Conditions: Ulcerative Colitis
Keywords: Ulcerative Colitis APD334 Etrasimod
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 54
Healthy volunteers: no

Brief summary:
The purpose of this Japan-only study is to assess the safety and efficacy of etrasimod at 2 doses in Japanese subjects with moderately to severely active ulcerative colitis (UC) when administered for 12 weeks.

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None

Interventions: intervention 1: Etrasimod intervention 2: Etrasimod intervention 3: Placebo
Intervention descriptions: intervention 1: Etrasimod tablet by mouth, once daily for 12 weeks intervention 2: Etrasimod tablet by mouth, once daily for 12 weeks intervention 3: Etrasimod matching placebo tablet by mouth, once daily up to 12 weeks

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL
Protocol title:
A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 12-Week 
Dose-Ranging Study to Assess the Efficacy and Safety of Etrasimod in Japanese 
Participants with Moderately to Severely Active Ulcerative Colitis
Brief title:
Etrasimod Dose-Ranging Versus Placebo as Induction Therapy in Moderately to 
Severely Active Ulcerative Colitis
Protocol 
number:
APD334-203(C5041007)
Version:
Amendment 1.0, 12 January 2023
Study drug:
Etrasimod (APD334)
Indication:
Ulcerative colitis
Phase:
2
Sponsor name:
Arena Pharmaceuticals Inc., a wholly owned subsidiary of Pfizer Inc.
Confidentiality Statement
This document contains confidential information of Arena Pharmaceuticals Inc., a wholly owned 
subsidiary of Pfizer Inc. Unauthorized distribution, copying, or disclosure is strictly prohibited unless 
required by applicable law. Persons receiving this information must be notified that it is confidential 
and may not be further distributed, copied, or disclosed.
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Clinical Study Protocol
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Phase 2, 12-Week Study in UC
Amendment 1.0
Arena Pharmaceuticals Inc.
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PROTOCOL HISTORY
Document
Amendment Type
Date
Amendment 1.0
Global
12 January 2023
Original Protocol
Not applicable
09 February 2021
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Clinical Study Protocol
APD334-203 (C5041007)
Phase 2, 12-Week Study in UC
Amendment 1.0
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PROTOCOL SYNOPSIS
Sponsor: Arena Pharmaceuticals Inc.
Name of investigational study drug: Etrasimod (APD334)
Protocol number: APD334-203
Protocol title: A Phase 2, Randomized, Double-Blind, Placebo-Controlled, 12-Week 
Dose-Ranging Study to Assess the Efficacy and Safety of Etrasimod in Japanese participants with 
Moderately to Severely Active Ulcerative Colitis
Phase: 2
Region: Japan
Objectives:
Primary:
The primary objective is to assess the efficacy of etrasimod at 2 doses (1 and 2 mg) on clinical 
remission in Japanese participants with moderately to severely active ulcerative colitis (UC) when 
administered for 12 weeks.
Secondary:
The secondary objective is to assess the efficacy of etrasimod at 2 doses (1 and 2 mg) on clinical 
response, symptomatic remission, endoscopic improvements, and mucosal healing in Japanese 
participants with moderately to severely active UC when administered for 12 weeks.
Safety:
The safety objective is to assess the safety of etrasimod at 2 doses (1 and 2 mg) for 12 weeks in 
Japanese participants with moderately to severely active UC.
Other:
Other objectives include evaluation of etrasimod pharmacokinetics (PK) and the effect of 
etrasimod on health-related patient-reported outcomes and biomarkers.
Study Design:
This is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate 
the efficacy and safety of etrasimod 1 and 2 mg in Japanese participants with moderately to 
severely active UC. The study consists of a 28-Day Screening Period, a 12-Week Induction 
Treatment Period, and a 4-Week Follow-Up Period.
The target participant population will include those who have had an inadequate response to, loss 
of response to, or intolerance to the following:
1. Conventional therapy, and are naïve to biologic or Janus kinase (JAK) inhibitor therapy
2. Biologics or JAK inhibitors (participants in this category may have received prior conventional 
therapy)
Participant 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 participants will be randomized (1:1:1 ratio) to receive either etrasimod (1 mg once daily), 
etrasimod (2 mg once daily), or matching placebo (once daily) in a double-blind fashion for 
12 weeks. Randomization will be stratified by (a) naive 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).
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Phase 2, 12-Week Study in UC
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At the end of the 12-Week Induction Treatment Period, participants will undergo the Week 12 
study assessments. Participants will then have the option to enter an open-label extension (OLE) 
study (Study APD334-303) following completion of Week 12 study procedures provided they meet 
all eligibility criteria for the OLE. Participants must complete Week 12 to be eligible for the OLE. 
Participants who do not participate in the OLE study will have 2-Week and 4-Week Follow-Up 
visits after the last treatment administration.
Number of Participants (planned):
A total of 96 participants are planned to be randomized in the study, with 32 participants expected 
in each of the 3 treatment groups.
Eligibility criteria:
Inclusion criteria:
Participants must meet ALL of the following inclusion criteria to be eligible for enrollment into the 
study:
1.
Japanese ancestry (ie, both parents and 4 grandparents are/were of Japanese descent)
2.
18 to 80 years of age, inclusive, at the time of consent
3.
Ability to provide written informed consent and to be compliant with the schedule of protocol 
assessments
Disease-specific inclusion criteria:
4. 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.
5. Active UC confirmed by endoscopy with ≥10 cm rectal involvement
6. Moderately to severely active UC defined as MMS of 4 to 9, including an ES ≥2 and RB 
subscore ≥1
7. Received a surveillance colonoscopy (performed according to local standard) within 12 months 
before baseline to rule out dysplasia in participants with pancolitis > 8 years duration or 
participants with left-sided colitis > 12 years duration. Participants 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:
8. 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.
Systemic (oral or IV) Corticosteroids
c.
Thiopurines (eg, azathioprine [AZA], or 6-mercaptopurine [6-MP])

Biologics or JAK inhibitors therapy
a.
Anti-tumor necrosis factor alpha (TNFα) antibodies (eg, infliximab, adalimumab, 
golimumab, or biosimilars)
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Phase 2, 12-Week Study in UC
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b.
Anti-integrin antibodies (eg, vedolizumab, carotegrast methyl)
c.
Anti-interleukin 12/23 antibodies (eg, ustekinumab)
d.
JAK inhibitors (eg, tofacitinib)

Note: To be considered inadequate response, loss of response, and intolerance after treatment 
with a biologic or JAK inhibitor, the participant should have received a dosing regimen 
consistent with the local product labeling, local guidelines for the treatment of UC and/or 
institutional standard of care.
Concomitant treatments:
9. Participants 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 or equivalent 
steroid) provided the dose has been stable for the 4 weeks immediately prior to the 
screening endoscopy assessment

Thiopurines such as oral AZA or 6-MP must be discontinued ≥2 weeks prior to 
randomization

Probiotics (eg, 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:
10. 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
11. 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. Participants with an isolated total bilirubin and normal AST and ALT diagnosed 
with Gilbert’s syndrome may participate
12. 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
13. 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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Phase 2, 12-Week Study in UC
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b.
Non-pregnant female of childbearing potential must agree to using a highly 
effective contraception method during treatment and for 30 days following 
treatment that can achieve a failure rate of less than 1% per year when used 
consistently and correctly. The following are considered highly effective birth 
control methods:

Combined (estrogen and progestogen containing) oral hormonal contraception 
associated with inhibition of ovulation

Progestogen-only oral hormonal contraception associated with inhibition of 
ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system

Bilateral tubal occlusion

Vasectomized partner, provided that partner is the sole sexual partner of the
women of childbearing potential trial participant and that the vasectomized partner 
has received medical assessment of the surgical success

Sexual abstinence (complete sexual abstinence defined as refraining from 
heterosexual intercourse for the entire period of risk associated with study 
treatments). The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the clinical study and the preferred and usual lifestyle of the 
participant. Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
is not acceptable.
c.
A male participant 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:
Participants 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 participant 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 (CD) or indeterminate colitis or the presence or history of a 
fistula consistent with CD
3.
Diagnosis of isolated proctitis (defined as proctitis with < 10 cm rectal involvement), 
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 intravenous (IV) steroids given is acceptable)
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Phase 2, 12-Week Study in UC
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5.
Positive assay or stool culture for pathogens (ova and parasite examination, bacteria) or 
positive test for Clostridioides difficile toxin at screening (If C. difficile is positive, the 
participant 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 participant 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 (AV) 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 pre-randomization 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 pre-randomization 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 
participants with diabetes with significant comorbid conditions such as retinopathy
11. History of macular edema or retinopathy
12. History of active tuberculosis (TB), history of untreated or inadequately treated latent TB 
infection, active or latent TB infection at screening. The following are EXCEPTIONS to this 
exclusion criterion:

Participants 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

Participants 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. Participants will complete their prophylactic regimen during the trial
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Phase 2, 12-Week Study in UC
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13. A clinically significant active infection (eg, serious and/or atypical) ≤28 days prior to 
randomization, required IV medication ≤14 days prior to randomization, or that may worsen 
(in the opinion of the Investigator) if the participant 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 (positive for hepatitis B surface antigen [HBsAg]), or 

negative for HBsAg and positive for hepatitis B core antibody [HBcAb] and negative 
for hepatitis B surface antibody [HBsAb] in conjunction with detectable HBV DNA, or 

negative for HBsAg and negative for HBcAb and positive for HBsAb in conjunction 
with detectable HBV DNA, or

negative for HBsAg and positive for HBcAb and positive for HBsAb 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 [PML]) or a history of disseminated herpes 
simplex or disseminated herpes zoster
18. History of or currently active primary or secondary immunodeficiency
19. History of cancer within the last 5 years, including solid tumors and hematological 
malignancies (except basal cell and in situ squamous cell carcinomas of the skin that have 
been excised and resolved) or colonic mucosal dysplasia
20. History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, or 
multiple myeloma
Exclusions related to medications:
21. Hypersensitivity to etrasimod or any of the excipients or placebo compounds
22. Prior treatment with sphingosine 1-phosphate (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. Prior treatment with ≥ 3 advanced therapies (eg, biologics or JAK inhibitors) approved or 
recommended for treatment of UC
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 or 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
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Phase 2, 12-Week Study in UC
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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. Use of moderate or strong inhibitors or inducers that inhibit or induce at least 2 of the 
following: cytochrome P450 (CYP) 2C8, CYP2C9 and CYP3A4 (eg, fluconazole, rifampin, 
enzalutamide) within 4 weeks prior to randomization
Test product, dose, and mode of administration:
Etrasimod, 1 and 2 mg tablets, by mouth, once daily
Study duration:
The overall duration of this study is expected to be approximately 2 years.
Reference therapy, dose, and 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.
Definitions:

Clinical remission: Defined as an 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)

Symptomatic remission: SF subscore = 0 (or = 1 with a ≥1-point decrease from baseline) 
and RB subscore = 0

Mucosal healing: ES ≤1 (excluding friability) with histologic remission defined as a 
Geboes Index score < 2.0

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

Endoscopic normalization: ES = 0
Primary efficacy endpoint:

Proportion of participants achieving clinical remission at Week 12
Secondary efficacy endpoints:

The proportion of participants achieving endoscopic improvement at Week 12

The proportion of participants achieving symptomatic remission at Week 12

The proportion of participants with mucosal healing at Week 12

The proportion of participants achieving clinical response at Week 12

The proportion of participants achieving endoscopic normalization at Week 12
Pharmacokinetic assessments:
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Phase 2, 12-Week Study in UC
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Plasma concentrations of etrasimod will be assessed from samples collected predose and 4 hours 
postdose (after 12-lead ECG) on Week 0/Day 1, and predose (trough) at Weeks 2, 4, 8, and 12, and 
at 2--Week and 4--Week Follow--Up visits. A PK sample should also be drawn, if possible, at the 
time of any serious adverse event (SAE) or adverse event leading to study treatment 
discontinuation.
Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method 
validation purposes, stability assessments, metabolite assessments, or to assess other actions of 
etrasimod with plasma constituents.
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
Other assessments:
Biomarker endpoints:

Change from baseline in level of fecal calprotectin at Weeks 2, 4, 8, and 12

Change from baseline in level of high-sensitivity C reactive protein at Weeks 2, 4, 8, and 12

Change and percentage change from baseline in lymphocyte counts at Weeks 2, 4, 8, and 12
Health-related Patient-Reported Outcome endpoints:

Scores and change from baseline at Week 12 for the following:

Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms (UC-PRO/SS), if 
available

Medical Outcomes Study 36-Item Short Form Health Survey, version 2 physical and 
mental component and domain scores (SF-36)

