
There is no specific treatment for an overdose.
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.
5.
Obtain a blood sample for PK analysis within 7 days from the date of the last dose 
of study intervention if requested by the study medical monitor (determined on a 
case-by-case basis).
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the study medical monitor as needed based on the clinical evaluation of the 
participant.
6.9. Prior and Concomitant Therapy
Use of prescription or nonprescription drugs and dietary and herbal supplements are 
prohibited within 7 days or 5 half-lives (whichever is longer) prior to the first dose of study 
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intervention. Limited use of nonprescription medications that are not believed to affect 
participant safety or the overall results of the study may be permitted on a case-by-case basis 
following approval by the sponsor. Acetaminophen/paracetamol may be used at doses of 
≤2 g/day.
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4). Postmenopausal hormonal therapy is 
allowed.
All concomitant treatments taken during the study must be recorded with indication, daily 
dose, and start and stop dates of administration. All participants will be questioned about 
concomitant treatment at each clinic visit.
Treatments taken within 28 days before the first dose of study intervention will be 
documented as a prior treatment. Treatments taken after the first dose of study intervention 
will be documented as concomitant treatments.
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 event

Pregnancy

Withdrawal by participant
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, posttreatment study follow-up, 
and/or future collection of additional information.
7.1.1. Liver Injury 
A participant who meets the criteria as described in Appendix 5 will be withdrawn from 
study intervention. 
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7.1.2. ECG Changes
Participants must permanently discontinue study intervention if suspected intolerance
associated with first dose cardiac effects (Section 2.3.1).
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 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 treatment 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 Medical Monitor.
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.
7.1.3. Pregnancy
Pregnancy tests are conducted as per SoA and dosing of study intervention will occur only in 
the presence of a negative pregnancy test. If a participant is confirmed to be pregnant (See 
Section 8.3.6) during study, further dosing with study intervention will be discontinued 
immediately and permanently. 
7.1.4. 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. 
It is recommended that the investigator discuss temporary or permanent discontinuation of 
study intervention with the study medical monitor. 
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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 the study include the following:

