Conditions: Ulcerative Colitis
Keywords: Ulcerative Colitis Etrasimod APD334
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 433
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether oral etrasimod is a safe and effective treatment for moderately to severely active ulcerative colitis.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Etrasimod intervention 2: Placebo
Intervention descriptions: intervention 1: Etrasimod 2 mg tablet by mouth, once daily up to 52 weeks of treatment intervention 2: Etrasimod matching placebo tablet by mouth, once daily up to 52 weeks of treatment

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL  
Protocol number: 
APD334-301 
 
 
Protocol title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 52-Week 
Study to Assess the Efficacy and Safety of Etrasimod in Subjects with 
Moderately to Severely Active Ulcerative Colitis 
Brief title: 
ELEVATE UC 52: Etrasimod Versus Placebo for the Treatment of 
Moderately to Severely Active Ulcerative Colitis 
 
 
Study drug: 
Etrasimod (APD334) 
Indication: 
Ulcerative colitis 
Phase: 
3 
IND number: 
 
EudraCT number: 
2018-003985-15 
NCT number: 
03945188 
 
 
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 4.0, 22 December 2020 
Sponsor approval: 
This protocol was approved by the Sponsor’s Responsible Medical 
Officer or delegate. The electronic signature manifest is appended. 
Confidentiality Statement 
This document contains confidential information of Arena Pharmaceuticals, Inc. Unauthorized 
distribution, copying, or disclosure is strictly prohibited unless required by applicable law. Persons 
receiving this information must be notified that it is confidential and may not be further distributed, 
copied, or disclosed. 


Clinical Study Protocol 
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PROTOCOL HISTORY 
Document 
Amendment Type 
Date 
Amendment 4.0 
Global 
22 December 2020 
Amendment 3.1 
Region-Specific 
21 February 2020 
Amendment 3.0 
Global 
07 February 2020 
Amendment 2.1 
Region-specific 
21 February 2020 
Amendment 2.0 
Global 
20 December 2019 
Amendment 1.1 
Region-specific 
12 June 2019 
Amendment 1 
Global 
05 March 2019 
Original Protocol 
Not applicable 
19 December 2018 
 


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PROTOCOL SYNOPSIS  
Sponsor: Arena Pharmaceuticals, Inc. 
Name of investigational study drug: Etrasimod (APD334) 
Protocol number: APD334-301 
Protocol title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 52-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 on clinical remission in subjects 
with moderately to severely active ulcerative colitis (UC) after 12 and 52 weeks of treatment. 
Secondary: 
The secondary objective is to assess the efficacy of etrasimod on clinical response, 
symptomatic response and remission, endoscopic changes, corticosteroid-free remission, and 
mucosal healing in subjects with moderately to severely active UC at timepoints up to 
52 weeks of treatment. 
Safety: 
The safety objective is to assess the long-term safety of etrasimod after daily doses of 2 mg for 
up to 52 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 Treatment Period, a 40-Week 
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 näive 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). 


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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. 
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 up to 52 weeks (12-Week 
Treatment Period + 40-Week Treatment Period). 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). 
End of 12-Week Double-Blind Treatment Period 
At the end of the 12-Week Treatment Period, subjects will undergo the Week 12 efficacy and 
safety assessments and procedures. Subjects whose disease is stable or improving compared 
with baseline (Week 0/Day 1) will continue with their double-blind treatment and move into 
the 40-Week Treatment Period. 
Subjects must complete Week 12 to be eligible for the OLE. Subjects who do not meet disease 
worsening criteria, including those demonstrating clinical response/remission at Week 12 will 
continue into the 40-Week Treatment Period and continue their double-blind treatment. 
Disease worsening will continue to be monitored by Investigators through the 40-Week 
Treatment Period (ie, from Weeks 13 to 52). Subjects who either experience disease 
worsening in the 40-Week Treatment Period or complete all study procedures at Week 52 will 
have the option to enroll into the OLE study if they meet all eligibility criteria. 
Subjects may be eligible to enroll in the OLE provided their ES is ≥ 2 and they meet one of the 
following entry criteria: 
• RB subscore ≥ 2 at 2 timepoints at least 7 days and no more than 14 days apart 
• RB + SF subscores ≥ 4 at 2 timepoints at least 7 days and no more than 14 days apart 
• RB subscore ≥ 2 or RB + SF subscores ≥ 4 (in any order) at 2 timepoints at least 7 days 
and no more than 14 days apart 
For subjects discontinuing prior to Week 52, an endoscopic evaluation is required to confirm 
eligibility for the OLE. An endoscopy should be performed upon the appearance of UC 
symptoms but no more than 14 days after the second timepoint for symptom criteria above. 
A proctosigmoidoscopy does not need to be repeated if performed within the last 4 weeks. 
Subjects who do not participate in the OLE study will have 2-Week and 4-Week Follow-Up 
visits after their last treatment administration 
End of 40-Week Double-Blind Treatment Period (Week 52) 
At the end of the 40-Week Treatment Period (ie, Week 52) and following completion of all 
study procedures, subjects will have the option to enter into the OLE study (APD334-303) 
provided they meet all eligibility criteria. 
Subjects who do not participate in the OLE study will have 2-Week and 4-Week Follow-Up 
visits after their last treatment administration  
Number of subjects (planned): 
Approximately 420 subjects are planned to be enrolled into this study. 


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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. 
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) 


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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 (Note: 
Subjects on existing oral corticosteroid therapy will be tapered during the 40-Week 
Treatment Period.) 
• 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 
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 


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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 non-pregnant female of childbearing potential 
partner must agree to using condoms during treatment and for 30 days following 
treatment. 
Exclusion criteria: 
Subjects who meet any of the following exclusion criteria will not be eligible for enrollment 
into the study: 
Exclusions related to general health: 
1. Severe extensive colitis as evidenced by: 
• 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 
• 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 


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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 
• 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 


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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 
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 


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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 
Test product, formulation, mode of administration, and dose: 
Etrasimod, 2 mg tablets, by mouth, once daily 
Study duration: 
The overall duration of this study is expected to be approximately 2.5 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. 


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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 endpoints: 
• The proportion of subjects achieving clinical remission at Week 12 
• The proportion of subjects achieving clinical remission at Week 52 
Key secondary efficacy endpoints: 
• The proportion of subjects achieving endoscopic improvement at Week 52 
• The proportion of subjects achieving endoscopic improvement at Week 12 
• The proportion of subjects achieving symptomatic remission at Week 52 
• The proportion of subjects achieving symptomatic remission at Week 12 
• The proportion of subjects in clinical remission at Week 52 and who had not been 
receiving corticosteroids for ≥ 12 weeks prior to Week 52 
• The proportion of subjects with mucosal healing at Week 52 
• The proportion of subjects with mucosal healing at Week 12 
• The proportion of subjects achieving clinical remission at both Weeks 12 and 52 
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, 16, 20, 24, 32, 40, 
48, 52, and at the 2-Week and 4-Week Follow-Up visits. A PK sample should also be drawn, 
if possible, at the time of any 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, 12, 24, and 52 
• Change from baseline in level of high-sensitivity C-reactive protein at Weeks 2, 4, 8, 12, 
16, 20, 24, 32, 40, 48, and 52 
• Change and percentage change from baseline in lymphocyte counts at Weeks 2, 4, 8, 12, 
16, 20, 24, 32, 40, 48, and 52 


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Health-related quality of life endpoints: 
• Scores and change from baseline at Weeks 12 and 52 in 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) 
− 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 Fisher’s exact test, a 1-sided significance level of 0.025, and a 2:1 
randomization ratio, 420 total subjects (280 etrasimod, 140 placebo) are required to achieve 
93.4% power to detect a difference of 13.5% in the primary endpoint of clinical remission at 
Week 52 between the etrasimod treatment group (23.5%) and the placebo treatment group 
(10.0%). With this sample size, there will be 96% power to detect a difference of 12.5% in the 
other primary endpoint of clinical remission at Week 12, assuming a placebo rate at 6.0%. The 
lower bound of overall power for both primary endpoints (as coprimary endpoints) is at least 
90%; and since the two primary endpoints are expected to be at least moderately positively 
correlated, the actual overall power to reject both of their null hypotheses is likely to be greater 
than 90%. 
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. 


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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 both primary endpoints. This study will be considered as an overall success 
only if both primary null hypotheses are rejected, each at the α level (as coprimary 
hypotheses). This study will be considered as a partial success if only one of the two primary 
null hypotheses are rejected at α/2 if the other has p > α. 
Only if both of the primary null hypotheses are rejected, each at the α level, can testing 
proceed for the 8 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 8 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. 
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. 
Interim analysis 
The Sponsor may conduct an interim analysis for sample size re-estimation based on blinded 
(aggregate) data to assess the appropriateness of the assumptions used in the original sample 
size calculation. The planned sample size will not be reduced as a result of the sample size re-
estimation- to ensure sufficient exposure data for safety assessment. An interim SAP will 
provide detailed interim analysis specifications. The SAP charter will be finalized prior to any 
interim analysis and will be provided to regulatory agencies in a timely manner. This interim 
analysis will not be used to evaluate efficacy or safety. 
 


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TABLE OF CONTENTS 
CLINICAL STUDY PROTOCOL ..................................................................................................1 
PROTOCOL SYNOPSIS ................................................................................................................3 
TABLE OF CONTENTS ...............................................................................................................14 
LIST OF APPENDICES ................................................................................................................18 
LIST OF TABLES .........................................................................................................................19 
LIST OF FIGURES .......................................................................................................................19 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................20 
1. 
INTRODUCTION ......................................................................................................23 
1.1. 
Ulcerative Colitis ........................................................................................................23 
1.2. 
Etrasimod ....................................................................................................................23 
1.3. 
Benefit/Risk Assessment ............................................................................................24 
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 .....................................................................................25 
3.1. 
Summary of Study Design ..........................................................................................25 
3.2. 
Rationale for Study Design .........................................................................................26 
3.3. 
Study Duration ............................................................................................................27 
3.4. 
Independent Data Monitoring Committee ..................................................................28 
4. 
SELECTION OF STUDY POPULATION ................................................................28 
4.1. 
Inclusion Criteria ........................................................................................................28 
4.2. 
Exclusion Criteria .......................................................................................................31 
5. 
REMOVAL OF SUBJECTS FROM STUDY TREATMENT OR 
ASSESSMENT ...........................................................................................................34 
5.1. 
Discontinuation from Study Treatment ......................................................................34 
5.1.1. 
Discontinuation from Double-Blind Treatment for Disease Worsening ....................36 
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............................................................................................37 


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6.1. 
Treatments Administered ............................................................................................37 
6.2. 
Investigational Study Treatment .................................................................................38 
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 
6.7.2.2. 
Corticosteroid Taper ...................................................................................................41 
6.7.3. 
Prohibited Concomitant Therapy ................................................................................41 
7. 
SUBJECT RESTRICTIONS ......................................................................................43 
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 ...................................................................44 
9. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................45 
9.1. 
General Instructions ....................................................................................................45 
9.2. 
Subject Information ....................................................................................................45 
9.2.1. 
Informed Consent .......................................................................................................45 
9.3. 
Screening and Eligibility ............................................................................................45 
9.3.1. 
Tuberculosis Screening and Chest X-Ray ..................................................................46 
9.3.2. 
Rescreening .................................................................................................................46 
9.3.3. 
Demography and Other Subject Characteristics .........................................................46 
9.3.4. 
Social History .............................................................................................................46 
9.3.5. 
Prior and Ongoing Therapies ......................................................................................46 
9.3.6. 
Ulcerative Colitis History/Medical History ................................................................47 
9.3.7. 
Vital Signs ..................................................................................................................47 


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9.3.8. 
Pulmonary Function Test ............................................................................................47 
9.3.9. 
Ophthalmoscopy and Optical Coherence Tomography ..............................................47 
9.3.10. 
Clinical Laboratory Assessments ...............................................................................47 
9.3.11. 
Proctosigmoidoscopy/Colonoscopy and Modified Mayo Score Derivation ..............47 
9.4. 
Randomization/Treatment Period ...............................................................................48 
9.4.1. 
Week 0/Day 1: Prerandomization ...............................................................................48 
9.4.2. 
Treatment Period ........................................................................................................48 
9.4.2.1. 
Guidance for Cardiac Monitoring Following Treatment Initiation or 
Re-Initiation ................................................................................................................49 
9.4.3. 
Enrollment in Open-Label Extension Study APD334-303 ........................................51 
9.5. 
Follow-Up Period .......................................................................................................51 
9.6. 
Virtual/Hybrid Visits ..................................................................................................52 
9.7. 
Pharmacokinetics ........................................................................................................53 
9.8. 
Efficacy Assessments .................................................................................................53 
9.8.1. 
Modified Mayo Score/Mayo Clinic Score ..................................................................53 
9.8.1.1. 
Endoscopy ...................................................................................................................54 
9.8.1.2. 
Endoscopic Biopsies ...................................................................................................55 
9.8.2. 
Extraintestinal Manifestations ....................................................................................55 
9.8.3. 
Additional Health-Related Subject-Reported Outcomes ............................................55 
9.8.4. 
Efficacy-Related Biomarkers ......................................................................................56 
 
 
9.9. 
Genetics ......................................................................................................................58 
9.10. 
Safety ..........................................................................................................................58 
9.10.1. 
Physical Examination .................................................................................................58 
9.10.2. 
Vital Signs ..................................................................................................................59 
9.10.3. 
12-Lead Electrocardiogram ........................................................................................59 
9.10.4. 
Pulmonary Function Test ............................................................................................59 
9.10.5. 
Ophthalmoscopy and Optical Coherence Tomography ..............................................60 
9.10.6. 
Tuberculosis Screening and Chest X-Ray ..................................................................61 
9.10.7. 
Clinical Laboratory Tests ...........................................................................................62 
9.10.7.1. 
Screening ....................................................................................................................64 
9.10.7.2. 
Clinical Chemistry, Hematology, Coagulation, and Urinalysis .................................65 
9.10.8. 
Adverse Events ...........................................................................................................65 


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9.10.8.1. 
Definitions ..................................................................................................................65 
9.10.8.2. 
Eliciting and Recording Adverse Events ....................................................................68 
9.10.8.3. 
Reporting Adverse Events ..........................................................................................69 
9.10.9. 
Pregnancy ...................................................................................................................69 
9.11. 
Procedures for Overdose .............................................................................................70 
10. 
PLANNED STATISTICAL METHODS ...................................................................70 
10.1. 
General Considerations ...............................................................................................70 
10.2. 
Determination of Sample Size ....................................................................................70 
10.3. 
Analysis Sets ...............................................................................................................71 
10.4. 
Missing Data ...............................................................................................................71 
10.5. 
Efficacy Endpoint Definitions ....................................................................................73 
10.5.1. 
Calculation of Modified Mayo Score Component Scores ..........................................73 
10.6. 
Primary Endpoints ......................................................................................................73 
10.7. 
Secondary Endpoints ..................................................................................................74 
10.7.1. 
Key Secondary Efficacy Endpoints ............................................................................74 
10.7.2. 
Other Secondary Efficacy Endpoints ..........................................................................74 
 
 
10.9. 
Other Efficacy-Related Endpoints ..............................................................................75 
10.9.1. 
Health-Related Quality of Life ...................................................................................75 
10.9.2. 
Pharmacokinetics ........................................................................................................76 
10.9.3. 
Biomarkers ..................................................................................................................76 
10.10. 
Subgroup Analyses .....................................................................................................76 
10.11. 
Safety Endpoints .........................................................................................................77 
10.12. 
Testing Strategy ..........................................................................................................77 
10.12.1. 
Efficacy Analysis ........................................................................................................77 
10.12.2. 
Safety Analysis ...........................................................................................................77 
10.13. 
Interim Analysis ..........................................................................................................78 
11. 
ETHICAL CONSIDERATIONS................................................................................78 
11.1. 
Ethical Conduct of the Study ......................................................................................78 
11.2. 
Institutional Review Board or Independent Ethics Committee Approval ..................78 
11.3. 
Informed Consent and Assent .....................................................................................78 
11.4. 
Confidentiality ............................................................................................................79 
11.5. 
Protocol Compliance ..................................................................................................79 


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................80 
12.1. 
Training of Study Site Personnel ................................................................................80 
12.2. 
Monitoring ..................................................................................................................80 
12.3. 
Audit ...........................................................................................................................80 
13. 
DATA HANDLING AND RECORD KEEPING ......................................................81 
13.1. 
Data Management .......................................................................................................81 
13.1.1. 
Case Report Forms .....................................................................................................81 
13.1.2. 
Source Documents ......................................................................................................81 
13.2. 
Study Documentation and Records Retention ............................................................81 
13.3. 
Clinical Study Report .................................................................................................82 
13.4. 
Disclosure of Study Results ........................................................................................82 
14. 
RESPONSIBILITIES .................................................................................................82 
14.1. 
Investigator Responsibilities .......................................................................................82 
14.2. 
Sponsor Responsibilities .............................................................................................83 
15. 
REFERENCES ...........................................................................................................84 
16. 
APPENDICES ............................................................................................................86 
LIST OF APPENDICES  
APPENDIX 1: SCHEDULES OF ASSESSMENTS ..................................................................87 
APPENDIX 2: TUBERCULOSIS SCREENING .......................................................................94 
APPENDIX 3: MAYO CLINIC SCORE – SAMPLE ................................................................99 
APPENDIX 4: HISTOLOGICAL SCORING INDICES .........................................................100 
APPENDIX 5: GUIDANCE FOR THE ASSESSMENT OF POTENTIAL 
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY .........................101 
APPENDIX 6: INVESTIGATOR SIGNATURE .....................................................................102 
APPENDIX 7: SPONSOR SIGNATURE ................................................................................103 
 


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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 .......................................50 
Table 4: 
Discharge Criteria After Cardiac Monitoring .............................................................50 
Table 5: 
Discontinuation of Study Treatment-Related to Post-dose Cardiac 
Monitoring ..................................................................................................................51 
Table 6: 
Clinical Laboratory Tests ...........................................................................................63 
Table 7: 
Schedule of Assessments – Screening and 12-Week Treatment Period .....................87 
Table 8: 
Schedule of Assessments – 40-Week Treatment Period ............................................91 
 
LIST OF FIGURES  
Figure 1: 
Study Design ...............................................................................................................26 
Figure 2: 
Progressive Multifocal Leukoencephalopathy Case Evaluation Algorithm .............101 
 
 


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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 
End-of-treatment 
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 
MDR 
multi-drug resistant 
MedDRA 
Medical Dictionary for Regulatory Activities 
mFAS 
modified Full Analysis Set 
MMF 
mycophenolate mofetil 
MMS 
modified Mayo score 
6-MP 
6-mercaptopurine 


