Clinical trial NCT03996369
Conditions: Ulcerative Colitis
Keywords: Ulcerative Colitis Etrasimod APD334
Sponsor: Arena Pharmaceuticals
Start date: 2020-09-15; Completion date: 2021-12-07
Enrollment: 354 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the efficacy of etrasimod on clinical remission in participants with moderately to severely active ulcerative colitis (UC).

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 12-Week Induction Treatment Period intervention 2: Etrasimod matching placebo tablet by mouth, once daily up to 12-Week Induction Treatment Period

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL  
Protocol number: 
APD334-302 
 
 
Protocol title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 12-Week 
Study to Assess the Efficacy and Safety of Etrasimod in Subjects with 
Moderately to Severely Active Ulcerative Colitis 
Brief title: 
ELEVATE UC 12: Etrasimod Versus Placebo as Induction Therapy in 
Moderately to Severely Active Ulcerative Colitis 
 
 
Study drug: 
Etrasimod (APD334) 
Indication: 
Ulcerative colitis 
Phase: 
3 
IND number: 
 
EudraCT number: 
2018-003986-33 
NCT number: 
03996369 
 
 
Sponsor name: 
Arena Pharmaceuticals, Inc.  
6154 Nancy Ridge Drive  
San Diego, CA 92121 
 
 
Sponsor’s Responsible 
Medical Officer: 
 
Senior Vice President, Clinical Development, and Chief Medical Officer  
 
 
Clinical lead: 
 
Senior Director, Clinical Development,  
Arena Pharmaceuticals Inc., San Diego, CA 
 
 
 
 
SAE reporting: 
IQVIA Pharmacovigilance 
 
  
 
 
Version: 
Amendment 3.0, 22 February 2021 
Sponsor approval: 
This protocol was approved by the Sponsor’s Responsible Medical 
Officer or delegate. The electronic signature manifest is appended. 
Confidentiality Statement 
This document contains confidential information of Arena Pharmaceuticals, Inc. Unauthorized 
distribution, copying, or disclosure is strictly prohibited unless required by applicable law. Persons 
receiving this information must be notified that it is confidential and may not be further distributed, 
copied, or disclosed. 


Clinical Study Protocol  
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
Amendment 3.0 
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PROTOCOL HISTORY  
Document 
Amendment Type 
Date 
Amendment 3.0 
Global 
22 February 2021 
Amendment 2.1 
Region-specific 
21 February 2020 
Amendment 2.0 
Global 
07 February 2020 
Amendment 1.1 
Region-specific 
03 September 2019 
Amendment 1 
Global 
05 March 2019 
Original Protocol 
Not applicable 
19 December 2018 
 
 


Clinical Study Protocol  
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
Amendment 3.0 
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PROTOCOL SYNOPSIS  
Sponsor: Arena Pharmaceuticals, Inc. 
Name of investigational study drug: Etrasimod (APD334) 
Protocol number: APD334-302 
Protocol title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 12-Week Study to 
Assess the Efficacy and Safety of Etrasimod in Subjects with Moderately to Severely Active 
Ulcerative Colitis 
Phase: 3 
Regions: North America, South America, Asia Pacific, Europe, Middle East, Africa 
Objectives: 
Primary: 
The primary objective is to assess the efficacy of etrasimod when administered for 12 weeks 
on clinical remission in subjects with moderately to severely active ulcerative colitis (UC). 
Secondary: 
The secondary objective is to assess the efficacy of etrasimod when administered for 12 weeks 
on clinical response, symptomatic response and remission, endoscopic changes, and mucosal 
healing in subjects with moderately to severely active UC. 
Safety: 
The safety objective is to assess the safety of etrasimod after daily doses of 2 mg for 12 weeks 
in subjects with moderately to severely active UC. 
Other: 
Other objectives include evaluation of etrasimod pharmacokinetics (PK) and the effect of 
etrasimod on health-related subject-reported outcomes and biomarkers. 
Study design: 
This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the 
efficacy and safety of etrasimod 2 mg in subjects with moderately to severely active UC. The 
study consists of a 28-Day Screening Period, a 12-Week Induction Treatment Period, and a 
2-Week and 4-Week Follow-Up Period. 
The target subject population will include (approximately 50% of subjects in each of the 
following categories): 
1. Subjects who have had an inadequate response to, loss of response to, or intolerance to 
conventional therapy and are naïve to biologic or Janus kinase (JAK) inhibitor therapy 
2. Subjects who have had an inadequate response to, loss of response to, or intolerance to a 
biologic or JAK inhibitor (subjects in this category may have received prior conventional 
therapy). 
Subject eligibility will be determined during a 4-Week (28-Day) Screening Period. Entry 
criteria will be based on confirmation of moderately to severely active UC, defined by a 
modified Mayo score (MMS) of 4 to 9, which includes an endoscopic score (ES) ≥ 2 and rectal 
bleeding (RB) score ≥ 1. 


Clinical Study Protocol  
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Eligible subjects will be randomized (2:1 ratio) to receive either etrasimod (2 mg once daily) 
or matching placebo (once daily) in a double-blind fashion for 12 weeks. Randomization will 
be stratified by (a) naïve to biologic or JAK inhibitor therapy at 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). 
At the end of the 12-Week Induction Treatment Period, subjects will undergo the Week 12 
study assessments. Subjects will then have the option to enter an open-label extension (OLE) 
study (APD334-303) following completion of Week 12 study procedures provided they meet 
all eligibility criteria for the OLE. 
Subjects must complete Week 12 to be eligible for the OLE. 
Subjects who do not participate in the OLE study will have 2-Week and 4-Week Follow-Up 
visits after the last treatment administration. 
Number of subjects (planned): 
Approximately 330 subjects are planned to be enrolled into this study. 
Eligibility criteria: 
Inclusion criteria: 
Subjects must meet ALL of the following inclusion criteria to be eligible for enrollment into 
the study: 
1. Men or women 16 to 80 years of age, inclusive, at the time of assent/consent. Enrollment of 
subjects < 18 years should be conducted only if acceptable according to local laws and 
regulations 
2. Ability to provide written informed consent or assent (parent or legal guardian must 
provide consent for a subject < 18 years of age who has assented to participate in the study 
or as required per local regulations) and to be compliant with the schedule of protocol 
assessments 
Disease-specific inclusion criteria: 
3. Diagnosed with UC ≥ 3 months prior to screening. The diagnosis of UC must be confirmed 
by endoscopic and histologic evidence. The endoscopy and histology report should be 
present in the source documents; however, if not available, the screening endoscopy and 
histology may serve as such 
4. Active UC confirmed by endoscopy with ≥ 10 cm rectal involvement. Subjects with 
proctitis only at baseline who meet the other eligibility criteria for inclusion, including the 
endoscopic and rectal bleeding criteria for moderate to severe disease, will be capped at 
15% of the total subjects enrolled 
5. Moderately to severely active UC defined as MMS of 4 to 9, including an ES of ≥ 2 and 
RB score ≥ 1 
6. Received a surveillance colonoscopy (performed according to local standard) within 
12 months before baseline to rule out dysplasia in subjects with pancolitis > 8 years 
duration or subjects with left-sided colitis > 12 years duration. Subjects without a 
surveillance colonoscopy within the prior 12 months will have a colonoscopy at screening 
(ie, in place of screening proctosigmoidoscopy). Any adenomatous polyps must be 
removed according to routine practice prior to their first dose of study treatment. 


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Prior treatment: 
7. Demonstrated an inadequate response to, loss of response to, or intolerance to at least 1 of 
the following therapies as defined below: 
Conventional therapy 
a. Oral 5-aminosalicylic acid (5-ASA) compounds 
b. Corticosteroids 
c. Thiopurines 
Biologic therapy or JAK inhibitor therapy 
a. Antitumor necrosis factor alpha (TNFα) antibodies (eg, infliximab, adalimumab, 
golimumab, or biosimilars) 
b. Anti-integrin antibodies (eg, vedolizumab) 
c. Anti-interleukin 12/23 antibodies (eg, ustekinumab) 
d. JAK inhibitors (eg, tofacitinib) 
Note: The medication used to qualify the subject for entry into this category must be 
approved for the treatment of UC in the country of use and the subject must have 
received an adequate course of therapy based on local guidelines for that therapy. 
Concomitant treatments: 
8. Subjects are permitted to be receiving a therapeutic dose of the following drugs: 
• Oral 5-ASA compounds provided the dose has been stable for ≥ 2 weeks immediately 
prior to randomization 
• Oral corticosteroid therapy (prednisone at a stable dose ≤ 20 mg/day, budesonide at a 
stable dose ≤ 9 mg/day, or equivalent steroid) provided the dose has been stable for the 
4 weeks immediately prior to the screening endoscopy assessment 
• Immunosuppressive agents such as oral azathioprine or 6-mercaptopurine must be 
discontinued ≥ 2 weeks prior to randomization 
• Probiotics (eg, Culturelle®, Saccharomyces boulardii) provided the dose has been 
stable for the 2 weeks immediately prior to randomization 
If oral 5-ASA or corticosteroids have been recently discontinued, they must have been 
stopped for at least 2 weeks prior to the endoscopy used for the baseline MMS. 
Other general inclusion criteria: 
9. Adequate hematological function defined by white blood cell count ≥ 3.5 × 109/L with 
absolute neutrophil count (ANC) ≥ 1.5 × 109/L, lymphocyte count ≥ 0.8 × 109/L, platelet 
count ≥ 100 × 109/L, and hemoglobin ≥ 8 g/dL 
10. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of 
normal (ULN) range and aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) levels ≤ 2.0 × ULN. Subjects with an isolated total bilirubin and normal AST and 
ALT diagnosed with Gilbert’s syndrome may participate 
11. Adequate renal function defined by an estimated glomerular filtration rate 
≥ 30 mL/min/1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration 
equation at screening 


Clinical Study Protocol  
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12. 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) hormonal contraception 
associated with inhibition of ovulation, which may be oral, intravaginal, or 
transdermal 
− Progestogen-only hormonal contraception associated with inhibition of ovulation, 
which may be oral, injected, or implanted 
− Intrauterine device (IUD) 
− Intrauterine hormone-releasing system 
− Bilateral tubal occlusion 
− Vasectomized partner, provided that partner is the sole sexual partner of the 
female-of childbearing potential trial subject 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 nonpregnant female of childbearing potential 
partner must agree to using condoms during treatment and for 30 days following 
treatment. 


Clinical Study Protocol  
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Exclusion criteria: 
Subjects who meet any of the following exclusion criteria will not be eligible for enrollment 
into the study: 
Exclusions related to general health: 
1. Severe extensive colitis as evidenced by: 
• Physician judgement that the subject is likely to require hospitalization for medical care 
or surgical intervention of any kind for UC (eg, colectomy) within 12 weeks following 
randomization 
• Current evidence of fulminant colitis, toxic megacolon or recent history (within last 
6 months) of toxic megacolon, or bowel perforation 
• Previous total or partial colectomy 
2. Diagnosis of Crohn’s disease or indeterminate colitis or the presence or history of a fistula 
consistent with Crohn’s disease 
3. Diagnosis of microscopic colitis, ischemic colitis, or infectious colitis 
4. Hospitalization for exacerbation of UC requiring intravenous (IV) steroids within 12 weeks 
of screening (a single dose of IV steroids given is acceptable) 
5. Positive assay or stool culture for pathogens (ova and parasite examination, bacteria) or 
positive test for Clostridioides difficile (formerly known as Clostridium difficile) toxin at 
screening (If C. difficile is positive, the subject may be treated and retested ≥ 4 weeks after 
completing treatment.) 
6. Pregnancy, lactation, or a positive serum beta-human chorionic gonadotropin (β-hCG) 
measured during screening 
7. Clinically relevant neurological, endocrine, metabolic (including, but not limited to, 
hypo- and hyperkalemia), psychiatric, cognitive impairment, alcohol/drug 
abuse/dependence, or other major systemic disease making implementation of the protocol 
or interpretation of the study difficult or would put the subject at risk 
8. Have any of the following conditions or receiving treatments that may affect cardiovascular 
function: 
• 
Myocardial infarction, unstable angina, stroke/transient ischemic attack, 
decompensated heart failure requiring hospitalization or Class III/IV heart failure 
≤ 6 months prior to or during the Screening Period 
• 
History or presence of second-degree or third-degree atrioventricular block, sick 
sinus syndrome, or periods of asystole for > 3 seconds without a functional 
pacemaker 
• 
History or presence of recurrent symptomatic bradycardia or recurrent cardiogenic 
syncope 
• 
Screening or Week 0/Day 1 prerandomization vital signs (taken in the sitting 
position) with a heart rate (HR) < 50 bpm OR systolic blood pressure (BP) 
< 90 mm Hg OR diastolic BP < 55 mm Hg. Vital signs may be repeated up to 3 times 
during a visit to confirm abnormal readings 


Clinical Study Protocol  
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Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
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• 
Screening or Week 0/Day 1 prerandomization electrocardiogram (ECG) with PR 
interval > 200 ms or Fridericia’s corrected QT interval (QTcF) ≥ 450 ms in men or 
≥ 470 ms in women 
• Start, stop, change, or planned change in dosage of any anti-arrhythmic drugs 
(Class I to IV) ≤ 1 week before screening or within 1 week before or after 
randomization 
9. Forced expiratory volume at 1 second (FEV1) or forced vital capacity (FVC) < 70% of 
predicted values and FEV1/FVC ratio < 0.70 at screening 
10. Uncontrolled diabetes as determined by hemoglobin A1c (HbA1c) > 9% at screening, or 
subjects with diabetes with significant comorbid conditions such as retinopathy 
11. History of macular edema or retinopathy 
12. History of active tuberculosis (TB), history of untreated or inadequately treated latent TB 
infection, active or latent TB infection at screening. The following are EXCEPTIONS to 
this exclusion criterion: 
• Subjects with latent TB, who have been ruled out for active TB, have completed an 
appropriate course of TB prophylaxis treatment per national/local medical guidelines 
or WHO guidelines, have a chest radiograph without changes suggestive of active TB 
infection, and have not had recent close contact with a person with active TB are 
eligible to enroll in the study. It is the responsibility of the Investigator to verify the 
adequacy of previous TB treatment and provide appropriate documentation of 
treatment compliance 
• Subjects diagnosed with latent TB at screening, ruled out for active TB and received at 
least 4 weeks of an appropriate TB prophylaxis regimen may be rescreened for 
enrollment. Subjects will complete their prophylactic regimen during the trial 
13. A clinically significant active infection (eg, serious and/or atypical) ≤ 28 days prior to 
randomization, required intravenous medication ≤ 14 days prior to randomization, or that 
may worsen (in the opinion of the Investigator) if the subject is treated with a drug having 
immunosuppressant effects (ie, etrasimod). Fungal infection of nail beds is allowed 
14. Have human immunodeficiency virus (HIV)/acquired immune deficiency syndrome or test 
positive for HIV antibodies at screening 
15. Have acute or chronic hepatitis B infection or test positive for hepatitis B virus (HBV) at 
screening (detectable HBV DNA, or positive for hepatitis B surface antigen [HBsAg], or 
negative for HBsAg and positive for antihepatitis B core antibody in conjunction with 
detectable HBV DNA) 
16. Have current hepatitis C infection or test positive for hepatitis C virus (HCV) at screening 
as defined by positive for hepatitis C antibody and detectable HCV RNA 
17. History of an opportunistic infection (eg, Pneumocystis jirovecii, cryptococcal meningitis, 
progressive multifocal leukoencephalopathy) or history of disseminated herpes simplex or 
disseminated herpes zoster 
18. History of or currently active primary or secondary immunodeficiency 


Clinical Study Protocol  
APD334-302 
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19. History of cancer within the last 5 years, including solid tumors and hematological 
malignancies (except basal cell and in situ squamous cell carcinomas of the skin that have 
been excised and resolved) or colonic mucosal dysplasia 
20. History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, 
or multiple myeloma 
Exclusions related to medications: 
21. Hypersensitivity to etrasimod or any of the excipients or placebo compounds 
22. Prior treatment with sphingosine 1-phosphate receptor modulators 
23. Treatment with a biologic agent ≤ 8 weeks or a small molecule agent ≤ 5 elimination 
half-lives and detectable drug level prior to randomization 
24. Treatment with an investigational therapy ≤ 3 months prior to randomization 
25. Treatment with ≥ 3 biologic agents or ≥ 2 biologics plus a JAK inhibitor approved for 
treatment of UC 
26. Treatment with topical rectal 5-ASA, short-chain fatty acid enemas, or steroids ≤ 2 weeks 
prior to and during screening 
27. Treatment with topical rectal traditional medicine (eg, Chinese medicine), herb enemas, or 
suppositories ≤ 2 weeks prior to randomization 
28. Treatment with methotrexate ≤ 8 weeks prior to and during screening or cyclosporine, 
tacrolimus, sirolimus, or mycophenolate mofetil (MMS) ≤ 16 weeks prior to and during 
screening 
29. Receipt of a live vaccine ≤ 4 weeks prior to randomization 
30. Previous treatment with natalizumab 
31. Previous treatment with lymphocyte-depleting therapies (eg, alemtuzumab, anti-CD4, 
cladribine, rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, total body 
irradiation, bone marrow transplantation, daclizumab) 
32. Previous treatment with D-penicillamine, thalidomide, dimethyl fumarate, or pyrimidine 
synthesis inhibitors 
33. Treatment with IV immune globulin or plasmapheresis ≤ 3 months prior to randomization 
34. Chronic use of therapies that moderately/strongly inhibit/induce cytochrome P450 (CYP) 
2C8 and 2C9 metabolism and inhibitors of UGT1A7 ≤ 4 weeks prior to randomization 
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 1.5 years. 
Reference therapy, description, mode of administration: 
Placebo tablets, by mouth, once daily 
Efficacy assessments: 
The 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: stool frequency (SF), RB, and ES. The ES 
will be determined by central reading. 


Clinical Study Protocol  
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Definitions: 
• 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 endpoint: 
• The proportion of subjects achieving clinical remission at Week 12 
Key secondary efficacy endpoints: 
• The proportion of subjects achieving endoscopic improvement at Week 12 
• The proportion of subjects achieving symptomatic remission at Week 12 
• The proportion of subjects with mucosal healing at Week 12 
Pharmacokinetic assessments: 
Plasma concentrations of etrasimod, and if warranted M3 (AR503641) and other metabolite(s) 
of interest, will be assessed from samples collected pre-dose and 4 hours post-dose (after 
12-lead ECG) on Week 0/Day 1, and pre-dose (trough) at Weeks 2, 4, 8, 12, 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 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: 
Biomarker endpoints: 
• Change from baseline in level of fecal calprotectin at Weeks 2, 4, 8, and 12 
• Change from baseline in level of high-sensitivity C-reactive protein at Weeks 2, 4, 8, and 
12 
• Change and percentage change from baseline in lymphocyte counts at Weeks 2, 4, 8, and 
12 
Health-related quality of life endpoints: 
• Scores and change from baseline at Week 12 for the following: 
− Inflammatory Bowel Disease Questionnaire total score (IBDQ) 
− Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms (UC-PRO/SS) 
− Medical Outcomes Study 36-Item Short Form Health Survey, version 2 physical and 
mental component and domain scores (SF-36) 
− Work Productivity and Activity Impairment Questionnaire – Ulcerative Colitis 
(WPAI-UC) 
− Urgency numeric rating scale (NRS) 


Clinical Study Protocol  
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− Abdominal pain NRS 
• The proportion of subjects with UC-related hospitalizations 
• The proportion of subjects requiring UC-related surgeries, including colectomy 
Safety assessments: 
Safety will be assessed using monitoring of adverse events, clinical laboratory findings, 
12-lead 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 
Statistical methods: 
Sample size 
Based on a 2-group Fischer’s exact test, a 1-sided significance level of 0.025, and a 2:1 
randomization ratio, at least 330 total subjects (220 etrasimod, 110 placebo) are required to 
achieve at least 90% power to detect a difference of 12.5% in the primary endpoint of clinical 
remission between the etrasimod treatment group (18.5%) and the placebo treatment group 
(6.0%). 
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) naïve to biologic or JAK 
inhibitor therapy at 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) and p-values. 
Testing strategy 
There are multiple null hypotheses for the comparison of etrasimod and placebo in the primary 
and key secondary endpoints. The family-wise type-I error rate will be controlled at a fixed 
α level at 0.025 (1-sided) using the following testing procedure. First, the whole α will be 
spent on testing the primary endpoint. Only if the primary null hypothesis is rejected at the 
α level, can testing proceed for the 3 key secondary endpoints. The method for such testing 
will be specified in the Statistical Analysis Plan (SAP), and it will control for the multiplicity 
of the 3 key secondary endpoints. Any key secondary endpoint that fails to be significant at the 
α level by this method to control multiplicity will be considered exploratory and thereby 
would only have nominal p-values. All other endpoints will be evaluated at α level of 
significance and reported with nominal p-values, without multiplicity adjustment. 
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. 
Full details of PK analysis will be provided in the SAP. 


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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, serious 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. 
 


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TABLE OF CONTENTS 
PROTOCOL HISTORY ..................................................................................................................2 
PROTOCOL SYNOPSIS ................................................................................................................3 
LIST OF APPENDICES ................................................................................................................17 
LIST OF TABLES .........................................................................................................................17 
LIST OF FIGURES .......................................................................................................................18 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................19 
1. 
INTRODUCTION ......................................................................................................22 
1.1. 
Ulcerative Colitis ........................................................................................................22 
1.2. 
Etrasimod ....................................................................................................................22 
1.3. 
Benefit/Risk Assessment ............................................................................................23 
2. 
STUDY OBJECTIVES ..............................................................................................25 
2.1. 
Primary Objective .......................................................................................................25 
2.2. 
Secondary Objective ...................................................................................................25 
2.3. 
Safety Objective ..........................................................................................................25 
2.4. 
Other Objectives .........................................................................................................25 
3. 
INVESTIGATIONAL PLAN .....................................................................................26 
3.1. 
Summary of Study Design ..........................................................................................26 
3.2. 
Rationale for Study Design .........................................................................................27 
3.3. 
Study Duration ............................................................................................................28 
3.4. 
Independent Data Monitoring Committee ..................................................................28 
4. 
SELECTION OF STUDY POPULATION ................................................................29 
4.1. 
Inclusion Criteria ........................................................................................................29 
4.2. 
Exclusion Criteria .......................................................................................................32 
5. 
REMOVAL OF SUBJECTS FROM STUDY TREATMENT OR 
ASSESSMENT ...........................................................................................................35 
5.1. 
Discontinuation from Study Treatment ......................................................................35 
5.2. 
Discontinuation from the Study ..................................................................................36 
5.3. 
Subjects Lost to Follow-Up Prior to Last Scheduled Visit .........................................36 
5.4. 
Premature Termination of the Study ...........................................................................37 
6. 
STUDY TREATMENTS............................................................................................38 
6.1. 
Treatments Administered ............................................................................................38 
6.2. 
Investigational Study Treatment .................................................................................38 


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6.3. 
Dosage and Administration ........................................................................................38 
6.3.1. 
Instructions for Missed Dose(s) ..................................................................................38 
6.3.2. 
Dose Interruptions ......................................................................................................39 
6.4. 
Method of Assigning Subjects to Treatment ..............................................................39 
6.5. 
Blinding ......................................................................................................................39 
6.6. 
Treatment Compliance ................................................................................................40 
6.7. 
Concomitant Therapy .................................................................................................40 
6.7.1. 
Required Concomitant Therapy ..................................................................................40 
6.7.2. 
Allowed Concomitant Therapy ...................................................................................40 
6.7.2.1. 
Permitted Medications for the Treatment of Ulcerative Colitis .................................40 
6.7.3. 
Prohibited Concomitant Therapy ................................................................................41 
7. 
SUBJECT RESTRICTIONS ......................................................................................42 
8. 
STUDY TREATMENT MATERIALS AND MANAGEMENT ..............................43 
8.1. 
Packaging and Labeling ..............................................................................................43 
8.2. 
Study Treatment Storage and Handling ......................................................................43 
8.3. 
Study Treatment Preparation ......................................................................................43 
8.4. 
Study Treatment Accountability .................................................................................43 
8.5. 
Study Treatment Retention and Disposal ...................................................................43 
9. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................44 
9.1. 
General Instructions ....................................................................................................44 
9.2. 
Subject Information ....................................................................................................44 
9.2.1. 
Informed Consent .......................................................................................................44 
9.3. 
Screening and Eligibility ............................................................................................44 
9.3.1. 
Tuberculosis Screening and Chest X-Ray ..................................................................45 
9.3.2. 
Rescreening .................................................................................................................45 
9.3.3. 
Demography and Other Subject Characteristics .........................................................45 
9.3.4. 
Social History .............................................................................................................45 
9.3.5. 
Prior and Ongoing Therapies ......................................................................................45 
9.3.6. 
Ulcerative Colitis History/Medical History ................................................................46 
9.3.7. 
Vital Signs ..................................................................................................................46 
9.3.8. 
Pulmonary Function Test ............................................................................................46 
9.3.9. 
Ophthalmoscopy and Optical Coherence Tomography ..............................................46 
9.3.10. 
Clinical Laboratory Assessments ...............................................................................46 


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9.3.11. 
Proctosigmoidoscopy/Colonoscopy and Modified Mayo Score Derivation ..............46 
9.4. 
Randomization/Treatment Period ...............................................................................47 
9.4.1. 
Week 0/Day 1: Prerandomization ...............................................................................47 
9.4.2. 
Treatment Period ........................................................................................................47 
9.4.2.1. 
Guidance for Cardiac Monitoring Following Treatment Initiation or 
Re-Initiation ................................................................................................................48 
9.4.3. 
Study Treatment Discontinuation Related to Post-dose Cardiac Monitoring ............50 
9.5. 
Follow-Up Period .......................................................................................................50 
9.6. 
Virtual/Hybrid Visits ..................................................................................................51 
9.7. 
Pharmacokinetics ........................................................................................................51 
9.8. 
Efficacy Assessments .................................................................................................52 
9.8.1. 
Modified Mayo Score/Mayo Clinic Score ..................................................................52 
9.8.1.1. 
Endoscopy ...................................................................................................................53 
9.8.1.2. 
Endoscopic Biopsies ...................................................................................................53 
9.8.2. 
Extraintestinal Manifestations ....................................................................................54 
9.8.3. 
Additional Health-Related Subject-Reported Outcomes ............................................54 
9.8.4. 
Efficacy-Related Biomarkers ......................................................................................55 
 
 
9.9. 
Genetics ......................................................................................................................56 
9.10. 
Safety ..........................................................................................................................56 
9.10.1. 
Physical Examination .................................................................................................57 
9.10.2. 
Vital Signs ..................................................................................................................57 
9.10.3. 
12-Lead Electrocardiogram ........................................................................................57 
9.10.4. 
Pulmonary Function Test ............................................................................................58 
9.10.5. 
Ophthalmoscopy and Optical Coherence Tomography ..............................................59 
9.10.6. 
Tuberculosis Screening and Chest X-Ray ..................................................................60 
9.10.7. 
Clinical Laboratory Tests ...........................................................................................60 
9.10.7.1. 
Screening ....................................................................................................................63 
9.10.8. 
Adverse Events ...........................................................................................................64 
9.10.8.1. 
Definitions ..................................................................................................................64 
9.10.8.2. 
Eliciting and Recording Adverse Events ....................................................................67 
9.10.8.3. 
Reporting Adverse Events ..........................................................................................68 
9.10.9. 
Pregnancy ...................................................................................................................68 


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9.11. 
Procedures for Overdose .............................................................................................69 
10. 
PLANNED STATISTICAL METHODS ...................................................................70 
10.1. 
General Considerations ...............................................................................................70 
10.2. 
Determination of Sample Size ....................................................................................70 
10.3. 
Analysis Sets ...............................................................................................................70 
10.4. 
Missing Data ...............................................................................................................70 
10.5. 
Efficacy Endpoint Definitions ....................................................................................72 
10.5.1. 
Calculation of Modified Mayo Score Component Scores ..........................................72 
10.6. 
Primary Endpoint ........................................................................................................73 
10.7. 
Secondary Endpoints ..................................................................................................73 
10.7.1. 
Key Secondary Efficacy Endpoints ............................................................................73 
10.7.2. 
Other Secondary Efficacy Endpoints ..........................................................................73 
 
 
10.9. 
Other Efficacy -Related Endpoints .............................................................................74 
10.9.1. 
Health-Related Quality of Life ...................................................................................74 
10.9.2. 
Pharmacokinetics ........................................................................................................74 
10.9.3. 
Biomarkers ..................................................................................................................74 
10.10. 
Subgroup Analyses .....................................................................................................74 
10.11. 
Safety Endpoints .........................................................................................................75 
10.12. 
Testing Strategy ..........................................................................................................75 
10.12.1. 
Efficacy Analysis ........................................................................................................75 
10.12.2. 
Safety Analysis ...........................................................................................................76 
10.13. 
Interim Analysis ..........................................................................................................76 
11. 
ETHICAL CONSIDERATIONS................................................................................77 
11.1. 
Ethical Conduct of the Study ......................................................................................77 
11.2. 
Institutional Review Board or Independent Ethics Committee Approval ..................77 
11.3. 
Informed Consent and Assent .....................................................................................77 
11.4. 
Confidentiality ............................................................................................................78 
11.5. 
Protocol Compliance ..................................................................................................78 
12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................79 
12.1. 
Training of Study Site Personnel ................................................................................79 
12.2. 
Monitoring ..................................................................................................................79 
12.3. 
Audit ...........................................................................................................................79 


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13. 
DATA HANDLING AND RECORD KEEPING ......................................................80 
13.1. 
Data Management .......................................................................................................80 
13.1.1. 
Case Report Forms .....................................................................................................80 
13.1.2. 
Source Documents ......................................................................................................80 
13.2. 
Study Documentation and Records Retention ............................................................80 
13.3. 
Clinical Study Report .................................................................................................81 
13.4. 
Disclosure of Study Results ........................................................................................81 
14. 
RESPONSIBILITIES .................................................................................................82 
14.1. 
Investigator Responsibilities .......................................................................................82 
14.2. 
Sponsor Responsibilities .............................................................................................82 
15. 
REFERENCES ...........................................................................................................83 
16. 
APPENDICES ............................................................................................................85 
 
LIST OF APPENDICES  
APPENDIX 1: SCHEDULE OF ASSESSMENTS ....................................................................86 
APPENDIX 2: TUBERCULOSIS SCREENING .......................................................................90 
APPENDIX 3: MAYO CLINIC SCORE – SAMPLE ................................................................95 
APPENDIX 4: HISTOLOGICAL SCORING INDICES ...........................................................96 
APPENDIX 5: GUIDANCE FOR THE ASSESSMENT OF POTENTIAL 
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY ...........................97 
APPENDIX 6: INVESTIGATOR SIGNATURE .......................................................................98 
APPENDIX 7: SPONSOR SIGNATURE ..................................................................................99 
 
LIST OF TABLES  
Table 1: 
Study Treatment ..........................................................................................................38 
Table 2: 
Cytochrome P450 Inhibitors and Inducers .................................................................41 
Table 3: 
Procedures to be Performed During the Monitoring Period .......................................49 
Table 4: 
Discharge Criteria After Cardiac Monitoring .............................................................49 
Table 5: 
Discontinuation of Study Treatment-Related to Post-Dose Cardiac 
Monitoring ..................................................................................................................50 
Table 6: 
Clinical Laboratory Tests ...........................................................................................62 


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Table 7: 
Schedule of Assessments – Screening and Induction Treatment Period ....................86 
 
LIST OF FIGURES  
Figure 1: 
Study Design ...............................................................................................................27 
Figure 2: 
Progressive Multifocal Leukoencephalopathy Case Evaluation Algorithm ...............97 


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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 
CBC 
complete blood count 
CD 
Crohn’s disease 
CFR 
Code of Federal Regulations 
cGMP 
current Good Manufacturing Practices 
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 
EIMs 
extraintestinal manifestations 
ES 
endoscopic score 
ET 
Early Termination 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 


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Abbreviation 
Definition 
FEV1 
forced expiratory volume at 1 second 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
HbA1c 
hemoglobin A1c 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HIV 
human immunodeficiency virus 
HR 
heart rate 
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 
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 
IV 
intravenous 
IWRS 
Interactive Web Response System 
JAK 
Janus kinase 
MAR 
missing at random 
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 


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Abbreviation 
Definition 
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 
PPD 
purified protein derivative 
QTcF 
Fridericia’s corrected QT interval 
RB 
rectal bleeding 
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 procedures 
TB 
tuberculosis 
TBNK 
T lymphocytes, B lymphocytes, natural killer lymphocytes 
TMF 
trial master file 
TNF 
tumor necrosis factor 
TNFα 
tumor necrosis factor alpha 
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 
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 2020). 
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 (Sandborn 2020). Refer to the current edition 


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of the 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  
Considering the significant unmet need for safe and effective, orally administered treatments for 
UC, etrasimod may potentially provide therapeutic benefit via S1P receptor modulation. 
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 repeat 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 were 
within normal limits by 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. 