Refused further follow-up

Lost to follow-up

Death

Study terminated by sponsor

Adverse event
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.
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.
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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 return to the clinic for 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 follow-up, 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 and Baseline 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.
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.
Participants will be screened within 28 days prior to administration of the study intervention
to confirm that they meet the study population criteria for the study. If the time between 
screening and dosing exceeds 28 days as a result of unexpected delays (eg, delayed drug 
shipment), then participants do not require rescreening if the laboratory results obtained prior 
to first dose administration meet eligibility criteria.
A participant who qualified for this protocol but did not enroll from an earlier cohort/group
may be used in a subsequent cohort/group without rescreening, provided laboratory results 
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obtained prior to the first dose administration meet eligibility criteria for this study. In 
addition, other clinical assessments or specimen collections, eg, retained research samples, 
may not need to be repeated, as appropriate.
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.
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
382 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.
To prepare for study participation, participants will be instructed on the information in the 
Lifestyle Considerations and Prior and Concomitant Therapy sections of the protocol.
8.1.1. Baseline Procedures
All procedures listed in the SoA must be conducted at this visit.
SoA must be conducted at the screening visit.
8.2. Efficacy Assessments
Efficacy parameters are not evaluated in this study.
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, head, ears, eyes, nose, mouth, 
skin, heart and lung examinations, lymph nodes, and gastrointestinal, musculoskeletal, and 
neurological systems. 
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A brief physical examination will include, at a minimum, assessments of general appearance, 
the respiratory and cardiovascular systems, and participant reported symptoms.
Complete physical examination must either be conducted at screening or upon admission on 
Day -1 only; targeted physical examination may be performed as appropriate at the 
investigator’s discretion if there are findings during the previous examination, new/open 
adverse events.
Physical examinations may be conducted by a physician, trained physician’s assistant, or 
nurse practitioner as acceptable according to local regulation. 
Height and weight will also be measured and recorded as per the SoA. For measuring weight, 
a scale with appropriate range and resolution is used and must be placed on a stable, flat 
surface. Participants must remove shoes, bulky layers of clothing, and jackets so that only 
light clothing remains. They must also remove the contents of their pockets and remain still 
during measurement of weight. 
Physical examination findings collected during the study will be considered source record
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
Vital signs will be collected at times specified in the SoA section of this protocol. ECG will 
be taken first followed by vital signs.
8.3.2.1. Blood Pressure and Pulse Rate
Supine BP will be measured with the participant’s arm supported at the level of the heart, and 
recorded to the nearest mm Hg after approximately 5 minutes of rest. The same arm 
(preferably the dominant arm) will be used throughout the study. Participants should be 
instructed not to speak during measurements.
The same properly sized and calibrated BP cuff will be used to measure BP each time. The 
use of an automated device for measuring BP and pulse rate is acceptable; however, when 
done manually, pulse rate will be measured in the brachial/radial artery for at least 
30 seconds. When the timing of these measurements coincides with a blood collection, BP 
and pulse rate should be obtained prior to the nominal time of the blood collection.
Additional collection times, or changes to collection times, of BP and pulse rate will be 
permitted, as necessary, to ensure appropriate collection of safety data.
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.
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8.3.2.2. Temperature
Temperature will be measured orally. No eating, drinking, or smoking is allowed for 
15 minutes prior to the measurement.
8.3.3. Electrocardiograms
Standard 12-lead ECGs will be collected at times specified in the SoA section of this
protocol using an ECG system that automatically calculates the HR and measures PR, QT, 
QTcF, and QRS intervals. All scheduled ECGs should be performed after the participant has 
rested quietly in a supine position or in the most recumbent position possible for at least 
5 minutes.
The pre-etrasimod dose 12-lead ECGs will be done in triplicate. Triplicate 12-lead ECGs will 
be obtained approximately 2 to 4 minutes apart; the average of the triplicate ECG 
measurements collected pre-etrasimod dose on Day 1 of each period will serve as each 
participant’s baseline QTcF value. 
To ensure safety of the participants, a qualified individual at the investigator site will make 
comparisons to baseline measurements from the current period. Additional ECG monitoring 
will occur if a) the mean value from the triplicate measurements for any postdose QTcF
interval remains ≥60 ms from the baseline and is >450 ms; or b) an absolute QTcF value is 
≥500 ms for any scheduled ECG for greater than four hours (or sooner, at the discretion of 
the investigator); or c) QTcF values get progressively longer. If any of these conditions 
occurs, then a single ECG measurement must be repeated at least hourly until QTcF values 
from 2 successive ECGs fall below the threshold value that triggered the repeat 
measurement.
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 7.1.2 for guidance on QTcF changes management.
ECG values of potential clinical concern are listed in Appendix 7.
8.3.4. 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 
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the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant’s condition.
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 Appendix 5 for suggested actions and follow-up assessments in the event of potential 
DILI.
See Appendix 6 for instructions for laboratory testing to monitor kidney function and 
reporting laboratory test abnormalities.
Participants may undergo random urine drug testing at the discretion of the investigator.
Drug testing conducted prior to dosing must be negative for participants to receive study 
intervention. 
8.3.5. COVID-19 Specific Assessments
Participants will be tested for COVID-19 infection by PCR according to local procedure.
8.3.6. Pregnancy Testing
A urine or 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 
starting 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.
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).
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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 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 28 calendar days after the last 
administration of the study intervention.
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 completed the study, 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 
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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.
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 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.
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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 
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 or skin contact.
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
A male family member or healthcare provider who has been exposed to the study 
intervention by ingestion 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 using the CT SAE Report Form and 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 28 days after the last dose.

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 
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 
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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 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 
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
Not applicable.
8.4.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Not applicable.
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8.4.8. Adverse Events of Special Interest
Not applicable.
8.4.8.1. Lack of Efficacy
This section is not applicable because efficacy is not expected in the study population.
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.
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.

The administration of expired study intervention;

The administration of an incorrect study intervention;

The administration of an incorrect dosage;

