Clinical trial NCT04706793
Conditions: Ulcerative Colitis
Keywords: Ulcerative Colitis Etrasimod APD334 UC
Sponsor: Pfizer
Start date: 2020-12-25; Completion date: 2022-08-03
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether oral etrasimod is a safe and effective treatment in adult Japanese participants with moderately to severely active ulcerative colitis (UC). This study is an extension of study APD334-302 (NCT03996369). Participants 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).

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Etrasimod intervention 2: Placebo
Intervention descriptions: intervention 1: Etrasimod 2 mg tablet by mouth, once daily up to 52 weeks intervention 2: Etrasimod matching placebo tablet by mouth, once daily up to 52 weeks

Protocol documents:
SAP_002.pdf: 
 
 
PROTOCOL APD334-308 
Statistical Analysis Plan 
 
 
Document: 
\\quintiles.net\Enterprise\Apps\sasdata\SASb\SAS\Arena\APD334\RZA32161\Biostatistics\Documentation\SAP 
Author: 
 
Version Number: 
1.0 
 
Version Date: 26Sep2022 
Template No.:  
CS_TP_BS016 
Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 
02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
APD334-308 
 
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 
 
 
 
 
AUTHOR: 
 
VERSION NUMBER AND DATE: V1.0 26SEP2022 
 
 
 
PPD
PPD


 
  
APD334-308 
Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V0.1 (Dated 05Aug2021) for Protocol APD334-308. 
 
 
Name 
Signature 
Date (DDMMYYYY) 
Author: 
 
Refer to eSignature 
 
 
Position: 
 
 
Company: 
IQVIA 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, authorizing 
that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date (DDMMYYYY) 
Approved By: 
, PhD 
 
 
 
Position: 
, Biostatistics & Data Management 
 
Company: 
Arena Pharmaceuticals, Inc. 
 
Approved By: 
, PhD 
 
 
 
Position: 
, Biostatistics 
 
Company: 
Arena Pharmaceuticals, Inc. 
 
Approved By: 
 
 
 
 
Position: 
 
 
Company: 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD


 
  
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MODIFICATION HISTORY 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
Draft 0.1 
16Aug2021 
 
Not Applicable – First Version 
 
14Apr2022 
 
Adding Efficacy Section 
 
20Jun2022 
 
Removing hypothesis testing/multiple 
imputations/sensitivity analyses  
 
07Jul2022 
 
Making sentences consistent with 301 study 
Simplify the analyses in TEAE section 
 
03Aug2022 
 
Modified Key Secondary Efficacy outcomes to 
be a bullet form presentation./ Simplified 
Exploratory Efficacy outcomes./ Concomitant 
medication./ Added some terms to List of 
Abbreviation. 
 
26Sep2022 
 
Finalized. 
 
 
PPD
PPD
PPD
PPD
PPD
PPD


 
  
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Table of Contents 
STATISTICAL ANALYSIS PLAN ..........................................................................................1 
Statistical Analysis Plan Signature Page .............................................................................................................. 2 
Modification History ............................................................................................................................................ 3 
LIST OF TABLES ....................................................................................................................9 
LIST OF FIGURES ..................................................................................................................9 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  ..........................................1 
1. 
INTRODUCTION ...........................................................................................................1 
2. 
STUDY OBJECTIVES ...................................................................................................1 
2.1. 
Primary Objective ..................................................................................................................................... 1 
2.2. 
Secondary Objectives ................................................................................................................................ 1 
2.3. 
Safety Objective ........................................................................................................................................ 1 
2.4. 
Other Objectives ....................................................................................................................................... 1 
2.5. 
Estimands .................................................................................................................................................. 1 
3. 
STUDY DESIGN .............................................................................................................3 
3.1. 
General Description .................................................................................................................................. 3 
3.2. 
Schedule of Events .................................................................................................................................... 4 
3.3. 
Changes to Analysis from Protocol ........................................................................................................... 4 
4. 
PLANNED ANALYSES ..................................................................................................4 
4.1. 
Interim Analysis ........................................................................................................................................ 4 
4.2. 
Final Analysis ............................................................................................................................................ 5 
5. 
ANALYSIS SETS ............................................................................................................5 
5.1. 
Screened Set .............................................................................................................................................. 5 
5.2. 
Randomized Set......................................................................................................................................... 5 
5.3. 
Full Analysis Set [FAS] ............................................................................................................................. 5 


 
  
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5.4. 
Per Protocol Set  ........................................................................................................................................ 5 
5.5. 
Modified Full Analysis Set ........................................................................................................................ 6 
5.6. 
Safety Set ................................................................................................................................................... 6 
5.7. 
Pharmacokinetic Set ................................................................................................................................. 6 
6. 
GENERAL CONSIDERATIONS ...................................................................................6 
6.1. 
Reference Start Date and Study Day ........................................................................................................ 6 
6.2. 
Baseline ..................................................................................................................................................... 7 
6.3. 
Retests, Unscheduled Visits and Early Termination Data ....................................................................... 7 
6.4. 
Windowing Conventions ........................................................................................................................... 7 
6.5. 
Statistical Tests.......................................................................................................................................... 9 
6.6. 
Common Calculations ............................................................................................................................... 9 
6.7. 
General Study Information ....................................................................................................................... 9 
7. 
DETERMINATION OF SAMPLE SIZE .......................................................................9 
8. 
STATISTICAL CONSIDERATIONS ............................................................................9 
8.1. 
Multicenter Studies ................................................................................................................................... 9 
8.2. 
Adjustments for Covariates and Factors to be Included in Analyses .................................................... 10 
8.3. 
Missing data ............................................................................................................................................ 10 
8.4. 
Multiple Comparisons/ Multiplicity ....................................................................................................... 10 
8.5. 
Subgroup Analyses .................................................................................................................................. 10 
9. 
OUTPUT PRESENTATIONS ...................................................................................... 11 
10. 
DISPOSITION AND PROTOCOL DEVIATIONS ..................................................... 11 
11. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 12 
11.1. Derivations .............................................................................................................................................. 14 
12. 
MEDICAL HISTORY................................................................................................... 14 
13. 
MEDICATIONS AND NON-DRUG TREATMENT ................................................... 15 
13.1. Medications ............................................................................................................................................. 15 


 
  
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13.2. Non-Drug Treatment .............................................................................................................................. 15 
14. 
STUDY TREATMENT EXPOSURE ........................................................................... 15 
14.1. Derivations .............................................................................................................................................. 16 
15. 
STUDY TREATMENT COMPLIANCE ..................................................................... 16 
15.1. Derivations .............................................................................................................................................. 16 
16. 
EFFICACY OUTCOMES ............................................................................................. 17 
16.1. Primary Efficacy ..................................................................................................................................... 18 
16.1.1. 
Primary Efficacy Variable and Derivation .......................................................................................... 18 
16.1.2. 
Missing Data Methods for Primary Efficacy Variable ......................................................................... 18 
16.1.3. 
Primary Analysis of Primary Efficacy Variable .................................................................................. 19 
16.1.4. 
Supplementary Analysis of Primary Efficacy Variables ...................................................................... 19 
16.1.5. 
Key Secondary Efficacy Variables and Derivations ............................................................................ 19 
16.1.6. 
Missing Data Methods for Key Secondary Efficacy Variables ............................................................ 20 
16.1.7. 
Primary Analysis of Key Secondary Efficacy Variables  .................................................................... 20 
16.1.8. 
Supplementary Analysis of Key Secondary Efficacy Variables ........................................................... 20 
16.2. Other Secondary Efficacy Variables and Derivations ............................................................................ 20 
16.2.1. 
Missing Data Methods for Other Secondary Efficacy Variables .......................................................... 20 
16.2.2. 
Analysis of Other Secondary Efficacy Variables ................................................................................ 21 
 
 
 
 
 
 
 
 
17. 
HEALTH-RELATED QUALITY OF LIFE AND HEALTHCARE RESOURCE 
UTILIZATION ANALYSIS  .................................................................................................. 22 
17.1. Variables & Derivations.......................................................................................................................... 22 
17.1.1. Inflammatory Bowel Disease Questionnaire [IBDQ] ............................................................................. 22 
17.1.2. 36-Item Short Form Health Survey, Version 2 ....................................................................................... 22 
17.1.3. Work Productivity and Activity Impairment Questionnaire – Ulcerative Colitis ................................. 23 
17.1.4. Urgency Numeric Rating Scale [NRS] .................................................................................................... 23 
17.1.5. Abdominal Pain NRS .............................................................................................................................. 23 
17.1.6. UC-Related Hospitalizations and Surgeries ........................................................................................... 23 
CCI


 
  
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17.2. Missing Data Methods............................................................................................................................. 23 
18. 
SAFETY OUTCOMES ................................................................................................. 23 
18.1. Adverse Events ........................................................................................................................................ 24 
18.1.1. 
All TEAEs ........................................................................................................................................ 24 
18.1.2. 
TEAEs Leading to Discontinuation of Study Treatment ..................................................................... 25 
18.1.3. 
Serious and Non-Serious TEAEs ....................................................................................................... 25 
18.1.4. 
TEAEs Leading to Death ................................................................................................................... 25 
18.1.5. 
TEAEs of Special Interest .................................................................................................................. 25 
18.1.6. 
Overall Summary of Adverse Events ................................................................................................. 26 
18.2. Deaths ...................................................................................................................................................... 27 
18.3. Laboratory Evaluations .......................................................................................................................... 27 
18.3.1. Safety Laboratory Evaluations ............................................................................................................... 27 
18.3.2. Pregnancy Tests ...................................................................................................................................... 29 
18.3.3. Other Screening Laboratory Assessments .............................................................................................. 29 
18.4. ECG Evaluations ..................................................................................................................................... 29 
18.4.1. 
ECG Markedly Abnormal Criteria ..................................................................................................... 30 
18.5. Vital Signs ............................................................................................................................................... 31 
18.5.1. 
Vital Signs Specific Derivations ........................................................................................................ 32 
18.5.2. 
Vital Signs Markedly Abnormal Criteria ............................................................................................ 32 
18.6. Physical Examination .............................................................................................................................. 33 
18.7. Other Safety Assessments ....................................................................................................................... 33 
18.7.1. 
Pulmonary Function Tests ................................................................................................................. 33 
18.7.2. 
Ophthalmoscopy And Optical Coherence Tomography [OCT] ........................................................... 33 
18.7.3. 
Tuberculosis Screening and Chest X-Ray ........................................................................................... 34 
19. 
EFFICACY-RELATED BIOMARKERS .................................................................... 34 
20. 
PHARMACOKINETICS .............................................................................................. 34 
 
 
22. 
REFERENCES .............................................................................................................. 37 
APPENDIX 1. 
Programming Conventions for Outputs ................................................................................. 38 
IQVIA Output Conventions ............................................................................................................................... 38 
Decimals and Percentages .................................................................................................................................. 38 
Dates & Times .................................................................................................................................................... 38 
CC
I


 
  
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Spelling Format .................................................................................................................................................. 38 
Presentation of Treatment Groups .................................................................................................................... 38 
Presentation of Visits .......................................................................................................................................... 38 
Listings ............................................................................................................................................................... 39 
APPENDIX 2. 
Partial Date Conventions ........................................................................................................ 40 
Algorithm for Treatment Emergence of Adverse Events in study apd334-308: ............................................... 40 
Algorithm for Prior / Concomitant Medications: .............................................................................................. 41 
APPENDIX 3. 
IBDQ SCORING RULES ....................................................................................................... 43 
APPENDIX 4. 
SF-36 Domain Scores .............................................................................................................. 44 
APPENDIX 5. 
WPAI-UC SCORING RULES ............................................................................................... 45 
APPENDIX 6. 
CLASSIFICATION OF RESCUE THERAPY ...................................................................... 46 
 
 
 


 
  
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LIST OF TABLES 
Table 1 
List of Estimands ...................................................................................................... 2 
Table 2 
Visit Windows for Efficacy and Safety Analyses  ..................................................... 7 
Table 3 
Planned Analyses by Endpoint ................................................................................ 19 
Table 4 
Markedly Abnormal Criteria for Vital Signs ........................................................... 32 
 
LIST OF FIGURES 
Figure 1 Study Design ................................................................................................................. 4 


 
  
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Explanation 
5-ASA 
5-aminosalicylic acid 
AE 
adverse event 
AESI 
adverse events of special interest 
ALC 
absolute lymphocyte count 
ALP 
Alkaline phosphatase 
ALT 
alanine aminotransferase 
APD334 
etrasimod 
Arena 
Arena Pharmaceuticals, Inc. 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AV 
atrioventricular 
β-hCG 
beta-human chorionic gonadotropin 
BLQ 
below the limit of quantification 
BMI 
Body Mass Index 
bpm 
beats per minute 
CI 
confidence interval 
CM 
concomitant medication 
CMH 
Cochran-Mantel-Haenszel 
Covid-19 
coronavirus disease 2019 
CR 
Copy Reference 
CRP 
C-reactive protein 
CS 
Clinically Significant 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough,ss 
Average steady-state tough plasma concentration 
CV 
coefficient of variation 
DBP 
Diastolic blood pressure 
DLCO 
diffusing capacity of the lungs for carbon monoxide 
EAIR 
exposure-adjusted incidence rate 


