A Phase 3, Double-Blind, Placebo-Controlled, 40-Week Extension Study to Assess the Efficacy and Safety of Etrasimod in Japanese Subjects With Moderately to Severely Active Ulcerative Colitis
Phase: PHASE3
Conditions: Ulcerative Colitis
Sponsor: Pfizer

CLINICAL STUDY PROTOCOL 
Protocol number: 
APD334-308 
 
 
Protocol title: 
A Phase 3, Double-Blind, Placebo-Controlled, 40-Week Extension 
Study to Assess the Efficacy and Safety of Etrasimod in Japanese 
Subjects with Moderately to Severely Active Ulcerative Colitis 
Brief title: 
ELEVATE UC 40 JAPAN: Etrasimod Versus Placebo for the 
Treatment of Moderately to Severely Active Ulcerative Colitis in 
Japanese Subjects 
 
 
Study drug: 
Etrasimod (APD334) 
Indication: 
Ulcerative colitis 
Phase: 
3 
 
 
Sponsor name: 
Arena Pharmaceuticals, Inc.  
6154 Nancy Ridge Drive  
San Diego, CA 92121 USA 
 
 
Sponsor’s responsible 
medical officer 
MD, MHS, FACC 
 
 
 
Clinical lead: 
 PhD 
  
 
Tel: 
 
E-mail: 
 
 
 
SAE reporting: 
IQVIA Pharmacovigilance  
 
Phone: 1-800-761-6501 (access code 00-663-5111) 
Fax:  
0034-800-401163 
Email (preferred method):  
ArenaSafety@iqvia.com 
Version: 
Original 0.0, dated 15 April 2020 
Sponsor approval: 
This protocol was approved by the Sponsor’s Responsible Medical 
Officer or delegate. The electronic signature manifest is appended. 
 
Confidentiality Statement 
This document contains confidential information of Arena Pharmaceuticals, Inc. Unauthorized 
distribution, copying, or disclosure is strictly prohibited unless required by applicable law. Persons 
receiving this information must be notified that it is confidential and may not be further distributed, 
copied, or disclosed. 
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Clinical Study Protocol 
APD334-308 
Phase 3, 40-Week Treatment Study in UC (ELEVATE UC 40 JAPAN) 
Original 0.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 2 of 84 
PROTOCOL SYNOPSIS 
Sponsor: Arena Pharmaceuticals, Inc. 
Name of investigational study drug: Etrasimod (APD334) 
Protocol number: APD334-308 
Protocol title: A Phase 3, Double-Blind, Placebo-Controlled, 40-Week Extension Study to 
Assess the Efficacy and Safety of Etrasimod in Japanese Subjects with Moderately to Severely 
Active Ulcerative Colitis 
Phase: 3 
Region: Japan 
Objectives: 
Primary: 
The primary objective is to assess the efficacy of etrasimod on clinical remission in Japanese 
subjects with moderately to severely active ulcerative colitis (UC) at timepoints up to 
52 weeks of treatment (12 weeks in Study APD334-302 plus 40 weeks in Study APD334-308; 
Figure 1). 
Secondary: 
The secondary objective is to assess the efficacy of etrasimod on clinical response, 
symptomatic response and remission, endoscopic changes, corticosteroid-free remission, and 
mucosal healing in Japanese subjects with moderately to severely active UC at timepoints up 
to 52 weeks of treatment (12 weeks in Study APD334-302 plus 40 weeks in 
Study APD334-308). 
Safety: 
The safety objective is to assess the long-term safety of etrasimod in Japanese subjects with 
moderately to severely active UC after daily doses of 2 mg for up to 52 weeks (12 weeks in 
Study APD334-302 plus 40 weeks in Study APD334-308). 
 
 
 
Study design: 
This is a multicenter, double-blind, placebo-controlled extension study of APD334-302 
(12-week, randomized, double-blind, placebo-controlled induction study) to evaluate the 
efficacy and safety of etrasimod 2 mg in Japanese subjects with moderately to severely active 
UC. Study APD334-308 consists of a 40-Week Treatment Period and a 4-Week Follow-Up 
Period. 
Japanese subjects who completed the Week 12 visit of Study APD334-302 are eligible for the 
APD334-308 study. The Week 12 visit of Study APD334-302 serves as the Day 1 visit of 
Study APD334-308. Subjects will continue with the same blinded treatment assigned in 
Study APD334-302 for a total treatment duration of 52 weeks (12 weeks in 
Study APD334-302 plus 40 weeks in Study APD334-308). 
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Clinical Study Protocol 
APD334-308 
Phase 3, 40-Week Treatment Study in UC (ELEVATE UC 40 JAPAN) 
Original 0.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 3 of 84 
End of 40-Week Double-Blind Treatment Period 
Disease worsening will be monitored by Investigators through the Treatment Period. Subjects 
who either experience disease worsening or complete all study procedures at Week 52 will 
have the option to enroll into the APD334-303 open-label extension (OLE) study if they meet 
all eligibility criteria. Subjects may be eligible to enroll in the OLE study provided their 
endoscopic score (ES) is ≥ 2 and they meet one of the following entry criteria: 
• Rectal bleeding (RB) subscore ≥ 2 at 2 timepoints at least 7 days and no more than 
14 days apart 
• RB + stool frequency (SF) subscore ≥ 4 at 2 timepoints at least 7 days and no more 
than 14 days apart 
• RB subscore ≥ 2 or RB + SF subscores ≥ 4 (in any order) at 2 timepoints at least 7 days 
and no more than 14 days apart 
For subjects discontinuing prior to Week 52, an endoscopic evaluation is required to confirm 
eligibility for the OLE study. An endoscopy should be performed upon the appearance of UC 
symptoms but no more than 14 days after the second timepoint for entry criteria above. 
A proctosigmoidoscopy does not need to be repeated if performed within the last 4 weeks. 
Subjects who do not participate in the OLE study will have 2-Week and 4-Week Follow-Up 
visits after their last on treatment visit/Early Termination visit. 
Number of subjects (planned): 
Approximately 35 Japanese subjects are planned to be enrolled into this study. 
Eligibility criteria: 
Inclusion criteria: 
Subjects are eligible to enroll into this study if they fulfill ALL of the following: 
1. Must have completed the Week 12 visit of Study APD334-302 
2. Ability to provide written informed consent or assent (parent or legal guardian must 
provide consent for a subject < 20 years of age or as required per local regulations who 
has assented to participate in the study) and to be compliant with the schedule of 
protocol assessments. Enrollment of subjects < 20 years should be conducted only if 
acceptable according to local laws and regulations. 
3. Eligible women of childbearing potential must fulfill the following: 
a. Have a negative urine beta-human chorionic gonadotropin (β-hCG) pregnancy test 
at the Week 12 visit of Study APD334-302 
b. Not breastfeeding 
4. Females must meet either a or b of the following criteria and males must meet 
criterion c to qualify for the study: 
a. A female who is not of childbearing potential must meet 1 of the following:  
− Postmenopausal, defined as no menses for 12 months without an alternative 
medical cause 

Clinical Study Protocol 
APD334-308 
Phase 3, 40-Week Treatment Study in UC (ELEVATE UC 40 JAPAN) 
Original 0.0 
Arena Pharmaceuticals, Inc. 
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Page 4 of 84 
− Permanent sterilization procedure, such as hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy 
b. Nonpregnant female of childbearing potential must agree to using a highly effective 
contraception method during treatment and for 30 days following treatment that can 
achieve a failure rate of less than 1% per year when used consistently and correctly. 
The following are considered highly effective birth control methods: 
− Combined (estrogen and progestogen containing) oral hormonal contraception 
associated with inhibition of ovulation 
− Progestogen-only oral hormonal contraception associated with inhibition of 
ovulation 
− Intrauterine device (IUD) 
− Intrauterine hormone-releasing system 
− Bilateral tubal occlusion 
− Vasectomized partner, provided that partner is the sole sexual partner of the 
female of childbearing potential trial participant and that the vasectomized 
partner has received medical assessment of the surgical success 
− Sexual abstinence (complete sexual abstinence defined as refraining from 
heterosexual intercourse for the entire period of risk associated with study 
treatments). The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the clinical study and the preferred and usual lifestyle 
of the subject. Periodic abstinence (calendar, symptothermal, post-ovulation 
methods) is not acceptable. 
c. A male subject with a pregnant or non-pregnant female of childbearing potential 
must agree to using condoms during treatment and for 30 days following treatment 
Exclusion criteria: 
Subjects who meet any of the following exclusion criteria will not be eligible for enrollment 
into the study: 
1. If the Investigator considers the subject to be unsuitable for any reason to participate in 
the study 
Exclusions related to general health 
2. Subjects requiring partial or total colectomy during the APD334-302 study 
3. Subjects requiring treatment with prohibited concomitant medications as defined in 
Section 6.7.3 
Test product, formulation, mode of administration, and dose: 
Etrasimod, 2 mg tablets, by mouth, once daily 
Study duration: 
The overall duration of this study is expected to be approximately 2 years. 
Reference therapy, description, mode of administration: 
Placebo tablets, by mouth, once daily 

Clinical Study Protocol 
APD334-308 
Phase 3, 40-Week Treatment Study in UC (ELEVATE UC 40 JAPAN) 
Original 0.0 
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Confidential 
Page 5 of 84 
Efficacy assessments: 
Study visit labels in this protocol refer to the cumulative weeks of treatment from 
Week 0/Day 1 of Study APD334-302 (Figure 1). 
Figure 1: 
Study Visits 
Note: Weeks at the top refer to study weeks in Study APD334-308. Weeks at the bottom refer to the cumulative weeks of 
treatment starting with Study APD334-302 and continuing onto Study APD334-308. 
The modified Mayo score (MMS) and its component subscores will be used to assess efficacy. 
The MMS is a composite of 3 assessments, each rated from 0 to 3: SF, RB, and ES. The ES 
will be determined by central reading. 
Definitions: 
• Baseline: Baseline refers to the last non-missing measurement on or before the first 
dose in Study APD334-302. 
• Clinical remission: SF subscore = 0 (or = 1 with a ≥ 1-point decrease from baseline), 
RB subscore = 0, and ES ≤ 1 (excluding friability) 
• Endoscopic improvement: ES ≤ 1 (excluding friability) 
• Mucosal healing: ES ≤ 1 (excluding friability) with histologic remission measured by a 
Geboes Index score < 2.0 
• Symptomatic remission: SF subscore = 0 (or = 1 with a ≥ 1-point decrease from 
baseline) and RB subscore = 0 
Primary efficacy endpoints: 
• The proportion of subjects achieving clinical remission at Week 52 
Key secondary efficacy endpoints: 
• The proportion of subjects achieving endoscopic improvement at Week 52 
• The proportion of subjects achieving symptomatic remission at Week 52 
• The proportion of subjects, who had not been receiving corticosteroids for ≥ 12 weeks, 
achieving clinical remission at Week 52 among subjects receiving corticosteroids at 
APD334-302 study entry 
• The proportion of subjects with mucosal healing at Week 52 
• The proportion of subjects achieving clinical remission at both Week 12 of 
Study APD334-302 and Week 52 of Study APD334-308 

Clinical Study Protocol 
APD334-308 
Phase 3, 40-Week Treatment Study in UC (ELEVATE UC 40 JAPAN) 
Original 0.0 
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Confidential 
Page 6 of 84 
Pharmacokinetic assessments: 
Plasma concentrations of etrasimod and, if warranted, M3 (AR503641) and other metabolite(s) 
of interest, will be assessed from samples collected predose (trough) at Weeks 16, 20, 24, 32, 
40, 48, 52, and at the 2-Week and 4-Week Follow-Up visits. A PK sample should also be 
drawn, if possible, at the time of any serious adverse event (SAE) or adverse event leading to 
study treatment discontinuation. 
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical 
method validation purposes, stability assessments, metabolite assessments, or to assess other 
actions of etrasimod with plasma constituents. 
Other assessments: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety assessments: 
Safety will be assessed using monitoring of adverse events, clinical laboratory findings, 
12-lead electrocardiograms (ECGs), physical examinations, vital signs, pulmonary function 
tests, ophthalmoscopy, and optical coherence tomography. 
Safety endpoints: 
• Incidence and severity of adverse events 
• Incidence and severity of laboratory abnormalities, and change from baseline in 
laboratory values (to include hematology, serum chemistry, coagulation, and 
urinalysis) 
• Incidence of clinically significant vital sign abnormalities and changes from baseline 
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Clinical Study Protocol 
APD334-308 
Phase 3, 40-Week Treatment Study in UC (ELEVATE UC 40 JAPAN) 
Original 0.0 
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Confidential 
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Statistical methods: 
Sample size 
Approximately 35 Japanese subjects in the parent Study APD334-302, and those subjects may 
be eligible to enroll in Study APD334-308. 
Efficacy analysis 
The primary analysis of the proportion based efficacy endpoints will be carried out using the 
Cochran Mantel Haenszel (CMH) method, stratified by (a) naive to biologic or Janus kinase 
(JAK) inhibitor therapy at APD334-302 study entry (yes or no), (b) baseline corticosteroid use 
(yes or no), and (c) baseline disease activity (MMS: 4 to 6 or 7 to 9). Results will be expressed 
as the number of subjects in remission, remission percentages, difference in remission 
percentages, odds ratio, and associated 95% confidence intervals. 
Data from this study will be integrated with the global studies (Study APD334-301 and 
Study APD334-302) for the summaries of efficacy and safety, including the bridging analyses 
for the Japanese subjects to the global population. 
Pharmacokinetic analysis 
A descriptive summary of observed plasma concentration will be displayed by time and by 
treatment group. The Safety Set will be used to analyze plasma levels. 
Safety analysis 
All safety data will be listed and summarized by treatment group. All treatment-emergent 
adverse events will be coded using the latest version of the Medical Dictionary for Regulatory 
Activities and tabulated by System Organ Class and Preferred Term. Incidence of adverse 
events, SAEs, and adverse events leading to discontinuation will be summarized and presented 
in descending order of frequency. Associated laboratory parameters such as hepatic enzymes, 
renal function, and hematology values will be grouped and presented together. Individual 
subject values will be listed and values outside of the standard reference range will be flagged. 
Shift tables and analyses of changes from baseline will be produced. 
Full details of efficacy, safety, and PK analyses will be provided in the Statistical Analysis 
Plan (SAP). 
 

Clinical Study Protocol 
APD334-308 
Phase 3, 40-Week Treatment Study in UC (ELEVATE UC 40 JAPAN) 
Original 0.0 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................8 
LIST OF APPENDICES ................................................................................................................12 
LIST OF TABLES .........................................................................................................................12 
LIST OF FIGURES .......................................................................................................................12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................13 
1. 
INTRODUCTION ......................................................................................................16 
1.1. 
Ulcerative Colitis ........................................................................................................16 
1.2. 
Etrasimod ....................................................................................................................16 
1.3. 
Benefit/Risk Assessment ............................................................................................17 
1.4. 
Visit Labeling .............................................................................................................18 
2. 
STUDY OBJECTIVES ..............................................................................................19 
2.1. 
Primary Objective .......................................................................................................19 
2.2. 
Secondary Objective ...................................................................................................19 
2.3. 
Safety Objective ..........................................................................................................19 
 
 
3. 
INVESTIGATIONAL PLAN .....................................................................................20 
3.1. 
Summary of Study Design ..........................................................................................20 
3.2. 
Rationale for Study Design .........................................................................................20 
3.3. 
Study Duration ............................................................................................................21 
3.4. 
Independent Data Monitoring Committee ..................................................................21 
4. 
SELECTION OF STUDY POPULATION ................................................................23 
4.1. 
Inclusion Criteria ........................................................................................................23 
4.2. 
Exclusion Criteria .......................................................................................................24 
5. 
REMOVAL OF SUBJECTS FROM STUDY TREATMENT OR 
ASSESSMENT ...........................................................................................................25 
5.1. 
Discontinuation from Study Treatment ......................................................................25 
5.1.1. 
Discontinuation from Double-Blind Treatment for Disease Worsening ....................26 
5.2. 
Discontinuation from the Study ..................................................................................27 
5.3. 
Subjects “Lost to Follow-Up” Prior to Last Scheduled Visit .....................................27 
5.4. 
Premature Termination of the Study ...........................................................................27 
6. 
STUDY TREATMENTS............................................................................................29 
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Clinical Study Protocol 
APD334-308 
Phase 3, 40-Week Treatment Study in UC (ELEVATE UC 40 JAPAN) 
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6.1. 
Treatments Administered ............................................................................................29 
6.2. 
Investigational Study Treatment .................................................................................29 
6.3. 
Dosage and Administration ........................................................................................29 
6.3.1. 
Instructions for Missed Dose(s) ..................................................................................30 
6.3.2. 
Dose Interruptions ......................................................................................................30 
6.4. 
Method of Assigning Subjects to Treatment ..............................................................30 
6.5. 
Blinding ......................................................................................................................30 
6.6. 
Treatment Compliance ................................................................................................31 
6.7. 
Concomitant Therapy .................................................................................................31 
6.7.1. 
Required Concomitant Therapy ..................................................................................31 
6.7.2. 
Allowed Concomitant Therapy ...................................................................................31 
6.7.2.1. 
Permitted Medications for the Treatment of Ulcerative Colitis .................................31 
6.7.2.2. 
Corticosteroid Taper ...................................................................................................32 
6.7.3. 
Prohibited Concomitant Therapy ................................................................................32 
7. 
SUBJECT RESTRICTIONS ......................................................................................34 
8. 
STUDY TREATMENT MATERIALS AND MANAGEMENT ..............................35 
8.1. 
Packaging and Labeling ..............................................................................................35 
8.2. 
Study Treatment Storage and Handling ......................................................................35 
8.3. 
Study Treatment Preparation ......................................................................................35 
8.4. 
Study Treatment Accountability .................................................................................35 
8.5. 
Study Treatment Retention and Disposal ...................................................................35 
9. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................36 
9.1. 
General Instructions ....................................................................................................36 
9.2. 
Subject Information ....................................................................................................36 
9.2.1. 
Informed Consent .......................................................................................................36 
9.3. 
Eligibility ....................................................................................................................36 
9.4. 
Treatment Period ........................................................................................................36 
9.4.1. 
Guidance for Cardiac Monitoring Following Treatment Re-Initiation ......................37 
9.4.2. 
Enrollment in Open-Label Extension Study APD334-303 ........................................39 
9.5. 
Follow-Up Period .......................................................................................................40 
9.6. 
Pharmacokinetics ........................................................................................................40 
9.7. 
Efficacy Assessments .................................................................................................40 
9.7.1. 
Modified Mayo Score/Mayo Clinic Score ..................................................................41 