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Abbreviation 
Definition 
NF 
National Formulary 
NRS 
numeric rating scale 
NSAID 
nonsteroidal anti-inflammatory drugs 
OCT 
optical coherence tomography 
OLE 
open-label extension 
PFT 
pulmonary function test 
PGA 
Physicians Global Assessment  
Ph. Eur. 
European Pharmacopoeia 
PK 
pharmacokinetics 
PML 
progressive multifocal leukoencephalopathy 
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 
TMF 
trial master file 
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 repeated doses up to 4 mg once daily. Repeated doses of 
2 mg have been evaluated in Phase 2 studies of subjects with moderately to severely active UC 
(refer to the current edition of the IB). Etrasimod was found to be safe and well tolerated in these 
studies, with no clinically significant safety concerns with respect to vital signs, 
electrocardiograms (ECGs), pulmonary function tests (PFTs), ophthalmoscopy, or clinical 
laboratory tests. Etrasimod produced a dose-dependent sustained decrease in total lymphocyte 
count, which is expected given etrasimod’s mechanism of action. Lymphocyte counts 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. Subjects who complete the total 52-week treatment or subjects with worsening disease after 
the Week 12 visit assessments (Section 5.1.1) will have the opportunity to enroll into an 
open-label extension (OLE) study that will provide additional information on the long-term 
efficacy and safety of etrasimod. The results from this study will be used to support the 
regulatory approval of etrasimod for the treatment of patients with UC. 
2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective  
The primary objective is to assess the efficacy of etrasimod on clinical remission in subjects with 
moderately to severely active UC after 12 and 52 weeks of treatment. 
2.2. 
Secondary Objective  
The secondary objective is to assess the efficacy of etrasimod on clinical response, symptomatic 
response and remission, endoscopic changes, corticosteroid-free remission, and mucosal healing 
in subjects with moderately to severely active UC at timepoints up to 52 weeks of treatment. 
2.3. 
Safety Objective  
The safety objective is to assess the long-term safety of etrasimod after daily doses of 2 mg for 
up to 52 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. 
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 Treatment Period, a 40-Week Treatment 
Period, and a 2-Week and 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 up to 52 weeks of treatment (12-Week Treatment Period + 
40-Week Treatment Period). 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): 


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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). 
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 Treatment Period, subjects will undergo Week 12 efficacy and safety 
assessments and be evaluated for clinical response/remission as well as UC disease worsening. 
Subjects whose UC condition in the opinion of the Investigator has not improved or has 
worsened, compared with baseline (Week 0/Day 1), as defined in Section 5.1.1 and who meet 
other eligibility criteria will have the option to enter an OLE study (Study APD334-303). 
Subjects must complete Week 12 to be eligible for the OLE. Subjects who do not meet disease 
worsening criteria, including those demonstrating clinical response/remission at Week 12 will 
continue into the 40-Week Treatment Period and continue their double-blind treatment. Disease 
worsening will continue to be monitored by Investigators through the 40-Week Treatment Period 
(ie, from Weeks 13 to 52). Subjects who either experience disease worsening in the 40-Week 
Treatment Period or complete all study procedures at Week 52 will have the option to enroll into 
the OLE study if they meet all eligibility criteria. 
Subjects who discontinue from the study and do not participate in the OLE study will have 
2-Week and 4-Week Follow-Up visits after the last on-treatment visit/Early Termination visit 
(Table 7). 
Figure 1: 
Study Design  
 
JAK, Janus kinase; UC, ulcerative colitis 
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 


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(eg, 5-ASA, corticosteroids) per the concomitant medication and dose stabilization criteria. As 
preexisting background therapy is allowed, a placebo comparator is justified. 
The duration of study treatment is up to 52 weeks, which includes 12- and 40-Week Treatment 
Periods. The 40-Week Treatment Period is expected to provide adequate time for separation of 
efficacy effects between etrasimod and placebo. The 2-Week and 4-Week Follow-Up visits will 
provide off-treatment safety information. 
The etrasimod dose of 2 mg once daily is based on findings of previous Phase 1 and Phase 2 
studies, and in particular data from the Phase 2 APD334-003 placebo-controlled study. In the 
APD334-003 study, subjects received etrasimod 1 mg, etrasimod 2 mg, or placebo. Subjects in 
the etrasimod 2 mg group experienced a statistically significant improvement in the primary 
endpoint, the mean difference from placebo at Week 12 in the adapted Mayo score (least squares 
mean [standard error] difference: −0.99 [0.42]; p = 0.0091) compared with placebo. The 
etrasimod 2 mg group also experienced significant improvement in all secondary endpoints 
compared with the placebo group at Week 12 including, improvement in the total Mayo Score 
(estimated least squares mean [standard error] difference from placebo: −1.27 [0.55]; 
p = 0.0100), and higher percentage of subjects with endoscopic improvement (41.8%, difference 
from placebo: 24.4%, p = 0.003). 
Treatment-emergent adverse events (TEAEs) in the 1 mg, 2 mg, and placebo groups were 
reported for 59.6%, 56.0%, and 50.0% of subjects, respectively; treatment-related TEAEs were 
reported for 7.7%, 10.0%, and 5.6% of subjects, respectively; serious adverse events (SAEs) 
were reported for 5.8%, 0%, and 11.1% of subjects, respectively; and TEAEs leading to 
discontinuation of study treatment were reported for 5.8%, 8.0%, and 0% of subjects, 
respectively. No subjects died during the study. Overall, the 2 mg dose demonstrated a favorable 
safety profile and was chosen as the dose for the current Phase 3 program. 
The coprimary endpoints of clinical remission at Weeks 12 and 52 as assessed using the MMS, 
are standard, widely used, and are in accordance with the nonbinding US Food and Drug 
Administration (FDA) Draft Guidance for Industry, Ulcerative Colitis: Clinical Trials Endpoints 
(FDA 2016). Other endpoints for the study are widely used and considered reliable measures of 
efficacy and safety. 
As detailed in Section 10.2, the study is powered to the primary endpoint for demonstrating a 
statistically significant difference in clinical remission between etrasimod therapy and placebo at 
Week 52. The 2:1 randomization scheme will maximize the number of subjects receiving a 
potentially beneficial therapy. 
Subjects meeting predefined eligibility criteria from the end of the 12-Week Treatment Period 
and during the 40-Week Treatment Period will be eligible to enter the APD334-303 OLE study 
(Section 5.1.1) provided they meet all entry criteria. 
3.3. 
Study Duration  
The study consists of a 28-Day Screening Period, a 12-Week Treatment Period, a 40-Week 
Treatment Period, and a 2-Week and 4-Week Follow-Up Period. The study duration is expected 
to be approximately 2.5 years. 
The End of Study is the date when the last subject completes his/her last study visit. 


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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. 
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 


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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 
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. 
 


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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 (Note: Subjects 
on existing oral corticosteroid therapy will be tapered during the 40-Week Treatment 
Period.) 
• 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. 
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 


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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. 
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 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 
• 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 


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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 
• 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 criteria: 


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• 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 
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 


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26. Treatment with topical rectal 5-ASA, short-chain fatty acid enemas, or steroids ≤ 2 weeks 
prior to or 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 
5. 
REMOVAL OF SUBJECTS FROM STUDY TREATMENT OR 
ASSESSMENT  
5.1. 
Discontinuation from Study Treatment  
A subject’s double-blind treatment may be discontinued for any of the following reasons: 
• Worsening of disease (Note: If a subject discontinues double-blind treatment at any 
time starting with the Week 12 assessment, the subject may be eligible to enter the 
APD334-303 OLE [Section 5.1.1]) 
• Adverse event that in the judgement of the Investigator and/or Medical Monitor the 
subject should not continue study treatment 
• Subject noncompliance with the protocol or study treatment that is considered 
significant by the Medical Monitor 
• Investigator decision 
• Withdrawal by subject or parent/guardian 
• Lack of efficacy 
• Lost to follow-up 
• Study termination by Sponsor 
• Other, non-adverse event 


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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 on Day 1 after ≥ 4 hours of extended 
monitoring, or Day 2 by 4 hours post-dose (Table 4). 
• 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%) 
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 Table 8) 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 of 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. 


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5.1.1. 
Discontinuation from Double-Blind Treatment for Disease Worsening  
Starting with the Week 12 assessment, subjects whose UC condition in the opinion of the 
Investigator has not improved or has worsened, compared with baseline (Week 0/Day 1), may be 
eligible to enroll in the OLE Study (APD334-303) provided their ES is ≥ 2 and they meet one of 
the following entry criteria: 
• RB subscore ≥ 2 at 2 timepoints at least 7 days and no more than 14 days apart 
• RB + SF subscores ≥ 4 at 2 timepoints at least 7 days and no more than 14 days apart 
• RB subscore ≥ 2 or RB + SF subscores ≥ 4 (in any order) at 2 timepoints at least 
7 days and no more than 14 days apart 
For subjects discontinuing prior to Week 52, an endoscopic evaluation is required to confirm 
eligibility for the OLE. An endoscopy should be performed upon the appearance of UC 
symptoms but no more than 14 days after the second timepoint for symptom criteria above; 
however, a proctosigmoidoscopy does not need to be repeated if performed within the last 
4 weeks. 
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 
for Good Clinical Practice (GCP). 
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. 


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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 at the study site 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 
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 and Table 8. Subjects should be instructed to contact the 
Investigator if they miss more than 2 consecutive doses. 


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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 and Table 8). 
6.5. 
Blinding  
This is a double-blind study with limited access to the randomization code. The study treatment 
and placebo tablets and bottles are identical in physical appearance. The treatment each subject 
receives will not be disclosed to the Investigator, study site staff, subject, Sponsor personnel 
involved with the conduct of the study (with the exception of the clinical supply staff and 
designated safety staff), or study vendors. The IWRS will hold treatment codes and bottle 
numbers for study treatment. 
Treatment assignments should remain blinded unless that knowledge is necessary to determine 
subject emergency medical care. In case of an emergency, the Investigator has the sole 
responsibility for determining if unblinding of a subject’s treatment assignment is warranted to 
provide appropriate medical care. Subject safety must always be the first consideration in making 
such a determination. The IWRS is programmed with blind-breaking instructions to guide the 
Investigator on how to obtain treatment assignment in the event of an emergency unblinding. 
The Investigator is requested to contact the Medical Monitor promptly in case of any treatment 
unblinding. If a subject’s treatment assignment is unblinded, the Sponsor must be notified within 


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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 prior to Week 12 for any reason, they will be 
discontinued from the study. Subjects who are unblinded on or after Week 12 may be eligible to 
enroll into the OLE study (Section 5.1.1). 
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. 
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 Treatment 


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Period provided the dose has been stable for the 4 weeks immediately prior to the screening 
endoscopy assessment; however, subjects will be tapered off corticosteroids during the 40-Week 
Treatment Period (Section 6.7.2.2). 
6.7.2.2. 
Corticosteroid Taper  
During the 12-Week Treatment Period, subjects are to maintain their stable baseline 
corticosteroid dose. 
Following the Week 12 assessment, corticosteroids should be tapered for subjects entering the 
40-Week Treatment Period. The recommended tapering schedule for oral corticosteroids (other 
than budesonide extended-release tablets [budesonide MMX]) is as follows: 
a. Dose > 10 mg/day prednisone or equivalent: Taper daily dose by 5 mg/week until 
receiving 10 mg/day, and then continue tapering at 2.5 mg/week until 0 mg/day 
b. Dose ≤ 10 mg/day prednisone or equivalent: Taper daily dose by 2.5 mg/week until 
0 mg/day 
The recommended tapering schedule for subjects receiving oral budesonide MMX 9 mg/day is to 
reduce tablets to 9 mg every other day for 2 weeks, followed by 9 mg every third day for 
2 weeks, and then discontinue. 
For subjects who cannot tolerate the corticosteroid taper without recurrence of clinical symptoms 
of either UC or steroid withdrawal, the corticosteroid dose may be increased (up to the dose at 
study entry if required), but tapering should begin again within 2 weeks. 
6.7.3. 
Prohibited Concomitant Therapy  
The following concomitant medications are prohibited during the study: 
• Treatments for UC other than those listed in Section 6.7.2.1 (either approved or 
investigational) 
• All live vaccines, during study treatment and within 8 weeks after the last dose of 
study treatment 
• Moderate/strong inhibitors or inducers of CYP2C8 and CYP2C9 (Table 2; for 
additional information, refer to (Flockhart 2019) 
Table 2: 
Cytochrome P450 Inhibitors and Inducers 
Cytochrome P450 
Inhibitors (Strong/Moderate) 
Inducers (Strong/Moderate) 
CYP2C8 
Clopidogrel, gemfibrozil, deferasirox, 
teriflunomide 
Rifampin 
CYP2C9 
Fluconazole, amiodarone, felbamate, 
miconazole, piperine 
Aprepitant, carbamazepine, 
enzalutamide, rifampin, ritonavir 
CYP, cytochrome P450 
 


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• 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 
• 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. 


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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. 
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 (see 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. 


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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 Schedules of Assessments 
(Table 7 and Table 8). 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 
Schedules 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 (see Section 9.6 and Table 7 and Table 8), 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. pulmonary function tests [PFTs], optical coherence 


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tomography [OCT]) due to testing availability. The Medical Monitor must be consulted prior to 
extension in each case. 
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 rescreened 
≥ 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 of 
treatment to allow central reader review (may take approximately 5-12 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). For the Week 12 through Week 48 Visits, and ET 
Visit, a study visit window of ± 7 days is permitted. For the Week 52 Visit, a study visit window 
of ± 14 days is permitted. Study visits should be scheduled for the morning. 
The subscores for SF and RB are derived from the subject eDiary entries. On visits when MMS 
is calculated, these subscores are derived using the scores from the 3 most recent consecutive 
days within the 7 days prior to the day of bowel preparation (excluding the day of bowel 
preparation), averaged and rounded to the nearest integer. If 3 consecutive days are not available, 
then the average of the 2 most recent consecutive days within the 7 days will be used. 
On visits without endoscopy, the SF and RB subscores are derived using the scores from the 
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to the nearest integer. If 3 consecutive days are not available, then the average of the 2 most 
recent consecutive days within the 7 days will be used. 
It is recommended that procedures are performed in a consistent order and at approximately the 
same time of day for each visit. Below is the recommended sequence of events: 
• Questionnaire administration 
• Adverse event review 
• Vital signs 
• 12-lead ECG (as indicated in the Schedules of Assessments, Table 7 and Table 8) 
• Physical examination 
• EIMs (as indicated in the Schedules of Assessments, Table 7 and Table 8) 
• PFT (as indicated in the Schedules of Assessments, Table 7 and Table 8) 
• OCT (as indicated in the Schedules of Assessments, Table 7 and Table 8) 
• 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 
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described in Table 4. Subjects not meeting the discharge criteria will require extended 
monitoring as described below. 
• Subjects experiencing a clinically relevant treatment-related symptomatic event (eg, 
chest pain, dizziness, palpitations, or syncope) associated with reduction of the heart 
rate or clinically relevant 12-lead ECG changes at any time during the 4-hour 
monitoring period must be discontinued from treatment (Table 5). 
Table 3: 
Procedures to be Performed During the Monitoring Period  
Procedure 
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 


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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 
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). 
Study Treatment Discontinuation Related to Post-dose Cardiac Monitoring 
A complete list of reasons for study treatment discontinuation is provided in Section 5.1. 
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 
9.4.3. 
Enrollment in Open-Label Extension Study APD334-303  
At the Week 12 assessment a determination will be made regarding continuation into the 
40-Week Treatment Period or eligibility for entry into the OLE (Section 5.1.1). 
Subjects who discontinue treatment prematurely should have an ET visit as indicated in the 
Schedules of Assessments (Table 7 and Table 8). If the ET visit is within 4 weeks of the last 
proctosigmoidoscopy and biopsy, these procedures do not need to be repeated. 
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 Schedules of 
Assessments (Table 7 and Table 8). 
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 


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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). 
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: informed consent process including obtaining written informed 
consent, 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 and questionnaires. 
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. See 
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 and Table 8). 


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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 timepoints 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, 12, 16, 20, 24, 
32, 40, 48, and 52 
• At 2-Week and 4-Week Follow-Up visits 
• If possible, at the time of any SAE or adverse event leading to study treatment 
discontinuation 
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. 


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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 
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 and Table 8). 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), at Week 12, and at Week 52/Early Termination visit. Additional 
proctosigmoidoscopies may be performed to confirm disease worsening and are required for 
qualification into the OLE (Section 5.1.1). 
To ensure quality data and standardization, the same endoscopist should be used throughout the 
study wherever possible. Endoscopy images will be obtained during each endoscopy and will be 
sent for central reading and determination of the Mayo endoscopic score. A detailed image 
review charter from the central reading laboratory will outline the endoscopic procedures, video 
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. 


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Repeated flexible proctosigmoidoscopy may be permitted by the Sponsor when the central reader 
indicates that the video endoscope data were acquired incorrectly or did not meet the minimal 
required quality standards. 
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. 
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 (Appendix 4) indices will be performed by a blinded 
central histopathology reader (Geboes 2000, Marchal-Bressenot 2017, Mosli 2017). 
Biopsy specimen transfer, processing, slide preparation and digitization of slides for 
histopathologic scoring procedures will be detailed in a histopathology manual. Histopathology 
results will not be made available to study sites. 
9.8.2. 
Extraintestinal Manifestations  
During the specified full physical examinations (Table 7 and Table 8) 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 Schedules of Assessments (Table 7 and 
Table 8) 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). 


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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). 
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 Schedules of Assessments 
(Table 7 and Table 8). 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 


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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). 
9.10.1. 
Physical Examination  
Full and symptom-directed physical examinations will be performed according to the Schedules 
of Assessments (Table 7 and Table 8). 
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. 