 
  
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Abbreviation 
Explanation 
ECG 
electrocardiogram 
eCRF 
electronic caser report form 
eDISH 
evaluation of Drug-Induced Serious Hepatotoxicity 
 
 
ES 
endoscopic score 
FAS 
Full Analysis Set 
FCP 
fecal calprotectin 
FCS 
fully conditional specification 
FDA 
Food and Drug Administration 
FEF 
Forced Expiratory Flow 
FEV1 
Forced Expiratory Volume in 1 second 
FVC 
Forced Vital Capacity 
GGT 
gamma-glutamyl transferase 
HR 
heart rate 
HRQoL 
Health-Related Quality of Life 
hs-CRP 
high-sensitivity C-reactive protein 
IBDQ 
Inflammatory Bowel Disease Questionnaire 
ICF 
informed consent form 
JAK 
Janus kinase 
LLQ 
limit of quantification 
LOESS 
locally estimated scatterplot smoothing 
LS 
Least squares 
MAR 
missing at random 
MCMC 
Markov Chain Monte Carlo 
MCS 
mental component summary 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
modified Full Analysis Set 
MMRM 
mixed-effect model with repeated measures 
MMS 
modified Mayo score 
MNAR 
missing not at random 
NCS 
Not Clinically Significant 
CCI


 
  
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Abbreviation 
Explanation 
NHI 
Nancy Histologic Index 
NRI 
Nonresponder imputation 
NRS 
Numeric Rating Scale 
OCT 
optical coherence tomography 
OLE 
open-label extension 
PCS 
physical component summary 
PFT 
pulmonary function test 
PGA 
Physicians Global Assessment 
PK 
pharmacokinetics 
PRES 
posterior reversible encephalopathy syndrome 
PT 
preferred term 
RB 
rectal bleeding 
 
 
RNA 
ribonucleic acid 
SAE 
serious adverse events 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SF 
stool frequency 
SF-36 
36-Item Short Form Health Survey 
SI 
International System of Units 
SOC 
system organ class 
SS 
Steady state 
TB 
Tuberculosis 
TEAE 
treatment-emergent adverse event 
TLC 
Total Lung Capacity 
TME 
targeted medical event 
TMS 
total Mayo score 
TNFα 
tumor necrosis factor alpha 
UC 
ulcerative colitis 
CCI


 
  
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Abbreviation 
Explanation 
UC-PRO/SS 
ulcerative colitis patient-reported outcomes signs and symptoms 
ULN 
Upper limit of normal 
ULQ 
upper limit of quantification 
WHO 
World Health Organization 
WPAI-UC 
Work Productivity and Activity Impairment Questionnaire – Ulcerative Colitis 
 


 
  
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the statistical rationale, methods,  rules and 
conventions to be used in the presentation and analysis of efficacy, safety, pharmacokinetic, 
health-related subject-reported outcome and biomarker data for Protocol APD334-308. It 
describes the data to be summarized and analyzed, including specifics of the statistical analyses 
to be performed (ICH 1998). This SAP is based on protocol version Original 0.0, dated 15 April 
2020. 
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 ulcerative colitis (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 Objectives 
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). 
2.4. 
Other Objectives 
Other objectives include evaluation of etrasimod pharmacokinetics (PK) and the effect of 
etrasimod on health-related subject-reported outcomes and biomarkers. 
2.5. 
Estimands 
The primary and key secondary efficacy estimands to support regulatory decisions are described 
in Table 1. The analyses will be performed on the Full Analysis Set (FAS) as defined in 
Section 5.3. Other secondary efficacy variables (specified in Section 16.3.1) will have the 
population, intercurrent event handling strategy and population-level summary measure similar 
to the primary estimand. Supplementary analyses for the primary and the key secondary 
estimands will be performed on the modified Full Analysis Set (mFAS) and the Per Protocol 
populations, respectively . 


 
  
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Table 1 
List of Primary and Key Secondary Estimands  
Estimand 
Definition 
Attribute 
Population 
Variable/Endpoint 
Intercurrent Event 
Handling Strategy 
Population-Level 
Summary Measure 
Primary 
Estimand 1 
Efficacy of 
etrasimod on 
clinical 
remission at 
Week 52 
Enrolled 
subjects who 
receive at least 
1 dose of 
etrasimod 
The proportion of 
subjects with SF = 0 (or 
= 1 with a ≥ 1-point 
decrease from Baseline 
in APD334-302), 
RB = 0, and ES ≤ 1 
(excluding friability) at 
Week 52 
Subjects with 
missing data for any 
reason (including 
discontinuation due 
to lack of efficacy or 
adverse event 
related to UC) or 
any of the 
3 intercurrent 
eventsa before the 
efficacy assessment 
will be treated as 
nonresponders.  
Difference between 
etrasimod and 
placebo in 
proportion of 
responders at 
Week 52 
Key 
Secondary 
Estimand 1 
Efficacy of 
etrasimod on 
endoscopic 
improvement 
at Week 52 
Enrolled 
subjects who 
receive at least 
1 dose of 
etrasimod 
The proportion of 
subjects with ES of ≤ 1 
(excluding friability) at 
Week 52 
Same as the 
intercurrent event 
handling strategy for 
the primary 
estimand 
Difference between 
etrasimod and 
placebo in 
proportion of 
responders at 
Week 52 
Key 
Secondary 
Estimand 2 
Efficacy of 
etrasimod on 
symptomatic 
remission at 
Week 52 
Enrolled 
subjects who 
receive at least 
1 dose of 
etrasimod 
The proportion of 
subjects with SF = 0 (or 
= 1 with a ≥ 1-point 
decrease from Baseline 
in APD334-302) and 
RB = 0 at Week 52. 
Same as the 
intercurrent event 
handling strategy for 
the primary 
estimand 
Difference between 
etrasimod and 
placebo in 
proportion of 
responders at 
Week 52 
Key 
Secondary 
Estimand 3 
Efficacy of 
etrasimod on 
corticosteroid-
free clinical 
remission at 
Week 52 
Enrolled 
subjects who 
receive at least 
1 dose of 
etrasimod 
The proportion of 
subjects with clinical 
remission at Week 52, 
while not receiving 
corticosteroids for 12 
or more weeks in the 
40-Week Treatment 
Period 
Same as the 
intercurrent event 
handling strategy for 
the primary 
estimand 
Difference between 
etrasimod and 
placebo in 
proportion of 
responders at 
Week 52 
Key 
Secondar
y 
Estimand 
4 
Efficacy of 
etrasimod on 
mucosal 
healing at 
Week 52 
Enrolled 
subjects who 
receive at 
least 1 dose of 
etrasimod 
The proportion of 
subjects with ES of 
≤ 1 (excluding 
friability) with 
histologic remission 
measured by a Geboes 
Index score < 2.0 at 
Week 52 
Same as the 
intercurrent event 
handling strategy 
for the primary 
estimand 
Difference between 
etrasimod and 
placebo in 
proportion of 
responders at 
Week 52 


 
  
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Estimand 
Definition 
Attribute 
Population 
Variable/Endpoint 
Intercurrent Event 
Handling Strategy 
Population-Level 
Summary Measure 
Key 
Secondar
y 
Estimand 
5 
Efficacy of 
etrasimod on 
sustained 
clinical 
remission 
Enrolled 
subjects who 
receive at 
least 1 dose of 
etrasimod 
The proportion of 
subjects with 
sustained clinical 
remission (clinical 
remission at both 
Weeks 12 and 52) 
Same as the 
intercurrent event 
handling strategy 
for the primary 
estimand 
Difference between 
etrasimod and 
placebo in 
proportion of 
responders 
a Intercurrent events include: 1) initiate a rescue medication for UC, 2) have an increase in dose over Baseline levels in their 
existing UC medication, or 3) have colectomy or ileostomy before the efficacy assessment. 
 
This SAP will analyze on the data collected in APD334-308 (from Week 16 to Week 52). The 
scope of analysis will be specified in Table/Listing/Figure shells. To fully address study primary 
objective “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)”, after database lock and 
treatment unblinding, an integrated analysis of Study APD334-302 and Study APD334-308 will 
be performed for all Japanese subjects who had enrolled in ADP334-302 and covers the 
complete data from APD334-302 and to APD334-308. 
3. 
STUDY Design 
3.1. 
General Description 
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 1). 
Japanese subjects who completed the Week 12 visit of Study APD334-302 are eligible for Study 
APD334-308. 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 of Study 
APD334-308. 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. 


 
  
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3.2. 
Schedule of Events 
Schedule of events can be found in Appendix Table 7 of the protocol. 
3.3. 
Changes to Analysis from Protocol 
Note that Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms (UC-PRO/SS) was 
never implemented in Study APD334-308. Therefore, no summary is planned. 
Protocol Section 10.12.1 Efficacy Analysis specified “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).”  Due to the limited number of subjects enrolled in APD334-308 and globally stratified 
randomization do not control for treatment balance in Japanese subjects, above mentioned CMH 
method was remove from for APD334-308 efficacy analyses.   
4. 
PLANNED ANALYSES 
The following analyses will be performed for this study: 
 Final Analysis for APD334-308 data only 
 An integrated analysis that covers the complete data from APD334-302 and to 
APD334-308. This analysis will be specified in a separate analysis plan 
4.1. 
Interim Analysis  
There is no planned interim analysis for this study. 
Figure 1 Study Design 


 
  
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4.2. 
Final Analysis  
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics 
following Sponsor (Arena Pharmaceuticals, Inc., hereafter referred to as Arena) authorization of 
the SAP, database lock, analysis sets, and unblinding of treatment. After Arena has authorized 
breaking of the study blind, the final analysis will be performed. 
Any, post-hoc, 
 analyses completed to support planned study analyses, which were 
not identified in this SAP, will be documented and reported in the clinical study report (CSR). 
Any results from these unplanned analyses will also be clearly identified in the text of the CSR 
(ICH, 1995). 
5. 
ANALYSIS SETS 
Agreement and authorization of subjects included/excluded from each analysis set will be 
conducted prior to the unblinding of the study.  
5.1. 
SCREENED SET  
The Screened Set will consist of all subjects who sign informed consent to participate in the 
study.  No analysis is planned in this set. 
5.2. 
RANDOMIZED SET  
The Randomized Set will consist of all Japanese subjects who are randomized to study treatment 
at the start of Study APD334-302. No analysis is planned in this set. 
5.3. 
FULL ANALYSIS SET [FAS] 
The FAS will consist of all enrolled subjects who signed informed consent form and receive at 
least 1 dose of study treatment during Study APD334-308. Subjects will be summarized by the 
treatment group to which they were randomized in Study APD334-302, regardless of the 
treatment actually received during Study APD334-308. 
5.4. 
PER PROTOCOL SET  
Due to a small number of subjects in APD334-308 who meet the Per Protocol criteria, efficacy 
analyses in Per Protocol Set will not be performed. 
CCI


 
  
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5.5. 
MODIFIED FULL ANALYSIS SET 
The mFAS will consist of all enrolled subjects who receive at least 1 dose of study treatment and 
have a Baseline and at least 1 post enrollment measurement in APD334-308. Subjects will be 
summarized by treatment to which they were randomized, regardless of treatment actually 
received. Note that the mFAS can vary between endpoints since some subjects may have the data 
needed for inclusion in the mFAS for some endpoints, but not other endpoints. Also note, since 
the Mayo component scores on the disease worsening CRF are manually entered by sites from 
another CRF, these scores will not be used in the derivation of mFAS for measurement of either 
MMS or any of its component scores. 
5.6. 
SAFETY SET  
The Safety Set will include all subjects who receive at least 1 dose of study treatment in Study 
APD334-308. 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. 
5.7. 
PHARMACOKINETIC SET 
The Pharmacokinetic Set will include all subjects in the Safety Set with at least 1 quantifiable 
post-dose etrasimod concentration which is not impacted by protocol violations or events with 
potential to affect the etrasimod concentration. 
6. 
GENERAL CONSIDERATIONS 
6.1. 
Reference Start Date and Study Day 
Study Day will be calculated from the reference start date and will be used to show start/stop day 
of assessments and events. Reference start date is defined as the date of first dose (Day 1 in study 
APD334-302) will appear in every listing where an assessment date or event date appears.  
 If the date of the event is on or after the reference date, then:  
Study Day = (date of event – reference date) + 1 
 If the date of the event is prior to the reference date, then:  
Study Day = (date of event – reference date) 
In the situation where the event date is partial or missing, event dates will be displayed as partial 
or missing, Study Day and any corresponding durations will appear missing in the listings.  