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The current study is a Phase 3 multicenter, randomized, double-blind, placebo-controlled study 
to evaluate the efficacy and safety of etrasimod in subjects with moderately to severely active 
UC. At the completion of the study (completion of Week 12 assessments), subjects 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 patients with UC. 


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2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective  
The primary objective is to assess the efficacy of etrasimod when administered for 12 weeks on 
clinical remission in subjects with moderately to severely active UC. 
2.2. 
Secondary Objective  
The secondary objective is to assess the efficacy of etrasimod when administered for 12 weeks 
on clinical response, symptomatic response and remission, endoscopic changes, and mucosal 
healing in subjects with moderately to severely active UC. 
2.3. 
Safety Objective  
The safety objective is to assess the safety of etrasimod after daily doses of 2 mg for 12 weeks in 
subjects with moderately to severely active UC. 
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. 


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3. 
INVESTIGATIONAL PLAN  
3.1. 
Summary of Study Design  
This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy 
and safety of etrasimod 2 mg in subjects with moderately to severely active UC. The study 
consists of a 28-day Screening Period, a 12-Week Induction Treatment Period, and a 4-Week 
Follow-Up Period (Figure 1). Eligible subjects will be randomized (2:1 ratio) to receive either 
etrasimod (2 mg once daily) or matching placebo (once daily) in a double-blind fashion for 
12 weeks of induction treatment. Randomization will be stratified by (a) naïve to biologic or 
JAK inhibitor therapy at study entry (yes or no), (b) baseline corticosteroid use (yes or no), and 
(c) baseline disease activity (modified Mayo score [MMS]: 4 to 6 or 7 to 9). 
The target subject population will include (approximately 50% of subjects in each of the 
following categories): 
2. Subjects who have had an inadequate response to, loss of response to, or intolerance to 
conventional therapy and are naïve to biologic or JAK inhibitor therapy. 
3. Subjects who have had an inadequate response to, loss of response to, or intolerance to a 
biologic or JAK inhibitor (subjects in this category may have received prior conventional 
therapy). 
Subject eligibility will be determined during a 4-Week (28-Day) Screening Period. Entry criteria 
will be based on confirmation of moderately to severely active UC, defined by an MMS of 
4 to 9, which includes an endoscopic score (ES) ≥ 2 and rectal bleeding (RB) score ≥ 1. 
At the end of the 12-Week Induction Treatment Period, subjects will undergo Week 12 efficacy 
and safety assessments and be evaluated for clinical response/remission. Subjects will then have 
the option to enter an OLE study (APD334-303) following completion of Week 12 study 
procedures and provided they meet all eligibility criteria for the OLE. Subjects must complete 
Week 12 to be eligible for the OLE. 
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 their last treatment administration/Early Termination 
(ET) visit (Table 7). 


Clinical Study Protocol  
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Amendment 3.0 
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Figure 1: 
Study Design  
 
JAK, Janus kinase 
3.2. 
Rationale for Study Design  
This study is designed to evaluate the efficacy and safety of etrasimod in 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. 
The 12-Week Induction Treatment Period is based on the safety and efficacy findings of the 
Phase 2 APD334-002 placebo-controlled study. 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 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. 


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The primary endpoint of clinical remission at Week 12 as assessed using the MMS is standard, 
widely used, and in accordance with the nonbinding US Food and Drug Administration (FDA) 
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. 
As detailed in Section 10.2, the study is powered to the primary endpoint for demonstrating a 
statistically significant difference in achieving clinical remission between etrasimod therapy and 
placebo at Week 12. The 2:1 randomization scheme will maximize the number of subjects 
receiving a potentially beneficial therapy. 
At the end of the 12-Week Induction Treatment Period, subjects will be eligible to enter the 
APD334-303 OLE study provided they meet all entry criteria. 
3.3. 
Study Duration  
The study consists of a 28-day Screening Period, a 12-Week Induction Treatment Period, and a 
4-Week Follow-Up Period. The study duration is expected to be approximately 1.5 years. 
The End of Study Date 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. 
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 
study: 
1. Men or women 16 to 80 years of age, inclusive, at the time of assent/consent. Enrollment 
of subjects < 18 years should be conducted only if acceptable according to local laws and 
regulations 
2. Ability to provide written informed consent or assent (parent or legal guardian must 
provide consent for a subject < 18 years of age who has assented to participate in the 
study or as required per local regulations) and to be compliant with the schedule of 
protocol assessments 
Disease-specific inclusion criteria: 
3. Diagnosed with UC ≥ 3 months prior to screening. The diagnosis of UC must be 
confirmed by endoscopic and histologic evidence. The endoscopy and histology report 
should be present in the source documents; however, if not available, the screening 
endoscopy and histology may serve as such 
4. Active UC confirmed by endoscopy with ≥ 10 cm rectal involvement. Subjects with 
proctitis only at baseline who meet the other eligibility criteria for inclusion, including 
the endoscopic and rectal bleeding criteria for moderate to severe disease, will be capped 
at 15% of the total subjects enrolled 
5. Moderately to severely active UC defined as MMS of 4 to 9, including an ES of ≥ 2 and 
RB score ≥ 1 
6. Received a surveillance colonoscopy (performed according to local standard) within 
12 months before baseline to rule out dysplasia in subjects with pancolitis > 8 years 
duration or subjects with left-sided colitis > 12 years duration. Subjects without a 
surveillance colonoscopy within the prior 12 months will have a colonoscopy at 
screening (ie, in place of screening proctosigmoidoscopy). Any adenomatous polyps must 
be removed according to routine practice prior to their first dose of study treatment. 
Prior treatment: 
7. Demonstrated an inadequate response to, loss of response to, or intolerance to at least 
1 of the following therapies as defined below: 
Conventional therapy 
a. Oral 5-aminosalicylic acid (5-ASA) compounds 
b. Corticosteroids 
c. Thiopurines 


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Biologic therapy or JAK inhibitor therapy 
a. Antitumor necrosis factor alpha (TNFα) antibodies (eg, infliximab, adalimumab, 
golimumab or biosimilars) 
b. Anti-integrin antibodies (eg, vedolizumab) 
c. Anti-interleukin 12/23 antibodies (eg, ustekinumab) 
d. JAK inhibitors (eg, tofacitinib) 
Note: The medication used to qualify the subject for entry into this category must be 
approved for the treatment of UC in the country of use and the subject must have 
received an adequate course of therapy based on local guidelines for that therapy. 
Inadequate response, loss of response, and intolerance are defined as: 
• Inadequate response: Signs and symptoms of persistently active disease despite a 
history of completing a dosing regimen 
• Loss of response: Recurrence of symptoms of active disease during treatment 
following prior clinical benefit (discontinuation despite clinical benefit does not 
qualify as having failed or being intolerant to UC biologic therapy) 
• Intolerance: Including, but not limited to infusion- or injection related reaction, 
demyelination, congestive heart failure, infection, or any other related adverse event 
that led to a reduction in dose or discontinuation of the medication 
Note: To be considered inadequate response, loss of response, and intolerance after 
treatment with a biologic or tofacitinib, the subject must have received a dosing regimen 
consistent with the local product labeling and/or institutional standard of care. 
Concomitant treatments: 
8. Subjects are permitted to be receiving a therapeutic dose of the following drugs: 
• Oral 5-ASA compounds provided the dose has been stable for ≥ 2 weeks immediately 
prior to randomization 
• Oral corticosteroid therapy (prednisone at a stable dose ≤ 20 mg/day, budesonide at a 
stable dose ≤ 9 mg/day, or equivalent steroid) provided the dose has been stable for 
the 4 weeks immediately prior to the screening endoscopy assessment 
• Immunosuppressive agents such as oral azathioprine (AZA) or 6-mercaptopurine 
(6-MP) must be discontinued ≥ 2 weeks prior to randomization 
• Probiotics (eg, Culturelle®, Saccharomyces boulardii) provided the dose has been 
stable for the 2 weeks immediately prior to randomization 
If oral 5-ASA or corticosteroids have been recently discontinued, they must have been 
stopped for at least 2 weeks prior to the endoscopy used for the baseline MMS. 


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Other general inclusion criteria: 
9. Adequate hematological function defined by white blood cell count ≥ 3.5 × 109/L with 
absolute neutrophil count (ANC) ≥ 1.5 × 109/L, lymphocyte count ≥ 0.8 × 109/L, platelet 
count ≥ 100 × 109/L, and hemoglobin ≥ 8 g/dL 
10. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of 
normal (ULN) range and aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) levels ≤ 2.0 × ULN. Subjects with an isolated total bilirubin and normal AST and 
ALT diagnosed with Gilbert’s syndrome may participate 
11. Adequate renal function defined by an estimated glomerular filtration rate 
≥ 30 mL/min/1.73 m2 by the Chronic Kidney Disease Epidemiology Collaboration 
equation at screening 
12. 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) hormonal contraception 
associated with inhibition of ovulation, which may be oral, intravaginal, or 
transdermal 
− Progestogen-only hormonal contraception associated with inhibition of ovulation, 
which may be oral, injected, or implanted 
− Intrauterine device (IUD) 
− Intrauterine hormone-releasing system 
− Bilateral tubal occlusion 
− Vasectomized partner, provided that partner is the sole sexual partner of the 
women of childbearing potential trial subject 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 


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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: 
Exclusions related to general health: 
1. Severe extensive colitis as evidenced by: 
• Physician judgement that the subject is likely to require hospitalization for medical 
care or surgical intervention of any kind for UC (eg, colectomy) within 12 weeks 
following randomization 
• Current evidence of fulminant colitis, toxic megacolon or recent history (within last 
6 months) of toxic megacolon, or bowel perforation 
• Previous total or partial colectomy 
2. Diagnosis of CD or indeterminate colitis or the presence or history of a fistula consistent 
with CD 
3. Diagnosis of microscopic colitis, ischemic colitis, or infectious colitis 
4. Hospitalization for exacerbation of UC requiring intravenous (IV) steroids within 
12 weeks of screening (a single dose of IV steroids given is acceptable) 
5. Positive assay or stool culture for pathogens (ova and parasite examination, bacteria) or 
positive test for Clostridioides difficile (formerly known as Clostridium difficile) toxin at 
screening (If C. difficile is positive, the subject may be treated and retested ≥ 4 weeks 
after completing treatment.) 
6. Pregnancy, lactation, or a positive serum beta-human chorionic gonadotropin (β-hCG) 
measured during screening 
7. Clinically relevant neurological, endocrine, metabolic (including, but not limited to, 
hypo- and hyperkalemia), psychiatric, cognitive impairment, alcohol/drug 
abuse/dependence, or other major systemic disease making implementation of the 
protocol or interpretation of the study difficult or would put the subject at risk 
8. Have any of the following conditions or receiving treatments that may affect 
cardiovascular function: 
• Myocardial infarction, unstable angina, stroke/transient ischemic attack, 
decompensated heart failure requiring hospitalization or Class III/IV heart failure 
within ≤ 6 months prior to or during the Screening Period 
• History or presence of second-degree or third-degree atrioventricular block, sick sinus 
syndrome, or periods of asystole for > 3 seconds without a functional pacemaker 
• History or presence of recurrent symptomatic bradycardia or recurrent cardiogenic 
syncope 


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• Screening or Week 0/Day 1 prerandomization vital signs (taken in the sitting 
position) with a heart rate (HR) < 50 bpm OR systolic blood pressure (BP) 
< 90 mm Hg OR diastolic BP < 55 mm Hg. Vital signs may be repeated up to 3 times 
during a visit to confirm abnormal readings 
• Screening or Week 0/Day 1 prerandomization electrocardiogram (ECG) with PR 
interval > 200 ms or Fridericia’s corrected QT interval (QTcF) ≥ 450 ms in men or 
≥ 470 ms in women 
• Start, stop, change or planned change in dosage of any anti-arrhythmic drugs (Class I 
to IV) ≤1 week before screening or within 1 week before or after randomization 
9. Forced expiratory volume at 1 second (FEV1) or forced vital capacity (FVC) < 70% of 
predicted values and FEV1/FVC ratio < 0.70 at screening 
10. Uncontrolled diabetes as determined by hemoglobin A1c (HbA1c) > 9% at screening, or 
subjects with diabetes with significant comorbid conditions such as retinopathy 
11. History of macular edema or retinopathy 
12. History of active tuberculosis (TB), history of untreated or inadequately treated latent TB 
infection, active or latent TB infection at screening (refer to Appendix 2 for details on TB 
screening requirements and interpretation of test results). The following are 
EXCEPTIONS to this exclusion criterion: 
• Subjects with latent TB, who have been ruled out for active TB, have completed an 
appropriate course of TB prophylaxis treatment per national/local medical guidelines 
or WHO guidelines, have a chest radiograph without changes suggestive of 
active TB infection, and have not had recent close contact with a person with active 
TB are eligible to enroll in the study. It is the responsibility of the Investigator to 
verify the adequacy of previous TB treatment and provide appropriate documentation 
of treatment compliance 
• Subjects diagnosed with latent TB at screening, ruled out for active TB and received 
at least 4 weeks of an appropriate TB prophylaxis regimen may be rescreened for 
enrollment. Subjects will complete their prophylactic regimen during the trial 
13. A clinically significant active infection (eg, serious and/or atypical) ≤ 28 days prior to 
randomization, required intravenous medication ≤ 14 days prior to randomization, or that 
may worsen (in the opinion of the Investigator) if the subject is treated with a drug having 
immunosuppressant effects (ie, etrasimod). Fungal infection of nail beds is allowed. 
14. Have human immunodeficiency virus (HIV)/acquired immune deficiency syndrome or 
test positive for HIV antibodies at screening 
15. Have acute or chronic hepatitis B infection or test positive for hepatitis B virus (HBV) at 
screening (detectable HBV DNA, or positive for hepatitis B surface antigen [HBsAg], or 
negative for HBsAg and positive for antihepatitis B core antibody in conjunction with 
detectable HBV DNA) 
16. Have current hepatitis C infection or test positive for hepatitis C virus (HCV) at screening 
as defined by positive for hepatitis C antibody and detectable HCV RNA 


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17. History of an opportunistic infection (eg, Pneumocystis jirovecii, cryptococcal 
meningitis, progressive multifocal leukoencephalopathy) or a history of disseminated 
herpes simplex or disseminated herpes zoster 
18. History of or currently active primary or secondary immunodeficiency 
19. History of cancer within the last 5 years, including solid tumors and hematological 
malignancies (except basal cell and in situ squamous cell carcinomas of the skin that have 
been excised and resolved) or colonic mucosal dysplasia 
20. History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative 
disorder, or multiple myeloma 
Exclusions related to medications: 
21. Hypersensitivity to etrasimod or any of the excipients or placebo compounds 
22. Prior treatment with S1P receptor modulators 
23. Treatment with a biologic agent ≤ 8 weeks or a small molecule agent ≤ 5 elimination 
half-lives and detectable drug level prior to randomization 
24. Treatment with an investigational therapy ≤ 3 months prior to randomization 
25. Treatment with ≥ 3 biologic agents or ≥ 2 biologics plus a JAK inhibitor approved for 
treatment of UC 
26. Treatment with topical rectal 5-ASA, short-chain fatty acid enemas, or steroids ≤ 2 weeks 
prior to and during screening 
27. Treatment with topical rectal traditional medicine (eg, Chinese medicine), herb enemas, 
or suppositories ≤ 2 weeks prior to randomization 
28. Treatment with methotrexate ≤8 weeks prior to and during screening or cyclosporine, 
tacrolimus, sirolimus, or mycophenolate mofetil (MMF) ≤ 16 weeks prior to and during 
screening 
29. Receipt of a live vaccine ≤ 4 weeks prior to randomization 
30. Previous treatment with natalizumab 
31. Previous treatment with lymphocyte-depleting therapies (eg, alemtuzumab, anti-CD4, 
cladribine, rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, total body 
irradiation, bone marrow transplantation, daclizumab) 
32. Previous treatment with D-penicillamine, thalidomide, dimethyl fumarate, or pyrimidine 
synthesis inhibitors 
33. Treatment with IV immune globulin or plasmapheresis ≤ 3 months prior to randomization 
34. Chronic use of therapies that moderately/strongly inhibit/induce cytochrome P450 (CYP) 
2C8 and 2C9 metabolism and inhibitors of UGT1A7 ≤ 4 weeks prior to randomization 


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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: 
• 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 (FEV1 and/or FVC) below 50% of the predicted values 
• Confirmed diagnosis of clinically significant macular edema 
• Confirmed diagnosis of active 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 Day 1 or Day 2 (as 
applicable) (Section 9.4.2.1) 
• Subjects who have not met the discharge criteria (Table 4) on Day 1 after ≥ 4 hours of 
extended monitoring, or Day 2 by 4 hours post-dose 
• Pregnancy (Section 9.10.9) 
• Suspected drug induced liver injury as defined by the 2009 FDA Guidance for 
Industry (FDA 2009) 
− ALT or AST > 8 × ULN 
− ALT or AST > 5 × ULN for > 2 weeks 
− 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%) 


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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 (ET) visit within 7 days of the last administration of study 
treatment (Table 7) and before initiation of any new treatments to complete all of the ET 
assessments. If a subject discontinues due to pregnancy, they are not required to complete the 
endoscopy. If the ET visit is within 4 weeks of the last sigmoidoscopy and biopsy, these 
procedures do not need to be repeated. 
If the ET visit is ≥ 2 weeks after the last administration 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 ET visit is ≥ 4 weeks of the last administration of study treatment, the 4-Week 
Follow-Up visit is not required unless the absolute lymphocyte count (ALC) is not within normal 
limits. 
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. 


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The following actions must be taken if a subject fails to attend a required onsite, offsite, virtual, 
or hybrid 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: 
• 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 IECs/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 
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6. 
STUDY TREATMENTS  
6.1. 
Treatments Administered  
Subjects will be randomly assigned to 1 of 2 treatment groups (etrasimod or placebo) in a 
2:1 ratio. 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 
 
 
. APD334 
 is manufactured, 
packaged, tested, and released in compliance with cGMP. 
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 
 
 
 
. 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 after blood draws for PK and after all pre-dose 
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 eCRF. 
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 


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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), as indicated in the 
Schedule of Assessments, Table 7. 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 ≥ 2 consecutive days within the first week of 
treatment or for ≥ 7 consecutive days after the first week of treatment 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 9.4.2.1 
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 9.4.2.1 should be performed any time a subject 
misses study treatment as follows: 
• ≥ 2 consecutive days within the first week of treatment, or 
• ≥ 7 consecutive days after the first week of treatment 
6.4. 
Method of Assigning Subjects to Treatment  
Subjects will be centrally assigned to randomized study treatment using an Interactive Web 
Response System (IWRS). Before the study is initiated, the log in information and directions for 
the IWRS will be provided to each study site. 
Subjects will be randomized to study treatment via stratified randomization. Randomization will 
be stratified by (a) naïve to biologic or JAK inhibitor therapy at 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). 
Each subject will be dispensed blinded study treatment at study visits (Table 7). 
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 


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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 electronic case report form (eCRF), as applicable. 
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. 
If a subject’s treatment assignment is unblinded for any reason, they will be discontinued from 
the study. 
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 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. If there is a 
discrepancy between the tablet count and the subject’s compliance per the eDiary, it should be 
discussed with the subject and noted in the source documents. 
6.7. 
Concomitant Therapy  
All over-the-counter and prescribed concomitant medications, blood products, procedures, 
vitamins, and holistic products, administered during the Screening Period and during the study 
through the safety reporting period must be recorded in the eCRF, as appropriate. 
6.7.1. 
Required Concomitant Therapy  
Not applicable 
6.7.2. 
Allowed Concomitant Therapy  
Concomitant medication for medical conditions other than UC are permitted as clinically 
indicated subject to specific protocol requirements outlined in Section 4.1 and Section 4.2. 
6.7.2.1. 
Permitted Medications for the Treatment of Ulcerative Colitis  
Oral 5-ASA, AZA, 6-MP, oral corticosteroids, or medicinal probiotics are allowed at the time of 
screening and as per the inclusion criteria (Section 4.1); however, these products should not be 
started during screening or during the treatment period in subjects who are not already receiving 
them. Immunosuppressive agents such as oral AZA or 6-MP must be discontinued ≥ 2 weeks 
prior to randomization. 


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Subjects receiving 5-ASA or medicinal probiotics should maintain a stable dose throughout the 
study. 
Oral corticosteroid therapy (prednisone at a stable dose ≤ 20 mg/day, budesonide at a stable dose 
≤ 9 mg/day, or equivalent steroid) is allowed to be continued during the 12-Week Induction 
Treatment Period provided the dose has been stable for the 4 weeks immediately prior to the 
screening endoscopy assessment. 
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 
CYP, cytochrome P450 
• Start, stop, or change in dosage of any anti-arrhythmic drugs (Class I to IV) within 1 
week before or after treatment re-initiation following drug interruption as specified in 
Section 6.3.2 
• Inhibitors of UGT1A7 
• 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, AZA, 6-MP, tofacitinib) 
• Any per rectum therapy including enemas (eg, 5-ASA, corticosteroid), other than that 
required for endoscopy preparation 
• Cyclosporine, tacrolimus, sirolimus, methotrexate, or 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 


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• Treatment with D-penicillamine, thalidomide, dimethyl fumarate, or pyrimidine 
synthesis inhibitors 
• Treatment with lymphocyte-trafficking inhibitors (natalizumab, fingolimod, 
siponimod, ozanimod) 
• 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. 
• 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. 
7. 
SUBJECT RESTRICTIONS  
Prohibited concomitant therapy is described in Section 6.7.3. Additionally, subjects are restricted 
from the following: 
• Poppy seeds: Consumption of poppy seeds within 48 hours prior to drug screening 
may cause a positive drug screen. Subjects who report that they have consumed 
poppy seeds within 48 hours of the Screening Visit should not be screened. They may 
return 48 hours after the last poppy seed consumption for screening. Poppy seeds 
should not be eaten between screening and Week 0/Day 1. 
• 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 
metabolism of etrasimod. 


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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). In the case where a subject attends a 
virtual visit (refer to Section 9.6) and requires additional study treatment to continue on the 
study, study treatment may be dispensed and delivered by an approved courier where permitted 
by local law and regulation. Alternatively, a future supply of study medications may be 
dispensed to the subject at an onsite visit to cover study medications to be dispensed at the next 
planned virtual visit. Advanced planning and communication will be needed to dispense future 
supply of study medications at an earlier onsite visit. Shipping guidelines and instruction will be 
provided separately. 
8.3. 
Study Treatment Preparation  
Not applicable. 
8.4. 
Study Treatment Accountability  
At each visit, previously dispensed study treatment tablets will be collected by the Investigator or 
qualified individual and compliance assessed. 
The Investigator 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 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  
All study treatment will be reconciled by the clinical monitor and then returned or destroyed 
according to applicable country regulations. On-site destruction following all local regulations 
and in accordance with applicable site standard operating procedures (SOPs) is permitted. Prior 
to any action being taken with study treatment, the Investigator will contact the Sponsor (or 
contract research organization [CRO]) for approval of such action. Final reconciliation will be 
performed at Study Completion. 


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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 will be recorded in the eCRF whenever 
applicable. 
• 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 (Table 7), 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. 
• For onsite and offsite study visits (refer to Section 9.6 and Table 7), subjects should 
take their study treatment after blood draws for PK and after all pre-dose 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. 
Screening and Eligibility  
Subject eligibility will be assessed based on protocol inclusion and exclusion criteria. All 
screening evaluations must be completed and reviewed to confirm potential subjects meet all 
eligibility criteria. 
Screening procedures must be completed within 28 days prior to receiving the first dose of study 
treatment (Table 7). The Screening Period may be extended for subjects who require additional 
diagnostic testing/consults to determine status of either latent TB or C. difficile infection. If the 
subject is planned to be randomized > 28 days from the signing of the informed consent form 
(ICF), the Medical Monitor should be consulted to see if repeated testing is needed. The 28-Day 
Screening Period may also be extended on a case-by-case basis to accommodate reasonable 
delays in specific screening assessments (eg, PFTs, OCT] due to testing availability. The 
Medical Monitor must be consulted prior to extension in each case. 


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Subjects may have an abnormal laboratory assessment, repeated 1 time only. If additional retests 
are considered, the ability to repeat the laboratory assessment should be discussed with the 
Medical Monitor and the outcome of the conversation should be documented. 
9.3.1. 
Tuberculosis Screening and Chest X-Ray  
All subjects will complete TB screening to determine eligibility (refer to Appendix 2). If an 
Investigator feels the test for latent TB is abnormal, a retest to confirm latent TB status should be 
discussed and approved by the Medical Monitor. 
9.3.2. 
Rescreening  
Subjects who fail to meet the eligibility criteria can be rescreened per Investigator discretion. 
Additional screening attempts beyond the first should be approved by the Medical Monitor prior 
to rescreening. Each subject must be reconsented prior to each screening attempt. 
Subjects with a Screening Visit or Week 0/Day 1 prerandomization 12-lead ECG showing a 
second- or third-degree AV block, periods of asystole > 3 seconds, PR interval > 200 ms, or 
QTcF ≥ 450 ms (men) or QTcF ≥ 470 ms (women) are not eligible for rescreening. 
If a subject requires prophylactic therapy for latent TB, they may be rescreened as outlined in 
Section 4.2. 
If a subject is positive for C. difficile at screening, the subject may be treated and retested 
≥ 4 weeks after completing treatment. 
9.3.3. 
Demography and Other Subject Characteristics  
Demographics including year of birth, sex at birth, Hispanic ethnicity and race as described by 
the subject will be collected at screening. 
9.3.4. 
Social History  
At screening, a social history including the amount and duration of tobacco, alcohol, and caffeine 
usage will be collected. 
A standard urine drug screen will be performed. Subjects who test positive will be assessed for 
eligibility in study participation by the Investigator. 
9.3.5. 
Prior and Ongoing Therapies  
Prior therapies related to the treatment of UC will be collected during screening. In addition, 
documentation should also include the prior treatment response as one of the following: 
inadequate response to, loss of response to, or intolerance to (Section 4.1, Inclusion Criterion 7, 
for details). 
All medications taken and procedures carried out within 30 days prior to the first study treatment 
administration and all ongoing medications will be recorded at screening. Updates for new 
medications prior to dosing at the Day 1 visit should be made as needed. 


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9.3.6. 
Ulcerative Colitis History/Medical History  
In order to determine the subject’s eligibility to the study, a complete medical history of each 
subject will be collected and documented during screening. The history should include recent 
blood donations (≤ 30 days prior to the Screening Period), illnesses, and participation in other 
investigational drug studies. 
In addition, a detailed history of the subject’s UC, including date of diagnosis, disease severity, 
hospitalizations, and extraintestinal manifestations (EIMs), will be collected. 
9.3.7. 
Vital Signs  
At screening, vital signs (resting heart rate, systolic and diastolic BP, body temperature, and 
respiratory rate) will be measured while sitting. 
9.3.8. 
Pulmonary Function Test  
Pulmonary function tests including FEV1 and FVC measurements will be performed. In addition, 
diffusing capacity of the lungs for carbon monoxide (DLCO) measurements will be performed 
where locally available (sites where DLCO is not available should consult the Sponsor or 
Sponsor’s delegate). 
9.3.9. 
Ophthalmoscopy and Optical Coherence Tomography  
Ophthalmoscopy and OCT will be performed. A general ophthalmologist can do the 
examination; although, a retinal specialist would be preferred wherever possible. Subjects with a 
history of macular edema or retinopathy are not eligible for the study (Section 4.2). 
9.3.10. 
Clinical Laboratory Assessments  
Screening samples for complete blood count (CBC) with differential, platelet count, lymphocyte 
counts, T lymphocytes, B lymphocytes, natural killer lymphocytes (TBNK), serum chemistry, 
virology, thyroid panel, coagulation, urinalysis, high-sensitivity C-reactive protein (hs-CRP), TB 
screen, and stool sample should be obtained and results must be available and reviewed prior to 
randomization. In the case of new clinical laboratory abnormalities detected prior to 
randomization, the eligibility of the subject should be reconsidered with the guidance of the 
Medical Monitor. 
9.3.11. 
Proctosigmoidoscopy/Colonoscopy and Modified Mayo Score Derivation  
• Proctosigmoidoscopy/colonoscopy must be performed prior to randomization to 
treatment to allow central reader review (may take approximately 5 to 12 days) and 
confirmation of eligibility. Preferably, proctosigmoidoscopy/colonoscopy should be 
performed after other criteria for inclusion (eg, laboratory criteria) have been met. 
• Determination of MMS score to qualify for randomization: 
− The MMS will be evaluated at Day 1. The subscores for SF and RB are derived 
from the subject eDiary entries 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. The scoring will be calculated electronically. Subjects who do not have 


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3 consecutive days of eDiary data within that 7-day period and who do not have a 
minimum of 7 days of eDiary data prior to bowel preparation are not eligible for 
randomization. The MMS must be 4 to 9, including an ES ≥ 2 and RB score ≥ 1, 
for the subject to be eligible for randomization. 
− For the normal SF, it is essential for the subject to be asked to identify how many 
stools he or she has in a 24-hour period when in remission from UC. Subjects 
should be instructed that a stool is defined as a trip to the toilet when the subject 
has either a bowel movement, or passes blood alone, blood and mucus, or mucus 
only. If the subject does not report that he or she has achieved remission, then the 
subject should be asked to identify the number of stools he or she had before 
initial onset of signs and symptoms of UC. 
9.4. 
Randomization/Treatment Period  
9.4.1. 
Week 0/Day 1: Prerandomization  
At the Week 0/Day 1 visit (Table 7), prior to randomization, a 12-lead ECG in the supine 
position and resting vital signs in the sitting position (heart rate, systolic and diastolic BP, body 
temperature, and respiratory rate) will be collected. Caffeine and/or nicotine are not permitted 
within 30 minutes prior to BP measurements. 
Subjects with the following must not be randomized and should be considered screen failures: 
• Sitting vital sign assessment: heart rate < 50 bpm OR systolic BP < 90 mm Hg OR 
diastolic BP < 55 mm Hg 
• 12-lead ECG showing a second or third-degree AV block, periods of asystole 
> 3 seconds, PR interval > 200 ms, or QTcF ≥ 450 ms (men) or QTcF ≥ 470 ms 
(women). 
All pre-dose 12-lead ECGs should be obtained prior to blood sample collection. 
Subjects who continue to meet all eligibility criteria will be randomized as outlined in 
Section 6.4. 
9.4.2. 
Treatment Period  
After randomization, the 12-Week Treatment Period of the study will begin (Table 7). A study 
visit window of ± 3 days is permitted at each visit beginning with Week 2/Day 15 (PFT and OCT 
assessments have a window of ± 7 days). Study visits should be scheduled for the morning. 
The subscores for SF and RB are derived from the subject eDiary. 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. 


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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) 
• Physical examination 
• 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 pre-dose PK sampling 
9.4.2.1. 
Guidance for Cardiac Monitoring Following Treatment Initiation or 
Re-Initiation  
Prerandomization (ie, pre-dose/baseline) vital signs (resting heart rate, systolic and diastolic BP, 
body temperature, and respiratory rate) will be used as the Baseline measurement. The pre-dose 
heart rate measurement will be used for comparison to the post-dose measurement. Subjects 
should receive the first dose of study treatment before 12:00 PM (noon). 
First Dose Cardiac Monitoring 
In-clinic cardiac monitoring, of at least 4 hours, will occur on Day 1 and will include the 
following (Table 3): 
• Full baseline 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 prerandomization. 
• After the first dose of study treatment on Day 1, subjects must remain under 
observation in the clinic for at least 4 hours. 
• At Hours 1, 2, and 3 (± 15 minutes) post-dose, 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. 