Clinical Study Protocol 
APD334-308 
Phase 3, 40-Week Treatment Study in UC (ELEVATE UC 40 JAPAN) 
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9.7.1.1. 
Endoscopy ...................................................................................................................41 
9.7.1.2. 
Endoscopic Biopsy .....................................................................................................42 
9.7.2. 
Extraintestinal Manifestations ....................................................................................42 
 
 
 
 
 
 
9.8. 
Safety ..........................................................................................................................45 
9.8.1. 
Physical Examination .................................................................................................45 
9.8.2. 
Vital Signs ..................................................................................................................45 
9.8.3. 
12-Lead Electrocardiogram ........................................................................................46 
9.8.4. 
Pulmonary Function Test ............................................................................................46 
9.8.5. 
Ophthalmoscopy and Optical Coherence Tomography ..............................................47 
9.8.6. 
Tuberculosis Questionnaire ........................................................................................47 
9.8.7. 
Clinical Laboratory Tests ...........................................................................................47 
9.8.7.1. 
Pregnancy Testing ......................................................................................................49 
9.8.7.2. 
Clinical Chemistry, Hematology, Coagulation, and Urinalysis .................................49 
9.8.8. 
Adverse Events ...........................................................................................................50 
9.8.8.1. 
Definitions ..................................................................................................................50 
9.8.8.2. 
Eliciting and Recording Adverse Events ....................................................................52 
9.8.8.3. 
Reporting Adverse Events ..........................................................................................53 
9.8.9. 
Pregnancy ...................................................................................................................55 
9.9. 
Procedures for Overdose .............................................................................................55 
10. 
PLANNED STATISTICAL METHODS ...................................................................56 
10.1. 
General Considerations ...............................................................................................56 
10.2. 
Determination of Sample Size ....................................................................................56 
10.3. 
Analysis Sets ...............................................................................................................56 
10.4. 
Missing Data ...............................................................................................................56 
10.5. 
Efficacy Endpoint Definitions ....................................................................................58 
10.5.1. 
Calculation of Modified Mayo Score Component Scores ..........................................59 
10.6. 
Primary Endpoint ........................................................................................................59 
10.7. 
Secondary Endpoints ..................................................................................................59 
10.7.1. 
Key Secondary Efficacy Endpoints ............................................................................59 
10.7.2. 
Other Secondary Efficacy Endpoints ..........................................................................59 
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Clinical Study Protocol 
APD334-308 
Phase 3, 40-Week Treatment Study in UC (ELEVATE UC 40 JAPAN) 
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10.10. 
Subgroup Analyses .....................................................................................................61 
10.11. 
Safety Endpoints .........................................................................................................62 
10.12. 
Testing Strategy ..........................................................................................................62 
10.12.1. 
Efficacy Analysis ........................................................................................................62 
10.12.2. 
Safety Analysis ...........................................................................................................62 
10.13. 
Interim Analysis ..........................................................................................................62 
11. 
ETHICAL CONSIDERATIONS................................................................................63 
11.1. 
Ethical Conduct of the Study ......................................................................................63 
11.2. 
Institutional Review Board or Independent Ethics Committee Approval ..................63 
11.3. 
Informed Consent and Assent .....................................................................................63 
11.4. 
Confidentiality ............................................................................................................64 
11.5. 
Protocol Compliance ..................................................................................................64 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................65 
12.1. 
Training of Study Site Personnel ................................................................................65 
12.2. 
Monitoring ..................................................................................................................65 
12.3. 
Audit ...........................................................................................................................65 
13. 
DATA HANDLING AND RECORD KEEPING ......................................................66 
13.1. 
Data Management .......................................................................................................66 
13.1.1. 
Case Report Forms .....................................................................................................66 
13.1.2. 
Source Documents ......................................................................................................66 
13.2. 
Study Documentation and Records Retention ............................................................66 
13.2.1. 
Clinical Study Site ......................................................................................................67 
13.2.2. 
Principal Investigator ..................................................................................................67 
13.2.3. 
Institutional Review Board (IRB) ...............................................................................67 
13.2.4. 
Sponsor and ICCC ......................................................................................................68 
13.3. 
Clinical Study Report .................................................................................................68 
13.4. 
Disclosure of Study Results ........................................................................................68 
14. 
RESPONSIBILITIES .................................................................................................69 
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Clinical Study Protocol 
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14.1. 
Investigator Responsibilities .......................................................................................69 
14.2. 
Sponsor Responsibilities .............................................................................................69 
15. 
REFERENCES ...........................................................................................................70 
16. 
APPENDICES ............................................................................................................72 
LIST OF APPENDICES 
APPENDIX 1: SCHEDULE OF ASSESSMENTS ....................................................................73 
APPENDIX 2: TUBERCULOSIS SCREENING .......................................................................76 
APPENDIX 3: MAYO CLINIC SCORE – SAMPLE ................................................................80 
APPENDIX 4: HISTOLOGICAL SCORING INDICES ...........................................................81 
APPENDIX 5: GUIDANCE FOR THE ASSESSMENT OF POTENTIAL 
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY ...........................82 
APPENDIX 6: INVESTIGATOR SIGNATURE .......................................................................83 
APPENDIX 7: SPONSOR SIGNATURE ..................................................................................84 
 
LIST OF TABLES 
Table 1: 
Study Treatment ..........................................................................................................29 
Table 2: 
Cytochrome P450 Inhibitors and Inducers .................................................................32 
Table 3: 
Procedures to be Performed During the Monitoring Period .......................................38 
Table 4: 
Discharge Criteria After Cardiac Monitoring .............................................................38 
Table 5: 
Discontinuation of Study Treatment Related to Postdose Cardiac Monitoring .........39 
Table 6: 
Clinical Laboratory Tests ...........................................................................................48 
Table 7: 
Schedule of Assessments ............................................................................................73 
 
LIST OF FIGURES 
Figure 1: 
Study Visits ...................................................................................................................5 
Figure 2: 
Study Design ...............................................................................................................20 
Figure 3: 
Progressive Multifocal Leukoencephalopathy Case Evaluation Algorithm ...............82 
 

Clinical Study Protocol 
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Phase 3, 40-Week Treatment Study in UC (ELEVATE UC 40 JAPAN) 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADL 
activities of daily living 
ADR 
adverse drug reaction 
ALC 
absolute lymphocyte count 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
5-ASA 
5-aminosalicylic acid 
AST 
aspartate aminotransferase 
AV 
atrioventricular 
AZA 
azathioprine 
β-hCG 
beta-human chorionic gonadotropin 
BP 
blood pressure 
bpm 
beats per minute 
CBC 
complete blood count 
CD 
Crohn’s disease 
CFR 
Code of Federal Regulations 
CMH 
Cochran-Mantel-Haenszel 
CMP 
clinical monitoring plan 
CRO 
contract research organization 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DLCO 
diffusing capacity of the lungs for carbon monoxide 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eDiary 
electronic diary 
EDC 
electronic data capture 
EIMs 
extraintestinal manifestations 
ES 
endoscopic score 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FEV1 
forced expiratory volume at 1 second 
FVC 
forced vital capacity 

Clinical Study Protocol 
APD334-308 
Phase 3, 40-Week Treatment Study in UC (ELEVATE UC 40 JAPAN) 
Original 0.0 
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Abbreviation 
Definition 
GCP 
Good Clinical Practice 
HRQoL 
health-related quality of life 
hs-CRP 
high-sensitivity C-reactive protein 
IB 
Investigator’s Brochure 
IBD 
inflammatory bowel disease 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICCC 
In-Country Caretaker for Clinical Trial 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IGRA 
interferon-gamma release assay 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IWRS 
Interactive Web Response System 
JAK 
Janus kinase 
MAR 
missing at random 
J-GCP 
Japan Good Clinical Practice 
MCS 
Mayo clinic score 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
modified Full Analysis Set 
MMF 
mycophenolate mofetil 
MMS 
modified Mayo score 
6-MP 
6-mercaptopurine 
NF 
National Formulary 
NRS 
numeric rating scale 
NSAID 
nonsteroidal anti-inflammatory drugs 
OCT 
optical coherence tomography 
OLE 
open-label extension 
PFT 
pulmonary function test 
PGA 
Physicians Global Assessment 
Ph. Eur. 
European Pharmacopoeia 
PK 
pharmacokinetics 
PML 
progressive multifocal leukoencephalopathy 

Clinical Study Protocol 
APD334-308 
Phase 3, 40-Week Treatment Study in UC (ELEVATE UC 40 JAPAN) 
Original 0.0 
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Abbreviation 
Definition 
PP 
Per Protocol 
QTcF 
Fridericia’s corrected QT interval 
RB 
rectal bleeding 
RHI 
Robarts Histopathology Index 
S1P 
sphingosine 1-phosphate  
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SF 
stool frequency 
SF-36 
Medical Outcomes Study 36-Item Short Form Health Survey 
SOP 
standard operating procedure 
TB 
tuberculosis 
TEAE 
treatment-emergent adverse event 
TMF 
trial master file 
TNF 
tumor necrosis factor 
TST 
tuberculin skin test 
UC 
ulcerative colitis 
UC-PRO/SS 
Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms 
ULN 
upper limit of normal 
USP 
United States Pharmacopeia 
WBC 
white blood cell 
WHO 
World Health Organization 
WPAI-UC 
Work Productivity and Activity Impairment Questionnaire – Ulcerative Colitis  
 

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1. 
INTRODUCTION 
1.1. 
Ulcerative Colitis 
Inflammatory bowel disease (IBD) describes conditions with chronic or recurring immune 
response and inflammation of the gastrointestinal tract. There are 2 major types of IBD: Crohn’s 
disease (CD) and ulcerative colitis (UC). These are chronic recurrent, remittent, or progressive 
inflammatory conditions that may affect the entire gastrointestinal tract (CD) and the colonic 
mucosa (UC), and are associated with an increased risk for colon cancer (Kaser 2010). 
Ulcerative colitis is characterized by diffuse mucosal inflammation limited to the colon and 
involves the rectum in approximately 95% of cases and may extend proximally in a symmetrical, 
circumferential, and uninterrupted pattern to involve parts or all of the large intestine (Kornbluth 
2010). Symptoms for UC can vary, depending on the location and severity of inflammation, but 
some of the most common are diarrhea, abdominal cramps, and rectal bleeding. The hallmark 
clinical symptom is bloody diarrhea often with prominent symptoms of rectal urgency and 
tenesmus (Kornbluth 2010). 
Treatment for subjects with UC is generally for symptomatic care (relief of symptoms) and 
mucosal healing and includes 5 major classes of medications: 5-aminosalicylic acid (5-ASA), 
antibiotics, corticosteroids, immunomodulators, biologic therapies (eg, tumor necrosis factor 
[TNF] inhibitors and anti-integrins) and, most recently, Janus kinase (JAK) inhibitor therapy. 
These drugs may be prescribed in a “step-up” approach, with escalation of the medical regimen 
until a response is achieved, or a “step-down” manner, with initiation of treatment with biologics 
and immunomodulators (Rowe 2017). 
An unmet medical need exists for the development of targeted therapies for the treatment of UC 
with easily administered and stable oral drugs, particularly as most patients treated with biologics 
experience inadequate responses. Moreover, many patients who receive biologics lose 
responsiveness over time, even though their initial response may have been positive (Ungar 
2016). 
1.2. 
Etrasimod 
Etrasimod (APD334) is an orally administered, selective, synthetic sphingosine 1-phosphate 
(S1P) receptor 1, 4, 5 modulator that is being developed to treat immune-mediated inflammatory 
disorders, including UC. 
The S1P1 is a cell surface expressed protein that has been shown to regulate lymphocyte 
migration out of lymphoid tissues (Brinkmann 2010). 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 (Nielsen 2017); as such, etrasimod is 
expected to potentially provide therapeutic benefit to patients with UC. A Phase 2 study with 
etrasimod in subjects with moderately to severely active UC demonstrated consistent and 
clinically meaningful improvements in endpoint measures reflecting cardinal symptoms of UC 
and objective findings of endoscopic improvement. Refer to the current edition of the 

Clinical Study Protocol 
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Investigator’s Brochure (IB) for a complete summary of the clinical and nonclinical data relevant 
to the investigational product and its study in human subjects. 
1.3. 
Benefit/Risk Assessment 
Common adverse events that have been reported with S1P receptor modulators include 
bradycardia at the first dose or atrioventricular (AV) block, macular edema, hypertension, 
headache, cough, dyspnea, back pain, influenza, and diarrhea. 
Safety and tolerability of etrasimod has been evaluated in Phase 1 studies with healthy adult 
subjects at single doses up to 5 mg and repeated doses up to 4 mg once daily. Repeated doses of 
2 mg have been evaluated in Phase 2 studies of subjects with moderately to severely active UC 
(refer to the current edition of the IB). Etrasimod was found to be safe and well tolerated in these 
studies, with no clinically significant safety concerns with respect to vital signs, 
electrocardiograms (ECGs), pulmonary function tests (PFTs), ophthalmoscopy, or clinical 
laboratory tests. Etrasimod produced a dose-dependent sustained decrease in total lymphocyte 
count, which is expected given etrasimod’s mechanism of action. Lymphocyte counts returned to 
approximately baseline levels within 7 days after the last dose. 
Detailed information regarding the known and expected benefits and risks and reasonably 
expected adverse events of etrasimod can be found in the IB. 
Based on the mechanism of action of etrasimod and prior experience with other agents acting via 
a similar mechanism, monitoring for specific safety parameters are planned for this study, which 
include: auscultation of the lungs as part of the physical exam; PFT; exclusion of subjects with 
macular edema or retinopathy, with assessment of optical coherence tomography (OCT) 
occurring throughout the study; and exclusion of subjects with certain cardiac risks, with 
assessment of vital signs in the period following dosing. 
• Auscultation of lungs will be conducted as part of the physical examination. 
• Prospective subjects with a history of macular edema or retinopathy will be excluded 
from the study. All randomized subjects will be assessed by OCT at study entry, 
periodically throughout the treatment period, and as clinically indicated any time 
during the study. 
• Subjects with certain cardiac risks will also be excluded from the study. Randomized 
subjects will be monitored in a period following dosing, and vital signs will be 
assessed for determination of the subject’s health before discharge. Subjects requiring 
follow-up monitoring will be evaluated in the clinic until cardiac variances return to 
acceptable levels. 
Based on the preclinical and clinical data that has been generated from etrasimod studies and the 
precautions outlined above, the favorable benefit/risk assessment justifies the further clinical 
development of etrasimod in subjects with moderately to severely active UC and the current 
Phase 3 study. 
The current study is a multicenter, double-blind, placebo-controlled extension study of 
Study APD334-302 (12-week, randomized, double-blind, placebo-controlled induction study) to 
evaluate the efficacy and safety of etrasimod in Japanese subjects with moderately to severely 
active UC. The study consists of a 40-Week Treatment Period and a 4-Week Follow-Up Period. 

Clinical Study Protocol 
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Subjects who complete the total 52-week treatment or subjects with worsening disease 
(Section 5.1.1) will have the opportunity to enroll into an open-label extension (OLE) study that 
will provide additional information on the long-term efficacy and safety of etrasimod. The results 
from this study will be used to support the regulatory approval of etrasimod for the treatment of 
Japanese patients with UC. 
1.4. 
Visit Labeling 
Study APD334-308 is a 40-week extension study for Japanese subjects who completed 
Study APD334-302 (12-week, randomized, double-blind, placebo-controlled induction study). 
Subjects will maintain the same blinded treatment assignment as in Study APD334-302. The 
total duration of treatment for subjects who complete this study is 52 weeks. 
To maintain consistency with global Study APD334-301 (52-week, randomized, double-blind, 
placebo-controlled study), visit labels in this protocol will represent the cumulative treatment 
duration since first dose in Study APD334-302. The Week 12 visit in Study APD334-302 is the 
first visit in this protocol and is labeled as Week 12 (Figure 1). 

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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objective 
The primary objective is to assess the efficacy of etrasimod on clinical remission in Japanese 
subjects with moderately to severely active UC at timepoints up to 52 weeks of treatment 
(12 weeks in Study APD334-302 plus 40 weeks in Study APD334-308). 
2.2. 
Secondary Objective 
The secondary objective is to assess the efficacy of etrasimod on clinical response, symptomatic 
response and remission, endoscopic changes, corticosteroid-free remission, and mucosal healing 
in Japanese subjects with moderately to severely active UC at timepoints up to 52 weeks of 
treatment (12 weeks in Study APD334-302 plus 40 weeks in Study APD334-308). 
2.3. 
Safety Objective 
The safety objective is to assess the long-term safety of etrasimod in Japanese subjects with 
moderately to severely active UC after daily doses of 2 mg for up to 52 weeks (12 weeks in 
Study APD334-302 plus 40 weeks in Study APD334-308). 
 
 
 
 
CCI

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3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This is a multicenter, double-blind, placebo-controlled extension study of APD334-302 
(12-week, randomized, double-blind, placebo-controlled induction study) to evaluate the efficacy 
and safety of etrasimod 2 mg in Japanese subjects with moderately to severely active UC. The 
study consists of a 40-Week Treatment Period and a 4-Week Follow-Up Period (Figure 2). 
Japanese subjects who completed the Week 12 visit of Study APD334-302 are eligible for this 
study. The Week 12 visit of Study APD334-302 serves as the Day 1 visit of this study. Subjects 
will continue with the same blinded treatment assigned in Study APD334-302 for a total 
treatment duration of 52 weeks (12 weeks in Study APD334-302 plus 40 weeks in 
Study APD334-308). 
Disease worsening will be monitored by Investigators through the treatment period. Subjects 
who either experience disease worsening or complete all study procedures at Week 52 will have 
the option to enroll into the APD334-303 OLE study if they meet all eligibility criteria. 
Subjects who discontinue from the study and do not participate in the OLE study will have 
2-Week and 4-Week Follow-Up visits after the last on-treatment visit/Early Termination visit 
(Table 7). 
Figure 2: 
Study Design 
 
3.2. 
Rationale for Study Design 
This study is designed to evaluate the efficacy and safety of etrasimod in Japanese subjects with 
moderately to severely active UC. Subjects may continue existing nonbiologic therapy for UC 
(eg, 5-ASA, corticosteroids) per the concomitant medication and dose stabilization criteria. As 
preexisting background therapy is allowed, a placebo comparator is justified. 