 
  
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6.2. 
Baseline 
Subjects in Study APD334-308  will continue receiving the same study treatment of Study 
APD334-302. Unless otherwise specified, analysis baseline for efficacy and safety (for example 
in change from baseline analysis) is defined as the last non-missing measurement taken prior to 
the date of first dose in Study APD334-302 (including unscheduled assessments). If 
measurements include time (except for health-related quality of life [HRQoL] instruments), the 
date/time will be used to define Baseline. Otherwise, only dates will be compared. For HRQoL 
instruments, only the date will be used to derive Baseline. In the case where the last non-missing 
measurement and the date of first dose coincide and time is not collected, if the measurement 
was planned in the protocol to be done prior to the date of first dose, that measurement will be 
considered in defining Baseline. 
6.3. 
Retests, Unscheduled Visits and Early Termination Data 
For by-visit analyses and summaries, efficacy, safety, HRQoL, and biomarkers data (including 
scheduled, retests, unscheduled, and early termination) will be assigned to visits after the 
application of the windowing conventions described in Section 6.4. All measurements will be 
considered in summaries of abnormalities or worst-case values post Baseline.  
Listings will include scheduled, unscheduled, retest, and early termination data. 
6.4. 
Windowing Conventions  
All scheduled study visits are defined relative to Study Day 1 in ADP334-302, the date of first 
dose in Study APD334-302. Scheduled visit windows are defined in Study APD334-308 
Protocol Appendix 1. A windowing convention will be used to determine the analysis visit value 
for a given measurement and will be applicable for all by-visit summaries and analyses for 
efficacy and safety data. Refer to Table 2 for specific visit windows. 
Table 2 
Visit Windows for Efficacy and Safety Analyses  
For all efficacy (except endoscopy/MMS/histology), efficacy-related biomarkers, safety labs and vital signs. 
Scheduled Study Visit 
(Protocol Scheduled Day) 
Analysis Visit Window 
(Study Day) 
Baseline in Study APD334-302 
≤ 1 
Week 12 (Day 85 ± 3) in Study APD334-302 
72 to 99 
Week 16 (Day 113 ± 7) 
100 to 127 
Week 20 (Day 141 ± 7) 
128 to 155 
Week 24 (Day 169 ± 7) 
156 to 197 
Week 32 (Day 225 ± 7) 
198 to 253 
Week 40 (Day 281 ± 7) 
254 to 309 


 
  
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Week 48 (Day 337 ± 7) 
310 to 351 
Week 52 (Day 365 ± 7) 
> 351 
For endoscopy/MMS/histology/all composite endpoints that include an endoscopy component and/or 
RB/SF component, physician’s global assessment, health-related quality of life, ECGs, OCT, and PFT. 
Scheduled Study Visit 
(Protocol Scheduled Day) 
Analysis Visit Window 
(Study Day) 
Baseline in Study APD334-302 
≤ 1 
Week 12 (Day 85 ± 3)b in Study APD334-302    
66 to 113 (66 to 141 for assessments impacted by 
COVID-19 pandemic)c 
Week 32 (Day 225 ± 7) [PFT only] 
198 to 253 (198 to 281 for assessments impacted by 
COVID-19 pandemic)c 
Week 52 (Day 365 ± 7)b 
337 to 393 (337 to 421 for assessments impacted by 
COVID-19 pandemic)c 
a Applicable only for subjects who required extended monitoring on Day 2 for vital signs and ECGs. 
b Applicable to all Week 12 and Week 52 efficacy endpoints based on any component of Mayo clinic score, such as clinical 
remission and symptomatic remission. Protocol visit window for PFT and OCT at Week 12 is Day 85 ± 7 . 
c Assessments impacted by COVID-19 pandemic are reported in the Date of Visit eCRF. 
ECG, electrocardiogram; eCRF, electronic case report form; MMS, modified Mayo score; OCT, optical coherence tomography; 
PFT, pulmonary function test; RB, rectal bleeding; SF, stool frequency 
 
For cardiac remonitoring upon treatment reinitiation after Day 2, as manifested by more than 
1 timed measurement in vital signs or electrocardiogram (ECG) parameters on the same 
collection date of an unscheduled visit, measurement will be mapped to analysis visit of Cardiac 
Remonitoring 1, Cardiac Remonitoring 2, etc. in the respective analysis dataset. For analysis, 
each timed measurement will be programmatically assigned to the nearest hourly timepoint (e.g., 
Predose, 1-hour Postdose) based on their relationship to the dosing time on the same day. If the 
dosing date/time on the same day is missing, the timepoint will remain missing. Once mapped, 
these timed measurements from cardiac remonitoring visits will not be considered for any other 
analysis visit.  
Windowing will be applied prior to any missing data calculations. The last non-missing 
measurement taken prior to Day 1 (including unscheduled assessments) will be labeled as 
“Baseline”. Unless stated otherwise, data from all visits including scheduled, unscheduled, and 
ET visits will be eligible for allocation to an analysis visit. The 2-Week and 4-Week Follow-Up 
visits will not be included in the visit windows and will be summarized separately without any 
window applied. 
If one or more results for a variable are assigned to the same analysis visit, the result with the 
date closest to the protocol scheduled day will be used in the analysis, except for component 
subscores of MMS or TMS, in which case, the composite score and component subscores from 
the same date will be used in the analysis. If 2 measurements in the same analysis visit window 
are equidistant from the protocol scheduled study day, the earliest measurement will be used in 
the analysis. If multiple assessments are available on the same day, then the average of the 
assessment will be used in the analysis, except for laboratory and ECG data where the 


 
  
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assessment at the earliest time of the same day will be used. If both central and local assessments 
of the same ECG or lab test are available on the same day, the central result will take precedence 
over the local result. 
For the overlapping visit windows at Week 48 and Week 52, Week 52 will take priority.  
6.5. 
Statistical Tests 
Due to the limited number of subjects anticipated to enroll in this study and central 
randomization not designed to control for allocation ratio in Japan. Point estimate with 95% 
confidence intervals (CIs) and nominal p-values (2-sided) will be reported.  
6.6. 
Common Calculations 
For quantitative measurements: 
 
Change from Baseline = Test Value at Visit X – Baseline Value 
 
Percent change from Baseline = ((Test Value at Visit X – Baseline Value) / Baseline 
Value) × 100 
 
Proportion at Visit X = Number of subjects satisfying criteria at Visit X / Total 
number of subjects at Visit X 
6.7. 
General Study Information 
A general table with summary of study information will be generated, including the date of first 
subject signed informed consent form (ICF), the last subject visit date, and the database lock 
date. All analyses will be conducted using SAS® (v9.4 or later, SAS Institute Inc., Cary, NC). 
7. 
DETERMINATION OF SAMPLE SIZE 
There is no formal sample size estimation for Study APD334-308. The number of subjects to be 
enrolled in this study was determined by number of Japanese subjects enrolled in  Study 
APD334-302, and those subjects were eligible to enroll according to Study APD334-308 
protocol. 
8. 
STATISTICAL CONSIDERATIONS 
8.1. 
Multicenter Studies 
 
Study APD334-302, the parent study of ADP334-308, was conducted by multiple investigators 
at multiple centers internationally. Randomization to treatment groups is stratified by: 
 
Naïve to biologic/JAK inhibitor therapy at APD334-302 study entry (Yes/No) 


 
  
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 
Baseline corticosteroid use (Yes/No) 
 
Baseline disease activity (MMS: 4 to 6 or 7 to 9) 
There will be no adjustment for investigational site for this study. 
8.2. 
Adjustments for Covariates and Factors to be Included in Analyses 
Due to the limited number of subjects enrolled in this study and central randomization did not 
control treatment balance in Japanese subjects, unless otherwise specified, only endpoint 
Baseline measures are used as covariate in the analyses. For details of their inclusion in the 
models, refer to the specific analysis section.   
8.3. 
Missing data 
Missing adverse event (AE) relationship to study drug and AE seriousness will be imputed as 
described in Section 18.1.1.2 and Section 18.1.3, respectively. Partial or missing AE start dates 
and concomitant medication start dates will also be imputed as described in APPENDIX 2. No 
other missing safety data will be imputed. 
 
Missing efficacy data will be handled as described in Section 16.1.2, Section 16.2.2, and Section 
16.3.2. 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 biomarker measures, urgency Numeric Rating Scale (NRS), abdominal pain NRS, and health 
related quality of life measures, subjects with missing data will be handled using observed cases 
only. 
8.4. 
Multiple Comparisons/ Multiplicity 
There will be no adjustments for multiplicity. Due to the limited number of subjects anticipated 
to enroll in this study. Point estimate with 95% confidence intervals (CIs) and nominal p-values 
(2-sided) will be reported. 
8.5. 
 Subgroup Analyses 
The following subgroups will be assessed for the primary and key secondary endpoints. Baseline 
is referring to APD334-302: 
 
Sex (Female/Male) 
 
Age (≤ or > Median age, and < or ≥ 65). This refers to age collected at Screening in 
Study APD334-302. 
 
Baseline oral corticosteroid usage (Yes/No) 
 
Naïve to biologic/JAK inhibitor therapy at APD334-302 study entry (Yes/No) 


 
  
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 
Baseline disease activity (MMS: 4 to 6 or 7 to 9) 
 
Baseline fecal calprotectin (≤ or > median value) 
 
Baseline total Mayo score (≤ or > 8) 
 Duration of UC (≤ or > Median) 
 
Extent of disease (Proctosigmoiditis/Left-sided colitis, Pancolitis, Proctitis as 
reported on the eCRF)  
 
Proctitis (Yes or No, based on central read) 
 
Prior UC treatment of oral 5-aminosalicylic acid (5-ASA) only (Yes or No) 
 
Prior UC treatment failure of oral 5-ASA only (Yes or No) 
 
Number of prior biologic or JAK inhibitor therapies (1 or > 1) 
 
Prior UC treatment failure of anti-tumor necrosis factor alpha (anti-TNFα) 
(Yes or No) 
Additional subgroups may be assessed, if deemed necessary. The medians will be derived based 
on the FAS for all subgroups cut at the median.  
9. 
OUTPUT PRESENTATIONS 
APPENDIX 1APPENDIX 1 contains conventions for presentation of data in outputs.  
10. 
DISPOSITION AND PROTOCOL DEVIATIONS 
All subjects who provide informed consent will be accounted for in this study. Inclusion criteria 
not met and exclusion criteria met will be listed. 
Among the enrolled subjects, the number and percent of subjects who completed/ discontinued 
treatment, reasons off treatment, the number and percent of subjects who completed/discontinued 
the study, and reasons off study will be summarized. The number and percent of subjects in each 
analysis set will be summarized for all enrolled subjects. A listing of subjects whose blind was 
broken during Study APD334-308 will be provided. The number of subjects whose visit was 
impacted by the COVID-19 pandemic per eCRF will also be summarized by nominal visit. 
During site monitoring, protocol deviations will be graded as Critical, Major or Minor.  
According to ICH E3 and ICH E3(R1), important protocol deviations are a subset of protocol 
deviations that might significantly affect the completeness, accuracy, and/or reliability of the 
study data or that might significantly affect a subject's rights, safety, or well-being (ICH 1995, 
ICH 2012). For example, important protocol deviations might include enrolling subjects in 
violation of key eligibility criteria designed to ensure a specific subject population or failing to 
collect data necessary to interpret primary endpoints, as this may compromise the scientific value 
of the study. 


 
  
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During the review of all reported deviations, important deviations related to study inclusion or 
exclusion criteria, conduct of the study, patient management or patient assessment will be 
identified. Where relevant the importance of a potentially important protocol deviations will be 
assessed in the context of the study’s estimands to evaluate potential impact. 
All important protocol deviations will be summarized for the FAS in the following categories in 
descending frequency in the etrasimod group. 
All protocol deviations will be listed, including whether a deviation was impacted by the 
COVID-19 pandemic (Yes or No). Protocol deviation categories include but are not limited to 
the following: 
 
Informed Consent  
 
Eligibility and Entry Criteria 
 
Concomitant Medication 
 
Laboratory Assessment 
 
Study Procedures  
 
Serious Adverse Event 
 
Visit Schedule 
 
Investigational Product Compliance 
 
Efficacy  
 
Administrative 
 
Source Document 
 
Regulatory or Ethics Approvals 
 
Other 
Important protocol deviations will also be summarized by whether they were impacted by the 
COVID-19 pandemic (Yes or No). Additionally, a summary of missing endoscopy regardless of 
reason and missing endoscopy due to visit impacted by the COVID-19 pandemic will be 
presented by visit. 
11. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
The following demographic data and Baseline characteristics reported in the Study APD334-302 
will be summarized by treatment group for the FAS. 
 