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• 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 
Pre-Dose 
Hours 1, 2, 3 Post-Dosea   
Hour 4 Post-Dosea 
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. 
Table 4: 
Discharge Criteria After Cardiac Monitoring  
Subjects will be released from the clinical site after dosing on Day 1 (but no sooner than 4 hours post-dose) 
when they fulfill the following discharge criteria: 
• 
Heart rate ≥ 50 bpm or no more than 10 bpm lower than the pre-dose (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) 
AV, atrioventricular. 
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. 
Extended Cardiac Monitoring 
Subjects who do not meet discharge criteria at 4-hours post-dose 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). 
• 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 Day 1 must return on Day 2 for the 
second dose and will be re-monitored as on Day 1. These subjects will be 
discontinued from study treatment if they do not meet the discharge criteria at 4 hours 
after the second 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 Day 2 for the second dose and will be re-monitored as 


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on Day 1. These subjects must be discontinued from treatment if they do not meet the 
discharge criteria at 4 hours after the second dose on Day 2 and extended cardiac 
monitoring should be continued until the subject meets the discharge criteria 
(Table 4). 
9.4.3. 
Study Treatment Discontinuation Related to Post-dose Cardiac Monitoring  
A complete list of reasons for study treatment discontinuation is provided in Section 5. Reasons 
for study treatment discontinuation specific to post-dose 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 Post-Dose Cardiac 
Monitoring  
Reasons for Study Treatment Discontinuation Related to Post-Dose 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 Day 1 or Day 2 (as applicable). 
• 
Subjects who have not met the discharge criteria on Day 1 after ≥ 4 hours of extended monitoring, 
or Day 2 by 4 hours post-dose. 
a All treatment discontinuations should be discussed with the Medical Monitor. 
Cardiac Monitoring Upon Treatment Re-Initiation Following Dose Interruption 
Subjects should undergo the same first dose cardiac monitoring procedures as the original 
treatment initiation when study treatment dosing is interrupted for: 
• ≥ 2 consecutive days within the first week of treatment 
• ≥ 7 consecutive days after the first week of treatment 
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 administration of study treatment as indicated in the Schedule of 
Assessments (Table 7). 
If the ET or Study Completion visit is ≥ 2 weeks after the last administration 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 ET or Study Completion visit is ≥ 4 weeks after the last 
administration 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). 
All adverse events should be recorded for 30 days after last administration of study treatment 
(Section 9.10.8.2.2). 


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9.6. 
Virtual/Hybrid Visits  
Study visits after Day 1 may be conducted via onsite (in person at the study site or specialty lab), 
offsite (home health visit by study staff or designee), virtual (eg, telephone, video conference), or 
hybrid (a combination of aforementioned visit types) depending on the nature of the study 
assessment, technological capability, and acceptability with institutional practices and in 
alignment with local law and regulatory requirements. These may take place on different days 
within the study visit window. 
Certain assessments and/or procedures will not be performed in the home setting (eg, 
endoscopies, OCT, PFT, cardiac monitoring following treatment initiation or re-initiation, and 
12-lead ECG). 
Pregnancy testing and central laboratory assessments (eg, blood, stool, and urine samples) can be 
performed by either onsite visit or offsite visit. 
Assessments or procedures that may be conducted virtually, if allowed by local law and 
regulation, include for example: medical and medication history to assess eligibility criteria, 
review of demographic information, social history, AE query, review of concomitant 
medications, eDiary training, and compliance review/monitoring including study drug 
administration. 
During a virtual assessment, a subject may report an AE that requires a follow-up symptom-
focused physical exam or diagnostic test, as determined by the Investigator. In this scenario, the 
Investigator may have the subject return to the study site for an unscheduled study visit to 
perform the assessment. 
For study drug accountability, the medication bottle and remaining tablets may be visually 
inspected and counted on video conferencing. Subjects must return the dispensed bottle with the 
remaining tablets along with any empty bottles to the study site at the next onsite visit. Refer to 
Section 8 for study treatment management. 
Regardless of how a study visit and its associated procedures are conducted, all study procedures 
should be performed by qualified study site staff or qualified individual as delegated by the 
Principal Investigator. 
Study visits are designated accordingly in the Schedules of Assessments (Table 7). 
9.7. 
Pharmacokinetics  
Blood samples for analysis of etrasimod, and if warranted M3 (AR503641) and other 
metabolite(s) of interest, will be collected at the following time points from all subjects who 
received at least 1 dose of study drug (etrasimod or placebo): 
• Pre-dose and at 4 hours (± 15 minutes) post-dose (after 12-lead ECG) on 
Week 0/Day 1 
• Pre-dose (trough; within 60 minutes prior to dosing) at Weeks 2, 4, 8, and 12 
• At 2-Week and 4-Week Follow-Up visits 
• If possible, at the time of any SAE or adverse event leading to study treatment 
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Subjects should be instructed to document the time of their last dose prior to the study visit and 
the time must be recorded in the eCRF. The time of administration of study treatment during the 
study visit must also be recorded in the source along with the time of each PK sample. 
Blood samples will be processed for collection of plasma fractions for determination of the 
concentrations of etrasimod, and if warranted M3 (AR503641) and other metabolite(s) of 
interest. For the placebo group, a selected number of samples will be analyzed. 
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. 
No urine samples will be collected for PK analysis. 
Sample collection, preparation, and shipping will be detailed in a Laboratory Manual. 
9.8. 
Efficacy Assessments  
The components of the MMS are used to calculate several of the primary, secondary, 
 
 endpoints. The definitions for MMS components are outlined in Section 10.5. 
9.8.1. 
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 9.4.2. 
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 recorded 
electronically at the Screening Visit 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 


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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 9.4.2. 
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. 
9.8.1.1. 
Endoscopy  
A flexible proctosigmoidoscopy, performed with a video endoscope following cleansing 
preparation (oral or rectal cathartic), will be performed during screening (prior to 
Day 1/randomization) and at Week 12/ET visit. 
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 
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. 
Repeat 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. 
Note: For subjects with pancolitis > 8 years duration or subjects with left-sided colitis > 12 years 
without a surveillance colonoscopy within 12 months prior to baseline (Section 4.1, Inclusion 
Criterion 6), a colonoscopy and biopsies taken in accordance with local standard of care at 
screening to rule out dysplasia (ie, in place of screening proctosigmoidoscopy) is required. Any 
adenomatous polyps must be removed prior to their first administration of study treatment. 
9.8.1.2. 
Endoscopic Biopsies  
Per inclusion criteria (Section 4.1), a histopathology report supporting the diagnosis of UC must 
be available in the source documents prior to randomization. Post-randomization detected polyps 
or suspicious findings during endoscopy will be managed as per local standard of care. If a 
histopathology report is not available, the screening endoscopy may serve as such with histology 
evaluated at the local histology laboratory. 
Biopsies will be obtained at each endoscopy to support assessment of the histopathology 
endpoints 
. 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, biopsies should be taken 8 to 10 cm from the anal 
verge. 


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The original location (colonic segment) of biopsy specimens acquired at screening must be 
clearly indicated. 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 indices (Appendix 4) 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. 
9.8.2. 
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. 
9.8.3. 
Additional Health-Related Subject-Reported Outcomes  
Subject-reported quality of life instruments will be completed electronically and checked for 
completeness at the study site as indicated in the Schedule of Assessments (Table 7) and will be 
used in support of the efficacy outcomes. 
Inflammatory Bowel Disease Questionnaire (IBDQ): The IBDQ is a validated 32-item 
questionnaire used to assess health-related quality of life (HRQoL) in subjects with IBD (UC and 
CD). Response to each of the questions is graded from 1 to 7 with overall score ranging from 32 
(very poor HRQoL) to 224 (perfect HRQoL). 
Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms (UC-PRO/SS): The 
UC-PRO/SS is used to gather data on the gastrointestinal signs and symptoms of UC directly 
from the subject. The UC-PRO/SS is a 9-item questionnaire containing 2 domains: bowel 
movement signs and symptoms (6 items) and abdominal symptoms (3 items). An average score 
is calculated for each domain; a higher score indicates worse symptoms. The UC-PRO/SS will 
be administered if and when available. 
Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), Version 2 Physical 
and Mental Component and Domain Scores: The 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 be scored using 2 overall summary scores: physical component 
summary and mental component summary scores. 
Work Productivity and Activity Impairment Questionnaire – Ulcerative Colitis 
(WPAI-UC): The WPAI-UC consists of 6 questions asking about the effect of UC on the 
subject’s ability to work and perform regular activities. 
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). 


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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). 
9.8.4. 
Efficacy-Related Biomarkers  
Samples for biomarker assessments will be collected according to the Schedule of Assessments 
(Table 7). Blood, tissue, and stool samples will be analyzed by the central or specialty 
laboratory. Details for collection, processing, and storage will be provided in the Laboratory 
Manual. Residual samples will be stored and may be used for additional analyses if the subject 
has granted consent where allowed by the regulatory authorities and local ethics committees. 
C-reactive protein (CRP): CRP is an acute phase protein expressed by hepatocytes in response 
to inflammatory cytokines and will be assessed using a hs-CRP assay. Investigators will be 
blinded to the hs-CRP results during the treatment and follow-up periods. 
Fecal calprotectin: Fecal calprotectin is a complex consisting of calcium-binding proteins. It is 
expressed by activated neutrophils (and to a lesser extent by macrophages and monocytes) and 
fecal levels correlate with the number of neutrophils in the gut. It is used as a biomarker of 
intestinal inflammation. Investigators will be blinded to the fecal calprotectin results during the 
treatment and follow-up periods. 
Lymphocyte counts: Etrasimod is believed to modulate lymphocyte trafficking resulting in a 
reduction in peripheral lymphocyte count and lymphocyte availability for recruitment to sites of 
inflammation. During the treatment period, the Investigator will be blinded to the white blood 
cell (WBC) and differential counts during the treatment and follow-up periods. During the 
treatment period, WBC differential results will be assessed by an unblinded Medical Monitor 
(not providing direct medical oversight of study conduct). If either of the following occur, the 
unblinded Medical Monitor will notify the Investigator with additional instructions. 
• ANC < 1000 cells/μL 
• ALC < 200 cells/μL 
If the ANC is confirmed below the 1000 cells/µL limit, the Investigator will be requested to 
closely monitor for serious infection and institute appropriate follow-up at his or her discretion. 
If the ALC is confirmed below the 200 cells/µL limit, study treatment should be interrupted and 
should not be reinitiated if the ALC remains below this threshold. In this situation, the unblinded 
Medical Monitor will notify the Investigator and provide instructions on additional actions that 
the Investigator may need to take. When there is at least one measurement of ALC 
< 200 cells/µL, blinded values may be released to treating physicians and Investigators as 
deemed medically necessary to monitor infection and/or aid in diagnostic work-up as clinically 
indicated, and/or as a tool to assess the effectiveness of therapeutic interventions for an infection. 
Investigators will repeat CBC with differentials weekly until ALC > 500 cells/µL. 
Re-initiation of the study treatment can only be considered when ALC > 500 cells/µL. 
 
  
 
 


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9.9. 
Genetics  
Genetics will be evaluated in this study to assess genetic variation that may impact response to 
treatment, metabolism, and mechanism of action of etrasimod. DNA may be used for 
immunophenotyping by epigenetic profiling. 
A blood sample for DNA isolation will be collected from subjects who have consented to 
participate in the genetic analysis component of the study. Participation is optional. Subjects who 
do not wish to participate in the genetic research may still participate in the study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the subject. 
Details on the processes for collection and shipment and destruction of these samples can be 
found in the Laboratory Manual. 
9.10. 
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 9.10.8.1). Adverse events will be 
coded using the latest version of the Medical Dictionary for Regulatory Activities (MedDRA). 


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9.10.1. 
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/height (height at screening only) 
• 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. 
9.10.2. 
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. 
9.10.3. 
12-Lead Electrocardiogram  
All 12-lead ECGs will be performed according to Section 9.4.2.1 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 QTcF. If an ECG shows a new onset QTc interval > 500 ms during the treatment period, 
a repeat ECG is warranted. If this abnormal finding is confirmed, study treatment must be 
interrupted. Effective diagnostic and therapeutic strategies should be employed. 


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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. 
9.10.4. 
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 Screening, 
and Week 12, or at the ET visit. PFTs occurring at the ET visit that are within 4 weeks of the last 
assessment will only be required if clinically indicated. The 2-Week Follow-Up visit assessment 
is only required if clinically indicated. 
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. 
When available, DLCO measurements will also be performed. When DLCO is not available, 
sites should consult the Sponsor or Sponsor’s delegate). These tests will be performed at a 
qualified pulmonary function 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). 
The safety of trial subjects and site staff is paramount, so it is at the Investigator’s discretion 
whether PFT can be safely administered to trial subjects during the treatment period. The 
Investigator should evaluate on a case-by-case basis how best to proceed based on the subject’s 
medical history, the Investigator’s clinical judgement, and in consultation with the Medical 
Monitor. All reasonable efforts should be made to ensure safety and adherence to the protocol. 
When available, spirometry may be conducted at the clinical site instead of at the pulmonary 
laboratory. If the decision is made that it is not appropriate to conduct PFTs due to the safety 
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be appropriately captured in the subject’s source documentation. When available and safe (due to 
lifting of local restrictions, re-opening of local PFT labs, or improved safety conditions) the tests 
should be conducted as soon as possible and as close to the timepoints as outlined in the 
protocol. 
9.10.5. 
Ophthalmoscopy and Optical Coherence Tomography  
A complete ophthalmoscopy and OCT will be performed according to the Schedule of 
Assessments (Table 7). OCTs occurring at the ET visit that are within 4 weeks of the last 
assessment will only be required if clinically indicated. The 2-Week Follow-Up visit assessment 
is only required if clinically indicated. A standard visual acuity chart should be used for the 
visual acuity assessment. The OCT machine used should preferably not be changed during the 
study to allow for comparison of central foveal thickness measurements within each subject 
across time points. 
Screening Visit: 
At the screening ophthalmology visit, the eye examination will include: 
• Ophthalmologic history 
• Best corrected visual acuity measurement (using Snellen chart internationally [if 
available]) 
• Ophthalmoscopy (may include contact lens biomicroscopy to examine the macula and 
optic disc). A dilated fundus exam should be performed in all subjects at the 
Screening Visit and as needed at subsequent visits in subjects with significant 
abnormalities identified on the screening exam. 
• Measurement of central foveal thickness by OCT (recorded in micrometers; required 
for all subjects regardless of the results of visual acuity or ophthalmoscopy) 
• Slit lamp examination should be performed to establish uveitis disease status (yes/no). 
Uveitis should be characterized and graded using the Standardization of Uveitis 
Nomenclature criteria. Subjects with active uveitis without macular edema at 
Screening are eligible to enroll in the study 
• If there is a suspicion of macular edema by ophthalmoscopy and increased central 
foveal thickness by OCT, then additional testing should be considered at the 
discretion of the ophthalmologist (for example, fluorescein angiogram may be 
performed). Subjects with diagnosed macular edema at Screening should be deemed a 
screening failure and should not be randomized. 
• Optional procedures in case of clinically significant abnormalities on ophthalmic 
exam may include but are not limited to: 
− Retinal photographs 
− Intraocular pressure 


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Scheduled post-screening visits: 
At the scheduled ophthalmology visit, the eye examination will include 
• Best corrected visual acuity measurement 
• Ophthalmoscopy (may include contact lens biomicroscopy to examine the macula and 
optic disc) 
• Measurement of central foveal thickness by OCT 
• For subjects with uveitis findings on ophthalmic exam, additional testing should be 
considered (for example, fluorescein angiogram). 
Subjects experiencing unexpected ophthalmic symptoms without a known suspected etiology or 
experiencing a relevant ophthalmic AE may need to have repeated ophthalmoscopy and OCT 
testing performed. 
9.10.6. 
Tuberculosis Screening and Chest X-Ray  
All subjects will complete TB screening to determine eligibility. A TB screening questionnaire 
will be completed during the Screening Period by the PI or delegated site staff for each subject 
and applicable information will be entered into the eCRF. For subjects residing in countries with 
a high burden of TB or multi-drug resistant (MDR) TB as identified by WHO, the TB screening 
questionnaire will be completed at every study visit (Appendix 2). 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). 
9.10.7. 
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 pre-dose. 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 9.8.4). 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 
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 
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• All protocol-required laboratory assessments, as defined in the Schedules 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 9.8.4. 


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Table 6: 
Clinical Laboratory Tests  
SCREENING Only 
Virology 
HIV, HBsAg, HCV (RIBA) 
Stool Sample 
Bacterial culture, ova and parasites, C. difficile 
Drugs of Abuse 
Amphetamine, barbiturates, benzodiazepines, cocaine, methadone, 
methamphetamine, methylenedioxymethamphetamine, opiate, 
oxycodone, phencyclidine 
Others 
Hemoglobin A1C, QuantiFERON 
 
PREGNANCY TESTING 
Serum pregnancy test human beta-chorionic gonadotropin (β-hCG) - Screening 
Urine β-hCG (only for women of childbearing potential) 
CLINICAL CHEMISTRY, HEMATOLOGY, AND COAGULATION 
Hematology 
Serum Chemistry 
Hematocrit 
Hemoglobin 
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration 
Mean corpuscular volume 
Platelet count 
Red blood cell count 
White blood cell count with 
differentiala  
TBNKa  
Coagulation 
Prothrombin time 
Activated partial thromboplastin 
time 
International normalized ratio 
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Aspartate aminotransferase 
Bicarbonate 
Blood urea nitrogen 
C-reactive protein 
Calcium 
Chloride 
Creatinine 
Creatine kinase 
Direct bilirubin 
Glucose 
Gamma-glutamyl transferase 
Lactate dehydrogenase 
Phosphorus 
Potassium 
Sodium 
Thyroid-stimulating hormone 
Thyroxine free 
Total bilirubin 
Triiodothyronine free 
Total cholesterol 
Total protein 
Triglycerides 
Uric acid 
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) 
BIOMARKERS 
Lymphocytesa,b  
hs-CRPb 
Fecal calprotectinb 
Immunophenotyping 
Proteomics  
RNA Transcriptomics  
Fecal microbiome  
 
 
GENETICS 
Genomic DNA (optional) 
 
 
STOOL SAMPLEc  
Ova and parasites, C. difficile 
a Total WBC, neutrophil, lymphocyte, and TBNK will be available for review prior to randomization. After randomization, 
the total WBC, neutrophil, lymphocyte, and TBNK 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 after randomization. Refer to Section 9.8.4 for additional details. 
b Investigators will remain blinded to the results after randomization. 
c Stool sample for bacterial culture, ova, and parasite evaluation, and C. difficile assay at any point in the study when a subject 
becomes symptomatic, including worsening or return of disease activity. 
β-hCG, human beta-human chorionic gonadotropin; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human 
immunodeficiency virus; hs-CRP, high-sensitivity C-reactive protein; IgG, immunoglobulin G; RIBA, recombinant 
immunoblot assay; TBNK, T lymphocytes, B lymphocytes, and natural killer lymphocytes; WBC, white blood cells 
9.10.7.1. Screening  
9.10.7.1.1. Drugs of Abuse  
A standard urine drug screen will be performed (Table 6). Subjects who test positive will be 
assessed for eligibility for study participation by the Investigator. 
9.10.7.1.2. Pregnancy Testing  
A serum pregnancy test for β-hCG will be performed on women of childbearing potential to 
determine eligibility. Post-screening urine pregnancy tests (β-hCG) should be performed as 
indicated in the Schedule of Assessments (Table 7). 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 9.10.9. 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. 


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9.10.7.1.3. Virology  
Screening HIV antibody, hepatitis B (ie, HBsAg), and HCV (recombinant immunoblot assay, if 
positive HCV RNA should be used to confirm infection). 
9.10.7.1.4. 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). 
9.10.8. 
Adverse Events  
9.10.8.1. Definitions  
9.10.8.1.1. 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 
9.10.8.1.2. 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 
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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. 
9.10.8.1.3. 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). 
9.10.8.1.4. 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. 
9.10.8.1.5. 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): 


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Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL). 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, 
limiting self-care 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 
9.10.8.1.6. Relationship  
The Investigator (or designee) will make a determination of the causal relationship of the AE to 
the study drug using a 4-category system according to the following guidelines: 
Not Related: 
The AE is definitely caused by the subject’s clinical state or the study 
procedure/conditions. 
Unlikely Related: 
The temporal association between the AE and the drug is such that the 
drug is not likely to have any reasonable association with the AE. 
Probably Related: 
The AE follows a reasonable temporal sequence from administration of 
the drug and cannot be reasonably explained by the known 
characteristics of the subject’s clinical state, environmental, or toxic 
factors, or other modes of therapy administered to the subject. 
Related: 
The AE follows a reasonable temporal sequence from administration of 
the drug, abates upon discontinuation of the drug, follows a known or 
hypothesized cause-effect relationship, and (if appropriate) reappears 
when the drug is reintroduced. 
The Investigator will use clinical judgement 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. 


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9.10.8.2. Eliciting and Recording Adverse Events  
9.10.8.2.1. 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. 
9.10.8.2.2. 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 administration of study treatment. If an adverse event is not resolved or stabilized 
by this time, the Sponsor in consultation with the Investigator will decide whether to continue to 
monitor the adverse event or closeout the event in the database if no further follow-up is 
necessary. 
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 of study treatment. 
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. 
9.10.8.2.3. 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 


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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. 
9.10.8.3. Reporting Adverse Events  
All SAEs are subject to reporting requirements. 
9.10.8.3.1. Serious Adverse Events  
Any adverse event considered serious by the Investigator or Sub-Investigator or that meets 
serious criteria should be reported to the designated safety contact within 24 hours of becoming 
aware of the event (or in India within 24 hours of event occurrence). Enter the SAE 
information into eCRF, and send other available pertinent information (eg, hospital records, 
laboratory results, etc) to the designated Sponsor Contact. 
IQVIA Pharmacovigilance 
 
 
 
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. 
Elective hospitalization and/or surgery for clearly preexisting conditions (eg, a surgery that has 
been scheduled prior to the subject’s entry into the study) will not be reported as an SAE. 
Any SAE that is ongoing when the subject completes the study or discontinues the study will be 
followed by the Investigator until the event resolved, stabilized or returned to baseline status. 
9.10.8.3.2. 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. 
9.10.9. 
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 


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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. 
9.11. 
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 AE/SAE and laboratory abnormalities and follow the 
AE reporting process, including contacting the Medical Monitor. 
2. Obtain a plasma sample for PK analysis within 7 days from the date of the last dose of 
study treatment, if possible, and if requested by the Medical Monitor. 
3. Document the total quantity of the excess dose, taking into consideration the duration of 
the overdose in the eCRF and the time frame. 
Subjects who overdose will be counseled on correct dosing and administration of study 
treatment. Decisions regarding study discontinuation, dose interruptions, or dose modifications 
will be made by the Investigator in consultation with the Medical Monitor based on the clinical 
evaluation of the subject. 


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10. 
PLANNED STATISTICAL METHODS  
10.1. 
General Considerations  
All individual subject data for all randomized subjects will be presented in data listings. All 
efficacy and safety endpoints will be summarized by treatment group. Full details of statistical 
considerations and the planned analyses will be described in the study Statistical Analysis Plan 
(SAP). 
10.2. 
Determination of Sample Size  
Based on a 2-group Fischer’s exact test, a 1-sided significance level of 0.025, and a 
2:1 randomization ratio, 330 total subjects (220 etrasimod, 110 placebo) are required to achieve 
at least 90% power to detect a difference of 12.5% in the primary endpoint of clinical remission 
between the etrasimod treatment group (18.5%) and the placebo treatment group (6.0%). 
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 randomized 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, regardless of the treatment received during the study. 
Per Protocol Set: The Per Protocol 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 Per Protocol definition. 
Modified Full Analysis Set (mFAS): The mFAS will consist of all randomized subjects who 
receive at least 1 dose of study treatment and have a baseline and at least 1 post-randomization 
measurement. Under this approach, subjects will be counted in the treatment group to which they 
were randomized, regardless of the treatment received during the study. 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 randomized 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 a lack of efficacy adverse event related will be considered as having a treatment 
nonresponse outcome in the analysis of all endpoints, including the primary endpoint. In 


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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 nonresponders for binary responder-type endpoints thereafter or be handled 
by Per Protocol analysis. 
Subjects discussed above will be considered as having a known outcome at the analysis time 
point (ie, a treatment failure outcome) and not as having missing data. Subjects who discontinue 
the double-blind study for reasons other than a lack of efficacy 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 nonresponders. 
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 analyzed with their observed data only, or a 
mixed -effect model with repeated measures. Detailed methods will be provided in the SAP. 
Sensitivity analyses for missing data 
Sensitivity analyses will 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 
time points, 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 
nonresponders 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. 
• 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 


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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 time points. 
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: 
• 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 
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 time point (ie, Week 12). Complete details of the MMS symptom score 
computation method are provided in Section 9.3.10 and Section 9.4.2. 


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10.6. 
Primary Endpoint  
The primary efficacy endpoints will evaluate etrasimod versus placebo in: 
• The proportion of subjects achieving clinical remission at Week 12 
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 12 
• The proportion of subjects achieving symptomatic remission at Week 12 
• The proportion of subjects with mucosal healing at Week 12 
10.7.2. 
Other Secondary Efficacy Endpoints  
The other secondary endpoints are: 
• The proportion of subjects achieving clinical response at Week 12 
• The proportion of subjects achieving endoscopic normalization at Week 12 
• The proportion of subjects achieving symptomatic remission at Weeks 2, 4, 8 
• The proportion of subjects achieving complete symptomatic remission at each study 
visit (Weeks 2, 4, 8, 12) 
• The proportion of subjects achieving noninvasive clinical response at each study visit 
(Weeks 2, 4, 8, 12) 
• The proportion of subjects achieving symptomatic response at each study visit 
(Weeks 2, 4, 8, 12) 
 
  
 
 
 
 
 
 
 
 
 
 


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10.9. 
Other Efficacy -Related Endpoints  
10.9.1. 
Health-Related Quality of Life  
• Scores and change from baseline to Week 12 in the following: 
− IBDQ total score 
− UC-PRO/SS 
− SF-36, version 2, physical and mental component and domain scores 
− WPAI-UC 
− Urgency NRS 
− Abdominal pain NRS 
• The proportion of subjects with UC-related hospitalizations 
• The proportion of subjects requiring UC-related surgeries, including colectomy 
10.9.2. 
Pharmacokinetics  
• Plasma concentrations of etrasimod, and if warranted M3 (AR503641) and other 
metabolite(s) of interest, will be assessed from samples collected prior to dosing and 
4 hours (± 15 minutes) post-dose (after 12-lead ECG) on Week 0/Day 1 
• Plasma concentrations of etrasimod, and if warranted M3 (AR503641) and other 
metabolite(s) of interest, will be assessed from samples collected prior to dosing 
(trough) at Weeks 2, 4, 8, 12, and the 2-Week and 4-Week Follow-Up visits 
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. 
Full details of PK analysis will be provided in the SAP. 
10.9.3. 
Biomarkers  
• Change from baseline in level of fecal calprotectin at Weeks 2, 4, 8, and 12 
• Change from baseline in level of hs-CRP at Weeks 2, 4, 8, and 12 
• Change and percentage change from baseline in lymphocyte counts at Weeks 2, 4, 8, 
and 12 
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. The SAP will provide a complete list and definition of the subgroups and analysis 
methods. 


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• Sex (male, female) 
• Age: > or ≤ median age, ≥ or < 65 years 
• Race 
• Baseline oral corticosteroid usage (yes or no) 
• Naïve 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 
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) naïve to biologic or JAK 
inhibitor therapy at 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) and p-values. 
There are multiple null hypotheses for the comparison of etrasimod and placebo in the primary 
and key secondary endpoints. The family-wise type-I error rate will be controlled at a fixed 
α level at 0.025 (1-sided) using the following testing procedure. First, the whole α will be spent 
on testing the primary endpoint. 
Only if the primary null hypothesis is rejected at the α level, can testing proceed for the 3 key 
secondary endpoints. The method for such testing will be specified in the SAP, and it will control 
for the multiplicity of the 3 key secondary endpoints. Any key secondary endpoint that fails to be 
significant at the α level by this method to control multiplicity will be considered exploratory and 
thereby would only have nominal p-values. All other endpoints will be evaluated at α level of 
significance and reported with nominal p-values, without multiplicity adjustment. 
Full details of the efficacy analysis will be documented prior to database lock in the SAP. 


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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 ICF, subject recruitment materials and procedures (eg, 
advertisements or websites), and any other written information to be provided to subjects. 
Approval from the committee must be documented in a letter to the Investigator 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 < 18 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 
timely manner if new information becomes available that may be relevant to the subject’s 


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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 laws. 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 
13.3. 
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) or to other regulatory authorities 
that have similar requirements. The Investigator is responsible for compliance with applicable 
sections of ICH GCP requirements. The Investigator may also be responsible for compliance 
with 21 CFR Part 312, Subpart D, (Responsibilities of Investigators) and other ICH GCP 
guidelines and/or 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  ICH GCP 
guidelines and/or 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 ICH E6(R2) and 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, and ensuring proper monitoring of the investigation(s). Sponsors are also 
responsible for ensuring the investigation(s) is conducted in accordance with the general 
investigational plan and protocols contained in the Investigational New Drug (IND) application 
(or equivalent), maintaining an effective IND (or equivalent) with respect to the investigations, 
and ensuring the FDA, (and/or other regulatory authorities as applicable), 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.  
 A Phase 2, randomized, double-blind, placebo-controlled, parallel group, multi-
center study to investigate the safety and efficacy of APD334 in patients with moderately to 
severely active ulcerative colitis. San Diego, CA: Arena Pharmaceuticals, Inc.; July 30, 2018. 
Clinical Study Report APD334-003. On file at Arena. 
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 
Gastroenterology. 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.  