Proportion of participants with UC -related hospitalizations

Proportion of participants requiring UC -related surgeries, including colectomy
Statistical methods:
Sample size:
Based on a Chi-square test at 2-sided significance level of 0.05, a total of 96 participants (32 per 
treatment group) will provide at least 80% power to show pairwise superiority of etrasimod 2 mg to 
placebo in the primary endpoint assuming 5% remission rate in the placebo group and a 
31.5% remission rate in the etrasimod 2 mg group. The assumptions are based on the results from 
the completed Phase 2 Study APD334-003. Sample size is calculated using the EAST® software.
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Phase 2, 12-Week Study in UC
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Efficacy analysis
The analysis of all 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 
participants in remission, remission percentages, difference in remission percentages, odds ratio, 
and associated 95% confidence intervals and p-values. The stratified CMH analysis will be 
performed for each etrasimod dose (1 and 2 mg) versus placebo separately. The Cochran-Armitage 
trend test will also be carried out for all primary and secondary proportion-based efficacy 
endpoints.
Testing Strategy
There are multiple null hypotheses for the comparison of etrasimod and placebo in the primary and 
secondary efficacy 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.
A hierarchical testing procedure will be used to control family-wise Type I error rate at α level 0.05 
(2-sided). The comparison of etrasimod 2 mg versus placebo for the primary endpoint (Family 1; 
F1) is the main gatekeeper. The study is considered positive if F1 is rejected at the α level. Only if 
this test is significant will etrasimod 2 mg be compared with placebo for all the secondary 
endpoints (Family 2; F2). The truncated Hochberg method (Dmitrienko 2011, FDA 2017) will be 
applied to F2 at α level.
If none of the null hypotheses in F2 is rejected, then testing will stop with all nominal p-values 
reported for subsequent comparisons of etrasimod 1 mg versus placebo. Otherwise, etrasimod 1 mg 
be compared with placebo for the primary endpoint (Family 3; F3) with the unused α from testing 
F2. Only if this test is significant will etrasimod 1 mg be compared with placebo for all the 
secondary endpoints (Family 4; F4). The conventional Hochberg method (FDA 2017) will be 
applied to F4 with the same unused α for F3.
Pharmacokinetic analysis
A descriptive summary of observed plasma concentration will be displayed by time and by 
treatment group.
Safety analysis
All safety data will be listed and summarized by treatment group. All treatment-emergent adverse 
events will be coded using the latest version of the Medical Dictionary for Regulatory Activities 
and tabulated by System Organ Class and Preferred Term. Incidence of adverse events, SAEs, and 
adverse events leading to discontinuation will be summarized and presented in descending order of 
frequency. Associated laboratory parameters such as hepatic enzymes, renal function, and 
hematology values will be grouped and presented together. Individual participant values will be 
listed and values outside of the standard reference range will be flagged. Shift tables and analyses 
of changes from baseline will be produced.
Full details of efficacy, safety, and PK analyses will be provided in the Statistical Analysis Plan. 
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TABLE OF CONTENTS
PROTOCOL HISTORY............................................................................................................2
PROTOCOL SYNOPSIS ..........................................................................................................3
LIST OF TABLES...................................................................................................................12
LIST OF FIGURES .................................................................................................................12
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................13
LIST OF TABLES
Table 1:
Study Treatments......................................................................................31
Table 2:
Procedures to be Performed During the Monitoring Period.....................41
Table 3:
Discharge Criteria After Cardiac Monitoring...........................................42
Table 4:
Discontinuation of Study Treatment Related to Postdose Cardiac 
Monitoring................................................................................................43
Table 5:
Clinical Laboratory Tests .........................................................................53
Table 6:
Schedule of Assessments – Screening and Induction Treatment 
Period........................................................................................................75
LIST OF FIGURES
Figure 1:
Study Design.............................................................................................21
Figure 2:
Progressive Multifocal Leukoencephalopathy Case Evaluation 
Algorithm..................................................................................................86
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
5-ASA
5-aminosalicylic acid
ADL
activities of daily living
ADR
adverse drug reaction
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
APD334
etrasimod
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AV
atrioventricular
AZA
azathioprine
β-hCG
beta-human chorionic gonadotropin
BP
blood pressure
bpm
beats per minute
CBC
complete blood count
CD
Crohn’s disease
CFR
Code of Federal Regulations
cGMP
current Good Manufacturing Practices
CI
confidence interval
Cmax
maximum observed plasma or serum concentration
CMH
Cochran-Mantel-Haenszel
CMP
clinical monitoring plan
COVID-19
coronavirus disease 2019
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
DNA
deoxyribonucleic acid
ECC
emergency contact card
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Abbreviation
Definition
ECG
electrocardiogram
eCRF
electronic case report form
EDB
exposure during breastfeeding
EDC
electronic data capture
EDP
exposure during pregnancy
eDiary
electronic diary
EIMs
extraintestinal manifestations
ES
endoscopic score
ET
Early Termination
FAS
Full Analysis Set
FDA
Food and Drug Administration
FEV1
forced expiratory volume at 1 second
FVC
forced vital capacity
GCP
Good Clinical Practice
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
heart rate
hs-CRP
high-sensitivity C-reactive protein
IB
Investigator’s Brochure
IBD
inflammatory bowel disease
ICCC
In-Country Caretaker for Clinical Trial
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IGRA
interferon-gamma release assay 
IND
Investigational New Drug
IOIBD
International Organization for the Study of Inflammatory Bowel Diseases
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Abbreviation
Definition
IRB
Institutional Review Board
IUD
intrauterine device
IV
intravenous
IWRS
Interactive Web Response System
JAK
Janus kinase
6-MP
6-mercaptopurine
MAR
missing at random
MCS
Mayo Clinic score
MedDRA
Medical Dictionary for Regulatory Activities
mFAS
modified Full Analysis Set
MMF
mycophenolate mofetil
MMS
modified Mayo score
MQI
medically qualified individual
NF
National Formulary
NRS
numeric rating scale
NSAID
nonsteroidal anti-inflammatory drugs
OCT
optical coherence tomography
OLE
open-label extension
PD
protocol deviation
PD
pharmacodynamic(s)
PFT
pulmonary function test
PGA
Physicians Global Assessment 
Ph. Eur.
European Pharmacopoeia
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PPD
purified protein derivative
QTcF
Fridericia’s corrected QT interval
RB
rectal bleeding
RNA
ribonucleic acid
S1P
sphingosine 1-phosphate 
S1P1,4,5
sphingosine 1-phosphate receptor subtypes 1, 4, and 5
SAE
serious adverse event
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Abbreviation
Definition
SAP
Statistical Analysis Plan
SARS CoV 2
Severe acute respiratory syndrome coronavirus 2
SF
stool frequency
SF-36
Medical Outcomes Study 36-Item Short Form Health Survey
SOP
standard operating procedures
TB
tuberculosis
TBNK
T cell, B cell, natural killer cell
TEAE
treatment-emergent adverse event
TMF
Trial Master File
TMS
Total Mayo Score
TNF
tumor necrosis factor
TNFα
tumor necrosis factor alpha
TST
tuberculin skin test
UC
ulcerative colitis
UC-PRO/SS
Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms
UGT
uridine 5’-diphospho-glucuronosyltransferase
ULN
upper limit of normal
US
United States
USP
United States Pharmacopeia
WBC
white blood cell
WHO
World Health Organization
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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 patients 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 subtypes 1, 4, 5 (S1P1,4,5) 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 participants 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. 
In 2 recently completed Phase 3 studies (APD334-301 and APD334-302), treatment with etrasimod 2 
mg resulted in statistically significant and clinically meaningful improvements based on clinical, 
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endoscopic, symptomatic, and endo-histologic endpoints in adults with moderately to severely active 
UC. No new safety findings were observed with etrasimod 2 mg treatment for up to 52 weeks 
(Sandborn 2022). An Open-Label Extension (OLE) study (APD334-303) to evaluate the long-term 
efficacy and safety of etrasimod in participants with moderately to severely active UC is currently 
ongoing.
Refer to the current edition 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 participants.
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 
participants at single doses up to 5 mg and repeat doses up to 4 mg once daily. Repeated doses of 
2 mg have been evaluated in Phase 2 studies of participants 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.
A Japanese/Caucasian ethnobridging pharmacokinetic (PK) and pharmacodynamic (PD) study 
(Study APD334-109) was conducted that demonstrated etrasimod 1 mg and 2 mg once-daily dosing 
regimens were safe and generally well tolerated by both Japanese and Caucasian participants. In that 
study, single and multiple dose etrasimod (1 mg and 2 mg) mean exposure (maximum observed 
plasma or serum concentration [Cmax] and area under the plasma concentration-time curve [AUC]) 
were slightly to moderately higher in Japanese participants compared to Caucasian participants, but 
this was attributable to differences in body weight rather than ethnicity. No differences were observed 
in absolute lymphocyte counts (ALCs) between Japanese and Caucasian participants following 
multiple dose administration of etrasimod and levels returned to near baseline during the 7-day 
washout period. Additionally, there were no clinically relevant first-dose heart rate (HR) differences.
Detailed information regarding the known and expected benefits and risks and reasonably expected 
adverse events of etrasimod can be found in the IB, which serves as the single reference safety 
document for this study.
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 participants with 
macular edema or retinopathy, with assessment of optical coherence tomography (OCT) occurring 
throughout the study; and exclusion of participants 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.
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
Prospective participants with a history of macular edema or retinopathy will be excluded 
from the study. All randomized participants will be assessed by OCT at study entry, 
periodically throughout the treatment period, and as clinically indicated any time during 
the study.

Participants with certain cardiac risks will also be excluded from the study. Randomized 
participants will be monitored in a period following dosing, and vital signs will be 
assessed for determination of the participant’s health before discharge. Participants 
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 participants with moderately to severely active UC and the current 
Phase 2 study.
The current study is a Phase 2, dose-ranging, multicenter, randomized, double-blind, 
placebo-controlled study to evaluate the efficacy and safety of etrasimod in Japanese participants with 
moderately to severely active UC. At the completion of the study (completion of Week 12 
assessments), participants will have the opportunity to enroll into open-label extension (OLE) 
Study APD334-303 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 in Japan.
2. STUDY OBJECTIVES
2.1. Primary Objective
The primary objective is to assess the efficacy of etrasimod at 2 doses (1 and 2 mg) on clinical 
remission in Japanese participants with moderately to severely active UC when administered for 
12 weeks.
2.2. Secondary Objective
The secondary objective is to assess the efficacy of etrasimod at 2 doses (1 and 2 mg) on clinical 
response, symptomatic remission, endoscopic improvements, and mucosal healing in Japanese 
participants with moderately to severely active UC when administered for 12 weeks.
2.3. Safety Objective
The safety objective is to assess the safety of etrasimod at 2 doses (1 and 2 mg) for 12 weeks in 
Japanese participants 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 
patient-reported outcomes and biomarkers.
3. INVESTIGATIONAL PLAN
3.1. Summary of Study Design
This is a dose-ranging, multicenter, randomized, double-blind, placebo-controlled study to evaluate 
the efficacy and safety of etrasimod 1 and 2 mg in Japanese participants with moderately to severely 
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active UC. The study consists of a 28-Day Screening Period, a 12-Week Induction Treatment Period, 
and a 4-Week Follow-Up Period (Figure 1). Eligible participants will be randomized (1:1:1 ratio) to 
receive either etrasimod (1 mg once daily), etrasimod (2 mg once daily), or matching placebo (once 
daily) in a double-blind fashion for 12 weeks. Randomization will be stratified by (a) naïve to 
biologic or JAK inhibitor therapy at study entry (yes or no), (b) baseline corticosteroid use 
(yes or no), and (c) baseline disease activity (modified Mayo score [MMS]: 4 to 6 or 7 to 9).
The target participant population will include those who have had an inadequate response to, loss of 
response to, or intolerance to the following: 