Age on consent (years)  
 
Sex 


 
  
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 
Woman of childbearing potential (Yes/No) 
 
Height (cm) 
 
Weight (kg) 
 
Body Mass Index (BMI) (kg/m2) 
 
Alcohol consumption (Yes/No) 
 
Caffeine consumption (Yes/No) 
 
Tobacco use (Yes/No) 
The following Baseline characteristics related to UC reported in the Study APD334-302 will also 
be summarized by treatment group: 
 
Extent of disease (Proctosigmoiditis, Left-sided colitis, Pancolitis, Proctitis reported 
on the electronic case report form [eCRF], and Proctitis reported from Bioclinica 
Central Read) at APD334-302 study entry 
 
Baseline MMS  
 
Baseline rectal bleeding (RB) subscore 
 
Baseline stool frequency (SF) subscore 
 
Baseline endoscopic subscore  
 
Baseline physician’s global assessment (PGA) 
 
Baseline TMS 
 
Duration of UC (years) 
 
Any acute exacerbations within past 12 months prior to APD334-302 study entry 
(Yes/No), including the number of acute exacerbations among those with any acute 
exacerbation = Yes 
 
Colonoscopy within past 12 months prior to APD334-302 study entry (Yes/No) 
 
Surgery for UC (Yes/No) at APD334-302 study entry, including the number of 
surgeries among those with surgery for UC = Yes 
 
Hospitalizations for UC (Yes/No), including the number of hospitalizations at 
APD334-302 study entry 
 
Naïve to biologic/JAK inhibitor therapy at APD334-302 study entry (Yes/No) – 
Reported (used for stratification at randomization) 
 
Naïve to biologic/JAK inhibitor therapy at APD334-302 study entry (Yes/No) – 
Actual (medications reported on the eCRF) 
 
Baseline Corticosteroid use (Yes/No) – Reported (used for stratification at 
randomization) 


 
  
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 
Baseline Corticosteroid use (Yes/No) – Actual (medications reported on the eCRF) 
 
Baseline MMS group (4 to 6, 7 to 9) – Reported (used for stratification at 
randomization) 
 
Baseline MMS group (4 to 6, 7 to 9) – Actual (scores reported on the eCRF) 
 
Naïve to biologic/JAK inhibitor therapy at APD334-302 study entry – Difference 
between the Reported and the Actual  
 
Baseline Corticosteroid use (Yes/No) – Difference between the Reported and the 
Actual 
 
Baseline MMS group (4 to 6, 7 to 9) – Difference between the Reported and the 
Actual 
 
Prior failure of oral 5-ASA only (Yes or No) 
 
Prior failure of anti-TNFα (Yes or No) 
 
Prior failure of anti-TNFα or vedolizumab (Yes or No) 
Prior treatment for UC will be summarized, including category of treatment, reason for 
discontinuation, and estimated duration (weeks) of corticosteroid use over the last 12 months. 
11.1. 
Derivations 
 
Duration of UC (year) = (Informed consent date at APD334-302 – Date of diagnosis 
+ 1) / 365.25 
 
Weight (kg) = Weight (lb) × 0.4536  
 
Height (cm) = Height (in) × 2.54 
 
Height (m) = Height (in) × 0.0254 = Height (cm) × 0.01 
 
BMI (kg/ m2) = weight (kg)/ height (m)2 
12. 
MEDICAL HISTORY 
Medical history not previously collected in Study APD334-302 will be collected on the medical 
history eCRF and coded using Medical Dictionary for Regulatory Activities (MedDRA, v24.1). 
The version used to code medical history will be displayed in the outputs. All medical history in 
APD334-308 will be summarized for the Safety Set by system organ class (SOC) and preferred 
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13. 
MEDICATIONS AND NON-DRUG TREATMENT 
13.1. 
Medications 
Medications will be captured on the Concomitant Medications eCRF and coded using the WHO 
Drug dictionary (WHODDE01SEP2021). Refer to APPENDIX 2 for handling of partial dates for 
medications. In the case where it is not possible to define a medication as prior or concomitant, 
the medication will be classified by the worst case (ie, concomitant). 
 
‘Prior’ medications are medications which started and stopped prior to the first dose 
of study treatment in study APD334-302. 
 
‘Concomitant’ medications in study APD334-308 are medications which started prior 
to, on or after the first dose of study treatment in APD334-308 AND ended on or after 
the date of first dose of study treatment in APD334-308 or were ongoing at the end of 
this study. 
All medications will be listed. Concomitant medications in ADP334-308 that continue from the 
Study APD334-302 will be flagged in the listing. 
13.2. 
Non-Drug Treatment 
Non-drug treatment will be captured on the Concomitant Non-drug treatment eCRF and coded 
using MedDRA Version 23.1 or newer. 
 
‘Prior’ medications are medications which started and stopped prior to the first dose 
of study treatment in Study APD334-302. 
 
‘Concomitant’ medications in study APD334-308 are medications which started prior 
to, on or after the first dose of study treatment in APD334-308 AND ended on or after 
the date of first dose of study treatment in APD334-308 or were ongoing at the end of 
this study. 
Concomitant non-drug treatment in ADP334-308 will be reported in listing and those continue 
form the Study APD334-302 will be flagged in the listing.  
14. 
STUDY TREATMENT EXPOSURE 
The date of first and last study treatment administration in Study APD334-308 will be taken 
from eCRF. Interruptions, compliance, and dose changes are taken into account for duration of 
exposure. Exposure to study treatment in weeks will be summarized for the Safety Set. 
Dose interruptions will be recorded on the Dosing Administration eCRF, and overdose will be 
recorded on the Overdose eCRF. The frequency and percentage of subjects who had at least one 
dose interruption, who had at least 1 dose interruption of > 7 days, who had at least 1 dose 
interruption of > 14 days, who had 1 overdose, and who had > 1 overdose will be summarized. 


 
  
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14.1. 
Derivations 
Duration of exposure (weeks) in Study APD334-308 = (date of last study treatment 
administration – date of Week 12 study treatment administration in Study APD334-302 + 1) / 7. 
For subjects with missing Date of Last Dose on the End of Study eCRF, their date of last study 
treatment administration will be imputed by the last date of all dosing administration start/stop 
dates recorded. 
15. 
STUDY TREATMENT COMPLIANCE  
The total number of tablets expected, total number of tablets taken, total number of tablets 
missed, overall compliance with study treatment, frequency and percentage of subjects with 
overall compliance of < 80% or > 120% will be summarized for the Safety Set of APD334-308. 
 
15.1. 
Derivations 
Compliance to study treatment is based on the Drug Accountability eCRF and will be calculated 
as the total number of tablets taken (total dispensed – total returned) divided by the number of 
tablets expected during the treatment period, expressed as a percentage, refer to calculations 
below.  
The total number of tablets expected is defined as the number of tablets that a subject is expected 
to have taken between their first and last study treatment administration and is numerically 
identical to the subject’s overall study treatment exposure, since the medication is to be taken 
once daily. On any site visit day, the medication is to be held and taken at the site, after all 
predose assessments have been completed. For example, if a subject took their last dose of study 
treatment on Day 200 and returned to the site on Day 207 to return the study treatment bottle, 
then the total number of tablets expected would be 200, not 206.  
 Overall compliance to study treatment will be calculated as follows: The total number 
of tablets returned subtracted from total number of tablets dispensed, divided by the 
duration of treatment, multiplied by 100  
For all bottles not returned, it will be assumed that all dispensed tablets were taken. For each 
subject, if a high percentage (> 25%) of bottles were not returned by a subject, additional 
analyses may be done where bottles not returned are excluded from the overall compliance 
calculation for the subject. In such analysis, the date of last dose or the date of last bottle return, 
whichever is earlier, will be used as the “date of last dose” in the calculation above.  
Both scheduled and unscheduled study treatment dispensations will be used in the compliance 
calculation. Overall compliance calculations will be performed for the study of APD334-308 and 
will be used in determining inclusion/exclusion of subjects in the respective Per Protocol Set. 


 
  
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16. 
EFFICACY OUTCOMES  
Unless otherwise stated, the primary efficacy analyses will be based on subject stratum used at 
the time of randomization in Study APD334-302 for the FAS. Primary and key secondary 
efficacy analyses will be repeated for all subjects. The following definitions will be used to 
assess efficacy outcomes: 
 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 of 0 
 Symptomatic response: Decrease from Baseline ≥ 30% in both 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 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CCI


 
  
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 Corticosteroid free clinical remission: Clinical remission at Week 52, while not 
receiving corticosteroids for 12 or more weeks in the 40 Week Treatment Period 
 Sustained clinical remission: Clinical remission at both Week 12 and Week 52 
 Loss of response: 
- 
Achieved clinical response at Week 12 in Study APD334-302 
- 
A ≥ 2-point increase from Week 12 in the combined SF + RB scores and 
combined SF + RB score of ≥ 4, on 2 consecutive visits (≥ 7 days apart), and 
- 
Confirmed by centrally read ES ≥ 2 and, 
- 
Exclusion of other causes for loss of response unrelated to underlying UC (eg, 
infection) 
16.1. 
Primary Efficacy 
16.1.1. 
Primary Efficacy Variable and Derivation 
The primary efficacy endpoints will compare etrasimod to placebo for:  
 The proportion of subjects achieving clinical remission at Week 52 
Clinical remission is defined in Section 15. The SF, RB, and ES subscores will be based on the 
Mayo Clinic Score eCRF. Subjects who achieve clinical remission will be referred to as 
responders. Subjects who do not achieve clinical remission will be referred to as non-responders. 
There will be no adjustments for multiplicity as discussed in Section 8.4.  
16.1.2. 
Missing Data Methods for Primary Efficacy Variable 
Subjects who 1) discontinue the study for lack of efficacy, or adverse event related to UC, 2) 
initiate a rescue medication for UC, 3) have an increase in dose over Baseline levels in their 
existing UC medication, or 4) have rescue medical procedure (e.g., colectomy, ileostomy, or 
sigmoidectomy) during the study as confirmed after blinded review by clinical and medical team 
members before study unblinding will be considered to have a known (i.e., non-missing) 
outcome of nonresponse in the analysis of all efficacy endpoints at any subsequent timepoints, 
including the primary endpoint. The rescue medications will be identified by the Arena clinical 
team during blinded data review. Refer to APPENDIX 6APPENDIX 6 for the definition of 
rescue therapies (medication and medical procedures). In scenarios #2 and #3 above, if a subject 
has efficacy measurement collected after the initiation or dose increase from Baseline of UC 
medication, the observed data will be censored at the time of initiation or dose increase and they 
will be considered having a nonresponse. Subjects in all 4 scenarios above may still be included 
in the respective Per Protocol Set, provided they do not violate other criteria for Per Protocol Set. 
For example, they will be excluded from the respective Per Protocol Set if they initiate a 
prohibited medication before Week 52 efficacy assessment that can affect efficacy of the study 


 
  
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treatment and the indication is unrelated to UC.  
Analysis visits will be mapped as per Section 6.4 before any missing data imputation method is 
applied. 
Subjects with missing efficacy outcome will be included in the primary analyses using single 
imputation as nonresponder. Supplementary analyses of efficacy outcomes will be performed in 
modified Full Analysis Set with data as observed. 
16.1.3. 
Primary Analysis of Primary Efficacy Variable 
The primary efficacy analysis will be performed for the FAS. Results will be expressed as the 
number and percentage of subjects in remission, difference in remission percentages and 95% CI 
and nominal p-value from Fisher’s Exact test, odds ratio and 95% CI.  
16.1.4. 
Supplementary Analysis of Primary Efficacy Variables  
The primary analysis as described in Section 16.1.3 will be repeated using the mFAS (with data 
as observed) as supplementary analyses.  
Key Secondary Efficacy 
Key secondary efficacy endpoints are defined in Section 16.2. In general, all the primary and 
supplementary analyses planned for the primary endpoints in Section 16.1.3 and Section 16.1.4 
will be repeated for each key secondary efficacy endpoint (Table 3). No Multiplicity adjustments 
will be conducted as discussed in Section 8.4. 
Table 3 
Planned Analyses by Endpoint 
Endpoint 
Primary Analysis in FAS 
Supplementary Analyses in 
mFAS 
Primary endpoint: Clinical remission at Week 52 
X 
X 
Key secondary endpoints: 
 
 
Endoscopic improvement at Week 52 
X 
X 
Symptomatic remission at Week 52 
X 
X 
Corticosteroid-free clinical remission at Week 52 
X 
X 
Mucosal healing at Week 52 
X 
X 
Sustained clinical remission at Week 12 and at 
Week 52 
X 
X 
16.1.5. 
Key Secondary Efficacy Variables and Derivations 
 Endoscopic Improvement at Week 52.  
 Symptomatic Remission at Week 52.  