The administration of study intervention that has undergone temperature excursion 
from the specified storage range, unless it is determined by the sponsor that the 
study intervention under question is acceptable for use.
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 serious and nonserious AE(s) are recorded on the AE page of the 
CRF.
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In the event of a medication dosing error, the sponsor should be notified within 24 hours.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.5. Pharmacokinetics 
Blood samples of approximately 4 mL, to provide approximately 1.5 mL of plasma, will be 
collected for measurement of plasma concentrations of etrasimod as specified in the SoA.
Instructions for the collection and handling of biological samples will be provided in the 
laboratory manual or by the sponsor. The actual date and time (24-hour clock time) of each 
sample will be recorded.
The actual times may change, but the number of samples will remain the same. All efforts 
will be made to obtain the samples at the exact nominal time relative to dosing. Collection of 
samples up to and including 10 hours after dose administration that are obtained within 
10% of the nominal time relative to dosing (eg, within 6 minutes of a 60-minute sample) will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. Collection of samples more than 10 hours after dose
administration that are obtained ≤1 hour away from the nominal time relative to dosing will 
not be captured as a protocol deviation, as long as the exact time of the collection is noted on 
the source document and the CRF. This protocol deviation window does not apply to samples 
to be collected more than 10 hours after dose administration at outpatient/follow-up visits 
with visit windows.
Samples will be used to evaluate the PK of etrasimod. Samples collected for analyses of 
etrasimod plasma concentration may also be used to evaluate safety or efficacy aspects 
related to concerns arising during or after the study, for protein binding, metabolite 
identification and/or evaluation of the bioanalytical method, or for other internal exploratory 
purposes. The exploratory results may not be reported in the CSR.
Genetic analyses will not be performed on these PK samples.
Samples collected for measurement of plasma concentrations of etrasimod will be analyzed 
using a validated analytical method in compliance with applicable SOPs.
The PK samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity. Any deviations from the PK sample 
handling procedure (eg, sample collection and processing steps, interim storage or shipping 
conditions), including any actions taken, must be documented and reported to the sponsor. 
On a case-by-case basis, the sponsor may make a determination as to whether sample 
integrity has been compromised.
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol deviation. The IRB/EC will be 
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informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICD.
Additional blood samples of approximately 0.5 mL using a micro sampling device (Tasso)
will be collected, to provide approximately 0.25 mL serum into appropriately labeled tubes 
for measurement of etrasimod at selected timepoints as specified in the SoA.
The “Tasso device” is an integrated capillary blood collection device. This part of the study 
is designed to validate etrasimod PK concentrations in capillary blood collected using the 
Tasso device against PK samples collected from traditional venous blood samples. Findings 
from the validation may enable patient-centric blood sampling using this innovative device in 
future etrasimod pediatric clinical studies.
Blood samples from capillary blood vessels, collected using the Tasso device, should be
timed as close as possible to the collection of etrasimod blood samples. The Tasso device
should be attached to the upper arm. Details for collection and handling of the samples will
be provided in the laboratory manual.
The blood samples collected using Tasso device will be used for internal exploratory
purposes for comparing the etrasimod concentrations between venous and capillary blood.
The results from this comparison will be documented in a separate internal bioanalytical
report and will not be included in the CSR.
8.6. Genetics
8.6.1. Specified Genetics
Specified genetic analyses are not evaluated in this study.
8.6.2. Retained Research Samples for Genetics
Retained Research Samples for Genetics are not collected in this study.
8.7. Biomarkers
8.7.1. Safety Biomarker Sample
A 10-mL blood sample (Prep B2) for serum will be collected as indicated in the SoA for 
safety biomarker work by the Innovative Medicines Initiative (IMI) Consortium. Biomarker 
data may be generated to increase understanding of safety events associated with study 
interventions.
8.8. Immunogenicity Assessments
Immunogenicity assessments are not included in this study.
8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
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8.10. Palatability Assessments
Palatability assessment of the etrasimod mini tablets will be conducted in every period for 
Treatments B, C, D, E with the aid of a questionnaire (Appendix 9). The palatability
assessment questionnaire will be administered to participants by trained staff using a colored 
copy of the questionnaire. After study intervention administration, participants will be asked 
to rate the mouth feel, bitterness, tongue/mouth burn, throat burn, and overall liking. The 
participants will rate the above within 1 minute (immediately) after dosing, before drinking 
water that is given as part of dosing, and at 5 minutes, 10 minutes, 20 minutes after dosing is 
fully completed.
See Appendix 9 for the details about the palatability assessment questionnaire.
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 or their analyses will also be reflected in a 
protocol amendment.
9.1. Statistical Hypotheses
No statistical hypothesis will be tested in this study.
9.2. Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Participant Analysis Set
Description
Safety Analysis Set
All participants who take at least 1 dose of study 
intervention. Participants will be analyzed according to the 
product they actually received.
PK Concentration Set
All participants who take at least 1 dose of study 
intervention and in whom at least 1 concentration value is 
reported.
PK Parameter Set
All participants who take at least 1 dose of study 
intervention and in whom at least 1 of the PK parameters of 
interest are reported.
9.3. Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in 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.
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9.3.1. Efficacy Analyses
An efficacy analysis is not applicable to this study. 
9.3.2. Safety Analyses
All safety analyses will be performed on the safety population.
AEs, ECGs, BP, pulse rate, and safety laboratory data will be reviewed and summarized on 
an ongoing basis during the study to evaluate the safety of participants. Any clinical 
laboratory, ECG, BP, and pulse rate abnormalities of potential clinical concern will be 
described. Safety data will be presented in tabular and/or graphical format and summarized 
descriptively, where appropriate.
Medical history and physical examination information, as applicable, collected during the 
course of the study, will be considered source data and will not be required to be reported, 
unless otherwise noted. However, any untoward findings identified on physical and/or 
neurological examinations conducted during the active collection period will be captured as 
AEs, if those findings meet the definition of an AE (Appendix 3). Data collected at screening 
that are used for inclusion/exclusion criteria, such as laboratory data, ECGs, and vital signs, 
will be considered source data, and will not be required to be reported, unless otherwise 
noted. Demographic data collected at screening will be reported.
9.3.3. Pharmacokinetic Analyses
Plasma PK parameters of etrasimod will be derived (as data permit) from the 
concentration-time data using standard noncompartmental methods as outlined in the Table 3
below. Actual PK sampling times will be used in the derivation of PK parameters. In the case 
that actual PK sampling times are not available, nominal PK sampling time will be used in 
the derivation of PK parameters. 
Table 3.
Plasma Etrasimod PK Parameters Definitions
Parameter
Definition
Method of Determination
AUCinf