Clinical Study Protocol 
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The duration of study treatment is up to 52 weeks, which includes 12 weeks in 
Study APD334-302 and 40 weeks in Study APD334-308. This 40-week study will provide 
subjects with 52 weeks of treatment exposure and enable bridging of efficacy and safety of 
Japanese subjects to the global population treated in Study APD334-301. The 2-Week and 
4-Week Follow-Up visits will provide off-treatment safety information. 
The etrasimod dose of 2 mg once daily is based on findings of previous Phase 1 and Phase 2 
studies, and in particular data from the Phase 2 APD334-003 placebo-controlled study. In the 
APD334-003 study, subjects received etrasimod 1 mg, etrasimod 2 mg, or placebo. Subjects in 
the etrasimod 2 mg group experienced a statistically significant improvement in the primary 
endpoint, the mean difference from placebo at Week 12 in the adapted Mayo score (least squares 
mean [standard error] difference: −0.99 [0.42]; p = 0.0091) compared with placebo. The 
etrasimod 2 mg group also experienced significant improvement in all secondary endpoints 
compared with the placebo group at Week 12, including improvement in the total Mayo Score 
(estimated least squares mean [standard error] difference from placebo: −1.27 [0.55]; 
p = 0.0100), and higher percentage of subjects with endoscopic improvement (41.8%, difference 
from placebo: 24.4%, p = 0.003). 
Treatment-emergent adverse events (TEAEs) in the 1 mg, 2 mg, and placebo groups were 
reported for 59.6%, 56.0%, and 50.0% of subjects, respectively; treatment-related TEAEs were 
reported for 7.7%, 10.0%, and 5.6% of subjects, respectively; serious adverse events (SAEs) 
were reported for 5.8%, 0%, and 11.1% of subjects, respectively; and TEAEs leading to 
discontinuation of study treatment were reported for 5.8%, 8.0%, and 0% of subjects, 
respectively. No subjects died during the study. Overall, the 2 mg dose demonstrated a favorable 
safety profile and was chosen as the dose for the current Phase 3 program. 
The primary endpoint of clinical remission at Week 52 as assessed using the modified Mayo 
Score (MMS) is standard, widely used, and is in accordance with the nonbinding US Food and 
Drug Administration (FDA) Draft Guidance for Industry Ulcerative Colitis: Clinical Trials 
Endpoints (FDA 2016). Other endpoints for the study are widely used and considered reliable 
measures of efficacy and safety. 
The study is powered to the primary endpoint for demonstrating a statistically significant 
difference in clinical remission between etrasimod therapy and placebo at Week 52. 
Subjects meeting predefined eligibility criteria during the treatment period will be eligible to 
enter the APD334-303 OLE study (Section 5.1.1) provided they meet all entry criteria. 
3.3. 
Study Duration 
The APD334-308 study consists of a 40-Week Treatment Period and a 4-Week Follow-Up 
Period. The study duration is expected to be approximately 2 years. 
The End of Study is the date when the last subject completes his/her last study visit. 
3.4. 
Independent Data Monitoring Committee 
An independent Data Monitoring Committee (DMC) will be utilized to monitor the safety of 
subjects and to enhance the integrity and credibility of the study. The roles and responsibilities of 
the DMC are described in detail in the DMC Charter. 

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The DMC will abide by the principles set forth in the FDA Guidance for Industry, Clinical Trial 
Sponsors, Establishment and Operation of Clinical Trial Data Monitoring Committees (FDA 
2006). As part of its role, the DMC will conduct reviews of accumulating safety and efficacy 
data at specified intervals during the conduct of the trial, according to the guidelines detailed in 
the DMC Charter. DMC recommendations to the study team will be communicated in a blinded 
fashion (ie, treatment assignment for individual subjects will not be shared). To ensure the 
scientific integrity of the study, members of the DMC will not be directly involved in the 
ongoing management of the study. 
In addition to members of the DMC, an independent statistician responsible for interacting with 
the DMC will have access to unblinded study data. This statistician will not be directly involved 
in the conduct of the study. 

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4. 
SELECTION OF STUDY POPULATION 
The study population consists of men, women and adolescents (hereafter referred to as men and 
women), 16 to 80 years of age, inclusive, with moderately to severely active UC. 
4.1. 
Inclusion Criteria 
Subjects must meet ALL of the following inclusion criteria to be eligible for enrollment into the 
APD334-308 study: 
1. Must have completed the Week 12 visit of Study APD334-302 
2. Ability to provide written informed consent or assent (parent or legal guardian must 
provide consent for a subject < 20 years of age or as required per local regulations who 
has assented to participate in the study) and to be compliant with the schedule of protocol 
assessments. Enrollment of subjects < 20 years should be conducted only if acceptable 
according to local laws and regulations. 
3. Eligible women of childbearing potential must fulfill the following: 
a. Have a negative urine beta-human chorionic gonadotropin (β-hCG) pregnancy test at 
the Week 12 visit of Study APD334-302 
b. Not breastfeeding 
4. Females must meet either a or b of the following criteria and males must meet criterion c 
to qualify for the study: 
a. A female who is not of childbearing potential must meet 1 of the following:  
− Postmenopausal, defined as no menses for 12 months without an alternative 
medical cause 
− Permanent sterilization procedure, such as hysterectomy, bilateral salpingectomy, 
or bilateral oophorectomy 
b. Nonpregnant female of childbearing potential must agree to using a highly effective 
contraception method during treatment and for 30 days following treatment that can 
achieve a failure rate of less than 1% per year when used consistently and correctly. 
The following are considered highly effective birth control methods: 
− Combined (estrogen and progestogen containing) oral hormonal contraception 
associated with inhibition of ovulation 
− Progestogen-only oral hormonal contraception associated with inhibition of 
ovulation 
− Intrauterine device (IUD) 
− Intrauterine hormone-releasing system 
− Bilateral tubal occlusion 
− Vasectomized partner, provided that partner is the sole sexual partner of the 
female of childbearing potential trial participant and that the vasectomized partner 
has received medical assessment of the surgical success 

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− Sexual abstinence (complete sexual abstinence defined as refraining from 
heterosexual intercourse for the entire period of risk associated with study 
treatments). The reliability of sexual abstinence needs to be evaluated in relation 
to the duration of the clinical study and the preferred and usual lifestyle of the 
subject. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is 
not acceptable. 
c. A male subject with a pregnant or nonpregnant female of childbearing potential 
partner must agree to using condoms during treatment and for 30 days following 
treatment 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following exclusion criteria will not be eligible for enrollment into 
the study: 
1. If the Investigator considers the subject to be unsuitable for any reason to participate in 
the study 
Exclusions related to general health 
2. Subjects requiring partial or total colectomy during the APD334-302 study 
3. Subjects requiring treatment with prohibited concomitant medications as defined in 
Section 6.7.3 

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5. 
REMOVAL OF SUBJECTS FROM STUDY TREATMENT OR 
ASSESSMENT 
5.1. 
Discontinuation from Study Treatment 
A subject’s double-blind treatment may be discontinued for any of the following reasons: 
• Worsening of disease (Note: If a subject discontinues double-blind treatment at any 
time, the subject may be eligible to enter the APD334-303 OLE study [Section 5.1.1]) 
• Adverse event that in the judgement of the Investigator and/or Medical Monitor the 
subject should not continue study treatment 
• Subject noncompliance with the protocol or study treatment that is considered 
significant by the Medical Monitor 
• Investigator decision 
• Withdrawal by subject or parent/guardian 
• Lack of efficacy 
• Lost to follow-up 
• Study termination by Sponsor 
• Other, non-adverse event 
A subject’s double-blind treatment must be discontinued for any of the following reasons: 
• Decline in PFT values (forced expiratory volume at 1 second [FEV1] and/or forced 
vital capacity [FVC]) below 50% of the predicted values 
• Confirmed diagnosis of clinically significant macular edema 
• Confirmed diagnosis of active tuberculosis (TB) 
• Subjects who have a cardiovascular treatment-related symptomatic event (eg, chest 
pain, dizziness, palpitations, lightheadedness, shortness of breath, or syncope) 
associated with reduction of the heart rate or associated with clinically relevant ECG 
changes at any time during the 4-hour monitoring period on the first or second day 
after re-initiation of treatment after a dose interruption of ≥ 7 days (Section 9.4.1) 
• Subjects who have not met the discharge criteria on the first day of re-initiation of 
treatment after ≥ 4 hours of extended monitoring, or on the second day of re-initiation 
by 4 hours postdose. 
• Pregnancy (Section 9.8.9) 
• Suspected drug-induced liver injury as defined by the 2009 FDA Guidance for 
Industry (FDA 2009): 
− Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 8 × upper 
limit of normal (ULN) 
− ALT or AST > 5 × ULN for > 2 weeks 

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− ALT or AST > 3 × ULN and (total bilirubin > 2 × ULN or international 
normalized ratio > 1.5) 
− ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%) 
Because transient fluctuations of ALT or AST are common, and progression to severe 
drug-induced liver injury or acute liver failure is uncommon, automatic discontinuation of study 
treatment upon finding a greater than 3 × ULN elevation of ALT or AST may be unnecessary. 
Subjects who discontinue treatment prematurely, regardless of the reason, should be instructed to 
return for an Early Termination visit within 7 days of the last study treatment administration 
(Table 7) and before initiation of any new treatments to complete all of the early termination 
assessments. If a subject discontinues due to pregnancy, they are not required to complete the 
endoscopy. If the Early Termination visit is within 4 weeks of the last sigmoidoscopy and 
biopsy, these procedures do not need to be repeated. 
If the Early Termination visit is ≥ 2 weeks of the last dose of study treatment, the 2-Week 
Follow-Up visit is not required; however, the 4-Week Follow-Up visit should be scheduled and 
completed. If the Early Termination visit is ≥ 4 weeks of the last dose of study treatment, the 
4-Week Follow-Up visit is not required unless the absolute lymphocyte count (ALC) is not 
within normal limits. 
5.1.1. 
Discontinuation from Double-Blind Treatment for Disease Worsening 
Subjects whose UC condition in the opinion of the Investigator has not improved or has 
worsened compared with baseline assessment (Week 0/Day 1 in Study APD334-302), may be 
eligible to enroll in the OLE study (Study APD334-303) provided their ES is ≥ 2 and they meet 
one of the following entry criteria during Study APD334-308: 
• Rectal bleeding (RB) subscore ≥ 2 at 2 timepoints at least 7 days and no more than 
14 days apart 
• RB + stool frequency (SF) subscore ≥ 4 at 2 timepoints at least 7 days and no more 
than 14 days apart 
• RB subscore ≥ 2 or RB + SF subscores ≥ 4 (in any order) at 2 timepoints at least 
7 days and no more than 14 days apart 
For subjects discontinuing prior to Week 52, an endoscopic evaluation is required to confirm 
eligibility for the OLE. An endoscopy should be performed upon the appearance of UC 
symptoms but no more than 14 days after the second timepoint for symptom criteria above; 
however, a proctosigmoidoscopy does not need to be repeated if performed within the last 
4 weeks. 

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5.2. 
Discontinuation from the Study 
Subjects may be discontinued from the study at any time for any of the following reasons: 
• Withdrawal by subject or parent/guardian 
• Deviation/noncompliance with the study protocol that in the judgement of the 
Investigator and/or Medical Monitor the subject should not continue study treatment 
• Study termination by Sponsor 
• Lost to follow-up 
• Death 
• Other 
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. If a subject withdraws consent, no 
further evaluation should be performed, and no additional data should be collected. The Sponsor 
may retain and continue to use any data collected before such withdrawal of consent. The 
Investigator should make a reasonable attempt to document the specific reason why consent was 
withdrawn. 
In the event that a subject fails to attend any follow-up visits, all reasonable efforts will be made 
to contact the subject to ensure that he/she is in satisfactory health. All contacts and contact 
attempts must be documented in the subject’s file. 
5.3. 
Subjects “Lost to Follow-Up” Prior to Last Scheduled Visit 
A subject will be considered lost to follow-up if he or she 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 subject fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the subject and reschedule the missed visit as soon as 
possible and counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and or should continue in 
the study. 
• Before a subject is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the subject (where possible, 3 telephone calls and 
if necessary, a certified letter to the subject’s last know mailing address or local 
equivalent methods). These contact attempts should be documented in the subject’s 
file. 
Should the subject continue to be unreachable, he/she will be considered to have withdrawn from 
the study. 
5.4. 
Premature Termination of the Study 
The Sponsor has the right to terminate this study at any time. Reasons for terminating the study 
may include, but are not limited to, the following: 

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• The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to subjects 
• Subject enrollment is unsatisfactory 
• Upon request of health authorities 
The Sponsor will notify Investigators if the study is placed on hold or if the Sponsor decides to 
discontinue the study or development program. Health authorities and Independent Ethics 
Committees (IECs)/Institutional Review Boards (IRBs) will be informed about the termination 
of the study in accordance with applicable regulations. 
The Sponsor has the right to replace a study site at any time. Reasons for replacing a study site 
may include, but are not limited to: 
• Excessively slow recruitment 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• Non-compliance with the International Council for Harmonisation (ICH) guideline 
for Good Clinical Practice (GCP) 

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6. 
STUDY TREATMENTS 
6.1. 
Treatments Administered 
During Study APD334-302, subjects were randomly assigned to 1 of 2 treatment groups 
(etrasimod or placebo) in a 2:1 ratio. Subjects will continue their treatment assignments during 
this study. Study treatment is outlined in Table 1. 
Table 1: 
Study Treatment 
Study treatment name 
Etrasimod 
Placebo 
Dosage formulation 
2 mg tablet 
Matching tablet 
Unit dose strength/dosage level 
1 tablet once daily 
1 tablet once daily 
Route of administration 
By mouth 
By mouth 
Packaging and labeling 
Study treatment will be provided in 
40-cc, induction-sealed, high-density 
polyethylene bottles with 
child-resistant screw caps. Each 
bottle will be labeled as required per 
country requirement. These bottles 
should be stored at 15 to 25°C 
(59 to 77°F). 
Study treatment will be provided in 
40-cc, induction-sealed, high-density 
polyethylene bottles with 
child-resistant screw caps. Each 
bottle will be labeled as required per 
country requirement. These bottles 
should be stored at 15 to 25°C 
(59 to 77°F). 
6.2. 
Investigational Study Treatment 
The active pharmaceutical ingredient in etrasimod tablets is APD334 L-arginine (the arginine salt 
of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-
3-yl)acetic acid), which is an off-white to light-brown solid with an aqueous solubility of 
approximately 1.38 mg/mL at pH = 8.9 and 30°C. APD334 L-arginine is manufactured, 
packaged, tested, and released in compliance with current Good Manufacturing Practice. 
The drug product is a blue, round, biconvex, plain, immediate-release, film-coated tablet. 
Etrasimod tablets are supplied in the dosage strength (based on etrasimod free acid content) of 
2 mg. 
The placebo tablet formulation is composed of excipients (microcrystalline cellulose NF, 
Ph. Eur.; mannitol USP, Ph. Eur.; sodium starch glycolate NF, Ph. Eur.; magnesium stearate NF, 
Ph. Eur.; and Opadry® II Blue 85F90951). Placebo tablets are identical in appearance to the 
active-drug tablets as described above. 
6.3. 
Dosage and Administration 
One tablet is to be taken each day (with water, either with or without food). Tablets should be 
taken at approximately the same time each day, preferably in the morning. On study visit days, 
subjects should wait and take their dose at the study site after blood draws for PK and after all 
predose assessments and procedures have been completed. The time of PK sample collection and 
last dosing prior to the PK sample should be documented in the electronic case report form 
(eCRF). 

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6.3.1. 
Instructions for Missed Dose(s) 
Subjects should be instructed that if they forget to take a dose, they can take the dose within 
8 hours of the normal dosing time; otherwise, they should take their next dose at the regular time 
on the following day. If the subject vomits the tablet, he/she should be instructed not to take 
another tablet on the same day, but to take the next dose at the regular time on the following day. 
Missed doses should be recorded in the subject’s electronic diary (eDiary). Subjects should be 
instructed to contact the Investigator if they miss more than 2 consecutive doses. 
Subjects who do not take the study treatment for ≥ 7 consecutive days must contact the 
Investigator to discuss treatment re-initiation. The subject must take the next dose of study 
treatment at the study site, and the in-clinic cardiac monitoring as outlined in Section 9.4.1 
should be performed. 
6.3.2. 
Dose Interruptions 
If the Investigator deems it necessary to withhold study treatment, temporary withholding is 
permitted for up to 6 days without obtaining prior approval from the Medical Monitor. If study 
treatment interruption ≥ 7 days is required for a medical reason, the Investigator must contact the 
Medical Monitor. 
The first-dose monitoring as outlined in Section 9.4.1 should be performed any time a subject 
misses study treatment for ≥ 7 consecutive days.  
6.4. 
Method of Assigning Subjects to Treatment 
During Study APD334-302, subjects were randomly assigned to 1 of 2 treatment groups 
(etrasimod or placebo) in a 2:1 ratio and will continue their treatment assignments in this study. 
Each subject will be dispensed blinded study treatment at study visits (Table 7) using an 
Interactive Web Response System (IWRS). 
6.5. 
Blinding 
This is a double-blind study with limited access to the randomization code. The study treatment 
and placebo tablets and bottles are identical in physical appearance. The treatment each subject 
receives will not be disclosed to the Investigator, study site staff, subject, Sponsor personnel 
involved with the conduct of the study (with the exception of the clinical supply staff and 
designated safety staff), or study vendors. The IWRS will hold treatment codes and bottle 
numbers for study treatment. 
Treatment assignments should remain blinded unless that knowledge is necessary to determine 
subject emergency medical care. In case of an emergency, the Investigator has the sole 
responsibility for determining if unblinding of a subject’s treatment assignment is warranted to 
provide appropriate medical care. Subject safety must always be the first consideration in making 
such a determination. The IWRS is programmed with blind-breaking instructions to guide the 
Investigator on how to obtain treatment assignment in the event of an emergency unblinding. 
The Investigator is requested to contact the Medical Monitor promptly in case of any treatment 
unblinding. If a subject’s treatment assignment is unblinded, the Sponsor must be notified within 
24 hours after breaking the blind. The date and reason the blind was broken must be recorded in 
the source documentation and eCRF, as applicable. 