Conventional therapy, and are naïve to biologic or JAK inhibitor therapy

Biologics or JAK inhibitors (participants in this category may have received prior
conventional therapy)
Participant 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 ES ≥2 and RB subscore ≥1.
At the end of the 12-Week Induction Treatment Period, participants will undergo Week 12 efficacy 
and safety assessments and be evaluated for clinical response/remission. Participants will then have 
the option to enter an OLE study (Study APD334-303) following completion of Week 12 study 
procedures provided they meet all eligibility criteria for the OLE. Participants must complete 
Week 12 to be eligible for the OLE.
Participants 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 (ET) visit 
(Table 6).
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Figure 1:
Study Design
JAK, Janus kinase; UC, ulcerative colitis
3.2. Rationale for Study Design
Ulcerative colitis, along with CD, are currently the most prevalent intractable diseases in Japan. The 
clinical characteristics of UC in Japanese, and other East Asian ethnicities are similar in presentation 
to those in Caucasian patients. While Caucasian and Asian populations appear to have some shared 
genetic risk factors, others are distinct (Okabayashi 2020). As with all therapeutics, differences in 
ethnic factors (intrinsic factors as well as extrinsic factors such as local clinical practice and 
socioeconomic condition) may affect drug efficacy and safety (PMDA 2012). This dose-ranging 
study is designed to evaluate the efficacy and safety of etrasimod in Japanese participants with 
moderately to severely active UC.
The etrasimod doses of 1 mg and 2 mg once daily are based on findings of previous Phase 1 and 
Phase 2 studies, and in particular data from the Phase 1 APD334-109 Japanese/Caucasian 
ethnobridging PK and PD study and the Phase 2 APD334-003 placebo-controlled study (Sandborn 
2020). The APD334-109 study (described in Section 1.3) demonstrated that there were no significant 
differences in PK and PD of etrasimod in healthy Japanese and Caucasian participants; however, it 
was not designed to describe potential differences in Japanese and Caucasian UC patients. In the 
global APD334-003 study, UC participants received etrasimod 1 mg, 2 mg, or placebo. Participants 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 (TMS [Appendix 3]; 
estimated least squares mean [standard error] difference from placebo: 1.27 [0.55]; p = 0.0100), and 
higher percentage of participants 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 participants, respectively; treatment-related TEAEs were reported for 
7.7%, 10.0%, and 5.6% of participants, respectively; serious adverse events (SAEs) were reported for 
5.8%, 0%, and 11.1% of participants, respectively; and TEAEs leading to discontinuation of study 
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treatment were reported for 5.8%, 8.0%, and 0% of participants, respectively. No participants 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.
Participants may continue existing nonbiologic therapy for UC (eg, 5-ASA, corticosteroids) per the 
concomitant medication and stable dose criteria. As preexisting background therapy is allowed, a 
placebo comparator is justified. The 12-Week Induction Treatment Period in the current study is 
based on the safety and efficacy findings of the Phase 2 APD334-003 placebo-controlled study. The 
2-Week and 4-Week Follow-Up visits will provide off-treatment safety information.
The primary endpoint of clinical remission at Week 12 as assessed using the MMS is standard, widely 
used, and in accordance with the nonbinding US FDA Guidance for Industry, Ulcerative Colitis: 
Clinical Trials Endpoints (FDA 2016). Other endpoints for the study are widely used and considered 
reliable measures of efficacy and safety. The assessment of exposure in this study will provide further 
insight to the PK and PD of etrasimod in Japanese UC participants and facilitate bridging analyses 
efficacy and safety with the global data.
As detailed in Section 10.2, the study is powered to the primary endpoint for demonstrating a 
statistically significant difference in achieving clinical remission between etrasimod therapy and 
placebo at Week 12. The 1:1:1 randomization scheme will maximize the number of participants 
receiving a potentially beneficial therapy.
3.3. Study Duration
The study consists of a 28-day Screening Period, a 12-Week Induction Treatment Period, and a 
4-Week Follow-Up Period. The study duration is expected to be approximately 2 years.
The End of Study Date is the date when the last participant completes his/her last study visit.
3.4. Independent Data Monitoring Committee
This study will not use an E-DMC.
4. SELECTION OF STUDY POPULATION
The study population consists of Japanese men and women (hereafter referred to as men and women), 
18 to 80 years of age, inclusive, with moderately to severely active UC.
4.1. Inclusion Criteria
Participants must meet ALL of the following inclusion criteria to be eligible for enrollment into the 
study:
1.
Japanese ancestry (ie, both parents and 4 grandparents are/were of Japanese descent)
2.
18 to 80 years of age, inclusive, at the time of consent 
3.
Ability to provide written informed consent and to be compliant with the schedule of protocol 
assessments
Disease-specific inclusion criteria:
4.
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 
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source documents; however, if not available, the screening endoscopy and histology may serve 
as such.
5.
Active UC confirmed by endoscopy with ≥10 cm rectal involvement
6.
Moderately to severely active UC defined as MMS of 4 to 9, including an ES ≥2 and RB 
subscore ≥1
7.
Received a surveillance colonoscopy (performed according to local standard) within 12 months 
before baseline to rule out dysplasia in participants with pancolitis > 8 years duration or 
participants with left-sided colitis > 12 years duration. Participants 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:
8.
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-ASA compounds
b.
Systemic (oral or IV) Corticosteroids
c.
Thiopurines (eg, AZA, or 6-MP)

Biologics or JAK inhibitors 
a.
Anti-TNFα antibodies (eg, infliximab, adalimumab, golimumab or biosimilars)
b.
Anti-integrin antibodies (eg, vedolizumab, carotegrast methyl) 
c.
Anti-interleukin-12/23 antibodies (eg, ustekinumab)
d.
JAK inhibitors (eg, tofacitinib)
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 JAK inhibitor, the participant should have received a dosing regimen consistent with 
the local product labeling, local guidelines for the treatment of UC and/or institutional standard of 
care.
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Concomitant treatments: 
9.
Participants 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 or equivalent 
steroid) provided the dose has been stable for the 4 weeks immediately prior to the 
screening endoscopy assessment

Thiopurines such as oral AZA or 6-MP must be discontinued ≥2 weeks prior to 
randomization

Probiotics (eg, 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:
10. Adequate hematological function defined by white blood cell count ≥3.5 × 109/L with ANC 
≥1.5 × 109/L, lymphocyte count ≥0.8 × 109/L, platelet count ≥100 × 109/L, and hemoglobin 
≥8 g/dL
11. 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. Participants with an isolated total bilirubin and normal AST and ALT diagnosed 
with Gilbert’s syndrome may participate
12. 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
13. Females must meet either a or b of the following criteria and males must meet criterion c to 
qualify for the study: 
a.
A female who is not of childbearing potential must meet 1 of the following:

Postmenopausal, defined as no menses for 12 months without an alternative medical 
cause

Permanent sterilization procedure, such as hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy
b.
Non-pregnant female of childbearing potential must agree to using a highly effective 
contraception method during treatment and for 30 days following treatment that can achieve 
a failure rate of less than 1% per year when used consistently and correctly. The following 
are considered highly effective birth control methods:

Combined (estrogen and progestogen containing) oral hormonal contraception 
associated with inhibition of ovulation

Progestogen-only oral hormonal contraception associated with inhibition of ovulation

Intrauterine device (IUD)

Intrauterine hormone-releasing system
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
Bilateral tubal occlusion

Vasectomized partner, provided that partner is the sole sexual partner of the women 
of childbearing potential trial participant and that the vasectomized partner has 
received medical assessment of the surgical success

Sexual abstinence (complete sexual abstinence defined as refraining from 
heterosexual intercourse for the entire period of risk associated with study 
treatments). The reliability of sexual abstinence needs to be evaluated in relation to 
the duration of the clinical study and the preferred and usual lifestyle of the 
participant. Periodic abstinence (calendar, symptothermal, post-ovulation methods) is 
not acceptable.
c.
A male participant with a pregnant or non-pregnant female of childbearing potential partner 
must agree to using condoms during treatment and for 30 days following treatment.
4.2. Exclusion Criteria
Participants 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 participant is likely to require hospitalization for medical 
care or surgical intervention of any kind for UC (eg, colectomy) within 12 weeks 
following randomization

Current evidence of fulminant colitis, toxic megacolon or recent history (within last 
6 months) of toxic megacolon, or bowel perforation

Previous total or partial colectomy
2.
Diagnosis of CD or indeterminate colitis or the presence or history of a fistula consistent with CD
3.
Diagnosis of isolated proctitis (defined as proctitis with < 10 cm rectal involvement), microscopic 
colitis, ischemic colitis, or infectious colitis 
4.
Hospitalization for exacerbation of UC requiring 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 toxin at screening (If C. difficile is positive, the participant 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 
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systemic disease making implementation of the protocol or interpretation of the study difficult or 
would put the participant 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 AV 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 pre-randomization vital signs (taken in the sitting position) 
with a 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 pre-randomization 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 
participants with diabetes with significant comorbid conditions such as retinopathy
11. History of macular edema or retinopathy
12. History of active tuberculosis (TB), history of untreated or inadequately treated latent TB 
infection, active or latent TB infection at screening (refer to Appendix 2 for details on TB 
screening requirements and interpretation of test results). The following are EXCEPTIONS to 
this exclusion criterion:

Participants 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

Participants 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. Participants 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 IV medication ≤14 days prior to randomization, or that may worsen (in 
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the opinion of the Investigator) if the participant 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 (positive for hepatitis B surface antigen [HBsAg]), or

negative for HBsAg and positive for hepatitis B core antibody [HBcAb] and negative for 
hepatitis B surface antibody [HBsAb] in conjunction with detectable HBV DNA, or 

negative for HBsAg and negative for HBcAb and positive for HBsAb in conjunction with 
detectable HBV DNA, or

negative for HBsAg and positive for HBcAb and positive for HBsAb 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 [PML]) or a history of disseminated herpes simplex 
or disseminated herpes zoster
18. History of or currently active primary or secondary immunodeficiency
19. History of cancer within the last 5 years, including solid tumors and hematological malignancies 
(except basal cell and in situ squamous cell carcinomas of the skin that have been excised and 
resolved) or colonic mucosal dysplasia
20. History of lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorder, or 
multiple myeloma
Exclusions related to medications:
21. Hypersensitivity to etrasimod or any of the excipients or placebo compounds 
22. Prior treatment with S1P receptor modulators 
23. Treatment with a biologic agent ≤8 weeks or a small-molecule agent ≤5 elimination half-lives 
and detectable drug level prior to randomization
24. Treatment with an investigational therapy ≤3 months prior to randomization
25. Prior treatment with ≥ 3 advanced therapies (eg, biologics or JAK inhibitors) approved or 
recommended for treatment of UC
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 or during screening or cyclosporine, tacrolimus, 
sirolimus, or mycophenolate mofetil (MMF) ≤16 weeks prior to and during screening
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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. Use of moderate or strong inhibitors or inducers that inhibit or induce at least 2 of the following: 
cytochrome P450 (CYP) 2C8, CYP2C9 and CYP3A4 (eg, fluconazole, rifampin, enzalutamide) 
within 4 weeks prior to randomization
5. REMOVAL OF PARTICIPANTS FROM STUDY TREATMENT OR
ASSESSMENT
5.1. Discontinuation from Study Treatment
A participant’s double-blind treatment may be discontinued for any of the following reasons:

Adverse event that in the judgement of the Investigator and/or Medical Monitor indicate 
the participant should not continue study treatment

Participant noncompliance with the protocol or study treatment that is considered 
significant by the Medical Monitor

Investigator decision

Withdrawal by participant

Lack of efficacy

Lost to follow-up

Study termination by Sponsor

Other, non-adverse event
A participant’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

Participants who have a cardiovascular treatment-related symptomatic event (eg, chest 
pain, dizziness, palpitations, lightheadedness, shortness of breath, or syncope) associated 
with reduction of the HR 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)

Participants who have not met the discharge criteria (Table 3) on Day 1 after ≥4 hours 
of extended monitoring, or Day 2 by 4 hours postdose

Pregnancy (Section 9.9.9)
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
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. If a drug 
induced-liver injury is identified, refer to Section 16.6 for guidance.
Participants who discontinue treatment prematurely, regardless of the reason, should be instructed to 
return for an ET visit within 7 days of the last administration of study treatment (Table 6) and 
complete all of the ET assessments. If a participant discontinues due to pregnancy, they are not 
required to complete the endoscopy. If the ET visit is within 4 weeks of the last sigmoidoscopy and 
biopsy, these procedures do not need to be repeated.
If the ET visit is ≥2 weeks after the last administration of study treatment, the 2-Week Follow-Up 
visit is not required; however, the 4-Week Follow-Up visit should be scheduled and completed. If the 
ET visit is ≥4 weeks of the last dose of study treatment, the 4-Week Follow-Up visit is not required
unless the ALC is not within normal limits.
If treatment discontinuation is considered an adverse event, refer to Section 9.9.8.3. for AE/SAE 
reporting guidance.
5.2. Discontinuation from the Study
Participants may be discontinued from the study at any time for any of the following reasons:

Withdrawal by participant 

Deviation/noncompliance with the study protocol that in the judgement of the 
Investigator and/or Medical Monitor the participant should not continue study treatment

Study termination by Sponsor

Lost to follow-up

Death

Other
A participant 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 participant 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.
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In the event that a participant fails to attend any follow-up visits, all reasonable efforts will be made 
to contact the participant to ensure that he/she is in satisfactory health. All contacts and contact 
attempts must be documented in the participant’s file.
5.3. Participants Lost to Follow-Up Prior to Last Scheduled Visit
A participant will be considered lost to follow-up if they repeatedly fail to return for scheduled visits 
and are unable to be contacted by the study site.
The following actions must be taken if a participant fails to attend a required on-site, offsite, virtual or 
hybrid visit (Section 9.6):

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and or should continue in 
the study.

Before a participant is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and if 
necessary, a certified letter to the participant’s last know mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
file.
Should the participant 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 participants