Area under the concentration-time curve from 
time zero extrapolated to infinity
AUClast + (Clast*/kel),
where Clast* is the predicted plasma 
concentration at the last quantifiable 
time point from the log-linear 
regression analysis
AUClast
Area under the plasma concentration-time 
profile from time zero to the time of the last 
quantifiable concentration (Clast)
Linear/Log trapezoidal method.
Cmax
Maximum observed concentration
Observed directly from data
Tmax
Time for Cmax
Observed directly from data as time 
of first occurrence
t½
Terminal half-life
Loge(2)/kel,
where kel is the terminal phase rate 
constant calculated by a linear 
regression of the loglinear 
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Table 3.
Plasma Etrasimod PK Parameters Definitions
Parameter
Definition
Method of Determination
concentration-time curve. Only those 
data points judged to describe the 
terminal loglinear decline will be used 
in the regression.
CL/F
Apparent clearance
Dose/AUCinf
Vz/F
Apparent volume of distribution
Dose/(AUCinf • kel)
PK parameters will be summarized descriptively by treatment, in accordance with Pfizer data 
standards. Plasma concentrations will be listed and summarized descriptively by nominal PK 
sampling time and treatment. Individual participant and median profiles of the plasma 
concentration-time data will be plotted by treatment using actual and nominal times, 
respectively. Median profiles will be presented on both linear-linear and log-linear scales.
Natural log transformed AUCinf, AUClast and Cmax will be analyzed using a mixed effect 
model with sequence, period and treatment as fixed effects and participant within the 
sequence as a random effect. Estimates of the adjusted mean differences (Test-Reference)
and corresponding 90% CIs will be obtained from the model. The adjusted mean differences 
and 90% CIs for the differences will be exponentiated to provide estimates of the ratio of 
adjusted geometric means (Test/Reference) and 90% CI for the ratios. Treatment A 
(etrasimod 2 mg clinical IR tablets under fasted conditions) will be the Reference treatment 
while Treatment B (etrasimod 2 mg mini tablets mixed with applesauce under fasted 
conditions), Treatment C (etrasimod 2 mg mini tablets mixed with chocolate pudding under 
fasted conditions), and Treatment D (etrasimod 2 mg mini tablets mixed with water under 
fasted conditions) will be the Test treatments.
Natural log transformed AUCinf, AUClast and Cmax will be analyzed using a mixed effect 
model with sequence and treatment as fixed effects and participant within the sequence as a 
random effect. Treatment A (etrasimod 2 mg clinical IR tablets under fasted conditions) will 
be the Reference treatment while Treatment E (etrasimod 2 mg mini tablets mixed with 
yogurt under fasted conditions) will be the Test treatment.
9.3.4. Palatability Assessment Analyses
The data used in the palatability assessment analysis will be transcribed and rescaled to a 
score from 0 to 100 from the raw measurements on the palatability questionnaire. The 
sensory attributes (mouth feel, bitterness, tongue/mouth burn, throat burn, and overall liking) 
from the palatability assessment questionnaire (Appendix 9) for each treatment will be listed 
and descriptively summarized by collection time. Radar plots for each time point, 
summarizing all attributes, will be generated.
9.3.5. Micro Sampling and Venous Sampling
Etrasimod concentration at sampling time points, Cmax and AUC0-24 from paired samples 
obtained via micro sampling and venous sampling will be compared. Individual participant 
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differences and % differences of concentrations by PK sampling time, Cmax and AUC0-24 will 
be listed and summarized descriptively. 
9.4. Interim Analyses
No formal interim analysis will be conducted for this study.
9.5. Sample Size Determination
A sample size of 16 participants will provide adequate precision to estimate the rBA of 
etrasimod. The width of 90% confidence interval for different estimated effects, with 80% 
coverage probability, is presented in the Table 4.
Table 4.
Expected Width of 90% Confidence Interval for Different Possible 
Estimated Effects and Parameters of Interest
Parameter
Estimated Effect
(100*Test/Reference)
90% CI
CI Width
AUC
85%
80.96%
89.25%
8.29%
90%
85.72%
94.50%
8.78%
95%
90.48%
99.75%
9.27%
100%
95.24%
105.00%
9.75%
105%
100.00%
110.25%
10.24%
110%
104.77%
115.50%
10.73%
115%
109.53%
120.74%
11.22%
Cmax
85%
79.17%
91.26%
12.09%
90%
83.83%
96.63%
12.80%
95%
88.48%
102.00%
13.51%
100%
93.14%
107.36%
14.22%
105%
97.80%
112.73%
14.94%
110%
102.45%
118.10%
15.65%
115%
107.11%
123.47%
16.36%
These estimates are based on the assumption that within-participant standard deviations are 
0.064 and 0.0933 for lnAUCinf and lnCmax, respectively, as obtained from studies APD334-007 
and APD334-114. 
Participants who withdraw from the study or whose PK samples are determined to be 
non-analyzable may be replaced at the discretion of the investigator upon consultation with 
the sponsor.
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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 and answer all questions regarding the 
study. The participant 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 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 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 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.
The participant 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 is fully informed about their
right to access and correct their personal data and to withdraw consent for the processing of 
their personal data.
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 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.
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A copy of the ICD(s) must be provided to the participant.
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 SOPs on how to respond in the event of unauthorized access, use, or 
disclosure of sponsor information or systems.
10.1.5. Committees Structure
10.1.5.1. Data Monitoring Committee 
This study will not use an E-DMC.
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.
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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 
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 
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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.
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.
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.
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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 a source document and its origin can be found in the Source 
Document Locator, which is maintained by the Pfizer CRU.
Description of the use of the computerized system is documented in the Data Management 
Plan, which is maintained by the Pfizer CRU.
The investigator must maintain accurate documentation (source record) 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
There may be instances when copies of medical records for certain cases are requested by 
Pfizer Safety, 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).
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
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.
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. 
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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, subject 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 
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.
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 CTMS.
To facilitate access to their investigator and the sponsor’s MQI for study-related medical 
questions or problems from nonstudy 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, and (c) site 
emergency phone number active 24 hours/day, 7 days per week.
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. 
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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 5.
Protocol-Required Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
Platelet count
WBC count
Total neutrophils (Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
Urea/BUN and creatinine
eGFR (CKD-EPI [serum 
creatinine based])
Glucose (fasting)
Calcium
Sodium
Potassium
Chloride
Total CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Uric acid
Albumin
Total protein
Local dipstick:
Ph
Glucose (qual)
Protein (qual)
Blood (qual)
Ketones
Nitrites
Leukocyte esterase
Laboratory:
Microscopy and 
culturea