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9.10.2. 
Vital Signs  
Resting vital signs measurements will be performed according to the Schedules of Assessments 
(Table 7 and Table 8) 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 Schedules of 
Assessments (Table 7 and Table 8), 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 repeated ECG is warranted. If this abnormal finding is confirmed, study treatment must be 
interrupted. Effective diagnostic and therapeutic strategies should be employed. 
Reversible causes of prolonged QTc interval (eg, electrolyte abnormalities or hypomagnesemia), 
should be corrected as clinically indicated. When evaluating a subject with new onset QTc 
interval above 500 ms, referral to a cardiologist experienced in treating cardiac conduction 
disorders should be considered. Re-initiation of study treatment can only be considered after all 
of the following have occurred: 
• The QTcF interval is < 450 ms (men) or < 470 ms (women) 
• The QTc prolongation is considered by the Investigator and confirmed by the 
cardiologist as not related to study treatment and likely caused by other factors 
• Individual risk-benefit is favorable (as determined by the Investigator, in agreement 
with the cardiologist), AND 
• After discussion with the Medical Monitor. 
The Investigator will be responsible for review and interpretation of 12-lead ECGs on site and 
determining if the 12-lead ECG is normal, abnormal clinically insignificant, or abnormal 
clinically significant. Findings will be documented in the eCRF. 
All 12-lead ECGs performed should be available for collection upon request. 
9.10.4. 
Pulmonary Function Test  
Pulmonary function tests will be performed according to the Schedules of Assessments (Table 7 
and Table 8) and includes FEV1 and FVC measurements. All subjects will have PFTs performed 
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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 clinically indicated. 
Subjects with a history of mild pulmonary disease (eg, asthma, chronic obstructive pulmonary 
disease) will have additional PFTs performed at Week 32. Subjects reporting respiratory adverse 
events such as dyspnea during the treatment period may return at an unscheduled visit for 
assessment per Investigator discretion; additional PFTs may be performed as clinically indicated. 
Subjects experiencing a decline in PFT values (FEV1 and/or FVC) below 50% of the predicted 
values must be discontinued from study treatment and scheduled for a follow-up visit. 
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 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. 
9.10.5. 
Ophthalmoscopy and Optical Coherence Tomography  
A complete ophthalmoscopy and OCT assessment will be performed according to the Schedules 
of Assessments (Table 7 and Table 8). OCTs 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 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 timepoints. 
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 


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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 
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). 


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9.10.7. 
Clinical Laboratory Tests  
Refer to Table 6 for the list of clinical laboratory tests to be performed and the Schedules of 
Assessments (Table 7 and Table 8) 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 
should be notified. 
• All protocol-required laboratory assessments, as defined in the Schedules of 
Assessments (Table 7 and Table 8), 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 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. 
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 Schedules of Assessments (Table 7 and Table 8). A monthly home pregnancy 
test in non-visit months should be performed in countries where allowed per local regulation and 
any positive result immediately reported to the study site. If not allowed per local regulations, 
this pregnancy test will be performed on site during an unscheduled visit. If at any point there is 
a case of a positive urine β-hCG test, the subject will have study treatment interrupted and a 
serum sample submitted to the central laboratory for β-hCG testing. If the serum test confirms 
positive, the subject will be withdrawn from the study treatment and all the necessary follow-up 
assessments will be conducted as per Section 9.10.9. 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). 
9.10.7.2. Clinical Chemistry, Hematology, Coagulation, and Urinalysis  
Clinical chemistry, hematology, coagulation, and urinalysis parameters that will be assessed 
during the study are identified in Table 6. 
Subjects will be in a seated or supine position during blood collection. All laboratory samples 
should be collected prior to the administration of study treatment at applicable visits (Refer to 
Section 9.6 for timing of blood draws for PK). 
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. 


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Hospitalization: 
The adverse event required or prolonged an existing inpatient 
hospitalization. Hospitalizations for elective medical or surgical 
procedures or treatments planned before the signing of informed 
consent in the study or routine check-ups are not SAEs by this 
definition. 
Disabling/ 
incapacitating: 
The adverse event resulted in a persistent or significant incapacity or 
substantial disruption of the subject’s ability to conduct normal life 
functions. 
Congenital anomaly 
or birth defect: 
An adverse outcome in a child or fetus of a subject exposed to the 
molecule or study treatment regimen before conception or during 
pregnancy. 
Medically significant: The adverse event did not meet any of the above criteria but could 
have jeopardized the subject and might have required medical or 
surgical intervention to prevent one of the outcomes listed above or 
involves suspected transmission via a medicinal product of an 
infectious agent. 
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 
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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): 
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 judgment to determine the relationship. Alternative causes, 
such as underlying disease(s), concomitant therapy, and other risk factors, as well as the 
temporal relationship of the event to the study treatment administration should be considered and 
investigated. The Investigator should consult the IB and the Product Information of marketed 
products within the drug class, when applicable. For each adverse event/SAE, the Investigator 
must document in the medical notes that he/she has reviewed the adverse event/SAE and has 
provided an assessment of causality. There may be situations in which an SAE has occurred and 


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the Investigator has minimal information to include in the initial report to the Sponsor; however, 
it is very important that the Investigator always make an initial assessment of causality for every 
event before the initial transmission of the SAE to the Sponsor. The Investigator may change 
his/her opinion of causality based on subsequent receipt of information and send an SAE 
follow-up report with the updated causality assessment. The causality assessment is one of the 
criteria used when determining regulatory reporting requirements. 
9.10.8.2. 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 


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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 
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. 


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Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of study treatment and until 30 days after the last dose. 
Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an adverse event; however, to fulfill regulatory requirements, any pregnancy and/or pregnancy 
outcome should be reported via the Pregnancy Report Form to the designated Sponsor Contact 
within 24 hours of awareness to collect data on the pregnancy and on the outcome for both the 
mother and the fetus. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and should be reported as such (following 
the SAE reporting process) even if outside the SAE reporting period. 
9.11. 
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. 
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 the 
statistical considerations and planned analyses will be described in the study Statistical Analysis 
Plan (SAP). 
10.2. 
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, 420 total subjects (280 etrasimod, 140 placebo) are required to achieve 
93.4% power to detect a difference of 13.5% in the primary endpoint of clinical remission at 
Week 52 between the etrasimod treatment group (23.5%) and the placebo treatment group 


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(10.0%). With this sample size, there will be 96% power to detect a difference of 12.5% in the 
other primary endpoint of clinical remission at Week 12, assuming a placebo rate at 6.0%. The 
lower bound of overall power for both primary endpoints (as coprimary endpoints) is at least 
90%; and since the two primary endpoints are expected to be at least moderately positively 
correlated, the actual overall power to reject both of their null hypotheses is likely to be greater 
than 90%. 
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 worsening of disease before Week 12 and subjects who meet the criteria for 
worsening disease after Week 12, as defined in Section 5.1.1, will be considered as having a 
treatment nonresponse outcome in the analysis of all endpoints, including the primary endpoint. 
In addition, subjects who initiate an agent not allowed in combination with the study treatment 
that can affect the efficacy of the study treatment, such as an immunosuppressant or 
corticosteroid, or who have an increase in dose over baseline levels for treatment of worsening 
disease symptoms will be considered 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 
timepoint (ie, a treatment failure outcome) and not as having missing data. Subjects who 


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discontinue the double-blind study for reasons other than worsening disease or adverse event 
related to UC will be considered as having missing data and will be handled in the primary and 
sensitivity analyses as follows. 
A full description of the handling of missing data will be provided in the SAP. 
Primary Method of Handling Missing Data 
In the primary analysis of the primary endpoint and main analyses of all binary responder-type 
endpoints, all subjects with missing data, regardless of reason for missingness, will be considered 
as non-responders. 
In the main analysis of continuous or score endpoints, such as changes from baseline in MMS 
subscores, biomarker measures, urgency NRS, abdominal pain NRS, and health-related quality 
of life measures, subjects with missing data will be 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 
timepoints, will be imputed using multiple imputation methodology (Rubin 1987) 
under the MAR assumption. Binary responder-type endpoints will subsequently be 
computed from observed and imputed data and analyzed using the same method as in 
the primary analysis. Continuous endpoints will be analyzed using analysis of 
covariance based on observed and imputed values. 
• A tipping point analysis will be performed for the primary and key secondary 
endpoints by considering all possible combinations of the number of responders and 
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 
with available data in the placebo group. This is akin to modeling the missing 
outcomes as if the subjects continued on their background therapy only and 
accounting for the study effect observed in subjects on placebo. This will be 
implemented using a multiple imputation approach of Copy Reference to impute 
missing values, eg, component scores of MMS at the planned assessment timepoints. 
Complete descriptions of the sensitivity analyses and detailed multiple imputation method and 
procedures will be provided in the SAP prior to database lock. 


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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 timepoint (eg, Weeks 12 and 52). Complete details of the MMS symptom 
score computation method are provided Section 9.3.10 and Section 9.4.2. 
10.6. 
Primary Endpoints  
The primary efficacy endpoints will evaluate etrasimod versus placebo in: 
• The proportion of subjects achieving clinical remission at Week 12 
• The proportion of subjects achieving clinical remission at Week 52 
Clinical remission is based on the MMS as defined in Section 10.5. 


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10.7. 
Secondary Endpoints  
Mucosal healing is based on the MMS and Geboes Index, histologic response and remission are 
based on the Geboes Index, and all other endpoints are based on MMS as defined in 
Section 10.5. 
10.7.1. 
Key Secondary Efficacy Endpoints  
The key secondary efficacy endpoints are: 
• The proportion of subjects achieving endoscopic improvement at Week 52 
• The proportion of subjects achieving endoscopic improvement at Week 12 
• The proportion of subjects achieving symptomatic remission at Week 52 
• The proportion of subjects achieving symptomatic remission at Week 12 
• The proportion of subjects in clinical remission at Week 52 and who had not been 
receiving corticosteroids for ≥ 12 weeks prior to Week 52 
• The proportion of subjects with mucosal healing at Week 52 
• The proportion of subjects with mucosal healing at Week 12 
• The proportion of subjects achieving clinical remission at both Weeks 12 and 52 
10.7.2. 
Other Secondary Efficacy Endpoints  
The other secondary endpoints are: 
• The proportion of subjects who had not received corticosteroids for ≥4 weeks and 
achieved clinical remission at Week 52 among subjects receiving corticosteroids at 
baseline 
• The proportion of subjects achieving clinical response at Week 52 
• The proportion of subjects achieving clinical response at Week 12 
• The proportion of subjects achieving clinical response at both Weeks 12 and 52 
• The proportion of subjects with mucosal healing at both Weeks 12 and 52 
• The proportion of subjects achieving endoscopic normalization at Week 52 
• The proportion of subjects achieving endoscopic normalization at Week 12 
• The proportion of subjects achieving endoscopic normalization at both Weeks 12 and 
52 
• The proportion of subjects achieving symptomatic remission at Weeks 2, 4, 8, 16, 20, 
24, 32, 40, and 48 
• The proportion of subjects achieving complete symptomatic remission at each study 
visit (Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52) 
• The proportion of subjects achieving noninvasive clinical response at each study visit 
(Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52) 


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• The proportion of subjects achieving symptomatic response at each study visit 
(Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52) 
• The proportion of subjects achieving clinical remission at Week 52 among subjects 
achieving clinical response at Week 12 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
10.9. 
Other Efficacy-Related Endpoints  
10.9.1. 
Health-Related Quality of Life  
• Scores and change from baseline to Weeks 12 and 52 in the following: 
− IBDQ total score 
− UC-PRO/SS 
− SF-36, version 2, physical and mental component and domain scores 
− WPAI-UC 
− Urgency NRS 


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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 
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, 16, 20, 24, 32, 40, 48, 52 and at 2- 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, 12, 24, and 52 
• Change from baseline in level of hs-CRP at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, 
and 52 
• Change and percentage change from baseline in lymphocyte counts at Weeks 2, 4, 8, 
12, 16, 20, 24, 32, 40, 48, and 52 
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. 
• 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 


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10.11. 
Safety Endpoints  
• Incidence and severity of adverse events 
• Incidence and severity of laboratory abnormalities, and change from baseline in 
laboratory values (to include hematology, serum chemistry, coagulation, and 
urinalysis) 
• Incidence of clinically significant vital sign abnormalities and changes from baseline 
10.12. 
Testing Strategy  
10.12.1. 
Efficacy Analysis  
The primary analysis of the proportion-based efficacy endpoints will be carried out using the 
Cochran-Mantel-Haenszel (CMH) method, stratified by (a) 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 both of the primary endpoints. This study will be considered as an overall success only 
if both of the primary null hypotheses are rejected, each at the α level (as coprimary hypotheses). 
This study will be considered as a partial success if only one of the two primary null hypotheses 
are rejected at α/2 if the other has p > α. 
Only if both of the primary null hypotheses are rejected, each at the α level, can testing proceed 
for the 8 key secondary endpoints. The method for such testing will be specified in the SAP, and 
it will control for the multiplicity of the 8 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. 
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. 


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10.13. 
Interim Analysis  
The Sponsor may conduct an interim analysis for sample size re-estimation based on blinded 
(aggregate) data to assess the appropriateness of the assumptions used in the original sample size 
calculation. The planned sample size will not be reduced as a result of the re-estimation to ensure 
sufficient exposure data for safety assessment. An interim SAP will provide detailed interim 
analysis specifications. The SAP will be finalized prior to any interim analysis and will be 
provided to regulatory agencies in a timely manner. This interim analysis will not be used to 
evaluate efficacy or safety. 
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 
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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 
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 


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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. 
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. 
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 
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 


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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.  
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.  
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J. 
2005b;26(2):319-338.  
Mosli MH, Feagan BG, Zou G, et al. Development and validation of a histological index for UC. 
Gut. 2017;66(1):50-58.  


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Nielsen OH, Li Y, Johansson-Lindbom B, Coskun M. Sphingosine-1-phosphate signaling in 
inflammatory bowel disease. Trends Mol Med. 2017;23(4):362-374.  
Rowe WA, Lichtenstein GR. Inflammatory bowel disease. Medscape. 
https://emedicine.medscape.com/article/179037-overview. Published 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: 
SCHEDULES OF ASSESSMENTS  
Table 7: 
Schedule of Assessments – Screening and 12-Week 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 
Vital signsj  
Xj 
Xj,k 
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 
12-lead ECGl  
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 OCT 
Xr  
 
 
 
 
Xr 
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/ accountability 
 
X 
X 
X 
X 
Xaa  
 
 
Study treatment administrationbb  
 
X – Once daily 
 
 


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a All visits beyond W0/D1 may be virtual/hybrid visits (Section 9.6). Subjects discontinuing prior to Week 12/Day 85 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, the Week 12 visit will be used to begin assessing 
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 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 a screen failure. 
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. Details 
regarding additional ECGs are provided in Section 9.10.3. 
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/Early Termination 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, 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 during 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 (eg, Week 12), 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 of 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 (eg, Week 12) will only be required 


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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 must be performed prior to randomization of treatment 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. 
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; FEV1, forced expiratory volume at 1 second; FVC, forced vital capacity; 
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; MDR, multi-drug resistant; MMS, modified Mayo score; NRS, numeric rating scale; 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; TB, tuberculosis; 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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Table 8: 
Schedule of Assessments – 40-Week Treatment Period  
Evaluation 
40-Week Treatment Period 
 
 
W16/ 
D113 
± 7 Days 
W20/ 
D141 
± 7 Days 
W24/ 
D169 
± 7 Days 
W32/ 
D225 
± 7 Days 
W40/ 
D281 
± 7 Days 
W48/ 
D337 
± 7 Days 
W52/D365 
± 14 Days / 
Early 
Terminationa 
± 7 Days  
2-Week 
Follow-
Up 
Visitb 
± 3 Days 
4-Week 
Follow-
Up 
Visitb 
± 3 Days 
eDiary review 
X 
X 
X 
X 
X 
X 
X 
 
 
MMSc  
 
 
 
 
 
 
X 
 
 
Stool frequency and rectal bleeding 
subscored  
X 
X 
X 
X 
X 
X 
X 
 
 
PGA for total Mayo Clinic Score 
 
 
 
 
 
 
X 
 
 
IBDQ, UC-PRO/SS, SF-36, 
WPAI-UC, and pain and urgency NRS 
 
 
 
 
 
 
X 
 
 
Adverse event assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signse  
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
 
 
 
 
 
 
X 
 
 
Physical examinationf  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Extraintestinal manifestationsg  
 
 
 
 
 
 
X 
X 
X 
Pulmonary function testh  
 
 
 
Xh 
 
 
X 
Xh 
 
Ophthalmoscopy with OCTi  
 
 
 
 
 
 
X 
X 
 
Pregnancy testj  
X 
X 
X 
X 
X 
X 
X 
 
X 
CBC with differential and platelets 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TBNK 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory tests including hs-CRPk  
X 
X 
X 
X 
X 
X 
X 
X 
 
Stool sample/fecal calprotectinl  
 
 
X 
 
 
 
X 
 
 
Stool sample for microbiome 
 
 
 
 
 
 
X 
 
 


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Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
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Evaluation 
40-Week Treatment Period 
 
 
W16/ 
D113 
± 7 Days 
W20/ 
D141 
± 7 Days 
W24/ 
D169 
± 7 Days 
W32/ 
D225 
± 7 Days 
W40/ 
D281 
± 7 Days 
W48/ 
D337 
± 7 Days 
W52/D365 
± 14 Days / 
Early 
Terminationa 
± 7 Days  
2-Week 
Follow-
Up 
Visitb 
± 3 Days 
4-Week 
Follow-
Up 
Visitb 
± 3 Days 
Flexible proctosigmoidoscopy/ 
colonoscopy and biopsym  
 
 
 
 
 
 
X 
 
 
PK assessmentsn  
X 
X 
X 
X 
X 
X 
X 
Xn 
Xn 
Biomarkers blood sampleo  
 
 
 
 
 
 
X 
 
 
Concomitant medications and 
proceduresp  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tuberculosis questionnaireq  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tuberculosis testq 
 
 
 
 
 
 
X 
 
 
Drug dispensation/accountabilityr  
X 
X 
X 
X 
X 
X 
Xr 
 
 
Study treatment administrations  
Once daily 
 
 
a All visits beyond W0/D1 may be virtual/hybrid visits (Section 9.6). Subjects discontinuing treatment prior to Week 52/Day 365 should have an Early Termination (ET) visit 
within 7 days of the last study treatment administration and before initiation of any new treatments. If a subject discontinues at or before Week 16, a sigmoidoscopy and biopsy 
are not required. For subjects with worsening disease or who complete Week 52 and wish to enter the APD334-303 OLE study, the Week 52/Early Termination visit will be used 
to assess eligibility for the OLE study. 
b For subjects discontinuing study treatment, 2-Week and 4-Week Follow-Up visits should be scheduled 2 weeks and 4 weeks after the Week 52/Early Termination visit and the 
indicated assessments performed; however, if the ET or Week 52 visit is ≥ 2 weeks after the last dose of study treatment, the 2-Week Follow-Up visit is not required; however, 
the 4-Week Follow-Up visit should be scheduled and completed. If the ET or Week 52 visit is ≥ 4 weeks after the last dose of study treatment, the 4-Week Follow-Up visit is not 
required. If the absolute peripheral lymphocyte count is not within normal limits at the 4-Week Follow-Up visit, subjects should return for CBC with differential according to 
local standard of care (captured as subsequent Follow-Up visit or unscheduled visit). 
c The Week 52 MMS will be calculated using the Week 52 proctosigmoidoscopy and SF and RB scores completed by the subject 7 days prior to the visit using the 3 most recent 
consecutive days prior to the actual day of the study visit excluding the day of bowel preparation. 
d Stool frequency and RB subject-reported outcomes recorded daily using eDiary. The RB and SF subscores will be calculated as indicated in Section 9.4.2. 
e Safety vital signs will include resting heart rate and systolic and diastolic BP with subjects in the sitting position taken before dosing. The Day 1 safety monitoring 
(Section 9.4.2.1) should be repeated if a subject has had a dose interruption ≥ 2 consecutive days within the first week of treatment or ≥ 7 consecutive days after the first week of 
treatment. 
f At Week 52, a complete physical examination (including assessments of the skin, head, eyes, ears, nose, throat, neck, thyroid, lungs, heart, abdomen, back, lymph nodes, 
extremities, and body weight) should be performed. All other visits should have a focused (complaints, signs, and symptoms) physical examination. 
g During the specified full physical examination, specific systems (eyes, liver, skin, and joints) will be examined for EIMs. 