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For Suspected, Unexpected, Serious Adverse Reactions, the Sponsor’s Pharmacovigilance 
designee responsible for managing SAEs will access the IWRS to obtain the subject’s treatment 
assignment for the purpose of regulatory reporting. 
Subjects who are unblinded may be eligible to enroll into the OLE study (Section 5.1.1). 
During the clinical conduct of Study APD334-308, the Sponsor may lock and unblind 
Study APD334-302 for regulatory filings outside of Japan. Prior to unblinding 
Study APD334-302, a data disclosure plan will be finalized which will provide such details as 
access to and disclosure of treatment information, as well as description of the structure and 
process of blinded and unblinded study teams. 
6.6. 
Treatment Compliance 
It is the Investigator’s responsibility to ensure that subjects are correctly instructed on how to 
take their study treatment and that each subject is fully compliant with their assigned regimen. 
The study treatment should be dispensed by the Investigator, or by a qualified individual under 
the Investigator’s supervision. An up-to-date treatment inventory/dispensing record must be 
maintained as described in Section 8.4. 
Subject compliance will be based on tablet count. Tablet counts < 80% or > 120% of the 
expected value between visits should be documented as a protocol deviation. 
6.7. 
Concomitant Therapy 
All concomitant medications, blood products, vitamins, holistic products, and radiotherapy 
administered will be collected from the first day of this study through the safety reporting period. 
Any medication given for a study protocol-related adverse event should be recorded from the 
time of informed consent/assent. All concomitant therapy ongoing during Study APD334-302 at 
the time of transition into Study APD334-308 will be recorded in the APD334-308 eCRF. 
6.7.1. 
Required Concomitant Therapy 
Not applicable 
6.7.2. 
Allowed Concomitant Therapy 
All medications (over-the-counter and prescribed) that are taken by subjects and all procedures 
that are performed during the study must be recorded in the eCRF. Concomitant medications for 
medical conditions other than UC are permitted as clinically indicated with the exception of 
prohibited medications and procedures (Section 6.7.3). 
6.7.2.1. 
Permitted Medications for the Treatment of Ulcerative Colitis 
Oral 5-ASA, oral corticosteroids, medicinal probiotics, and antidiarrheals are allowed according 
to the following guidelines. These products should not be started during the treatment period in 
subjects who are not already receiving them. 
• Oral 5-ASA compounds provided the dose is stable 
• Oral corticosteroid therapy (prednisone at a stable dose ≤ 20 mg/day or equivalent 
steroid) provided the dose is stable 

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• Probiotics (eg, Saccharomyces boulardii) provided the dose is stable 
• Antidiarrheals (eg, loperamide) for control of chronic diarrhea 
Subjects on existing oral corticosteroid therapy will be tapered during the treatment period 
(Section 6.7.2.2). 
6.7.2.2. 
Corticosteroid Taper 
Corticosteroids should be tapered for subjects entering this study. The recommended tapering 
schedule for oral corticosteroids is as follows: 
a. Dose > 10 mg/day prednisone or equivalent: Taper daily dose by 5 mg/week until 
receiving 10 mg/day, and then continue tapering at 2.5 mg/week until 0 mg/day 
b. Dose ≤ 10 mg/day prednisone or equivalent: Taper daily dose by 2.5 mg/week until 
0 mg/day 
For subjects who cannot tolerate the corticosteroid taper without recurrence of clinical symptoms 
of either UC or steroid withdrawal, the corticosteroid dose may be increased (up to the dose at 
study entry if required), but tapering should begin again within 2 weeks. 
6.7.3. 
Prohibited Concomitant Therapy 
The following concomitant medications are prohibited during the study: 
• Treatments for UC other than those listed in Section 6.7.2.1 (either approved or 
investigational) 
• All live vaccines, during study treatment and within 8 weeks after the last dose of 
study treatment 
• Moderate/strong inhibitors or inducers of CYP2C8 and CYP2C9 (Table 2; for 
additional information, refer to (Flockhart 2019) 
Table 2: 
Cytochrome P450 Inhibitors and Inducers 
Cytochrome P450 
Inhibitors (Strong/Moderate) 
Inducers (Strong/Moderate) 
CYP2C8 
Clopidogrel, gemfibrozil, deferasirox, 
teriflunomide 
Rifampin 
CYP2C9 
Fluconazole, amiodarone, felbamate, 
miconazole, piperine 
Aprepitant, carbamazepine, 
enzalutamide, rifampin, ritonavir 
• Inhibitors of UGT1A7 (there are currently no known UGT1A7 inhibitors) 
• Chronic nonsteroidal anti-inflammatory drugs (NSAID) use (Note: Occasional use of 
NSAIDs and acetaminophen [eg, headache, arthritis, myalgias, or menstrual cramps] 
and aspirin up to 325 mg/day is permitted) 
• Marketed biologic therapies 
• Immunosuppressive agents (eg, azathioprine [AZA], 6-mercaptopurine [6-MP], 
tofacitinib) 
• Any per rectum therapy including enemas (eg, 5-ASA, corticosteroid), other than that 
required for endoscopy preparation 

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• Cyclosporine, tacrolimus, sirolimus, methotrexate, or mycophenolate mofetil (MMF) 
• Cholestyramine or other drugs interfering with enterohepatic circulation, unless the 
treatment has been stable for > 6 months prior to screening 
• Any investigational drug other than the study treatment 
• Treatment with D-penicillamine, thalidomide, dimethyl fumarate, or pyrimidine 
synthesis inhibitors 
• Treatment with lymphocyte-trafficking inhibitors (natalizumab, fingolimod) 
• Immunosuppressive agents that deplete lymphocytes (eg, alemtuzumab, anti-CD4, 
cladribine, rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, daclizumab) 
The following concomitant procedures are prohibited during the study: 
• Major elective surgery while enrolled in this study 
• Immunoadsorption columns 
• Intravenous immunoglobulin or plasmapheresis 
• Blood donations during the study and for 14 days after the last dose of study 
treatment 
• Sperm or oocyte donations during the study and for 30 days after the last dose of 
study treatment 

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7. 
SUBJECT RESTRICTIONS 
Prohibited concomitant therapy is described in Section 6.7.3. Additionally, subjects are restricted 
from the following: 
• St John’s wort: Subjects should be instructed to abstain from consuming herbal 
remedies containing St John’s wort during the study as these may interfere with the 
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8. 
STUDY TREATMENT MATERIALS AND MANAGEMENT 
8.1. 
Packaging and Labeling 
Study treatment will be provided in 40 cc induction-sealed, high-density polyethylene bottles 
with child-resistant screw caps. Each bottle will be labeled as required per country requirement. 
8.2. 
Study Treatment Storage and Handling 
Bottles should be stored 15°C to 25°C (59°F to 77°F). 
8.3. 
Study Treatment Preparation 
Not applicable 
8.4. 
Study Treatment Accountability 
The head of the study site or the investigational product manager has overall responsibility for 
administering and dispensing investigational product. Where permissible, tasks may be delegated 
to a qualified designee (eg, a pharmacist) who is adequately trained in the protocol and who 
works under the direct supervision of the investigator. This delegation must be documented in 
the applicable study delegation of authority form. 
Subjects will record tablet self-administration daily in an eDiary that will be reviewed at each 
treatment visit by study site staff. At each visit, previously dispensed study treatment tablets will 
be collected by the Investigator or qualified individual and compliance assessed. 
The investigational product manager must maintain adequate records documenting the receipt, 
use, loss, or other disposition of the study treatment. To ensure adequate records, all drug 
supplies will be accounted for in the drug accountability inventory forms and will be monitored 
by counting of unused medication from individual bottles returned by the subject at each visit. 
8.5. 
Study Treatment Retention and Disposal 
Proteomics will be reconciled by the clinical monitor and then returned or destroyed according to 
applicable country regulations. On-site destruction following all local regulations and in 
accordance with applicable site standard operating procedures (SOPs) is permitted. Prior to any 
action being taken with study treatment, the Investigator or the investigational product manager 
will contact the Sponsor (or contract research organization [CRO]) for approval of such action. 
Final reconciliation will be performed at study completion. 

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9. 
STUDY ASSESSMENTS AND PROCEDURES 
9.1. 
General Instructions 
• Study procedures and their timing are summarized in the Schedule of Assessments 
(Table 7). Protocol waivers or exemptions are not allowed 
• Results of all protocol-required procedures must be recorded in the eCRF 
• Immediate safety concerns should be discussed with the Medical Monitor 
immediately upon occurrence or awareness to determine if the subject should 
continue or discontinue study treatment 
• Adherence to the study design requirements, including those specified in the Schedule 
of Assessments, is essential and required for study conduct 
• Study visits should be scheduled in the morning, whenever possible 
• All laboratory assessments required by the protocol will be performed by a central 
laboratory unless otherwise stated 
• On study day visits, subjects should take their study treatment at the study site after 
blood draws for PK and after all predose assessments and procedures have been 
completed 
The Investigator will maintain a screening log and enrollment log to record details of all subjects 
screened and to confirm eligibility or record reasons for screening failure, as applicable. 
9.2. 
Subject Information 
9.2.1. 
Informed Consent 
The Investigator, or a person designated by the Investigator, will obtain written informed consent 
from each subject or the subject’s legally acceptable representative, parent(s), or legal guardian 
and the subject’s assent (for a minor subject according to local regulations) when applicable, 
before any study-specific activity is performed (Section 11.3 for additional details). 
9.3. 
Eligibility 
Subject eligibility for this study will be assessed based on protocol inclusion and exclusion 
criteria (Section 4.1 and Section 4.2). 
9.4. 
Treatment Period 
At the Week 12 visit of Study APD334-302, subjects will have procedures performed according 
to the schedule for Study APD334-302. Eligibility for Study APD334-308 will be determined at 
the Week 12 visit of Study APD334-302 and subjects will be consented/assented. For female 
subjects, a negative pregnancy test as part of Week 12 APD334-302 procedures is required for 
entry into Study APD334-308. 

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After confirmation of eligibility, the 40-Week Treatment Period will begin (Table 7). A study 
visit window of ± 7 days is permitted at each visit. Study visits are labeled relative to Day 1 visit 
date in Study APD334-302 (Figure 1). 
The subscores for SF and RB are derived from the subject eDiary entries. On visits when MMS 
is calculated, these subscores are derived using the scores from the 3 most recent consecutive 
days within the 7 days prior to the day of bowel preparation (excluding the day of bowel 
preparation), averaged and rounded to the nearest integer. If 3 consecutive days are not available, 
then the average of the 2 most recent consecutive days within the 7 days will be used. 
On visits without endoscopy, the SF and RB subscores are derived using the scores from the 
3 most recent consecutive days within the 7 days prior to the date of visit, averaged and rounded 
to the nearest integer. If 3 consecutive days are not available, then the average of the 2 most 
recent consecutive days within the 7 days will be used. 
It is recommended that procedures are performed in a consistent order and at approximately the 
same time of day for each visit. Below is the recommended sequence of events: 
• Questionnaire administration 
• Adverse event review 
• Vital signs 
• 12-lead ECG (as indicated in the Schedule of Assessments; Table 7) 
• Physical examination 
• Extraintestinal manifestations (EIMs; as indicated in the Schedule of Assessments; 
Table 7) 
• PFT (as indicated in the Schedule of Assessments; Table 7) 
• OCT (as indicated in the Schedule of Assessments; Table 7) 
• Blood sample collection for laboratory tests and predose PK sampling 
9.4.1. 
Guidance for Cardiac Monitoring Following Treatment Re-Initiation 
If the dose is interrupted for ≥ 7 days, upon re-initiation of treatment subjects are to have cardiac 
monitoring performed. Predose vital signs (resting heart rate, systolic and diastolic blood 
pressure (BP), body temperature, and respiratory rate) will be used for comparison to postdose 
measurements. Re-initiation of study treatment should occur before 12:00 PM (noon). 
First Dose Cardiac Monitoring 
In-clinic cardiac monitoring, of at least 4 hours, will occur on the day of treatment re-initiation, 
and will include the following (Table 3): 
• Full vital signs (heart rate, systolic and diastolic BP, body temperature, and 
respiratory rate) and a 12-lead ECG (taken with the subject in the supine position) 
will be assessed predose 
• After the first dose of study treatment following re-initiation, subjects must remain 
under observation in the clinic for at least 4 hours 

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• At Hours 1, 2, and 3 (± 15 minutes) postdose, the heart rate and systolic and diastolic 
BP will be assessed with the subject in the sitting position, with the time recorded. If 
the subject has a heart rate < 50 bpm or if cardiovascular symptoms develop, then the 
subject should remain closely monitored, including 12-lead ECGs as clinically 
indicated, until the Hour 4 discharge assessment 
• At the Hour 4 (± 15 minutes) discharge assessment, heart rate and systolic and 
diastolic BP will be assessed with the subject in the sitting position and a 12-lead 
ECG (with the subject in the supine position) will be performed. Subjects may be 
discharged from the clinic after the 4-hour assessment if they meet the criteria 
described in Table 4. Subjects not meeting the discharge criteria will require extended 
monitoring as described below 
• Subjects experiencing a clinically relevant treatment-related symptomatic event (eg, 
chest pain, dizziness, palpitations, or syncope) associated with reduction of the heart 
rate or clinically relevant 12-lead ECG changes at any time during the 4-hour 
monitoring period must be discontinued from treatment (Table 5) 
Table 3: 
Procedures to be Performed During the Monitoring Period 
Procedure 
Predose 
Hours 1, 2, 3 Postdosea 
Hour 4 Postdosea 
Blood pressure and heart rateb 
X 
X 
X 
12-lead ECG 
X 
 
X 
Assess discharge criteria 
 
 
X 
a Measurements may be taken ± 15 minutes of the scheduled time. 
b Heart rate is based on vital signs 
ECG, electrocardiogram 
Table 4: 
Discharge Criteria After Cardiac Monitoring 
Subjects will be released from the clinical site after dosing on the first re-initiation day (but no sooner than 
4 hours postdose) when they fulfill the following discharge criteria: 
• 
Heart rate ≥ 50 bpm or no more than 10 bpm lower than the predose (baseline) value 
• 
No evidence of second-degree AV block or higher 
• 
No cardiac symptoms (eg, chest pain, dizziness, palpitations, lightheadedness, shortness of breath, 
or syncope) 
Note: Subjects should have written instructions on when to return to the clinic and a 24-hour contact phone number to call in the 
event of any new or worsened cardiovascular symptoms. 
AV, atrioventricular 
Extended Cardiac Monitoring 
Subjects who do not meet discharge criteria at 4-hours postdose will require extended cardiac 
monitoring: 
• Vital signs will be assessed hourly and 12-lead ECG may be performed, as clinically 
indicated, until the subject meets the discharge criteria (Table 4). 