Pregnancy test (β-Hcg)d

Urine drug screeningc
At screening:

FSHb

HbsAge

HbcAbe

HCVAbe

HIV

QuantiFERON- TB Gold 
Testf
a.
Only if UTI is suspected and urine dipstick is positive for nitrites or leukocyte esterase or both.
b.
For confirmation of postmenopausal status only in females <60 years old and not using hormonal or 
HRT only.
c.
The minimum requirement for drug screening includes cocaine, THC, opiates/opioids, benzodiazepines, 
and amphetamines (others are site and study-specific).
d.
Local urine testing will be standard for the protocol unless serum testing is required by local regulation 
or IRB/EC. See SoA for collection times.
e.
If HbsAg is negative and HbcAb is positive, HbsAb should be evaluated.
f.
Complete at screening.  Previous testing for QuantiFERON TB Gold Test will be accepted if completed 
within 12 weeks prior to screening. Otherwise, the testing should be completed at screening and results 
available prior to Day 1.
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.
Any remaining serum/plasma from samples collected for clinical safety laboratory 
measurements at baseline and at all times after dose administration may be retained and 
stored for the duration of the study. Upon completion of the study, these retained safety 
samples may be used for the assessment of exploratory safety biomarkers or unexpected 
safety findings. These data will not be included in the CSR. Samples to be used for this 
purpose will be shipped to either a Pfizer-approved BBS facility or other designated 
laboratory and retained for up to 1 year following the completion of the study.
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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 non-pathogenic 
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 to Pfizer Safety throughout the active 
collection period. These requirements are delineated for 3 types of events: (1) SAEs; (2) 
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nonserious AEs; and (3) exposure to the study intervention under study during 
pregnancy or breastfeeding, and occupational exposure. 
It should be noted that the CT SAE Report Form 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 for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form 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/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 SAE) is reported to Pfizer Safety using the CT SAE Report 
Form and EDP Supplemental Form. 
** EDB is reported to Pfizer Safety using the CT SAE Report Form, 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. 