Participant enrollment is unsatisfactory

Upon request of health authorities
The Sponsor will notify Investigators if the study is placed on hold or if the Sponsor decides to 
discontinue the study or development program. Health authorities and Independent Ethics 
Committees (IECs)/Institutional Review Boards (IRBs) will be informed about the termination of the 
study in accordance with applicable regulations.
The Sponsor has the right to replace a study site at any time. Reasons for replacing a study site may 
include, but are not limited to:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the ICH guideline for GCP
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6. STUDY TREATMENTS
6.1. Treatments Administered
Participants will be randomly assigned to 1 of 3 treatment groups (1 mg or 2 mg etrasimod or 
placebo) in a 1:1:1 ratio. Study treatment is outlined in Table 1.
Table 1:
Study Treatments
Study treatment name:
Etrasimod
Placebo
Dosage formulation:
1 mg tablet or 2 mg tablet
Matching tablet
Unit dose strength/dosage 
level:
1 tablet once daily
1 tablet once daily
Route of administration:
By mouth 
By mouth
Packaging and labeling:
Study treatment will be 
provided in 40 cc, 
induction-sealed, high-density 
polyethylene bottles with 
child-resistant screw caps. Each 
bottle will be labeled as required 
per country requirement. These 
bottles should be stored at 
15 to 25°C (59 to 77°F).
Study treatment will be provided 
in 40 cc, induction-sealed, 
high-density polyethylene 
bottles with child-resistant 
screw caps. Each bottle will be 
labeled as required per country 
requirement. These bottles 
should be stored at 15 to 25°C 
(59 to 77°F).
6.2. Investigational Study Treatment
The active pharmaceutical ingredient in etrasimod tablets is APD334 L-arginine (the arginine salt of 
(R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-
yl)acetic acid), which is an off-white to light-brown solid with an aqueous solubility of approximately 
1.38 mg/mL at pH = 8.9 and 30°C. APD334 L-arginine is manufactured, packaged, tested, and 
released in compliance with 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 1 mg and 2 mg.
The placebo tablet formulation is composed of excipients (microcrystalline cellulose NF, Ph. Eur.; 
mannitol USP, Ph. Eur.; sodium starch glycolate NF, Ph. Eur.; magnesium stearate NF, Ph. Eur.; and 
Opadry® II Blue 85F90951). Placebo tablets are identical in appearance to the active-drug tablets as 
described above.
6.3. Dosage and Administration
One tablet is to be taken each day (with water, either with or without food). Tablets should be taken at 
approximately the same time each day, preferably in the morning. On study visit days, participants 
should wait and take their dose after blood draws for PK and after all predose assessments and 
procedures have been completed. The time of PK sample collection and last dosing prior to the PK 
sample should be documented in the electronic case report form (eCRF).
6.3.1. Instructions for Missed Dose(s)
Participants 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 
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the following day. If the participant 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 participant’s electronic diary (eDiary). Participants should be 
instructed to contact the Investigator if they miss more than 2 consecutive doses. 
Participants must be educated to contact the Investigator to discuss treatment re-initiation if they 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.≥The participant 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 participant 
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 Participants to Treatment
Participants 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.
Participants 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 participant will be dispensed blinded study treatment at study visits (Table 6).
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 participant 
receives will not be disclosed to the Investigator, study site staff, participants, 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 
participant emergency medical care. In case of an emergency, the Investigator has the sole 
responsibility for determining if unblinding of a participant’s treatment assignment is warranted to 
provide appropriate medical care. Participant 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 
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unblinding. If a participant’s treatment assignment is unblinded, the Sponsor must be notified within 
24 hours after breaking the blind. The date and reason the blind was broken must be recorded in the 
source documentation and eCRF, as applicable.
For Suspected, Unexpected, Serious Adverse Reactions, the Sponsor’s Pharmacovigilance designee 
responsible for managing SAEs will access the IWRS to obtain the participant’s treatment assignment 
for the purpose of regulatory reporting.
If a participant’s treatment assignment is unblinded for any reason, they will be discontinued from the 
study.
6.6. Treatment Compliance
It is the Investigator’s responsibility to ensure that participants are correctly instructed on how to take 
their study treatment and that each participant 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. Participants will record the time of their dose each day in the participant 
eDiary. An up-to-date treatment inventory/dispensing record must be maintained as described in 
Section 8.4.
Overall treatment compliance will be calculated at the end of study treatment and tabletcounts < 80% 
or > 120% of the expected value at the end of treatment should be documented as a protocol 
deviation. If there is a discrepancy between the tablet count and the participant’s compliance per the 
eDiary between visits, or if overall treatment compliance is <80% or >120% between visits,it should 
be discussed with the participant to improve compliance and the discussion should be 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 
participant 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 participants who are not already receiving them. 
Immunosuppressive agents such as oral AZA or 6-MP must be discontinued ≥2 weeks prior to 
randomization.
Participants receiving 5-ASA or medicinal probiotics should maintain a stable dose throughout the 
study.
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Oral corticosteroid therapy (prednisone at a stable dose ≤20 mg/day or equivalent steroid) is allowed 
to be continued during the 12-Week Induction Treatment Period provided the dose has been stable for 
the 4 weeks immediately prior to the screening endoscopy assessment.
6.7.2.2. Vaccines
Vaccinations are permitted as clinically indicated except for live vaccines (refer to Section ). At this 
time, there are no data on the effect of etrasimod on vaccination including SARS-CoV-2 (COVID-19)
vaccines. The IOIBD has published recommendations that patients with IBD should be vaccinated 
against SARS-CoV-2; that SARS-CoV-2 vaccines, including messenger RNA, 
replication-incompetent vector, inactivated and recombinant vaccines are safe to administer to 
patients with IBD; and thus should not be deferred because a patient with IBD is receiving 
immune-modifying therapies (Siegel 2021).
If a participant receives a vaccination, the vaccination date and type (eg, SARS-CoV-2) will be 
captured as described in Section 9.3.5 in the Concomitant Medication eCRF. The vaccine brand, 
manufacturer, and lot number should be captured in the Concomitant Medication eCRF as available.
6.7.3. Prohibited Concomitant Therapy
The following concomitant medications are prohibited during the study:
Note: Participants who enter the 4-Week Follow-Up Period will no longer need to abstain from the 
medications that were prohibited during the treatment periods, unless noted otherwise (eg, live 
attenuated vaccines for 4 weeks after the last dose of study drug). Once a participant has discontinued 
their study medication and had their Week 12 / ET visit, a participant may have their worsening 
Ulcerative Colitis flare treated according to the local standard of care. The Investigator may initiate a 
rescue treatment during the Follow-Up period.

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 4 weeks after the last dose of study 
treatment

Moderate/strong inhibitors or inducers that inhibit or induce at least 2 of the following 
enzymes: CYP2C8, CYP2C9 and CYP3A4 (eg, fluconazole, rifampin, enzalutamide) 

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

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, traditional [ie, 
Chinese] medicine, suppositories), other than that required for endoscopy preparation 

Cyclosporine, tacrolimus, sirolimus, methotrexate, or MMF 
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
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 

IV immunoglobulin or plasmapheresis

Blood donations during the study and for 14 days after the last dose of study treatment.

Sperm or oocyte donations during the study and for 30 days after the last dose of study 
treatment
7. PARTICIPANT RESTRICTIONS
Prohibited concomitant therapy is described in Section 6.7.3. Additionally, participants are restricted 
from the following:

Poppy seeds: Consumption of poppy seeds within 48 hours prior to drug screening may 
cause a positive drug screen. Participants 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: Participants 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 Japan requirements.
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 participant attends a virtual 
visit (refer to Section 9.6) and requires additional study treatment to continue on the study, study 
treatment may be dispensed and delivered by an approved courier where permitted by local law and 
regulation. Alternatively, a future supply of study medications may be dispensed to the participant at 
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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
The head of the study site or the investigational product manager has overall responsibility for 
administering and dispensing investigational product. Where permissible, tasks may be delegated to a 
qualified designee (eg, a pharmacist) who is adequately trained in the protocol and who works under 
the direct supervision of the Investigator. This delegation must be documented in the applicable study 
delegation of authority form.
At each visit, previously dispensed study treatment tablets will be collected by the Investigator or 
qualified individual and compliance assessed. The investigational product manager must maintain 
adequate records documenting the receipt, use, loss, or other disposition of the study treatment. To 
ensure adequate records, all drug supplies will be accounted for in the drug accountability inventory 
forms and will be monitored by counting of unused medication from individual bottles returned by 
the participant at each visit.
8.5. Study Treatment Retention and Disposal
All study treatment will be reconciled by the clinical monitor (or delegate) and then returned or 
destroyed according to applicable country regulations. Study sites with a pharmacy performing study
treatment accountability and destruction before the clinical monitor can conduct reconciliation
activities are only permitted to do so with prior approval from the Sponsor. On-site destruction 
following all local regulations and in accordance with applicable site standard operating procedures 
(SOPs) is permitted. Prior to any action being taken with study treatment, the Investigator or the 
investigational product manager will contact the Sponsor (or contract research organization [CRO]) 
for approval of such action. Final reconciliation will be performed at study completion.
9. STUDY ASSESSMENTS AND PROCEDURES
9.1. General Instructions

Study procedures and their timing are summarized in the Schedule of Assessments 
(Table 6). 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 participant should continue or 
discontinue study treatment.

Adherence to the study design requirements, including those specified in the Schedule of 
Assessments (Table 6), is essential and required for study conduct.

Study visits should be scheduled in the morning, whenever possible. 
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
All laboratory assessments required by the protocol will be performed by a central 
laboratory unless otherwise stated.

For onsite and offsite study visits (refer to Section 9.6 and Table 6), participants 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 participants 
screened and to confirm eligibility or record reasons for screening failure, as applicable.
9.2.
Participant Information
9.2.1. Informed Consent
The Investigator, or a person designated by the Investigator, will obtain written informed consent 
from each participant before any study-specific activity is performed (Section  for additional 
details).
9.3. Screening and Eligibility
Participant eligibility will be assessed based on protocol inclusion and exclusion criteria. All 
screening evaluations must be completed and reviewed to confirm potential participants meet all 
eligibility criteria.
Screening procedures must be completed within 28 days prior to receiving the first dose of study 
treatment (Table 6). The Screening Period may be extended for participants who require additional 
diagnostic testing/consults to determine status of either latent TB or C. difficile infection. If the 
participant is planned to be randomized > 28 days from the signing of the informed consent form 
(ICF), the Medical Monitor should be consulted to see if repeated testing is needed. The 28-Day 
Screening Period may also be extended on a case-by-case basis to accommodate reasonable delays in 
specific screening assessments (eg, PFTs, OCT) due to testing availability. The Medical Monitor 
must be consulted prior to extension in each case.
Participants 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 participants 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
Participants 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 participant must be reconsented prior to each screening attempt.
Participants with a Screening visit or Week 0/Day 1 pre-randomization 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.
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If a participant requires prophylactic therapy for latent TB, they may be rescreened as outlined in 
Section 4.2.
If a participant is positive for C. difficile at screening, the participant may be treated and retested 
≥4 weeks after completing treatment.
9.3.3. Demography and Other Participant Characteristics
Demographics including year of birth and sex at birth as described by the participant 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. Participants 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 (refer to Section 4.1, Inclusion Criterion 8, for 
details).
All medications taken and procedures carried out within 30 days prior to the first dose 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.
9.3.6. Ulcerative Colitis History/Medical History
In order to determine the participant’s eligibility to the study, a complete medical history of each 
participant 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 participant’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 HR, 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).
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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. Participants 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) 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 randomization. In the case of new clinical laboratory abnormalities detected prior to 
randomization, the eligibility of the participant 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 512 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 stool frequency (SF) and RB 
are derived from the participant 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. Participants who do not have 
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 subscore ≥1, 
for the participant to be eligible for randomization.

For the normal SF, it is essential for the participant to be asked to identify how many 
stools he or she has in a 24-hour period when in remission from UC. Participants 
should be instructed that a stool is defined as a trip to the toilet when the participant 
has either a bowel movement, or passes blood alone, blood and mucus, or mucus 
only. If the participant does not report that he or she has achieved remission, then the 
participant 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: Pre-randomization
At the Week 0/Day 1 visit (Table 6), prior to randomization, a 12-lead ECG in the supine position 
and resting vital signs in the sitting position (HR, 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.
Participants with the following must not be randomized and should be considered screen failures:
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
Sitting vital sign assessment: HR < 50 bpm OR systolic BP < 90 mm Hg OR diastolic 
BP < 55 mm Hg

12-lead ECG showing a second-degree 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 predose 12-lead ECGs should be obtained prior to blood sample collection.
Participants 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 6). A study visit 
window of ± 3 days is permitted at each visit beginning with Week 2/Day 15 (PFT and OCT 
assessments have a window of ± 7 days). Study visits should be scheduled for the morning.
The subscores for SF and RB are derived from the participant eDiary entries. On visits when MMS is 
calculated, these subscores are derived using the scores from the 3 most recent consecutive days 
within the 7 days prior to the day of bowel preparation (excluding the day of bowel preparation), 
averaged and rounded to the nearest integer. If 3 consecutive days are not available, then the average 
of the 2 most recent consecutive days within the 7 days will be used.
On visits without endoscopy, the SF and RB subscores are derived using the scores from the 3 most 
recent consecutive days within the 7 days prior to the date of visit, averaged and rounded to the 
nearest integer. If 3 consecutive days are not available, then the average of the 2 most recent 
consecutive days within the 7 days will be used.
It is recommended that procedures are performed in a consistent order and at approximately the same 
time of day for each visit. Below is the recommended sequence of events (refer to Schedule of 
Assessments, Table 6):

Questionnaire administration

Adverse event review

Vital signs

12lead ECG

Physical examination

EIMs

PFT

OCT

Blood sample collection for laboratory tests and predose PK sampling
9.4.2.1. Guidance for Cardiac Monitoring Following Treatment Initiation or 
Re-Initiation
Pre-randomization (ie, pre-dose/baseline) vital signs (resting HR, systolic and diastolic BP, body 
temperature, and respiratory rate) will be used as the baseline measurement. The pre-dose HR 
measurement will be used for comparison to the postdose measurement. It is recommended that 
participants receive the first dose of study treatment before 12:00 PM (noon).
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9.4.2.1.1. First Dose Cardiac Monitoring
In-clinic cardiac monitoring, of at least 4 hours, will occur on Day 1 and will include the following 
(Table 2):

Full baseline vital signs (HR, systolic and diastolic BP, body temperature, and respiratory 
rate) and a 12-lead ECG (taken with the participant in the supine position) will be 
assessed pre-randomization.

After the first dose of study treatment on Day 1, participants must remain under 
observation in the clinic for at least 4 hours.

At Hours 1, 2, and 3 (± 15 minutes) postdose, the HR and systolic and diastolic BP will 
be assessed with the participant in the sitting position, with the time recorded. If the 
participant has an HR < 50 bpm or if cardiovascular symptoms develop, then the 
participant 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, HR and systolic and diastolic BP will 
be assessed with the participant in the sitting position and a 12-lead ECG (with the 
participant in the supine position) will be performed. Participants may be discharged 
from the clinic after the 4-hour assessment if they meet the criteria described in Table 3. 
Participants not meeting the discharge criteria will require extended monitoring as 
described below.