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h Pulmonary function tests will include FEV1 and FVC measurements. Where locally available, DLCO measurements will also be performed (sites where DLCO is not available 
should consult the Sponsor or Sponsor’s delegate). The Week 32 assessment is only required for subjects with a history of mild pulmonary disease (eg, asthma, chronic 
obstructive pulmonary disease). The 2-Week Follow-Up visit assessment is only required if clinically indicated. Details regarding additional PFTs are provided in Section 9.10.4. 
i Details regarding ophthalmoscopy and OCT assessments are provided in Section 9.10.5. The 2-Week Follow-Up visit assessment is only required if clinically indicated. 
j Urine pregnancy test for women of childbearing potential. A monthly home pregnancy test in non-visit months should be performed in countries where allowed per local 
regulation and any positive result immediately reported to the study site and a serum pregnancy test performed for confirmation. If not allowed per local regulations, this 
pregnancy test will be performed on site during an unscheduled visit. 
k Clinical laboratory tests will include serum chemistry, hematology (including coagulation), urinalysis, and hs-CRP and should be obtained prior to the daily dosing. 
l Stool sample is for fecal calprotectin (all indicated visits) and bacterial culture, ova, and parasite evaluation for C. difficile assay at any point in the study when a subject becomes 
symptomatic, including worsening or return of disease activity. 
m To be read by a blinded central reader. If the ET visit is within 4 weeks of the last sigmoidoscopy and biopsy, these procedures do not need to be repeated. 
n Pharmacokinetic blood samples are to be collected pre-dose (within the 60-minute period prior to dosing). 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. 
o Blood samples for biomarkers should be collected on the indicated day prior to the daily dose as applicable. Biomarker sample collection is not required at ET visit. 
p All concomitant medications and procedures should be collected through the safety reporting period (Section 6.7). For subjects receiving corticosteroid therapy during the 
12-Week Treatment Period, corticosteroids should be tapered for subjects entering the 40-Week Treatment Period (Section 6.7.2.2). 
q The QuantiFERON TB Gold and tuberculin skin test should not be performed in subjects previously diagnosed with TB infection. 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). 
r Study treatment should be dispensed as indicated. For subjects who consent and are eligible for the APD334-303 OLE study prior to Week 52, double-blinded study treatment 
may be dispensed in the event there is a gap between the last on treatment visit of the parent study and W0/D1 of the OLE. Study treatment may be dispensed at Week 52 if the 
subject qualifies for and has opted to participate in the APD334-303 OLE study but who do not enter the OLE study on the same day as their Week 52 visit. 
s 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 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; eDiary, electronic diary; EIM, extraintestinal manifestations; FEV1, forced expiratory volume at 1 second; FVC, forced vital capacity; HR, heart rate; hs-CRP, 
high-sensitivity C-reactive protein; IBDQ, Inflammatory Bowel Disease Questionnaire; MMS, modified Mayo score; NRS, numeric rating scale; OCT, optical coherence 
tomography; OLE, open-label extension; PGA, Physicians Global Assessment; PK, pharmacokinetics; RB, rectal bleeding; SF, stool frequency; SF-36, Medical Outcomes Study 
36-Item Short Form Health Survey; TB, tuberculosis; UC, ulcerative colitis; UC-PRO/SS, Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms; W, week; 
WHO, World Health Organization; WPAI UC, Work Productivity and Activity Impairment Questionnaire – Ulcerative Colitis 
 


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Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
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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 schedules 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 


Clinical Study Protocol 
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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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Clinical Study Protocol 
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Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
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Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
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APPENDIX 3: 
MAYO CLINIC SCORE – SAMPLE  
Mayo Scoring System for Assessment of Ulcerative Colitis Activity 
Stool frequencya 
0 = Normal number of stools for this subject 
1 = 1 to 2 stools more than normal 
2 = 3 to 4 stools more than normal 
3 = 5 or more stools more than normal 
Subscore: 0 to 3 
Rectal bleedingb 
0 = No blood seen 
1 = Streaks of blood with stool less than half the time 
2 = Obvious blood with stool most of the time 
3 = Blood alone passes 
Subscore: 0 to 3 
Findings on endoscopyc 
0 = Normal or inactive disease 
1 = Mild disease (erythema, decreased vascular pattern) 
2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions) 
3 = Severe disease (spontaneous bleeding, ulceration) 
Subscore: 0 to 3 
Physician’s Global Assessmentd 
0 = Normal 
1 = Mild disease 
2 = Moderate disease 
3 = Severe disease 
Subscore: 0 to 3 
The Mayo score ranges from 0 to 12, with higher scores indicating more severe disease. 
a Each subject serves as his or her own control to establish the degree of abnormality of the stool 
frequency. 
b The daily bleeding score represents the most severe bleeding of the day. 
c The endoscopy subscore will be determined by qualified personnel at a central laboratory. 
d The Physician’s Global Assessment acknowledges the 3 other criteria, the subject’s daily 
recollection of abdominal discomfort and general sense of well-being, and other observations, 
such as physical findings and the subject’s performance status. 
 


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APPENDIX 4: 
HISTOLOGICAL SCORING INDICES  
Geboes Grading System 
The Geboes Grading System is a stepwise grading system used for the evaluation of microscopic 
inflammation and histopathologic disease activity in UC. The microscopic appearance of the 
mucosa is categorized into 6 grades. A decrease of the Geboes Score grading system to Grade 
zero (0) or one (1) indicates mucosal healing (Geboes 2000). 
Nancy Histological Index 
The Nancy Histological Index is a validated index for assessing histological disease activity in 
UC. It is composed of three histological items defining five grades of disease activity: absence of 
significant histological disease (grade 0), chronic inflammatory infiltrate with no acute 
inflammatory infiltrate (Grade 1), mildly active disease (Grade 2), moderately active disease 
(Grade 3), and severely active disease (Grade 4). The presence of ulceration on the biopsy 
specimen corresponds to severely active disease (Grade 4). If there is no ulceration, acute 
inflammatory cells infiltrate (presence of neutrophils) is assessed. Moderate or severe acute 
inflammatory cells infiltrate corresponds to moderately active disease (Grade 3), while mild 
acute inflammatory cells infiltrate correspond to mildly active disease (Grade 2). If there is no 
acute inflammatory cells infiltrate, assessment of chronic inflammatory infiltrate (lymphocytes 
and plasmacytes) is made. A biopsy specimen showing moderate or marked chronic 
inflammatory infiltrate corresponds to moderate or marked chronic acute inflammatory infiltrate 
(Grade 1). A biopsy specimen showing mild or no chronic inflammatory infiltrate corresponds to 
absence of significant histological disease (Grade 0) (Marchal-Bressenot 2017). 
Robarts Histopathology Index 
The 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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APPENDIX 5: 
GUIDANCE FOR THE ASSESSMENT OF POTENTIAL 
PROGRESSIVE MULTIFOCAL 
LEUKOENCEPHALOPATHY  
If a subject exhibits signs and symptoms suspicious for PML, the Investigator must interrupt 
study treatment and perform a targeted neurologic examination to assess for signs of PML, 
which are diverse, progress over days to weeks, and may include progressive weakness on one 
side of the body or clumsiness of limbs or difficulty with walking or writing or fine motor skills, 
disturbance of vision, changes in thinking, memory and orientation leading to confusion and 
(expressive aphasia), and/or agnosia (receptive aphasia). Consultation with a local neurologist 
may be warranted, as presented in the PML case evaluation algorithm in Figure 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 subject does not have PML, or the IAC’s review of the evidence concludes that 
PML is ruled out. 
 


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Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
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APPENDIX 6: 
INVESTIGATOR SIGNATURE  
 
Study title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 52-Week Study to 
Assess the Efficacy and Safety of Etrasimod in Subjects with Moderately to 
Severely Active Ulcerative Colitis 
Study number: APD334-301 
 
 
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 
 
 
 
 
 
 
 
 
 
 




Name: Clinical Study Protocol: APD334-301 Amendment 4.0
Description: A Phase 3, Randomized, Double‑Blind, Placebo‑Controlled, 52‑Week St
User Name: 
Capacity: Cl
Meaning: Approval Task
Date: 23-Dec-2020 02:10:14 GMT+0000


CLINICAL STUDY PROTOCOL 
SUMMARY OF CHANGES 
Protocol title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 
52-Week Study to Assess the Efficacy and Safety of Etrasimod in
Subjects with Moderately to Severely Active Ulcerative Colitis
Protocol number: 
APD334-301 
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. 
Confidential 
Arena Pharmaceuticals, Inc.


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
Amendment 1 
Arena Pharmaceuticals, Inc. 
Confidential 
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, post-dose safety 
vital signs, 12-lead ECGs, monitoring of subjects who do not meet the discharge criteria, and 
discontinuation rules have been revised.  
Page 2 of 6 


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
Amendment 1 
Arena Pharmaceuticals, Inc. 
Confidential 
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
(Table 4) on Day 1 after ≥ 4 hours of extended
monitoring, or Day 2 by 4 hours post-dose
Added as an extra safety precaution 
Page 3 of 6 


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
Amendment 1 
Arena Pharmaceuticals, Inc. 
Confidential 
Section No. and Name 
Description of Change 
Brief Rationale 
5.1.1.  Discontinuation from 
Double-Blind Treatment for 
Disease Worsening 
Updated language specifying criteria for entry into the 
APD334-303 open-label extension study 
To provide more clarity and guidance to 
Investigators 
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 
Not relevant to this protocol 
Page 4 of 6 


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
Amendment 1 
Arena Pharmaceuticals, Inc. 
Confidential 
Section No. and Name 
Description of Change 
Brief Rationale 
target disease need not be captured as SAEs” from the 
definition of SAE 
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). 
10.10.   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 
Page 5 of 6 


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
Amendment 1 
Arena Pharmaceuticals, Inc. 
Confidential 
Section No. and Name 
Description of Change 
Brief Rationale 
Table 8, Schedule of Assessments, 
Footnote “a” 
Modified text to clarify that the Week 52/Early 
Termination 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 8, Schedule of Assessments 
Added an additional row entitled “12-lead ECG”, 
indicating that a 12-lead ECG will be conducted at the 
Week 52/Early Termination visit. 
Sponsor decision 
Appendix 5: Investigator Signature 
Page  
Updated to new signature page format 
Formatting revision 
Added Appendix 6:  Country 
Specific Requirements 
Insertion of Sponsor signature page for a hand-written 
signature  
To meet signature requirements in countries 
that do not recognize electronic signature 
Page 6 of 6 


CLINICAL STUDY PROTOCOL 
SUMMARY OF CHANGES 
 
Protocol title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 
52-Week Study to Assess the Efficacy and Safety of Etrasimod in 
Subjects with Moderately to Severely Active Ulcerative Colitis 
 
 
Protocol number: 
APD334-301 
Version: 
Amendment 2.0, 20 December 2019 
Replaces version: 
Amendment 1, 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 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
Amendment 2.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 2 of 14 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment 2.0, 20 December 2019 
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 address update criteria for early (ie, prior to 
Week 52) enrollment in the open-label study and eligibility criteria (eg, list of prior therapy 
failures or non-response, contraception use, cardiovascular disease history, and prior therapy 
washout period). Additional instructions for safety monitoring related to 12-lead 
electrocardiogram, pulmonary function tests, and ophthalmoscopy and optical coherence 
tomography testing. Further instructions for Quantiferon TB Gold and tuberculin skin test were 
added. In addition, a 4-Week Follow-Up visit was added. 
 


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 2.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 3 of 14 
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 
Added NCT number 
Administrative change 
 
Updated title of Sponsor’s Responsible Medical Officer to: 
 
 
Administrative change due to organizational 
update 
 
Updated Amendment 2.0 Version date: 20 December 2019 
Administrative change 
 
Added Protocol History table 
To summarize protocol amendment history 
Synopsis: Study design 
3.1. Summary of Study Design 
Removed “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 additional clarity and guidance to 
Investigators 
Synopsis: Study design 
3.1. Summary of Study Design 
Revised entry criteria into open-label extension starting at the 
Week 12 visit and continuing through the 40-Week Treatment 
Period for subjects who experience UC worsening 
To provide greater clarity 
3.3. Study Duration 
Added “The End of Study is the date when the last subject 
completes his/her last study visit.” 
For additional clarity and guidance to 
Investigators 
Synopsis: Eligibility criteria: Inclusion 
Criterion 1 
4.1. Inclusion Criteria: Inclusion 
Criterion 1 
Added “Enrollment of subjects < 18 years should be conducted 
only if acceptable according to local laws and regulations” 
To satisfy local regulations that allow inclusion 
of minors (under 18 years) in clinical trials only 
after the results from adults are available 
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 


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 2.0 
 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 4 of 14 
Section No. and Name 
Description of Change 
Brief Rationale 
Synopsis: Eligibility criteria: Inclusion 
Criterion 6 
4.1. Inclusion Criteria: Inclusion 
Criterion 6 
Added “according to routine practice” to removal of any 
adenomatous polyps 
For clarification on eligibility criteria 
Synopsis: Eligibility criteria: Inclusion 
Criterion 7 
4.1. Inclusion Criteria: Inclusion 
Criterion 7 
Added interleukin 12/23 antibodies (eg, ustekinumab) to list of 
biologic therapies for JAK inhibitor therapies 
Added due to recent FDA approval for treatment 
of moderately to severely active ulcerative colitis 
 
Added to note regarding qualifying therapy that “the subject 
must have received an adequate course of therapy based on 
local guidelines for that therapy” 
To ensure that subjects had received adequate 
prior qualifying therapy 
Synopsis: Eligibility criteria: Inclusion 
Criteria 9 and 10 
4.1. Inclusion Criteria: Inclusion 
Criteria 9 and 10 
Vital signs and screening ECG have been deleted 
Now covered in new Exclusion Criterion 8 
Synopsis: Eligibility criteria: Inclusion 
Criterion 10 (formerly Inclusion 
Criterion 12) 
4.1. Inclusion Criteria: Inclusion 
Criterion 10 (formerly Inclusion 
Criterion 12 
Updated adequate hepatic function for ALT and AST to levels 
≤ 2.0 × ULN (from levels ≤ 3.0 × ULN) 
Extra safety precaution 
Synopsis: Eligibility criteria: Inclusion 
Criterion 12 (formerly Inclusion 
Criterion 15) 
4.1. Inclusion Criteria: Inclusion 
Criterion 12 (formerly Inclusion 
Criterion 15) 
Updated contraception language 
To be in accordance with the contraception 
guidance from Clinical Trials Facilitation and 
Coordination Group (CTFG) 
Synopsis: Eligibility criteria: Exclusion 
Criterion 7 
4.2. Exclusion Criteria: Exclusion 
Criterion 7 
Deleted hematologic, hepatic, pulmonary, and 
ophthalmological conditions from criterion. Alcohol/drug 
abuse/dependence (formerly Exclusion Criterion 21) and 
cognitive impairment were added. 
Covered in other specific exclusion criteria 


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 2.0 
 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 5 of 14 
Section No. and Name 
Description of Change 
Brief Rationale 
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 
To be in compliance with the precautions 
mentioned in previous study protocols submitted 
in France and in line with the fingolimod 
information 
Synopsis: Eligibility criteria: Exclusion 
Criterion 8  
4.2. Exclusion Criteria: Exclusion 
Criterion 8 
and throughout 
Updated PR interval criterion from ≤ 200 ms for inclusion to 
> 200 ms for exclusion 
More appropriately fits within new 
cardiovascular function exclusion criterion 
Synopsis: Eligibility criteria: Exclusion 
Criterion 12 
4.2. Exclusion Criteria: Exclusion 
Criterion 12 (formerly Inclusion 
Criterion 13) 
Updated TB exclusion criterion language 
For greater clarity and additional guidance to 
Investigators and to harmonize with 
programmatic language 
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 
worsen (in the opinion of the Investigator) if the subject is 
treated with a drug having immunosuppressant effects (ie, 
etrasimod).” 
To better define infection source as any active 
infection 
Synopsis: Eligibility criteria: Exclusion 
Criterion 17 
4.2. Exclusion Criteria: Exclusion 
Criterion 17 
Updated and modified history of opportunistic infection 
exclusion criterion to “History of an opportunistic infection 
(eg, Pneumocystis jirovecii, cryptococcal meningitis, 
progressive multifocal leukoencephalopathy) or history of 
disseminated herpes simplex or disseminated herpes zoster.” 
To better define infection history 
Synopsis: Eligibility criteria: Exclusion 
Criterion 21 
4.2. Exclusion Criteria: Exclusion 
Criterion 21 
Added “21. 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. 
Synopsis: Eligibility criteria: Exclusion 
Criterion 21  
4.2. Exclusion Criteria: Exclusion 
Criterion 21 
Deleted criterion and moved to Exclusion Criterion 7 
To avoid redundancies 


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 2.0 
 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 6 of 14 
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” 
To improve clarity and provide additional 
guidance to Investigators regarding wash-out 
period 
Synopsis: Eligibility criteria: Exclusion 
Criterion 27 (formerly Exclusion 
Criterion 28) 
4.2. Exclusion Criteria: Exclusion 
Criterion 27 (formerly Exclusion 
Criterion 28) 
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 
To add classes rather than specific drugs 
Synopsis: Efficacy assessments: 
Definitions 
Updated symptomatic remission: SF subscore = 0 (or = 1 with 
a ≥ 1-point decrease from baseline) and RB subscore = 0 
Minor update to symptomatic remission 
definitions to align with regulatory authority 
requests 
Synopsis: Efficacy assessments: Key 
secondary efficacy endpoints 
10.7.1. Key Secondary Efficacy 
Endpoints 
Updated key secondary endpoints to include:  
• 
The proportion of subjects achieving symptomatic 
remission at Week 52 
• 
Proportion of subjects achieving symptomatic remission at 
Week 12 
Update to key secondary efficacy endpoints to 
align with regulatory authority requests 
Synopsis: Pharmacokinetic 
Assessments 
10.9.2. Pharmacokinetics 
Table 7: Schedule of Assessments – 
Screening and 12-Week Treatment 
Period 
Added PK samples at the 2-Week and 4-Week Follow-Up 
visits  
To ensure appropriate PK data are available after 
end of treatment 