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.
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
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.

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.
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
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.

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 
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.
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
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.
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 methods to 
transmit this information to Pfizer Safety.

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
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 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 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 
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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 or oligomenorrhea) 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.
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 old 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 
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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*

Transdermal + barrier*
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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:
o
Male or female condom with or without spermicide;
o
Cervical cap, diaphragm, or sponge with spermicide;
o
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.
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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).

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, ALT, and T bili for suspected Hy’s law cases, 
additional laboratory tests should include albumin, CK, direct and indirect bilirubin, GGT, 
PT/INR, eosinophils (%), 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, total bile acids, 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]). Obtaining Screening or Baseline Scys and postbaseline reflex Scys (if confirmed 
Screat increase ≥0.3 mg/dL) makes it feasible to distinguish AKI from DICI. If Screat 
increase is confirmed after baseline, then reflex measurement of Scys is indicated (for adult 
and for pediatric participants):
ADULTS: 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
eGFR (mL/min/1.73m²)10
2021 
CKD-EPI
Screat Only
Screat
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤ 0.7
N/A
eGFR = 143 × (Screat/0.7)-0.241  ×  (0.9938)Age
Female
if > 0.7
N/A
eGFR = 143 × (Screat/0.7)-1.200  ×  (0.9938)Age
Male
if ≤ 0.9
N/A
eGFR = 142 × (Screat/0.9)-0.302  ×  (0.9938)Age
Male
if > 0.9
N/A
eGFR = 142 × (Screat/0.9)-1.200  ×  (0.9938)Age
2021 
CKD-EPI     
Screat-Scys 
Combined
Screat
(mg/dL)
Scys
(mg/L)
Recommended eGFR Equation
Female
if ≤ 0.7
if ≤ 0.8
eGFR = 130 × (Screat/0.7)-0.219  × (Scys/0.8)-0.323  ×
(0.9961)Age
Female
if ≤ 0.7
if > 0.8
eGFR = 130 × (Screat/0.7)-0.219  × (Scys/0.8)-0.778  ×
(0.9961)Age
Female
if > 0.7
if ≤ 0.8
eGFR = 130 × (Screat/0.7)-0.544  × (Scys/0.8)-0.323  ×
(0.9961)Age
Female
if > 0.7
if > 0.8
eGFR = 130 × (Screat/0.7)-0.544  × (Scys/0.8)-0.778  ×
(0.9961)Age
Male
if ≤ 0.9
if ≤ 0.8
eGFR = 135 × (Screat/0.9)-0.144  × (Scys/0.8)-0.323  ×
(0.9961)Age
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Male
if ≤ 0.9
if > 0.8
eGFR = 135 × (Screat/0.9)-0.144  × (Scys/0.8)-0.778  ×
(0.9961)Age
Male
if > 0.9
if ≤ 0.8
eGFR = 135 × (Screat/0.9)-0.544  ×  (Scys/0.8)-0.323  ×
(0.9961)Age
Male
if > 0.9
if > 0.8
eGFR = 135 × (Screat/0.9)-0.544  ×  (Scys/0.8)-0.778  ×
(0.9961)Age
10.6.3. Kidney Function Calculation Tool
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 
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 Kidney 
Disease: Improving Global Outcomes (KDIGO) criteria.
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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).

New prolongation of QTcF 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-second duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive 
ventricular complexes.
ECG Findings That May Qualify as SAEs

QTcF prolongation >500 ms.