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• The Medical Monitor should be contacted if the subject does not meet the discharge 
criteria after ≥ 4 hours of extended cardiac monitoring. 
• Any subject who requires extended monitoring on the first re-initiation day must 
return on the second re-initiation day for the second dose and will be re-monitored as 
on the first day. These subjects will be discontinued from study treatment if they do 
not meet the discharge criteria at 4 hours after the second re-initiation dose. Extended 
cardiac monitoring should be continued until the subject meets the discharge criteria 
(Table 4). 
• Subjects experiencing a symptomatic event (eg, chest pain, dizziness, palpitations, 
lightheadedness, shortness of breath, or syncope) at any time during the 4-hour 
monitoring period that is not associated with either a reduction in heart rate or 
clinically relevant change in 12-lead ECG, may be discharged provided they meet the 
discharge criteria (Table 4), and as deemed appropriate by the Investigator; however, 
these subjects must return on the second re-initiation day for the second dose and will 
be re-monitored as on the first day. These subjects must be discontinued from 
treatment if they do not meet the discharge criteria at 4 hours after the second 
re-initiation dose and extended cardiac monitoring should be continued until the 
subject meets the discharge criteria (Table 4). 
Study Treatment Discontinuation Related to Postdose Cardiac Monitoring 
A complete list of reasons for study treatment discontinuation is provided in Section 5.1. 
Reasons for study treatment discontinuation specific to postdose cardiac monitoring are provided 
in Table 5. The Medical Monitor should be contacted before discontinuing a subject. 
Table 5: 
Discontinuation of Study Treatment Related to Postdose Cardiac Monitoring 
Reasons for Study Treatment Discontinuation Related to Postdose Cardiac Monitoringa 
• 
Subjects who have a cardiovascular treatment-related symptomatic event (eg, chest pain, dizziness, 
palpitations, lightheadedness, shortness of breath, or syncope) associated with reduction of the heart 
rate or associated with clinically relevant 12-lead ECG changes at any time during the 4-hour 
monitoring period on the first and second re-initiation days (as applicable). 
• 
Subjects who have not met the discharge criteria on the first re-initiation day after ≥ 4 hours of 
extended monitoring, or on the second day by 4 hours postdose. 
a All treatment discontinuations should be discussed with the Medical Monitor. 
ECG, electrocardiogram 
9.4.2. 
Enrollment in Open-Label Extension Study APD334-303 
Subjects whose UC condition in the opinion of the Investigator has not improved or has 
worsened compared with baseline assessment (obtained on or before the first dose in 
Study APD334-302) may be eligible for entry into OLE Study APD334-303 (Section 5.1.1). 
Subjects who discontinue treatment prematurely should have an Early Termination visit as 
indicated in the Schedule of Assessments (Table 7). If the Early Termination visit is within 
4 weeks of the last proctosigmoidoscopy and biopsy, these procedures do not need to be 
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9.5. 
Follow-Up Period 
For subjects not participating in the OLE study, a follow-up visit will be performed at 2 and 
4 weeks after the last dose of study treatment as indicated in the Schedule of Assessments 
(Table 7). 
If the Early Termination or Study Completion visit is ≥ 2 weeks after the last dose of study 
treatment, the 2-Week Follow-Up visit is not required; however, the 4-Week Follow-Up visit 
should be scheduled and completed. If the Early Termination or Study Completion visit is 
≥ 4 weeks after the last dose of study treatment, the 4-Week Follow-Up visit is not required. 
If the absolute peripheral lymphocyte count is not within normal limits at the 4-Week Follow-Up 
visit, subjects should return for complete blood count (CBC) with differential according to local 
standard of care (captured as subsequent follow-up visit or unscheduled visit). 
All adverse events should be recorded for 30 days after last dose of study treatment 
(Section 9.8.8.2.2). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9.7. 
Efficacy Assessments 
The components of the MMS are used to calculate several of the primary, secondary, and 
 The definitions for MMS components are outlined in Section 10.5. 
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9.7.1. 
Modified Mayo Score/Mayo Clinic Score 
This study utilizes the MMS, which includes the ES, RB, and SF components of the Mayo Clinic 
score (MCS; Appendix 3) to assess UC disease activity in support of the primary and secondary 
endpoints. The total score range of the MMS is from 0 to 9, with each component ranging from 
0 to 3 (0 = normal, 1 = mild, 2 = moderate, 3 = severe). 
The MMS requires daily subject-reported RB and SF scores; therefore, the importance of daily 
recording of RB and SF by subjects in their daily eDiary should be stressed by the Investigators. 
Endoscopy will be used to visualize the mucosa to enable calculation of the ES. 
Endoscopic score (ES): The ES reports the worst appearance of the mucosa on flexible 
sigmoidoscopy or colonoscopy, on a 4-point scale (Appendix 3). Consistent with regulatory 
advice, this study excludes friability from the definition of an ES of 1. The ES will be 
determined by a blinded central reader. 
Rectal bleeding (RB): The RB subscore is a subject-reported measure. This item reports the 
most severe amount of blood passed per rectum in a 24-hour period, on a 4-point scale 
(Appendix 3). The subject will record this in their daily eDiary. The method for calculating the 
RB subscore is described in Section 9.4. 
Stool frequency (SF): The SF subscore is a subject-reported measure. This item reports the 
number of stools in a 24-hour period, relative to the normal number of stools for that subject in 
the same period, on a 4-point scale (Appendix 3). A stool is defined as a trip to the toilet when 
the subject has either a bowel movement, passage of blood alone, passage of blood and mucus, 
or passage of mucus only. The total number of stools passed in a 24-hour period will be recorded 
by the subject in a daily eDiary. The reference “normal” SF for that subject will be carried over 
from the parent Study APD334-302 and is the number of stools in a 24-hour period when the 
subject is in remission. If the subject has never achieved remission, the reported SF before initial 
onset of signs and symptoms of UC will be used as the reference SF. The method for calculating 
the SF subscore is described in Section 9.4. 
Physician’s Global Assessment (PGA): The PGA is a physician-reported measure that is a 
component of the MCS and is used in the calculation of the total Mayo Score. The PGA 
summarizes the Investigator’s assessment of the subject’s UC disease activity on a 4-point scale 
(Appendix 3). The Investigator will record the PGA in the site tablet at the specified study visits 
(Table 7). Consistent with regulatory guidance, the PGA will not be used for primary or 
secondary efficacy assessment in this study. 
9.7.1.1. 
Endoscopy 
A flexible proctosigmoidoscopy, performed with a video endoscope following cleansing 
preparation (oral or rectal cathartic), will be performed at the Week 52/Early Termination visit. 
Additional proctosigmoidoscopies may be performed to confirm disease worsening and are 
required for qualification into the OLE (Section 5.1.1). 
To ensure quality data and standardization, the same endoscopist should be used throughout the 
study wherever possible. Endoscopy images will be obtained during each endoscopy and will be 
sent for central reading and determination of the Mayo endoscopic score. A detailed image 
review charter from the central reading laboratory will outline the endoscopic procedures, video 

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recordings, and equipment. For each subject, a video recording of the entire endoscopic 
procedure will be performed using an acceptable storage medium. The endoscopic recordings 
will be read centrally in a blinded manner for mucosal lesions and endoscopic severity by a 
qualified gastroenterologist according to the image review charter. The ES will be evaluated by 
the Investigator and the central reader. The central read will be used for determination of efficacy 
endpoints; however, treatment decisions will be made by the treating Investigator. 
Repeated flexible proctosigmoidoscopy may be permitted by the Sponsor when the central reader 
indicates that the video endoscope data were acquired incorrectly or did not meet the minimal 
required quality standards. 
9.7.1.2. 
Endoscopic Biopsy 
Biopsies will be obtained at each endoscopy to support assessment of the histopathology 
endpoints and, where permitted, for the assessment of 
. Up to 4 biopsy 
pairs (ie, total 8) will be collected from the most affected area 15 to 25 cm from the anal verge. 
For subjects with proctitis only at baseline of Study APD334-302, biopsies should be taken 
8 to 10 cm from the anal verge. 
Detailed instructions for endoscopic biopsies (eg, number of biopsies, anatomic site, normal or 
inflamed mucosa) will be provided. 
Biopsy samples will be processed by a central laboratory and histopathologic scoring using the 
Geboes, Robarts, and Nancy histopathology (Appendix 4) indices will be performed by a blinded 
central histopathology reader (Geboes 2000, Marchal-Bressenot 2017, Mosli 2017). 
Biopsy specimen transfer, processing, slide preparation and digitization of slides for 
histopathologic scoring procedures will be detailed in a histopathology manual. Histopathology 
results will not be made available to study sites. 
9.7.2. 
Extraintestinal Manifestations 
During the specified full physical examinations (Table 7), specific systems (such as eyes, liver, 
skin, and joints) will be examined for EIMs for UC. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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9.8. 
Safety 
The Investigator or site staff will be responsible for detecting, documenting, and reporting events 
that meet the definition of an adverse event or SAE (Section 9.8.8.1). Adverse events will be 
coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA). 
9.8.1. 
Physical Examination 
Full and symptom-directed physical examinations will be performed according to the Schedule 
of Assessments (Table 7). 
Full physical examination includes the following assessments: 
• General inspection 
• Weight 
• Skin 
• Head/ears/eyes/nose/throat examination 
• Neck 
• Cardiac examination 
• Auscultation of lungs  
• Abdominal examination (liver, spleen, and lower abdomen) 
• Neurological assessment 
• Musculoskeletal assessment to include lower extremity edema evaluation 
Symptom-directed (focused) physical examinations should assess clinically significant changes 
from full physical examinations or any new signs or symptoms. 
9.8.2. 
Vital Signs 
Resting vital signs measurements will be performed according to the Schedule of Assessments 
(Table 7) with the subject in the sitting position. Vital signs will be measured prior to any blood 
draws that occur at the same study visit. 
Blood pressure may be measured manually or by automated device. Proper technique should be 
utilized during the measurement of BP to include the following: 
• The subject’s arm should be bare and supported at heart level. 
• An appropriately sized cuff (cuff bladder encircling at least 80% of the arm) should 
be utilized. Subject’s legs should not be crossed during the evaluation. 
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9.8.3. 
12-Lead Electrocardiogram 
All 12-lead ECGs will be performed according to Section 9.4.1 and the Schedule of Assessments 
(Table 7), and if clinically indicated at any time during the treatment period per Investigator 
discretion. All ECGs will be recorded from a 12-lead ECG machine with the subject in the 
supine position. Every attempt should be made to ensure the subject 12-lead ECG readings are 
obtained using the same machine throughout the study. 
Intervals to be provided on the confirmed read for each safety 12-lead ECG are: RR, PR, QRS, 
QT, and Fridericia’s corrected QT interval (QTcF). If an ECG shows a new onset QTc interval 
> 500 ms during the treatment period, a repeated ECG is warranted. If this abnormal finding is 
confirmed, study treatment 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 subject 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 (men) or < 470 ms (women). 
• 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. 
The Investigator will be responsible for review and interpretation of 12-lead ECGs on site and 
determining if the 12-lead ECG is normal, abnormal clinically insignificant, or abnormal 
clinically significant. Findings will be documented in the eCRF. 
All 12-lead ECGs performed should be available for collection upon request. 
9.8.4. 
Pulmonary Function Test 
Pulmonary function tests will be performed according to the Schedule of Assessments (Table 7) 
and includes FEV1 and FVC measurements. All subjects will have PFTs performed at Week 52 
or at the Early Termination visit. 
Subjects with a history of mild pulmonary disease (eg, asthma, chronic obstructive pulmonary 
disease) will have additional PFTs performed at Week 32. Subjects reporting respiratory adverse 
events such as dyspnea during the treatment period may return at an unscheduled visit for 
assessment per Investigator discretion; additional PFTs may be performed as clinically indicated. 
Subjects experiencing a decline in PFT values (FEV1 and/or FVC) below 50% of the predicted 
values must be discontinued from study treatment and scheduled for a follow-up visit. 
At sites where available, diffusing capacity of the lungs for carbon monoxide (DLCO) 
measurements will also be performed (sites where DLCO is not available should consult the 
Sponsor or Sponsor’s delegate). These tests will be performed at a qualified pulmonary function 

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laboratory or respiratory department. Please refer to the American Thoracic Society/European 
Respiratory Society guidelines for standardization of spirometry and single breath determination 
of carbon monoxide uptake in the lung (MacIntyre 2005, Miller 2005a, Miller 2005b). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
9.8.6. 
Tuberculosis Questionnaire 
For subjects who are receiving TB prophylaxis treatment, the TB questionnaire will be 
completed at every study visit (until TB prophylaxis treatment course is completed). 
9.8.7. 
Clinical Laboratory Tests 
Refer to Table 6 for the list of clinical laboratory tests to be performed and the Schedule of 
Assessments (Table 7) for timing and frequency for each test. Details regarding clinical 
laboratory sample collection, preparation, and shipment are provided in the Laboratory Manual 
by the central laboratory. 
Clinical safety laboratory tests should be completed predose. The Investigator must review the 
laboratory report, document this review, and record any clinically relevant changes occurring 
during the study in the adverse event section of the eCRF (results of the total WBC and ALC will 
be reviewed and monitored as described in Section 9.7.4). The laboratory reports must be filed 
with the source documents. Clinically significant abnormal laboratory findings are those that are 
not associated with the underlying disease, unless judged by the Investigator to be more severe 
than expected for the subject’s condition. 
All laboratory tests with values considered clinically significantly abnormal during participation 
in the study or within 30 days after the last dose of study treatment should be repeated until the 
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values return to normal or baseline or are no longer considered clinically significant by the 
Investigator or 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 
should be notified. 
• All protocol-required laboratory assessments, as defined in the Schedule of 
Assessments (Table 7) must be conducted in accordance with the Laboratory Manual. 
• If laboratory values from non-protocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in subject management or are 
considered clinically significant by the Investigator (eg, adverse event, SAE, or dose 
modification), then the results must be recorded in the eCRF. 
For guidance on monitoring subjects with notable lymphopenia, please refer to Section 9.7.4. 
Table 6: 
Clinical Laboratory Tests 
PREGNANCY TESTING 
Urine β-hCG (only for women of childbearing potential) 
CLINICAL CHEMISTRY, HEMATOLOGY, AND COAGULATION 
Hematology 
Serum Chemistry 
CD4 T-cell counta 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell count 
White blood cell count with 
differentiala 
Coagulation 
Activated partial thromboplastin 
time 
International normalized ratio 
Prothrombin time 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
C-reactive protein 
Calcium 
Chloride 
Creatinine 
Creatine kinase 
Direct bilirubin 
Gamma-glutamyl transferase 
Glucose 
Lactate dehydrogenase 
Phosphorus 
Potassium 
Sodium 
Thyroid-stimulating hormone 
Thyroxine free 
Total bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
Triiodothyronine free 
Uric acid 
TUBERCULOSIS TESTING 
QuantiFERON 
 
 
URINALYSIS 
Appearance 
Bilirubin 
Color 
Glucose 
Ketones 
 
Microscopic examination of 
sediment  
Nitrite  
Occult blood 
pH 
Protein 
Specific gravity 
Urobilinogen 

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Table 6: 
Clinical Laboratory Tests (Continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
a Total WBC, neutrophil, lymphocyte, and CD4 T-cell counts will be reviewed by an unblinded Medical Monitor who will 
provide instructions to the site investigator in the event of significant lymphopenia. Investigators will remain blinded to the 
results. Refer to Section 9.7.4 for additional details. 
b 
 
 
 
 
 
 
9.8.7.1. 
Pregnancy Testing 
Urine pregnancy tests (β-hCG) should be performed as indicated in the Schedule of Assessments 
(Table 7). A monthly home pregnancy test in non-visit months should be performed and any 
positive result immediately reported to the study site. If a home pregnancy test is unavailable, the 
pregnancy test will be performed on site during an unscheduled visit. If at any point there is a 
case of a positive urine β-hCG test, the subject will have study treatment interrupted and a serum 
sample submitted to the central laboratory for β-hCG testing. If the serum test confirms positive, 
the subject will be withdrawn from the study treatment and all the necessary follow-up 
assessments will be conducted as per Section 9.8.9. If the serum test is negative, the subject may 
resume study treatment. 
Negative pregnancy test results must be documented for all women of childbearing potential 
prior to dosing at applicable study visits. Women who are surgically sterile or who are 
postmenopausal are not considered to be of childbearing potential. Postmenopausal is defined as 
12 consecutive months with no menses without an alternative medical cause. 
9.8.7.2. 
Clinical Chemistry, Hematology, Coagulation, and Urinalysis 
Clinical chemistry, hematology, coagulation, and urinalysis parameters that will be assessed 
during the study are identified in Table 6. 
Subjects will be in a seated or supine position during blood collection. All laboratory samples 
should be collected prior to the administration of study treatment at applicable visits (refer to 
Section 9.6 for timing of blood draws for PK). 
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9.8.8. 
Adverse Events 
9.8.8.1. 
Definitions 
9.8.8.1.1. Adverse Event 
An adverse event is any untoward medical occurrence in a subject or clinical investigational 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any unfavorable and 
unintended sign, symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
Adverse events can be any of the following: 
• Unfavorable changes in general condition 
• Subjective or objective signs/symptoms 
• Concomitant disease or accidents 
• Clinically relevant adverse changes in laboratory parameters over the course of the 
study 
• Preexisting conditions that worsen in severity, increase in frequency, or have new 
signs/symptoms 
9.8.8.1.2. Serious Adverse Event 
An adverse event should be classified as an SAE if it meets one of the following criteria: 
Fatal: 
Adverse event resulted in death. 
Life-threatening: 
The adverse event placed the subject at immediate risk of death. This 
classification does not apply to an adverse event that hypothetically 
might cause death if it were more severe. 
Hospitalization: 
The adverse event required or prolonged an existing inpatient 
hospitalization. Hospitalizations for elective medical or surgical 
procedures or treatments planned before the signing of informed consent 
in the study or routine check-ups are not SAEs by this definition. 
Disabling/ 
incapacitating: 
The adverse event resulted in a persistent or significant incapacity or 
substantial disruption of the subject’s ability to conduct normal life 
functions. 
Congenital anomaly 
or birth defect: 
An adverse outcome in a child or fetus of a subject exposed to the 
molecule or study treatment regimen before conception or during 
pregnancy. 
Medically 
significant: 
The adverse event did not meet any of the above criteria but could have 
jeopardized the subject and might have required medical or surgical 
intervention to prevent one of the outcomes listed above or involves 
suspected transmission via a medicinal product of an infectious agent. 

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9.8.8.1.3. Adverse Drug Reaction 
An adverse drug reaction (ADR) in the pre-approval clinical experience with a new medicinal 
product or its new usages, particularly as the therapeutic dose(s) may not be established, is any 
noxious and unintended response to a medicinal product related to any dose. The phrase 
“responses to a medicinal product” means that a causal relationship between a medicinal product 
and an adverse event is at least a reasonable possibility (ie, the relationship cannot be ruled out). 
9.8.8.1.4. Adverse Events of Special Interest 
Based on the mechanism of action of etrasimod and prior experience with other agents acting via 
a similar mechanism, potential adverse events of special interest may be identified. In addition to 
appropriate reporting of these events as an adverse event or SAE, supplementary detailed 
information may be collected. 
If there are any signs of progressive multifocal leukoencephalopathy (PML)-related symptoms, 
the Investigator should withhold study treatment and perform appropriate diagnostic evaluation 
per local standard of care at the first signs suggestive of PML. Typical symptoms associated with 
PML are diverse, progress over days to weeks, and may include progressive weakness on one 
side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, 
and orientation leading to confusion and personality changes. The Investigator must notify the 
Medical Monitor of such an event. 
Guidance for the Assessment of Potential Progressive Multifocal Leukoencephalopathy is 
provided in Appendix 5. 
9.8.8.1.5. Severity 
The severity of each adverse event will be assessed at the onset by a nurse/or physician. When 
recording the outcome of the adverse event the maximum severity of the adverse event 
experienced will also be recorded. The severity of each adverse event will be graded according to 
the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0): 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL). 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care ADL (eg, preparing meals, shopping for groceries or 
clothes, using the telephone, managing money). 
Grade 4: 
Life-threatening consequences, urgent intervention indicated. 
Grade 5: 
Death related to adverse event. 
9.8.8.1.6. Relationship 
The Investigator (or designee) will make a determination of the causal relationship of the adverse 
event to the study drug using a 4-category system according to the following guidelines: 

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Not Related: 
The adverse event is definitely caused by the subject’s clinical state or 
the study procedure/conditions. 
Unlikely Related: 
The temporal association between the adverse event and the drug is such 
that the drug is not likely to have any reasonable association with the 
adverse event. 
Probably Related: 
The adverse event follows a reasonable temporal sequence from 
administration of the drug and cannot be reasonably explained by the 
known characteristics of the subject’s clinical state, environmental, or 
toxic factors, or other modes of therapy administered to the subject. 
Related: 
The adverse event follows a reasonable temporal sequence from 
administration of the drug, abates upon discontinuation of the drug, 
follows a known or hypothesized cause-effect relationship, and (if 
appropriate) reappears when the drug is reintroduced. 
The Investigator will use clinical judgment to determine the relationship. Alternative causes, 
such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to the study treatment administration should be considered and 
investigated. The Investigator should consult the IB and the Product Information of marketed 
products within the drug class, when applicable. For each adverse event/SAE, the Investigator 
must document in the medical notes that he/she has reviewed the adverse event/SAE and has 
provided an assessment of causality. There may be situations in which an SAE has occurred and 
the Investigator has minimal information to include in the initial report to the Sponsor; however, 
it is very important that the Investigator always make an initial assessment of causality for every 
event before the initial transmission of the SAE to the Sponsor. The Investigator may change 
his/her opinion of causality based on subsequent receipt of information and send an SAE 
follow-up report with the updated causality assessment. The causality assessment is one of the 
criteria used when determining regulatory reporting requirements. 
9.8.8.2. 
Eliciting and Recording Adverse Events 
9.8.8.2.1. Eliciting Adverse Events 
Subjects will be instructed that they may report adverse events at any time. An open-ended or 
nondirected method of questioning should be used at each study visit to elicit the reporting of 
adverse events. 
9.8.8.2.2. Recording Adverse Events 
The adverse event reporting period for safety surveillance begins when the subject is initially 
included in the study (date of first signature of informed consent) and continues up to 30 days 
after the last study treatment administration. If an adverse event is not resolved or stabilized by 
this time, the Sponsor in consultation with the Investigator will decide whether to continue to 
monitor the adverse event or closeout the event in the database if no further follow-up is 
necessary. 