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 2.0 
 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 7 of 14 
Section No. and Name 
Description of Change 
Brief Rationale 
Table 8: Schedule of Assessments – 
40-Week Treatment Period 
Synopsis: Statistical Methods – Interim 
analysis – Testing strategy 
10.13. Testing strategy, Interim 
analysis 
Updated number of key secondary endpoints from 6 to 8 
For internal consistency due to addition of new 
key secondary endpoints 
Synopsis: Statistical Methods – Interim 
analysis 
10.13. Interim Analysis 
Deleted DMC review and clarified analysis would be on 
blinded data to assess the appropriateness of the assumptions 
used in the original sample size calculation to ensure sufficient 
exposure data for safety assessment. Also clarified that the 
interim analysis will not be used to evaluate efficacy or safety. 
To clarify DMC oversight and that the interim 
analysis will not be used to evaluate efficacy or 
safety 
1.3. Benefit/Risk Assessment 
Updated to state that repeated doses of up to 4 mg (changed 
from 3 mg) once daily have been assessed in healthy adult 
subjects and repeated doses of 2 mg have been evaluated in 
Phase 2 studies of subjects with moderately to severely active 
UC. 
To be up to date with the IB 
 
Added “and as clinically indicated any time during the study.” 
to times when OCT will be performed 
As an extra safety precaution 
3.1. Summary of Study Design 
Updated text regarding entry/rollover into the OLE 
For greater clarity 
3.3. Study Duration 
Added “The End of Study is the date when the last subject 
completes his/her last study visit.” 
To define the “End of the Study” 
4.1. Inclusion Criteria, Inclusion 
Criterion 7 
Modified definition of inadequate response to be “Signs and 
symptoms of persistently active disease despite a history of 
completing a dosing regimen.” A new note was added that 
says: “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.” 
For additional guidance to Investigators 
5.1. Discontinuation from Study 
Treatment 
Added confirmed diagnosis of active TB to list of reasons for 
discontinuation of study treatment 
Added safety precaution 
 
Modified criteria 
To provide greater clarity and guidance for 
Investigators 


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 2.0 
 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 8 of 14 
Section No. and Name 
Description of Change 
Brief Rationale 
5.1. Discontinuation from Study 
Treatment 
9.5. Follow-Up Period 
Table 7: Schedule of Assessments – 
Screening and 12-Week Treatment 
Period (footnote “b”) 
Table 8: Schedule of Assessments – 
40-Week Treatment Period (footnote 
“b”) 
Changed ALC criterion for continued follow-up from “80% of 
baseline value” to “within normal limits” 
To provide guidance to Investigators 
5.1.1. Discontinuation from 
Double-Blind Treatment for Disease 
Worsening 
Modified criteria for entry into the OLE prior to Week 52 to 
include 2 symptom assessments (previously 1) at least 7 days 
and no more than 14 days apart 
For confirmation of non-improvement or disease 
worsening 
 
Modified statement regarding required endoscopic evaluation 
to confirm eligibility for OLE prior to Week 52 to state the 
endoscopy should be performed “upon the appearance of UC 
symptoms but no more than 14 days after the second timepoint 
for symptom criteria” 
To provide additional guidance for 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 
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 compliance and additional safety 
precaution 
6.5. Blinding 
Modified text regarding unblinding and added statement that 
“If a subject’s treatment assignment is unblinded prior to 
Week 12 for any reason, they will be discontinued from the 
To provide additional clarity 


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 2.0 
 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 9 of 14 
Section No. and Name 
Description of Change 
Brief Rationale 
study. Subjects who are unblinded on or after week 12 may be 
eligible to enroll into the OLE study (Section 5.1.1).” 
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 
 
Changed the duration of time after stopping study treatment 
that subjects should not receive live vaccines from 2 weeks to 
8 weeks 
Safety precaution 
 
Added tofacitinib to list of prohibited immunosuppressive 
agents 
Added for completeness 
 
Deleted leflunamide and added dimethyl fumarate, or 
pyrimidine synthesis inhibitors 
For consistency with Exclusion Criterion 31 
 
Moved immunoadsorption columns and intravenous 
immunoglobulin or plasmapheresis from prohibited 
concomitant medications to prohibited concomitant procedures 
More accurately reflect the prohibited procedure 
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.” 
Additional safety precaution 
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 by “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 
 
Modified language regarding screening proctosigmoidoscopy/ 
colonoscopy review by “Proctosigmoidoscopy/colonoscopy 
should be performed prior to randomization to treatment to 
For clarity regarding timing of review with 
respect to procedure. 


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 2.0 
 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 10 of 14 
Section No. and Name 
Description of Change 
Brief Rationale 
allow central reader review (may take approximately 
5-12 days) and confirmation of eligibility. 
9.3.10. Proctosigmoidoscopy/ 
Colonoscopy and Modified Mayo 
Score Derivation – Determination of 
MMS score to qualify for 
randomization 
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 diastolic BP < 55 mm Hg” as part of vital sign 
criterion for exclusion from randomization 
Added to match Section 4.2 Exclusion Criteria 
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 
available, 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. Treatment Period – First Dose 
Cardiac Monitoring 
Updated language for 5th bullet point to “…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 
9.4.3. Enrollment in Open-Label 
Extension Study APD334-303 
Table 7: Schedule of Assessments – 
Screening and 12-Week Treatment 
Period – Footnote “a” 
Table 8: Schedule of Assessments – 
40-Week Treatment Period – Footnote 
“a” 
Deleted language stating that for eligible subjects, the Week 12 
visit (or Week 52 visit) could be used as the Day 1 visit for the 
OLE 
No longer applicable 


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 2.0 
 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 11 of 14 
Section No. and Name 
Description of Change 
Brief Rationale 
9.5. Follow-Up Period 
Updated text to add additional description of the eye 
examination 
Updated for internal consistency and to provide 
additional guidance to Investigators 
9.5. Follow-Up Period 
Table 7: Schedule of Assessments – 
Screening and 12-Week Treatment 
Period 
Table 8: Schedule of Assessments – 
40-Week Treatment Period 
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.” 
Added for additional safety follow-up 
9.7.3. Additional Health-Related 
Subject-Reported Outcomes 
Corrected WPAI UC description to state it consists of 
6 questions 
Corrected the number of questions in the WPAI 
9.7.4. Efficacy-Related Biomarkers 
Updated language when ALC is confirmed to be 
< 200 cells/µL to state “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 the risk of 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 
9.9.3. 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 
9.9.4. Pulmonary Function Test 
Added new text describing PFTs to state “All subjects will 
have PFTs performed at Screening, Week 12, and Week 52, or 
at the Early Termination visit. 
For clarity and additional guidance to 
Investigators 


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 2.0 
 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 12 of 14 
Section No. and Name 
Description of Change 
Brief Rationale 
Subjects with a history of mild pulmonary disease (eg, asthma, 
chronic obstructive pulmonary disease) will have additional 
PFTs performed at Week 32. Subjects reporting respiratory 
adverse events such as dyspnea during the treatment period 
may return at an unscheduled visit for assessment per 
Investigator discretion; additional PFTs may be performed as 
clinically indicated.” 
9.9.5. Ophthalmoscopy and Optical 
Coherence Tomography 
Detailed the rationale and procedure for the ophthalmoscopy 
and OCT assessment. 
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 as identified by WHO or if receiving TB 
prophylaxis therapy, a TB screening questionnaire will be 
administered prior to randomization and at every study visit 
(Appendix 2). 
As an added safety precaution 
9.9.7. Clinical Laboratory Tests 
Table 6 
Moved QuantiFERON from “Virology” to “Others” 
Not a virology test 
9.9.7.1.1. Drugs of Abuse 
Updated text 
To provide greater clarity to Investigators 
9.9.7.1.2. Pregnancy Testing 
Added language stipulating home pregnancies tests will be 
performed “in countries where allowed per local regulation” 
and “If not allowed per local regulations, this pregnancy test 
will be performed on site during an unscheduled visit.” 
To be in compliance with local regulations 
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 
9.9.8.3.2. 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” 
The previous language was incomplete and the 
new is consistent with CTFG guidance regarding 
RSI/IB 
9.10. Procedures for Overdose 
Added text and guidance for monitoring subjects 
For additional guidance to Investigators 
10.4. Missing Data 
Clarified that subjects with worsening of disease prior to 
Week 12 and subjects who meet the criteria for worsening 
disease after Week 12, as defined in Section 5.1.1, will be 
considered as having a treatment nonresponse outcome in the 
analysis of all endpoints, including the primary endpoint. 
For clarification and internal document 
consistency 


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 2.0 
 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 13 of 14 
Section No. and Name 
Description of Change 
Brief Rationale 
10.5. Efficacy Endpoint Definitions 
Added definitions for symptomatic remission, clinical 
remission using the Total Mayo Clinic score, and clinical 
response using the Total Mayo Clinic score 
To provide definitions for selected endpoints in 
the protocol 
10.7.1. Key Secondary Efficacy 
Endpoints 
Added 2 additional key secondary endpoints: 
• 
The proportion of subjects achieving symptomatic 
remission at Week 52 
• 
The proportion of subjects achieving symptomatic 
remission at Week 12 
Added to align with regulatory authority requests 
10.12.1. Efficacy Analysis 
Deleted “using Hochberg’s method” from “This study will be 
considered as a partial success if only one of the two primary 
null hypotheses are rejected at α/2 if the other has p > α.” 
The method will be specified in the SAP 
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 
Table 7, Schedule of Assessments, 
Footnote “a” 
Modified text to clarify that for subjects who complete 
Week 12 the Week 12 visit will be used to assess eligibility for 
the OLE 
For clarification and guidance for Investigators 
Table 7, Schedule of Assessments, 
Footnote “e” 
Added additional language to the TB Footnote stipulating that 
the Quantiferon TB Gold and tuberculin skin test 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 as identified by the WHO. 
To facilitate TB assessments of study subjects 
 
Added “…or if receiving TB prophylaxis therapy” 
To ensure screening inclusion for individuals 
diagnosed with TB even if they do not reside in 
countries with a high TB burden as identified by 
the WHO 
Table 7, Schedule of Assessments, 
Footnote “k” 
Deleted “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.” 
No longer applicable 


Clinical Study Protocol - Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 2.0 
 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 14 of 14 
Section No. and Name 
Description of Change 
Brief Rationale 
Table 8, Schedule of Assessments 
Added new rows for TB Screening and Questionnaire and 
Week 52/Early Termination visit TB testing and associated 
footnote “q” 
Additional safety precaution 
 
Added “…or if receiving TB prophylaxis therapy” 
To ensure screening inclusion for individuals 
diagnosed with TB even if they do not reside in 
countries with a high TB burden as identified by 
the WHO 
Table 8, Schedule of Assessments, 
Footnote “a” 
Deleted text “and may also serve as the Day 1 visit of the 
OLE” to clarify that the Week 52/Early Termination visit will 
be used to assess eligibility for the OLE  
For clarification and guidance for Investigators 
Table 8, Schedule of Assessments 
Footnote “r” 
Added language that subjects who consent and are eligible for 
the APD334-303 OLE study prior to Week 52 may also be 
dispensed study treatment. 
To ensure subjects can continue study treatment 
without interruption prior to entry into the OLE 
Appendix 2 Tuberculosis Screening 
Updated Appendix 
For additional guidance to Investigators and to 
harmonize across studies 
Appendix 5: Guidance for The 
Assessment Of Potential Progressive 
Multifocal Leukoencephalopathy 
Added new Appendix 5 Guidance for The Assessment Of 
Potential Progressive Multifocal Leukoencephalopathy 
Added to align with regulatory authority requests 
Appendix 6: Investigator Signature 
Page 
Updated to new signature page format 
Formatting revision 
Appendix 7: Country-Specific 
Requirements 
Deleted Appendix 7 
Appendix was not relevant 
 


CLINICAL STUDY PROTOCOL 
SUMMARY OF CHANGES 
 
Protocol title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 
52-Week Study to Assess the Efficacy and Safety of Etrasimod in 
Subjects with Moderately to Severely Active Ulcerative Colitis 
 
 
Protocol number: 
APD334-301 
Version: 
Amendment 3.0, 07 February 2020 
Replaces version: 
Amendment 2.0, 20 December 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 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 2 of 7 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Amendment 3.0, 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 provide clarification and further instructions for 
tuberculosis testing and to update the tuberculosis screening questionnaire. A correction was 
made to the entry criteria for enrollment in the OLE study. Additionally, lack of efficacy was 
added as a reason a subject may discontinue from double-blind treatment. Clarifications were 
made to Ophthalmoscopy and Optical Coherence Tomography testing. In addition, minor 
corrections were made for consistency within the protocol. 
 


Clinical Study Protocol – Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 3 of 7 
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: 07 February 2020 
Administrative change 
Protocol History 
Updated protocol history table 
Administrative change 
Synopsis: Study design 
5.1.1 Discontinuation from Double-Blind 
Treatment for Disease Worsening 
Entry criteria for enrollment in the OLE study was updated 
by changing “RB subscore ≥ 2 and RB + SF subscores ≥ 4 
(in any order) at 2 timepoints at least 7 days and no more 
than 14 days apart” to “RB subscore ≥ 2 or RB + SF 
subscores ≥ 4 (in any order) at 2 timepoints at least 7 days 
and no more than 14 days apart”. 
Correction 
Synopsis: Eligibility criteria 
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 
4.2 Exclusion Criteria (Exclusion 
Criterion 8) 
9.9.3 12-Lead Electrocardiogram 
Table 7, Schedule of Assessments 
Footnote “l” 
The use of the terms “males” and “females” was updated to 
“men” and “women” in reference to QTcF ranges. 
Standardization of terms for consistency with 
Study APD334-302 and Study APD334-303 
protocol terminology. 
Synopsis: Eligibility criteria 
4.2 Exclusion Criteria (Exclusion 
Criterion 12) 
A change was made to clarify that subjects with history of 
untreated or inadequately treated latent TB infection, active 
or latent TB infection at screening will be excluded. No 
changes were made to the list of exceptions to this exclusion 
criteria. 
Clarification 
Synopsis: Efficacy assessments 
“The proportion of subjects in clinical remission at Week 12” 
was changed to “The proportion of subjects achieving 
clinical remission at Week 12”. 
“The proportion of subjects in clinical remission at Week 52” 
was changed to “The proportion of subjects achieving 
clinical remission at Week 52”. 
Update in terminology was made for consistency 
with other efficacy endpoints. 


Clinical Study Protocol – Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 4 of 7 
Section No. and Name 
Description of Change 
Brief Rationale 
Synopsis: Pharmacokinetic assessments 
The following sentence was restructured from “Plasma 
concentrations of etrasimod, M3 (AR503641), and other 
metabolite(s) of interest (if warranted) will be assessed from 
samples collected pre-dose…” to “Plasma concentrations of 
etrasimod, and if warranted M3 (AR503641) and other 
metabolite(s) of interest, will be assessed from samples 
collected pre-dose…”. 
For clarity to Investigator 
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 term “analysis” was updated to “primary analysis”. 
For consistency with terminology in Section 10.4 
(Missing Data) 
5.1 Discontinuation from Study 
Treatment 
Lack of efficacy was added as a reason why a subject may 
discontinue from double-blind treatment.  
Correction 
9.3.1 Tuberculosis Screening and Chest 
X-Ray 
Added additional instructions on TB testing with regards to 
retesting. 
For clarity to Investigator 
9.3.10 Proctosigmoidoscopy/ 
Colonoscopy and Modified Mayo Score 
Derivation 
Changed “should” to “must”. 
For clarity to Investigator 
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, will be collected…”. 
For clarity to Investigator 
 
Week 16 was added to the list of pre-dose pharmacokinetic 
samples. 
Correction. Added for consistency with Table 8, 
Schedule of Assessments for PK assessments. 
 