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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.  
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 2020. Accessed July 13, 
2020. 
Rubin DB. Multiple imputation for nonresponse in surveys. New York, NY: John Wiley and 
Sons; 1987. On file at Arena. 
Sandborn WJ, Peyrin-Biroulet L, Zhang J, et al. Efficacy and safety of etrasimod in a Phase 2 
randomized trial of patients with ulcerative colitis. Gastroenterology. 2020;158:550-561.  
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 – Screening and Induction Treatment Period  
Evaluation 
Screening 
Period 
12-Week Treatment Period 
 
 
−28 to −1 
W0/D1 
W2/D15 
± 3 Days 
W4/D29 
± 3 Days 
W8/D57 
± 3 Days 
W12/D85 /  
Early Terminationa 
± 3 Days   
2-Week 
Follow-Up 
Visitb 
± 3 Days 
4-Week 
Follow-Up 
Visitb 
± 3 Days 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical and social historyc    
X 
 
 
 
 
 
 
 
Ulcerative colitis history 
X 
 
 
 
 
 
 
 
Chest X-rayd   
X 
 
 
 
 
 
 
 
Tuberculosis teste   
X 
 
 
 
 
 
 
 
Tuberculosis questionnairee 
X 
X 
X 
X 
X 
X 
X 
X 
Virology screen (HIV, HBV, HCV)f   
X 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
eDiary instructiong   
X 
 
 
 
 
 
 
 
eDiary review 
 
X 
X 
X 
X 
X 
 
 
MMSh   
 
X 
 
 
 
X 
 
 
Stool frequency and rectal bleeding 
subscorei   
 
X 
X 
X 
X 
X 
 
 
PGA for total Mayo Clinic Score 
 
X 
 
 
 
X 
 
 
IBDQ, UC-PRO/SS, SF-36, WPAI-UC, 
and abdominal pain and urgency NRS 
 
X 
 
 
 
X 
 
 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
X 


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Evaluation 
Screening 
Period 
12-Week Treatment Period 
 
 
−28 to −1 
W0/D1 
W2/D15 
± 3 Days 
W4/D29 
± 3 Days 
W8/D57 
± 3 Days 
W12/D85 /  
Early Terminationa 
± 3 Days   
2-Week 
Follow-Up 
Visitb 
± 3 Days 
4-Week 
Follow-Up 
Visitb 
± 3 Days 
Vital signsj,k   
Xj 
Xj,k 
X 
X 
X 
X 
X 
X 
12-lead ECGl,m   
Xl 
Xl,m 
 
 
 
X 
 
 
Physical examinationn   
X 
X 
X 
X 
X 
X 
X 
X 
Extraintestinal manifestationso   
X 
 
 
 
 
X 
X 
X 
Pulmonary function testp   
Xq 
 
 
 
 
Xq 
Xq 
 
Ophthalmoscopy with OCTr   
X 
 
 
 
 
X 
Xr 
 
Urine drug screens   
X 
 
 
 
 
 
 
 
Pregnancy testt   
X 
X 
 
X 
X 
X 
 
X 
Genomic DNA (optional) 
 
X 
 
 
 
 
 
 
CBC with differential and platelets 
X 
X 
X 
X 
X 
X 
X 
X 
TBNK 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory tests including hs-CRPu   
X 
X 
X 
X 
X 
X 
X 
 
Stool sample/fecal calprotectinv   
X 
 
X 
X 
X 
X 
 
 
Stool sample for microbiome 
X 
 
 
 
 
X 
 
 
Flexible proctosigmoidoscopy/ 
colonoscopy and biopsyw   
X 
 
 
 
 
X 
 
 
PK assessmentsx   
 
X 
X 
X 
X 
X 
Xx 
Xx 
Biomarkers blood sampley   
 
X 
 
 
 
X 
 
 
Concomitant medications and 
proceduresz   
 
X 
X 
X 
X 
X 
X 
X 
Drug dispensation/accountabilityaa   
 
X 
X 
X 
X 
Xaa 
 
 


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Amendment 3.0 
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Evaluation 
Screening 
Period 
12-Week Treatment Period 
 
 
−28 to −1 
W0/D1 
W2/D15 
± 3 Days 
W4/D29 
± 3 Days 
W8/D57 
± 3 Days 
W12/D85 /  
Early Terminationa 
± 3 Days   
2-Week 
Follow-Up 
Visitb 
± 3 Days 
4-Week 
Follow-Up 
Visitb 
± 3 Days 
Study treatment administrationbb   
 
X – Once daily 
 
 
a All visits beyond W0/D1 may be virtual/hybrid visits (Section 9.6). Subjects discontinuing prior to Week 12 should have an Early Termination (ET) visit within 7 days of the last 
study treatment administration and before initiation of any new treatments. For subjects who complete Week 12 and wish to enter the APD334-303 OLE study, the Week 12 visit 
will be used to assess eligibility for the APD334-303 OLE study. 
b For subjects not participating in the APD334-303 OLE study, a follow-up visit will be performed at 2 weeks and 4 weeks after the last administration of study treatment. If the 
ET 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 ET or Study Completion visit is ≥ 4 weeks after the last administration 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). 
c Medical history, including prior and ongoing medication use, will be collected during screening and should be updated for any new conditions or medications as needed prior to 
dosing at the D1 visit (Section 9.3.5). 
d A chest X-ray taken within the previous 6 months from the Screening Visit may also be used. 
e All subjects will complete TB screening to determine eligibility (refer to Appendix 2). The QuantiFERON TB Gold and tuberculin skin test should not be performed in subjects 
previously diagnosed with TB infection. The TB questionnaire will be completed for all subjects during the Screening Period and at every study visit for subjects residing in 
countries with a high TB burden or MDR TB as identified by the WHO. 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). 
f Subjects will be tested for HIV antibodies as well as HBV and HCV infection at screening (Section 9.10.7.1.3). 
g Subjects will begin eDiary entries beginning the first day of screening after eDiary training is completed. The eDiary should be completed daily to capture data including daily 
SF and RB (the 2 subject-reported outcome measures contributing to the calculation of the MMS), and study treatment administration. The subject eDiary will be reviewed by 
study site staff at each treatment visit. 
h The MMS will be calculated electronically at the Day 1 and Week 12/Early termination visits. The subscores for SF and RB are derived from the subject eDiary entries 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 (Section 9.3.10). 
i Stool frequency and RB subject-reported outcomes will be recorded daily using electronic subject eDiaries. The RB and SF subscores will be calculated as indicated in 
Section 9.4.2. 
j Safety vital signs (resting heart rate and systolic and diastolic BP, body temperature, and respiratory rate) taken with subjects in the sitting position will be performed at 
Screening and prior to randomization on Week 0/Day 1 (baseline). If the subject’s heart rate is < 50 bpm, or systolic BP < 90 mm Hg, or diastolic BP < 55 mm Hg, or has 
symptoms of low HR or low BP, the subject must not be randomized and should be considered a Screen Failure. 
k On Day 1, vital sign assessments will be conducted as described in Section 9.4.2.1. 
l Safety 12-lead ECGs with the subject in the supine position will be obtained prior to blood sample collection at Screening and prior to randomization on Week 0/Day 1 
(baseline). Subjects with a 12-lead ECG showing a second or third-degree AV block, periods of asystole > 3 seconds, PR interval > 200 ms, QTcF ≥ 450 ms (men) or 
QTcF ≥ 470 ms (women) must not be randomized and should be considered screen failures. 
m After dosing on Day 1, a 12-lead ECG with the subject in the supine position will be performed 4 hours (± 15 minutes) post-dose as described in Section 9.4.2.1. 


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n Complete physical examination (including assessments of the skin, head, eyes, ears, nose, throat, neck, thyroid, lungs, heart, abdomen, back, lymph nodes, extremities, body 
weight, and height [height collected at Screening Visit only]) should be performed at screening and the Week 12/ET visit. All other visits during the 12-Week Treatment Period 
should have a focused (complaints, signs, and symptoms) physical examination. 
o During the specified full physical examinations (screening and Week 12/ET visits), specific systems (eyes, liver, skin and joints) will be examined for EIMs. 
p A PFT will include FEV1 and FVC measurements. When available, DLCO measurements will also be performed (when DLCO is not available, sites should consult the Sponsor 
or Sponsor’s delegate). 
q The Screening pulmonary function test (PFT) should be done within the 28-day Screening Period. PFTs should be performed ± 7 days in the study treatment period and 
posttreatment period (ie, 2-Week Follow-Up visit). PFTs occurring at the ET visit that are within 4 weeks of the last assessment will only be required if clinically indicated. The 
2-Week Follow-Up visit assessment is only required if clinically indicated. Details regarding additional PFTs are provided in Section 9.10.4. 
r The Screening OCT should be performed within the 28-day Screening Period. Subsequent ophthalmoscopy with OCT should be performed ± 7 days in the study treatment period 
and posttreatment period (ie, 2-Week Follow-Up visit). OCTs occurring at the ET visit that are within 4 weeks of the last assessment will only be required if clinically indicated. 
The 2-Week Follow-Up visit assessment is only required if clinically indicated. Details regarding ophthalmoscopy and OCT assessments are provided in Section 9.10.5. 
s Urine drug screen according to Table 6. 
t Only for women of childbearing potential. Serum β-hCG test required at screening; urine pregnancy test at all other visits. If at any point there is a positive urine β-hCG test, the 
subject will have study treatment interrupted and a serum sample submitted to the central laboratory for β-hCG testing (Section 9.10.7.1.2). 
u Clinical laboratory tests will include serum chemistry, hematology (including coagulation), urinalysis, and hs-CRP. Screening samples should be obtained and results must be 
available and reviewed prior to the first dose of study treatment. On other study visits, samples should be obtained prior to the daily dosing. 
v Stool sample is for fecal calprotectin (Screening, Weeks 2, 4, 8, and 12) and bacterial culture, ova and parasite evaluation, and C. difficile assay at screening and at any point in 
the study when a subject becomes symptomatic, including worsening or return of disease activity. 
w To be read by a blinded central reader. Proctosigmoidoscopy/colonoscopy should be performed prior to randomization to allow central reader review (may take approximately 
5 to 12 days) and confirmation of eligibility (Section 9.8.1.1). If the ET visit is within 4 weeks of the last sigmoidoscopy and biopsy, these procedures do not need to be repeated. 
x Pharmacokinetic blood samples are to be collected pre-dose, 4 hours (± 15 minutes) post-dose on Week 0/Day 1 (PK sample to be collected after 12-lead ECG), and pre-dose 
(for trough level, within the 60-minute period prior to dosing) on all other indicated days. A PK sample should be taken, if possible, at the time of any SAE or adverse event 
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. 
y Blood samples for biomarkers should be collected on the indicated days prior to the daily dosing as applicable. Biomarker sample collection is not required at ET visit. 
z All concomitant medications and procedures should be collected from Day 1 (pre-dose) through the safety reporting period (Section 6.7). 
aa Study treatment should be dispensed at Week 12 if the subject continues treatment in the 40-Week Treatment Period. Additionally, subjects who consent and are eligible for the 
APD334-303 OLE study but do not enter the OLE on the same day as the Week 12 visit may also be dispensed study treatment. 
bb On days with scheduled study visits, subjects should not take their dose of study treatment at home in order to complete pre-dose study procedures. The dose will be taken at the 
study site after blood draws for PK and after all pre-dose assessments and procedures have been completed. 
AV, atrioventricular; β-hCG, beta-human chorionic gonadotropin; 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; ET, early termination; FEV1, forced expiratory volume at 1 second; FVC, forced 
vital capacity; HbA1c, hemoglobin A1c; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HR, heart rate; 
hs-CRP, high-sensitivity C-reactive protein; IBDQ, Inflammatory Bowel Disease Questionnaire; MMS, modified Mayo score; OCT, optical coherence tomography; OLE, 
open-label extension; PGA, Physicians Global Assessment; PK, pharmacokinetics; QTcF, Fridericia’s corrected QT interval; RB, rectal bleeding; SF, stool frequency; SF-36, 
Medical Outcomes Study 36-Item Short Form Health Survey; TBNK, T lymphocytes, B lymphocytes, and natural killer lymphocytes; UC, ulcerative colitis; UC-PRO/SS, 
Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms; W, week; WHO, World Health Organization; WPAI-UC, Work Productivity and Activity Impairment 
Questionnaire – Ulcerative Colitis 
 


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Amendment 3.0 
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APPENDIX 2: 
TUBERCULOSIS SCREENING  
All subjects must undergo screening for a history of TB infection and testing for latent/active TB 
infection. 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. Subjects without a history of latent or active TB who have a negative IGRA or TST 
result at screening are eligible to enroll in the study. 
b. A TB questionnaire will be completed for all subjects (refer to questionnaire below) 
during the Screening Period. 
c. For subjects residing in countries with a high burden of TB or MDR TB as identified 
by WHO, the TB screening questionnaire will be completed at every study visit (per 
protocol Schedule of Assessments). 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). This questionnaire will monitor for any 
emergent symptoms of active TB and compliance with any TB prophylaxis treatment. 
− For a complete list of TB high burden and MDR TB high burden countries during 
the period 2016 to 2020, visit: 
− http://www.stoptb.org/countries/tbdata.asp 
− https://www.who.int/tb/publications/global_report/high_tb_burdencountrylists
2016-2020.pdf?ua=1 
d. The IGRA or TST is NOT required at screening (or annually) for subjects with a 
history of active/latent TB infection. 
− Subjects with past or current history of active TB, regardless of treatment history, 
are excluded from enrollment. 
− Subjects with a history of latent TB infection diagnosed prior to screening must 
have documentation of treatment with at least four weeks of an acceptable TB 
prophylaxis treatment regimen 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). 
e. 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. 
f. Subjects with a newly identified positive IGRA (one retest is allowed with approval 
from the Medical Monitor per Section 9.3.1) or TST result at Screening must be 
considered a Screen Failure, however they are eligible for rescreening once they 
undergo an evaluation to rule out active TB (chest x-ray to rule out pulmonary TB) 
and initiate an acceptable TB prophylaxis treatment regimen for latent TB at least 4 
weeks prior to rescreening (with a plan to complete the TB treatment course during 
study participation) before they can be considered for enrollment. For subjects 


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diagnosed with latent TB infection and reside in countries with high burden of TB or 
MDR TB: A chest CT scan should be performed to rule out current/past pulmonary 
TB in the event the chest x-ray is equivocal. 
g. An assessment of adequacy of the TB prophylaxis treatment regimen and duration of 
treatment must be performed by an infectious disease consultant or physician TB 
expert. 
h. IGRA and TST interpretation 
− Subjects will be considered to have a negative diagnostic test for TB if at least 
one of the following circumstances applies: 
− Negative QuantiFERON-TB Gold test. 
− Combination of a negative QuantiFERON-TB Gold test and negative 
purified protein derivative (PPD) TST (in countries where IGRA is not 
considered a validated test). 
− A combination of two indeterminant QuantiFERON-TB Gold tests and a negative 
PPD TST (in countries where IGRA is not considered a validated test). An 
indeterminant IGRA test result should be repeated. In the event that the second 
IGRA test result is also indeterminate, the subject may be enrolled without 
treatment for latent TB if his/her chest radiograph shows no abnormality 
suggestive of TB (active or old, inactive TB) and the subject has no additional 
risk factors for TB as determined by a physician TB expert physician. 
− If the IGRA is not considered a validated test or is not registered for use in the 
subject’s country, a negative TST result is required to rule out latent TB infection. 
− A positive TST reaction is ≥ 10 mm of induration, or ≥ 5 mm of induration for 
subjects receiving equivalent of prednisone > 15 mg/day for any medical 
conditions and subjects residing in countries identified by WHO as a high TB 
burden country or high MDR TB burden country. 
i. 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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Tuberculosis Screening Questionnaire 
 


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Amendment 3.0 
Arena Pharmaceuticals, Inc. 
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Clinical Study Protocol  
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Amendment 3.0 
Arena Pharmaceuticals, Inc. 
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Amendment 3.0 
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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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Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
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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 Robarts Histopathology Index (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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APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
Amendment 3.0 
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Page 97 of 99 
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 
personality changes, paresthesia/anesthesia (of any domain: peripheral to central), dysarthria 
(expressive aphasia), and/or agnosia (receptive aphasia). Consultation with a local neurologist 
may be warranted, as presented in the PML case evaluation algorithm in Figure 2. 
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 2: 
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 patient does not have PML, or the IAC’s review of the 
evidence concludes that PML is ruled out. 
 


Clinical Study Protocol  
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
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Page 98 of 99 
APPENDIX 6: 
INVESTIGATOR SIGNATURE  
 
Study title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 12-Week Study to 
Assess the Efficacy and Safety of Etrasimod in Subjects with Moderately to 
Severely Active Ulcerative Colitis 
Study number: APD334-302 
 
 
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 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol  
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
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Page 99 of 99 
APPENDIX 7: 
SPONSOR SIGNATURE  
 
Study title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 12-Week Study to 
Assess the Efficacy and Safety of Etrasimod in 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. 
 
 
 
 
 
Senior Vice President, Clinical Development, and Chief Medical Officer 
Arena Pharmaceuticals, Inc. 
 
 
 
 
 
 
Sponsor Signature 
 
Date 
 
 
 
 
 




CLINICAL STUDY PROTOCOL 
SUMMARY OF CHANGES 
 
Protocol title: 
A Phase 3, Randomized, Double Blind, Placebo Controlled, 
12-Week Study to Assess the Efficacy and Safety of Etrasimod in 
Subjects with Moderately to Severely Active Ulcerative Colitis 
 
 
Protocol number: 
APD334-302 
Version: 
Amendment 1, 05 March 2019 
Replaces version: 
Original, 19 December 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document contains confidential information of Arena Pharmaceuticals, Inc. Unauthorized 
distribution, copying, or disclosure is strictly prohibited unless required by applicable law. Persons 
receiving this information must be notified that it is confidential and may not be further distributed, 
copied, or disclosed. 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 1 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 2 of 6 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment 1, 05 March 2019 
Overall Rationale for the Amendment 
The overall rationale for this amendment is to provide additional guidance for the cardiac monitoring 
procedures required on Day 1 after the first dose of study treatment.  These additional monitoring 
procedures are based feedback from the Food and Drug Administration.  In particular, postdose safety 
vital signs, 12-lead ECGs, monitoring of subjects who do not meet the discharge criteria, and 
discontinuation rules have been revised. 
 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 1 
 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 3 of 6 
Summary of Changes 
Section No. and Name 
Description of Change 
Brief Rationale 
Throughout 
Minor editorial, formatting, and nomenclature revisions 
Minor; therefore, have not been summarized 
Synopsis: Study Design 
Synopsis: Statistical methods 
3.1.  Summary of Study Design 
6.4.  Method of Assigning Subjects 
to Treatment 
10.12.1.  Efficacy Analysis 
Changed the first stratification factor from “failed 
biologic/JAK inhibitor therapy (yes/no)” to “naïve to 
biologic or JAK inhibitor therapy at study entry (yes/no)”  
The terminology was changed from “failed” 
to “naïve” because the term “naïve” was 
originally intended when the protocol was 
written. 
4.1.  Inclusion Criteria: Prior 
treatment failure criteria: 
Inadequate response 
Deleted the word “induction” from the description of 
prior therapy 
The criterion applies to any regimen; not 
limited to induction 
4.1.  Inclusion Criteria: Prior 
treatment: Loss of response 
Deleted “approved maintenance dosing” from prior 
treatment description 
For clarification 
Synopsis: “Other general inclusion 
criteria” 
4.1.  Inclusion Criteria: Other 
general inclusion criteria: 
Updated criteria for hematological function  
Given the mechanism of action of the drug in 
reducing peripheral lymphocytes, these 
changes in hematologic parameters may be 
important for safety reasons. 
5.1.  Discontinuation of Study 
Treatment 
Added:  
• Subjects will be discontinued from the study 
treatment if they experience a cardiovascular 
treatment-related symptomatic event (eg, chest pain, 
dizziness, palpitations, lightheadedness, shortness of 
breath, or syncope) associated with reduction of heart 
rate with clinically relevant ECG changes at any time 
during the post-dose 4-hour monitoring period. 
• Subjects who have not met the discharge criteria 
(Error! Reference source not found.) on Day 1 
after ≥ 4 hours of extended monitoring, or Day 2 by 4 
hours post-dose 
Added as an extra safety precaution 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 1 
 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 4 of 6 
Section No. and Name 
Description of Change 
Brief Rationale 
6.3.1.  Instructions for Missed 
Dose(s) 
Deleted instruction that vomiting of the tablet should be 
recorded in the subject’s electronic diary (eDiary). 
It is not intended that subjects record 
vomiting of study treatment 
6.3.2. Dose Interruptions 
Moved the description of symptoms and treatment for 
PML from Section 6.3.2 to Section 9.9.8.1.4 (Adverse 
Events of Special Interest). 
Aligns the topic of the text with the Section 
header. 
9.3.5.  Prior and Ongoing Therapies 
Modified text to state documentation of prior UC 
therapies should include the prior treatment response as 
one of the following: inadequate response to, loss of 
response to, or intolerance to 
For proper documentation of response to 
prior UC therapies 
9.3.10.  Proctosigmoidoscopy/ 
Colonoscopy and Modified Mayo 
Score Derivation 
For SF changed from “baseline” to “normal” 
For consistency with Section 9.7.1 and for 
more appropriate description of the 
assessment 
9.4.2.1.  Guidance for Cardiac 
Monitoring Following Treatment 
Initiation or Re Initiation 
Added new Section “Guidance for Cardiac Monitoring 
Following Treatment Initiation or Re-Initiation,” with 
details relating to first dose cardiac monitoring, extended 
cardiac monitoring, and study treatment discontinuation 
related to post-dose cardiac monitoring 
To provide additional guidance and details 
for vital sign and cardiac monitoring 
9.7.1.  Modified Mayo Score/Mayo 
Clinic Score 
Deleted that stool frequency before initial onset of signs 
and symptoms of UC to be used as the reference SF 
would be recorded in the subject’s eDiary 
This will be recorded at screening in the 
eCRF, not in the subject’s eDiary.  
9.7.1.2.  Endoscopic Biopsies 
Modified the language on the biopsy location to specify 
collection from the most affected area 15 to 25 cm from 
the anal verge 
To provide additional guidance 
9.9.8.1.2.   Serious Adverse Event 
Deleted “Admission to a palliative unit or hospice care 
facility is not considered to be a hospitalization. 
Hospitalizations or prolonged hospitalizations for 
scheduled therapy of the underlying cancer or study 
target disease need not be captured as SAEs” from the 
definition of SAE 
Not relevant to this protocol 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 1 
 
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Page 5 of 6 
Section No. and Name 
Description of Change 
Brief Rationale 
9.9.8.2.2.   Recording Adverse 
Events 
Updated language that SAEs should be described in the 
narrative description field of the eCRF 
To provide more clarity and guidance to 
Investigators and to align with updates in the 
Protocol template 
9.9.8.3.1.  Serious Adverse Events 
Added contact information for reporting of SAEs 
To provide more clarity and guidance to 
Investigators 
9.10.  Procedures for Overdose 
Added new section 
Provide information for investigators relating 
to subject overdose.  
10.3.  Analysis Sets 
Renamed the analysis sets as follows: 
• Intent-to-treat population renamed Full Analysis 
Set (FAS) 
• Modified intent-to-treat population renamed 
Modified Full Analysis Set (mFAS) 
• Per-protocol population renamed Per Protocol Set 
• Safety population renamed Safety Set 
For consistency with FDA Guidance “E9 
Statistical Principles for Clinical Trials” 
(Section V. B. 1.), ICH E9 “Statistical 
Principles” (Section 5.2), and EMEA 
Guidance “ICH Topic 39 Statistical 
Principles for Clinical Trials” (Section V.2). 
10.7.1 and 10.7.1.2 
Moved the endpoint, “Proportion of subjects with 
mucosal healing at Week 12” from “Other Secondary 
Endpoints” to “Key Secondary Endpoints” 
To create consistency with the Synopsis and 
the intended endpoints of the study. 
10.10.   Subgroup Analyses 
Added new section describing subgroup analyses 
Sponsor decision 
Table 7, Schedule of Assessments, 
12-lead ECG row 
Added a 12-lead ECG at the Week 12/Early Termination 
visit. 
Sponsor decision 
Table 7, Schedule of Assessments, 
Footnote “a” 
 
Modified text to clarify that for subjects who complete 
Week 12 and are eligible to enter the APD334 303 OLE 
study, the Week 12 visit will be used to assess eligibility 
for the OLE and may also serve as the Day 1 visit of the 
OLE 
For clarification and guidance for 
Investigators 
Table 7, Schedule of Assessments, 
Footnote “k” 
 
Rewrote to be consistent with new cardiac monitoring 
text 
For document consistency 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 1 
 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 6 of 6 
Section No. and Name 
Description of Change 
Brief Rationale 
Appendix 5: Investigator Signature 
Updated to new signature page format 
Formatting revision 
Added Appendix 6:  Country 
Specific Requirements 
Insertion of Sponsor signature page for hand-written 
signature to meet signature requirements in countries that 
do not recognize electronic signature 
To meet signature requirements in countries 
that do not recognize electronic signature 
 


CLINICAL STUDY PROTOCOL 
SUMMARY OF CHANGES 
 
Protocol title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 
12-Week Study to Assess the Efficacy and Safety of Etrasimod in 
Subjects with Moderately to Severely Active Ulcerative Colitis 
 
 
Protocol number: 
APD334-302 
Version: 
Amendment 2.0, 07 February 2020 
Replaces version: 
Amendment 1.0, 05 March 2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document contains confidential information of Arena Pharmaceuticals, Inc. Unauthorized 
distribution, copying, or disclosure is strictly prohibited unless required by applicable law. Persons 
receiving this information must be notified that it is confidential and may not be further distributed, 
copied, or disclosed. 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 2.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 2 of 16 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment 2.0, 07 February 2020 
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it significantly impacts the safety or physical/mental integrity of subjects. 
Overall Rationale for the Amendment 
The overall rationale for this amendment is to update eligibility criteria (eg, contraception use). 
Additional instructions for safety monitoring related to ophthalmoscopy and optical coherence 
tomography testing were included. The prohibition of concomitant use of QT prolonging drugs 
was removed based on the results of the QT study (Study APD334-008). In addition, a 4-Week 
Safety Follow-Up visit was added. Clarification and further instructions for tuberculosis testing 
were added and the tuberculosis screening questionnaire was updated. 
 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 2.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 3 of 16 
Summary of Changes 
Section No. and Name 
Description of Change 
Brief Rationale 
Throughout 
Minor editorial, formatting, and nomenclature revisions 
Minor and do not affect the conduct of the 
protocol; therefore, have not been summarized 
Sponsor Signature page 
Added Sponsor Signature Page 
Administrative change 
Title Page 
Added NCT number 
Administrative change 
Title Page 
Appendix 7, Sponsor Signature Page 
Updated title of Sponsor’s Responsible Medical Officer to: 
  
 
Administrative change due to organizational 
update 
Title Page 
Updated Amendment 2.0; Version date: 07 February 2020 
Administrative change 
Protocol History 
Added Protocol History table 
To summarize protocol amendment history 
Synopsis: Study design 
3.1 Summary of Study Design 
Added 4-Week Follow-Up visit and modified language to 
include a 2-Week and 4-Week Follow-Up Period.  
Added for additional safety follow-up 
Deleted “Randomized subjects who experience UC 
exacerbation during the 12-Week Treatment Period will be 
considered as having a treatment nonresponse and should be 
managed according to the local standard of care.” 
For consistency with Section 10.4, where “lack of 
efficacy” prior to Week 12 defines treatment 
nonresponse 
Deleted “All” from “Subjects will then have the option to enter 
an open-label extension (OLE) study (APD334-303)” 
For additional clarity and guidance to Investigators 
Added “subjects must complete Week 12 to be eligible for the 
OLE”. Edits were made to include the 4-Week Follow-Up visit. 
The terminology “Early termination visit” was added. 
For additional clarity and guidance to 
Investigators, additional safety follow-up, and for 
consistency with the schedule of assessments 
Synopsis: Eligibility criteria: 
Inclusion Criterion 1 
4.1 Inclusion Criteria: Inclusion 
Criterion 1 
11.3 Informed Consent and Assent 
Added “Enrollment of subjects < 18 years should be conducted 
only if acceptable according to local law and regulations” 
This language is intended to allow for the 
enrollment of subjects ≥ 16 years of age up to 
< 18 years of age in countries where law and 
regulation allows and also allows for the study to 
be acceptable in countries where the enrollment of 
subjects < 18 years of age is not deemed 
appropriate 
 
 
 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 2.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 4 of 16 
Section No. and Name 
Description of Change 
Brief Rationale 
Synopsis: Eligibility criteria: 
Inclusion Criterion 4 
4.1 Inclusion Criteria: Inclusion 
Criterion 4 
Changed to state “Subjects with proctitis only at baseline who 
meet the other eligibility criteria for inclusion, including the 
endoscopic and rectal bleeding criteria for moderate to severe 
disease, will be capped at 15% of the total subjects enrolled”  
For additional clarity and guidance to Investigators 
Synopsis: Eligibility criteria: 
Inclusion Criterion 6 
4.1 Inclusion Criteria: Inclusion 
Criterion 6 
Added “according to routine practice” regarding the removal of 
any adenomatous polyps 
For additional clarity and guidance to Investigators 
Synopsis: Eligibility criteria: 
Inclusion Criterion 7 
4.1 Inclusion Criteria: Inclusion 
Criterion 7 
Added interleukin 12/23 (eg, ustekinumab) to list of biologic 
therapies or JAK inhibitor therapies 
Added due to recent regulatory authority approval 
for the use of interleukin 12/23 in the treatment of 
patients with moderately to severely active 
ulcerative colitis 
Synopsis: Eligibility criteria: 
Inclusion Criterion 7 
4.1 Inclusion Criteria: Inclusion 
Criterion 7 
Added to note regarding qualifying therapy that “the subject 
must have received an adequate course of therapy based on 
local guidelines for that therapy” 
For additional clarity and guidance to Investigators 
in the recognition that adequate courses of therapy 
and local guidelines regarding these agents may 
differ from country to country 
Synopsis: Eligibility criteria: 
Inclusion Criteria 9 and 10 
4.1 Inclusion Criteria: Inclusion 
Criteria 9 and 10 
Vital signs and screening ECG were moved and integrated with 
Exclusion Criterion 8. 
For consistency with Global Protocol APD334-301 
Amendment 3.0 
Synopsis: Eligibility criteria: 
Inclusion Criterion 10 (formerly 
Inclusion Criterion 12) 
4.1 Inclusion Criteria: Inclusion 
Criterion 10 (formerly Inclusion 
Criterion 12) 
Updated the requirement for ALT and AST to be ≤ 2.0 × ULN. 
Prior version allowed ALT and AST to be ≤ 3.0 × ULN. 
To ensure appropriate eligibility for enrollment 
Synopsis: Eligibility criteria: 
Inclusion Criterion 12 (formerly 
Inclusion Criterion 14) 
4.1 Eligibility criteria: Inclusion 
Criterion 12 (formerly Inclusion 
Criterion 14) 
Updated contraception language 
To be in accordance with the contraception 
guidance from Clinical Trials Facilitation and 
Coordination Group (CTFG) 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 2.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 5 of 16 
Section No. and Name 
Description of Change 
Brief Rationale 
Synopsis: Eligibility criteria: 
Exclusion Criterion 5 
4.2 Exclusion Criteria: Exclusion 
Criterion 5 
Updated pathogen nomenclature to Clostridioides difficile 
(formerly known as Clostridium difficile) 
Update was made due to the reclassification of 
Clostridium difficile to Clostridioides difficile 
based on the adoption by the US Centers for 
Disease Control and Prevention. 
Synopsis: Eligibility criteria: 
Exclusion Criterion 7 
4.2 Exclusion Criteria: Exclusion 
Criterion 7 
Deleted hematologic, hepatic, pulmonary and ophthalmological 
conditions from Exclusion Criterion 7. Added cognitive 
impairment. Added alcohol/drug abuse/dependence (formerly 
Exclusion Criterion 22). 
Covered in other specific eligibility criteria 
Synopsis: Eligibility criteria: 
Exclusion Criteria 8 and 9 
4.2 Exclusion Criteria: Exclusion 
Criteria 8 and 9 
Combined Exclusion Criteria 8 and 9 and updated the criterion 
for cardiovascular function exclusion 
For consistency with protocol APD334-301 
Amendment 3.0 
Synopsis: Eligibility criteria: 
Exclusion Criterion 12 
4.2 Exclusion Criteria: Exclusion 
Criterion 12 
Updated TB exclusion criterion language 
For greater clarity and additional guidance to 
Investigators and for consistency with protocol 
APD334-301, Amendment 3.0. 
Synopsis: Eligibility criteria: 
Exclusion Criterion 13 (formerly 
Exclusion Criterion 14) 
4.2 Exclusion Criteria: Exclusion 
Criterion 13 (formerly Exclusion 
Criterion 14) 
Updated and modified active infection exclusion criterion to 
“≤ 28 days prior to randomization, required intravenous 
medication ≤ 14 days prior to randomization, or that may 
worsened (in the opinion of the investigator) if the subject is 
treated with a drug having immunosuppressant effects (ie, 
etrasimod).” 
For greater clarity and additional guidance to 
Investigators and for consistency with protocol 
APD334-301, Amendment 3.0. 
Synopsis: Eligibility criteria: 
Exclusion Criterion 17 (formerly 
Exclusion Criterion 18) 
4.2 Exclusion Criteria: Exclusion 
Criterion 7 (formerly Exclusion 
Criterion 18) 
Updated the exclusion regarding history of opportunistic 
infection to: “History of an opportunistic infection (eg, 
Pneumocystis jirovecii, cryptococcal meningitis, progressive 
multifocal leukoencephalopathy) or a history of disseminated 
herpes simplex or disseminated herpes zoster”. 
For consistency with protocol APD334-301, 
Amendment 3.0. 
Synopsis: Eligibility criteria: 
Exclusion Criterion 21 
4.2 Exclusion Criteria: Exclusion 
Criterion 21 
Added “Hypersensitivity to etrasimod or any of the excipients 
or placebo compounds” as a new exclusion criterion 
Added at the request of regulatory authorities. All 
subsequent exclusion criteria were renumbered 
accordingly. 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 2.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 6 of 16 
Section No. and Name 
Description of Change 
Brief Rationale 
Synopsis: Eligibility criteria: 
Exclusion Criterion 23 (formerly 
Exclusion Criterion 24) 
4.2 Exclusion Criteria: Exclusion 
Criterion 23 (formerly Exclusion 
Criterion 24) 
Updated washout period for therapy to “Treatment with a 
biologic agent within 8 weeks or within 5 elimination half-lives 
for a small-molecule agent prior to randomization” 
For clarity and additional guidance to Investigators 
Synopsis: Eligibility criteria: 
Exclusion Criterion 25 
4.1 Exclusion Criteria: Exclusion 
Criterion 25 
Removed “failure” from “Treatment failure with ≥ 3 biologic 
agents or ≥ 2 biologics plus a JAK inhibitor approved for 
treatment of UC” 
For clarity 
Synopsis: Eligibility criteria: 
Exclusion Criterion 27 
4.2 Exclusion Criteria: Exclusion 
Criterion 27 
Changed methotrexate washout from within 16 weeks to 
8 weeks of screening 
To provide greater access to the study 
Synopsis: Eligibility criteria: 
Exclusion Criterion 31 (formerly 
Exclusion Criterion 32) 
4.2 Exclusion Criteria: Exclusion 
Criterion 31 (formerly Exclusion 
Criterion 32) 
Modified exclusionary drugs by deleting leflunomide and 
adding dimethyl fumarate, or pyrimidine synthesis inhibitors 
For clarity and additional guidance to Investigators 
Synopsis: Efficacy assessments: 
Definitions 
10.5 Efficacy Endpoint Definitions 
Added a definition for symptomatic remission in the synopsis. 
The definition of symptomatic remission in Section 10.5 was 
updated. 
Based on the addition of a key secondary endpoint 
and for consistency with Section 10.5. 
Synopsis: Efficacy assessments: Key 
secondary endpoints 
10.7.1 Key Secondary Efficacy 
Endpoints 
Updated key secondary endpoints to include:  
The proportion of subjects achieving symptomatic remission at 
Week 12 
Update to key secondary efficacy endpoints to 
align with regulatory authority requests 
Synopsis: Pharmacokinetic 
Assessments 
9.6 Pharmacokinetics 
10.9.2 Pharmacokinetics 
Revised text to state “Plasma concentrations of etrasimod, and 
if warranted M3 (AR503641) and other metabolite(s) of 
interest” 
For additional clarity 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 2.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 7 of 16 
Section No. and Name 
Description of Change 
Brief Rationale 
Synopsis: Pharmacokinetic 
assessments 
9.6 Pharmacokinetics 
10.9.2 Pharmacokinetics 
Table 7: Schedule of Assessments – 
Screening and 12-Week Treatment 
Period 
Added PK samples from 2-Week and 4-Week Follow-up visits 
For additional PK information following end of 
treatment due to the addition of the 4-Week safety 
follow-up visit 
Synopsis: Other Assessments 
10.9.3 Biomarkers 
Table 7, Schedule of Assessments 
Footnote “u” 
Added the Week 2 timepoint to the endpoint of change from 
baseline in level of fecal calprotectin. 
Correction was made for consistency with the 
schedule of assessments, Table 7. 
Synopsis 
10.12.1 Efficacy Analysis 
The testing strategy for efficacy analysis was updated. There 
are no changes to the overall analysis method. 
For consistency with protocol APD334-301, 
Amendment 3.0 
Synopsis: Statistical Methods 
10.12.1 Efficacy Analysis 
Updated number of key secondary endpoints to 3 
For internal consistency due to addition of new key 
secondary endpoints 
Deleted “With this sample size, there will be 93% power to 
detect a difference of 17% in the key secondary endpoint of 
endoscopic normalization, assuming a placebo rate at 15%”. 
For internal consistency and clarity  
1.3 Benefit/Risk Assessment 
Updated the paragraph regarding the history of etrasimod 
studies, “Safety and tolerability of etrasimod have been 
evaluated in Phase 1 studies with healthy adult subjects at 
single doses up to 5 mg and repeat doses up to 4 mg once daily. 
Repeat doses of 2 mg have been evaluated in Phase 2 studies of 
subjects with moderately to severely active UC (refer to the 
latest IB)”. 
For consistency with other etrasimod protocols. 
Updated the timepoints at which OCT should be performed to 
include “as clinically indicated any time during the study”. 
3.2 Rationale for Study Design 
Modified language to include a 2-Week and 4-Week Follow-Up 
Period. 
Added for additional safety follow-up 
 