Participants experiencing a clinically relevant treatment-related symptomatic event (eg, 
chest pain, dizziness, palpitations, or syncope) associated with reduction of the HR or 
clinically relevant 12-lead ECG changes at any time during the 4-hour monitoring period 
must be discontinued from treatment (Table 4).
Table 2:
Procedures to be Performed During the Monitoring Period
Procedure
Predose
Hours 1, 2, 3 
Postdosea  
Hour 4 Postdosea
Blood pressure and heart 
rateb  
X
X
X
12-lead ECG
X
X
Assess discharge criteria
X
a Measurements may be taken ± 15 minutes of the scheduled time.
b Heart rate is based on vital signs.
ECG, electrocardiogram
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Table 3:
Discharge Criteria After Cardiac Monitoring
Participants will be released from the clinical site after dosing on Day 1 (but no sooner than 4 
hours postdose) when they fulfill the following discharge criteria:

Heart rate ≥50 bpm or no more than 10 bpm lower than the predose (baseline) value

No evidence of second-degree AV block or higher

No cardiac symptoms (eg, chest pain, dizziness, palpitations, lightheadedness, shortness of 
breath, or syncope)
Note: Participants should have written instructions on when to return to the clinic and a 24-hour 
contact phone number to call in the event of any new or worsened cardiovascular symptoms.
AV, atrioventricular; bpm, beats per minute
9.4.2.1.2. Extended Cardiac Monitoring
Participants who do not meet discharge criteria at 4-hours postdose will require extended cardiac 
monitoring:

Vital signs will be assessed hourly and 12-lead ECG may be performed, as clinically 
indicated, until the participant meets the discharge criteria (Table 3).

The Medical Monitor should be contacted if the participant does not meet the discharge 
criteria after ≥4 hours of extended cardiac monitoring.

Any participant 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 participants 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 
participant meets the discharge criteria (Table 3).

Participants 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 HR or clinically 
relevant change in 12-lead ECG, may be discharged provided they meet the discharge 
criteria (Table 3), and as deemed appropriate by the Investigator; however, these 
participants must return on Day 2 for the second dose and will be re-monitored as on 
Day 1. These participants 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 participant meets the discharge criteria 
(Table 3).
9.4.2.1.3. Study Treatment Discontinuation Related to Postdose Cardiac Monitoring
A complete list of reasons for study treatment discontinuation is provided in Section 5.1. Reasons for 
study treatment discontinuation specific to postdose cardiac monitoring are provided in Table 4. The 
Medical Monitor should be contacted before discontinuing a participant.
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Table 4:
Discontinuation of Study Treatment Related to Postdose Cardiac Monitoring
Reasons for Study Treatment Discontinuation Related to Postdose Cardiac Monitoringa  

Participants 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).

Participants who have not met the discharge criteria on Day 1 after ≥4 hours of extended 
monitoring, or Day 2 by 4 hours postdose.
a All treatment discontinuations should be discussed with the Medical Monitor.
ECG, electrocardiogram
9.4.2.1.4. Cardiac Monitoring Upon Treatment Re-Initiation Following Dose 
Interruption
Participants should undergo the same first dose cardiac monitoring procedures as the original 
treatment initiation when study treatment dosing is re-initiated after interruption for:

≥2 consecutive days within the first week of treatment

≥7 consecutive days after the first week of treatment
9.5. Follow-Up Period
For participants not participating in the OLE study, follow-up visits will be performed at 2 and 
4 weeks after the last administration of study treatment as indicated in the Schedule of Assessments 
(Table 6).
If the ET or Study Completion visit is ≥2 weeks after the last administration of study treatment, the 
2-Week Follow-Up visit is not required; however, the 4-Week Follow-Up visit should be scheduled 
and completed. If the ET or Study Completion visit is ≥4 weeks after the last administration of study 
treatment, the 4-Week Follow-Up visit is not required.
If the absolute peripheral lymphocyte count is not within normal limits at the 4-Week Follow-Up 
visit, participants 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 9.9.8.2.2).
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 or mobile visit), virtual or telehealth visit (eg, 
telephone, video conference), 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 different days 
within the study visit window. 
During a virtual assessment, a participant may report an AE that requires a follow-up 
symptom-focused physical exam or diagnostic test, as determined by the Investigator. In this 
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scenario, the Investigator may have the participant 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. Participants must return the dispensed bottle with the remaining 
tablets along with any empty bottles to the study site at the next onsite visit. Refer to Section 8 for 
study treatment management.
Regardless of how a study visit and its associated procedures are conducted, all study procedures 
should be performed by qualified study site staff or qualified individual as delegated by the Principal 
Investigator.
Study visits are designated accordingly in the Schedule of Assessments (Table 6).
9.6.1. Telehealth Visits
Telehealth visits may be used to assess participant safety and collect data points. Telehealth includes 
the exchange of healthcare information and services via telecommunication technologies (eg, audio, 
video, videoconferencing software) remotely, allowing the participant and the investigator to 
communicate on aspects of clinical care, including medical advice, reminders, education, and safety 
monitoring. The following assessments must be performed during a telehealth visit (see the SoA; 
Table 6):

Review and record study treatment(s), including compliance and missed doses. 

Review and record any AEs and SAEs since the last contact. Refer to Section 9.9.8 .  

Review and record any new concomitant medications or changes in concomitant medications 
since the last contact. 

Review and record contraceptive method and results of pregnancy testing. Confirm that the 
participant is adhering to the contraception method(s) required in the protocol. Refer to 
Section 4.1. 
Study participants must be reminded to promptly notify site staff about any change in their health 
status. 
9.6.2. Home Health Visits
A home health care service may be utilized to facilitate scheduled visits. Home health visits include a 
healthcare provider conducting an in-person study visit at the participant’s location, rather than an in-
person study visit at the site. The following may be performed during a home health visit (see the 
SoA; Table 6):  

Review and record study treatment(s), including compliance and missed doses. 

Review and record any AEs and SAEs since the last contact. Refer to Section 9.9.8

Review and record any new concomitant medications or changes in concomitant medications 
since the last contact. 

Review and record contraceptive method and results of pregnancy testing. Confirm that the 
participant is adhering to the contraception method(s) required in the protocol. Refer to 
Section 4.1. 
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
Pregnancy testing and central laboratory assessments (eg, blood, stool, and urine samples are 
taken)
It is recommended that the investigator discuss temporary or permanent discontinuation of study 
treatment with the study medical monitor.
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).
9.6.3. Mobile Visits
In the event that an in-person visit is not feasible at the site, the following may be performed by a 
licensed healthcare professional at an alternate site approved by the investigator (see the SoA; 
Table 6):

Pregnancy testing and central laboratory assessments (eg, blood, stool, and urine samples)
9.7. Pharmacokinetics
Blood samples for analysis of etrasimod will be collected at the following timepoints from all 
participants who received at least 1 dose of study drug (etrasimod or placebo):

Predose and at 4 hours (± 15 minutes) postdose (after 12-lead ECG) on Week 0/Day 1

Predose (trough; within 60 minutes prior to dosing) at Weeks 2, 4, 8, and 12, for 
participants enrolling in the OLE at the Week 12 visit, the PK sample can be collected as 
part of the OLE.

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
Participants 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. 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, 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, and exploratory 
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 
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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 participant-reported RB and SF scores; therefore, the importance of daily 
recording of RB and SF by participants in their daily eDiary should be stressed by the Investigators.
Endoscopy will be used to visualize the mucosa to enable calculation of the ES.
Endoscopic score (ES): The ES reports the worst appearance of the mucosa on flexible 
sigmoidoscopy or colonoscopy, on a 4-point scale (Appendix 3). Consistent with regulatory advice, 
this study excludes friability from the definition of an ES of 1. The ES will be determined by a 
blinded central reader.
Rectal bleeding (RB): The RB subscore is a participant-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 
participant 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 participant-reported measure. This item reports the 
number of stools in a 24-hour period, relative to the normal number of stools for that participant in the 
same period, on a 4-point scale (Appendix 3). A stool is defined as a trip to the toilet when the 
participant 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 
participant in their daily eDiary. The reference “normal” SF for that participant will be recorded 
electronically at the Screening Visit and is the number of stools in a 24-hour period when the 
participant is in remission. If the participant 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 TMS. The PGA summarizes the 
Investigator’s assessment of the participant’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 6). 
Consistent with regulatory guidance, the PGA will not be used for primary or secondary efficacy 
assessment in this study.
9.8.1.1. Endoscopy
A flexible proctosigmoidoscopy, performed with a video endoscope following cleansing preparation 
(oral or rectal cathartic), will be performed during screening (prior to Day 1/randomization) and at 
Week 12/ET visit.
To ensure quality data and standardization, the same endoscopist should be used throughout the study 
wherever possible. Endoscopy images will be obtained during each endoscopy and will be sent for 
central reading and determination of the Mayo ES. A detailed image review charter from the central 
reading laboratory will outline the endoscopic procedures, video recordings, and equipment. For each 
participant, 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 
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will be used for determination of efficacy endpoints; however, treatment decisions will be made by 
the treating Investigator.
Repeated flexible proctosigmoidoscopy may be permitted by the Sponsor when the central reader 
indicates that the video endoscope data were acquired incorrectly or did not meet the minimal 
required quality standards.
Note: For participants with pancolitis > 8 years duration or participants with left-sided colitis 
> 12 years without a surveillance colonoscopy within 12 months prior to baseline (refer to 
Section 4.1, Inclusion Criterion 7), 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 
and, where permitted, for the assessment of exploratory biomarkers. Up to 2 biopsy pairs (ie, total 4) 
will be collected from the most affected area 10 to 25 cm from the anal verge.  Samples should be 
collected, stored, and shipped as described in the laboratory manual.
The original location (colonic segment) of biopsy specimens acquired at screening must be clearly 
indicated. Detailed instructions for endoscopic biopsies (eg, number of biopsies, anatomic site, 
normal or inflamed mucosa) will be provided.
Biopsy samples will be processed by a central laboratory and histopathologic scoring using the 
Geboes, Robarts, and Nancy histopathology indices (Appendix 4) will be performed by a blinded 
central histopathology reader (Geboes 2000, Marchal-Bressenot 2017, Mosli 2017).
Biopsy specimen transfer, processing, slide preparation and digitization of slides for histopathologic 
scoring procedures will be detailed in a histopathology manual. Histopathology results will not be 
made available to study sites.
9.8.2. Extraintestinal Manifestations
During the specified full physical examinations (Table 6), specific systems (such as eyes, liver, skin, 
and joints) will be examined for EIMs for UC.
9.8.3. Additional Health-Related Patient-Reported Outcomes
Participant-reported quality of life instruments will be completed electronically and checked for 
completeness at the study site as indicated in the Schedule of Assessments (Table 6) and will be used 
in support of the efficacy outcomes.
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 
participant. The UC-PRO/SS is a 9-item questionnaire containing 2 domains: Bowel movement signs 
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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 (Table 6) if 
and when available.
Medical Outcomes Study 36-Item Short Form Health Survey, Version 2 Physical and Mental 
Component and Domain Scores (SF-36): The SF-36 is a 36-item, participant-reported survey of 
participant 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 participant’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.
9.8.4. Efficacy-Related Biomarkers
Samples for biomarker assessments will be collected according to the Schedule of Assessments 
(Table 6). 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 participant 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 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 
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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.
9.8.4.1. Exploratory Efficacy-Related Biomarkers
Samples for exploratory biomarker assessments will be collected according to the Schedule of 
Assessments (Table 6). Blood and biopsy samples will be analyzed by a specialty laboratory 
following completion of the study. 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 to 
further understand response to treatment and mechanism of action of etrasimod if the participant has 
granted consent. These additional analyses (as appropriate) will only be conducted where allowed by 
the regulatory authorities and local ethics committees.
Immunophenotyping: Intestinal biopsies will be collected during endoscopy for 
immunophenotyping (eg, T cell subsets, B cells, dendritic cell subsets, natural killer cells) and 
molecular markers of mucosal healing (eg, junctional proteins such as ZO-1, occludin, claudins) to 
further assess efficacy and the mechanism of action of etrasimod. Assessments will be made using 
protein-based methods such as immunofluorescence microscopy or comparable methodology.
Proteomics: Blood will be collected for exploratory proteomic analysis to assess the efficacy and 
mechanism of action of etrasimod. Proteins will be measured by enzyme-linked immunosorbent 
assay, proximity-extension assay, or comparable technology.
9.9. 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 9.9.8.1). Adverse events will be coded using 
the latest version of the Medical Dictionary for Regulatory Activities (MedDRA).
9.9.1. Physical Examination
Full and symptom-directed physical examinations will be performed according to the Schedule of 
Assessments (Table 6).
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
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
Musculoskeletal assessment to include lower extremity edema evaluation
Symptom-directed (focused) physical examinations should assess clinically significant changes from 
full physical examinations or any new signs or symptoms.
9.9.2. Vital Signs
Resting vital signs measurements will be performed according to the Schedule of Assessments 
(Table 6) with the participant 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 participant’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. Participant’s legs should not be crossed during the evaluation.
9.9.3. 12-Lead Electrocardiogram
All 12-lead ECGs will be performed according to Section 9.4.2.1 and the Schedule of Assessments 
(Table 6), 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 participant in the supine 
position. Every attempt should be made to ensure the participant 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 participant with new onset QTc 
interval above 500 ms, referral to a cardiologist experienced in treating cardiac conduction disorders 
should be considered. Re-initiation of study treatment (refer to Section 9.4.2.1) 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.
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9.9.4. Pulmonary Function Test
Pulmonary function tests will be performed according to the Schedule of Assessments (Table 6) and 
includes FEV1 and FVC measurements. All participants will have PFTs performed at Screening, and 
Week 12, or at the ET visit. PFTs occurring at the ET visit that are within 4 weeks of the last 
assessment (eg, Week 12) will only be required if clinically indicated. The 2-Week Follow-Up visit 
PFT assessment is only required if clinically indicated.
Participants 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.
Participants 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 participants and site staff is paramount, so it is at the Investigator’s discretion 
whether PFT can be safely administered to trial participants during the treatment period. The 
Investigator should evaluate on a case-by-case basis how best to proceed based on the participant’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, coronavirus disease 
2019 [COVID-19] transmission), then this decision and rationale should be appropriately captured in 
the participant’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.
9.9.5. Ophthalmoscopy and Optical Coherence Tomography
A complete ophthalmoscopy and OCT will be performed according to the Schedule of Assessments 
(Table 6). 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 OCT 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 participant across 
timepoints.
Screening visit:
At the screening ophthalmology visit, the eye examination will include:

Ophthalmologic history

Best corrected visual acuity measurement (using Landolt C chart)

Ophthalmoscopy (may include contact lens biomicroscopy to examine the macula and 
optic disc). A dilated fundus exam should be performed in all participants at the 
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screening visit and as needed at subsequent visits in participants with significant 
abnormalities identified on the screening exam.