 
 
 
 
 


Clinical Study Protocol – Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 5 of 7 
Section No. and Name 
Description of Change 
Brief Rationale 
9.6 Pharmacokinetics (continued) 
The following sentence was restructured from “Blood 
samples will be processed for collection of plasma fractions 
for determination of the concentrations of etrasimod, M3 
(AR503641), and other metabolite(s) of interest (if 
warranted) will be collected at the following timepoints…” to 
“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, will be collected at the following 
timepoints…”. 
For clarity to Investigator 
9.7.1 Modified Mayo Score/Mayo Clinic 
Score 
Changed “daily subject-reported RB and SF subscores” to 
“daily subject-reported RB and SF scores”. 
Correction in terminology 
Changed “for a given day” to “in a 24-hour period”. 
For clarity to Investigator 
9.9.1 Physical Examination 
Added “skin” to the list of assessments for the full physical 
examination. 
For consistency with Table 7, Footnote “n” and 
Table 8, Footnote “f”. 
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. 
Clarification was made to include fluorescein angiogram as 
an example of testing of subjects with a suspicion of macular 
edema or subjects with uveitis findings on ophthalmic exam. 
For clarity to Investigator 
9.9.6 Tuberculosis Screening and Chest 
X-Ray 
Added a statement to clarify that a TB screening 
questionnaire will be completed during the Screening Period 
for all subjects. Clarified that 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. Added 
additional instructions that subjects receiving TB prophylaxis 
treatment will complete a TB questionnaire at every study 
visit (until TB prophylaxis treatment course is completed). 
For clarity to Investigator 
Removed “prior to randomization” with regards to 
administration of the TB screening questionnaire. 
Correction 
 
 
 


Clinical Study Protocol – Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 6 of 7 
Section No. and Name 
Description of Change 
Brief Rationale 
9.9.7 Clinical Laboratory Tests, Table 6 
9.9.7.1.2 Pregnancy Testing 
Table 7 (Footnote “s”) 
Table 8 (Footnote “j”) 
Changed “females of childbearing potential” to “women of 
childbearing potential”. 
For consistency with terminology in Clinical 
Trials Facilitation Group, Recommendations 
related to contraception and pregnancy testing in 
clinical trials. 
10.4 Missing Data 
“Subjects who experience worsening of disease prior to 
Week 12…” was changed to “Subjects with worsening of 
disease before Week 12”. 
For consistency with Study APD334-302 and 
Study APD334-303 protocol. 
“Subjects who discontinue the double-blind study for reasons 
other than worsening disease or missing study assessments 
while continuing with the study treatment will be considered 
as having missing data...” was changed to “Subjects who 
discontinue the double-blind study for reasons other than 
worsening disease or adverse event related to UC will be 
considered as having missing data...” 
Correction 
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 
10.9.2 Pharmacokinetics 
Changed “Plasma concentrations of etrasimod, M3 
(AR503641), and other metabolite(s) of interest (if 
warranted) will be assessed…” to “Plasma concentrations of 
etrasimod, and if warranted M3 (AR503641) and other 
metabolite(s) of interest, will be assessed…”. 
For clarity to Investigator 
Table 7, Schedule of Assessments  
Tuberculosis “screening” was changed to “test”. 
“Flexible proctosigmoidoscopy and biopsy” was changed to 
“Flexible proctosigmoidoscopy/colonoscopy and biopsy”. 
Updated terminology for consistency with other 
etrasimod protocols. 
Table 7, Schedule of Assessments, 
Footnote “e” 
Added a statement to clarify that a TB screening 
questionnaire will be completed for all subjects during the 
Screening Period. Clarified that 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. Added 
additional instructions that for 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 


Clinical Study Protocol – Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 3.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 7 of 7 
Section No. and Name 
Description of Change 
Brief Rationale 
Table 7, Schedule of Assessments, 
Footnote “v” 
Modified language regarding screening 
proctosigmoidoscopy/ colonoscopy to state 
“Proctosigmoidoscopy/colonoscopy must be performed prior 
to randomization of treatment to allow central reader review 
(may take approximately 5 to 12 days)”. 
For clarity to Investigator and consistency with 
Section 9.3.10. 
Table 8, Schedule of Assessments 
Tuberculosis screening was removed from Week 16. 
Correction 
“Flexible proctosigmoidoscopy and biopsy” was changed to 
“Flexible proctosigmoidoscopy/colonoscopy and biopsy”. 
Updated terminology for consistency with other 
etrasimod protocols. 
Table 8, Schedule of Assessments, 
Footnote “q” 
Removed “All subjects will complete TB screening to 
determine eligibility”. 
A correction was made as result of removing the 
Week 16 tuberculosis screening from the 
Schedule of Assessments. 
Added additional instructions that for 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 
Appendix 2, Tuberculosis Screening 
Added a statement to clarify that a TB questionnaire will be 
completed for all subjects (see below) during the Screening 
period. Removed “prior to randomization” with regards to 
administration of the TB screening questionnaire. 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 regarding 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. 
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. 
The Tuberculosis Screening Questionnaire was updated. 
Updates were made to the source document 
worksheet. 
 


CLINICAL STUDY PROTOCOL 
SUMMARY OF CHANGES 
 
Protocol title: 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 
52-Week Study to Assess the Efficacy and Safety of Etrasimod in 
Subjects with Moderately to Severely Active Ulcerative Colitis 
 
 
Protocol number: 
APD334-301 
Version: 
Amendment 4.0, 22 December 2020 
Replaces version: 
Amendment 3.0, 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 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
Amendment 4.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 2 of 15 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
Amendment 4.0, 22 December 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 the subject enrollment number and include 
guidance for conducting virtual and offsite visits. Also, information on anti-arrhythmic drugs 
was added to prohibited concomitant therapies and the corticosteroid-free remission secondary 
endpoint was updated. 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 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 4.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 4 of 15 
Section No. and Name 
Description of Change 
Brief Rationale 
Protocol Synopsis: Eligibility criteria 
4.2. Exclusion Criteria (Exclusion Criterion 8) 
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 
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 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 on 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  


Clinical Study Protocol – Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 4.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 5 of 15 
Section No. and Name 
Description of Change 
Brief Rationale 
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 
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 
Protocol Synopsis, Efficacy assessments 
10.7.1. Key Secondary Efficacy Endpoints 
Revised the following endpoint: 
“The proportion of subjects in clinical remission at 
Week 52 and who had not been receiving 
corticosteroids for ≥ 12 weeks prior to Week 52” 
To evaluate the overall impact of etrasimod 
treatment on long-term treatment and achievement 
of clinical remission while either eliminating or 
preventing the use of corticosteroids. 
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  
 
 
 
 


Clinical Study Protocol – Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 4.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 6 of 15 
Section No. and Name 
Description of Change 
Brief Rationale 
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. 
6.7. Concomitant Therapy 
Revised first paragraph as follows: 
“All over-the-counter and prescribed concomitant 
medications, blood products, all 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 clarify that the exclusion criterion about any 
change or expected (planned) change to 
anti-arrhythmic drugs should be 1 week before and 
after randomization 
 
Added siponimod and ozanimod to list of prohibited 
concomitant medications 
Due to recent approvals for these agents 


Clinical Study Protocol – Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 4.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 7 of 15 
Section No. and Name 
Description of Change 
Brief Rationale 
6.7.3. Prohibited Concomitant Therapy 
(Continued) 
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 (see 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. 
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” 
 
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.” 
Revised the seventh bullet point as follows: 
“OnFor onsite and offsite study day visits (see 
Section 9.6 and Table 7 and Table 8), subjects 
should take their study treatment at the study site 
after blood draws for PK and after all pre-dose 
assessments and procedures have been completed.” 
To indicate that only those procedures which require 
eCRF documentation should be documented. 
To account for multiple visit types. 
 
 
 
 
 
 


Clinical Study Protocol – Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 4.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 8 of 15 
Section No. and Name 
Description of Change 
Brief Rationale 
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. This 
will replace the provisions provided in the 
Pulmonary Function Testing communication of 
07 April 2020 and theCOVID-19 Memo 2. This will 
serve to replace the memo and communication. 
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 
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 
Revised the following sentences: 
“For the Week 12 through Week 48Visits, and ET 
Visit, a study visit window of ± 7 days is permitted. 
For the Week 52 Visit, a study visit window of 
± 14 days is permitted.” 
To enable critical visit assessments to be made in 
the event that facilities are inaccessible due to 
various logistic or operational constraints 


Clinical Study Protocol – Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 4.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 9 of 15 
Section No. and Name 
Description of Change 
Brief Rationale 
9.5. Follow-Up Period 
Appendix 1: Schedules of Assessments, 
Table 7: Schedule of Assessments, Footnote b 
Revised the following sentence: “If the Early 
Termination or Study Completion visit is ≥ 2 weeks 
after the last administration of study treatment, the 
2-Week Follow-Up visit is not required” 
For clarity and internal consistency given that the 
objective of the follow-up is to understand any 
withdrawal effect, so it must be timed from last dose 
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 completion 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 
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 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol – Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 4.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 10 of 15 
Section No. and Name 
Description of Change 
Brief Rationale 
9.10.4. Pulmonary Function Test 
Appendix 1: Schedules of Assessments, 
Table 7: Schedule of Assessments, Footnote q 
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 
Revised text to: 
“When available, DLCO measurements will also be 
performed. When DLCO is not available, sites 
should consult the Sponsor or Sponsor’s delegate.” 
To provide flexibility in location and capacity for 
DLCO measurements 
9.10.4. Pulmonary Function Test 
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. 


Clinical Study Protocol – Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 4.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 11 of 15 
Section No. and Name 
Description of Change 
Brief Rationale 
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 (eg, Week 12) 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 
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 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: 
o 
Retinal photographs 
o 
Intraocular pressure  
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol – Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 4.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 12 of 15 
Section No. and Name 
Description of Change 
Brief Rationale 
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” 
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” instead of “using last 
observation carry forward”. 
To reflect Arena’s current thinking on the missing 
data handling method 
 
 
 
 
 
 
 
 




Clinical Study Protocol – Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 4.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 14 of 15 
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: Schedules of Assessments, 
Table 7: Schedule of Assessments, Screening 
and 12-Week Treatment Period, 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) 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol – Summary of Changes 
APD334-301 
Phase 3, 52-Week Study in UC (ELEVATE UC 52) 
 
Amendment 4.0 
Arena Pharmaceuticals, Inc. 
Confidential 
Page 15 of 15 
Section No. and Name 
Description of Change 
Brief Rationale 
Appendix 1: Schedules of Assessments, 
Table 7: Schedule of Assessments, Footnotes p 
and q 
Split footnote “p” into “p” and “q” as follows: 
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 during 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 
(eg, Week 12), 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. 
To delineate and clarify the PFT timing information 
for the specific PFT assessments 
Appendix 1: Schedules of Assessments, 
Table 8: Schedule of Assessments 
Revised column header as follows: 
“W52/D365 ± 14 Days/Early Terminationa 
± 7 Days”  
To enable critical visit assessments to be made in 
the event that facilities are inaccessible due to 
various logistic or operational constraints 
Appendix 1: Schedules of Assessments 
Table 7: Schedule of Assessments, Footnote y 
Table 8: Schedule of Assessments, Footnote o 
Added “Biomarker sample collection is not required 
at Early Termination visit.” 
Footnote added to clarify sample collection needed 
at Early Termination 
Appendix 1: Schedules of Assessments, 
Table 7: Schedule of Assessments, Footnote r 
Table 8: Schedule of Assessments, Footnote h 
and Footnote i 
Revised second sentence in the footnote to: 
“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 
 

SAP_001.pdf: 
 
PROTOCOL APD334-301 
Statistical Analysis Plan 
 
 
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  
 
 
APD334-301 
 
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, 52-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 APD334-301 
Statistical Analysis Plan 
Page 1 of 79 
 
 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE  
Statistical Analysis Plan V1.0 (dated 19 January 2022) for Clinical Study Protocol APD334-301 
Amendment 4.0 
 
 
Name 
Signature 
Date 
Author: 
 
 
 
 
Position: 
Senior Biostatistician 
 
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 APD334-301 
Statistical Analysis Plan 
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MODIFICATION HISTORY  
Version 
Date of the 
Document Version 
Author 
Significant Changes from Previous 
Authorized Version 
1.0 
19 January 2022 
 
Not Applicable – First Version 
 


 
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Statistical Analysis Plan 
Page 3 of 79 
 
 
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 ......................................................................................................12 
2. 
STUDY OBJECTIVES ..............................................................................................12 
2.1. 
Primary Objective .......................................................................................................12 
2.2. 
Secondary Objectives .................................................................................................12 
2.3. 
Safety Objectives ........................................................................................................12 
2.4. 
Other Objectives .........................................................................................................12 
2.5. 
Estimands ....................................................................................................................12 
3. 
STUDY DESIGN .......................................................................................................15 
3.1. 
General Description ....................................................................................................15 
3.2. 
Schedules of Assessments ..........................................................................................16 
3.3. 
Changes to Analysis from Protocol ............................................................................16 
4. 
PLANNED ANALYSES ............................................................................................16 
4.1. 
Interim Analysis ..........................................................................................................16 
4.2. 
Final Analysis .............................................................................................................17 
5. 
ANALYSIS SETS ......................................................................................................17 
5.1. 
Screened Set ................................................................................................................17 
5.2. 
Randomized Set ..........................................................................................................17 
5.3. 
Full Analysis Set .........................................................................................................17 
5.4. 
Per Protocol Sets .........................................................................................................17 
5.5. 
Modified Full Analysis Set .........................................................................................18 
5.6. 
Safety Set ....................................................................................................................18 
5.7. 
Pharmacokinetic Set ...................................................................................................18 
6. 
GENERAL CONSIDERATIONS ..............................................................................19 
6.1. 
Reference Start Date and Study Day ..........................................................................19 
6.2. 
Baseline .......................................................................................................................19 
6.3. 
Retests, Unscheduled Visits, and Early Termination Data .........................................19 


 
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6.4. 
Windowing Conventions ............................................................................................19 
6.5. 
Statistical Tests ...........................................................................................................21 
6.6. 
Common Calculations ................................................................................................21 
6.7. 
General Study Information .........................................................................................22 
7. 
DETERMINATION OF SAMPLE SIZE ...................................................................22 
8. 
STATISTICAL CONSIDERATIONS .......................................................................23 
8.1. 
Multicenter Studies .....................................................................................................23 
8.2. 
Adjustments for Covariates and Factors to be Included in Analyses .........................23 
8.3. 
Missing Data ...............................................................................................................24 
8.4. 
Multiple Comparisons and Multiplicity......................................................................24 
8.5. 
Subgroup Analyses .....................................................................................................25 
9. 
OUTPUT PRESENTATIONS....................................................................................26 
10. 
DISPOSITION AND PROTOCOL DEVIATIONS ...................................................27 
11. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ....................................28 
11.1. 
Derivations ..................................................................................................................30 
12. 
MEDICAL HISTORY ................................................................................................30 
13. 
MEDICATIONS .........................................................................................................30 
14. 
STUDY TREATMENT EXPOSURE ........................................................................30 
14.1. 
Derivations ..................................................................................................................31 
15. 
STUDY TREATMENT COMPLIANCE ...................................................................31 
15.1. 
Derivations ..................................................................................................................31 
16. 
EFFICACY OUTCOMES ..........................................................................................32 
16.1. 
Primary Efficacy .........................................................................................................33 
16.1.1. 
Primary Efficacy Variables and Derivations ..............................................................33 
16.1.2. 
Missing Data Methods for Primary Efficacy Variables .............................................33 
16.1.3. 
Primary Analysis of Primary Efficacy Variables .......................................................34 
16.1.4. 
Sensitivity Analysis of Primary Efficacy Variables ...................................................35 
16.1.4.1. 
Multiple Imputation Under MAR ...............................................................................35 
16.1.4.2. 
Tipping Point Analysis ...............................................................................................36 
16.1.4.3. 
Multiple Imputation with Copy Reference .................................................................37 
16.1.4.4. 
Multiple Imputation with NRI to Handle Missing Data Due to COVID-19 
Pandemic .....................................................................................................................38 


 
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16.1.5. 
Supplementary Analysis of Primary Efficacy Variables ............................................38 
16.2. 
Key Secondary Efficacy .............................................................................................38 
16.2.1. 
Key Secondary Efficacy Variables and Derivations ..................................................39 
16.2.1.1. 
Endoscopic Improvement ...........................................................................................39 
16.2.1.2. 
Symptomatic Remission .............................................................................................39 
16.2.1.3. 
Corticosteroid-Free Clinical Remission and Sustained Clinical Remission ...............39 
16.2.1.4. 
Mucosal Healing .........................................................................................................40 
16.2.2. 
Missing Data Methods for Key Secondary Efficacy Variables ..................................40 
16.2.3. 
Primary Analysis of Key Secondary Efficacy Variables ............................................40 
16.2.4. 
Sensitivity Analysis of Key Secondary Efficacy Variables .......................................40 
16.2.5. 
Supplementary Analysis of Key Secondary Efficacy Variables ................................40 
16.3. 
Other Secondary Efficacy ...........................................................................................40 
16.3.1. 
Other Secondary Efficacy Variables ..........................................................................41 
16.3.2. 
Missing Data Methods for Other Secondary Efficacy Variables ...............................41 
16.3.3. 
Analysis of Other Secondary Efficacy Variables .......................................................41 
 
 
 
 
 
 
 
 
17. 
HEALTH-RELATED QUALITY OF LIFE AND HEALTHCARE 
RESOURCE UTILIZATION ANALYSIS ................................................................43 
17.1. 
Variables and Derivations ...........................................................................................44 
17.1.1. 
Inflammatory Bowel Disease Questionnaire ..............................................................44 
17.1.2. 
36-Item Short Form Health Survey, Version 2 ...........................................................44 
17.1.3. 
Work Productivity and Activity Impairment Questionnaire – Ulcerative 
Colitis ..........................................................................................................................44 
17.1.4. 
Urgency Numeric Rating Scale ..................................................................................44 
17.1.5. 
Abdominal Pain NRS .................................................................................................45 
17.1.6. 
UC-Related Hospitalizations and Surgeries ...............................................................45 
17.2. 
Missing Data Methods ................................................................................................45 
18. 
SAFETY OUTCOMES ..............................................................................................45 
18.1. 
Adverse Events ...........................................................................................................45 


 
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18.1.1. 
All TEAEs ..................................................................................................................45 
18.1.1.1. 
Severity .......................................................................................................................45 
18.1.1.2. 
Relationship to Study Treatment ................................................................................46 
18.1.2. 
TEAEs Leading to Discontinuation of Study Treatment ............................................46 
18.1.3. 
Serious and Non-Serious TEAEs ................................................................................46 
18.1.4. 
TEAEs Leading to Death ............................................................................................47 
18.1.5. 
TEAEs of Special Interest ..........................................................................................47 
18.1.6. 
Overall Summary of Adverse Events .........................................................................48 
18.2. 
Deaths .........................................................................................................................49 
18.3. 
Laboratory Evaluations ...............................................................................................49 
18.3.1. 
Safety Laboratory Evaluations ...................................................................................49 
18.3.2. 
Pregnancy Tests ..........................................................................................................51 
18.3.3. 
Other Screening Laboratory Assessments ..................................................................51 
18.4. 
ECG Evaluations ........................................................................................................51 
18.4.1. 
ECG Markedly Abnormal Criteria .............................................................................52 
18.5. 
Vital Signs ..................................................................................................................53 
18.5.1. 
Vital Signs Specific Derivations .................................................................................54 
18.5.2. 
Vital Signs Markedly Abnormal Criteria ...................................................................54 
18.6. 
Physical Examination .................................................................................................54 
18.7. 
Other Safety Assessments ...........................................................................................54 
18.7.1. 
Pulmonary Function Tests ..........................................................................................54 
18.7.1.1. 
PFT Markedly Abnormal and Potentially Important Criteria .....................................55 
18.7.2. 
Ophthalmoscopy and Optical Coherence Tomography ..............................................55 
18.7.3. 
Tuberculosis Screening and Chest X-Ray ..................................................................55 
19. 
EFFICACY-RELATED BIOMARKERS ..................................................................56 
20. 
PHARMACOKINETICS ...........................................................................................56 
21. 
DATA NOT SUMMARIZED OR PRESENTED ......................................................58 
REFERENCES ..............................................................................................................................60 
APPENDICES ...............................................................................................................................61 
 
 
 


 
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LIST OF APPENDICES  
APPENDIX 1: PROGRAMMING CONVENTIONS FOR OUTPUTS ....................................61 
APPENDIX 2: PARTIAL DATE CONVENTIONS ..................................................................63 
 
 
APPENDIX 4: IBDQ SCORING RULES ..................................................................................71 
APPENDIX 5: SF-36 SCORING RULES ..................................................................................72 
APPENDIX 6: WPAI-UC SCORING RULES ...........................................................................73 
APPENDIX 7: CLASSIFICATION OF RESCUE THERAPY ..................................................74 
 