Absolute value of QTcF > 450 ms AND QTcF change from baseline >60 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 
asystolic pauses ≥3 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 asystolic pauses of at least 5 seconds or longer. 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.
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
Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

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-second 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 major events of potential clinical concern listed above 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 is to be reported as AEs/SAEs.
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10.8. Appendix 8: Prohibited Concomitant Medications That May Result in DDI
The prohibited concomitant medications listed below should not be taken with etrasimod for 
the period of time at least equal to the required washout period listed in the table, and 
throughout the conduct of the study.  
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), if the 
overall benefit:risk assessment is not impacted or if the changes do not significantly impact 
the safety of participants or the scientific value of the trial.
This is not an all-inclusive list. Site staff should consult with the sponsor or designee with 
any questions regarding potential DDI.
Drug Category 
Drugs
Required Washout Period Requirement
CYP2C9 and 
CYP3A4
fluconazole
2 weeks 
or
5 half-lives
whichever is longer
CYP2C8, 
CYP2C9 and 
CYP3A4
Inducer
enzalutamide 
rifampicin
5 half-lives plus 14 days
For example, carbamazepine:
The average half-life of carbamazepine after 
repeat dosing is on average 15 hours, so the 
washout period is calculated as the sum of 5 half-
lives (approximately 3 days) and an additional 14 
days for a total of 17 days.
Investigators should consult the SRSD for active comparator for information regarding 
medication that is prohibited for concomitant use. 
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: Palatability Questionnaire
Etrasimod Palatability Questionnaire
1. Questionnaire should be filled out by adult participants, preferably with the assistance 
from a nurse.
2. Use colored copy of the Palatability Questionnaire.
3. Do not alter (reduce or enlarge) the original size of the Palatability Questionnaire.
4. Please collect the following background information:
Background information
Study #/Study Site
Period and Day
Participant ID (Rand ID)
Treatment
Collection Date
Collected by
Entered in PIMS by
Checked in PIMS by
Questionnaire Fully Completed (circle one)
Yes/No
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Please answer the following questions and provide a mark () on the color bar at 
1 (immediately), 5, 10 and 20 minutes after dosing. Please ensure participant has access 
to these descriptions when completing the questionnaire. 
Q1: Mouth feel – Please tell us about the mouth feel (such as grittiness, stickiness, 
waxiness) of the product you tasted.
Q2: Bitterness – Please tell us about the degree of bitterness of the product you tasted.
Q3: Tongue/mouth burn – Please tell us about the degree of tongue/mouth burn of the 
product you tasted.
Q4: Throat burn – Please tell us about the degree of throat burn of the product you 
tasted.
Q5: Overall liking – Please indicate how much you like or dislike the product you 
tasted.
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Example: How to provide a mark () on the color bar.