 
 
 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 2.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 8 of 16 
Section No. and Name 
Description of Change 
Brief Rationale 
3.2 Rationale for Study Design 
(continued) 
Text was updated to “The primary endpoint of clinical 
remission at Week 12 as assessed using the MMS, is standard, 
widely used, and is in accordance with the nonbinding US Food 
and Drug Administration (FDA) 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.” 
Correction since there is a single primary endpoint 
in APD334-302. 
3.3 Study Duration 
Added “The End of Study Date is the date when the last subject 
completes his/her last study visit”. 
To define the “End of the Study” 
5.1 Discontinuation from Study 
Treatment (formerly Discontinuation 
of Study Treatment in APD334-302, 
Amendment 1) 
Recategorized the criteria into reasons treatment “may be 
discontinued” and reasons treatment “must be discontinued.”  
For additional clarity and guidance to Investigators 
Added additional guidance that adverse event and 
noncompliance with the protocol or study treatment as a reason 
for treatment discontinuation may be at the discretion of 
Investigator/Medical Monitor for adverse events and the  
For additional clarity and guidance to investigators 
Added confirmed diagnosis of active TB to list of reasons that 
treatment must be discontinued. 
Added “If the Early Termination visit is ≥ 2 weeks of 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 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 Discontinuation from Study 
Treatment 
9.5 Follow-Up Period 
Table 7: Schedule of Assessments – 
Screening and 12-Week Treatment 
Period, Footnote “b” 
Updated guidance for continued follow-up of subjects with 
ALC that is not within normal limits at the 4-Week Follow-Up 
visit 
To provide more appropriate guidance to 
Investigators 
5.2 Discontinuation from the Study 
Added “Deviation/noncompliance with the study protocol that 
in the judgement of the Investigator and/or Medical Monitor the 
subject should not continue study treatment” to list of reasons 
for discontinuation from the study 
To provide additional guidance for Investigators 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 2.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 9 of 16 
Section No. and Name 
Description of Change 
Brief Rationale 
6.3 Dosage and Administration 
Clarified that the time of PK sample collection and last dosing 
prior to the PK sample should be documented in the eCRF 
For additional clarification and guidance to 
Investigators 
6.3.1 Instructions for Missed Dose(s) 
Statement added that “Subjects who do not take the study 
treatment for ≥ 2 consecutive days within the first week of 
treatment or for ≥ 7 consecutive days after the first week of 
treatment 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 9.4.2.1 should be performed.” 
Added for additional clarity 
6.5 Blinding 
Modified text regarding unblinding 
To provide additional clarity 
6.7.3 Prohibited Concomitant 
Therapy 
Deleted “Treatment with medications with a known impact on 
the cardiac conduction system and QT prolonging drugs with a 
known risk of torsades de pointes 
(https://www.uspharmacist.com/article/drug-induced-qt-
prolongation for additional information)” 
Based on results of the QT study (APD334-008) 
Changed the duration of time after stopping study treatment that 
subjects should not receive live vaccines from “for at least 
2 weeks” to “within 8 weeks” 
In response to regulatory authority requests 
Added tofacitinib to list of prohibited immunosuppressive 
agents 
For additional guidance to Investigators in order to 
avoid potential cumulative immunosuppression 
resulting from the use of multiple agents 
Added dimethyl fumarate, or pyrimidine synthesis inhibitors 
For consistency with global protocol APD334-301 
Recategorized section to include list of prohibited concomitant 
medications and concomitant procedures. 
For additional clarification and guidance to 
Investigators 
Moved immunoadsorption columns and intravenous 
immunoglobulin or plasmapheresis from prohibited 
concomitant medications to prohibited concomitant procedures 
For additional clarification and guidance to 
Investigators 
9.3 Screening and Eligibility 
Updated text to state “The Screening Period may be extended 
for subjects who require additional diagnostic testing/consults 
to determine status of either latent TB or C. difficile infection.” 
For additional clarification and guidance to 
Investigators 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 2.0 
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Confidential 
Page 10 of 16 
Section No. and Name 
Description of Change 
Brief Rationale 
9.3.1 Tuberculosis Screening and 
Chest X-Ray 
Added “If an investigator feels the test for latent TB is 
abnormal, a retest to confirm latent TB status should be 
discussed and approved by the Medical Monitor.” 
For clarity to Investigator 
9.3.4 Social History 
Added language regarding standard drug test at screening 
“A standard urine drug screen will be performed. Subjects who 
test positive will be assessed for eligibility in study 
participation by the Investigator.” 
For additional clarification and guidance to 
Investigators 
9.3.8 Pulmonary Function Test 
Deleted “Subjects experiencing a decline in PFT values (FEV1 
and/or FVC) below 50% of the predicted values should be 
discontinued from study treatment and scheduled for a 
follow-up visit.” 
Covered in Section 5.1 – Discontinuation from 
Study Treatment 
9.3.10 Proctosigmoidoscopy/ 
Colonoscopy and Modified Mayo 
Score Derivation 
Modified language regarding screening proctosigmoidoscopy/ 
colonoscopy to state “Proctosigmoidoscopy/colonoscopy 
should be performed prior to randomization to treatment to 
allow central reader review (may take approximately 
5 to 12 days) and added “Preferably, 
proctosigmoidoscopy/colonoscopy should be performed after 
other criteria for inclusion (eg, laboratory criteria) have been 
met.” 
For clarity to Investigator. New statement added to 
minimize unnecessary 
proctosigmoidoscopies/colonoscopies 
Added “TB screen and stool sample” to results which must be 
available and reviewed prior to the first dose of study treatment 
For clarity and internal document consistency 
Added language that subjects “who do not have a minimum of 
7 days of eDiary data prior to bowel preparation” will not be 
eligible for randomization 
To ensure adequate and reliable baseline MMS 
score 
Deleted “Note that the day prior to, day of, and day after 
proctosigmoidoscopy cannot be used for calculating MMS 
because of the required bowel preparation for the procedure.” 
Not necessary as the scoring algorithm described in 
the paragraph above clearly “ignores” the diary 
entries on and after the bowel preparation day. 
9.4.1 Week 0/Day 1: 
Prerandomization 
Added “OR systolic BP < 90 mm Hg OR diastolic BP 
< 55 mm Hg” as part of vital sign criterion for exclusion from 
randomization 
Added to match Section 4.2, Exclusion Criteria 
 
 
 
 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 2.0 
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Confidential 
Page 11 of 16 
Section No. and Name 
Description of Change 
Brief Rationale 
9.4.2 Treatment Period 
Added additional language describing the MMS calculation “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 
found, then the average of the 2 most recent consecutive days 
within the 7 days will be used.” 
For additional guidance to Investigators 
9.4.2.1 Guidance for Cardiac 
Monitoring Following Treatment 
Initiation or Re-Initiation 
Added a clarification regarding in-clinic cardiac monitoring to 
specify that 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. 
For clarity and additional guidance to Investigators 
Added a clarification that subjects experiencing a “symptomatic 
event” during the 4-hour monitoring period must be 
discontinued from treatment if they do not meet the discharge 
criteria at 4 hours after the second dose on Day 2 and extended 
cardiac monitoring should be continued until the subject meets 
the discharge criteria 
For clarity and additional guidance to Investigators 
9.5 Follow-Up Period 
Table 7: Schedule of Assessments – 
Screening and 12-Week Treatment 
Period, Footnote “b” 
Added 4-Week Follow-Up visit and modified language to 
include “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.” 
Updated for internal consistency with new 4-Week 
Follow-Up visit and for additional safety follow-up 
9.6 Pharmacokinetics 
The following sentence was restructured from “Blood samples 
for analysis of etrasimod, M3 (AR503641), and other 
metabolite(s) of interest (if warranted) levels will be 
collected…” to “Blood samples for analysis of etrasimod, and if 
warranted M3 (AR503641) and other metabolite(s) of interest 
levels will be collected…”. 
For clarity to Investigator 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 2.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 12 of 16 
Section No. and Name 
Description of Change 
Brief Rationale 
9.7.1 Modified Mayo Score/Mayo 
Clinic Score 
Changed “for a given day” to “in a 24-hour period”. 
For clarity to Investigator 
Revised RB and SF “subscores” to “scores” 
Correction 
9.7.3 Additional Health-Related 
Subject-Reported Outcomes 
Corrected WPAI UC description to state it consists of 
6 questions 
Correction 
9.7.4 Efficacy-Related Biomarkers 
Updated language when ALC is confirmed to be < 200 cells/µL 
to state “If the ALC is confirmed below the 200 cells/µL limit, 
study treatment should be interrupted and should not be 
reinitiated if the ALC remains below this threshold. In this 
situation, the unblinded Medical Monitor will notify the 
Investigator and provide instructions on additional actions that 
the Investigator may need to take. When there is at least one 
measurement of ALC < 200 cells/µL, blinded values may be 
released to treating physicians and Investigators as deemed 
medically necessary to monitor infection and/or aid in 
diagnostic work-up as clinically indicated, and/or as a tool to 
assess the effectiveness of therapeutic interventions for an 
infection. Investigators will repeat CBC with differentials 
weekly until ALC > 500 cells/µL. 
Re-initiation of the study treatment can only be considered 
when ALC > 500 cells/µL.” 
For clarity and additional guidance to Investigators 
9.9.1 Physical Examination 
Added “skin” to list of full physical examination assessments 
For clarity and internal document consistency 
9.9.3 12-Lead Electrocardiogram 
Updated text to describe when unscheduled ECGs should be 
performed and provide additional information regarding QTc 
prolongation and criteria under which restart of study treatment 
may be permissible 
For clarity and additional guidance to Investigators 
 
 
 
 
 
 
 
 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 2.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 13 of 16 
Section No. and Name 
Description of Change 
Brief Rationale 
9.9.4 Pulmonary Function Test 
Added new text describing PFTs to state “All subjects will have 
PFTs performed at Screening, Week 12, or at the Early 
Termination visit.  
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.” 
In accordance with regulatory authority request / 
comment and for clarity and additional guidance to 
Investigators 
9.9.5 Ophthalmoscopy and Optical 
Coherence Tomography 
Updated language to allow use of Snellen chart for best 
corrected visual acuity measurement if available. 
To provide allowance on methods to measure best 
corrected visual acuity in the scenario where 
Snellen chart may not be available. 
Listed the specific requirements for the screening and 
scheduled post-screening ophthalmology visits 
For clarity and additional guidance to Investigators 
9.9.6 Tuberculosis Screening and 
Chest X-Ray 
Added that for subjects residing in countries with a high burden 
of TB, multi-drug resistant TB as identified by WHO, or 
subjects who are receiving TB prophylaxis treatment, a TB 
screening questionnaire will be administered at every study 
visit (Appendix 2). 
To provide appropriate guidance to Investigators 
9.9.7 Clinical Laboratory Tests 
Noted that “For guidance on monitoring subjects with notable 
lymphopenia, please refer to Section 9.7.4.” 
For additional clarity 
9.9.7 Clinical Laboratory Tests 
(Table 6) 
Moved QuantiFERON from “Virology” to “Others” 
Correction 
9.9.7.1.1 Drugs of Abuse 
Updated text to “standard urine drug screen will be performed 
(Table 6). Subjects who test positive will be assessed for 
eligibility for study participation by the Investigator.” 
To provide greater clarity to Investigators 
9.9.8.1.4 Adverse Events of Special 
Interest 
Added “Guidance for the Assessment of Potential Progressive 
Multifocal Leukoencephalopathy is provided in Appendix 5.” 
To provide extra guidance to Investigators 
9.9.8.3.1 Serious Adverse Events 
Added “(or in India within 24 hours of event occurrence)” for 
reporting serious adverse events 
To provide extra guidance to Investigators and for 
consistency with other global etrasimod UC 
Phase 3 protocols. 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 2.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 14 of 16 
Section No. and Name 
Description of Change 
Brief Rationale 
9.9.8.3.2 Serious, Unexpected 
Adverse Drug Reactions 
Updated wording to specify that “the IB in effect during the 
study will serve as the Reference Safety Information for 
determining whether an AE is expected or unexpected” 
For additional clarity and guidance to Investigators 
9.10 Procedures for Overdose 
Added text and guidance for monitoring subjects 
For additional guidance to Investigators 
10.4 Missing Data 
Revised text to state “lack of efficacy” before Week 12 and 
“lack of efficacy adverse event related to UC” regarding 
subjects discontinuing the double-blind study for reasons other 
than “worsening of disease” 
“Worsening of disease” was removed because 
prior to Week 12, is not worsening disease, it is 
lack of efficacy 
10.7 Secondary Endpoints 
Moved text from Section 10.7.2 to Section 10.7 and updated the 
text to provide a reference and detail on all endpoints. 
For clarity to Investigator 
10.7.2 Other Secondary Efficacy 
Endpoints 
Endpoints added: 
The proportion of subjects achieving symptomatic remission at 
Weeks 2, 4, 8 
The proportion of subjects achieving complete symptomatic 
remission at each study visit (Weeks 2, 4, 8, 12) 
The proportion of subjects achieving noninvasive clinical 
response at each study visit (Weeks 2, 4, 8, 12) 
The proportion of subjects achieving symptomatic response at 
each study visit (Weeks 2, 4, 8, 12) 
Correction and for consistency with APD334-301 
Global Protocol Amendment 3.0 
 
 
 
 
 
13.2 Study Documentation and 
Records Retention 
Updated language regarding record availability to record 
retention for “2 years after the appropriate regulatory 
authorities have been notified of the discontinuation of clinical 
development of the investigational product.” 
To provide greater clarity regarding the regulatory 
requirements 
Table 7, Schedule of Assessments 
Added TB Questionnaire 
To facilitate TB assessments of study subjects 
Revised Tuberculosis “screening” to “test” 
Correction 
 
 
 
 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 2.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 15 of 16 
Section No. and Name 
Description of Change 
Brief Rationale 
Table 7, Schedule of Assessments, 
Footnote “a” 
Modified text to clarify that for subjects who complete Week 
12 and are eligible to enter the APD334-303 OLE study, the 
Week 12 visit will be used to assess eligibility for the OLE 
Deleted language stating that for eligible subjects, the Week 12 
visit could be used as the Day 1 visit for the OLE 
For clarification and guidance for Investigators 
Table 7, Schedule of Assessments, 
Footnote “d” 
Revised text from 12 months to 6 months to state that “a chest 
X-ray taken within the previous 6 months from the Screening 
Visit may also be used” 
To align all protocols globally 
Table 7, Schedule of Assessments, 
Footnote “e” 
Added additional language to the TB footnote stipulating that 
the QuantiFERON TB Gold and TST should not be performed 
in subjects previously diagnosed with TB infection and that the 
TB questionnaire will be administered at every study visit for 
subjects residing in countries with a high TB burden or MDR 
TB as identified by the WHO. 
To facilitate TB assessments of study subjects 
Table 7, Schedule of Assessments, 
Footnote “p” 
Revised to state that pulmonary function tests should be 
performed ± 7 days of the study treatment period 
For clarity to Investigator 
Table 7, Schedule of Assessments, 
Footnote “q” 
Revised to state that “the screening OCT should be done within 
the 28-day Screening period” and “details regarding 
ophthalmoscopy and OCT assessments are provided in 
Section 9.9.5.” 
Table 7, Schedule of Assessments, 
Footnote “v” 
Revised to include “colonoscopy” and state that central reader 
review “may take approximately 5 to 12 days” 
Table 7, Schedule of Assessments, 
fecal calprotectin entry and 
Footnote “u” 
Revised footnote to add a screening timepoint at Week 2 
For clarification and guidance for Investigators 
Table 7, Schedule of Assessments, 
Footnote “w” 
Revised to state that “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” 
For clarification and guidance for Investigators 
 
 
 
 
 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 2.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 16 of 16 
Section No. and Name 
Description of Change 
Brief Rationale 
Appendix 2, Tuberculosis Screening 
Added a statement to clarify that a TB questionnaire will be 
completed for all subjects during the Screening period. Added 
additional instructions that subjects receiving TB prophylaxis 
treatment the TB questionnaire will be completed at every study 
visit (until TB prophylaxis treatment course is completed). 
For clarity to Investigator 
 
Added additional details on the purpose of the TB 
questionnaire. 
For clarity to Investigator 
 
Added clarification that “one retest is allowed with approval 
from Medical Monitor per Section 9.3.1” for a newly identified 
positive IGRA at Screening. 
For additional guidance to Investigators and for 
consistency with changes made to Section 9.3. in 
APD334-301, Amendment 2.0. 
 
Removed list of countries identified as having a high TB 
burden or MDR TB. 
A link with reference to the complete list of 
countries with TB high burden and multi-drug 
resistant TB high burden was also added so this 
text was no longer necessary. 
 
Tuberculosis Screening Questionnaire was updated 
Updates were made to the source document 
worksheet. 
Appendix 2, Tuberculosis Screening 
(continued) 
Added sentence “An assessment of adequacy of the TB 
prophylaxis treatment regimen and duration of treatment must 
be performed by an infectious disease consultant or physician 
TB expert”. 
For clarity to Investigator 
 
Revised guidelines for IGRA and TST interpretation 
For clarity to Investigator 
 
Added links for the WHO guidelines for the treatment of latent 
TB 
For clarification and guidance for Investigators 
Appendix 5 
Added Appendix 5: Guidance for The Assessment of Potential 
Progressive Multifocal Leukoencephalopathy 
For additional guidance to Investigators and to 
harmonize across studies 
Appendix 6 
Removed appendix for “Country-Specific Requirements” 
(formerly Appendix 6 in APD334-302, Amendment 1). Moved 
“Investigator Signature” to Appendix 6. 
Appendix is no longer relevant 
 


CLINICAL STUDY PROTOCOL 
SUMMARY OF CHANGES 
 
Protocol title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 
12-Week Study to Assess the Efficacy and Safety of Etrasimod in 
Subjects with Moderately to Severely Active Ulcerative Colitis 
 
 
Protocol number: 
APD334-302 
Version: 
Amendment 3.0, 22 February 2021 
Replaces version: 
Amendment 2.0, 07 February 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document contains confidential information of Arena Pharmaceuticals, Inc. Unauthorized 
distribution, copying, or disclosure is strictly prohibited unless required by applicable law. Persons 
receiving this information must be notified that it is confidential and may not be further distributed, 
copied, or disclosed. 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 2 of 13 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
Amendment 3.0, 22 February 2021  
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union 
because it significantly impacts the safety or physical/mental integrity of subjects. 
Overall Rationale for the Amendment  
The overall rationale for this amendment is to include guidance for conducting virtual and offsite 
visits. Also, information on anti-arrhythmic drugs was added to prohibited concomitant therapies. 
Language was updated regarding timing of screening optical coherence tomography (OCTs) and 
pulmonary function tests (PFTs). Additionally, an exclusion criterion was added regarding treatment 
with topical rectal Chinese medicine, enemas or suppositories prior to randomization. Minor 
corrections were made for consistency within the protocol. 
 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 3 of 13 
Summary of Changes  
Section No. and Name  
Description of Change  
Brief Rationale  
Throughout  
Minor editorial, formatting, and nomenclature revisions  
Minor and do not affect the conduct of the 
protocol; therefore, have not been summarized  
Title Page  
Updated Amendment 3.0; Version date: 22 February 2021  
Administrative change  
Title Page  
Appendix 7, Sponsor Signature  
Revised Sponsor’s Responsible Medical Officer name and title 
to  
 
  
Administrative change  
Protocol History  
Updated protocol history table  
Administrative change  
Protocol Synopsis: Eligibility criteria  
4.1. Inclusion Criteria (Inclusion 
Criterion 7c [Biologic therapy or 
JAK inhibitor therapy])  
Revised “interleukin 12/23 antibodies” to “anti-interleukin 
12/23 antibodies”  
For nomenclature accuracy and consistency with 
Inclusion Criterion 7b 
Protocol Synopsis: Eligibility criteria  
4.1. Inclusion Criteria (Inclusion 
Criterion 8)  
Removed “antidiarrheals (eg, loperamide, diphenoxylate with 
atropine) for control of chronic diarrhea”  
To avoid potentially confounding medication use  
Protocol Synopsis: Eligibility criteria  
4.2. Exclusion Criteria (Exclusion 
Criterion 1)  
Revised to:  
“Physician judgment that the subject is likely to require 
hospitalization for medical care or surgical intervention of any 
kind for UC (eg, colectomy) within 12 weeks following 
randomization”  
Revised to make the reference point within the 
12 weeks following randomization, not before 
randomization  
Protocol Synopsis: Eligibility criteria  
4.2. Exclusion Criteria (Exclusion 
Criterion 8)  
Revised the first bullet to:  
“Myocardial infarction, unstable angina, stroke/transient 
ischemic attack, decompensated heart failure requiring 
hospitalization or Class III/IV heart failure ≤ 6 months prior to 
or during the Screening Period”  
Revised to clarify exclusion applies to the 
6 months preceding screening and the screening 
period (inclusive)  
 
Revised second bullet to:  
“History or presence of second-degree or third-degree 
atrioventricular block, sick sinus syndrome, or periods of 
asystole for > 3 seconds without a functional pacemaker”  
Corrected “defibrillator” to “pacemaker” as this is 
the appropriate device for these conditions  


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 4 of 13 
Section No. and Name  
Description of Change  
Brief Rationale  
Protocol Synopsis: Eligibility criteria  
4.2. Exclusion Criteria (Exclusion 
Criterion 8) 
(Continued) 
Revised bullets 4 and 5 to:  
“Screening or Week 0/Day 1 prerandomization…”  
Corrected use of “and” and replaced with “or,” an 
error that was not updated when the text was 
moved from an inclusion to exclusion criterion in 
the ELEVATE protocols  
 
Revised sixth bullet to:  
“Start, stop, change, or planned change in dosage of any 
anti-arrhythmic drugs (Class I to IV) ≤ 1 week before screening 
or within 1 week before or after randomization”  
To clarify that the exclusion criterion about any 
change or expected (planned) change to anti-
arrhythmic drugs should be 1 week before or after 
randomization  
Protocol Synopsis: Eligibility criteria  
4.2. Exclusion Criteria (Exclusion 
Criterion 23)  
Revised language to:  
“Treatment with a biologic agent ≤ 8 weeks or a small molecule 
agent ≤ 5 elimination half-lives and detectable drug level prior 
to randomization”  
Refined for clarity and to add exclusion based on 
detectable drug levels. For example, a subject with 
≤ 8 weeks since receiving a biologic but no 
detectable drug levels will not be excluded  
Protocol Synopsis: Eligibility criteria  
4.2. Exclusion Criteria (Exclusion 
Criterion 24)  
Revised criterion to:  
“Treatment with an investigational therapy ≤ 3 months prior to 
randomization”  
“Within” implies before and after randomization 
but investigational therapies cannot be received 
after randomization  
Protocol Synopsis: Eligibility criteria  
4.2. Exclusion Criteria (Exclusion 
Criterion 26)  
Revised text about timing of topical treatments to:  
“Treatment with topical rectal 5-ASA, short-chain fatty acid 
enemas, or steroids ≤ 2 weeks prior to and during screening”  
Revised to ensure clarity and consistent 
descriptions as to the timing and potential impact 
of other treatments and procedures relative to the 
screening period and start of treatment. This will 
ensure that screening results can be best interpreted 
and reduce potential safety or confounding impacts 
on etrasimod treatment  
Protocol Synopsis: Eligibility criteria  
4.2. Exclusion Criteria (Exclusion 
Criterion 27)  
Added exclusion criterion “Treatment with topical rectal 
traditional medicine (eg, Chinese medicine), herb enemas, or 
suppositories ≤ 2 weeks prior to randomization”  
Added to avoid potentially confounding treatments 
that could impact the ability to evaluate etrasimod  
Protocol Synopsis: Eligibility criteria  
4.2. Exclusion Criteria (Exclusion 
Criterion 28)  
Revised language about timing of methotrexate to:  
“Treatment with methotrexate ≤ 8 weeks prior to and during 
screening or cyclosporine, tacrolimus, sirolimus, or 
mycophenolate mofetil (MMF) ≤ 16 weeks prior to and during 
screening”  
Revised to ensure clarity and consistent 
descriptions as to the timing and potential impact 
of other treatments and procedures relative to the 
screening period and start of treatment. This will 
ensure that screening results can be best interpreted 
and reduce potential safety or confounding impacts 
on etrasimod treatment  


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 5 of 13 
Section No. and Name  
Description of Change  
Brief Rationale  
Protocol Synopsis: Eligibility criteria  
4.2. Exclusion Criteria (Exclusion 
Criterion 29)  
Revised criterion to:  
“Receipt of a live vaccine ≤ 4 weeks prior to randomization”  
“Within” implies before and after randomization 
but live vaccines cannot be received after 
randomization  
Protocol Synopsis: Eligibility criteria  
4.2. Exclusion Criteria (Exclusion 
Criterion 33)  
Revised criterion to:  
“Treatment with IV immune globulin or plasmapheresis 
≤ 3 months prior to randomization”  
“Within” implies before and after randomization 
but IV immune globulin or plasmapheresis 
treatments cannot be administered after 
randomization  
Protocol Synopsis: Eligibility criteria  
4.2. Exclusion Criteria (Exclusion 
Criterion 34)  
Revised criterion to:  
“Chronic use of therapies that moderately/strongly 
inhibit/induce cytochrome P450 (CYP) 2C8 and 2C9 
metabolism and inhibitors of UGT1A7 ≤ 4 weeks prior to 
randomization”  
“Within” implies before and after randomization 
but therapies that moderately/strongly 
inhibit/induce cytochrome P450 (CYP) 2C8 and 
2C9 metabolism and inhibitors of UGT1A7 cannot 
be administered after randomization  
1.3. Benefit/Risk Assessment  
Added the following sentence:  
“Considering the significant unmet need for safe and effective, 
orally administered treatments for UC, etrasimod may 
potentially provide therapeutic benefit via S1P receptor 
modulation.”  
Added a statement regarding potential benefit of 
S1P-receptor modulation in UC to add balance to 
the Benefit/Risk section 
Revised the following sentence as follows:  
Lymphocyte counts returned to approximately baseline levels 
were within normal limits by 7 days after the last dose. 
Updated to more accurately reflect results 
5.3. Subjects “Lost to Follow-Up” 
Prior to Last Scheduled Visit  
Added “onsite, offsite, virtual, or hybrid” to read “the following 
actions must be taken if a subject fails to attend a required 
onsite, offsite, virtual or hybrid visit”  
Modification to include offsite, virtual, and hybrid 
study visit types  
6.6. Treatment Compliance  
Added the following sentence:  
“If there is a discrepancy between the tablet count and the 
subject’s compliance per the eDiary, it should be discussed with 
the subject and noted in the source documents.”  
To provide further guidance on drug accountability 
procedures.  


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 6 of 13 
Section No. and Name  
Description of Change  
Brief Rationale  
6.7. Concomitant Therapy  
Revised first paragraph as follows:  
“All over-the-counter and prescribed concomitant medications, 
blood products, procedures, vitamins, and holistic products, and 
radiotherapy administered during the Screening Period and 
during the study will be collected from Day 1 (pre dose) 
through the safety reporting period must be recorded in the 
eCRF, as appropriate. Any medication given for a study 
protocol related adverse event should be recorded from the time 
of informed consent/assent. 
To expand the collection of concomitant 
medications starting with the screening period and 
through the duration of the study and to provide 
additional clarity for information to be captured.  
6.7.2. Allowed Concomitant Therapy  Removed “All medications (over-the-counter and prescribed) 
that are taken by subjects and all procedures that are performed 
during the Screening Period and during the study must be 
recorded in the eCRF”  
Relocated to Section 6.7.  
6.7.3. Prohibited Concomitant 
Therapy 
Added the following bullet to the list of prohibited concomitant 
medications:  
“Start, stop, or change in dosage of any anti-arrhythmic drugs 
(Class I to IV) within 1 week before or after treatment 
re-initiation following drug interruption as specified in 
Section 6.3.2”  
To align with the exclusion criterion about any 
change or expected (planned) change to anti-
arrhythmic drugs should be 1 week before and 
after treatment re-initiation.  
Added siponimod and ozanimod to list of prohibited 
concomitant medications  
Due to recent approvals for these agents 
Removed “while enrolled in this study” in reference to major 
elective surgery  
Redundant text  
8.2. Study Treatment Storage and 
Handling 
Added “In the case where a subject attends a virtual visit (refer 
to Section 9.6) and requires additional study treatment to 
continue on the study, study treatment may be dispensed and 
delivered by an approved courier where permitted by local law 
and regulation. Alternatively, a future supply of study 
medications may be dispensed to the subject at an onsite visit to 
cover study medications to be dispensed at the next planned 
virtual visit. Advanced planning and communication will be 
needed to dispense future supply of study medications at an 
earlier onsite visit. Shipping guidelines and instructions will be 
provided separately.”  
To address potential need for an alternate method 
to provide study treatment in accordance with 
information in the Instructions for IP shipment 
from Site to Subject(s) for ELEVATE UC 52 
(Study APD334-301)/ELEVATE UC OLE 
(Study APD334-303) memo and to align with other 
protocols.  