 
  
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 Corticosteroid-Free Clinical Remission at Week 52.  
 Mucosal Healing at Week 52.  
 Sustained Clinical Remission (i.e., at both Week 12 in APD334-302 and Week 52 in 
APD334-308).  
There is no multiplicity adjustment in examining any of the key secondary efficacy variables and 
derivations stated above. 
16.1.6. 
Missing Data Methods for Key Secondary Efficacy Variables  
In general, the same missing data methods used for the primary endpoints in Section 16.1.2 will 
be used for the key secondary endpoints. 
16.1.7. 
Primary Analysis of Key Secondary Efficacy Variables  
The primary analysis of these key secondary efficacy endpoints will be performed for the FAS. 
For all key secondary endpoints, the model described in Section 16.1.3 will be used. 
16.1.8. 
Supplementary Analysis of Key Secondary Efficacy Variables  
For all key secondary endpoints, the primary model as described in Section 16.1.3 Section will 
be repeated using the mFAS (with data as observed) as supplementary analyses. 
16.2. 
Other Secondary Efficacy Variables and Derivations 
Other secondary efficacy endpoints are defined in Section 16.  
 The proportion of subjects achieving clinical response at Week 52 
 The proportion of subjects achieving endoscopic normalization at Week 52 
 The proportion of subjects achieving symptomatic remission at Weeks 16, 20, 24, 32, 
40, 48 and 52 
 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) 
16.2.1. 
Missing Data Methods for Other Secondary Efficacy Variables  
All subjects with missing data, regardless of reason for missingness, will be considered as 
nonresponders. The intercurrent events that are considered in the primary efficacy analysis will 
be handled similarly for the other secondary efficacy endpoints, as specified in Section 16.1.2. 


 
  
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16.2.2. 
Analysis of Other Secondary Efficacy Variables  
The analysis of other secondary efficacy endpoints will be performed for the FAS. The primary 
analysis method planned for the primary endpoints in Section 16.1.3 will be repeated for each 
other secondary efficacy endpoint.  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
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17. 
HEALTH-RELATED QUALITY OF LIFE AND HEALTHCARE 
RESOURCE UTILIZATION ANALYSIS  
Subject reported HRQoL instruments will be electronically captured and used in support of the 
efficacy outcomes. All HRQoL are administered at Week 52/Early Termination Visit. The 
HRQoL analyses will be performed using the mFAS data as observed. 
All HRQoL endpoints will be analyzed using  descriptive statistics (n, mean, SD, median, 
minimum, and maximum) 
Healthcare resource utilization endpoints, ie, the proportion of concomitant UC-related 
hospitalizations and the proportion of concomitant UC-related surgeries, including colectomy, 
will be analyzed using the analysis method described in Section 16.1.3. 
17.1. 
VARIABLES & DERIVATIONS 
17.1.1. INFLAMMATORY BOWEL DISEASE QUESTIONNAIRE [IBDQ]  
The IBDQ is a 32-item self-administered questionnaire which has 4 dimensions: bowel 
symptoms (10 items), systemic symptoms (5 items), emotional health (12 items), and social 
function (5 items). Responses are graded on a 7-point Likert scale where 7 denotes “not a 
problem at all” and 1 denotes “a very severe problem”. Scores range from 32 to 224, a higher 
score indicates better quality of life.  
The IBDQ total score and 4 domain subscores will be derived on the eCRF directly. Details 
about scoring rules can be found in APPENDIX 3. 
17.1.2. 
36-ITEM SHORT FORM HEALTH SURVEY, VERSION 2  
The 36-Item Short Form Health Survey (SF-36) is a 36 item, subject-reported survey of subject 
health. The SF-36 consists of 36 questions measuring 8 health domains: Physical functioning, 
bodily pain, role limitations due to physical problems, role limitations due to emotional 
problems, general health perceptions, mental health, social function, and vitality. The subject’s 
responses are solicited using Likert scales that vary in length, with 3 to 6 response options per 
item. The SF-36 will also be scored using 2 overall summary scores: Physical component 
summary (PCS) and mental component summary (MCS) scores. A higher score indicates better 
health status. 
The Physical Component Summary Score (norm based), the Mental Component Summary Score 
(norm based), 8 domain subscores (0 to100 based), and the SF-6D health utility index score are 
derived by Optum and integrated into the SF-36 eCRF. Details about domain scores can be found 
in APPENDIX 4. 
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17.1.3. 
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT QUESTIONNAIRE – ULCERATIVE 
COLITIS 
The Work Productivity and Activity Impairment Questionnaire – Ulcerative Colitis (WPAI-UC) 
consists of 6 questions asking about the effect of UC on the subject’s ability to work and perform 
regular activities. 
The percent work time missed due to problem (absenteeism), percent impairment while working 
due to problem (presenteeism), percent overall work impairment due to problem, and percent 
activity impairment due to problem are derived on the eCRF directly. Details about derivations 
can be found in APPENDIX 7. 
17.1.4. 
URGENCY NUMERIC RATING SCALE [NRS]  
The urgency NRS is a single item that measures the severity for the urgency (sudden or 
immediate need) to have a bowel movement in the past 24 hours using an 11-point NRS ranging 
from 0 (no urgency) to 10 (worst possible urgency). 
17.1.5. 
ABDOMINAL PAIN NRS  
The abdominal pain NRS is a single item that measures the “worst abdominal pain in the past 24 
hours” using an 11-point NRS ranging from 0 (no pain) to 10 (pain as bad as can imagine). 
17.1.6. 
UC-RELATED HOSPITALIZATIONS AND SURGERIES  
The UC-related hospitalizations will be captured on the Adverse Event eCRF. The UC-related 
surgeries, including colectomy, are captured on the Non-Drug Treatment eCRF. Blinded review 
of AE preferred terms will be performed to determine UC-related hospitalizations. 
The UC-related surgeries, including colectomy, will be captured on the Concomitant Non-Drug 
Treatment eCRF.  
17.2. 
MISSING DATA METHODS  
No missing data will be imputed for HRQoL endpoints. 
18. 
Safety Outcomes 
All safety outcomes will be based on the Safety Analysis Set. There will be no statistical 
comparisons between the treatment groups for safety data, unless otherwise specified.  
 


 
  
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18.1. 
Adverse Events 
Adverse Events (AEs) will be coded using MedDRA (version 24.1). The version used to code 
AEs will be displayed in the analyses. Treatment emergent adverse events (TEAEs) are defined 
as AEs that started or worsened in severity on or after the first dose of study treatment in Study 
APD334-308.  
 
An event that was on-going at end of APD334-302 will be reported in APD334-308 only if it 
became worsened (increase in severity) after the first dose of study treatment in Study APD334-
308. In an integrated report combining APD334-302 and APD334-308 data, this event will be 
counted only once.  
 
Refer to APPENDIX 2 for handling of partial dates for AEs for the purpose of assigning 
treatment-emergent flags. In the case where it is not possible to define an AE as treatment 
emergent or not, the AE will be classified as treatment emergent. 
18.1.1. 
All TEAEs 
All TEAEs will be summarized by SOC and PT and presented by descending frequency in the 
etrasimod group. All AEs, regardless of treatment-emergent status, will be included in an AE 
listing. Additionally, a listing of other AE details as collected on the CRF will be presented. 
Exposure-adjusted incidence rate (EAIR) of TEAEs will be summarized by SOC and PT.  
Exposure is defined as the sum of either time (year) from first dose in Study APD334-308 to the 
onset of first such event for those who experienced this AE in Study APD334-308, or time (year) 
from first dose in Study APD334-308 to last participation for those who did not experience this 
AE. The EAIR is calculated as the number of subjects with the AE divided by the total exposure 
in subject-years.  
18.1.1.1. Severity 
Severity is classified as Grade 1: Mild, Grade 2: Moderate, Grade 3: Severe, Grade 4: Life 
Threatening, Grade 5: Death Related to AE, using the Common Terminology Criteria for 
Adverse Events, version 5.0 (CTCAE v5.0). 
All TEAEs will be summarized by SOC, PT, and maximum severity, with SOC and PT 
presented by descending frequency. If a subject reports a TEAE more than once within a 
SOC/PT, the AE with the worst-case severity will be used in this summary. 
18.1.1.2. Relationship to Study Treatment 
Relationship is classified as “not related”, “unlikely related”, “probably related”, or “related” by 
the Investigator. 
All related TEAEs will be summarized by SOC and PT. A “related TEAE” for the purpose of 
this summary is defined as a TEAE with relationship to study drug of “probably related” or 


 
  
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“related”. 
All TEAEs will be summarized by SOC, PT, and highest relationship (as reported on the eCRF, 
not grouped), with SOC and PT presented by descending frequency. If a subject reports a TEAE 
more than once within a SOC/PT, the AE with the worst-case relationship to study treatment will 
be used in this summary. TEAEs with a missing relationship to study treatment will be regarded 
as “Related” to study treatment for summary tabulation purpose only. 
18.1.2. 
TEAEs Leading to Discontinuation of Study Treatment 
TEAEs leading to discontinuation of study treatment will be identified by action taken being 
recorded as “Drug withdrawal” on the Adverse events eCRF. 
All TEAEs leading to discontinuation of study treatment will be summarized by SOC and PT. A 
listing of all TEAEs leading to discontinuation of study treatment will also be presented. 
Liver-related AEs are defined by either SOC of hepatobiliary disorders or PT of alanine 
aminotransferase abnormal, alanine aminotransferase increased, aspartate aminotransferase 
abnormal, aspartate aminotransferase increased, hepatic enzyme abnormal, hepatic enzyme 
increased, liver function test abnormal, liver function test increased, transaminases abnormal, or 
transaminases increased. 
18.1.3. 
Serious and Non-Serious TEAEs  
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Events 
page of the eCRF. A summary of serious TEAEs by SOC and PT will be prepared. 
All serious TEAEs will be summarized by SOC and PT. If the seriousness is missing, the AE 
will be considered as “Serious” for the summary tabulation purpose only. A serious TEAE listing 
will also be presented. All non-serious TEAEs will also be summarized by SOC and PT. 
18.1.4. 
TEAEs Leading to Death 
TEAEs leading to Death are those events which are recorded with an outcome as “Fatal” on the 
Adverse Events eCRF. A listing of TEAEs leading to death will be presented. 
18.1.5. 
TEAEs of Special Interest  
Categories of Targeted Medical Events (TMEs) and a list of preferred terms associated with 
these TME categories were developed based on the mechanism of action of etrasimod, prior 
experience with other agents acting via a similar mechanism, and disease-specific clinical 
judgment. In addition, where standard testing has been implemented to screen for potential AESI 
(eg, electrocardiograms, spirometry, serum transaminases, etc.), the relevant data will be 
reviewed to identify potential cases of AESI that investigators may not have identified and to 
provide quantitative data for AESIs. The proposed candidate terms will be reviewed to identify 
which events reflect AESI. 
Treatment-emergent AESIs will be summarized by category, subcategory, and PT by descending 
frequency by treatment group. Categories and subcategories of TEAEs of special interest are the 


 
  
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following: 
 
Cardiovascular Events 
− Bradycardia 
− AV conduction delay 
− Hypertension 
 
Macular Edema 
 
Pulmonary Disorders 
− Airflow obstruction (forced expiratory volume in 1 second [FEV1], forced vital 
capacity [FVC]) 
− Decrease gas exchange (diffusing capacity of the lungs for carbon monoxide 
[DLCO]) 
 
Infections 
− Severe infections 
− Opportunistic infections (Narrow) 
− Herpes simplex and herpes zoster 
 
Liver Injury 
− Liver transaminases elevation 
− Bilirubin elevation 
 
Posterior Reversible Encephalopathy Syndrome (PRES) 
 
Malignancies 
Exposure-adjusted incidence rate of AESI by category, by subcategory and by PT with 95% CI, 
and rate difference from placebo and 95% CI will be reported in an integrated analysis 
combining APD334-302 and APD334-308 data. 
18.1.6. 
Overall Summary of Adverse Events  
In addition to the summaries above, an overview of TEAEs will be summarized (not broken 
down by SOC or PT) by number and percentage of subjects and by number of AEs: 
 
Any TEAEs 
 
Any related TEAEs 
 
Any serious TEAEs 
 
Any related serious TEAEs 
 
TEAEs leading to death 


 
  
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 
Liver-related TEAEs leading to death 
 
TEAEs leading to study drug discontinuation 
 
Related TEAEs leading to study drug discontinuation 
 
Liver-related TEAEs leading to study drug discontinuation 
 
TEAEs leading to study drug interruption 
 
Related TEAEs leading to study drug interruption 
 
TEAEs by maximum severity 
 
Related TEAEs by maximum severity 
 
TEAEs by relationship to study drug 
*Related TEAEs’ refers to TEAEs related or probably related to study drug. 
Comparative analyses will be performed for: 
 
Deaths 
 
Serious TEAEs 
 
TEAEs leading to study treatment discontinuation 
 
TEAEs of special interest 
 
Serious infections 
 
Opportunistic infections (Narrow) 
 
Malignancies 
18.2. 
Deaths 
Information collected about deaths (e.g., date of death, primary cause of death) will be presented 
in a data listing, as described in Section 18.1.4. 
18.3. 
Laboratory Evaluations 
No local laboratory assessments will be used in any summaries except for lipid panel and thyroid 
panel tests. No local laboratory assessments will be used to derive maximum/minimum/worst 
value. Local laboratory assessments will only be listed.  
18.3.1. 
SAFETY LABORATORY EVALUATIONS  
Hematology, serum chemistry, coagulation, and urinalysis are analyzed and reported by central 
laboratory and sometimes by local laboratory. Results out of reference range are flagged by the 
performing laboratory (e.g., low, high). A full list of laboratory assessments to be included in the 
outputs is included in Clinical Study Protocol APD334-308 Table 7. 