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Any SAE suspected to be related to the study treatment must be reported whenever it occurs, 
irrespective of the time elapsed since the last administration. 
Investigators and study personnel will record all adverse events and SAEs whether received 
through an unsolicited report by a subject, elicited during subject questioning, discovered during 
physical examination, laboratory testing, and/or other means by recording them on the eCRF 
and/or SAE Form, as appropriate. The following information should be recorded on the adverse 
event eCRF: 
• Description including onset and resolution dates 
• Whether it met SAE criteria 
• Severity 
• Relationship to study treatment or other causality 
• Outcome 
For SAEs, events occurring secondary to the primary event should be described on the eCRF in 
the narrative description field. 
The following should be considered when recording SAEs: 
• Death is an outcome of an event. The event that resulted in the death should be 
recorded and reported on the eCRF. 
• For hospitalizations, surgical, or diagnostic procedures, the illness leading to the 
surgical or diagnostic procedure should be recorded as the SAE, not the procedure 
itself. The procedure should be captured in the narrative as part of the action taken in 
response to the illness. 
9.8.8.2.3. Diagnosis Versus Signs or Symptoms 
In general, the use of a unifying diagnosis is preferred to the listing out of individual symptoms. 
Grouping of symptoms into a diagnosis should only be done if each component sign and/or 
symptom is a medically confirmed component of a diagnosis as evidenced by standard medical 
textbooks. If any aspect of a sign or symptom does not fit into a classic pattern of the diagnosis, 
report the individual symptom as a separate adverse event. 
9.8.8.3. 
Reporting Adverse Events 
All SAEs are subject to reporting requirements.  
9.8.8.3.1. Serious Adverse Events 
Any adverse event considered serious by the Investigator or that meets serious criteria must be 
reported to the designated safety contact within 24 hours of becoming aware of the event. 
Enter the SAE information into eCRF, and send other available pertinent information (eg, 
hospital records, laboratory results) to the designated Sponsor Contact (IQVIA). If additional 
information is required or becomes available for a previously reported SAE, entry of the new 
information into eCRF should be completed within 24 hours of awareness. 

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In case of electronic data capture (EDC) connectivity issues (eg, the eCRF cannot be accessed by 
the Investigator), the Investigator must complete a Back-Up Paper SAE Report Form and send 
the form to the designated Sponsor Contact (IQVIA) within 24 hours of investigator awareness 
of the event. Once the EDC connectivity is restored, the investigator must enter all pertinent 
information from the Back-Up Paper SAE Report Form into the eCRF as soon as possible. 
For the reporting of Pregnancy/Pregnancy Outcome SAEs, and SAEs occurring after the 
protocol-defined collection period, the investigator must complete a Back-Up Paper SAE Report 
Form and send the form to the Sponsor Contact (IQVIA) within 24 hours of investigator 
awareness of the event. 
IQVIA Pharmacovigilance 
Phone: 1-800-761-6501 (access code 00-663-5111) 
Fax: 0034-800-401163 
Email (preferred method): ArenaSafety@iqvia.com 
Elective hospitalization and/or surgery for clearly preexisting conditions (eg, a surgery that has 
been scheduled prior to the subject’s entry into the study) will not be reported as an SAE. All 
other hospitalizations, including elective hospitalizations for any condition that was not 
preexisting, will be reported as an SAE. 
Any SAE that is ongoing when the subject completes the study or discontinues the study will be 
followed by the Investigator until the event resolved, stabilized, or returned to baseline status. 
The Sponsor (via the In-Country Caretaker for Clinical Trial [ICCC]) is responsible for notifying 
the relevant regulatory authorities of any adverse event assessed by the Reporter (PI) or the 
Sponsor as:  
a) Serious, unexpected, and related, or  
b) Serious, expected, related and life-threatening or fatal 
In addition, the ICCC is responsible for notifying the investigator(s) of active sites, the head(s) of 
the active study sites, and, if applicable, the institutional review boards (IRBs) of all SAEs 
occurring during the study that are assessed by the Reporter (PI) or the Sponsor as related and 
unexpected.  
The investigator is responsible for notifying the head of the study site of SAEs and significant 
safety findings that occur at his or her site. The investigator is also responsible for responding to 
requests for additional information made by the Sponsor, the head of the study site, or the IRB.  
9.8.8.3.2. Serious, Unexpected Adverse Drug Reactions 
All ADRs that are both serious and unexpected are subject to expedited reporting to regulatory 
agencies. An unexpected ADR is one for which the nature or severity is not consistent with 
information in the relevant source documents. 
Since etrasimod is an investigational medicinal product that has not yet been approved for 
marketing in any country, the IB in effect during the study will serve as the Reference Safety 
Information for determining whether an AE is expected or unexpected. 

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9.8.9. 
Pregnancy 
If at any point a serum β-hCG pregnancy test is positive, the subject will be withdrawn from the 
study treatment. 
Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of study treatment and until 30 days after the last dose. 
Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an adverse event; however, to fulfill regulatory requirements, any pregnancy and/or pregnancy 
outcome should be reported via the Pregnancy Report Form to the designated Sponsor Contact 
within 24 hours of awareness to collect data on the pregnancy and on the outcome for both the 
mother and the fetus. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and should be reported as such (following 
the SAE reporting process) even if outside the SAE reporting period. 
9.9. 
Procedures for Overdose 
The current edition of the IB should be referenced for overdose procedures. 
There is no established overdose threshold for this clinical study, nor is there any recommended 
specific treatment for an overdose but to provide supportive care if clinically indicated. 
In the event of a suspected overdose, the Investigator and/or treating physician should: 
1. Closely monitor the subject for any adverse event/SAE and laboratory abnormalities and 
follow the adverse event reporting process, including contacting the Medical Monitor. 
2. Obtain a plasma sample for PK analysis within 7 days from the date of the last dose of 
study treatment, if possible, and if requested by the Medical Monitor. 
3. Document the total quantity of the excess dose, taking into consideration the duration of 
the overdose in the eCRF and the time frame. 
Subjects who overdose will be counseled on correct dosing and administration of study 
treatment. Decisions regarding study discontinuation, dose interruptions, or dose modifications 
will be made by the Investigator in consultation with the Medical Monitor based on the clinical 
evaluation of the subject. 

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10. 
PLANNED STATISTICAL METHODS 
10.1. 
General Considerations 
All individual subject data for all subjects will be presented in data listings. All efficacy and 
safety endpoints will be summarized by treatment group. Full details of the statistical 
considerations and planned analyses will be described in the study Statistical Analysis Plan 
(SAP). Unless stated otherwise, baseline refers to the last non-missing measurement on or before 
the first dose in Study APD334-302. 
10.2. 
Determination of Sample Size 
Approximately 35 Japanese subjects in the parent Study APD334-302, and those subjects may be 
eligible to enroll in Study APD334-308. 
10.3. 
Analysis Sets 
All analysis sets will be defined in the SAP prior to database lock. The following analysis sets 
may be used in the statistical analysis: 
Full Analysis Set (FAS): The FAS will consist of all subjects who receive at least 1 dose of 
study treatment. Under this approach, subjects will be counted in the treatment group to which 
they were randomized in Study APD334-302, regardless of the treatment received during 
Study APD334-308. 
Per Protocol (PP) Set: The PP Set will consist of all subjects in the FAS who adhere to the 
protocol. This set will be used in sensitivity analyses of the primary and key secondary endpoints 
to evaluate the influence of major protocol violators and protocol deviators on the primary 
results. Subjects may be excluded from this set if they violate the eligibility criteria or 
significantly deviate from the study plan. Specific reasons for warranting exclusion from this set 
will be documented prior to database lock and may include, but are not limited to, study 
treatment noncompliance, receiving incorrect study treatment, and missing a defined number of 
visits while still on study. The SAP, which will be finalized prior to database lock, will be the 
final documentation for the PP definition. 
Modified Full Analysis Set (mFAS): The mFAS will consist of all subjects who receive at least 
1 dose of study treatment and have a baseline and at least 1 post-Week 12 measurement. Under 
this approach, subjects will be counted in the treatment group to which they were randomized in 
Study APD334-302, regardless of the treatment received during Study APD334-308. Note that 
the mFAS can vary with endpoints since some subjects may have the needed data for inclusion in 
the mFAS for some endpoints but others may not. 
Safety Set: The Safety Set will include all subjects who receive at least 1 dose of study 
treatment. For this set, subjects will be analyzed according to the treatment received, regardless 
of randomization. The Safety Set will be used for all safety analyses. 
10.4. 
Missing Data 
Subjects with worsening of disease, as defined in Section 5.1.1, will be considered as having a 
treatment nonresponse outcome in the analysis of all endpoints, including the primary endpoint. 

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In addition, subjects who initiate an agent not allowed in combination with the study treatment 
that can affect the efficacy of the study treatment, such as an immunosuppressant or 
corticosteroid, or who have an increase in dose over baseline levels for treatment of worsening 
disease symptoms will be considered non-responders thereafter or be handled by per protocol 
analysis. 
Subjects discussed above will be considered as having a known outcome at the analysis 
timepoint (ie, a treatment failure outcome) and not as having missing data. Subjects who 
discontinue the double-blind study for reasons other than worsening disease or adverse event 
related to UC will be considered as having missing data and will be handled in the primary and 
sensitivity analyses as follows. 
A full description of the handling of missing data will be provided in the SAP. 
Primary Method of Handling Missing Data 
In the primary analysis of the primary endpoint and main analyses of all binary responder-type 
endpoints, all subjects with missing data, regardless of reason for missingness, will be considered 
as non-responders. 
In the main analysis of continuous or score endpoints, such as changes from baseline in MMS 
subscores, biomarker measures, urgency NRS, abdominal pain NRS, and health-related quality 
of life measures, subjects with missing data will be handled using last observation carry forward, 
or a mixed-effect model with repeated measures. Detailed methods will be provided in the SAP. 
Sensitivity Analyses for Missing Data 
Sensitivity analyses may be performed under several alternative assumptions regarding missing 
data, ie, data missing intermittently, after discontinuation from the double-blind study for reasons 
other than worsening diseases, or after initiation of excluded medications. 
• An assumption of data missing at random (MAR) within each treatment group will be 
investigated. Missing data, eg, component scores of MMS at the planned assessment 
timepoints, will be imputed using multiple imputation methodology (Rubin 1987) 
under the MAR assumption. Binary responder-type endpoints will subsequently be 
computed from observed and imputed data and analyzed using the same method as in 
the primary analysis. Continuous endpoints will be analyzed using analysis of 
covariance based on observed and imputed values. 
• A tipping point analysis will be performed for the primary and key secondary 
endpoints by considering all possible combinations of the number of responders and 
non-responders among subjects with missing data in each treatment group. The 
results of analysis for all possible combinations will be summarized graphically, 
depicting a boundary between combinations that result in a statistically significant 
treatment effect versus not statistically significant. Clinical plausibility of the 
combinations on the boundary will be discussed in the clinical study report to 
evaluate robustness of study conclusions to missing data. 

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• A mechanism of missingness not at random will be investigated for subjects with 
missing data. These subjects, regardless of the randomized treatment group, will be 
assumed to have a similar distribution of outcomes after discontinuation as subjects 
with available data in the placebo group. This is akin to modeling the missing 
outcomes as if the subjects continued on their background therapy only and 
accounting for the study effect observed in subjects on placebo. This will be 
implemented using a multiple imputation approach of Copy Reference to impute 
missing values, eg, component scores of MMS at the planned assessment timepoints. 
Complete descriptions of the sensitivity analyses and detailed multiple imputation method and 
procedures will be provided in the SAP prior to database lock. 
10.5. 
Efficacy Endpoint Definitions 
The following definitions will be used to assess efficacy outcomes: 
• Baseline: Refer to Section 10.1 
• Clinical response: A ≥ 2-point and ≥ 30% decrease from baseline in MMS, and a 
≥ 1-point decrease from baseline in RB subscore or an absolute RB subscore ≤ 1 
• Clinical remission: SF subscore = 0 (or = 1 with a ≥ 1-point decrease from baseline), 
RB subscore = 0, and ES ≤ 1 (excluding friability) 
• Endoscopic improvement: ES of ≤ 1 (excluding friability)  
• Endoscopic normalization: ES = 0 
• Mucosal healing: ES of ≤ 1 (excluding friability) with histologic remission measured 
by a Geboes Index score < 2.0 
• Symptomatic remission: SF subscore = 0 (or = 1 with a ≥ 1-point decrease from 
baseline) and RB subscore = 0 
• Complete symptomatic remission: SF subscore = 0 and RB subscore = 0 
• Symptomatic response: Decrease from baseline ≥ 30% in composite RB and SF 
subscores 
• Noninvasive clinical response: A ≥ 30% decrease from baseline in composite RB and 
SF, and a ≥ 1-point decrease from baseline in RB subscore or an absolute RB 
subscore ≤ 1 
• Histologic improvement: Geboes Index score < 3.1 
• Histologic remission: Geboes Index score < 2.0 
• Clinical remission using Total Mayo Clinic score: Total Mayo Clinic Score of 
≤ 2 points with no individual subscore of > 1 point 
• Clinical response using Total Mayo Clinic score: A ≥ 3-point and ≥ 30% decrease 
from baseline in Total Mayo Clinic score, and a ≥ 1-point decrease from baseline in 
RB subscore or an absolute RB subscore ≤ 1 

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10.5.1. 
Calculation of Modified Mayo Score Component Scores 
In general, the MMS symptom scores will be computed from the eDiary data within 7 days prior 
to the target analysis timepoint (eg, Week 52). Complete details of the MMS symptom score 
computation method is provided Section 9.4. 
10.6. 
Primary Endpoint 
The primary efficacy endpoint will evaluate etrasimod versus placebo in: 
• The proportion of subjects achieving clinical remission at Week 52 
Clinical remission is based on the MMS as defined in Section 10.5. 
10.7. 
Secondary Endpoints 
Mucosal healing is based on the MMS and Geboes Index, histologic response and remission are 
based on the Geboes Index, and all other endpoints are based on MMS as defined in 
Section 10.5. 
10.7.1. 
Key Secondary Efficacy Endpoints 
The key secondary efficacy endpoints are: 
• The proportion of subjects achieving endoscopic improvement at Week 52 
• The proportion of subjects achieving symptomatic remission at Week 52 
• The proportion of subjects, who had not been receiving corticosteroids for 
≥ 12 weeks, achieving clinical remission at Week 52 among subjects receiving 
corticosteroids at APD334-302 study entry 
• The proportion of subjects with mucosal healing at Week 52 
• The proportion of subjects achieving clinical remission at both Week 12 of 
Study APD334-302 and Week 52 of Study APD334-308 
10.7.2. 
Other Secondary Efficacy Endpoints 
The other secondary endpoints are: 
• The proportion of subjects achieving clinical response at Week 52 
• The proportion of subjects achieving clinical response at both Week 12 of 
Study APD334-302 and Week 52 of Study APD334-308 
• The proportion of subjects with mucosal healing at both Week 12 of 
Study APD334-302 and Week 52 of Study APD334-308 
• The proportion of subjects achieving endoscopic normalization at Week 52 
• The proportion of subjects achieving endoscopic normalization at both Week 12 of 
Study APD334-302 and Week 52 of Study APD334-308 
• The proportion of subjects achieving symptomatic remission at Weeks 16, 20, 24, 32, 
40, and 48 

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• The proportion of subjects achieving complete symptomatic remission at each study 
visit (Weeks 16, 20, 24, 32, 40, 48, and 52) 
• The proportion of subjects achieving noninvasive clinical response at each study visit 
(Weeks 16, 20, 24, 32, 40, 48, and 52) 
• The proportion of subjects achieving symptomatic response at each study visit 
(Weeks 16, 20, 24, 32, 40, 48, and 52) 
• The proportion of subjects achieving clinical remission at Week 52 and 
corticosteroid-free since Weeks 16, 24, 32, 40, and 48 
• The proportion of subjects achieving clinical remission at Week 52 among subjects in 
clinical response at Week 12 of Study APD334-302 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
CCI
CCI
CCI
CCI
CCI
CCI

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10.10. 
Subgroup Analyses 
The following major subgroup analyses for the primary and key secondary endpoints will be 
performed in order to explore whether the treatment effects are consistent across different 
subgroups, provided there are at least 3 etrasimod subjects and 3 placebo subjects within each 
level of a subgroup. The SAP will provide a complete list and definition of the subgroups and 
analysis methods: 
• Sex (male, female) 
• Age: > or ≤ median age, ≥ or < 65 years. This refers to age collected at Screening in 
Study APD334-302. 
• Baseline oral corticosteroid usage (yes or no) 
• Naive to biologic or JAK inhibitor therapy at study entry (yes or no) 
• Baseline disease activity (MMS: 4 to 6 or 7 to 9) 
• Baseline fecal calprotectin > or ≤ median value 
• Baseline CRP > or ≤ median value 
• Baseline Total Mayo score ≤ 8 vs. > 8 
CCI
CCI
CCI