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 7 of 13 
Section No. and Name  
Description of Change  
Brief Rationale  
8.4. Study Treatment Accountability  
Relocated and revised the following sentences to Section 9.6, 
Virtual/Hybrid Visits:  
“Subjects will record tablet self-administration daily in an 
eDiary that will be reviewed at each treatment visit by study 
site staff.”  
To provide guidance on drug accountability 
procedures in the event of a virtual visit in the 
context of other virtual visit activities.  
Removed “in the IWRS”  
The method for drug accountability is detailed in 
the CCG and pharmacy manual. 
9.1. General Instructions  
Revised the second bullet point as follows:  
“Results of all protocol required procedures must will be 
recorded in the eCRF whenever applicable.” 
To indicate that only those procedures which 
require eCRF documentation should be 
documented.  
Revised the seventh bullet point as follows:  
“OnFor onsite and offsite study day visits (refer to Section 9.6 
and Table 7), 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.” 
To account for multiple visit types. 
9.3. Screening and Eligibility  
Added the following sentences:  
“The 28-day Screening Period may also be extended on a 
case-by-case basis to accommodate reasonable delays in 
specific screening assessments (eg, pulmonary function tests 
[PFTs], optical coherence tomography [OCT]) due to testing 
availability. The Medical Monitor must be consulted prior to 
extension in each case.”  
To protect the health of the subjects and provide 
flexibility in light of the COVID-19 pandemic. 
Upon approval of this amendment, this will replace 
the provisions provided in the Pulmonary Function 
Testing communication of 07 April 2020 and the 
COVID-19 Memo 2.  
9.3.6. Ulcerative Colitis 
History/Medical History  
Revised the following sentence as follows:  
“The history should include recent blood donations (within 
≤ 30 days prior to the Screening Period), illnesses, and 
participation in other investigational drug studies”  
For clarity about timing relative to screening 
period.  


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 8 of 13 
Section No. and Name  
Description of Change  
Brief Rationale  
9.3.10. Clinical Laboratory 
Assessments  
New section. Added and modified section as follows and 
moved the following text from Section 9.3.11 (formerly 
Section 9.3.10) to this new section:  
Screening samples for complete blood count (CBC) with 
differential, platelet count, lymphocyte counts, T lymphocytes, 
B lymphocytes, natural killer lymphocytes (TBNK), CD4 T cell 
counts, serum chemistry, virology, thyroid panel, coagulation, 
urinalysis, high-sensitivity C-reactive protein (hs-CRP), TB 
screen, and stool sample should be obtained and results must be 
available and reviewed prior to randomizationthe first dose of 
study treatment. In the case of new clinical laboratory 
abnormalities detected prior to randomizationthe first dose, the 
eligibility of the subject should be reconsidered with the 
guidance of the Medical Monitor.  
Subsequent sections were renumbered accordingly.  
Correction. The text in this section was 
erroneously contained in Section 9.3.11 
“Proctosigmoidoscopy/Colonoscopy and Modified 
Mayo Score Derivation”  
Revised timing of screening samples for clarity.  
9.4.2. Treatment Period 
Deleted the second-to-last sentence: 
“After the Week 12 Visit and ET Visit, a study visit window of 
± 7 days is permitted.” 
Removed as this is a 12-week study and the 
follow-up visit study windows are detailed 
elsewhere. 
9.6. Virtual/Hybrid Visits  
New section.  
Subsequent sections were renumbered accordingly.  
To reduce patient burden and allow flexibility, 
certain procedures may now be conducted offsite 
and/or virtually while ensuring subject safety and 
study integrity.  
To address items previously accounted for in the 
“Instruction for IP Shipment from Site to Subjects 
and Performing Associated Drug Accountability, 
Pulmonary Function Testing”, and “Coronavirus 
Disease 2019 (COVID-19) Memo 2” memos 
related to the COVID-19 pandemic, which should 
become inactive upon approval of this amendment  
9.8.1.1. Endoscopy  
Revised the following sentence as follows:  
“For subjects with pancolitis > 8 years duration or subjects with 
left-sided colitis > 12 years without a surveillance colonoscopy 
within 12 months of prior to baseline …”  
For clarity in regards to timing of surveillance 
colonoscopy which cannot occur after baseline  


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 9 of 13 
Section No. and Name  
Description of Change  
Brief Rationale  
9.8.1.2. Endoscopic Biopsies 
Added the following sentence:  
“Post-randomization detected polyps or suspicious findings 
during endoscopy will be managed as per local standard of 
care.”  
To provide instructions for handling of polyps or 
suspicious findings after randomization  
9.10.4. Pulmonary Function Test 
Added the following sentences:  
“PFTs occurring at the ET visit that are within 4 weeks of the 
last assessment (eg, Week 12) will only be required if clinically 
indicated. The 2-Week Follow-Up visit assessment is only 
required if results from the Week 12/Early Termination visit are 
abnormal. The 2-Week Follow-Up visit assessment is only 
required if results from the Week 12/Early Termination visit are 
abnormal.”  
To clarify timing and reduce patient burden, the 
necessity of conducting PFTs has been updated if 
they have been performed in the last 4 weeks  
 
Added paragraph:  
“The safety of trial subjects and site staff is paramount, so it is 
at the Investigator’s discretion whether PFT can be safely 
administered to trial subjects during the treatment period. The 
Investigator should evaluate on a case-by-case basis how best to 
proceed based on the subject’s medical history, the 
Investigator’s clinical judgment, and in consultation with the 
Medical Monitor. All reasonable efforts should be made to 
ensure safety and adherence to the protocol. When available, 
spirometry may be conducted at the clinical site instead of at 
the pulmonary laboratory. If the decision is made that it is not 
appropriate to conduct PFTs due to the safety concerns (eg, 
COVID-19 transmission), then this decision and rationale 
should be appropriately captured in the subject’s source 
documentation. When available and safe (due to lifting of local 
restrictions, re-opening of local PFT labs, or improved safety 
conditions) the tests should be conducted as soon as possible 
and as close to the timepoints as outlined in the protocol.”  
To ensure subject safety, PFT may be conducted as 
deemed appropriate by the Investigator while 
maintaining study integrity and in accordance with 
the Pulmonary Function Test communication of 
07 April 2020 as related to the COVID-19 
pandemic and will replace that communication 
instruction upon approval of this amendment.  
9.10.5. Ophthalmoscopy and Optical 
Coherence Tomography  
Appendix 1: Schedules of 
Assessments, Table 7: Schedule of 
Assessments, Footnote r  
Added the following sentence:  
“OCTs occurring at the ET visit that are within 4 weeks of the 
last assessment will only be required if clinically indicated.”  
To clarify timing and reduce patient burden, the 
necessity of conducting OCTs has been updated if 
they have been performed in the last 4 weeks  


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 10 of 13 
Section No. and Name  
Description of Change  
Brief Rationale  
9.10.5. Ophthalmoscopy and Optical 
Coherence Tomography  
Added the following sentence:  
“The 2-Week Follow-Up visit assessment is only required if 
clinically indicated.”  
To reduce patient burden, the necessity of 
conducting OCTs during follow up is only required 
if clinically indicated  
Removed “for example, autorefraction” revising the following 
sentence as follows:  
“Best corrected visual acuity measurement (using Snellen chart 
internationally [if available])”  
Removed example to avoid confusion at some sites  
Removed the following sentence from the Screening Visit and 
Scheduled Post-Screening Visits lists:  
“Retinal photographs will be taken”  
To provide flexibility, clarity, and guidance as to 
necessary vs optional procedures as pertains to 
assessment of the eye exams as this is not 
considered an essential safety evaluation given that 
OCT is being conducted  
Changed the following procedures to optional and provided 
additional detail as follows:  
Optional procedures in case of clinically significant 
abnormalities on ophthalmic exam may include but are not 
limited to:  
• 
Retinal photographs 
• 
Intraocular pressure 
9.10.7. Clinical Laboratory Tests, 
Table 6 
Revised Footnote a as follows:  
“Total WBC, neutrophil, lymphocyte, and CD4 T cell 
countsTBNK will be available for review prior to 
randomization. After randomization, the 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 after 
randomization. Refer to Section 9.8.4 for additional details.”  
Correction for accuracy given that Investigators 
can access the whole blood cell and differential 
values at Screening  
Revised Footnote b as follows:  
“Investigators will remain blinded to the results after 
randomization”  


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 11 of 13 
Section No. and Name  
Description of Change  
Brief Rationale  
9.10.8.3.1. Serious Adverse Events  
Removed the following sentence:  
“All other hospitalizations, including elective hospitalizations 
for any condition that was not preexisting, will be reported as 
an SAE.”  
To correct the SAE definition of “elective 
hospitalization” to eliminate the inclusion of non-
urgent/non-emergent events not requiring hospital 
admission, which would result in an inaccurate 
assessment of the safety profile of the study drug  
10.4. Missing Data  
Added “for binary responder type endpoints” for handling 
missing data  
Additional detail provided for clarity  
Revised for continuous or score endpoints as follows:  
“subjects with missing data will be handled using last 
observation carry forward analyzed with their observed data 
only”.  
To reflect Arena’s current thinking on the missing 
data handling method  
14.1. Investigator Responsibilities  
Revised sentences below as follows:  
“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) or to other regulatory authorities that 
have similar requirements.”  
“The Investigator is responsible for compliance with applicable 
sections of ICH GCP requirements.”  
“The Investigator may also be responsible for compliance with 
21 CFR Part 312, Subpart D, (Responsibilities of Investigators) 
and other ICH GCP requirements, federal, and local laws, 
applicable to conducting drug studies.”  
“An Investigator will, in accordance with the provisions of ICH 
GCP guidelines and/or 21 CFR Part 50, obtain the informed 
consent of each human subject to whom the drug is 
administered.”  
Updated language to reflect Arena standard 
protocol language for this section and account for 
current standards  


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 12 of 13 
Section No. and Name  
Description of Change  
Brief Rationale  
14.2. Sponsor Responsibilities  
Revised the paragraph as follows:  
“The Sponsor is responsible for compliance with applicable 
sections of ICH E6(R2) and 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, and 
ensuring proper monitoring of the investigation(s). Sponsors are 
also responsible for ensuring the investigation(s) is conducted 
in accordance with the general investigational plan and 
protocols contained in the Investigational New Drug (IND) 
application (or equivalent), maintaining an effective IND (or 
equivalent) with respect to the investigations, and ensuring the 
FDA (and/or other regulatory authorities as applicable), other 
applicable health authorities, and all participating Investigators 
are promptly informed of significant new adverse effects or 
risks with respect to the drug.”  
Updated language to reflect Arena standard 
protocol language for this section and account for 
current standards  
Appendix 1: Schedule of 
Assessments, Table 7, Footnote a  
Added the following sentence:  
“All visits beyond W0/D1 may be virtual or hybrid visits 
(Section 9.6).”  
Updated to account for modifications in 
Section 9.6 (see above)  
Appendix 1: Schedules of 
Assessments, Table 7, Footnote p 
Revised footnote to the following: 
“A PFT will include FEV1 and FVC measurements. When 
available, DLCO measurements will also be performed (when 
DLCO is not available, sites should consult the Sponsor or 
Sponsor’s delegate).” 
Footnotes were divided into 2 and were revised for 
clarity and to match the updates in Section 9.10.4. 
To provide flexibility in location and capacity for 
DLCO measurements 
Appendix 1: Schedules of 
Assessments, Table 7, Footnote q 
Added footnote (the list of subsequent footnotes was updated 
accordingly): 
“The Screening pulmonary function test (PFT) should be done 
within the 28-day Screening Period. PFTs should be performed 
± 7 days in the study treatment period and posttreatment period 
(ie, 2-Week Follow-Up visit). PFTs occurring at the ET visit 
that are within 4 weeks of the last assessment will only be 
required if clinically indicated. The 2-Week Follow-Up visit 
assessment is only required if clinically indicated. Details 
regarding additional PFTs are provided in Section 9.10.4.” 
Footnotes were divided into 2 and were revised for 
clarity and to match the updates in Section 9.10.4. 


Clinical Study Protocol – Summary of Changes 
APD334-302 
Phase 3, 12-Week Study in UC (ELEVATE UC 12) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 13 of 13 
Section No. and Name  
Description of Change  
Brief Rationale  
Appendix 1: Schedule of 
Assessments, Table 7, Footnote r 
Added and revised the following sentences: 
“OCTs occurring at the ET visit that are within 4 weeks of the 
last assessment will only be required if clinically indicated. The 
2-Week Follow-Up visit assessment is only required if 
clinically indicated.”  
To clarify timing and reduce patient burden, the 
necessity of conducting OCTs has been updated if 
they have been performed in the last 4 weeks 
Appendix 1: Schedules of 
Assessments, Table 7, Footnote y  
Added “Biomarker sample collection is not required at ET 
visit.”  
Footnote added to clarify sample collection needed 
at Early Termination  
 

SAP_001.pdf: 
 
Statistical Analysis Plan 
PROTOCOL APD334-302 
 
Document: 
 
Author: 
 
Version Number: 
1.0 Final 
 
Version Date:  
19 January 2022 
Template No.:  CS_TP_BS016 Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01 April 2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 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  
 
 
 
 
 
APD334-302 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 12-Week Study to Assess the 
Efficacy and Safety of Etrasimod in Subjects with Moderately to Severely Active Ulcerative 
Colitis 
 
 
 
 
 
 
Author: 
 
Version Number and Date: V1.0 Final, 19 January 2022 
 
 
 
 
 


 
PROTOCOL APD334-302 
Statistical Analysis Plan 
Page 1 of 70 
 
 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE  
Statistical Analysis Plan V1.0 (dated 19 January 2022) for Clinical Study Protocol APD334-302 
Amendment 3.0. 
 
 
Name 
Signature 
Date 
Author: 
 
 
 
 
Position: 
Statistical Scientist 
 
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 
Approved By: 
 
 
 
 
Position: 
Associate Director, Biostatistics 
 
Company: 
IQVIA 
 
Approved By: 
 
 
 
 
Position: 
Vice President, Biostatistics & Data Management 
 
Company: 
Arena Pharmaceuticals, Inc. 
 
Approved By: 
 
 
 
 
Position: 
Senior Director, Biostatistics 
 
Company: 
Arena Pharmaceuticals, Inc. 
 
 
 


 
PROTOCOL APD334-302 
Statistical Analysis Plan 
Page 2 of 70 
 
 
MODIFICATION HISTORY  
 
Version 
Date of the 
Document Version 
Author 
Significant Changes from Previous 
Authorized Version 
1.0 
19 January 2022 
 
Not Applicable – First Version 


 
PROTOCOL APD334-302 
Statistical Analysis Plan 
Page 3 of 70 
 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................1 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE .............................................................1 
MODIFICATION HISTORY ..........................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................8 
1. 
INTRODUCTION ......................................................................................................11 
2. 
STUDY OBJECTIVES ..............................................................................................11 
2.1. 
Primary Objective .......................................................................................................11 
2.2. 
Secondary Objectives .................................................................................................11 
2.3. 
Safety Objectives ........................................................................................................11 
2.4. 
Other Objectives .........................................................................................................11 
2.5. 
Estimands ....................................................................................................................11 
3. 
STUDY DESIGN .......................................................................................................12 
3.1. 
General Description ....................................................................................................12 
3.2. 
Schedule of Assessments ............................................................................................13 
3.3. 
Changes to Analysis from Protocol ............................................................................13 
4. 
PLANNED ANALYSES ............................................................................................14 
4.1. 
Interim Analysis ..........................................................................................................14 
4.2. 
Final Analysis .............................................................................................................14 
5. 
ANALYSIS SETS ......................................................................................................14 
5.1. 
Screened Set ................................................................................................................14 
5.2. 
Randomized Set ..........................................................................................................14 
5.3. 
Full Analysis Set .........................................................................................................14 
5.4. 
Per Protocol Set ..........................................................................................................15 
5.5. 
Modified Full Analysis Set .........................................................................................15 
5.6. 
Safety Set ....................................................................................................................15 
5.7. 
Pharmacokinetic Set ...................................................................................................15 
6. 
GENERAL CONSIDERATIONS ..............................................................................16 
6.1. 
Reference Start Date and Study Day ..........................................................................16 
6.2. 
Baseline .......................................................................................................................16 
6.3. 
Retests, Unscheduled Visits, and Early Termination Data .........................................16 
6.4. 
Windowing Conventions ............................................................................................16 


 
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6.5. 
Statistical Tests ...........................................................................................................18 
6.6. 
Common Calculations ................................................................................................18 
6.7. 
General Study Information .........................................................................................18 
7. 
DETERMINATION OF SAMPLE SIZE ...................................................................18 
8. 
STATISTICAL CONSIDERATIONS .......................................................................19 
8.1. 
Multicenter Studies .....................................................................................................19 
8.2. 
Adjustments for Covariates and Factors to Be Included in Analyses ........................19 
8.3. 
Missing Data ...............................................................................................................20 
8.4. 
Multiple Comparisons and Multiplicity......................................................................20 
8.5. 
Subgroup Analyses .....................................................................................................21 
9. 
OUTPUT PRESENTATIONS....................................................................................22 
10. 
DISPOSITION AND PROTOCOL DEVIATIONS ...................................................22 
11. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .....................24 
11.1. 
Derivations ..................................................................................................................25 
12. 
MEDICAL HISTORY ................................................................................................25 
13. 
MEDICATIONS .........................................................................................................26 
14. 
STUDY TREATMENT EXPOSURE ........................................................................26 
14.1. 
Derivations ..................................................................................................................26 
15. 
STUDY TREATMENT COMPLIANCE ...................................................................26 
15.1. 
Derivations ..................................................................................................................26 
16. 
EFFICACY OUTCOMES ..........................................................................................27 
16.1. 
Primary Efficacy .........................................................................................................28 
16.1.1. 
Primary Efficacy Variable and Derivation .................................................................28 
16.1.2. 
Missing Data Methods for Primary Efficacy Variable ...............................................28 
16.1.3. 
Primary Analysis of Primary Efficacy Variable .........................................................29 
16.1.4. 
Sensitivity Analysis of Primary Efficacy Variable .....................................................29 
16.1.4.1. 
Multiple Imputation Under MAR ...............................................................................30 
16.1.4.2. 
Tipping Point Analysis ...............................................................................................31 
16.1.4.3. 
Multiple Imputation with Copy Reference .................................................................32 
16.1.4.4. 
Multiple Imputation with NRI to Handle Missing Data Due to COVID-19 
Pandemic .....................................................................................................................33 
16.1.5. 
Supplementary Analysis of Primary Efficacy Variable ..............................................33 
16.2. 
Key Secondary Efficacy .............................................................................................33 


 
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16.2.1. 
Key Secondary Efficacy Variables and Derivations ..................................................34 
16.2.1.1. 
Endoscopic Improvement at Week 12 ........................................................................34 
16.2.1.2. 
Symptomatic Remission at Week 12 ..........................................................................34 
16.2.1.3. 
Mucosal Healing at Week 12 ......................................................................................34 
16.2.2. 
Missing Data Methods for Key Secondary Efficacy Variables ..................................34 
16.2.3. 
Primary Analysis of Key Secondary Efficacy Variables ............................................34 
16.2.4. 
Sensitivity Analysis of Key Secondary Efficacy Variables .......................................34 
16.2.5. 
Supplementary Analysis of Key Secondary Efficacy Variables ................................34 
16.3. 
Other Secondary Efficacy ...........................................................................................35 
16.3.1. 
Other Secondary Efficacy Variables ..........................................................................35 
16.3.2. 
Missing Data Methods for Other Secondary Efficacy Variables ...............................35 
16.3.3. 
Analysis of Other Secondary Efficacy Variables .......................................................35 
 
 
 
 
 
 
 
 
17. 
HEALTH RELATED QUALITY OF LIFE AND HEALTHCARE 
RESOURCE UTILIZATION ANALYSIS ................................................................37 
17.1. 
Variables And Derivations .........................................................................................37 
17.1.1. 
Inflammatory Bowel Disease Questionnaire ..............................................................37 
17.1.2. 
Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms ........................37 
17.1.3. 
36-Item Short Form Health Survey, Version 2 ...........................................................37 
17.1.4. 
Work Productivity and Activity Impairment Questionnaire – Ulcerative 
Colitis ..........................................................................................................................38 
17.1.5. 
Urgency Numeric Rating Scale ..................................................................................38 
17.1.6. 
Abdominal Pain NRS .................................................................................................38 
17.1.7. 
UC-Related Hospitalizations and Surgeries ...............................................................38 
17.2. 
Missing Data Methods ................................................................................................38 
18. 
SAFETY OUTCOMES ..............................................................................................38 
18.1. 
Adverse Events ...........................................................................................................38 
18.1.1. 
All TEAEs ..................................................................................................................39 
18.1.1.1. 
Severity .......................................................................................................................39 
18.1.1.2. 
Relationship to Study Treatment ................................................................................39 


 
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18.1.2. 
TEAEs Leading to Discontinuation of Study Treatment ............................................39 
18.1.3. 
Serious and Non-Serious TEAEs ................................................................................40 
18.1.4. 
TEAEs Leading to Death ............................................................................................40 
18.1.5. 
TEAEs of Special Interest ..........................................................................................40 
18.1.6. 
Overall Summary of Adverse Events .........................................................................41 
18.2. 
Deaths .........................................................................................................................42 
18.3. 
Laboratory Evaluations ...............................................................................................42 
18.3.1. 
Safety Laboratory Evaluations ...................................................................................42 
18.3.2. 
Pregnancy Tests ..........................................................................................................44 
18.3.3. 
Other Screening Laboratory Assessments ..................................................................44 
18.4. 
ECG Evaluations ........................................................................................................44 
18.4.1. 
ECG Markedly Abnormal Criteria .............................................................................45 
18.5. 
Vital Signs ..................................................................................................................46 
18.5.1. 
Vital Signs Specific Derivations .................................................................................47 
18.5.2. 
Vital Signs Markedly Abnormal Criteria ...................................................................47 
18.6. 
Physical Examination .................................................................................................47 
18.7. 
Other Safety Assessments ...........................................................................................47 
18.7.1. 
Pulmonary Function Tests ..........................................................................................47 
18.7.1.1. 
PFT Markedly Abnormal and Potentially Important Criteria .....................................48 
18.7.2. 
Ophthalmoscopy and Optical Coherence Tomography ..............................................48 
18.7.3. 
Tuberculosis Screening and Chest X-Ray ..................................................................48 
19. 
EFFICACY-RELATED BIOMARKERS ..................................................................49 
20. 
PHARMACOKINETICS ...........................................................................................49 
21. 
DATA NOT SUMMARIZED OR PRESENTED ......................................................51 
REFERENCES ..............................................................................................................................52 
APPENDICES ...............................................................................................................................53 
 
 
 


 
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LIST OF APPENDICES  
APPENDIX 1: PROGRAMMING CONVENTIONS FOR OUTPUTS ....................................53 
APPENDIX 2: PARTIAL DATE CONVENTIONS ..................................................................55 
 
 
APPENDIX 4: IBDQ SCORING RULES ..................................................................................61 
APPENDIX 5: SF-36 SCORING RULES ..................................................................................62 
APPENDIX 6: WPAI-UC SCORING RULES ...........................................................................63 
APPENDIX 7: UC-PRO/SS SCORING RULES .......................................................................64 
APPENDIX 8: CLASSIFICATION OF RESCUE THERAPY ..................................................66 
 
LIST OF TABLES  
Table 1: 
List of Primary and Key Secondary Estimands ..........................................................12 
Table 2: 
Visit Windows for Efficacy and Safety Analyses ......................................................17 
Table 3: 
Planned Analyses by Endpoint ...................................................................................33 
Table 4: 
Markedly Abnormal Criteria for Vital Signs ..............................................................47 
 
LIST OF FIGURES  
Figure 1: 
Study Design ...............................................................................................................13 
Figure 2: 
Gatekeeping Procedure Summary ..............................................................................20 
 
 
 
 
 


 
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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 quantitation 
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 trough plasma concentration 
CV 
coefficient of variation 
DBP 
diastolic blood pressure 
DLCO 
diffusing capacity of the lungs for carbon monoxide 
EAIR 
exposure-adjusted incidence rate 
ECG 
electrocardiogram 
eCRF 
electronic case report form 


 
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Abbreviation 
Explanation 
eDISH 
evaluation of drug-induced serious hepatotoxicity 
EIM 
extraintestinal manifestation 
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 
lower limit of quantification 
LOESS 
locally estimated scatterplot smoothing 
LS 
least squares 
MAR 
missing at random 
MCMC 
Markov Chain Monte Carlo 
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 
NHI 
Nancy Histological Index 
NRI 
nonresponder imputation 
NRS 
numeric rating scale 
OCT 
optical coherence tomography 


 
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Abbreviation 
Explanation 
OLE 
open-label extension 
PFT 
pulmonary function test 
PGA 
Physician’s Global Assessment 
PK 
pharmacokinetics 
PRES 
posterior reversible encephalopathy syndrome 
PT 
preferred term 
RB 
rectal bleeding 
RHI 
Robarts Histopathology Index 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SE 
standard error 
SF 
stool frequency 
SF-36 
Medical Outcomes Study 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 
UC-PRO/SS 
Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms 
ULN 
upper limit of normal 
ULQ 
upper limit of quantitation 
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 (PK), 
and efficacy-related biomarker data for Clinical Study Protocol APD334-302. It describes the 
data to be summarized and analyzed, including specifics of the statistical analyses to be 
performed (ICH 1998). This SAP is based on the Clinical Study Protocol APD334-302 
Amendment 3.0, dated 22 February 2021.  
Analyses of the genetics (Clinical Study Protocol Amendment 3.0 Section 9.9) 
 
 will be 
specified in a separate biomarker analysis plan. 
2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective  
The primary objective is to assess the efficacy of etrasimod when administered for 12 weeks on 
clinical remission in subjects with moderately to severely active ulcerative colitis (UC).  
2.2. 
Secondary Objectives  
The secondary objective is to assess the efficacy of etrasimod when administered for 12 weeks 
on clinical response, symptomatic response and remission, endoscopic changes, and mucosal 
healing in subjects with moderately to severely active UC.  
2.3. 
Safety Objectives  
The safety objective is to assess the safety of etrasimod after daily doses of 2 mg for up to 
12 weeks in subjects with moderately to severely active UC. 
2.4. 
Other Objectives  
Other objectives include evaluation of etrasimod PK and the effect of etrasimod on health-related 
subject-reported outcomes and biomarkers.  
2.5. 
Estimands  
The primary and the key secondary estimands to support regulatory decisions are described in 
Table 1 below. 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 (ICH 2019). 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 a rescue non-drug treatment (eg, colectomy, ileostomy, or sigmoidectomy) before the 
efficacy assessment. Refer to Appendix 8 for the definition of rescue therapies (medication and 
medical procedures). 


 
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Table 1: 
List of Primary and Key Secondary Estimands  
Estimand 
Definition 
Attributes 
Population 
Variable/ Endpoint 
Intercurrent event 
handling strategy 
Population-level 
summary measure 
Primary 
Estimand 
Efficacy of 
etrasimod 
on clinical 
remission 
at Week 12 
Randomized 
subjects who 
receive at least 
1 dose of study 
treatment and 
with Baseline 
MMS 5 to 9 
The proportion of 
subjects with SF = 0 
(or = 1 with a ≥ 1 
point decrease from 
Baseline), RB = 0, 
and ES ≤ 1 
(excluding 
friability) at Week 
12 
Subjects with any 
of the 3 
intercurrent eventsa 
before the efficacy 
assessment will be 
treated as 
nonresponders.  
Difference between 
etrasimod and 
placebo in the 
endpoint at Week 
12 
Key 
Secondary 
Estimand 1 
Efficacy of 
etrasimod 
on 
endoscopic 
improveme
nt at Week 
12 
Randomized 
subjects who 
receive at least 
1 dose of study 
treatment and 
with Baseline 
MMS 5 to 9 
The proportion of 
subjects with ES of 
≤ 1 (excluding 
friability) at Week 
12.  
Same as the 
intercurrent event 
handling strategy 
for the primary 
estimand 
Difference between 
etrasimod and 
placebo in the 
endpoint at Week 
12 
Key 
Secondary 
Estimand 2 
Efficacy of 
etrasimod 
on 
symptomati
c remission 
at Week 12 
Randomized 
subjects who 
receive at least 
1 dose of study 
treatment and 
with Baseline 
MMS 5 to 9 
The proportion of 
subjects with SF = 0 
(or = 1 with a 
≥ 1-point decrease 
from Baseline) and 
RB = 0 at Week 12. 
Same as the 
intercurrent event 
handling strategy 
for the primary 
estimand 
Difference between 
etrasimod and 
placebo in the 
endpoint at Week 
12 
Key 
Secondary 
Estimand 3 
Efficacy of 
etrasimod 
on mucosal 
healing at 
Week 12 
Randomized 
subjects who 
receive at least 
1 dose of study 
treatment and 
with Baseline 
MMS 5 to 9 
The proportion of 
subjects with ES of 
≤ 1 (excluding 
friability) with 
histologic remission 
measured by a 
Geboes Index score 
< 2.0 at Week 12.  
Same as the 
intercurrent event 
handling strategy 
for the primary 
estimand 
Difference between 
etrasimod and 
placebo in the 
endpoint at Week 
12 
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 a rescue non-drug treatment (eg colectomy, ileostomy, or sigmoidectomy) before the efficacy 
assessment. Refer to Appendix 8 for the definition of rescue therapies (medication and medical procedures).  
ES, endoscopic score; RB, rectal bleeding, SF, stool frequency; UC, ulcerative colitis. 
3. 
STUDY DESIGN  
3.1. 
General Description  
This is a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy 
and safety of etrasimod 2 mg in subjects with moderately to severely active UC. The study 
consists of a 28-Day Screening Period, a 12-Week Induction Treatment Period, and a 2-Week 
and 4-Week Follow-up Period. The study design diagram can be found in Figure 1. Eligible 
subjects will be randomized (2:1 ratio) to receive either etrasimod (2 mg once daily) or matching 


 
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placebo (once daily) in a double-blind fashion for up to 12 weeks of treatment. Randomization 
will be stratified by (a) naïve to biologic or Janus kinase (JAK) inhibitor therapy at study entry 
(Yes or No), (b) Baseline corticosteroid use (Yes or No), and (c) Baseline disease activity 
(modified Mayo score [MMS]: 4 to 6 or 7 to 9). 
Approximately 330 subjects are planned to be enrolled. The target subject population will 
include (approximately 50% of subjects in each of the following categories): 
1. Subjects who have had an inadequate response to, loss of response to, or intolerance to 
conventional therapy and are naïve to biologic or JAK inhibitor therapy. 
2. Subjects who have had an inadequate response to, loss of response to, or intolerance to a 
biologic or JAK inhibitor (subjects in this category may have received prior conventional 
therapy). 
At the end of the 12-Week Induction Treatment Period, subjects will undergo Week 12 efficacy 
and safety assessments and be evaluated for clinical response/remission. Subjects will then have 
the option to enter an open-label extension (OLE) study (APD334-303) following completion of 
Week 12 study procedures, providing they meet all eligibility criteria for the OLE. Subjects must 
complete Week 12 to be eligible for the OLE. 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 
treatment administration/Early Termination (ET) visit. The study design is outlined in Figure 1.  
Figure 1: 
Study Design  
 
JAK, Janus kinase; UC, ulcerative colitis. 
3.2. 
Schedule of Assessments  
Schedule of assessments can be found in Clinical Study Protocol APD334-302 Appendix 1. 
3.3. 
Changes to Analysis from Protocol  
The primary analysis set for the efficacy endpoints is updated to the Full Analysis Set (FAS) 
with MMS 5 to 9. Subgroup definition related to MMS is updated accordingly. The entire FAS 
will be used in supplementary analyses.  