Measurement of central foveal thickness by OCT (recorded in micrometers; required for 
all participants 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. Participants 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). Participants 
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 participants with uveitis findings on ophthalmic exam, additional testing should be 
considered (for example, fluorescein angiogram)
Participants experiencing unexpected ophthalmic symptoms without a known suspected etiology or 
experiencing a relevant ophthalmic adverse event may need to have repeated ophthalmoscopy and 
OCT testing performed.
9.9.6. Tuberculosis Screening and Chest X-Ray
All participants will complete TB screening to determine eligibility. A TB screening questionnaire 
will be completed during the Screening Period by the Investigator or delegated site staff for each 
participant and applicable information will be entered into the eCRF. For participants who are 
receiving TB prophylaxis treatment, the TB questionnaire will be completed at every study visit (until 
TB prophylaxis treatment course is completed).
9.9.7. Clinical Laboratory Tests
Refer to Table 5 for the list of clinical laboratory tests to be performed and the Schedule of 
Assessments (Table 6) for timing and frequency for each test. All scheduled clinical laboratory tests 
will be completed by a central lab or a sponsor approved regional lab for analysis unless extenuating 
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circumstances prevent shipments to a central lab (eg, natural disasters, war, etc.) in which case a 
qualified local laboratory can perform tests only once permission is granted by the Sponsor (or 
delegate). If a local laboratory is used for protocol-specified tests (even in parallel), this will be 
captured as a PD. Laboratory tests for a documented new or ongoing AE are not a PD. Details 
regarding clinical laboratory sample collection, preparation, and shipment are provided in the 
Laboratory Manual by the central laboratory.
Clinical safety laboratory tests should be completed predose. The Investigator must review the 
laboratory report, document this review, and record any clinically relevant changes occurring during 
the study in the adverse event section of the eCRF (results of the total WBC and ALC will be 
reviewed and monitored as described in Section 9.8.4). 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 participant’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 6), 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 participant 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 participants with notable lymphopenia, please refer to Section 9.8.4.
See Section 16.6 for suggested actions and Follow-up assessments in the event of potential DILI.
Table 5:
Clinical Laboratory Tests
SCREENING Only
Virology
HIV, HBsAg, HBcAb, HBsAb, HBV DNA, 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, Interferon gamma releasing assay (IGRA) (eg, QuantiFERON or T-SPOT-TB)
PREGNANCY TESTING
Serum pregnancy test beta-human chorionic gonadotropin (β-hCG) - Screening
Urine β-hCG (only for women of childbearing potential)
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Table 5:
Clinical Laboratory Tests (Continued)
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
BIOMARKERS
Lymphocytesa,b
hs-CRPb
Fecal calprotectinb
Immunophenotyping 
Proteomics
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 
participant becomes symptomatic, including worsening or return of disease activity.
β-hCG, beta-human chorionic gonadotropin; HBcAb, hepatitis B core antibody; HBsAb, hepatitis B surface antibody; 
HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; 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, natural killer lymphocytes; WBC, white blood cell
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9.9.7.1. Screening
9.9.7.1.1. Drugs of Abuse
A standard urine drug screen will be performed (Table 5). Participants who test positive will be 
assessed for eligibility for study participation by the Investigator.
9.9.7.1.2. Pregnancy Testing
A serum pregnancy test for β-hCG will be performed on women of childbearing potential to 
determine eligibility. Post-screening urine pregnancy tests (β-hCG) should be performed as indicated 
in the Schedule of Assessments (Table 6). If at any point there is a case of a positive urine β-hCG 
test, the participant 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 participant will be withdrawn 
from the study treatment and all the necessary follow-up assessments will be conducted as per 
Section 9.9.9. If the serum test is negative, the participant may resume study treatment.
Negative pregnancy test results must be documented for all women of childbearing potential prior to 
dosing at applicable study visits. Women who are surgically sterile or who are postmenopausal are 
not considered to be of childbearing potential. Postmenopausal is defined as 12 consecutive months 
with no menses without an alternative medical cause.
9.9.7.1.3. Virology
Screening HIV antibody, hepatitis B (ie, HBsAg, HBcAb, HBsAb, and HBV DNA), and HCV 
(recombinant immunoblot assay, if positive HCV RNA should be used to confirm infection).
9.9.7.1.4. Clinical Chemistry, Hematology, Coagulation, and Urinalysis
Clinical chemistry, hematology, coagulation, and urinalysis parameters that will be assessed during 
the study are identified in Table 5.
Participants 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 9.7 for timing of blood draws for PK).
9.9.8. Adverse Events
9.9.8.1. Definitions
9.9.8.1.1. Adverse Event
An adverse event is any untoward medical occurrence in a participant or clinical investigational 
participant 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
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
Preexisting conditions that worsen in severity, increase in frequency, or have new 
signs/symptoms
9.9.8.1.2. 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 participant at immediate risk of death. This 
classification does not apply to an adverse event that hypothetically might 
cause death if it were more severe.
Hospitalization:
The adverse event required or prolonged an existing inpatient 
hospitalization. Hospitalizations for elective medical or surgical 
procedures or treatments planned before the signing of informed consent 
in the study or routine check-ups are not SAEs by this definition.
Disabling/ 
incapacitating:
The adverse event resulted in a persistent or significant incapacity or 
substantial disruption of the participant’s ability to conduct normal life 
functions.
Congenital anomaly or 
birth defect:
An adverse outcome in a child or fetus of a participant 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 participant 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.
9.9.8.1.3. 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).
9.9.8.1.4. 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 PML-related symptoms, the Investigator should withhold study treatment and 
perform appropriate diagnostic evaluation per local standard of care at the first signs suggestive of 
PML. Typical symptoms associated with PML are diverse, progress over days to weeks, and may 
include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, 
and changes in thinking, memory, and orientation leading to confusion and personality changes. The 
Investigator must notify the Medical Monitor of such an event. 
Guidance for the Assessment of Potential Progressive Multifocal Leukoencephalopathy is provided in 
Appendix 5.
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9.9.8.1.5. 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
9.9.8.1.6. Relationship
The Investigator (or designee) will make a determination of the causal relationship of the adverse 
event to the study drug using a 4-category system according to the following guidelines: 
Not Related: 
(Unrelated = flag 
no on the AEM 
Report form)
The adverse event is definitely caused by the participant’s clinical state or 
the study procedure/conditions.
Unlikely Related: 
(Unrelated = flag 
no on the AEM 
Report form)
The temporal association between the adverse event and the drug is such that 
the drug is not likely to have any reasonable association with the adverse 
event.
Probably Related: 
(Related = flag yes 
on the AEM Report 
form)
The adverse event follows a reasonable temporal sequence from 
administration of the drug and cannot be reasonably explained by the known 
characteristics of the participant’s clinical state, environmental, or toxic 
factors, or other modes of therapy administered to the participant.
Related: (Related = 
flag yes on the 
AEM Report form)
The adverse event follows a reasonable temporal sequence from 
administration of the drug, abates upon discontinuation of the drug, follows a 
known or hypothesized cause-effect relationship, and (if appropriate) 
reappears when the drug is reintroduced.
The Investigator will use clinical judgment to determine the relationship. Alternative causes, such as 
underlying disease(s), concomitant therapy, and other risk factors, as well as the temporal relationship 
of the event to the study treatment administration should be considered and investigated. The 
Investigator should consult the IB and the Product Information of marketed products within the drug 
class, when applicable. For each adverse event/SAE, the Investigator must document in the medical 
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notes that he/she has reviewed the adverse event/SAE and has provided an assessment of causality. 
There may be situations in which an SAE has occurred and the Investigator has minimal information 
to include in the initial report to the Sponsor; however, it is very important that the Investigator 
always make an initial assessment of causality for every event before the initial transmission of the 
SAE to the Sponsor. The Investigator may change his/her opinion of causality based on subsequent
receipt of information and send an SAE follow-up report with the updated causality assessment. The 
causality assessment is one of the criteria used when determining regulatory reporting requirements.
9.9.8.2. Eliciting and Recording Adverse Events
9.9.8.2.1. Eliciting Adverse Events
Participants 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.
9.9.8.2.2. Recording Adverse Events
The adverse event reporting period for safety surveillance begins when the participant 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.
Investigators are not obligated to actively seek information on AEs or SAEs after the participant has 
concluded study participation. 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 participant, elicited during participant 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 captured and reported via the
established safety reporting mechanism. .
The following should be considered when recording SAEs:

Death is an outcome of an event. The event that resulted in the death should be recorded 
and reported on the eCRF.

For hospitalizations, surgical, or diagnostic procedures, the illness leading to the surgical 
or diagnostic procedure should be recorded as the SAE, not the procedure itself. The 
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procedure should be captured in the narrative as part of the action taken in response to the 
illness.
9.9.8.2.3. 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.
9.9.8.3. Reporting Adverse Events
All SAEs are subject to reporting requirements.
9.9.8.3.1. Serious Adverse Events
Any adverse event considered serious by the Investigator or that meets serious criteria must be 
reported to Pfizer Safety on the CT SAE Report Form upon awareness and under no circumstances 
should the time to report exceed 24 hours of becoming aware of the event.
If additional information is required or becomes available for a previously reported SAE, entry into 
CRF of the new or updated information should be completed and reported to Pfizer Safety on a new 
CT SAE Report Form within 24 hours of awareness. 
Elective hospitalization and/or surgery for clearly preexisting conditions (eg, a surgery that has been 
scheduled prior to the participant’s entry into the study) will not be reported as an SAE. 
Any SAE that is ongoing when the participant completes the study or discontinues the study will be 
followed by the Investigator until the event resolved, stabilized, or returned to baseline status. 
The Sponsor (via the In-Country Caretaker for Clinical Trial [ICCC]) is responsible for notifying the 
relevant regulatory authorities of any adverse event assessed by the Reporter (Investigator) or the 
Sponsor as: 
a) Serious, unexpected, and related, or 
b) Serious, expected, related and life-threatening or fatal
In addition, the ICCC is responsible for notifying the Investigator(s) of active sites, the head(s) of the 
active study sites, and, if applicable, the IRBs of all SAEs occurring during the study that are assessed 
by the Reporter (Investigator) or the Sponsor as related and unexpected. 
The Investigator is responsible for notifying the head of the study site of SAEs and significant safety 
findings that occur at his or her site. The Investigator is also responsible for responding to requests for 
additional information made by the Sponsor, the head of the study site, or the IRB.
9.9.8.3.2. Serious, Unexpected Adverse Drug Reactions
All ADRs that are both serious and unexpected are subject to expedited reporting to regulatory 
agencies in accordance with regional or national regulatory requirements. 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 adverse event is expected or unexpected.
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9.9.9. Exposure During Pregnancy and Breast Feeding
9.9.10. Environmental Exposure, Exposure During Pregnancy or Breastfeeding, and 
Occupational Exposure
Environmental exposure occurs when a person not enrolled in the study as a participant receives 
unplanned direct contact with or exposure to the study treatment. Such exposure may or may not lead 
to the occurrence of an AE or SAE. Persons at risk for environmental exposure include healthcare 
providers, family members, and others who may be exposed. An environmental exposure may include 
EDP, EDB, and occupational exposure. Examples of environmental exposure may include oral 
ingestion of, inhalation of, or skin contact with a tablet that is broken/crushed. 
Any such exposures to the study intervention under study are reportable to Pfizer Safety within 24 
hours of investigator awareness irrespective of whether an AE has occurred.
9.9.10.1. Exposure During Pregnancy
If at any point a serum β-hCG pregnancy test is positive, the participant will be withdrawn from the 
study treatment.
Details of all pregnancies in female participants and female partners of male participants 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 to Pfizer Safety via the CT SAE Report Form and the EDP Supplemental 
Form 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.
An environmental exposure during pregnancy (EDP) occurs if:   

A female non-participant is found to be pregnant while being exposed or having been 
exposed to study treatment because of environmental exposure.