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10.11. 
Safety Endpoints 
• Incidence and severity of adverse events 
• Incidence and severity of laboratory abnormalities, and change from baseline in 
laboratory values (to include hematology, serum chemistry, coagulation, and 
urinalysis) 
• Incidence of clinically significant vital sign abnormalities and changes from baseline 
10.12. 
Testing Strategy 
10.12.1. 
Efficacy Analysis 
The primary analysis of the proportion-based efficacy endpoints will be carried out using the 
Cochran-Mantel-Haenszel (CMH) method, stratified by (a) naive to biologic or JAK inhibitor 
therapy at APD334-302 study entry (yes or no), (b) baseline corticosteroid use (yes or no), and 
(c) baseline disease activity (MMS: 4 to 6 or 7 to 9). Results will be expressed as the number of 
subjects in remission, remission percentages, difference in remission percentages, odds ratio, and 
associated 95% confidence intervals (CIs). 
Due to the limited number of subjects anticipated to enroll in this study, there will be no 
hypothesis testing on any efficacy endpoint. Inferential statistics will be limited to 95% CIs. 
Full details of the efficacy analysis will be documented prior to database lock in the SAP. 
10.12.2. 
Safety Analysis 
All safety data will be listed and summarized by treatment group. All TEAEs will be coded using 
the latest version of MedDRA and tabulated by System Organ Class and Preferred Term. 
Incidence of adverse events, SAEs, and adverse events leading to discontinuation will be 
summarized and presented in descending order of frequency. Associated laboratory parameters 
such as hepatic enzymes, renal function, and hematology values will be grouped and presented 
together. Individual subject values will be listed and values outside of the standard reference 
range will be flagged. Shift tables and analyses of changes from baseline will be produced. The 
change from baseline for each of the vital signs and 12-lead ECG parameters will be 
summarized. Incidence of abnormal vital signs parameters and outlier 12-lead ECG results will 
be tabulated. 
10.13. 
Interim Analysis 
Not applicable 

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11. 
ETHICAL CONSIDERATIONS 
11.1. 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki and that are consistent with GCP, ICH guidelines, and applicable 
regulatory requirements. 
11.2. 
Institutional Review Board or Independent Ethics Committee 
Approval 
Before initiating a study, the Investigator must have written and dated approval from the 
IRB/IEC for the study protocol, written informed consent form (ICF), subject recruitment 
materials and procedures (eg, advertisements or websites), and any other written information to 
be provided to subjects, via the head of the study site. Approval from the committee must be 
documented in a letter to the head of the study site specifying the protocol number, protocol 
version, documents reviewed, and the date on which the committee met and granted the 
approval. 
All documents subject to review during the study, including any modifications made to the 
protocol after receipt of IRB/IEC approval, must also be submitted to the committee for approval 
prior to implementation. The Investigator must also provide periodic reports as required and 
promptly report important safety information (ie, SAEs, new information that may adversely 
affect the safety of study subjects or the conduct of the study, deviations from or changes in the 
protocol to eliminate immediate harm to study subjects) and protocol violations, as appropriate, 
to the IRB/IEC. 
As part of the Investigator’s written application to the IRB/IEC, the Investigator should provide 
the committee with a current copy of the etrasimod IB. If the IB is updated during the study, the 
Investigator should supply an updated copy to the committee. 
11.3. 
Informed Consent and Assent 
The Investigator will fully inform the subject of all pertinent aspects of the study, including the 
approval of the study by the IRB/IEC. Before informed consent/assent (parent or legal guardian 
must provide consent for a subject < 20 years of age who has assented to participate in the study 
or as required per local regulations) may be obtained, the Investigator should provide the subject 
ample time and opportunity to inquire about details of the study and to decide whether to 
participate. 
Prior to a subject’s participation in the study, the IRB/IEC-approved ICF must be signed and 
personally dated by the subject and by the person who conducted the informed consent 
discussion. If a subject is unable to read, an impartial witness will be present during the entire 
informed consent discussion. 
The written ICF and any other written information to be provided to subjects should be revised 
whenever important new information becomes available that may be relevant to the subject’s 
consent. Any revised written ICF or study materials to be available and/or supplied to subjects 
should receive the IRB/IEC’s approval in advance of use. The subject will be informed in a 

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timely manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the study. The communication of this information should 
be documented. 
During a subject’s participation in the study, the subject will receive an updated version of the 
IRB/IEC-approved signed and dated consent document, as applicable, and any updates to the 
IRB/IEC-approved written information provided to subjects. 
11.4. 
Confidentiality 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is provided from the Sponsor. 
Prior to study participation, the Investigator shall inform the subject that the monitor(s), 
auditor(s), IRB/IEC, and the regulatory authorities will be granted direct access to the subject’s 
original medical records for verification of clinical study procedures and/or data, and that, by 
signing a written ICF, the subject is authorizing such access. 
In addition, prior to study participation, the subject must be informed that the records identifying 
the subject will not be made publicly available; if the results of the study are published, the 
subject’s identity will remain confidential. 
11.5. 
Protocol Compliance 
The Investigator/institution will conduct the study in compliance with the protocol agreed to by 
the Sponsor and regulatory authorities (if applicable) and that was approved by the IRB/IEC. The 
Investigator/institution and the Sponsor should sign the protocol, or if applicable an alternative 
contract, to confirm agreement. 
The Investigator should not implement any deviation from, or changes to, the protocol without 
agreement by the Sponsor and prior review and documented approval from the IRB/IEC of an 
amendment, except where necessary to eliminate immediate hazard(s) to study subjects or when 
the change involves only logistical or administrative aspects of the study (eg, change in monitor, 
change of telephone number). 
When an important deviation from the protocol is deemed necessary for an individual subject, 
the Investigator must contact the Medical Monitor for the study. Such contact must be made as 
soon as possible to permit a review by the Sponsor to determine the impact of the deviation on 
the subject’s participation and/or the assessment of safety or efficacy in the study. Any 
significant protocol deviations affecting subject eligibility and/or safety must be reported by 
Investigator or site delegate to the IRB/IEC and regulatory authorities, as applicable, prior to 
implementation. 
The Investigator should document and explain any deviation from the approved protocol. 

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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Quality assurance and quality control systems shall be implemented and maintained with written 
SOPs to ensure that the study is conducted, and data are generated, documented (recorded), and 
reported in compliance with the study protocol, GCP, and the applicable regulatory 
requirement(s). Quality control shall be applied to each stage of data handling to ensure that all 
data are reliable and have been processed correctly. 
An agreement must be secured from all involved parties to ensure direct access to all 
study-related sites, source documents, and reports for the purpose of monitoring and auditing by 
the Sponsor and/or designee and inspection by regulatory authorities. 
12.1. 
Training of Study Site Personnel 
Prior to study activities being initiated at the study site, the Sponsor or designee will train study 
site personnel on the protocol and applicable procedures. Training must be documented. 
Note: If new study site personnel are assigned to the study after the initial training, study sites 
should contact the study monitor to coordinate training. Qualified study personnel may conduct 
training, as appropriate. Training of new study personnel must also be documented. 
12.2. 
Monitoring 
Study site monitoring is conducted to ensure the study is progressing as expected, the rights and 
well-being of human subjects are protected, the reported study data are accurate, complete, and 
verifiable, and the conduct of the study is in compliance with the currently approved protocol, 
with GCP and with applicable regulatory requirements and local law. Protocol deviations 
identified will be documented. 
Details of study site monitoring are documented in the study Clinical Monitoring Plan (CMP) or 
similar document. The CMP describes in detail who will conduct the monitoring, at what 
frequency monitoring will be done, at what level of detail monitoring will be performed (eg, 
targeted and/or risk based), and the distribution of monitoring reports. Monitoring may include a 
study site selection visit, which may be conducted in person or via communication media (eg, 
teleconference, online meeting) or may be waived in accordance with policy and procedures 
being followed for the study, if appropriate. Monitoring will include a study site initiation visit, 
interim monitoring visit(s), and a study site closeout visit. An interim monitoring visit may be 
combined with a closeout visit, if applicable. 
12.3. 
Audit 
An audit of one or more participating study sites may be performed independently of, and 
separately from, routine monitoring to evaluate clinical study conduct and compliance with the 
protocol, SOPs, GCP, and the applicable regulatory requirements. 

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13. 
DATA HANDLING AND RECORD KEEPING 
13.1. 
Data Management 
13.1.1. 
Case Report Forms 
An eCRF must be completed for each subject screened/enrolled in this study. These forms will 
be used to transmit information collected during the study to the Sponsor and regulatory 
authorities, as applicable. 
The documentation related to the validation of the eCRFs will be maintained in the Trial Master 
File (TMF). The TMF will be maintained by the CRO and the Sponsor. 
The Investigator will document subject data in his/her own subject files. These subject files will 
serve as source data for the study. All eCRF data required by this protocol will be recorded by 
study site personnel. All data entered into the eCRF will be supported by source documentation. 
The Investigator or an authorized member of the Investigator’s staff will make any necessary 
corrections to the eCRF. All changed information, including the date and person performing the 
corrections, will be available via the audit trail, which will be part of the electronic data capture 
system. For any correction, a reason for the alteration will be provided. The eCRFs will be 
reviewed periodically for completeness and acceptability by Sponsor personnel (or their 
representatives). The Sponsor (or their representatives) will also be allowed access to all source 
documents pertinent to the study in order to verify eCRF entries. The Investigator will review the 
eCRFs for completeness and accuracy and provide his or her electronic signature and date to the 
eCRFs as evidence thereof. 
13.1.2. 
Source Documents 
Per regulatory requirements, the Investigator or designee will maintain accurate and up-to-date 
study documentation, including source documentation for each study subject. Source documents 
are defined as original documents, data, and records. These may include, but are not limited to, 
hospital records, clinical and office charts, endoscopy reports, laboratory data/information, 
subjects’ eDiaries or evaluation checklists, pharmacy dispensing and other records, recorded data 
from automated instruments, ECGs, X-rays, ultrasounds, right heart catheterization reports, 
echocardiograms. Data collected during this study must be recorded on the appropriate source 
documents. 
The Investigator(s)/institution(s) will permit study-related monitoring, audits, IRB/IEC review, 
and regulatory inspection(s) and will provide direct access to the source data. 
13.2. 
Study Documentation and Records Retention 
The Investigator and study staff have the responsibility of maintaining a comprehensive and 
centralized filing system containing all study-related documentation. These files must be 
available for inspection by the Sponsor, representatives of the Sponsor, the IRB/IEC, and 
regulatory authorities (ie, FDA or international regulatory authorities) at any time, and should 
consist of the following elements: 

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• Subject files: containing the completed eCRFs (if applicable), supporting source 
documentation including medical records, laboratory data, and signed ICFs 
• Regulatory files: containing the protocol with all amendments and Investigator 
signature pages, copies of all other regulatory documentation, all correspondence 
between the study site and the IRB/IEC and Sponsor, and drug accountability files, 
including a complete account of the receipt and disposition of the study treatment. 
Records are to be available for 2 years after the last marketing application approval, or if the 
application is not approved or never submitted, 2 years after the appropriate regulatory 
authorities have been notified of the discontinuation of clinical development of the 
investigational product. The Sponsor will provide written notification when it is appropriate for 
the Investigator to discard the study-specific documents referenced above. 
During the record retention period, the Investigator or designee must inform the Sponsor or 
designee (eg, CRO), of the following:  
• Location of study documentation 
• If the custody of documentation will be transferred or moved to another location 
• If the Investigator is unable to retain documentation for the specified period 
13.2.1. 
Clinical Study Site 
Materials to be retained: 
The head of clinical study site shall retain records, including documents and data, which relate to 
clinical study in accordance with ICH guideline for Good Clinical Practice (GCP) and 
Japan-GCP (J-GCP). 
Retention period: 
The head of clinical study sites shall retain records for a required period in accordance with ICH-
GCP and J-GCP. However, the Investigator/the study center must arrange for retention of study 
records at the study center for at least 2 years after the last marketing application approval, or if 
the application is not approved or never submitted, 2 years after the appropriate regulatory 
authorities have been notified of the discontinuation of clinical development of the 
investigational product. The Sponsor will provide written notification when it is appropriate for 
the Investigator to discard the study specific documents referenced above. A record keeping 
manager shall be designated in retaining each record. 
13.2.2. 
Principal Investigator 
The Principal Investigator shall retain records, including documents and data, which relate to the 
clinical study in accordance with instruction from the head of the clinical study site.  
13.2.3. 
Institutional Review Board (IRB) 
Materials to be retained: 
The person who establishes the IRB shall retain records, including documents and data, which 
relate to the clinical study in accordance with ICH-GCP and J-GCP. 

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Retention period: 
The person who establishes the IRB shall retain records for required period in accordance with 
ICH-GCP and J-GCP. However, if the Sponsor requests to retain records longer than described, 
the person who establishes the IRB will discuss retention period and method with the Sponsor. 
13.2.4. 
Sponsor and ICCC 
Materials to be retained: 
Sponsor and ICCC shall retain records, including documents and data, which relate to the clinical 
study in accordance with ICH-GCP and Japan GCP (J-GCP). 
Retention period: 
The Sponsor and the ICCC shall retain records for required period in accordance with ICH-GCP 
and J-GCP. 
13.3. 
Clinical Study Report 
Whether the study is completed or prematurely terminated, a clinical study report will be 
prepared and provided to the regulatory agencies according to applicable regulatory 
requirement(s). 
13.4. 
Disclosure of Study Results 
The Sponsor will post the results of the study in a publicly accessible database in accordance 
with the applicable laws and regulations. 

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14. 
RESPONSIBILITIES 
14.1. 
Investigator Responsibilities 
The Investigator must comply with this protocol and the conduct of all study procedures. The 
Investigator will disclose to the Sponsor sufficient, accurate, financial information to allow the 
Sponsor to submit accurate disclosure statements to the FDA per 21 Code of Federal Regulations 
(CFR) Part 54 (Financial Disclosure by Clinical Investigators). The Investigator is responsible 
for compliance with applicable sections of 21 CFR Part 312, Subpart D, (Responsibilities of 
Investigators) and other ICH GCP requirements, federal, and local laws, applicable to conducting 
drug studies. 
The Investigator is responsible for ensuring an investigation is conducted according to the signed 
Investigator statement, the investigational plan, and applicable regulations; for protecting the 
rights, safety, and welfare of subjects under the Investigator’s care; and for the control of drugs 
under investigation. An Investigator will, in accordance with the provisions of 21 CFR Part 50, 
obtain the informed consent of each human subject to whom the drug is administered. 
14.2. 
Sponsor Responsibilities 
The Sponsor is responsible for compliance with applicable sections of 21 CFR Part 312, 
Subpart D (Responsibilities of Sponsors). The Sponsor is responsible for selecting qualified 
Investigators, providing them with the information they need to conduct an investigation 
properly, ensuring proper monitoring of the investigation(s), ensuring the investigation(s) is 
conducted in accordance with the general investigational plan and protocols contained in the 
Investigational New Drug (IND) application, maintaining an effective IND with respect to the 
investigations, and ensuring the FDA, other applicable health authorities, and all participating 
Investigators are promptly informed of significant new adverse effects or risks with respect to the 
drug. 

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15. 
REFERENCES 
Brinkmann V, Billich A, Baumruker T, et al. Fingolimod (FTY720): Discovery and development 
of an oral drug to treat multiple sclerosis. Nat Rev Drug Discov. 2010;9(11):883-897.  
FDA. Establishment and operation of clinical trial data monitoring committees. U.S. Department 
of Health and Human Services, Food and Drug Administration. Guidance for Clinical Trial 
Sponsors Web site. 
https://www.fda.gov/downloads/regulatoryinformation/guidances/ucm127073.pdf. Published 
2006. Accessed March 4, 2019. 
FDA. Drug-induced liver injury: Premarketing clinical evaluation. U.S. Department of Health 
and Human Services, Food and Drug Administration. Guidance for Industry Web site. 
https://www.fda.gov/downloads/guidances/UCM174090.pdf. Published 2009. Accessed April 
25, 2019. 
FDA. Ulcerative colitis: Clinical trial endpoints. Guidance for Industry Web site. 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM515143.pdf. Published 2016. Accessed March 1, 2019. 
Flockhart DA. Drug Interactions Flockhart TableTM. Indiana University, Department of 
Medicine, Clinical Pharmacology. https://drug-interactions.medicine.iu.edu/MainTable.aspx. 
Published 2019. Accessed November 15, 2019. 
Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Lofberg R. A reproducible grading scale for 
histological assessment of inflammation in ulcerative colitis. Gut. 2000;47(3):404-409.  
Kaser A, Zeissig S, Blumberg RS. Inflammatory bowel disease. Annu Rev Immunol. 
2010;28:573-621.  
Kornbluth A, Sachar DB, Practice Parameters Committee of the American College of G. 
Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice 
Parameters Committee. Am J Gastroenterol. 2010;105(3):501-523.  
MacIntyre N, Crapo RO, Viegi G, et al. Standardisation of the single-breath determination of 
carbon monoxide uptake in the lung. Eur Respir J. 2005;26(4):720-735.  
Marchal-Bressenot A, Salleron J, Boulagnon-Rombi C, et al. Development and validation of the 
Nancy histological index for UC. Gut. 2017;66(1):43-49.  
Miller MR, Crapo R, Hankinson J, et al. General considerations for lung function testing. Eur 
Respir J. 2005a;26(1):153-161.  
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 
2005b;26(2):319-338.  
Mosli MH, Feagan BG, Zou G, et al. Development and validation of a histological index for UC. 
Gut. 2017;66(1):50-58.  

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Nielsen OH, Li Y, Johansson-Lindbom B, Coskun M. Sphingosine-1-phosphate signaling in 
inflammatory bowel disease. Trends Mol Med. 2017;23(4):362-374.  
Rowe WA, Lichtenstein GR. Inflammatory bowel disease. Medscape. 
https://emedicine.medscape.com/article/179037-overview. Published 2017. Updated October, 
2017. Accessed May, 2019. 
Rubin DB. Multiple imputation for nonresponse in surveys. New York, NY: John Wiley and 
Sons; 1987. On file at Arena. 
Ungar B, Kopylov U. Advances in the development of new biologics in inflammatory bowel 
disease. Ann Gastroenterol. 2016;29(3):243-248. On file at Arena. 
 