 
  
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In general, presentations will use SI Units. Quantitative laboratory measurements reported as “< 
X” or “> X”, where X may be the lower limit of quantification (LLQ) or the upper limit of 
quantification (ULQ), respectively, will be converted to X for the purpose of quantitative 
summaries, but will be presented as recorded, i.e. as “< X” or “> X” in the listings. For 
urinalysis, only pH and specific gravity are considered as quantitative tests. If local and central 
laboratory assessments are available from the same day, central laboratory assessments will be 
used in the summary as per Section 18.3.1.  
The following summaries will be provided for laboratory data: 
 
Value and change from Baseline by visit (for hematology, serum chemistry, 
quantitative urinalysis [pH and specific gravity], and coagulation) 
 
Incidence of abnormal values according to laboratory reference ranges by visit 
 
Incidence of lymphocytes < 0.2 x 109/L, 0.5 x 109/L, or neutrophils < 0.5 x 109/L, 1 x 
109/L at Week 52 and anytime after first dose in Study APD334-308 
 
Shift from end of treatment to each followup visit in incidence of lymphocytes in 
normal range and in incidence of lymphocytes of at least 80% percent of Baseline, by 
visit (2-Week Follow-Up, 4-Week Follow-Up, and Last FollowUp)Shift from 
Baseline to Week 52/Early Termination Visit according to laboratory reference range 
(for quantitative measurements and categorical measurements) 
 
Evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) plots for the following 
laboratory assessments (using values after the first administration of study treatment): 
 Maximum aspartate aminotransferase (AST) versus same-day total bilirubin 
 Maximum alanine aminotransferase (ALT) versus same-day total bilirubin 
 Maximum gamma-glutamyl transferase (GGT) versus same-day total bilirubin 
 Maximum alkaline phosphatase (ALP) versus same-day total bilirubin 
The eDISH plots above will be repeated with adjustment for elevated Baseline.  
 
Incidence of hepatic enzyme elevations by visit 
− > 1 ×, 2 ×, 3 ×, 5 ×, 8 ×, 10 ×, 20 × upper limit of normal (ULN) elevation in ALT 
− > 1 ×, 2 ×, 3 ×, 5 ×, 8 ×, 10 ×, 20 × ULN elevation in AST 
− > 3 ×, 5 ×, 10 ×, 20 × ULN elevation in either ALT or AST 
− > 1 ×, 1.5 ×, 2 ×, 3 × ULN elevation in total bilirubin 
− > 1 ×, 1.5 ×, 2 ×, 3 ×, 5 ×, 8 × ULN elevation in ALP 
− > 1 ×, 2 ×, 3 ×, 5 ×, 8 × ULN elevation in GGT 
− > 3 × ULN elevation in either ALT or AST and > 1.5 × ULN elevation in total 
bilirubin 
− > 3 × ULN elevation in either ALT or AST and > 2 × ULN elevation in total 


 
  
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bilirubin 
− > 3 × ULN elevation in either ALT or AST and > 1.5 × ULN elevation in ALP 
− > 3 × ULN elevation in either ALT or AST in temporal association with 
treatment-emergent nausea, vomiting, anorexia, abdominal pain, or fatigue identified 
by PT, where temporal association is defined as ±14 days of onset date from the 
time of elevation. 
If both central and local assessments of total bilirubin are available on the same day, the central 
result will take precedence over the local result in the eDISH plot. If the maximum 
AST/ALT/GGT assessment occurs at two 2 different dates, the assessment with the higher 
accompanying Bilirubin value will be used. Two versions of the eDISH plots will be presented, 
with one showing values as multiples of upper limit of normal, and the other one showing values 
as multiples of upper limit of normal, or subject’s baseline, whichever is higher.  
Subject’s laboratory assessments at all timepoints will be listed in chronological order. Values 
outside of the laboratory reference range will be flagged. Values obtained from local laboratory 
will be flagged. Listing of lymphocytes and neutrophils over time in subjects ever with 
lymphocytes <0.5 x 109/L or neutrophils < 1 x 109/L will also be provided. 
18.3.2. 
PREGNANCY TESTS  
Urine beta-human chorionic gonadotropin (β-hCG) and/or serum β-hCG pregnancy tests are 
performed throughout the study in female subjects of childbearing potential. All pregnancy test 
results (positive or negative) will be listed in chronological order. 
18.3.3. 
OTHER SCREENING LABORATORY ASSESSMENTS  
Screening laboratory assessments for virology, drug screen/toxicology, QuantiFERON 
Tuberculosis (TB) Gold, stool pathogens, and Clostridioides difficile (formerly known as 
Clostridium difficile) will be listed. Analyses of genetics and exploratory efficacy-related 
biomarkers data based on samples collected at Screening in subjects who provided consent will 
be described in a separate plan. 
18.4. 
 ECG EVALUATIONS 
ECGs are recorded on a 12-lead ECG machine and read centrally. The following ECG 
parameters will be reported for this study: 
 
HR (bpm) 
 
RR Interval (msec) 
 
PR Interval (msec) 


 
  
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 
QRS Interval (msec) 
 
QT Interval (msec) 
 
QTcF Interval (msec)  
 
Overall assessment of ECG (Investigator’s judgment): 
o Normal 
o Abnormal, Not Clinically Significant (Abnormal NCS) 
o Abnormal, Clinically Significant (Abnormal CS)  
 
Overall interpretation of ECG (central reader): 
o Normal 
o Abnormal NCS 
o Abnormal CS 
 
 
AV conduction abnormalities 
o First-degree AV block 
o Second-degree AV block type 1 
o Second-degree AV block type 2  
o Third-degree AV block  
The following summaries will be provided for ECG data: 
 
Value and change from Baseline by visit (for quantitative measurements)  
 
Incidence of markedly abnormal values (defined in Section 18.4.1) and AV blocks by 
visit  
 
Shift in normal/abnormal NCS/abnormal CS in the overall interpretation (by 
investigator) from Baseline to Week 52/Early Termination Visit and to the worst-case 
post-Baseline result 
 
Shift in markedly abnormal categories from Baseline to post-Baseline by visit 
Listings of ECG results, including first dose cardiac monitoring, and discharge criteria for first 
dose cardiac monitoring will be provided.  
A listing of all ECG assessments over time in subjects meeting markedly abnormal criteria will 
also be provided. For each subject, only ECG parameters ever meeting markedly abnormal 
criteria will be included. 
18.4.1. 
ECG Markedly Abnormal Criteria 
Markedly abnormal quantitative ECG measurements will be identified in accordance with the 


 
  
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following predefined markedly abnormal criteria: 
 
Absolute values in QT and QTcF: 
o ≥ 450 msec (male) or ≥ 470 msec (female) in QTcF 
o > 500 msec in QT 
 
Change from Baseline in QT and QTcF: 
o > 30 msec increase from Baseline 
o > 60 msec increase from Baseline 
In shift tables, subjects will be classified according to the binary category for each parameter and 
the predefined markedly abnormal criterion (i.e., Markedly abnormal vs. Not markedly 
abnormal). 
18.5. 
Vital Signs 
The following vital signs measurements will be reported for this study:  
 
Systolic Blood Pressure (mmHg)  
 
Diastolic Blood Pressure (mmHg)  
 
Heart Rate (bpm)  
 
Respiratory Rate (resp/min)  
 
Temperature (⁰C)  
The following summaries will be provided for vital signs data: 
 
Value and change from Baseline by visit 
 
Value and change from predose on Day 1 (as reported on the eCRF) by timepoint 
o For heart rate only, value and change from predose to minimum postdose heart 
rate on Day 1 will be included in the same table 
 
Incidence of markedly abnormal values (defined in Table 4) by visit, including 
anytime after first dose in Study APD334-308 
 
Listing of subjects meeting markedly abnormal criteria 
 
Incidence of minimum heart rate on Day 1 in Study APD334-302 by postdose 
timepoint (1, 2, 3, 4, and > 4 hours postdose, and Day 1 overall) and heart rate 
interval (≥ 65, 60 to 64, 55 to 59, 50 to 54, 45 to 49, 40 to 44, < 40 bpm) 
o If minimum heart rate is attained at multiple postdose timepoints, only the earliest 
timepoint will be counted in this incidence summary. 


 
  
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 
Time to minimum heart rate on Day 1 in Study APD334-302 by planned hourly 
timepoint (if minimum heart rate is attained at multiple postdose timepoints, only the 
earliest timepoint will be counted). 
o Actual time elapsed from first dose to minimum heart rate on Day 1 will also be 
summarized using descriptive statistics (n, mean, SD, median, minimum, and 
maximum) in the same table. 
 
Line plots for mean value and mean change from predose on Day 1 in Study 
APD334-302, up to 4 hours postdose by parameter and timepoint (systolic blood 
pressure, diastolic blood pressure, and heart rate) 
 
Line plots for mean value and mean change from Baseline by parameter and visit 
(systolic blood pressure, diastolic blood pressure, heart rate, body temperature, and 
respiratory rate) 
Listings of all vital signs, including first dose cardiac monitoring, and discharge criteria for first 
dose cardiac monitoring will be provided. A listing of vital signs assessments over time in 
subjects meeting a markedly abnormal criterion will also be provided. For each subject, only the 
parameters with at least one markedly abnormal criterion satisfied will be included. 
For subjects with extended monitoring or remonitoring, a listing of systolic blood pressure, 
diastolic blood pressure, heart rate values, and change from predose in all parameters on Day 1, 
Day 2, and any remonitoring visit will be provided. 
18.5.1. 
 Vital Signs Specific Derivations 
 
Temperature (°C) = (5/9) (Temperature (°F) – 32) 
18.5.2. 
Vital Signs Markedly Abnormal Criteria 
Markedly abnormal quantitative Vital Signs measurements will be identified in accordance with 
the following predefined markedly abnormal criteria: 
Table 4 
Markedly Abnormal Criteria for Vital Signs 
Variable 
Unit 
Low 
High 
SBP 
mmHg 
≤ 90 mmHg  
> 150 mmHg  
DBP 
mmHg 
≤ 50 mmHg  
> 90 mmHg  
Heart rate 
bpm 
< 40 bpm 
< 50 bpm 
< 50 bpm and decrease from predose 
(Baseline) of > 10 bpm at 4 hours on 
Day 1 or Day 2 or remonitoring visit 
>100 bpm 
bpm, beats per minute; DBP, diastolic blood pressure; SBP, systolic blood pressure. 