LIST OF TABLES  
Table 1: 
List of Primary and Key Secondary Estimands ..........................................................13 
Table 2: 
Visit Windows for Efficacy and Safety Analyses ......................................................20 
Table 3: 
Planned Analyses by Endpoint ...................................................................................39 
Table 4: 
Markedly Abnormal Criteria for Vital Signs ..............................................................54 
 
LIST OF FIGURES  
Figure 1: 
Study Design ...............................................................................................................16 
Figure 2: 
Gatekeeping Procedure Summary ..............................................................................24 
 
 


 
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Statistical Analysis Plan 
Page 8 of 79 
 
 
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 


 
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Abbreviation 
Explanation 
eCRF 
electronic case report form 
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 quantitation 
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 


 
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Abbreviation 
Explanation 
NRS 
numeric rating scale 
OCT 
optical coherence tomography 
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 
ULN 
upper limit of normal 
ULQ 
upper limit of quantitation 


 
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Abbreviation 
Explanation 
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 APD334-301. 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 Amendment 4.0, dated 
22 December 2020.  
Analyses of the genetics (Clinical Study Protocol APD334-301 Section 9.9) 
 
 data 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 on clinical remission in subjects with 
moderately to severely active ulcerative colitis (UC) after 12 and 52 weeks of treatment. 
2.2. 
Secondary Objectives  
The secondary objective is to assess the efficacy of etrasimod on clinical response, symptomatic 
response and remission, endoscopic changes, corticosteroid-free remission, and mucosal healing 
in subjects with moderately to severely active UC at timepoints up to 52 weeks of treatment. 
2.3. 
Safety Objectives  
The safety objective is to assess the long-term safety of etrasimod after daily doses of 2 mg for 
up to 52 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 key secondary efficacy estimands to support regulatory decisions are described 
in Table 1. The analyses will be performed on the Full Analysis Set (FAS) as defined in 
Section 5.3. Other secondary efficacy variables (specified in Section 16.3.1) will have the 
population, intercurrent event handling strategy and population-level summary measure similar 
to the primary estimand. Supplementary analyses for the primary and the key secondary 
estimands will be performed on the modified Full Analysis Set (mFAS) and the Per Protocol 
populations, respectively (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 


 
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efficacy assessment. Refer to APPENDIX 7 for the definition of rescue therapies (medication 
and medical procedures). 
Table 1: 
List of Primary and Key Secondary Estimands  
Estimand 
Definition 
Attribute 
Population 
Variable/Endpoint 
Intercurrent Event 
Handling Strategy 
Population-Level 
Summary Measure 
Primary 
Estimand 1 
Efficacy of 
etrasimod on 
clinical 
remission at 
Week 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 
Primary 
Estimand 2 
Efficacy of 
etrasimod on 
clinical 
remission at 
Week 52 
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 52 
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 52 
Key 
Secondary 
Estimand 1 
Efficacy of 
etrasimod on 
endoscopic 
improvement 
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 
endoscopic 
improvement 
at Week 52 
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 52 
Same as the 
intercurrent event 
handling strategy for 
the primary 
estimand 
Difference between 
etrasimod and 
placebo in the 
endpoint at Week 52 
Key 
Secondary 
Estimand 3 
Efficacy of 
etrasimod on 
symptomatic 
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 


 
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Estimand 
Definition 
Attribute 
Population 
Variable/Endpoint 
Intercurrent Event 
Handling Strategy 
Population-Level 
Summary Measure 
Key 
Secondary 
Estimand 4 
Efficacy of 
etrasimod on 
symptomatic 
remission at 
Week 52 
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 52. 
Same as the 
intercurrent event 
handling strategy for 
the primary 
estimand 
Difference between 
etrasimod and 
placebo in 
proportion of 
responders at 
Week 52 
Key 
Secondary 
Estimand 5 
Efficacy of 
etrasimod on 
corticosteroid
-free clinical 
remission at 
Week 52 
Randomized 
subjects who 
receive at least 
1 dose of study 
treatment and 
with Baseline 
MMS 5 to 9 
The proportion of 
subjects with clinical 
remission at Week 52 
and who had not been 
receiving 
corticosteroids for ≥ 
12 weeks prior to 
Week 52 
Same as the 
intercurrent event 
handling strategy for 
the primary 
estimand 
Difference between 
etrasimod and 
placebo in 
proportion of 
responders at 
Week 52 
Key 
Secondary 
Estimand 6 
Efficacy of 
etrasimod on 
sustained 
clinical 
remission 
Randomized 
subjects who 
receive at least 
1 dose of study 
treatment and 
with Baseline 
MMS 5 to 9 
The proportion of 
subjects with sustained 
clinical remission 
(clinical remission at 
both Weeks 12 and 52) 
Same as the 
intercurrent event 
handling strategy for 
the primary 
estimand 
Difference between 
etrasimod and 
placebo in 
proportion of 
responders 
Key 
Secondary 
Estimand 7 
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 
proportion of 
responders at 
Week 12 
Key 
Secondary 
Estimand 8 
Efficacy of 
etrasimod on 
mucosal 
healing at 
Week 52 
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 52 
Same as the 
intercurrent event 
handling strategy for 
the primary 
estimand 
Difference between 
etrasimod and 
placebo in 
proportion of 
responders at 
Week 52 
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 7 for the definition of rescue therapies (medication and medical procedures). 
ES, endoscopic score; RB, rectal bleeding; SF, stool frequency; UC, ulcerative colitis. 


 
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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 Treatment Period, a 40-Week 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 placebo (once daily) in a double-blind fashion for up to 52 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 420 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, loss of response, or intolerance to 
conventional therapy and are naïve to biologic or JAK inhibitor therapy 
2. Subjects who have had an inadequate response, loss of response, 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 Treatment Period, subjects will undergo Week 12 efficacy and safety 
assessments and be evaluated for clinical response/remission as well as UC disease worsening. 
Subjects whose UC condition in the opinion of the Investigator has not improved or has 
worsened, compared with Baseline (Week 0/Day 1), as defined in Clinical Study 
Protocol APD334-301 Section 5.1.1 and who meet other eligibility criteria will have the option 
to enter an open-label extension (OLE) study (Study APD334-303). Subjects must complete 
Week 12 to be eligible for the OLE. Subjects who do not meet disease worsening criteria, 
including those demonstrating clinical response/remission at Week 12 will continue into the 
40-Week Treatment Period and continue their double-blind treatment. Subjects who either 
experience disease worsening in the 40-Week Treatment Period or complete all study procedures 
at Week 52 will have the option to enroll into the OLE study if they meet all eligibility criteria. 
Subjects who 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 The study design is 
outlined in Figure 1.  
 


 
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Figure 1: 
Study Design  
 
JAK, Janus kinase; UC, ulcerative colitis 
3.2. 
Schedules of Assessments  
Schedules of Assessments can be found in Clinical Study Protocol APD334-301 Appendix 1. 
3.3. 
Changes to Analysis from Protocol  
The primary analysis set for the efficacy endpoints is updated to the Full Analysis Set with MMS 
5 to 9. Subgroup definition related to MMS is updated accordingly. The entire FAS will be used 
in supplementary analyses. 
Definition of histologic improvement based on Geboes in Section 16 is updated from Geboes 
Index score < 3.1 to Geboes Index score ≤ 3.1. 
The criterion of “Exclusion of other causes for loss of response unrelated to underlying UC (eg, 
infection)” is removed from the definition of “loss of response” in Section 16 since a more 
conservative approach is used. 
 
 
4. 
PLANNED ANALYSES  
The following analyses will be performed for this study: 
• Final Analysis  
4.1. 
Interim Analysis  
There is no planned or unplanned interim analysis for this study.  


 
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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, which were not 
identified in this SAP, will be documented and reported in the clinical study report (CSR). Any 
results from these unplanned analyses will also be clearly identified in the text of the CSR (ICH 
1995). 
5. 
ANALYSIS SETS  
Agreement and authorization 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 the treatment to which they were randomized, regardless of 
treatment actually received. 
5.4. 
Per Protocol Sets  
The Per Protocol Set will be derived for Week 12 and Week 52, separately, and will consist of all 
subjects in the FAS who adhere to the protocol and complete Week 12 and Week 52, 
respectively. These sets 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 Week 12 Per Protocol Set if they meet any of the following 
criteria: 
• Overall study treatment noncompliance in the first 12 weeks (< 80 or > 120%) 
• Receive incorrect study treatment for > 7 days in total in the first 12 weeks 
• 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  


 
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• 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  
Subjects may be excluded from the Week 52 Per Protocol Set if they meet any of the following 
criteria: 
• Overall study treatment noncompliance (< 80 or > 120%) 
• Receive incorrect study treatment for > 7 days in total 
• Use rescue medication (new or dose increase from the highest dose received during 
Screening) or rescue medical procedure that may affect efficacy endpoint at Week 52 
• Miss Week 52 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 7 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 each of the Per Protocol Sets. 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 postrandomization 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. Also note, since the Mayo 
component scores on the disease worsening CRF are manually entered by sites from another 
CRF, these scores will not be used in the derivation of mFAS for measurement of either MMS or 
any of its component scores. 
5.6. 
Safety Set  
The Safety Set will include all randomized subjects who receive at least 1 dose of study 
treatment. Subjects will be analyzed 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 nonmissing 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 nonmissing 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 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 APD334-301 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. 


 
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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) 
72 to 99 
Week 16 (Day 113 ± 7) 
100 to 127 
Week 20 (Day 141 ± 7) 
128 to 155 
Week 24 (Day 169 ± 7) 
156 to 197 
Week 32 (Day 225 ± 7) 
198 to 253 
Week 40 (Day 281 ± 7) 
254 to 309 
Week 48 (Day 337 ± 7) 
310 to 351 
Week 52 (Day 365 ± 14) 
> 351 
For endoscopy/MMS/histology/all composite endpoints that include an endoscopy component and/or 
RB/SF component, Physician’s Global Assessment, health-related quality of life, ECGs, OCT, and PFT 
Scheduled Study Visit 
(Protocol Scheduled Day) 
Analysis Visit Window 
(Study Day) 
Baseline 
≤ 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 
Week 32 (Day 225 ± 7) [PFT only] 
198 to 253 (198 to 281 for assessments impacted by COVID-19 
pandemic)d 
Week 52 (Day 365 ± 14)b,d 
337 to 393 (337 to 421 for assessments impacted by COVID-19 
pandemic)e           
a Applicable only for subjects who require extended monitoring on Day 2 for vital signs and ECGs. 
b Applicable to all Week 12 and Week 52 efficacy endpoints based on any component of Mayo clinic score, such as clinical 
remission and symptomatic remission. Protocol visit window for PFT and OCT at Week 12 is Day 85 ± 7 (FDA 2020). 
c Due to overlapping windows at Week 12 and Week 8/16, a hierarchical algorithm will be used for the mapping. Week 12 will 
always be mapped first, then assess records for the Week 8/16 mapping. If a scheduled Week 8 and 12, or Week 12 and 16 visits 
are both present in the same visit window, they will be mapped to separate visits (ie, Week 8 and Week 12 or Week 12 and 
Week 16). 
d Due to overlapping windows in the RB/SF components at Week 52 and Week 48, a hierarchical algorithm will be used for the 
mapping. Week 52 will always be mapped first, then assess records for the Week 48 mapping. If a scheduled Week 48 and 52 
visits are both present in the same visit window, they will be mapped to separate visits (ie, Week 48 and Week 52). 
e 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. 


 
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For cardiac remonitoring upon treatment reinitiation after Day 2, as manifested by more than 
1 timed measurement in vital signs or electrocardiogram (ECG) parameters on the same 
collection date of an unscheduled visit, measurements will be mapped to analysis visit of Cardiac 
Remonitoring 1, Cardiac Remonitoring 2, etc. in the respective analysis dataset. For analysis, 
each timed measurement will be programmatically assigned to the nearest hourly timepoint (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 nonmissing 
measurement taken prior to Day 1 (including unscheduled assessments) will be labeled as 
“Baseline”. Unless stated otherwise, data from all visits including scheduled, unscheduled, and 
ET visits will be eligible for allocation to an analysis visit. The 2-Week and 4-Week Follow-Up 
visits will not be included in the visit windows and will be summarized separately without any 
window applied. 
If one or more results for a variable are assigned to the same analysis visit, the result with the 
date closest to the protocol scheduled day will be used in the analysis, except for component 
subscores of MMS or TMS, in which case, the composite score and component subscores from 
the same date will be used in the analysis. If 2 measurements in the same analysis visit window 
are equidistant from the protocol scheduled study day, the earliest measurement will be used in 
the analysis. If multiple assessments are available on the same day, then the average of the 
assessment will be used in the analysis, except for laboratory and ECG data where the 
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 8/16, a hierarchical algorithm will be 
applied as follows: 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 or Week 16 
study visit. The same algorithm will be used for Week 48 and Week 52, with Week 52 taking 
priority.  
6.5. 
Statistical Tests  
The default significance level will be 0.05; confidence intervals (CIs) 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 


 
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• 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, 420 total subjects (280 etrasimod, 140 placebo) are required to achieve 
93.4% power to detect a difference of 13.5% in the primary endpoint of clinical remission at 
Week 52 between the etrasimod treatment group (23.5%) and the placebo treatment group 
(10.0%). With this sample size, there will be 96% power to detect a difference of 12.5% in the 
other primary endpoint of clinical remission at Week 12, assuming a placebo rate at 6.0%. The 
lower bound of overall power for both primary endpoints (as coprimary endpoints), is at least 
90%; since the 2 primary endpoints are expected to be at least moderately, positively correlated, 
the actual overall power to reject both of their null hypotheses is likely to be greater than 90%. 
Workbook calculations from EAST® 6 statistical software are included below. 
 


 
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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 Section 16.1.2, Section 16.2.2, and 
Section 16.3.2. In the primary analysis of the primary endpoint and main analyses of all binary 
responder-type endpoints, all subjects with missing data, regardless of reason for missingness, 
will be considered as nonresponders. In the main analysis of continuous or score endpoints, such 
as biomarker measures, urgency Numeric Rating Scale (NRS), abdominal pain NRS, and 
HRQoL 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. First, the whole α will be spent on 
testing family 1 (F1) consisting of the coprimary endpoints. This study will be considered as an 
overall success only if both of the primary null hypotheses are rejected, each at the α level. This 
study will be considered as a partial success if only 1 of the 2 primary null hypotheses are 
rejected at α/2 if the other has p-value > α (FDA 2017). 
Figure 2 illustrates the parallel gatekeeping procedure, which will be followed to control the 
family-wise error rate. 
Figure 2: 
Gatekeeping Procedure Summary  
 
F1, family 1; F2, family 2, F3, family 3 
 
 


 
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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. 
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. 
• All 4 null hypotheses in F2 are rejected:  
α(F3) = α(F2) = 0.05 
• 3 of 4 null hypotheses in F2 are rejected:  
α(F3) = α(F2)-[fα(F2)+(1-f)*α(F2)/4] = 0.0075 
• 2 of 4 null hypotheses in F2 are rejected:  
α(F3) = α(F2)-2*[fα(F2)/2+(1-f)*α(F2)/4] = 0.005 
• 1 of 4 null hypotheses in F2 is rejected:  
α(F3) = α(F2)-3*[fα(F2)/3+(1-f)*α(F2)/4] = 0.0025 
8.5. 
Subgroup Analyses  
The following subgroups will be assessed for the primary and key secondary endpoints: 
• Sex (Female or Male) 


 
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• Age (≤ or > Median, < or ≥ 65) 
• Race (White or Non-White) 
• Region (North America, Western Europe, Eastern Europe, Other) 
• 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) 
• Baseline high-sensitivity C-reactive protein (≤ 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.  


 
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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 COVID-19 pandemic per 
CRF will also be summarized by nominal visit.  
During site monitoring, protocol deviations will be graded as Critical, Major, or Minor.  
According to ICH E3 and ICH E3(R1), important protocol deviations are a subset of protocol 
deviations that might significantly affect the completeness, accuracy, and/or reliability of the 
study data or that might significantly affect a subject's rights, safety, or well-being (ICH 1995, 
ICH 2012). For example, important protocol deviations might include enrolling subjects in 
violation of key eligibility criteria designed to ensure a specific subject population or failing to 
collect data necessary to interpret primary endpoints, as this may compromise the scientific value 
of the study.  
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 


 
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• 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 
COVID-19 pandemic (Yes or No). Additionally, a summary of missing endoscopy regardless of 
reason and missing endoscopy due to visit impacted by the COVID-19 pandemic will be 
presented by visit.  
11. 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS  
The following demographic data 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 


 
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• 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 
• 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 
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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). 
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 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 


 
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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 for both the first 
12 weeks and the entire study. 
15.1. 
Derivations  
Compliance to study treatment is based on the Drug Accountability eCRF and will be calculated 
as the total number of tablets taken (total dispensed – total returned) divided by the number of 
tablets expected during the Treatment Period, expressed as a percentage, refer to calculations 
below.  
The total number of tablets expected is defined as the number of tablets that a subject is expected 
to have taken between their first and last study treatment administration and is numerically 
identical to the subject’s overall study treatment exposure, since the medication is to be taken 
once daily. On any site visit day, the medication is to be held and taken at the site, after all 
predose assessments have been completed. For example, if a subject took their last dose of study 
treatment on Day 200 and returned to the site on Day 207 to return the study treatment bottle, 
then the total number of tablets expected would be 200, not 206.  
• Overall compliance to study treatment will be calculated as follows; total number of 
tablets returned subtracted from total number of tablets dispensed, divided by the 
duration of treatment, multiplied by 100  
For all bottles not returned, it will be assumed that all dispensed tablets were taken. For each 
subject, if a high percentage (> 25%) of bottles were not returned by a subject, additional 
analyses may be done where bottles not returned are excluded from the overall compliance 
calculation for the subject. In such analysis, the date of last dose or the date of last bottle return, 
whichever is earlier, will be used as the “date of last dose” in the calculation above.  
Both scheduled and unscheduled study treatment dispensations will be used in the compliance 
calculation. Overall compliance calculations will be performed for both the 12-Week Treatment 
Period and the entire study and will be used in determining inclusion/exclusion of subjects in the 
respective Per Protocol Set. For subjects discontinued prior to Week 12, their overall compliance 
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remained in the study beyond Week 12, the 12-Week total tablets expected will be defined as 
Date of Week 12 visit – Date of first dose, since their last dose in the 12-Week Treatment Period 
should have been taken on the day before Week 12 visit. 
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 a 
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 of 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 
• 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 


 
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• 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 
• Corticosteroid-free clinical remission: Clinical remission at Week 52 and who had not 
been receiving corticosteroids for ≥ 12 weeks prior to Week 52 
• Sustained clinical remission: Clinical remission at both Week 12 and Week 52 
• Loss of response: 
− Achieved clinical response at Week 12 
− A ≥ 2-point increase from Week 12 in the combined SF + RB scores and 
combined SF + RB score of ≥ 4, on 2 consecutive visits (≥ 7 days apart), and 
− Confirmed by centrally read ES ≥ 2 
16.1. 
Primary Efficacy  
16.1.1. 
Primary Efficacy Variables and Derivations  
The primary efficacy endpoints will compare etrasimod to placebo for:  
• The proportion of subjects achieving clinical remission at Week 12 
• The proportion of subjects achieving clinical remission at Week 52 
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. 
Multiplicity adjustments for the coprimary endpoints are discussed in Section 8.4. 
16.1.2. 
Missing Data Methods for Primary Efficacy Variables  
Subjects who 1) discontinue the study for worsening of disease, 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, nonmissing) 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 7 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 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 


 
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Protocol Set. For example, they will be excluded from the respective Per Protocol Set if they 
initiate a prohibited medication before the Week 12 or Week 52 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 analyses 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 the COVID-19 pandemic impact and nonresponder 
imputation (NRI) for missing data not due to the 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 (Week 12 Per Protocol Set for Week 12 endpoints and Week 52 Per Protocol 
Set for Week 52 endpoints) 
16.1.3. 
Primary Analysis of Primary Efficacy Variables  
The following hypotheses (H01 and H02) for the coprimary endpoints will be tested: 
H01: The proportion of subjects achieving clinical remission at Week 12 is the same between 
etrasimod and placebo.  
H11: The proportion of subjects achieving clinical remission at Week 12 is different between 
etrasimod and placebo.  
H02: The proportion of subjects achieving clinical remission at Week 52 is the same between 
etrasimod and placebo.  
H12: The proportion of subjects achieving clinical remission at Week 52 is different between 
etrasimod and placebo.  
Both hypotheses will be tested at the 2-sided α level, 0.05.  
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 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. 