 
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Definition of histologic improvement based on Geboes in Section 16 is updated from Geboes 
Index score < 3.1 to Geboes Index score ≤ 3.1. 
 
 
4. 
PLANNED ANALYSES  
The following analyses will be performed for this study: 
• Final Analysis  
4.1. 
Interim Analysis  
There are no planned or unplanned interim analysis for this study. 
4.2. 
Final Analysis  
All final, planned analyses identified in this SAP will be performed 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 posthoc exploratory analyses completed to support planned study analyses 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 by Arena 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.  
5.2. 
Randomized Set  
The Randomized Set will consist of all subjects who are randomized to study treatment. 
5.3. 
Full Analysis Set  
The FAS will consist of all randomized subjects who receive at least 1 dose of study treatment. 
Subjects will be summarized by treatment to which they were randomized, regardless of 
treatment actually received.  


 
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5.4. 
Per Protocol Set  
The Per Protocol 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 
influences of important protocol deviations on the primary results. Subjects may be excluded 
from the Per Protocol Set if they violate the eligibility criteria or significantly deviate from the 
study plan, including, but not limited to:  
• Overall study treatment noncompliance (< 80 or > 120%) 
• Receive incorrect study treatment for > 7 days 
• Use rescue medication (new or dose increase from the highest dose of background 
treatment for UC received during Screening) or undergo rescue medical procedure 
that may affect efficacy endpoint at Week 12  
• Miss Week 12 endoscopic score (ES) in prespecified analysis window (per 
Section 6.4) for reasons other than UC flare or discontinued due to disease worsening 
or lack of efficacy   
Refer to Appendix 8 for the definition of rescue therapies (medication and medical procedures). 
All protocol deviations will be reviewed in addition to the programmable deviations (eg, study 
treatment noncompliance) to determine if any deviation is significant enough to exclude a 
subject from the Per Protocol Set. All exclusion flags will be finalized before study unblinding. 
Subjects excluded from each Per Protocol Set will be listed along with the reason category 
above. Subjects will be summarized by treatment to which they were randomized, regardless of 
treatment actually received.  
5.5. 
Modified Full Analysis Set  
The mFAS will consist of all randomized subjects who receive at least 1 dose of study treatment 
and have a Baseline and at least 1 post-randomization measurement. 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.  
5.6. 
Safety Set  
The Safety Set will consist of all randomized subjects who receive at least 1 dose of study 
treatment. Subjects will be classified according to 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 
postdose etrasimod concentration which is not impacted by protocol violations or events with 
potential to affect the etrasimod concentration. 


 
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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) and 
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 start date, then:  
Study Day = (date of event – reference start date) + 1 
• If the date of the event is prior to the reference start date, then:  
Study Day = (date of event – reference start date) 
In the situation where the event date is partial or missing, Study Day and any corresponding 
durations will appear missing in the listings. 
6.2. 
Baseline  
Unless otherwise specified, Baseline is defined as the last non-missing measurement taken prior 
to the first dose (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 biomarker 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 still 
be considered in summaries of abnormalities or worst-case values post-Baseline. 
The visit windowing will be applied before missing data are imputed. 
Listings will include scheduled, unscheduled, retest, and early termination data. 
6.4. 
Windowing Conventions  
All scheduled study visits are defined relative to Study Day 1, the date of first dose. Scheduled 
visit windows are defined in Clinical Study Protocol APD334-302 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. 
For cardiac remonitoring upon treatment reinitiation after Day 2, as evidenced by more than 1 
timed measurement in vital signs or electrocardiogram (ECG) parameters on the same collection 
date of an unscheduled visit, measurements will be mapped to analysis visit of Cardiac 
Remonitoring 1, Cardiac Remonitoring 2, etc. in the respective analysis dataset. For analysis, 


 
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each timed measurement will be programmatically assigned to the nearest hourly timepoint (eg, 
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 two 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 
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 12 and Week 8, a hierarchical algorithm will be 
applied as following: always map to the Week 12 study visit if the study day falls within the visit 
window of the Week 12 study visit, then assess the other records for the Week 8 study visit. 
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 
≤ 1 
Week 0 (Day 1) 
1 
Week 0 (Day 2)a         
2 
Week 2 (Day 15 ± 3) 
2 to 22, or 3 to 22a 
Week 4 (Day 29 ± 3) 
23 to 43 
Week 8 (Day 57 ± 3) 
44 to 71  
Week 12 (Day 85 ± 7) 
> 71 


 
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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 
≤ 1 
Week 0 (Day 1) 
1 
Week 0 (Day 2)a 
2 
Week 12 (Day 85 ± 7)b,c         
66 to 113 (66 to 141 for assessments impacted by COVID-19 pandemic)d 
a Applicable only for subjects who required extended monitoring on Day 2 for vital signs and ECGs 
b Applicable to all Week 12 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(FDA 
2020) 
c Due to overlapping windows at Week 12 and Week 8, a hierarchical algorithm will be used for the mapping. Week 
12 will always be mapped first, then assess records for the Week 8 mapping. If scheduled Week 8 and 12 visits are 
both present in the same visit window, they will be mapped to separate visits (ie, Week 8 and Week 12) 
d Assessments impacted by the COVID-19 pandemic are reported in the Date of Visit eCRF 
COVID-19, Coronavirus disease 2019; 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 
6.5. 
Statistical Tests  
The default significance level will be 0.05; confidence intervals (CI) will be 95%, and all tests 
will be 2-sided, unless otherwise specified in the description of the analyses. 
6.6. 
Common Calculations  
For quantitative measurements: 
• Change from Baseline = 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  
Based on a 2-group Fisher’s exact test, a 1-sided significance level of 0.025, and a 
2:1 randomization ratio, 330 total subjects (220 etrasimod, 110 placebo) are required to achieve 
at least 90% power to detect a difference of 12.5% in the primary endpoint of clinical remission 


 
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between the etrasimod treatment group (18.5%) and the placebo treatment group (6.0%). 
Workbook calculation from EAST® 6 statistical software is included below. 
 
8. 
STATISTICAL CONSIDERATIONS  
8.1. 
Multicenter Studies  
This study will be conducted by multiple investigators at multiple centers internationally. 
Randomization to treatment groups is stratified by: 
• Naïve to biologic or JAK inhibitor therapy at study entry (Yes or No) 
• Baseline corticosteroid use (Yes or No) 
• Baseline disease activity (MMS: 4 to 6 or 7 to 9) 
Data from all sites will be pooled and statistical analyses will not be adjusted for investigational 
site, country, or geographic region. 
8.2. 
Adjustments for Covariates and Factors to Be Included in Analyses  
The following covariates and factors, and/or endpoint Baseline measure are used in the analyses. 
For details of their inclusion in the models, refer to the specific analysis section. 
• Naïve to biologic or JAK inhibitor therapy at study entry (Yes or No) 
• Baseline corticosteroid use (Yes or No) 
• Baseline disease activity (MMS: 4 to 6 or 7 to 9) 
If a subject was assigned the wrong stratum at randomization, their stratum based on the 
randomization system will be used for the statistical analyses. Analyses may be repeated using 
actual stratum if mis-randomization occurs in more than 10% of randomized subjects.  


 
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8.3. 
Missing Data  
Missing adverse event (AE) relationship to study treatment 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, concomitant medication (CM) start dates, and hospitalization dates will also be imputed as 
described in Appendix 2. No other missing safety data will be imputed. 
Missing efficacy data will be handled as described in Sections 16.1.2, 16.2.2, and 16.3.2. In the 
primary analysis of the primary endpoint and main analyses of all binary responder-type 
endpoints, all subjects with missing data, regardless of reason for missingness, will be considered 
as nonresponders. In the main analysis of continuous or score endpoints, 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, multiple 
imputation, or a mixed-effect model with repeated measures.  
8.4. 
Multiple Comparisons and Multiplicity  
There are multiple null hypotheses for the comparison of etrasimod and placebo in the primary 
and key secondary endpoints. The family-wise type-I error rate will be controlled at a fixed 
α level at 0.05 (2-sided) using the following testing procedure.  
Figure 2 illustrates the parallel gatekeeping procedure, which will be followed to control the 
family-wise error rate (FDA 2017).  
Figure 2: 
Gatekeeping Procedure Summary  
 
F1, family 1; F2, family 2, F3, family 3 
Traditional Hochberg procedure: 
Consider testing the family of hypotheses H0i; i = 1… k. Let pi, for i = 1… k, denote the sample 
p-values of tests for H0i; i = 1…k, computed without multiplicity adjustment. Let [1] … [k] 
denote the random indices such that p[1] ≤ … ≤ p[k] (p[1]  is the smallest p-value, p[k] is the largest 
p-value). Hochberg procedure is implemented as follows: 
Step 1: if p[k] < α, reject H0[i], i=1, …, k and stop; otherwise proceed to next step. 


 
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Step 2: if p[k-1] < α/2, reject H0[i], i=1, …, k-1, and stop; otherwise proceed to next step. 
… 
Step k: if p[1] < α/k, reject H0[1], and stop; otherwise no null hypothesis is rejected. 
Truncated Hochberg procedure (with truncation fraction f where 0 < f < 1): 
Consider testing the family of hypotheses H0i; i = 1… k. Let pi, for i = 1… k, denote the sample 
p-values of tests for H0i; i = 1…k, computed without multiplicity adjustment. Let [1] … [k] 
denote the random indices such that p[1] ≤ … ≤ p[k] (p[1]  is the smallest p-value, p[k] is the 
largest p-value). Truncated Hochberg procedure is implemented as follows: 
Step 1: if p[k] < fα+(1-f)*α/k, reject H0[i], i = 1, …, k and stop; otherwise proceed to next step. 
Step 2: if p[k-1] < fα/2+(1-f)*α/k, reject H0[i], i = 1, …, k-1, and stop; otherwise proceed to next 
step. 
… 
Step k: if p[1] < fα/k+(1-f)*α/k = α/k, reject H0[1], and stop; otherwise no null hypothesis is 
rejected. 
A demonstration of alpha level for F3:  
A truncation fraction f = 0.8 will be used in the truncated Hochberg procedure in testing F2, 
which results in the following alpha level to be passed to F3 for testing. 
• Both null hypotheses in F2 are rejected:  
α(F3) = α(F2) = 0.05 
• 1 of 2 null hypotheses in F2 is rejected:  
α(F3) = α(F2)-[fα(F2)+(1-f)*α(F2)/2] = 0.05 
8.5. 
Subgroup Analyses  
The following subgroups will be assessed for the primary and key secondary endpoints: 
• Sex (Female or Male) 
• Age (≤ or > Median, < or ≥ 65) 
• Race (White or Non-White)   
• Region (North America, Western Europe, Eastern Europe, Other) 
• Country (Japan, Non-Japanese) 
• Baseline oral corticosteroid usage (Yes or No) 
• Naïve to biologic or JAK inhibitor therapy at study entry (Yes or No) 
• Baseline disease activity (MMS: 4 to 6, 7 to 9) 
• Actual Baseline MMS (5 to 7, 8 to 9) 
• Baseline fecal calprotectin (≤ or > Median) 


 
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• Baseline high-sensitivity C-reactive protein (hs-CRP) (≤ or > Median) 
• Baseline total Mayo score (TMS) (≤ 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. It should be noted that the study was not 
designed to detect treatment differences with high statistical power within subgroups. If any 
subgroup includes < 5% of all subjects, no inferential statistics will be generated. 
The actual stratum at Baseline will be used for all subgroup analyses.  
Forest plots of the overall analysis set, and all subgroups will be presented for each of the 
primary and key secondary endpoints. Inference from the model described in Section 16.1.3 will 
be used and differences in remission percentages along with 95% CIs will be displayed.  
9. 
OUTPUT PRESENTATIONS  
Appendix 1 contains the conventions for presentation of data in outputs.  
10. 
DISPOSITION AND PROTOCOL DEVIATIONS  
All subjects who provide informed consent will be accounted for in this study. Inclusion criteria 
not met and exclusion criteria met will be listed. 
Among the randomized subjects, the number and percent of subjects who 
completed/discontinued treatment, reasons off treatment, the number and percent of subjects who 
completed/discontinued the study, and reasons off study will be summarized. This summary will 
also be provided by region and country. The number and percent of subjects in each analysis set 
will be summarized for all randomized subjects. An additional summary of the number of 
subjects screened, the number of screen-failed subjects, and reason for screen failure will be 
presented for all screened subjects. A listing of subjects whose blind was broken will be 
provided. The number of subjects whose visit was impacted by the coronavirus disease 2019 
(COVID-19) pandemic per eCRF will also be summarized by nominal visit. 
During site monitoring, protocol deviations are graded as Critical, Major or Minor.  


 
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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.  
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 
• Randomization 
• 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.  


 
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11. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS  
The following demographic and Baseline characteristics will be summarized for the FAS. 
• Age on consent (years)  
• Sex 
• Race  
• Ethnicity 
• Woman of childbearing potential (Yes or No) 
• Height (cm) 
• Weight (kg) 
• Body mass index (BMI) (kg/m2) 
• Alcohol consumption (Yes or No) 
• Caffeine consumption (Yes or No) 
• Tobacco use (Yes or No) 
This summary will be repeated for age, sex, race, ethnicity, or woman of childbearing potential 
for subjects who fail screening.  
The following Baseline characteristics related to UC will be summarized: 
• Extent of disease (Proctosigmoiditis/Left-sided colitis, Pancolitis, Proctitis reported 
on the electronic case report form [eCRF], and Proctitis reported from central reader 
review) 
• 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 (Yes or No), including the number of 
acute exacerbations among those with any acute exacerbation = Yes 
• Colonoscopy within past 12 months (Yes or No) 
• Surgery for UC (Yes or No), including the number of surgeries among those with 
surgery for UC = Yes 
• Hospitalizations for UC (Yes or No), including the number of hospitalizations 


 
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• Naïve to biologic or JAK inhibitor therapy (Yes or No) – Reported (used for 
stratification at randomization) 
• Naïve to biologic or JAK inhibitor therapy (Yes or No) – Actual (medications 
reported on the eCRF) 
• Baseline corticosteroid use (Yes or No) – Reported (used for stratification at 
randomization) 
• Baseline corticosteroid use (Yes or 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, and 5 to 9) – Actual (scores reported on the 
eCRF) 
• Naïve to biologic or JAK inhibitor therapy – Difference between the Reported and the 
Actual 
• Baseline corticosteroid use (Yes or 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 – 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 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 will be summarized for the Safety 
Set by system organ class (SOC) and preferred term (PT).  


 
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13. 
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 
• ‘Concomitant’ medications are medications which started prior to, on or after the first 
dose of study treatment AND ended on or after the date of first dose of study 
treatment or were ongoing at the end of the study 
Concomitant medications will be summarized by Anatomical Therapeutic Chemical (ATC) 
Level 2 and Preferred Drug name for the Safety Set. Concomitant medications being used for UC 
will be flagged as such on the Concomitant Medications eCRF and summarized by ATC Level 2 
and Preferred Drug name for the Safety Set.  
14. 
STUDY TREATMENT EXPOSURE  
The date of first and last study treatment administration will be taken from the Day 1 Onsite 
Dosing Administration eCRF and the End of Study eCRF, respectively. Interruptions, 
compliance, and dose changes are not 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 1 
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.  
14.1. 
Derivations  
Duration of exposure (weeks) = (date of last study treatment administration – date of first study 
treatment administration + 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, and frequency and percentage of subjects with 
overall compliance of < 80% or > 120% will be summarized for the Safety Set. 
15.1. 
Derivations  
Compliance with 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 


 
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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 60 and returned to the site on Day 78 to return the study treatment bottle, then 
the total number of tablets expected would be 60, not 77. 
• Overall compliance to study treatment will be calculated as follows; 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 that 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 12-Week Treatment 
Period and will be used in determining inclusion/exclusion of subjects in the respective Per 
Protocol Set.  
16. 
EFFICACY OUTCOMES  
Unless otherwise stated, the primary efficacy analyses will be based on subject stratum used at 
the time of randomization for the FAS with Baseline MMS 5 to 9. Primary and key secondary 
efficacy analyses will be repeated for all subjects in FAS with Baseline MMS 4 to 9 as 
supplementary analysis. 
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 = 0 


 
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• 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 
• Histologic improvement using Robarts Histopathology Index (RHI): ≥ 50% reduction 
from Baseline in RHI or RHI ≤ 3 
• Histologic remission using RHI: RHI ≤ 3, with scores of 0 (zero) for both Geboes 
Grade 2B (lamina propria neutrophils) and Grade 3 (neutrophils in epithelium) 
• Histologic improvement using Nancy Histologic Index (NHI): ≥ 1 point reduction 
from Baseline NHI 
• Histologic remission using NHI: ≤ 1 
• 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 
16.1. 
Primary Efficacy  
16.1.1. 
Primary Efficacy Variable and Derivation  
The primary efficacy endpoint will compare etrasimod to placebo for:  
• The proportion of subjects achieving clinical remission at Week 12 
Clinical remission is defined in Section 16. 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 nonresponders. 
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 (eg, 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 (ie, 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 8 for the definition of rescue therapies 
(medication and medical procedures). In scenarios 2 and 3 above, if a subject has an efficacy 
measurement collected after the initiation or dose increase from Baseline of UC medication, the 


 
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observed data will be censored at the time of initiation or dose increase and they will be 
considered as 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 Per Protocol Set if they initiate a prohibited medication 
before the Week 12 efficacy assessment that can affect efficacy of the study 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 a missing efficacy outcome will be included in the primary analysis using the 
following missing data methods: 
• Primary method: single imputation as nonresponder 
• Sensitivity analyses: multiple imputation under missing at random (MAR), tipping point 
analysis, multiple imputation with Copy Reference (CR) under missing not at random 
(MNAR), and a hybrid imputation with multiple imputation to handle missing endoscopy 
data due to COVID-19 pandemic impact and nonresponder imputation (NRI) for missing 
data not due to COVID-19 pandemic impact. More details are provided in Section 16.1.4 
• Supplementary analyses: mFAS analysis with data as observed, Per Protocol Set analysis 
16.1.3. 
Primary Analysis of Primary Efficacy Variable  
The following hypothesis will be tested at the 2-sided α level, 0.05. 
H0: The proportion of subjects achieving clinical remission at Week 12 is the same between 
etrasimod and placebo.  
H1: The proportion of subjects achieving clinical remission at Week 12 is different between 
etrasimod and placebo.  
The primary efficacy analysis will be performed for the FAS with Baseline MMS 5 to 9. The 
Cochran-Mantel-Haenszel (CMH) test will be used, stratified by naïve to biologic or JAK 
inhibitor therapy status at study entry (Yes or No), Baseline corticosteroid use (Yes or No), and 
Baseline disease activity (MMS: 4 to 6 or 7 to 9). Reported randomization stratum will be used 
in the model. Results will be expressed as the number and percentage of subjects in remission, 
difference in remission percentages and 95% CI and p-value, odds ratio and 95% CI. If there are 
no responders in both treatment groups in any stratum, the difference in remission percentages 
and associated inferences can still be made. However, the odds ratio and its CI may be calculated 
from the unstratified CMH. 
16.1.4. 
Sensitivity Analysis of Primary Efficacy Variable  
Four sensitivity analyses will be implemented to explore different types of missing data 
approaches: multiple imputation under MAR, tipping point analysis, multiple imputation with 
CR under MNAR, and multiple imputation under MAR/NRI imputation hybrid. These sensitivity 
analyses will use the FAS with Baseline MMS 5 to 9. There are two different types of missing 
data patterns: non-monotone and monotone. A subject with missing data at any post-Baseline 
visit, and a non-missing data point after that visit is said to have intermittent missing data (non-


 
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monotone). A subject with missing data at any post-Baseline visit and at all subsequent visits is 
said to have monotone missing data. 
16.1.4.1. Multiple Imputation Under MAR  
Any missing component scores of MMS at the planned assessments will be imputed using 
multiple imputation under MAR. MAR assumes the missing value is independent of unobserved 
outcomes given observed data (ie, subjects with missing RB subscores can be modeled based on 
subjects with observed RB subscores) (Rubin 1987). 
The following steps will be implemented: 
Step 1: 
Regardless of the arbitrary missing data pattern (ie, non-monotone or monotone), a fully 
conditional specification (FCS) method with predictive mean matching for continuous variables 
will be used to impute the missing data at all timepoints. The FCS method allows for separate 
conditional distributions for each imputed variable. The predictive mean matching approach 
creates a regression model using parameters sampled from the posterior distribution and then a 
predicted value for each missing value is computed. The missing value is replaced by randomly 
selecting an observation from a set of ‘k’ values that are the closest predicted values to the 
missing predicted value. Missing data imputation will be performed using the SAS PROC MI 
procedure. The number of imputations will be 40 and is based on a projected overall dropout rate 
of 10% and relative efficiency of > 99%. A separate imputation model will be used for each 
treatment group. The RB subscore, SF subscore, ES, PGA, stratification variables, a binary 
variable indicating if a subject is a prior UC treatment failure of oral 5-ASA only (ie, subject had 
an inadequate response, loss of response, or intolerance to previous treatment with oral 5-ASA 
and did not have an inadequate response, loss of response, or intolerance to any other previous 
UC medication), Geboes index score and biomarker measurements (absolute lymphocyte count 
[ALC], fecal calprotectin [FCP], hs-CRP, log-transformed) at each planned visit will be included 
in the imputation models. Refer to Appendix 3 for the order of variables and timepoints in the 
model. 
Step 2: 
For each of the imputed datasets at Week 12, subjects will be classified as responder or 
nonresponder based on the criteria specified in Section 16. For each dataset, the proportion of 
responders will be calculated. For endpoints requiring MMS, MMS will be recomputed by 
summing the scores of ES, SF, and RB. 
Step 3: 
The CMH test, stratified by naïve to biologic or JAK inhibitor therapy at study entry (Yes or 
No), Baseline corticosteroid use (Yes or No), and Baseline disease activity (MMS: 4 to 6 or 7 to 
9) will be run for each of the 40 datasets to obtain 40 estimators of interest. 
Step 4: 
Use SAS PROC MIANALYZE to produce an overall pooled estimate (mean of 40 estimates) 
with its associated standard error (SE), CI, and pooled p-value. 


 
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 However, there could be certain 
adjustments due to unexpected data issues after unblinding treatment. All post-unblinding 
modifications to the multiple imputation model or approaches to address missing data will be 
described in the CSR.  
16.1.4.2. Tipping Point Analysis  
A tipping point approach based on multiple imputation of values through Week 12 will be used 
with a specified adjustment (referred to as delta adjustment or shift) applied to values imputed 
under a MNAR-based imputation model. To find a tipping point, a series of imputations will be 
performed with increasing values of delta.   
The goal is to evaluate the plausibility of the assumed expected values for missing outcomes on 
each treatment group under which the conclusions change, ie, under which values of delta there 
are no longer evidence of significant treatment difference.  
The following steps will be implemented: 
Step 1:  
Same as Step 1 described in Section 16.1.4.1 .  
Step 2: 
Impute missing RB, SF, and ES subscores, then apply a random shift under the MNAR 
assumption to the imputed subscores and rounded to the nearest integer at Week 12 in both 
treatment groups, so that the expected value of the additive shift in RB, SF, and ES subscores 
combined is delta. The same variables used in Step 1 will be used in the MNAR model. The 
tipping point analysis sample code is specified in Appendix 3. After the shift, if any assessments 
have values less than 0, the value will be set to 0. Similarly, if any assessments have values 
greater than 3, the value will be set to 3. MMS will then be rederived for each of the 40 imputed 
datasets, using the shifted values. Next, classify subjects as a responder or nonresponder at Week 
12 based on the criteria specified in Study APD334-302 Protocol Section 10.5. For each dataset, 
the proportion of responders and nonresponders will be calculated.  
Step 3: 
Same as Step 3 described in Section 16.1.4.1.  
Step 4: 
Same as Step 4 described in Section 16.1.4.1.  
Note: Imputations with delta adjustment will be performed with progressively increasing delta 
values until a tipping point is reached based on the significance of the CMH test. A tipping point 
will correspond to the smallest value of delta for which the primary hypothesis is no longer 
rejected. The shift parameter (delta) for the etrasimod treatment group will take increasing values 
from 0 with increments of 1 (maximum MMS of 9) at the MMS level, representing adjustments 
towards worse outcomes (ie, after dropout, on average, subjects on treatment will have MMS 
worsen). For the placebo arm, delta adjustments will decrease with increments of 1, representing 
adjustments in the direction of better outcomes. The adjustments in each treatment group will be 
continued until the CMH test for the primary hypotheses are no longer significant at the 2-sided 


 
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α level, 0.05. The corresponding shift parameters in both treatment groups at the tipping point 
will be reported along with the proportions and p-values from each CMH test.  
Results will be plotted as a heat map on a two-dimensional plot with axes corresponding to the 
delta values used in each treatment group respectively, and different colors will be used to 
represent the magnitude of the 2-sided p-values corresponding to analysis with each combination 
of delta values.  The clinical interpretation about the plausibility of the assumptions underlying 
the tipping point will be provided in the CSR.  
16.1.4.3. Multiple Imputation with Copy Reference  
Missing data will also be explored assuming an MNAR approach. MNAR assumes the missing 
values depend on unobserved outcomes even after accounting for the observed data. Therefore, 
subjects cannot be modelled based on subjects with observed data, and more assumptions are 
needed. Copy reference is a type of MNAR approach where each missing value for subjects in 
the treatment group will be imputed using observed data in the placebo group, and missing 
values for subjects in the placebo group will be imputed under the MAR approach.  
The following steps will be implemented: 
Step 1: 
Step 1 (a): 
Intermittent missing data (before discontinuation from study) at each scheduled visit will be 
imputed, separately for each treatment group, under the MAR assumption using a multivariate 
normal imputation model and the Markov Chain Monte Carlo (MCMC) method with multiple 
chains. The number of imputations will be 40. The resulting data will have a monotone missing 
data pattern. The imputed data will be used together with observed data to impute 
postdiscontinuation missing values. 
Step 1 (b): 
Only after Step 1 (a) is completed, the remaining monotone missing data after discontinuation 
will be imputed using the FCS predictive mean matching method based on data from the placebo 
group only. The RB, SF, ES, and PGA subscores, stratification variables, a binary variable 
indicating if a subject is a treatment failure, and biomarker measurements (ALC, FCP, hs-CRP, 
log-transformed) at each planned visit will be included in the imputation model. 
Step 2: 
Same as Step 2 described in Section 16.1.4.1. 
Step 3: 
Same as Step 3 described in Section 16.1.4.1. 
Step 4: 
Same as Step 4 described in Section 16.1.4.1. 


 
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16.1.4.4. Multiple Imputation with NRI to Handle Missing Data Due to COVID-19 
Pandemic  
The COVID-19 pandemic introduces unexpected and unknown impact on the clinical study due 
to unforeseen intercurrent events. As a sensitivity analysis, missing endoscopy data will be 
handled using a hybrid approach combining NRI and multiple imputation, where subjects with 
missing endoscopy data due to COVID-19 pandemic impact will be imputed using multiple 
imputation method under a MAR assumption, as described in Section 16.1.4.1. Missing data for 
any other reason will be considered a nonresponse. 
16.1.5. 
Supplementary Analysis of Primary Efficacy Variable  
The primary model as described in Section 16.1.3 will be repeated using the mFAS (with data as 
observed) and Per Protocol Set as supplementary analyses in subjects with Baseline MMS 5 to 9.  
Analysis with the primary model as described in Section 16.1.3 will be repeated for the primary 
endpoint using the FAS with Baseline MMS 4 to 9. The multiple imputations, tipping point 
analysis, mFAS and Per Protocol Set analyses will also be repeated for all subjects in the 
analysis set with Baseline MMS 4 to 9. 
16.2. 
Key Secondary Efficacy  
Key secondary efficacy endpoints are defined in Section 16. In general, all the primary and 
supplementary analyses planned for the primary endpoints in Sections 16.1.3 and 16.1.5 will be 
repeated for each key secondary efficacy endpoint (Table 3). Additionally, the sensitivity 
analyses planned for the primary endpoints in Section 16.1.4 will be repeated for key secondary 
endpoints of endoscopic improvements and symptomatic remission (Table 3). Multiplicity 
adjustments for the family of the key secondary endpoints are discussed in Section 8.4. 
Table 3: 
Planned Analyses by Endpoint  
Endpoint 
Primary 
Analysis of 
Stratified CMH 
Sensitivity Analyses of MI, 
Tipping Point Analysis, MI with 
CR, and NRI + MI 
Supplementary 
Analyses in mFAS 
and Per Protocol Set 
Primary endpoints 
Xa   
X 
X 
Key secondary endpoints 
  Endoscopic improvement 
X 
X 
X 
  Symptomatic remission 
X 
X (MI, Tipping Point Analysis, and 
MI with CR only)b 
X 
  Mucosal healing 
X 
X (MI, MI-CR, and NRI+MI only) 
X 
a Inference from the primary analysis method on the primary endpoints will be the gatekeeper for testing in the 
family of key secondary endpoints as per Section 8.4.  
b The hybrid missing data handling approach of NRI + MI will not be applied to the symptomatic remission endpoint 
since COVID-19 pandemic is not expected to impact subject eDiary entries. 
Analyses in the table will be repeated for subjects in the specified analysis population with Baseline MMS 4 to 9.  
CMH, Cochran-Mantel-Haenszel; CR, copy reference; mFAS, modified Full Analysis Set; MI, multiple imputation; 
NRI, nonresponder imputation.  
 


 
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16.2.1. 
Key Secondary Efficacy Variables and Derivations  
16.2.1.1. Endoscopic Improvement at Week 12  
The null hypothesis is that the proportion of subjects achieving endoscopic improvement at 
Week 12 is the same between etrasimod and placebo.  
The alternative hypothesis is that the proportion of subjects achieving endoscopic improvement 
at Week 12 is different between etrasimod and placebo.  
16.2.1.2. Symptomatic Remission at Week 12  
The null hypothesis is that the proportion of subjects achieving symptomatic remission at Week 
12 is the same between etrasimod and placebo.  
The alternative hypothesis is that the proportion of subjects achieving symptomatic remission at 
Week 12 is different between etrasimod and placebo. 
16.2.1.3. Mucosal Healing at Week 12  
The null hypothesis is that the proportion of subjects with mucosal healing at Week 12 is the 
same between etrasimod and placebo.  
The alternative hypothesis is that the proportion of subjects with mucosal healing at Week 12 is 
different between etrasimod and placebo. 
16.2.2. 
Missing Data Methods for Key Secondary Efficacy Variables  
The same missing data methods used for the primary endpoint described in Section 16.1.2 will 
be used for the key secondary endpoints.  
16.2.3. 
Primary Analysis of Key Secondary Efficacy Variables  
The primary analysis of these key secondary efficacy endpoints will be performed for the FAS 
with Baseline MMS 5 to 9. For all key secondary endpoints, the same model that was described 
in Section 16.1.3 will be used.  
16.2.4. 
Sensitivity Analysis of Key Secondary Efficacy Variables  
For all key secondary endpoints, the same sensitivity analyses that were described in 
Section 16.1.4 will be used, except that the tipping point analysis will not be performed for 
mucosal healing.  
16.2.5. 
Supplementary Analysis of Key Secondary Efficacy Variables  
For all key secondary endpoints, the primary model as described in Section 16.1.3 will be 
repeated using the mFAS (with data as observed) and Per Protocol Set with Baseline MMS 5 to 9 
as supplementary analyses. 
For the key secondary endpoints, analyses listed in Table 3 will be repeated in subjects with 
Baseline MMS 4 to 9.  