Good (score = 0)
Bad (score = 100)
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Within 1 minute (immediately) after dosing,
before drinking water
Collection time:
Provide a mark ( ) on the color bar
Mouth Feel
Bitterness
Tongue/Mouth 
Burn
Throat Burn
Overall Liking
Good
Bad
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5 minutes after dosing
Collection time:
Provide a mark ( ) on the color bar
Mouth Feel
Bitterness
Tongue/Mouth 
Burn
Throat Burn
Overall Liking
Good
Bad
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10 minutes after dosing
Collection time:
Provide a mark ( ) on the color bar
Mouth Feel
Bitterness
Tongue/Mouth 
Burn
Throat Burn
Overall Liking
Good
Bad
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20 minutes after dosing
Collection time:
Provide a mark ( ) on the color bar
Mouth Feel
Bitterness
Tongue/Mouth 
Burn
Throat Burn
Overall Liking
Good
Bad
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Additional feedback – After completing the “20 minute after dosing” palatability questions,
please provide any additional descriptive feedback in the box below regarding the taste or 
odor of the product.
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10.10. Appendix 10: Abbreviations
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
AA
alopecia areata
Abs
absolute
AD
atopic dermatitis
ADL
activity/activities of daily living
AE
adverse event
AKI
acute kidney injury
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-24
area under the plasma concentration-time curve over the last 24 h 
dosing interval
AUCinf
Area under the concentration-time curve from time zero 
extrapolated to infinity
AUClast
Area under the plasma concentration-time profile from time zero to 
the time of the last quantifiable concentration (Clast)
AV
atrioventricular
AxMP
auxiliary medicinal product
BA
bioavailability
BBS
Biospecimen Banking System
-Hcg
-human chorionic gonadotropin
BMI
body mass index
BP
blood pressure
bpm
beats per minute
BUN
blood urea nitrogen
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 Collaboration
CL/F
apparent clearance
Cmax
maximum observed concentration
CNS
cardiopulmonary nervous system
CO2
carbon dioxide (bicarbonate)
COVID-19
coronavirus disease 2019
CRF
case report form
CRO
Contract Research Organization
CRU
clinical research unit
CSR
Clinical Study Report
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Abbreviation
Term
Ctrough
predose trough concentration
CT
clinical trial
CTMS
Clinical Trial Management System
CTIS
Clinical Trial Information System
CV
cardiovascular
CYP
cytochrome P450
DAI
Dosage and Administration Instructions
DCT
data collection tool/decentralized clinical trial
DDI
drug-drug interaction 
DICI
drug-induced creatinine increase
DILI
drug-induced liver injury
EBV
Epstein-Barr virus
EC50
half maximal effective concentration
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
EoE
eosinophilic esophagitis
eSAE
electronic serious adverse event
ET
early termination
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
FSH
follicle-stimulating hormone
F/U
follow-up
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HbcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HbsAg
hepatitis B surface antigen
HCVAb
hepatitis C antibody
HDPE
high-density polyethylene
hERG
human ether-a-go-go gene
HIV
human immunodeficiency virus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure
IC50
half maximal inhibitory concentration
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Abbreviation
Term
ICD
informed consent document
ICH
International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use
ID
identification
IMI
Innovative Medicines Initiative
IMP
investigational medicinal product
IND
Investigational New Drug 
INR
international normalized ratio
IPAL
Investigational Product Accountability Log
IPM
investigational product manual
IR
immediate-release
IRB
Institutional Review Board
IV
intravenous
KDIGO
Kidney Disease Improving Global Outcomes
LBBB
left bundle branch block
LFT
liver function test
MMR
Measles, Mumps, Rubella
MQI
medically qualified individual
NDA
New Drug Application
NIMP
noninvestigational medicinal product
PCR
polymerase chain reaction
PCRU
Pfizer Clinical Research Unit
PD
pharmacodynamic(s)
PE
physical examination
PIMS
Phase 1 management system
PK
pharmacokinetic(s)
PPD
purified protein derivative
PR
pulse rate
PSSA
Pfizer's Serious Adverse Event Submission Assistant
PT
prothrombin time
PVC
premature ventricular contraction/complex
QFT-G
QuantiFERON-TB Gold
QTc
corrected QT interval
QTcF
QTc corrected using Fridericia’s formula
qual
qualitative
Rac
accumulation ratio
rBA
relative bioavailability
RBC
red blood cell
SAE
serious adverse event
SAP
Statistical Analysis Plan
Screat
serum creatinine
Scys
serum cystatin C
S1P
sphingosine 1-phosphate
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Abbreviation
Term
S1P1
S1P receptor 1
S1P1,4,5
S1P receptors 1, 4, and 5
SoA
schedule of activities
SOP
standard operating procedure
SRSD
Single Reference Safety Document
SUSAR
Suspected Unexpected Serious Adverse Reaction
t½
terminal half-life
TB
tuberculosis 
T bili
total bilirubin
TEAE
treatment emergent adverse event
THC
tetrahydrocannabinol
Tmax
time for Cmax
UC
ulcerative colitis
ULN
upper limit of normal
US
United States
UTI
urinary tract infection
Vz/F
apparent volume of distribution
WBC
white blood cell
WOCBP
woman/women of childbearing potential
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11. REFERENCES
1
Ivanova-Nikolova TT, Nikolov EN, Hansen C, et al. Muscarinic K+ channel in the
heart. Modal regulation by G protein beta gamma subunits. J Gen Physiol. 
1998;112(2):199-210.
2
Camm J, Hla T, Bakshi R, Brinkmann V. Cardiac and vascular effects of fingolimod:
mechanistic basis and clinical implications. Am Heart J. 2014;168(5):632-44.
3
Sykes DA, Riddy DM, Stamp C, et al. Investigating the molecular mechanisms through 
which FTY720-P causes persistent S1P1 receptor internalization. Br J Pharmacol. 
2014;171(21):4797-807.
4
Taylor S, Gray JR, Willis R, et al. The utility of pharmacokinetic-pharmacodynamic 
modeling in the discovery and optimization of selective S1P1 agonists. Xenobiotica. 
2012;42(7):671-86.
5
GILENYA® (fingolimod) United States Prescribing Information. Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/022527s031lbl.pdf. 
Accessed: 05 Feb 2023.
6
Mayzent® (siponimod) United States Prescribing Information. Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/209884s015lbl.pdf. 
Accessed: 05 Feb 2023.
7
Zeposia® (ozanimod) United States Prescribing Information. Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/209899s005lbl.pdf.
Accessed: 05 Feb 2023.
8
Ponvory™ (ponesimod) United States Prescribing Information. Available from:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/213498s001lbl.pdf. 
Accessed: 05 Feb 2023.
9
Cartier A, Hla T. Sphingosine 1-phosphate: Lipid signaling in pathology and therapy. 
Science. 366(6463):eaar5551.
10
Inker LA, Eneanya ND, Coresh J, et al. New Creatinine- and Cystatin C-Based 
Equations to Estimate GFR without Race. N Engl J Med. 2021;385(19):1737-49.
                                                
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