 
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16.1.4. 
Sensitivity Analysis of Primary Efficacy Variables  
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 all use the FAS with Baseline MMS 5 to 9. There are 2 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-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 (eg, 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 50% 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 and Week 52, 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. 


 
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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 at Week 12 and 
Week 52. 
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. 
 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 and Week 52 
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 and Week 52 
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 and Week 52 based on the criteria specified in Clinical Study Protocol APD334-301 
Section 10.5. For each dataset, the proportion of responders and nonresponders will be 
calculated. 


 
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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 hypotheses are 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 
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 the observed data to impute 
postdiscontinuation missing values. 


 
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Step 1 (b)  
Only after Step 1a 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. 
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 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 Variables  
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 both primary 
endpoints 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 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 Section 16.1.3 and Section 16.1.4.4 
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. 


 
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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 
Corticosteroid-free clinical remission 
X 
 
X 
Mucosal healing 
X 
X (MI, MI-CR, and 
NRI + MI only) 
X 
Sustained clinical remission 
X 
 
X 
a Inference from the primary analysis method on the primary endpoints will be the gatekeeper for testing in the families 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. 
16.2.1. 
Key Secondary Efficacy Variables and Derivations  
16.2.1.1. Endoscopic Improvement  
For each of the 2 timepoints (Week 12 and Week 52): 
The null hypothesis is that the proportion of subjects achieving endoscopic improvement is the 
same between etrasimod and placebo.  
The alternative hypothesis is that the proportion of subjects achieving endoscopic improvement 
is different between etrasimod and placebo.  
16.2.1.2. Symptomatic Remission  
For each of the 2 timepoints (Week 12 and Week 52): 
The null hypothesis is that the proportion of subjects achieving symptomatic remission is the 
same between etrasimod and placebo. 
The alternative hypothesis is that the proportion of subjects achieving symptomatic remission is 
different between etrasimod and placebo. 
16.2.1.3. Corticosteroid-Free Clinical Remission and Sustained Clinical Remission  
For corticosteroid-free clinical remission: 


 
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The null hypothesis is that the proportion of subjects achieving corticosteroid-free clinical 
remission at Week 52 is the same between etrasimod and placebo. 
The alternative hypothesis is that the proportion of subjects achieving corticosteroid-free clinical 
remission at Week 52 is different between etrasimod and placebo. 
For sustained clinical remission: 
The null hypothesis is that the proportion of subjects achieving sustained clinical remission (ie, 
at both Week 12 and Week 52) is the same between etrasimod and placebo. 
The alternative hypothesis is that the proportion of subjects achieving sustained clinical 
remission (ie, at both Week 12 and Week 52) is different between etrasimod and placebo. 
16.2.1.4. Mucosal Healing  
For each of the 2 timepoints (Week 12 and Week 52): 
The null hypothesis is that the proportion of subjects with mucosal healing is the same between 
etrasimod and placebo. 
The alternative hypothesis is that the proportion of subjects with mucosal healing 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 endpoints 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 model described in 
Section 16.1.3 will be used. 
16.2.4. 
Sensitivity Analysis of Key Secondary Efficacy Variables  
For the key secondary endpoints of endoscopic improvement, symptomatic remission, and 
mucosal healing, the sensitivity analyses described in Section 16.1.4 will be used. 
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 as supplementary analyses 
with Baseline MMS 5 to 9. 
For the key secondary endpoints, analyses listed in Table 3 will be repeated in subjects with 
Baseline MMS 4 to 9.  
16.3. 
Other Secondary Efficacy  
Other secondary efficacy endpoints are defined in Section 16.  


 
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16.3.1. 
Other Secondary Efficacy Variables  
The other secondary endpoints are: 
• The proportion of subjects who had not received corticosteroids for ≥ 4 weeks and 
achieved clinical remission at Week 52 among subjects receiving corticosteroids at 
baseline 
• The proportion of subjects achieving clinical response at Week 52 
• The proportion of subjects achieving clinical response at Week 12 
• The proportion of subjects achieving clinical response at both Weeks 12 and 52 
• The proportion of subjects with mucosal healing at both Weeks 12 and 52 
• The proportion of subjects achieving endoscopic normalization at Week 52 
• The proportion of subjects achieving endoscopic normalization at Week 12 
• The proportion of subjects achieving endoscopic normalization at both Weeks 12 and 
52 
• The proportion of subjects achieving symptomatic remission at Weeks 2, 4, 8, 16, 20, 
24, 32, 40, and 48 
• The proportion of subjects achieving complete symptomatic remission at each study 
visit (Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52) 
• The proportion of subjects achieving noninvasive clinical response at each study visit 
(Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52) 
• The proportion of subjects achieving symptomatic response at each study visit 
(Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52) 
• The proportion of subjects achieving clinical remission at Week 52 among subjects in 
clinical response at Week 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, Week 12, and Week 52. 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, 


 
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will be analyzed using the stratified CMH model 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. 
36-Item Short Form Health Survey, Version 2  
The 36-Item Short Form Health Survey (SF-36) is a 36-item, subject-reported survey of subject 
health. The SF-36 consists of 36 questions measuring 8 health domains: Physical functioning, 
bodily pain, role limitations due to physical problems, role limitations due to emotional 
problems, general health perceptions, mental health, social function, and vitality. The subject’s 
responses are solicited using Likert scales that vary in length, with 3 to 6 response options per 
item. The SF-36 will 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 scores can be found in Appendix 5. 
17.1.3. 
Work Productivity and Activity Impairment Questionnaire – Ulcerative Colitis  
The Work Productivity and Activity Impairment Questionnaire – Ulcerative Colitis (WPAI-UC) 
consists of 6 questions asking about the effect of UC on the subject’s ability to work and perform 
regular activities. 
The percent work time missed due to problem (absenteeism), percent impairment while working 
due to problem (presenteeism), percent overall work impairment due to problem, and percent 
activity impairment due to problem are derived on the eCRF directly. Details about derivations 
can be found in Appendix 6. 
17.1.4. 
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). 


 
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17.1.5. 
Abdominal Pain NRS  
The abdominal pain NRS is a single item that measures the “worst abdominal pain in the past 
24 hours” using an 11-point NRS ranging from 0 (no pain) to 10 (pain as bad as can imagine). 
17.1.6. 
UC-Related Hospitalizations and Surgeries  
The UC-related hospitalizations 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. 
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 CRF will be presented. 
Exposure-adjusted incidence rate (EAIR) of TEAEs will be summarized by SOC and PT. 
Exposure is defined as the sum of either time (year) from first dose 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). 


 
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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, 
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 52 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 nonserious TEAEs will be summarized by SOC and PT. 


 
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18.1.4. 
TEAEs Leading to Death  
TEAEs leading to Death are those events which are recorded with an outcome as “Fatal” on the 
Adverse Events eCRF. A listing of TEAEs leading to death will be presented. 
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 52 will be used. If no event is 
observed, then the 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.  
TEAEs of special interest 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 
− 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 


 
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• 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 kth 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 52, 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 TEAE 
• Any related TEAE* 
• Any serious TEAEs 
• Any related serious TEAEs* 
• 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 


 
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* “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 differences between etrasimod and placebo along with 95% CIs using the Wilson’s score 
method will be presented.  
18.2. 
Deaths  
Information collected about death (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 
performing laboratory (eg, low, high). A full list of laboratory assessments to be included in the 
outputs is included in Clinical Study Protocol APD334-301 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) 


 
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• 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 × upper limit of normal (ULN) elevation in ALT 
− > 1 ×, 2 ×, 3 ×, 5 ×, 8 ×, 10 ×, 20 × ULN elevation in AST 
− > 3 ×, 5 ×, 10 ×, 20 × ULN elevation in either ALT or AST 
− > 1 ×, 1.5 ×, 2 ×, 3 × ULN elevation in total bilirubin 
− > 1 ×, 1.5 ×, 2 ×, 3 ×, 5 ×, 8 × ULN elevation in ALP 
− > 1 ×, 2 ×, 3 ×, 5 ×, 8 × ULN elevation in GGT 
− > 3 × ULN elevation in either ALT or AST and > 1.5 × ULN elevation in total 
bilirubin 
− > 3 × ULN elevation in either ALT or AST and > 2 × ULN elevation in total 
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 


 
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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 the 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. A 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  
ECGs are recorded on a 12-lead ECG machine and read centrally. The following ECG 
parameters are reported for this study: 
• HR (bpm) 
• PR interval (ms) 
• RR interval (ms) 
• QRS interval (ms) 
• QT interval (ms) 
• QTcF interval (ms)  
• Overall interpretation of ECG (Investigator’s judgment): 
− Normal 
− Abnormal, Not Clinically Significant (Abnormal NCS) 
− Abnormal, Clinically Significant (Abnormal CS) 


 
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• 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: 
− > 30 ms increase from Baseline 
− > 60 ms increase from Baseline 
In shift tables, subjects will be classified according to each 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). 


 
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18.5. 
Vital Signs  
The following vital signs measurements are 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) 
• 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) 


 
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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 mm Hg  
> 150 mm Hg 
DBP 
mm Hg 
≤ 50 mm Hg 
> 90 mm Hg 
Heart rate 
bpm 
< 40 bpm 
> 100 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 
 
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 
• Forced Expiratory Flow (FEF) 25-75 


 
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• 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 TB results and chest X-rays will be listed. Results of TB 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. Additionally, PK samples will be collected prior to dosing 
(trough) at Weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, 48, and 52, 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 


 
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average steady-state trough plasma concentration (Ctrough,ss) based on Week 2 to Week 52 trough 
concentrations (Ctrough,ss,W2-W52), exposure-response analysis, and/or population PK analysis, but 
will still be reported in the study result listings. 
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, tobacco use, nominal timepoint, actual blood collection date/time, concentration, 
and time since last dose and also summarized using descriptive statistics (n, mean, SD, %  CV, 
geometric mean, geometric % CV, median, minimum, and maximum) by nominal timepoint. 
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 52 trough concentrations (Ctrough,ss,W2-W52) 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 52) will be plotted on 
linear scales. Additionally, a mean (± SD) concentration-time plot with etrasimod and 
metabolites overlaid on linear and semi-logarithmic 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 52), and Ctrough,ss,W2-W52 will be plotted versus nominal 
timepoint on ordinal scale.  
Individual subject plasma concentrations versus actual time (Weeks 0 to 52) will be plotted since 
start of treatment on linear and semi-logarithmic scales. Individual subject plots with etrasimod 
and metabolite concentration data will be overlaid on the same plot. 
Scatter plots of individual subject average steady-state Ctrough ss,W2-W52 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, 
p-value, and locally estimated scatterplot smoothing (LOESS) trend line. 
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, p-value, and LOESS trend line (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 absolute change from Baseline in MMS versus etrasimod 
steady-state Ctrough at Week 52 
• Individual subject lymphocytes versus etrasimod steady-state Ctrough at Week 52 and 
grouped all visits (Weeks 2 through 52 pooled) 


 
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• Individual subject absolute changes from Baseline in lymphocytes versus etrasimod 
steady-state Ctrough at Week 52 and grouped all visits (Weeks 2 through 52 pooled) 
• Individual subject percent changes from Baseline in lymphocytes versus etrasimod 
steady-state Ctrough at Week 52 and grouped all visits (Weeks 2 through 52 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 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 52) 
• Mean (SD) absolute change from Baseline in lymphocytes and mean (SD) etrasimod 
concentration versus nominal timepoint (Weeks 0 through 52) 
• Mean (SD) percent change from Baseline in lymphocytes and mean (SD) etrasimod 
concentration versus nominal timepoint (Weeks 0 through 52) 
• Mean (SD) heart rate and mean (SD) etrasimod concentration versus nominal 
timepoint (Weeks 0 through 52) 
• Mean (SD) absolute change from Baseline in heart rate and mean (SD) etrasimod 
concentration versus nominal timepoint (Weeks 0 through 52)  
All summary figures for etrasimod plasma concentrations and for change from Baseline in MMS 
versus etrasimod steady-state Ctrough will be repeated by: 
• 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 


 
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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. 
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. Statistical considerations for clinical trials during the COVID-19 public health emergency. 
U.S. Department of Health and Human Services, Food and Drug Administration. Guidance for 
Industry Web site. https://www.fda.gov/media/139145/download. Published 2020. Accessed 
February 19, 2021. 
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). 
• 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 bioanalytical 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. 


 
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DATES AND TIMES 
Depending on data available, dates and times will take the form DDMMMYYYY or 
DDMMMYYYY:hh:mm. 
SPELLING FORMAT 
English US. 
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in 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, Week 2, Week 4, Week 8, Week 12, 
Week 16, Week 20, Week 24, Week 32, Week 40, 
Week 48, and Week 52 
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 health (4 items), role limitations due to emotional problems (3 items), 
vitality (4 items), mental health (5 items), social functioning (2 items), bodily pain (2 items), and 
general health (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 health: 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 functioning: Questions 20, 32 
• Bodily Pain: Questions, 21, 22 
• General health: 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: 
CLASSIFICATION OF RESCUE THERAPY  
This appendix outlines the algorithm for the Arena clinical team/medical reviewers to classify 
rescue therapies for ulcerative colitis (UC) in a blinded manner. This will help establish 1) 
intercurrent events for the efficacy estimands, and 2) whether a subject will be excluded from the 
Per Protocol Set(s). All rescue therapies identified by the medical reviewers per the algorithm 
below will be imported in programming. This process will be repeated until database lock and 
the list of all rescue therapies identified will be finalized before study unblinding. 
Only medications and medical procedures reported on the electronic case report forms (eCRFs) 
can be assessed whether they are rescue therapy for UC. If the exposure happens in the follow-up 
period (beginning on or after the date of last study treatment administration), then it would not be 
considered as a rescue therapy. Impact of rescue therapy use in the analysis is timing-dependent, 
eg, if a subject starts a rescue therapy between their Week 12 and Week 52 endpoint 
assessments, then it may have potential impact on Week 52 endpoint analysis but will have no 
impact on Week 12 endpoints. The rules outlined below apply to both new use and increase in 
dose from Baseline. 
 
Biologics with immunomodulatory properties 
• Rule:  
o Any exposure after first dose 
• List of medications: 
o AntiTNFα antibodies:  
▪ ADALIMUMAB 
▪ CERTOLIZUMAB 
▪ CERTOLIZUMAB PEGOL 
▪ GOLIMUMAB 
▪ INFLIXIMAB 
o Other Biologics: 
▪ USTEKINUMAB 
▪ VEDOLIZUMAB 
Nonbiologics with immunomodulatory properties  
• Immunosuppressants 
o Rules to consider for Week 12 efficacy endpoints: 
▪ After first dose and up to and including Week 8: any increase from 
baseline for more than 5 days  
▪ After Week 8: Any dose above baseline  


 
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o Rules to consider for Week 52 efficacy endpoints: 
▪ After Week 12 and up to and including Week 40: any increase from 
baseline for more than 5 days  
▪ After Week 40: Any dose above baseline  
o List of medications:  
▪ MERCAPTOPURINE 
▪ AZATHIOPRINE 
▪ TIOGUANINE 
▪ METHOTREXATE 
▪ METHOTREXATE SODIUM 
• 5-ASA COMPOUNDS 
o Rules to consider for Week 12 efficacy endpoints: 
▪ After first dose and up to and including Week 8: any increase from 
baseline for more than 5 days  
▪ After Week 8: Any dose above baseline  
o Rules to consider for Week 52 efficacy endpoints: 
▪ After Week 12 and up to and including Week 40: any increase from 
baseline for more than 5 days  
▪ After Week 40: Any dose above baseline  
o List of medications:  
▪ MESALAZINE 
▪ BALSALAZIDE 
▪ BALSALAZIDE DISODIUM DIHYDRATE 
▪ BALSALAZIDE SODIUM 
▪ OLSALAZINE SODIUM 
▪ SULFASALAZINE 
▪ BECLOMETASONE W/MESALAZINE 
o Routes: 
▪ ORAL 
▪ RECTAL 
• Other small molecule immunomodulatory active agents  
o Rules to consider for Week 12 efficacy endpoints:  


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


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


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


 
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▪ BECLOMETASONE DIPROPIONATE 
▪ BECLOMETASONE W/MESALAZINE 
o Routes: 
▪ ORAL 
▪ RECTAL 
Medical procedures 
• Leukocyte apheresis, other apheresis, and plasma exchange  
o Rule:  
▪ Any exposure after first dose 
o List of medical procedures  
▪ APHERESIS 
▪ LEUKAPHERESIS 
▪ COLECTOMY (partial or total) 
▪ SIGMOIDECTOMY 
▪ COLOSTOMY 
▪ ILEOSTOMY 
 


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