 
  
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18.6. 
Physical Examination  
A listing of all physical examination assessments in subjects who had at least 1 abnormal 
finding. 
18.7. 
Other Safety Assessments 
18.7.1. 
Pulmonary Function Tests 
The following pulmonary function test (PFT) measurements (actual and % Predicted) will be 
reported for this study: 
 
FEV1 
 
FVC 
 
Total Lung Capacity (TLC)  
 
FEV1/FVC ratio 
 
Forced Expiratory Flow (FEF) 25-75 
 
DLCO (if available) 
The following summaries will be provided for PFT data: 
 
Value and change from Baseline by visit 
 
Incidence of markedly abnormal values by visit (Section 18.7.1) 
All PFT data will be listed. A listing in subjects who ever reported an abnormality in PFT will 
also be provided, including a flag for whether markedly abnormal criterion is also met. 
18.7.1.1. PFT Markedly Abnormal Criteria 
Markedly abnormal quantitative PFT measurements will be identified in accordance with the 
following predefined markedly abnormal criteria: 
 
• % Predicted FEV1 < 50% 
 
• % Predicted FVC < 50% 
 
• % Predicted FEV1/FVC ratio < 50% 
Potentially important PFT measurements will also be identified using the criteria below: 
 
• Decrease from Baseline > 20% in FEV1, ie, percent change from Baseline < -20% 
 
• Decrease from Baseline > 20% in FVC, ie, percent change from Baseline < -20% 
 
• Decrease from Baseline > 20% in DLCO, ie, percent change from Baseline < -20% 
18.7.2. 
Ophthalmoscopy And Optical Coherence Tomography [OCT] 
The following summaries will be provided for ophthalmoscopy and optical coherence 
tomography (OCT) data: 


 
  
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 
Values and change from Baseline in central foveal thickness and intraocular pressure 
by visit 
 
Categorical results in ophthalmoscopy with OCT parameters by visit (the categories 
are listed on the eCRF) 
Only PFT and OCT assessments completed by 50 or more subjects in the Safety Set will be 
presented in the summaries. 
A listing of all ophthalmoscopy and OCT assessments will be provided. A listing of subjects who 
ever reported an abnormality in OCT will also be provided. Additionally, a listing of retinal 
photograph and eye pressure assessments will be provided for subjects who experienced an AE 
related to eye disorders.  
18.7.3. 
Tuberculosis Screening and Chest X-Ray 
Screening TB results and chest X-rays will be listed. Results of TB questionnaires will also be 
listed. 
19. 
Efficacy-RELATED BIOMARKERS 
Value and change from Baseline in level of FCP, hs-CRP, and lymphocyte counts at protocol-
specified visits will be summarized by visit and treatment for the FAS. Additionally, percent of 
change from Baseline in lymphocyte counts will also be summarized. Change from Baseline in 
these biomarkers to Week 12 of ADP334-302 and all scheduled visits up to Week 52 in 
APD334-308 will also be summarized using descriptive statistics (n, mean, SD, median, 
minimum, and maximum). Additionally, the following summaries will be provided for 
biomarker data: 
 Line plots over time for mean with 95% CI  for the following laboratory assessments: 
 Change from Baseline in lymphocytes 
 Percent change from Baseline in lymphocytes 
 Change from Baseline in hsCRP 
 Change from Baseline in FCP 
The exploratory efficacy-related biomarker analyses for immunophenotyping, proteomics, RNA 
transcriptomics, and fecal microbiome will be described in a separate biomarker analysis plan. 
20. 
Pharmacokinetics 
PK samples to access plasma etrasimod concentrations will be collected prior to dosing (trough) 
at Weeks 16, 20, 24, 32, 40, 48, and 52; and at 2-Week and 4-Week Follow-Up visits for subjects 
that do not enroll into any extension study. A descriptive summary of observed plasma etrasimod 
concentration will be displayed by time and treatment group. Summary of observed plasma 


 
  
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etrasimod concentrations by time and treatment group will be repeated by sex (male or female), 
weight (≤ Median or > Median) and age group (< 18, 18 to < 65, or ≥ 65 years).  Concentrations 
below the limit of quantitation (BLQ) will be assigned a numerical value of zero for the 
calculation of descriptive statistics. For geometric mean and geometric % coefficient of variation 
[CV], the zero values will be excluded. 
The pharmacokineticist will determine the strategy for dealing with data affected by protocol 
deviations or events which may impact the quality of etrasimod concentration data on a 
case-by-case basis with input from the Arena study physician and Arena clinical pharmacologist, 
as needed. Examples for protocol deviations or events include, but may not be limited to, sample 
processing errors that lead to inaccurate bioanalytical results, and/or inaccurate dosing prior to 
PK sampling. In the case of an important protocol deviation or event, the affected PK data 
collected may be excluded from the summaries, calculation of the average steady-state trough 
plasma concentration (Ctrough,ss) based on Week 16 to Week 52 trough concentrations 
(Ctrough,ss,W16W16W16-W52), and population PK analysis, but will be reported in the study result 
listings. 
Individual subject etrasimod plasma concentrations (and etrasimod metabolite concentrations, if 
applicable) will be presented in the data listings, including subject ID, treatment received, sex, 
age, weight, tobacco use, nominal timepoint, actual blood collection date/time, concentration, 
and time since last dose and also summarized using descriptive statistics (n, mean, SD, % CV, 
geometric mean, geometric % CV, median, minimum, and maximum) by nominal timepoint. 
Individual subject steady-state trough (predose) plasma concentration will be averaged across 
Weeks 16 to 52 (Ctrough,ss,W16-W52) and presented in a data listing and summarized using 
descriptive statistics.  
Mean (± SD) etrasimod concentration versus nominal time (Weeks 16 to 52) will be plotted on 
linear scales. Plot will be repeated by sex (male and female).   
Individual subject plasma etrasimod concentrations versus actual time (Weeks 16 to 52) will be 
plotted on linear scale.  
Scatter plots of individual subject average steady-state Ctrough ss,W2-W52 versus Baseline body 
weight as a continuous variables will be generated for the Pharmacokinetic Set, which will also 
include the Spearman’s rank correlation coefficient, p-value, and locally estimated scatterplot 
smoothing (LOESS) trend line. 
Furthermore, the following overlay plots will be generated for the Pharmacokinetic Set within 
the etrasimod group only: 
 Mean (SD) absolute lymphocyte counts and mean (SD) etrasimod concentration 
versus nominal timepoint (Weeks 16 through 52) 
 Mean (SD) absolute change from Baseline in lymphocytes and mean (SD) etrasimod 
concentration versus nominal timepoint (Weeks 16 through 52) 
 Mean (SD) percent change from Baseline in lymphocytes and mean (SD) etrasimod 
concentration versus nominal timepoint (Weeks 16 through 52) 


 
  
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 Mean (SD) heart rate and mean (SD) etrasimod concentration versus nominal 
timepoint (Weeks 16 through 52) 
 Mean (SD) absolute change from Baseline in heart rate and mean (SD) etrasimod 
concentration versus nominal timepoint (Weeks 16 through 52)  
The plasma etrasimod concentrations over time will be used in a population PK analysis, 
etrasimod concentration and specific efficacy endpoints will be used in a population  PK/PD 
exposure-efficacy response analysis and etrasimod concentration and absolute lymphocyte count 
will be used in a population  PK/PD exposure-lymphocyte response analysis, which will be 
described in a separate plan. 
 
 
 
 
 
 
 
CCI


 
  
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22. 
References  
 
FDA. (2020) Statistical considerations for clinical trials during the COVID-19 public health emergency. 
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for 
Industry Web site. https://www.fda.gov/media/139145/download. 
ICH. (2019) Addendum on estimands and sensitivity analysis in clinical trials to the guideline on 
statistical principles for clinical trials, E9(R1). Retrieved from International Council for 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use: 
https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf. 
 
ICH. (2012) Structure and content of clinical study reports questions & answers (R1). 
https://database.ich.org/sites/default/files/E3_Q%26As_R1_Q%26As.pdf. 
ICH. (1998) Statistical principles for clinical trials, E9. Retrieved from International Council for 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use: 
https://database.ich.org/sites/default/files/E9_Guideline.pdf. 
ICH. (1995). Structure and content of clinical study reports, E3. Retrieved from International Conference 
on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human: 
https://database.ich.org/sites/default/files/E3_Guideline.pdf. 
 
Ware, M. K. (2001). How to score version 2 of the SF-36 health survey (standard & acute forms). Quality 
Metric Incorporated. 
 
 
 
 
 
 
 
 


 
  
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APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
IQVIA OUTPUT CONVENTIONS 
Outputs will be presented as shown in the Output shells. 
DECIMALS AND PERCENTAGES 
 
If the original data has N decimal places, then the summary statistics should have the following decimal places: 
o 
Minimum and maximum: N 
o 
Mean (and LS Means), median: N + 1 
o 
SD or SE: N + 2 
 
Percentages will be reported to one decimal place. Where counts are zero, percentages will not appear in the 
output. 
DATES & TIMES 
Depending on data available, dates and times will take the form DDMMMYYYY or DDMMMYYYY:hh:mm.. 
SPELLING FORMAT 
English US.  
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in the given order: 
Treatment Group 
For Tables, Graphs, and Listings 
Etrasimod 2 mg 
Etrasimod 2 mg 
Placebo 
Placebo 
Screen Failure 
Screen Failure 
Not Treateda    
Not Treated 
a To be used for subjects in safety listings who are randomized but do not receive study drug. 
PRESENTATION OF VISITS 
For outputs, visits will be represented as follows and in that order: 


 
  
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Visit Name 
Study Period 
Eligibility Assessment 
Screening 
Baseline, Week 12, Week 16, Week 20, Week 24, Week 32, 
Week 40, Week 48, and Week 52 
Treatment 
Early Termination 
Dependent on Analysis Visit assigned 
2-Week Follow-Up, 4-Week Follow-Up 
Follow-Up 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
 
Randomized treatment group (or treatment received if it’s a safety output), first by Etrasimod, then 
Placebo, then Not Randomized and then No Treatment (only in safety listings if there are any 
randomized subjects who did not receive study drug)  
 
Subject ID,  
 
Date (where applicable), 
 
For listings where non-randomized subjects are included, these will appear in a category after the 
randomized treatment groups labeled ‘Not Randomized’. 
 
 


 
  
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APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS IN STUDY 
APD334-308: 
START DATE 
STOP DATE 
ACTION 
Known 
Known/Partial/ 
Missing 
If start date < study drug first dose date in APD334-308, then 
not TEAE 
If start date < study drug first dose date in APD334-308 AND 
event worsened (increase in severity) after first dose date in 
APD334-308, then TEAE 
If start date >= study drug first dose date in APD334-308, 
then TEAE 
 
 
 
Partial, but known 
components show that it 
cannot be on or after study 
drug first dose date in 
APD334-308 
Known/Partial/ 
Missing 
Not TEAE 
 
 
 
Partial, could be on or after 
study drug first dose date in 
APD334-308 
OR Missing 
Known 
If stop date < study drug first dose date in APD334-308, then 
not TEAE 
If stop date >= study drug first dose date in APD334-308, 
then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month 
if day unknown or 31st December if day and month are 
unknown), then: 
If stop date < study drug first dose date in APD334-308, then 
not TEAE 
If stop date >= study drug first dose date in APD334-308, 
then TEAE 
 
Missing 
Assumed TEAE 


 
  
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START DATE 
STOP DATE 
ACTION 
 
 
 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS:  
Start Date 
Stop Date 
Action 
Known 
Known 
If medication stop date < study med first dose date in APD334-308, 
assign as prior  
If medication stop date ≥ study med first dose date in APD334-308, 
assign as concomitant  
 
Partial 
Impute stop date as latest possible date (ie, last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If medication stop date < study med first dose date in APD334-308, 
assign as prior 
If medication stop date ≥ study med first dose date in APD334-308, 
assign as concomitant 
 
Missing 
If medication stop date is missing could never be assumed a prior 
medication, assign as concomitant 
Partial 
Known 
Impute start date as earliest possible date (ie, first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If medication stop date < study med first dose date in APD334-308, 
assign as prior 
If medication stop date ≥ study med first dose date in APD334-308, 
assign as concomitant 
 
Partial 
Impute start date as earliest possible date (ie, first day of month if day 
unknown or 1st January if day and month are unknown) and impute 
stop date as latest possible date (ie, last day of month if day unknown 
or 31st December if day and month are unknown), then: 
If medication stop date < study med first dose date in APD334-308, 
assign as prior 
If medication stop date ≥ study med first dose date in APD334-308, 
assign as concomitant 
 
Missing 
Impute start date as earliest possible date (ie, first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If medication stop date is missing could never be assumed a prior 
medication, assign as concomitant 
Missing 
Known 
If medication stop date < study med first dose date in APD334-308, 
assign as prior 
Else assign as concomitant 


 
  
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Start Date 
Stop Date 
Action 
 
Partial 
Impute stop date as latest possible date (ie, last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If medication stop date < study med first dose date in APD334-308, 
assign as prior 
If medication stop date ≥ study med first dose date in APD334-308, 
assign as concomitant 
 
Missing 
Assign as concomitant 
  
 


 
  
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APPENDIX 3. IBDQ SCORING RULES  
The IBDQ is a 32-item self-administered questionnaire which has 4 dimensions: Bowel symptoms (10 items), 
systemic symptoms (5 items), emotional health (12 items), and social function (5 items). Responses are graded on a 
7-point Likert scale where 7 denotes “not a problem at all” and 1 denotes “a very severe problem”. Scores range 
from 32 to 224, a higher score indicates better quality of life. 
The 4 dimensions are defined as: 
Bowel symptoms: Questions 1, 5, 9, 13, 17, 20, 22, 24, 26, 29 
Systemic symptoms: Questions 2, 6, 10, 14, 18 
Emotional health: Questions 3, 7, 11, 15, 19, 21, 23, 25, 27, 30, 31, 32 
Social function: Questions 4, 8, 12, 16, 28 
 
 


 
  
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APPENDIX 4. SF-36 DOMAIN SCORES 
The SF-36 is a 36-item self-administered questionnaire which has 8 scales: Physical functioning (10 items), role 
limitations due to physical health (4 items), role limitations due to emotional problems (3 items), energy/fatigue 
(4 items), emotional wellbeing (5 items), social functioning (2 items), pain (2 items), and general (5 items). Each 
item response is scored from 0 to 100 and items in the same scale are averaged together to create 8 subscores. Scores 
range from 0 to 100. A higher score indicates a more favorable health state. 
The 8 dimensions are defined as: 
Physical functioning: Questions 3-12 
Role limitations due to physical health: Questions 13-16 
Role limitations due to emotional problems: Questions 17-19 
Energy/fatigue: Questions 23, 27, 29, 31 
Emotional wellbeing: Questions 24-26, 28, 30 
Social functioning: Questions 20, 32 
Pain: Questions, 21, 22 
General health: Questions 1, 33-36 
 
 
 


 
  
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APPENDIX 5. WPAI-UC SCORING RULES  
The WPAI-UC questionnaire was developed to measure the effect of general health and symptom severity on work 
productivity and regular activities.  The questionnaire includes the following questions. 
Questions: 
1 =  Are you currently employed? 
2 =  During the past seven days, how many hours did you miss from work due to your problems associated with 
UC? 
3 =  During the past seven days, how many hours did you miss from work because of any other reasons? 
4 =  During the past seven days, how many hours did you actually work? 
5 =   During the past seven days, how much did your UC affect your productivity while you were working? 
6 =   During the past seven days, how much did your UC affect your ability to do your regular daily activities, other 
than work at a job? 
 