 
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16.3. 
Other Secondary Efficacy  
Other secondary efficacy endpoints are defined in Section 16.  
16.3.1. 
Other Secondary Efficacy Variables  
The other secondary endpoints are: 
• The proportion of subjects achieving clinical response at Week 12 
• The proportion of subjects achieving endoscopic normalization at Week 12 
• The proportion of subjects achieving symptomatic remission at Weeks 2, 4, 8 
• The proportion of subjects achieving complete symptomatic remission at each study 
visit (Weeks 2, 4, 8, 12) 
• The proportion of subjects achieving noninvasive clinical response at each study visit 
(Weeks 2, 4, 8, 12) 
• The proportion of subjects achieving symptomatic response at each study visit 
(Weeks 2, 4, 8, 12) 
16.3.2. 
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. 
16.3.3. 
Analysis of Other Secondary Efficacy Variables  
The analysis of other secondary efficacy endpoints will be performed for the FAS with Baseline 
MMS 5 to 9. The primary analysis method planned for the primary endpoints in Section 16.1.3 
will be repeated for each other secondary efficacy endpoint. No multiplicity adjustment will be 
made. 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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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 Baseline and Week 12. The HRQoL analyses 
will be performed using the mFAS with Baseline MMS 5 to 9 and data as observed.  
All HRQoL endpoints will be analyzed using an MMRM for the change from Baseline, with 
factors for naïve to biologic or JAK inhibitor therapy at study entry (Yes or No), Baseline 
corticosteroid use (Yes or No), Baseline disease activity (MMS: 4 to 6 or 7 to 9), treatment, visit, 
treatment by visit interaction, a covariate of the corresponding HRQoL Baseline value, and a 
random subject effect. Reported randomization stratum will be used in the model. Unstructured 
covariance will be used. If there is a convergence issue in fitting the unstructured covariance, a 
compound symmetry covariance structure will be used.  
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 same stratified CMH model as described in Section 16.1.3 for the FAS 
with Baseline MMS 5 to 9. 
17.1. 
Variables And Derivations  
17.1.1. 
Inflammatory Bowel Disease Questionnaire  
The Inflammatory Bowel Disease Questionnaire (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 are derived on the eCRF directly. Details about 
scoring rules can be found in Appendix 4. 
17.1.2. 
Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms  
The Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms (UC-PRO/SS) is a 
9-item daily diary designed to quantify the effects of treatment on patient-reported signs and 
symptoms of UC. Two separate weekly average scores will be calculated, one for bowel signs 
and symptoms score (6 items), and the other for functional symptoms (3 items). The higher the 
score, the worse the symptoms. The UC-PRO/SS scores and change from Baseline at Week 12 
will be evaluated. Details about scoring rules can be found in Appendix 7. 
17.1.3. 
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 


 
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item. The SF-36 will be scored using 2 overall summary scores: physical component summary 
and mental component summary 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 to 100 based), and the SF-6D health utility index score are 
derived by Optum and integrated into the SF-36 eCRF. Details about scoring rules and 
derivations of domain/component scores can be found in Appendix 5.   
17.1.4. 
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 6.  
17.1.5. 
Urgency Numeric Rating Scale  
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).  
17.1.6. 
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).  
17.1.7. 
UC-Related Hospitalizations and Surgeries  
The UC-related hospitalizations are captured on the Adverse Events 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. 
17.2. 
Missing Data Methods  
No missing data will be imputed for HRQoL endpoints. 
18. 
SAFETY OUTCOMES  
All outputs for safety outcomes will be based on the Safety Set. There will be no statistical 
comparisons between the treatment groups for safety data, unless otherwise specified.  
18.1. 
Adverse Events  
AEs will be coded using MedDRA (v24.1). 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.  


 
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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. This summary table and all other TEAE 
summaries by SOC and PT will be 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 eCRF, 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 to the onset of first such 
event for those who experienced this AE, or time (year) from first dose 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, v5.0 (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 treatment of “probably related” or 
“related”.  
All TEAEs will be summarized by SOC, PT, and highest relationship (as reported on the eCRF, 
not grouped), with SOC and PT presented by descending frequency. If a subject reports a TEAE 
more than once within a SOC/PT, the AE with the worst-case relationship to study treatment will 
be used in this summary. TEAEs with a missing relationship to study treatment will be regarded 
as “Related” to study treatment for summary tabulation purpose only.  
18.1.2. 
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. 
Time to study treatment discontinuation due to liver-related AE will be summarized for the 
Safety Set for subjects who had such an event reported during the study. Descriptive statistics, 


 
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Kaplan-Meier estimate of 25th, 50th, and 75th percentile time to event, 95% CIs, and p-value 
from the log-rank test will be displayed. If a subject did not have the event, they will be censored 
at the date of last dose. If the date of last dose is missing, the date of last study visit up to 
Week 12 will be used. If no event is ever observed, then summary will not be generated. 
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 
eCRF.  
All serious TEAEs will be summarized by SOC and PT. If the seriousness is missing, the AE 
will be considered as “Serious” for summary tabulation purpose only. A serious TEAE listing 
will also be presented. All non-serious TEAEs will 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. All TEAEs leading to death will be listed. 
Time to death due to liver-related AE will be summarized for the Safety Set for subjects who had 
such an event reported during the study. Descriptive statistics, Kaplan-Meier estimate of 25th, 
50th, and 75th percentile time to event, 95% CIs, and p-value from the log-rank test will be 
displayed. If a subject did not have the event, they will be censored at the date of last dose. If the 
date of last dose is missing, the date of last study visit up to Week 12 will be used. If no event is 
ever observed, then summary will not be generated. 
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 
following: 
• Cardiovascular Events 
− Bradycardia 
− AV conduction delay 


 
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− 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 
For each category, subcategory and PT, model-based analysis will be performed to compare 
treatment effect between etrasimod and placebo. An extended Cox regression model will be used 
to handle recurring AEs (Cao 2011). The stratification variables, naïve to biologic or JAK 
inhibitor therapy status at study entry (Yes or No), Baseline corticosteroid use (Yes or No), and 
Baseline disease activity (MMS: 4 to 6 or 7 to 9), will be included in the model. A subject with K 
events contributes (K+1) observations to the input data set; here K might be 0. The k-th 
observation of the subject identifies the time interval from the start date of the (k-1)-th event, or 
time 0 (if k = 1), to the start date of the k th event, k = 1,..., K. The (K+1)-th observation 
represents the time interval from the K-th event to the date of censorship, ie, the date of last dose 
or date of last study visit up to Week 12, whichever is later. Hazard ratios, 95% CIs, and p-values 
for treatment effect comparison will be presented. 
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 frequency of subjects and by number of AEs: 
• Any TEAEs 
• Any related TEAEs* 
• Any serious TEAEs 
• Any related serious TEAEs* 


 
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• TEAEs leading to death 
− Liver-related TEAEs leading to death 
• TEAEs leading to study treatment discontinuation 
− Related TEAEs leading to study treatment discontinuation* 
− Liver-related TEAEs leading to study treatment discontinuation 
• TEAEs leading to study treatment interruption 
− Related TEAEs leading to study treatment interruption* 
• TEAEs by maximum severity 
• Related TEAEs by maximum severity* 
• TEAEs by relationship to study treatment 
* “Related TEAEs” refers to TEAEs related or probably related to study treatment or are missing 
relationship. 
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 
Risk difference between etrasimod and placebo and the 95% CI using the Wilson’s score method 
will be presented.   
18.2. 
Deaths  
Information collected about deaths (eg, 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 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 


 
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performing laboratory (eg, low, high). A full list of laboratory assessments to be included in the 
outputs is included in Clinical Study Protocol APD334-302 Table 6.  
In general, presentations will use SI units. Quantitative laboratory measurements reported as 
“< X” or “> X”, where X may be the lower limit of quantitation (LLQ) or the upper limit of 
quantitation (ULQ), respectively, will be converted to X for the purpose of quantitative 
summaries, but will be presented as recorded, ie, as “< X” or “> X” in the listings. For urinalysis, 
only pH and specific gravity are considered as quantitative tests. If local and central laboratory 
assessments are available from the same day, central laboratory assessments will be used in the 
summary as per Section 6.4.  
The following summaries will be provided for laboratory data: 
• Value and change from Baseline by visit (for hematology, 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 × 109/L, 0.5 × 109/L, or neutrophils < 0.5 × 109/L, 
1 × 109/L at end of treatment and anytime in the study  
• Shift from end of treatment to each follow-up 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 Follow-Up) 
• Shift from Baseline to end of treatment 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 × 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  


 
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− > 3 × ULN elevation in either ALT or AST and > 2 × ULN elevation in total 
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, or ALP assessment occurs at 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 ULN, and the other one showing values as multiples of 
ULN, or subject’s baseline, whichever is higher.  
Only laboratory tests completed by 50 or more subjects in Safety Set will be presented in the 
summaries. All laboratory tests will be listed.   
Subject’s laboratory assessments at all timepoints will be listed in chronological order. Values 
outside of the laboratory reference range will be flagged. Values obtained from local laboratory 
will be flagged. Listing of lymphocytes and neutrophils over time in subjects who ever had 
lymphocytes < 0.5 × 109/L or neutrophils < 1 × 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 
 
data based on samples collected at Screening in subjects who provided consent will 
be described in a separate plan. 
18.4. 
ECG Evaluations  
ECG are recorded on a 12-lead ECG machine and read centrally. The following ECG parameters 
will be reported for this study: 
• HR (bpm) 
• PR interval (ms) 
• RR interval (ms) 
• QRS interval (ms) 
• QT interval (ms) 


 
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• QTcF interval (ms)  
• Overall interpretation of ECG (Investigator’s judgment): 
− Normal 
− Abnormal, Not Clinically Significant (Abnormal NCS) 
− Abnormal, Clinically Significant (Abnormal CS) 
• Overall interpretation of ECG (central reader): 
− Normal 
− Abnormal NCS 
− Abnormal CS 
• AV conduction abnormalities 
− First-degree AV block 
− Second-degree AV block type 1 
− Second-degree AV block type 2  
− 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 end of treatment and to the worst-case post-Baseline 
• 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 
following predefined markedly abnormal criteria: 
• Absolute values in QT and QTcF: 
− ≥ 450 ms (male) or ≥ 470 ms (female) in QTcF 
− > 500 ms in QT 
• Change from Baseline in QT and QTcF: 


 
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− > 30 ms increase from Baseline 
− > 60 ms increase from Baseline 
In shift tables, subjects will be classified according to the binary category for each parameter and 
the predefined markedly abnormal criterion (ie, Markedly abnormal versus Not markedly 
abnormal, with Markedly abnormal defined in the footnote). 
18.5. 
Vital Signs  
The following vital signs measurements will be reported for this study: 
• Systolic Blood Pressure (mm Hg) 
• Diastolic Blood Pressure (mm Hg) 
• Heart Rate (bpm) 
• Respiratory Rate (resp/min) 
• Temperature (°C) 
• Weight (kg) 
• Height (cm) (Screening only) 
The following summaries will be provided for vital signs data: 
• Value and change from Baseline by visit  
• Value and change from predose on Day 1 (as reported on the eCRF) by timepoint  
− 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 
• Listing of subjects meeting markedly abnormal criteria  
• Incidence of minimum heart rate on Day 1 by postdose timepoint (1, 2, 3, 4, and 
> 4 hours postdose, and Day 1 overall) and heart rate interval (≥ 65, 60 to 64, 55 to 
59, 50 to 54, 45 to 49, 40 to 44, < 40 bpm)  
− If minimum heart rate is attained at multiple postdose timepoints, only the earliest 
timepoint will be counted in this incidence summary. 
• Time to minimum heart rate on Day 1 by planned hourly timepoint (if minimum heart 
rate is attained at multiple postdose timepoints, only the earliest timepoint will be 
counted).  
− Actual time elapsed from first dose to minimum heart rate on Day 1 will also be 
summarized using descriptive statistics (n, mean, SD, median, minimum, and 
maximum) in the same table. 
• Line plots for mean value and mean change from predose on Day 1, up to 4 hours 
postdose by parameter and timepoint (systolic blood pressure, diastolic blood 
pressure, and heart rate) 


 
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• 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 
mm Hg 
≤ 90 mmHg  
 > 150 mmHg 
DBP 
mm Hg 
≤ 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.  
18.6. 
Physical Examination  
A listing of all physical examination assessments in subjects who had at least 1 abnormal 
physical examination finding will be provided.   
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 


 
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• 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 18.7.1.1) 
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 and Potentially Important 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  
The following summaries will be provided for ophthalmoscopy and optical coherence 
tomography (OCT) data: 
• Values and change from Baseline in central foveal thickness and intraocular pressure 
by visit 
• Categorical result in ophthalmoscopy with OCT parameters by visit (the categories 
are listed on the eCRF) 
Only PFT and OCT assessments completed by 50 or more subjects in the 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 tuberculosis results and chest X-rays will be listed. Results of tuberculosis 
questionnaires will also be listed. 


 
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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 with Baseline MMS 5 to 
9. Additionally, percent change from Baseline in lymphocyte counts will also be summarized. 
Change from Baseline in these biomarkers will also be analyzed using an MMRM, with factors 
for naïve to biologic or JAK inhibitor therapy at study entry (Yes or No), Baseline corticosteroid 
use (Yes or No), Baseline disease activity (MMS: 4 to 6 or 7 to 9), treatment, visit, treatment by 
visit interaction, a covariate of the corresponding Baseline value, and a random subject effect. 
Reported randomization stratum will be used in the model. Unstructured covariance will be used. 
If there is a convergence issue in fitting the unstructured covariance, a compound symmetry 
covariance structure will be used. The same model will be fit to the percent change from 
Baseline in lymphocytes. LS means, SEs, CIs, and p-values by visit will be reported. 
Additionally, the following summaries will be provided for biomarker data: 
• Line plots over time for LS mean and SE for the following laboratory assessments: 
− Change from Baseline in lymphocytes 
− Percent change from Baseline in lymphocytes 
− Change from Baseline in hs-CRP 
− 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  
Plasma concentrations of etrasimod, and if warranted M3 (AR503641) and M6 (AR504344), will 
be assessed from PK samples collected prior to dosing and 4 hours (±15 minutes) postdose (after 
12-lead ECG) on Week 0/Day 1, for PK samples collected prior to dosing (trough) at Weeks 2, 4, 
8, 12, and for PK samples collected at the 2-Week and 4-Week Follow-Up visits for subjects not 
enrolled into any extension study. 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, 
vomiting within 4 hours after etrasimod dose administration on Week 0/Day 1 or on the day prior 
to trough sample collection, sample processing errors that lead to inaccurate bioanalytical results, 
and/or inaccurate dosing prior to PK sampling.  In the case of an important protocol deviation or 
event, the affected PK data collected may be excluded from the summaries, calculation of the 
average steady-state trough plasma concentration (Ctrough) based on Week 2 to Week 12 trough 
concentrations (Ctrough,ss,W2-W12), exposure-response analysis, and/or population PK analysis, but 
will still be reported in the study result listings.   


 
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Unless otherwise specified, PK summaries will use the Pharmacokinetic Set. Exposure-response 
analysis will use the Safety Set. 
Individual subject etrasimod plasma concentrations (and etrasimod metabolite concentrations, if 
applicable) will be presented in the data listings, including subject ID, treatment received, sex, 
age, weight, nominal timepoint, actual blood collection date/time, concentration, and time since 
last dose and also summarized using descriptive statistics (n, mean, standard deviation [SD], 
% CV, geometric mean, geometric % CV, median, minimum, and maximum) by nominal 
timepoint. 
All subjects are expected to achieve steady-state plasma concentration by Week 2. For each 
subject, the average steady state trough (predose) plasma concentration based on Week 2 to 
Week 12 trough concentrations (Ctrough,ss,W2-W12) per subject will also be calculated and presented 
in a data listing and summarized using descriptive statistics. 
Mean (±SD) etrasimod concentration versus nominal time (Weeks 0 to 12) will be plotted on 
linear scale. Additionally, a mean (±SD) concentration-time plot with etrasimod and metabolites 
overlaid on linear scale will be generated. 
Box plots of etrasimod, M3, and M6 concentrations at Day 1, 4 hour postdose timepoint (C4h), 
steady-state Ctrough (Weeks 2 through 12), and Ctrough,ss,W2-W12 will be plotted versus nominal 
timepoint on ordinal scale.  
Individual subject plasma concentrations versus actual time (Weeks 0 to 12) will be plotted since 
start of treatment on linear and semi-log scale. Individual subject plots with etrasimod and 
metabolite concentration data will be overlaid on the same plot. 
Scatter plots of individual subject Ctrough,ss,W2–W12 versus Baseline body weight and versus 
Baseline age (age at consent) as continuous variables will be generated for the Pharmacokinetic 
Set, which will also include the Spearman's rank correlation coefficient, locally estimated 
scatterplot smoothing (LOESS) trend line, and p-value. 
To explore potential etrasimod plasma exposure-response relationships, the following scatter 
plots will be generated for the Safety Set, including data from placebo subjects (plotted at ‘zero’ 
concentration). Any contributing data from the placebo subjects will be annotated with a 
different color or symbol. All scatter plots will include the Spearman's rank correlation 
coefficient, (LOESS) trend line, and p-value (based on subjects that received active treatment 
only). 
• Individual subject absolute change from Baseline in MMS versus etrasimod steady-state 
Ctrough at Week 12  
• Individual subject lymphocytes versus etrasimod steady-state Ctrough at Week 12 and 
grouped all visits (Weeks 2 through 12 pooled) 
• Individual subject absolute changes from Baseline in lymphocytes versus etrasimod 
steady-state Ctrough at Week 12 and grouped all visits (Week 2 and Week 12 pooled) 
• Individual subject percent changes from Baseline in lymphocytes versus etrasimod 
steady-state Ctrough at Week 12 and grouped all visits (Week 2 and Week 12 pooled)   
• Individual subject heart rate versus etrasimod concentration at matching visit/timepoint: 
for Week 0/Day 1; the 4-hour postdose vital results will be presented on the left panel and 


 
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safety ECG on the right panel. 
• Individual subject absolute changes from Day 1 Predose in heart rate versus etrasimod 
concentration at matching visit/timepoint for Week 0/Day 1; the 4-hour postdose vital 
results will be presented on the left panel and safety ECG on the right panel. 
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 0 through 12) 
• Mean (SD) absolute change from Baseline in lymphocytes and mean (SD) etrasimod 
concentration versus nominal timepoint (Weeks 0 through 12) 
• Mean (SD) percent change from Baseline in lymphocytes and mean (SD) etrasimod 
concentration versus nominal timepoint (Weeks 0 through 12) 
• Mean (SD) heart rate and mean (SD) etrasimod concentration versus nominal timepoint 
(Weeks 0 through 12) 
• Mean (SD) absolute change from Baseline in heart rate and mean (SD) etrasimod 
concentration versus nominal timepoint (Weeks 0 through 12) 
All summary figures for etrasimod plasma concentrations and for change from Baseline in MMS 
versus etrasimod steady state Ctrough: 
• Sex (Male or Female) 
• Weight (≤ Median or > Median) 
• Age group (< 18, 18 to < 65, or ≥ 65 years) 
• Tobacco use (Yes or No) 
The plasma concentrations over time will be used in a population PK analysis, which will be 
described in a separate plan. 
21. 
DATA NOT SUMMARIZED OR PRESENTED  
The other variables and/or domains not summarized are: 
• Comments 
These domains and/or variables will not be summarized but will be available in the clinical study 
database and Study Data Tabulation Model (SDTM) datasets. 


 
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REFERENCES  
Cao D, He X. Statistical analysis of adverse events in randomized clinical trials using SAS. Cao 
D, He X. Statistical analysis of adverse events in randomized clinical trials using SAS. 
PharmaSUG Conference Proceedings; 2011.  
FDA. Multiple endpoints in clinical trials. U.S. Department of Health and Human Services, Food 
and Drug Administration. Guidance for Industry Web site. 
https://www.fda.gov/media/102657/download. Published 2017. Accessed February 19, 2021. 
FDA. FDA guidance on conduct of clinical trials of medical products during COVID-19 public 
health emergency. U.S. Department of Health and Human Services, Food and Drug 
Administration. Guidance for Industry, Investigators, and Institutional Review Boards Web site. 
https://www.fda.gov/media/136238/download. Published 2020. Accessed July 8, 2020. 
ICH. Structure and content of clinical study reports, E3. International Conference on 
Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. 
https://database.ich.org/sites/default/files/E3_Guideline.pdf. Published 1995. Accessed March 
10, 2021. 
ICH. Statistical principles for clinical trials, E9. International Council for Harmonisation of 
Technical Requirements for Registration of Pharmaceuticals for Human Use. 
https://database.ich.org/sites/default/files/E9_Guideline.pdf. Published 1998. Accessed March 
19, 2021. 
ICH. Structure and content of clinical study reports questions & answers (R1). 
https://database.ich.org/sites/default/files/E3_Q%26As_R1_Q%26As.pdf. Published 2012. 
Accessed Dec 14, 2021. 
ICH. Addendum on estimands and sensitivity analysis in clinical trials to the guideline on 
statistical principles for clinical trials, E9(R1). 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. Published 
2019. Accessed March 19, 2021. 
Rubin DB. Multiple imputation for nonresponse in surveys. New York, NY: John Wiley and 
Sons; 1987. On file at Arena. 
 
 
 


 
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APPENDICES  
APPENDIX 1: 
PROGRAMMING CONVENTIONS FOR OUTPUTS  
OUTPUT CONVENTIONS 
Outputs will be presented as shown in the Output shells. 
DECIMALS, PERCENTAGES, AND P-VALUES 
• If the original data has N decimal places, then the summary statistics should have the 
following decimal places: 
− Minimum and maximum: N 
− Mean (and LS Means), median: N + 1 
− SD or SE: N + 2 
• Percentages will be reported to one decimal place. Where counts are zero, 
percentages will not appear in the output.  
• P-values will be reported to three decimal places, except values < 1.000 but > 0.999 
will be presented as ‘> 0.999’ (eg, 0.9998 is presented as > 0.999); and 
• Values < 0.001 will be presented as ‘< 0.001’ (eg, 0.0009 is presented as < 0.001). 
Rounding will be applied after the < 0.001 and > 0.999 rule. 
CONVENTIONS RELATED TO PHARMACOKINETIC DATA 
All etrasimod concentrations will be reported and analyzed with the same precision as the source 
data provided by the bio-analytical laboratory regardless of how many significant figures or 
decimals the data carry. The derived PK data (etrasimod concentration) will be rounded to carry 
3 significant digits and considered the source data for the calculation of descriptive statistics and 
the statistical analysis. source data. 
For the reporting of descriptive statistics, the mean, geometric mean, median, SD, % CV, and % 
geometric CV will be presented with 4 significant digits. The minimum and maximum will be 
presented with 3 significant digits. 
DATES AND TIMES 
Depending on data available, dates and times will take the form DDMMMYYYY or 
DDMMMYYYY:hh:mm. 
SPELLING FORMAT 
English US. 
 
 


 
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PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in that order: 
Treatment Group 
For Tables, Graphs and Listings 
Etrasimod 
Etrasimod 
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 treatment. 
PRESENTATION OF VISITS AND STUDY PERIOD 
For outputs, visits and study periods will be represented as follows and in that order: 
Visit Name 
Study Period  
Screening 
Screening 
Baseline, Day 1, Day 2, Week 2, Week 4, 
Week 8, Week 12 
Treatment 
End of Study/Early Termination 
Dependent on Analysis Visit assigned, described in Section 6.4 
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 is a safety output), first by 
Etrasimod, then Placebo, then Screen Failure and then No Treatment (only in safety 
listings if there are any randomized subjects who did not receive study treatment) 
• Subject number (which is expected to incorporate study site/center) 
• Date (where applicable) 


 
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APPENDIX 2: 
PARTIAL DATE CONVENTIONS  
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
AE Start Date 
AE Stop 
Date 
Action 
Known 
Known, 
Partial or 
Missing 
If AE start date < study treatment first dose date, then not TEAE 
If AE start date ≥ study treatment first dose date, then TEAE 
Partial, but known 
components show that 
it cannot be on or after 
date of first dose of 
study treatment 
Known, 
Partial or 
Missing 
Not TEAE 
Partial, could be on or 
after date of first dose 
of study treatment 
Known 
If AE stop date < study treatment first dose date, then not TEAE 
If AE stop date ≥ study treatment first dose date, then TEAE 
Partial 
Impute AE 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 AE stop date < study treatment first dose date, then not TEAE 
If AE stop date ≥ study treatment first dose date, then TEAE 
Missing 
Assumed TEAE 
Missing 
Known 
If AE stop date < study treatment first dose date, then not TEAE 
If AE stop date ≥ study treatment first dose date, then TEAE 
Partial 
Impute AE 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 AE stop date < study treatment first dose date, then not TEAE 
If AE stop date ≥ study treatment first dose date, then TEAE 
Missing 
Assumed TEAE 
 
 


 
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ALGORITHM FOR PRIOR AND CONCOMITANT MEDICATIONS: 
Start Date 
Stop Date 
Action 
Known 
Known 
If medication stop date < study treatment first dose date, assign as prior  
If medication stop date ≥ study treatment first dose date, 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 treatment first dose date, assign as prior 
If medication stop date ≥ study treatment first dose date, assign as 
concomitant 
Missing 
If medication stop date is missing could never be assumed a prior 
medication, assign as concomitant 
Partial 
Known 
Impute start date as earliest possible date (ie, first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If medication stop date < study treatment first dose date, assign as prior 
If medication stop date ≥ study treatment first dose date, 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 treatment first dose date, assign as prior 
If medication stop date ≥ study treatment first dose date, 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 treatment first dose date, assign as prior 
Else 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 treatment first dose date, assign as prior 
If medication stop date ≥ study treatment first dose date, assign as 
concomitant 
Missing 
Assign as concomitant 


 
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ALGORITHM FOR STARTING DATE OF HOSPITALIZATION AND START/STOP 
DATES OF CONCOMITANT MEDICATIONS: 
Start Date 
Stop Date 
Action 
Partial 
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). Impute stop date to latest possible date 
(ie, last day of month if day unknown or 31st December if day and month are 
unknown). 
No partial stop date imputation for hospitalization. 
Missing 
Missing 
Impute start date as informed consent date. Impute stop date as last visit date when 
the concomitant medication timepoint is not ongoing. 
No missing stop date imputation for hospitalization. 
 
 


 
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APPENDIX 4: 
IBDQ SCORING RULES  
The Inflammatory Bowel Disease Questionnaire (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 5: 
SF-36 SCORING RULES  
The Medical Outcomes Study 36 Item Short Form Health Survey (SF-36) is a 36-item 
self-administered questionnaire which has 8 scales: Physical functioning (10 items), role 
limitations due to physical problems (4 items), role limitations due to emotional problems (3 
items), vitality (4 items), mental health (5 items), social function (2 items), bodily pain (2 items), 
and general health perceptions (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 to 12 
• Role limitations due to physical problems: Questions 13 to 16 
• Role limitations due to emotional problems: Questions 17 to 19 
• Vitality: Questions 23, 27, 29, 31 
• Mental health: Questions 24 to 26, 28, 30 
• Social function: Questions 20, 32 
• Bodily pain: Questions, 21, 22 
• General health perceptions: Questions 1, 33 to 36 
 
 


 
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APPENDIX 6: 
WPAI-UC SCORING RULES  
The Work Productivity and Activity Impairment Questionnaire – Ulcerative Colitis (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 7: 
UC-PRO/SS SCORING RULES  
The Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms (UC-PRO/SS) is a 
9-item daily diary, designed for electronic administration. Patients/respondents are instructed to 
complete the diary each evening, reflecting back on their experiences “during the past 24 hours.” 
Daily administration is essential in order to capture change in the patient’s condition consistent 
with symptom variability. The UC-PRO/SS takes approximately three minutes to complete. 
The UC-PRO/SS yields two separate weekly average scores: Bowel signs and symptoms 
(6 items) and functional symptoms (3 items). There is no single total score. The weekly scores 
can be used alone or as part of a profile. 
Questions: 
1. In the past 24 hours, how many bowel movements did you have?  
 0=0  
 1=1-2  
 2=3-4  
 3=5-6  
 4=7-9  
 5=10-12  
 6=13-17  
 7=18 or more  
2. In the past 24 hours, how often were your bowel movements mostly or completely liquid?  
 0=Never  
 1=Rarely  
 2=Sometimes  
 3=Often  
 4=Always  
3. In the past 24 hours, did you have blood in your bowel movements?  
 0=No  
 1=Rarely  
 2=Sometimes  
 3=Often  
 4=Always  
4. In the past 24 hours, did you have mucus (white material) in your bowel movements?  
 0=No  
 1=Rarely  
 2=Sometimes  
 3=Often  
 4=Always  
5. In the past 24 hours, did stool, blood, or liquid leak out before you reached a toilet?  
 0=No  
 1=Rarely  


 
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 2=Sometimes  
 3=Often  
 4=Always  
6. In the past 24 hours, did you pass gas?  
 0=No  
 1=Rarely  
 2=Sometimes  
 3=Often  
 4=Very often  
7. In the past 24 hours, did you feel the need to have a bowel movement right away?  
 0=No  
 1=Mild  
 2=Moderate  
 3=Severe  
 4= Very Severe  
8. In the past 24 hours, did you feel pain in your belly?  
 0=No  
 1=Mild  
 2=Moderate  
 3=Severe  
 4=Very Severe  
9. In the past 24 hours, did you feel bloating in your belly?  
 0=No  
 1=Mild  
 2=Moderate  
 3=Severe  
 4=Very Severe  
Derivation: 
A daily score is the mean of responses to items for each scale: Bowel signs and symptoms 
(Questions 1-5 and 7), and functional symptoms (Questions 6, 8 and 9). A weekly average score 
for each scale is then calculated with no imputation using the mean of at least four out of the 
seven daily scores. If four or more days of data are missing for any week, the weekly average 
score for each scale is set to missing for that week. 


 
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APPENDIX 8: 
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.  
Biologics with immunomodulatory properties 
• Rule:  
o Any exposure after first dose 
• List of medications 
o Anti-TNFα antibodies:  
▪ ADALIMUMAB 
▪ CERTOLIZUMAB 
▪ CERTOLIZUMAB PEGOL 
▪ GOLIMUMAB 
▪ INFLIXIMAB 
o Other Biologics: 
▪ USTEKINUMAB 
▪ VEDOLIZUMAB 
Nonbiologics with immunomodulatory properties  
• Immunosuppressants 
o Rules: 
▪ 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 List of medications  
▪ MERCAPTOPURINE 
▪ AZATHIOPRINE 
▪ TIOGUANINE 
▪ METHOTREXATE 


 
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▪ METHOTREXATE SODIUM 
• 5-ASA compounds 
o Rules: 
▪ 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 List of medications  
▪ MESALAZINE 
▪ BALSALAZIDE 
▪ BALSALAZIDE DISODIUM DIHYDRATE 
▪ BALSALAZIDE SODIUM 
▪ OLSALAZINE SODIUM 
▪ SULFASALAZINE 
▪ BECLOMETASONE W/MESALAZINE 
o Routes 
▪ ORAL 
▪ RECTAL 
• Other small molecule immunomodulatory active agents  
o Rules:  
▪ 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 List of medications  
▪ CICLOSPORIN  
▪ TACROLIMUS 
▪ TOFACITINIB  
▪ TOFACITINIB CITRATE  
• Systemic glucocorticoids  
o Systemic glucocorticoids given via oral or rectal routes of administration  
▪ Rules:  
• 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 


 
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▪ 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 
▪ Routes 
• ORAL 
• RECTAL 
o Systemic glucocorticoids given via parenteral routes of administration  
▪ Rule:  
• Any exposure after first dose 
▪ 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 
• INTRAVENOUS 
• INTRAMUSCULAR 
• Topical Glucocorticoids 
o Rules  
▪ 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 List of medications  
▪ BUDESONIDE 
o Routes 
▪ ORAL 
▪ RECTAL 
• Beclomethasone 
o Rules 
▪ 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 List of medications  
▪ BECLOMETASONE 
▪ BECLOMETASONE DIPROPIONATE 


 
PROTOCOL APD334-302 
Statistical Analysis Plan 
Page 70 of 70 
 
 
▪ 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 - Final Version 1.0 - 19-Jan-2022
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