 

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16. 
APPENDICES 
 

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APPENDIX 1: 
SCHEDULE OF ASSESSMENTS 
Table 7: 
Schedule of Assessments 
Visit Label 
(Based on Continuation from 
Study APD334-302) 
W12/ 
D85a 
± 7 Days 
W16/ 
D113 
± 7 Days 
W20/ 
D141 
± 7 Days 
W24/ 
D169 
± 7 Days 
W32/ 
D225 
± 7 Days 
W40/ 
D281 
± 7 Days 
W48/ 
D337 
± 7 Days 
W52/D365 / 
Early 
Terminationb 
± 7 Days 
2-Week 
Follow-Up 
Visitc 
± 3 Days 
4-Week 
Follow-Up 
Visitc 
± 3 Days 
Evaluation 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
eDiary reviewd 
 
X 
X 
X 
X 
X 
X 
X 
 
 
MMSe 
 
 
 
 
 
 
 
X 
 
 
Stool frequency and rectal 
bleeding subscoref 
 
X 
X 
X 
X 
X 
X 
X 
 
 
PGA for total Mayo Clinic Score 
 
 
 
 
 
 
 
X 
 
 
IBDQ, UC-PRO/SS, SF-36, 
WPAI-UC, and pain and urgency 
NRS 
 
 
 
 
 
 
 
X 
 
 
Adverse event assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
 
 
 
 
 
 
 
X 
 
 
Physical examinationh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Extraintestinal manifestationsi 
 
 
 
 
 
 
 
X 
X 
X 
Pulmonary function testj 
 
 
 
 
X 
 
 
X 
X 
 
Ophthalmoscopy with OCTk 
 
 
 
 
 
 
 
X 
X 
 
Pregnancy testl 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
CBC with differential and platelets 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CD4 T-cell count 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Visit Label 
(Based on Continuation from 
Study APD334-302) 
W12/ 
D85a 
± 7 Days 
W16/ 
D113 
± 7 Days 
W20/ 
D141 
± 7 Days 
W24/ 
D169 
± 7 Days 
W32/ 
D225 
± 7 Days 
W40/ 
D281 
± 7 Days 
W48/ 
D337 
± 7 Days 
W52/D365 / 
Early 
Terminationb 
± 7 Days 
2-Week 
Follow-Up 
Visitc 
± 3 Days 
4-Week 
Follow-Up 
Visitc 
± 3 Days 
Evaluation 
 
Laboratory tests including 
hs-CRPm 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Stool sample/fecal calprotectinn 
 
 
 
X 
 
 
 
X 
 
 
Stool sample for microbiome 
 
 
 
 
 
 
 
X 
 
 
Flexible proctosigmoidoscopy/ 
colonoscopy and biopsy o 
 
 
 
 
 
 
 
X 
 
 
PK assessmentsp 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarkers blood sampleq 
 
 
 
 
 
 
 
X 
 
 
Concomitant medications and 
proceduresr 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tuberculosis questionnaires 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tuberculosis tests 
 
 
 
 
 
 
 
X 
 
 
Drug dispensation/accountabilityt 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study treatment administrationu 
Once daily 
 
 
a Subjects are continuing treatment from 12-week Study APD334-302. The Week 12 visit of Study APD334-302 serves as the Day 1 visit of this study. Subjects will be 
reconsented for this study. Screening for eligibility will be performed for Study APD334-302 and only modified eligibility criteria will be assessed for this study (Section 4.1 and 
Section 4.2). Visit labels and windows are relative to Week 0/Day 1 of Study APD334-302. 
b Subjects discontinuing treatment prior to Week 52/Day 365 should have an Early Termination visit within 7 days of the last study treatment administration and before initiation 
of any new treatments. If a subject discontinues at or before Week 16, a sigmoidoscopy and biopsy are not required. For subjects with worsening disease or who complete 
Week 52 and wish to enter the APD334-303 OLE study, the Week 52/Early Termination visit will be used to assess eligibility for the OLE study. 
c For subjects discontinuing study treatment, 2-Week and 4-Week Follow-Up visits should be scheduled 2 weeks and 4 weeks after the Week 52/Early Termination visit and the 
indicated assessments performed; however, if the Early Termination or Week 52 visit is ≥ 2 weeks after the last dose of study treatment, the 2-Week Follow-Up visit is not 
required; however, the 4-Week Follow-Up visit should be scheduled and completed. If the Early Termination or Week 52 visit is ≥ 4 weeks after the last dose of study treatment, 
the 4-Week Follow-Up visit is not required. If the absolute peripheral lymphocyte count is not within normal limits at the 4-Week Follow-Up visit, subjects should return for 
CBC with differential according to local standard of care (captured as subsequent Follow-Up visit or unscheduled visit). 
d Subjects will continue eDiary entries through the Eligibility Visit and during the treatment period. The subject eDiary will be reviewed by study site staff at each treatment visit. 
e The Week 52 MMS will be calculated using the Week 52 proctosigmoidoscopy and SF and RB scores completed by the subject 7 days prior to the visit using the 3 most recent 
consecutive days prior to the actual day of the study visit excluding the day of bowel preparation. 

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f Stool frequency and RB subject-reported outcomes recorded daily using eDiary. The RB and SF subscores will be calculated as indicated in Section 9.7.1. 
g Safety vital signs will include resting heart rate and systolic and diastolic BP with subjects in the sitting position taken before dosing. Safety monitoring (Section 9.4.1) should be 
performed if a subject has had a dose interruption ≥ 7 consecutive days. 
h At Week 52, a complete physical examination (including assessments of the skin, head, eyes, ears, nose, throat, neck, thyroid, lungs, heart, abdomen, back, lymph nodes, 
extremities, and body weight) should be performed. All other visits should have a focused (complaints, signs, and symptoms) physical examination. 
i During the specified full physical examination, specific systems (eyes, liver, skin, and joints) will be examined for EIMs. 
j Pulmonary function tests will include FEV1 and FVC measurements. Where locally available, DLCO measurements will also be performed (sites where DLCO is not available 
should consult the Sponsor or Sponsor’s delegate). The Week 32 assessment is only required for subjects with a history of mild pulmonary disease (eg, asthma, chronic 
obstructive pulmonary disease). The 2-Week Follow-Up visit assessment is only required if results from the Week 52/Early Termination visit are abnormal. Details regarding 
additional PFTs are provided in Section 9.8.4. 
k Details regarding ophthalmoscopy and OCT assessments are provided in Section 9.8.5. The 2-Week Follow-Up visit assessment is only required if results from the 
Week 52/Early Termination visit are abnormal. 
l Urine pregnancy test for women of childbearing potential. A monthly home pregnancy test in non-visit months should be performed and any positive result immediately reported 
to the study site and a serum pregnancy test performed for confirmation. If home pregnancy test is not available, the pregnancy test will be performed on site during an 
unscheduled visit. 
m Clinical laboratory tests will include serum chemistry, hematology (including coagulation), urinalysis, and hs-CRP and should be obtained prior to the daily dosing. 
n Stool sample is for fecal calprotectin (all indicated visits) and bacterial culture, ova, and parasite evaluation for C. difficile assay at any point in the study when a subject becomes 
symptomatic, including worsening or return of disease activity. 
o To be read by a blinded central reader. If the Early Termination visit is within 4 weeks of the last sigmoidoscopy and biopsy, these procedures do not need to be repeated. 
p Pharmacokinetic blood samples are to be collected predose (within the 60-minute period prior to dosing). A PK sample should be taken, if possible, at the time of any SAE or AE 
leading to study treatment discontinuation. In addition, for subjects not enrolling into the APD334-303 study, a blood sample for PK should be drawn at the 2-Week and 4-Week 
Follow-Up visits. For all PK blood draws, the time of the last dose should be documented. 
q Blood samples for biomarkers should be collected on the indicated day prior to the daily dose as applicable. 
r All concomitant medications and procedures should be collected through the safety reporting period (Section 6.7). For subjects who received corticosteroid therapy during the 
APD334-302 study, corticosteroids should be tapered entering this study (Section 6.7.2.2). 
s QuantiFERON TB Gold and tuberculin skin test should not be performed in subjects previously diagnosed with TB infection. The TB questionnaire will be completed at every 
study visit for subjects receiving TB prophylaxis therapy. 
t Study treatment should be dispensed as indicated. For subjects who consent and are eligible for the APD334-303 OLE study prior to Week 52, double-blinded study treatment 
may be dispensed in the event there is a gap between the last on treatment visit of Study APD334-308 and W0/D1 of the OLE. Study treatment may be dispensed at Week 52 if 
the subject qualifies for and has opted to participate in the APD334-303 OLE study but who do not enter the OLE study on the same day as their Week 52 visit. 
u On days with scheduled study visits, subjects should not take their dose of study treatment at home in order to complete predose study procedures. The dose will be taken at the 
study site after all predose assessments and procedures have been completed. At the Week 12 visit, subjects should take study treatment after confirmation of eligibility and 
enrollment into Study APD334-308. 
BP, blood pressure; CBC, complete blood count; D, day; DLCO, diffusing capacity of the lungs for carbon monoxide; ECG, electrocardiogram; eDiary, electronic diary; EIM, 
extraintestinal manifestations; FEV1, forced expiratory volume at 1 second; FVC, forced vital capacity; hs-CRP, high-sensitivity C-reactive protein; IBDQ, Inflammatory Bowel 
Disease Questionnaire; MMS, modified Mayo score; NRS, numeric rating scale; OCT, optical coherence tomography; OLE, open-label extension; PGA, Physicians Global 
Assessment; PK, pharmacokinetics; RB, rectal bleeding; SAE, serious adverse event; SF, stool frequency; SF-36, Medical Outcomes Study 36-Item Short Form Health Survey; 
TB, tuberculosis; UC, ulcerative colitis; UC-PRO/SS, Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms; W, week; WPAI-UC, Work Productivity and Activity 
Impairment Questionnaire – Ulcerative Colitis 
 

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APPENDIX 2: 
TUBERCULOSIS SCREENING 
All subjects will have undergone screening for a history of TB infection and testing for 
latent/active TB infection in the APD334-302 study. Their medical history review must include 
specific questions about a history of TB or known occupational or other personal exposure to 
individuals with active TB. Subjects should be asked about past testing for TB, including chest 
radiograph results and results of interferon-gamma release assay (IGRA, eg, QuantiFERON-TB 
Gold In-Tube, T-SPOT TB) or response to tuberculin skin test (TST) and history of Bacillus 
Calmette-Guérin vaccination.  
a. The IGRA or TST is NOT required at Week 52 for subjects with a history of 
active/latent TB infection.  
− Subjects receiving TB prophylaxis treatment during the APD334-302 must have 
documentation of treatment with an acceptable TB prophylaxis treatment regimen 
(with a plan to complete the TB treatment course during study participation) to 
qualify for enrollment. It is the responsibility of the investigator to verify the 
adequacy of previous TB treatment and provide appropriate documentation 
(Direct Observation Therapy report where available).  
b. Acceptable TB prophylaxis treatment regimens for latent TB is defined according to 
local country guidelines. If no local country guidelines for the treatment of latent TB 
exist, WHO guidelines must be followed.  
c. Resources 
− For the WHO guidelines for the treatment of latent TB visit: 
https://apps.who.int/iris/bitstream/handle/10665/44165/9789241547833_eng.pdf;j
sessionid=115F807C3008D688F75118AF16EA53F0?sequence=1 
 
 

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Clinical Study Protocol 
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Phase 3, 40-Week Treatment Study in UC (ELEVATE UC 40 JAPAN) 
Original 0.0 
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Phase 3, 40-Week Treatment Study in UC (ELEVATE UC 40 JAPAN) 
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APPENDIX 3: 
MAYO CLINIC SCORE – SAMPLE 
Mayo Scoring System for Assessment of Ulcerative Colitis Activity 
Stool frequencya 
0 = Normal number of stools for this subject 
1 = 1 to 2 stools more than normal 
2 = 3 to 4 stools more than normal 
3 = 5 or more stools more than normal 
Subscore: 0 to 3 
Rectal bleedingb 
0 = No blood seen 
1 = Streaks of blood with stool less than half the time 
2 = Obvious blood with stool most of the time 
3 = Blood alone passes 
Subscore: 0 to 3 
Findings on endoscopyc 
0 = Normal or inactive disease 
1 = Mild disease (erythema, decreased vascular pattern) 
2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions) 
3 = Severe disease (spontaneous bleeding, ulceration) 
Subscore: 0 to 3 
Physician’s Global Assessmentd 
0 = Normal 
1 = Mild disease 
2 = Moderate disease 
3 = Severe disease 
Subscore: 0 to 3 
The Mayo score ranges from 0 to 12, with higher scores indicating more severe disease.  
a Each subject serves as his or her own control to establish the degree of abnormality of the stool 
frequency. 
b The daily bleeding score represents the most severe bleeding of the day. 
c The endoscopy subscore will be determined by qualified personnel at a central laboratory. 
d The Physician’s Global Assessment acknowledges the 3 other criteria, the subject’s daily 
recollection of abdominal discomfort and general sense of well-being, and other observations, 
such as physical findings and the subject’s performance status. 
 

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APPENDIX 4: 
HISTOLOGICAL SCORING INDICES 
Geboes Grading System 
The Geboes Grading System is a stepwise grading system used for the evaluation of microscopic 
inflammation and histopathologic disease activity in UC. The microscopic appearance of the 
mucosa is categorized into 6 grades. A decrease of the Geboes Score grading system to Grade 
zero (0) or one (1) indicates mucosal healing (Geboes 2000). 
Nancy Histological Index 
The Nancy Histological Index is a validated index for assessing histological disease activity in 
UC. It is composed of three histological items defining five grades of disease activity: absence of 
significant histological disease (Grade 0), chronic inflammatory infiltrate with no acute 
inflammatory infiltrate (Grade 1), mildly active disease (Grade 2), moderately active disease 
(Grade 3), and severely active disease (Grade 4). The presence of ulceration on the biopsy 
specimen corresponds to severely active disease (Grade 4). If there is no ulceration, acute 
inflammatory cells infiltrate (presence of neutrophils) is assessed. Moderate or severe acute 
inflammatory cells infiltrate corresponds to moderately active disease (Grade 3), while mild 
acute inflammatory cells infiltrate correspond to mildly active disease (Grade 2). If there is no 
acute inflammatory cells infiltrate, assessment of chronic inflammatory infiltrate (lymphocytes 
and plasmacytes) is made. A biopsy specimen showing moderate or marked chronic 
inflammatory infiltrate corresponds to moderate or marked chronic acute inflammatory infiltrate 
(Grade 1). A biopsy specimen showing mild or no chronic inflammatory infiltrate corresponds to 
absence of significant histological disease (Grade 0) (Marchal-Bressenot 2017). 
Robarts Histopathology Index 
The RHI is an evaluative index, derived from the Geboes score, that is designed to be 
reproducible and responsive to clinically meaningful change in disease activity over time. The 
total RHI score ranges from 0 (no disease activity) to 33 (severe disease activity) and is 
calculated as follows: RHI = 1×Chronic inflammatory infiltrate + 2×Lamina propria neutrophils 
+ 3×Neutrophilis in epithelium + 5×Erosion or ulceration (Mosli 2017). 
 

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APPENDIX 5: 
GUIDANCE FOR THE ASSESSMENT OF POTENTIAL 
PROGRESSIVE MULTIFOCAL 
LEUKOENCEPHALOPATHY 
If a subject exhibits signs and symptoms suspicious for PML, the Investigator must interrupt 
study treatment and perform a targeted neurologic examination to assess for signs of PML, 
which are diverse, progress over days to weeks, and may include progressive weakness on one 
side of the body or clumsiness of limbs or difficulty with walking or writing or fine motor skills, 
disturbance of vision, changes in thinking, memory and orientation leading to confusion and 
(expressive aphasia), and/or agnosia (receptive aphasia). Consultation with a local neurologist 
may be warranted, as presented in the PML case evaluation algorithm in Figure 3. 
The Medical Monitor should be informed of any suspected cases of PML and, if needed, will 
facilitate investigator/local neurologist consultation with PML medical experts on the 
independent adjudication committee. 
Figure 3: 
Progressive Multifocal Leukoencephalopathy Case Evaluation Algorithm 
 
CE, contrast-enhanced; CSF, cerebral spinal fluid; IAC, independent adjudication committee; IP, investigational 
product; JCV, John Cunningham Virus; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PML, 
progressive multifocal leukoencephalopathy; r/o, rule out. 
Note: IP dosing may resume, and no further evaluation is needed if the Investigator assessment reveals no objective 
signs of PML, the local neurologist confirms that the subject does not have PML, or the IAC’s review of the 
evidence concludes that PML is ruled out. 
 

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APPENDIX 6: 
INVESTIGATOR SIGNATURE 
 
Study title: 
A Phase 3, Double-Blind, Placebo-Controlled, 40-Week Extension Study to 
Assess the Efficacy and Safety of Etrasimod in Japanese Subjects with 
Moderately to Severely Active Ulcerative Colitis 
Study number: APD334-308 
 
 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol. 
 
 
 
 
 
 
 
Investigator Signature 
 
Date 
 
 
 
 
 
 
Investigator Name and Credentials - Printed 
 
 
 
 
 
 
 
 
Institution Name – Printed 
 
 
 
 
 
 
 
 
 

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APPENDIX 7: 
SPONSOR SIGNATURE 
 
Study Title:  A Phase 3, Double-Blind, Placebo-Controlled, 40-Week Extension Study to 
Assess the Efficacy and Safety of Etrasimod in Japanese Subjects with 
Moderately to Severely Active Ulcerative Colitis 
 
 
This document is signed electronically; the electronic signature is the signature of record in 
countries and regions that recognize electronic signature. This signature page is provided to meet 
signature requirements in countries that do not recognize electronic signature; the hand-written 
signature on this page is the signature of record in countries and regions that do not recognize 
electronic signature. 
 
 
 
 
 MD, MHS, FACC 
 
. 
 
 
 
 
 
 
Sponsor Signature 
 
Date 
 
 
 
PPD
PPD