Derivation: 
1) 
Calculate work time missed score as: Q2/(Q2+Q4) 
2) 
Calculate impairment while working score as: Q5/10 
3) 
Calculate overall work impairment score as: Q2/(Q2+Q4) + [ (1 - Q2/(Q2+Q4)) x (Q5/10) ] 
4) 
Calculate activity impairment score as: Q6/10 
 
Multiply each score by 100 in order to express as percentages.   
 
 


 
  
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APPENDIX 6. CLASSIFICATION OF RESCUE THERAPY   
This appendix outlines the algorithm for the Arena clinical team/medical reviewers to classify 
rescue therapies for ulcerative colitis (UC) in a blinded manner. This will help establish 1) 
intercurrent events for the efficacy estimands, and 2) whether a subject will be excluded from the 
Per Protocol Set(s). All rescue therapies identified by the medical reviewers per the algorithm 
below will be imported in programming. This process will be repeated until database lock and 
the list of all rescue therapies identified will be finalized before study unblinding. 
Only medications and medical procedures reported on the electronic case report forms (eCRFs) 
can be assessed whether they are rescue therapy for UC. If the exposure happens in the follow-up 
period (beginning on or after the date of last study treatment administration), then it would not be 
considered as a rescue therapy. Impact of rescue therapy use in the analysis is timing-dependent, 
eg, if a subject starts a rescue therapy between their Week 12 and Week 52 endpoint 
assessments, then it may have potential impact on Week 52 endpoint analysis but will have no 
impact on Week 12 endpoints. The rules outlined below apply to both new use and increase in 
dose from Baseline. 
 
Biologics with immunomodulatory properties 
 Rule:  
o Any exposure after first dose 
 List of medications 
o Anti-TNFs:  
 ADALIMUMAB 
 CERTOLIZUMAB 
 CERTOLIZUMAB PEGOL 
 GOLIMUMAB 
 INFLIXIMAB 
o Other Biologics: 
 USTEKINUMAB 
 VEDOLIZUMAB 
Non-biologics with immunomodulatory properties  
 Immunosuppressants 
o Rule to consider for Week 12 efficacy endpoints: 
 After first dose and up to and including Week 8: any increase from 
baseline for more than 5 days  


 
  
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 After Week 8: Any dose above baseline  
o Rule to consider for Week 52 efficacy endpoints: 
 After Week 12 and up to and including Week 40: any increase from 
baseline for more than 5 days  
 After Week 40: Any dose above baseline  
o List of medications  
 MERCAPTOPURINE 
 AZATHIOPRINE 
 TIOGUANINE 
 METHOTREXATE 
 METHOTREXATE SODIUM 
 5-ASA COMPONDS 
o Rules to consider for Week 12 efficacy endpoints: 
 After first dose and up to and including Week 8: any increase from 
baseline for more than 5 days  
 After Week 8: Any dose above baseline  
o Rules to consider for Week 52 efficacy endpoints: 
 After Week 12 and up to and including Week 40: any increase from 
baseline for more than 5 days  
 After Week 40: Any dose above baseline  
o List of medications  
 MESALAZINE 
 BALSALAZIDE 
 BALSALAZIDE DISODIUM DIHYDRATE 
 BALSALAZIDE SODIUM 
 OLSALAZINE SODIUM 
 SULFASALAZINE 
 BECLOMETASONE W/MESALAZINE 
o Route 
 ORAL 
 RECTAL 


 
  
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 Other small molecule immunomodulatory active agents  
o Rule:  
 Any exposure after first dose 
o List of medications  
 CICLOSPORIN  
 TACROLIMUS 
 TOFACITINIB  
 TOFACITINIB CITRATE  
 Systemic glucocorticoids  
o Systemic glucocorticoids given via oral or rectal routes of administration  
 Rule:  
 After first dose and up to and including Week 8: any increase from 
baseline for more than 7 days 
 After Week 8: Any dose above baseline 
 List of medications  
 BETAMETHASONE 
 BETAMETHASONE DIPROPIONATE 
 BETAMETHASONE SODIUM PHOSPHATE 
 DEXAMETHASONE 
 DEXAMETHASONE SODIUM PHOSPHATE 
 DEXAMETHASONE VALERATE 
 METHYLPREDNISOLONE 
 METHYLPREDNISOLONE SODIUM SUCCINATE 
 PREDNISOLONE 
 PREDNISOLONE SODIUM PHOSPHATE 
 PREDNISOLONE METASULFOBENZOATE SODIUM 
 PREDNISONE 
 TRIAMCINOLONE 
 HYDROCORTISONE 
 HYDROCORTISONE ACETATE 


 
  
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 HYDROCORTISONE BUTYRATE 
 HYDROCORTISONE SODIUM SUCCINATE 
 ROUTE 
 ORAL 
 RECTAL 
 Systemic glucocorticoids given via parenteral routes of administration  
o Rule:  
 Any exposure after first dose 
o List of medications  
 BETAMETHASONE 
 BETAMETHASONE DIPROPIONATE 
 BETAMETHASONE SODIUM PHOSPHATE 
 DEXAMETHASONE 
 DEXAMETHASONE SODIUM PHOSPHATE 
 DEXAMETHASONE VALERATE 
 METHYLPREDNISOLONE 
 METHYLPREDNISOLONE SODIUM SUCCINATE 
 PREDNISOLONE 
 PREDNISOLONE SODIUM PHOSPHATE 
 PREDNISOLONE METASULFOBENZOATE SODIUM 
 PREDNISONE 
 TRIAMCINOLONE 
 HYDROCORTISONE 
 HYDROCORTISONE ACETATE 
 HYDROCORTISONE BUTYRATE 
 HYDROCORTISONE SODIUM SUCCINATE 
o ROUTE 
 INTRAVENOUS 
 INTRAMUSCULAR 
 Topical Glucocorticoids 


 
  
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o Budesonide  
 Rule  
 Subjects not taking Budesonide at baseline: 
o After first dose and up to and including Week 8: more than 
9 mg/day for one day or any exposure for more than 5 days 
o After Week 8: Any dose above baseline 
 Subjects taking Budesonide at baseline 
o After first dose and up to and including Week 8: more than 
9 mg/day for one day or any increase for more than 5 days 
o After Week 8: Any dose above baseline 
 List of medications  
 BUDESONIDE 
 List of Routes 
ORAL 
 RECTAL 
 Beclomethasone 
o Rule 
 Subjects not taking Beclomethasone at baseline: 
 After first dose and up to and including Week 8: more than 5 
mg/day for one day OR any exposure for more than 5 days 
 After Week 8: Any dose above baseline 
 Subjects taking Beclomethasone at baseline 
 After first dose and up to and including Week 8: more than 5 
mg/day for one day or any increase for more than 5 days 
 After Week 8: Any dose above baseline 
o List of medications:  
 BECLOMETASONE 
 BECLOMETASONE DIPROPIONATE 
 BECLOMETASONE W/MESALAZINE 
o Routes: 
 ORAL 
 RECTAL 


 
  
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 Other small molecule immunomodulatory active agents  
o Rules to consider for Week 12 efficacy endpoints:  
 After first dose and up to and including Week 8: any increase from 
baseline (including new use) for more than 5 days  
 After Week 8: Any dose above baseline  
o Rules to consider for Week 52 efficacy endpoints: 
 After Week 12 and up to and including Week 40: any increase from 
baseline (including new use) for more than 5 days  
 After Week 40: Any dose above baseline 
o List of medications:  
 CICLOSPORIN  
 TACROLIMUS 
 TOFACITINIB  
 TOFACITINIB CITRATE  
 Systemic glucocorticoids  
o Systemic glucocorticoids given via oral or rectal routes of administration  
 Rules to consider for Week 12 efficacy endpoints: 
 After first dose and up to and including Week 8: any increase from 
baseline for more than 7 days 
 After Week 8: Any dose above baseline 
 Rules to consider for Week 52 efficacy endpoints: 
 After Week 12 and up to and including Week 40: any increase 
from baseline for more than 7 days  
 After Week 40: Any dose above baseline 
 List of medications:  
 BETAMETHASONE 
 BETAMETHASONE DIPROPIONATE 
 BETAMETHASONE SODIUM PHOSPHATE 
 DEXAMETHASONE 
 DEXAMETHASONE SODIUM PHOSPHATE 
 DEXAMETHASONE VALERATE 


 
  
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 METHYLPREDNISOLONE 
 METHYLPREDNISOLONE SODIUM SUCCINATE 
 PREDNISOLONE 
 PREDNISOLONE SODIUM PHOSPHATE 
 PREDNISOLONE METASULFOBENZOATE SODIUM 
 PREDNISONE 
 TRIAMCINOLONE 
 HYDROCORTISONE 
 HYDROCORTISONE ACETATE 
 HYDROCORTISONE BUTYRATE 
 HYDROCORTISONE SODIUM SUCCINATE 
 Routes: 
 ORAL 
 RECTAL 
 Systemic glucocorticoids given via parenteral routes of administration  
o Rule for Week 12 endpoint: 
 Any exposure after first dose up to Week 12 
o Rules for Week 52 endpoint: 
 After Week 12 and up to and including Week 40: more than one dose  
 Any exposure after Week 40  
o List of medications:  
 BETAMETHASONE 
 BETAMETHASONE DIPROPIONATE 
 BETAMETHASONE SODIUM PHOSPHATE 
 DEXAMETHASONE 
 DEXAMETHASONE SODIUM PHOSPHATE 
 DEXAMETHASONE VALERATE 
 METHYLPREDNISOLONE 
 METHYLPREDNISOLONE SODIUM SUCCINATE 
 PREDNISOLONE 


 
  
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 PREDNISOLONE SODIUM PHOSPHATE 
 PREDNISOLONE METASULFOBENZOATE SODIUM 
 PREDNISONE 
 TRIAMCINOLONE 
 HYDROCORTISONE 
 HYDROCORTISONE ACETATE 
 HYDROCORTISONE BUTYRATE 
 HYDROCORTISONE SODIUM SUCCINATE 
o Routes: 
 INTRAVENOUS 
 INTRAMUSCULAR 
 Topical Glucocorticoids 
o Rules for Week 12 endpoints: 
 After first dose and up to and including Week 8:  any exposure above 
baseline (or new use) for more than 5 days 
 After Week 8: Any dose above baseline 
o Rules for Week 52 endpoints: 
 After Week 12 and up to and including Week 40: any increase from 
baseline for more than 5 days 
 After Week 40 any increase above baseline 
o List of medications:  
 BUDESONIDE 
o Routes: 
 ORAL 
 RECTAL 
 Beclomethasone 
o Rules for Week 12 endpoints: 
 After first dose and up to and including Week 8: Any increase above 
baseline for more than 5 days 
 After Week 8: Any dose above baseline 
o Rules for Week 52 endpoints: 


 
  
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 After Week 12 and up to and including Week 40: Any increase from 
baseline for more than 5 days 
 After Week 40 any increase above baseline 
o List of medications:  
 BECLOMETASONE 
 BECLOMETASONE DIPROPIONATE 
 BECLOMETASONE W/MESALAZINE 
o Routes: 
 ORAL 
 RECTAL 
Medical procedures 
 Leukocyte apheresis, other apheresis, and plasma exchange  
o Rule:  
 Any exposure after first dose 
o List of medical procedures  
 APHERESIS 
 LEUKAPHERESIS 
 COLECTOMY (partial or total) 
 SIGMOIDECTOMY 
 COLOSTOMY 
 ILEOSTOMY 
 
 
 


Statistical Analysis Plan - non-PK part V1.0 - 28-Sep-2022
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Date and Time
 
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education, training and experience to perform this 
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education, training and experience to perform this 
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PPD
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PPD

Prot_000.pdf: 
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:  
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Email (preferred method):  
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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. 
 
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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 
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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 
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− 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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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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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 
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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 
 


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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 
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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 
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Phase 3, 40-Week Treatment Study in UC (ELEVATE UC 40 JAPAN) 
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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 


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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. 


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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. 


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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 
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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 
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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 
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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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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