A male non-participant who has been exposed to the study intervention then inseminates his 
female partner prior to or around the time of exposure.
When EDP occurs in the setting of environmental exposure, the investigator must report information 
to Pfizer Safety using the CT SAE Report Form and the EDP Supplemental Form. Since the exposure 
information does not pertain to the participant enrolled in the study, the information is not recorded 
on a CRF; however, a copy of the completed CT SAE Report Form are maintained in the investigator 
site file.
9.9.10.2. Exposure During Breastfeeding
An exposure during breastfeeding (EDB) occurs if:

A female participant is found to be breastfeeding while receiving or after discontinuing study 
intervention.
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The investigator must report EDB to Pfizer Safety within 24 hours of the investigator’s awareness, 
irrespective of whether an SAE has occurred. The information must be reported using the CT SAE 
Report Form. When EDB occurs in the setting of environmental exposure, the exposure information 
does not pertain to the participant enrolled in the study, so the information is not recorded on a CRF. 
However, a copy of the completed CT SAE Report Form is maintained in the investigator site file.
9.9.10.3. Occupational Exposure
The investigator must report any instance of occupational exposure to Pfizer Safety within 24 hours 
of the investigator’s awareness using the CT SAE Report Form, regardless of whether there is an 
associated SAE. Since the information about the occupational exposure does not pertain to a
participant enrolled in the study, the information is not recorded on a CRF; however, a copy of the 
completed CT SAE Report Form must be maintained in the investigator site file.
9.9.11. Lack of Efficacy
The investigator must report signs, symptoms, and/or clinical sequelae resulting from lack of efficacy. 
Lack of efficacy or failure of expected pharmacological action is reportable to Pfizer Safety only if 
associated with an SAE.
9.9.12. Medication Errors
Medication errors may result from the administration or consumption of the study intervention by the 
wrong participant, or at the wrong time, or at the wrong dosage strength. 
Medication errors not associated with an AE/SAE should be recorded as a protocol deviation.
A medication error with a potentially associated AE/SAE are recorded in the CRF. Medication errors 
associated with an SAE (per the Investigator’s assessment) should be reported to Pfizer Safety within 
24 hours on the CT SAE Report Form.
9.10. 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. Overdose has 
the potential to induce further dose-dependent reduction in peripheral lymphocyte count which may 
increase the risk of infections. Providers should employ effective diagnostic and therapeutic strategies
in patients with symptoms of infection.
In the event of a suspected overdose, the Investigator and/or treating physician should:
a.
Closely monitor the participant for any adverse event/SAE and laboratory abnormalities and 
follow the AE reporting process, including contacting the Medical Monitor.
b.
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.
c.
Document the total quantity of the excess dose, taking into consideration the duration of the 
overdose in the eCRF and the time frame.
Participants 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 
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the Investigator in consultation with the Medical Monitor based on the clinical evaluation of the 
participant.
10. PLANNED STATISTICAL METHODS
10.1. General Considerations
All individual participant data for all randomized participants will be presented in data listings. All 
efficacy and safety endpoints will be summarized by treatment group. Full details of statistical 
considerations and the planned analyses will be described in the study Statistical Analysis Plan
(SAP).
10.2. Determination of Sample Size
Based on a Chi-square test at 2-sided significance level of 0.05, a total of 96 participants (32 per 
treatment group) will provide at least 80% power to show pairwise superiority of etrasimod 2 mg to 
placebo in the primary endpoint assuming 5% remission rate in the placebo group and a 
31.5% remission rate in the etrasimod 2 mg group. The assumptions are based on the results from the 
completed Phase 2 Study APD334-003. Sample size is calculated using the EAST® software.
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 participants, who receive at least 
1 dose of study treatment. Under this approach, participants 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 participants 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. 
Participants 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 participants who 
receive at least 1 dose of study treatment and have a baseline and at least 1 post-randomization 
measurement. Under this approach, participants 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 participants 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 participants who receive at least 1 dose of 
study treatment. For this set, participants 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
Participants with a lack of efficacy adverse event related will be considered as having a treatment 
nonresponse outcome in the analysis of all endpoints, including the primary endpoint. In addition, 
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participants 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.
Participants 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. Participants who discontinue the 
double-blind study for reasons other than a lack of efficacy adverse event related to UC will be 
considered as having missing data and will be handled in the primary and sensitivity analyses as 
follows.
A full description of the handling of missing data will be provided in the SAP.
Primary method of handling missing data
In the primary analysis of the primary endpoint and main analyses of all binary responder-type 
endpoints, missing data, eg, component scores of MMS at the planned assessment timepoint, will be 
imputed using multiple imputation methodology (Rubin 1987) under the missing at random (MAR) 
assumption. Binary responder-type endpoints will subsequently be computed from observed and 
imputed data and analyzed using methods as outlined in Section 10.12.1.
In the main analysis of continuous or score endpoints, such as changes from baseline in MMS 
subscores, biomarker measures, urgency numeric rating scale (NRS), abdominal pain NRS, and 
health-related quality of life measures, missing data will be handled using the same multiple 
imputation methodology above and analyzed by either analysis of covariance 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 as follows.

All participants with missing data, regardless of reason for missingness, will be 
considered as nonresponders for binary responder-type endpoints.

A tipping point analysis will be performed for the primary and key secondary endpoints 
by considering all possible combinations of the number of responders and non-responders 
among participants 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 participants with 
missing data. These participants, regardless of the randomized treatment group, will be 
assumed to have a similar distribution of outcomes after discontinuation as participants 
with available data in the placebo group. This is akin to modeling the missing outcomes 
as if the participants continued on their background therapy only and accounting for the 
study effect observed in participants 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.
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Complete descriptions of the sensitivity analyses and detailed multiple imputation method and 
procedures will be provided in the SAP prior to database lock.
10.5. Efficacy Endpoint Definitions
The following definitions will be used to assess efficacy outcomes. Summary scores calculated from 
the components of the MMS and its component subscores will be used to assess efficacy.:

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) 

Symptomatic remission: SF subscore = 0 (or = 1 with a ≥1 point decrease from baseline) 
and RB subscore = 0

Mucosal healing: ES ≤1 (excluding friability) with histologic remission measured by a 
Geboes Index score < 2.0

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

Endoscopic normalization: ES = 0

Complete symptomatic remission: SF subscore = 0 and RB subscore = 0

Noninvasive clinical response: A ≥30% decrease from baseline in composite RB and SF, 
and a ≥1point decrease from baseline in RB subscore or an absolute RB subscore ≤1

Symptomatic response: Decrease from baseline ≥30% in composite RB and SF 
subscores

Clinical remission using TMS: TMS of ≤2 points with no individual subscore of 
> 1 point

Clinical response using TMS: A ≥3-point and ≥30% decrease from baseline in TMS, 
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
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 (ie, Week 12). Complete details of the MMS symptom score 
computation method are provided in Section 9.3.11 and Section 9.4.2.
10.6. Primary Endpoint
The primary efficacy endpoints will evaluate etrasimod versus placebo in:

The proportion of participants achieving clinical remission at Week 12
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 and all other endpoints are based on MMS 
as defined in Section 10.5.
The secondary efficacy endpoints are:

The proportion of participants achieving endoscopic improvement at Week 12

The proportion of participants achieving symptomatic remission at Week 12

The proportion of participants with mucosal healing at Week 12

The proportion of participants achieving clinical response at Week 12

The proportion of participants achieving endoscopic normalization at Week 12
10.8. Exploratory Endpoints
Exploratory efficacy endpoints are:

The proportion of participants achieving symptomatic remission at Weeks 2, 4, 8

The proportion of participants achieving complete symptomatic remission at each study 
visit (Weeks 2, 4, 8, 12)

The proportion of participants achieving noninvasive clinical response at each study visit 
(Weeks 2, 4, 8, 12)

The proportion of participants achieving symptomatic response at each study visit 
(Weeks 2, 4, 8, 12)

The proportion of participants with remission and response using TMS at Week 12

The proportion of participants with histologic improvement at Week 12 (as defined by 
the Geboes Index, Robarts Histopathology Index, and Nancy Histologic Index)

The proportion of participants with histologic remission at Week 12 (as defined by the 
Geboes Index, Robarts Histopathology Index, and Nancy Histologic Index)

The proportion of participants with improvement in EIMs at Week 12 in participants with 
EIMs at baseline
10.9. Pharmacokinetic Assessments

Plasma concentrations of etrasimod will be assessed from samples collected prior to 
dosing and 4 hours (± 15 minutes) postdose (after 12lead ECG) on Week 0/Day 1

Plasma concentrations of etrasimod will be assessed from samples collected prior to 
dosing (trough) at Weeks 2, 4, 8, 12, and the 2-Week and 4-Week Follow-Up visits
A descriptive summary of observed plasma concentration will be displayed by time and by treatment 
group. The Safety Set will be used to analyze plasma levels. 
Full details of PK analysis will be provided in the SAP.
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10.10. Other Assessments
10.10.1. Biomarker Endpoints

Change from baseline in level of fecal calprotectin at Weeks 2, 4, 8, and 12

Change from baseline in level of hs-CRP at Weeks 2, 4, 8, and 12

Change and percentage change from baseline in lymphocyte counts at Weeks 2, 4, 8, and 
12
10.10.2. Health-Related Patient-Reported Outcomes

Scores and change from baseline to Week 12 in the following:

UC-PRO/SS

SF-36, version 2, physical and mental component and domain scores

The proportion of participants with UC-related hospitalizations

The proportion of participants requiring UC-related surgeries, including colectomy
10.10.3. 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

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 TMS ≤8 versus > 8
10.11. Safety Endpoints

Incidence and severity of adverse events

Incidence and severity of laboratory abnormalities, and change from baseline in 
laboratory values (to include hematology, serum chemistry, coagulation, and urinalysis)

Incidence of clinically significant vital sign abnormalities and changes from baseline
10.12. Testing Strategy
10.12.1. Efficacy Analysis
The primary analysis of the proportion-based efficacy endpoints will be carried out using the 
Cochran-Mantel-Haenszel (CMH) method, stratified by (a) naïve to biologic or JAK 
inhibitor therapy at study entry (yes or no), (b) baseline corticosteroid use (yes or no), and (c) baseline 
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disease activity (MMS: 4 to 6 or 7 to 9). Results will be expressed as the number of participants in 
remission, remission percentages, difference in remission percentages, odds ratio, and associated 
95% confidence intervals (CIs) and p-values. The stratified CMH analysis will be performed for each 
etrasimod dose (1 and 2 mg) versus placebo separately. The Cochran-Armitage trend test will also be 
carried out for all primary and secondary proportion-based efficacy endpoints.
There are multiple null hypotheses for the comparison of etrasimod and placebo in the primary and 
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.
A hierarchical testing procedure will be used to control family-wise Type I error rate at α level 0.05 
(2-sided). The comparison of etrasimod 2 mg versus placebo for the primary endpoint (Family 1; F1) 
is the main gatekeeper. The study is considered positive if F1 is rejected at the α level. Only if this 
test is significant will etrasimod 2 mg be compared with placebo for all the secondary endpoints 
(Family 2; F2). The truncated Hochberg method (Dmitrienko 2011, FDA 2017) will be applied to F2 
at α level.
If none of the null hypotheses in F2 is rejected, then testing will stop with all nominal p-values 
reported for subsequent comparisons of etrasimod 1 mg versus placebo. Otherwise, etrasimod 1 mg 
be compared with placebo for the primary endpoint (Family 3; F3) with the unused α from testing F2. 
Only if this test is significant will etrasimod 1 mg be compared with placebo for all the secondary 
endpoints (Family 4; F4). The conventional Hochberg method (FDA 2017) will be applied to F4 with 
the same unused α for F3. Full details of the efficacy analysis and the hierarchical testing procedure 
above 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 
participant 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 ECG results will be tabulated.
10.13. Interim Analysis
Not applicable
11. ETHICAL CONSIDERATIONS
11.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines, including the Declaration 
of Helsinki and CIOMS International Ethical Guidelines;

Applicable ICH GCP guidelines;

Applicable laws and regulations, including applicable privacy laws.
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The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC by the 
investigator or designee, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of changes 
made to the study design, except for changes necessary to eliminate an immediate hazard to study 
participants.
Protocols and any substantial amendments to the protocol will require health authority approval prior 
to implementation of changes made to the study design except for changes necessary to eliminate an 
immediate hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by IRB/EC 
procedures;

Providing oversight of the conduct of the study at the site and adherence to requirements of 
21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 536/2014 for clinical 
studies, European Medical Device Regulation 2017/745 for clinical device research, and all 
other applicable local regulations.
11.2. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable regulatory 
authority in any area of the world, or if the investigator is aware of any new information that might 
influence the evaluation of the benefits and risks of the study intervention, the Sponsor should be 
informed immediately. 
In addition, the investigator will inform the sponsor immediately of any urgent safety measures taken 
by the investigator to protect the study participants against any immediate hazard, and of any serious 
breaches of this protocol or of the ICH GCP guidelines that the investigator becomes aware of.
11.3. Informed Consent
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 may be obtained, the Investigator 
should provide the participant ample time and opportunity to inquire about details of the study and to 
decide whether to participate.
Prior to a participant’s participation in the study, the IRB/IEC-approved ICF must be signed and 
personally dated by the participant and by the person who conducted the informed consent discussion. 
If a participant 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 participants should be revised 
whenever important new information becomes available that may be relevant to the participant’s 
consent. Any revised written ICF or study materials to be available and/or supplied to participants 
should receive the IRB/IEC’s approval in advance of use. The participant will be informed in a timely 
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manner if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information should be documented. 
During a participant’s participation in the study, the participant 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 participants.
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 participant that the monitor(s), 
auditor(s), IRB/IEC, and the regulatory authorities will be granted direct access to the participant’s 
original medical records for verification of clinical study procedures and/or data, and that, by signing 
a written ICF, the participant is authorizing such access.
In addition, prior to study participation, the participant must be informed that the records identifying 
the participant will not be made publicly available; if the results of the study are published, the 
participant’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 participants 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 participant, 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 
participant’s participation and/or the assessment of safety or efficacy in the study. Any significant 
protocol deviations affecting participant eligibility and/or safety must be reported by Investigator or 
site delegate to the IRB/IEC and regulatory authorities, as applicable, prior to implementation.
The Investigator should document and explain any deviation from the approved protocol.
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.
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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 participants 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.
13. DATA HANDLING AND RECORD KEEPING
13.1. Data Management
13.1.1. Case Report Forms
An eCRF must be completed for each participant 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 participant data in his/her own participant files. These participant 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.
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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 participant. 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, participants’ 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:

Participant 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
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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 participants under the Investigator’s care; and for the control of drugs under 
investigation. An Investigator will, in accordance with the provisions of ICH GCP guidelines and/or 
21 CFR Part 50, obtain the informed consent of each human subject to whom the drug is 
administered.
14.2. Sponsor’s Medically Qualified Individual
The contact information for the sponsor's MQI for the study is documented in the study contact list 
located in the supporting study documentation. 
To facilitate access to their investigator and the sponsor’s MQI for study related medical questions or 
problems from non-study healthcare professionals, participants are provided with an ECC at the time 
of informed consent. The ECC contains, at a minimum, (a) protocol and study treatment identifiers, 
(b) participant’s study identification number, (c) site emergency phone number active 24 hours/day, 7 
days per week, and (d) Pfizer Call Center number.
The ECC is intended to augment, not replace, the established communication pathways between the 
participant and their investigator and site staff, and between the investigator and sponsor study team. 
The ECC is only to be used by healthcare professionals not involved in the research study, as a means 
of reaching the investigator or site staff related to the care of a participant. The Pfizer Call Center 
number is to be used when the investigator and site staff are unavailable. The Pfizer Call Center 
number is not for use by the participant directly; if a participant calls that number directly, they will 
be directed back to the investigator site.
14.3. 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 
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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.
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. 
Dmitrienko A, Kordzakhia G, Tamhane AC. Multistage and mixture parallel gatekeeping procedures 
in clinical trials. J Biopharm Stat. 2011;21(4):726-747. 
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/UCM
515143.pdf. Published 2016. Accessed March 1, 2019.
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/files/drugs/published/Multiple-Endpoints-in-Clinical-Trials-Guidance-for-
Industry.pdf. Published 2017. Accessed October 20, 2020.
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. 
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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. 
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. 
Okabayashi S, Kobayashi T, Hibi T. Inflammatory bowel disease in Japan-is it similar to or different 
from Westerns? J Anus Rectum Colon. 2020;4(1):1-13. 
PMDA. Basic principles on global clinical trials (reference cases). Pharmaceuticals and Medical 
Devices Agency. https://www.pmda.go.jp/files/000152969.pdf. Published 2012. Updated Sep 5. 
Accessed August 26, 2020.
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. 
Sandborn WJ, Vermeire S, Peyrin-Biroulet L, et al. Etrasimod 2 mg once daily as treatment for 
moderately to severely active ulcerative colitis: results from the phase 3 ELEVATE UC 52 and 
ELEVATE UC 12 trials. Gastroenterology. 2022;162(suppl 1).
Siegel CA, Melmed GY, McGovern DPB, et al. SARS-CoV-2 vaccination for patients with 
inflammatory bowel diseases: Recommendations from an international consensus meeting. Gut. 
2021;70(4):635-640. 
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.
16. APPENDICES
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16.1. APPENDIX 1: SCHEDULE OF ASSESSMENTS
Table 6:
Schedule of Assessments – Screening and Induction Treatment Period
Evaluation
Screening 
Period
12-Week Treatment Period
28 to 1
W0/D1
W2/D15a
± 3 Days  
W4/D29a
± 3 Days
W8/D57a
± 3 Days
W12/D85 / 
Early 
Terminationb
± 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
UC-PRO/SS, SF-36
X
X
Adverse event assessment
X
X
X
X
X
X
X
X
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Evaluation
Screening 
Period
12-Week Treatment Period
28 to 1
W0/D1
W2/D15a
± 3 Days  
W4/D29a
± 3 Days
W8/D57a
± 3 Days
W12/D85 / 
Early 
Terminationb
± 3 Days 
2-Week
Follow-
Up Visitb
± 3 Days
4-Week
Follow-
Up Visitb
± 3 Days
Vital signsj,k  
Xj
Xj,k
X
X
X
X
X
X
12-lead ECGl,m  
Xl
Xl,m
X
Physical examinationn  
X
X
X
X
X
X
X
X
Extraintestinal manifestationso  
X
X
X
X
Pulmonary function testp  
Xq
Xq
Xq
Ophthalmoscopy with OCTr  
X
X
Xr
Urine drug screens  
X
Pregnancy testt  
X
X
X
X
X
X
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
Flexible proctosigmoidoscopy/ 
colonoscopy and biopsyw  
X
X
PK assessmentsx  
X
X
X
X
X
Xx
Xx
Biomarkers blood sampley  
X
Xz
Concomitant medications and 
proceduresaa  
X
X
X
X
X
X
X
Drug dispensation/accountabilitybb  
X
X
X
X
Xbb
Study treatment administrationcc  
X – Once daily
a All visits beyond W0/D1 may be virtual/hybrid visits (Section 9.6).
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b Participants discontinuing prior to Week 12 should have an ET visit within 7 days of the last study treatment administration and before initiation of any new treatments. For 
participants who complete Week 12 and wish to enter the APD334-303 OLE study, the Week 12 visit will be used to assess eligibility for the APD334-303 OLE study. For 
participants not participating in the APD334-303 OLE study, a follow-up visit will be performed at 2 weeks and 4 weeks after the last administration of study treatment. If the 
ET or Study Completion visit is ≥2 weeks after the last dose of study treatment, the 2-Week Follow-Up visit is not required; however, the 4-Week Follow-Up visit should be 
scheduled and completed. If the ET or Study Completion visit is ≥4 weeks after the last administration of study treatment, the 4-Week Follow-Up visit is not required. If the 
absolute peripheral lymphocyte count is not within normal limits at the 4-Week Follow-Up visit, participants 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 Day 1 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 participants will complete TB screening to determine eligibility (refer to Appendix 2). The IGRA (eg,QuantiFERON TB Gold In-Tube or T-SPOT-TB) and tuberculin skin 
test should not be performed in participants previously diagnosed with TB infection. The TB questionnaire will be completed for all participants during the Screening period. For 
participants who are receiving TB prophylaxis treatment, the TB questionnaire will be completed at every study visit (until TB prophylaxis treatment course is completed).
f Participants will be tested for HIV antibodies as well as HBV and HCV infection at screening (Section 9.9.7.1.3).
g Participants 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 participant 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/ET visits. The subscores for SF and RB are derived from the participant 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 participant 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 participants in the sitting position will be performed at 
Screening and prior to randomization on Week 0/Day 1 (baseline). If the participant’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 participant 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 participant in the supine position will be obtained prior to blood sample collection at Screening and prior to randomization on Week 0/Day 1 
(baseline). Participants with a 12-lead ECG showing a second or third-degree AV block, periods of asystole > 3 seconds, PR interval > 200 ms, QTcF ≥450 ms (men) or
QTcF ≥470 ms (women) must not be randomized and should be considered screen failures.
m After dosing on Day 1, a 12-lead ECG with the participant in the supine position will be performed 4 hours (± 15 minutes) postdose as described in Section 9.4.2.1.
n Complete physical examination (including assessments of the skin, head, eyes, ears, nose, throat, neck, thyroid, lungs, heart, abdomen, back, lymph nodes, extremities, body 
weight, and height [height collected at Screening Visit only]) should be performed at screening and the Week 12/ET visit. All other visits during the 12-Week Treatment Period 
should have a focused (complaints, signs, and symptoms) physical examination.
o During the specified full physical examinations (screening and Week 12/ET visits), specific systems (eyes, liver, skin, and joints) will be examined for EIMs.
p A PFT will include FEV1 and FVC measurements. When available, DLCO measurements will also be performed (when DLCO is not available, sites should consult the Sponsor 
or Sponsor’s delegate). The 2-Week Follow-Up visit assessment is only required if clinically indicated. Details regarding additional PFTs are provided in Section 9.9.4.
q The Screening 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 9.9.4.
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 
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 9.9.5.
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s Urine drug screen according to Table 5.
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 
participant will have study treatment interrupted and a serum sample submitted to the central laboratory for β-hCG testing (Section 9.9.7.1.2)
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 randomization. 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 participant becomes symptomatic, including worsening or return of disease activity.
w To be read by a blinded central reader. Proctosigmoidoscopy/colonoscopy should be performed prior to randomization to allow central reader review (may take approximately 
5 to 12 days) and confirmation of eligibility (Section 9.8.1.1). If the ET visit is within 4 weeks of the last sigmoidoscopy and biopsy, these procedures do not need to be repeated.
x Pharmacokinetic blood samples are to be collected predose, 4 hours (± 15 minutes) postdose on Week 0/Day 1 (PK sample to be collected after 12lead ECG), and predose (for 
trough level, within the 60minute 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 participants not enrolling into the APD334-303 study, a blood sample for PK should be drawn at the 2-Week and 4-Week 
Follow-Up visits. For all PK blood draws, the time of the last dose should be documented. For participants enrolling in the OLE at the Week 12 visit, the PK sample can be 
collected as part of the OLE.
y Blood samples for biomarkers should be collected on the indicated days prior to the daily dosing as applicable.
z Biomarkers will be collected at Week 12 but will not be collected at ET.
aa All concomitant medications and procedures should be collected from Day 1 (predose) through the safety reporting period (Section 6.7).
bbStudy treatment should be dispensed at Week 12 if the participant continues treatment in APD334-303 OLE. Additionally, participants 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.
cc On days with scheduled study visits, participants should wait to take their study treatment until after blood draws for PK and after all pre-dose assessments and procedures have 
been completed.
AV, atrioventricular; β-hCG, beta-human chorionic gonadotropin; BP, blood pressure; CBC, complete blood count; D, day; DLCO, diffusing capacity of the lungs for carbon 
monoxide; ECG, electrocardiogram; eDiary, electronic diary; EIM, extraintestinal manifestations; ET, Early Termination; FEV1, forced expiratory volume at 1 second; FVC, 
forced vital capacity; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; HR, heart rate; hs-CRP, high-sensitivity C-reactive protein; MMS, 
modified Mayo score; OCT, optical coherence tomography; OLE, open-label extension; PFT, pulmonary function test; PGA, Physicians Global Assessment; PK, 
pharmacokinetics; QTcF, Fridericia’s corrected QT interval; RB, rectal bleeding; SAE, serious adverse event; SF, stool frequency; SF-36, Medical Outcomes Study 36-Item Short 
Form Health Survey; TB, tuberculosis; TBNK, T cell, B cell, natural killer cell; UC-PRO/SS, Ulcerative Colitis Patient-Reported Outcomes Signs and Symptoms; W, week
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Phase 2, 12-Week Study in UC
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16.2. APPENDIX 2: TUBERCULOSIS SCREENING
All participants must undergo screening for a history of tuberculosis (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. 
Participants 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.
Participants 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 participants (refer to questionnaire below) 
during the Screening period.
c.
For participants 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.
d.
The IGRA or TST is NOT required at screening (or annually) for participants with a 
history of active/latent TB infection. 

Participants with past or current history of active TB, regardless of treatment history, 
are excluded from enrollment.

Participants 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.
Participants with a newly identified positive IGRA (one retest is allowed with approval 
from the Medical Monitor per Section 9.3.2) 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. 
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 

Participants will be considered to have a negative diagnostic test for TB if at least one 
of the following circumstances applies:
Negative IGRA.
Combination of a negative IGRA and negative purified protein derivative 
(PPD) TST (in countries where IGRA is not considered a validated test).
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Phase 2, 12-Week Study in UC
Amendment 1.0
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
A combination of two intermediate/indeterminant IGRAs and a negative PPD TST. 
An intermediate/indeterminant IGRA test result should be repeated. In the event that 
the second IGRA test result is also intermediate/indeterminate, the participant 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 participant 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 
participant’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 
participants receiving equivalent of prednisone > 15 mg/day for any medical 
conditions. 
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;jses
sionid=115F807C3008D688F75118AF16EA53F0?sequence=1
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Phase 2, 12-Week Study in UC
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Tuberculosis Screening Questionnaire
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Phase 2, 12-Week Study in UC
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Phase 2, 12-Week Study in UC
Amendment 1.0
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16.3. 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
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Phase 2, 12-Week Study in UC
Amendment 1.0
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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 Total Mayo Score (TMS) ranges from 0 to 12, with higher scores indicating more severe disease. 
The modified Mayo score (MMS) ranges from 0 to 9 and comprises the subscores for stool 
frequency, rectal bleeding, and endoscopy.
a Each participant serves as his or her own control to establish the degree of abnormality of the stool 
frequency.
b The daily bleeding score represents the most severe bleeding of the day.
c The endoscopy subscore will be determined by qualified personnel at a central laboratory.
d The Physician’s Global Assessment acknowledges the 3 other criteria, the subject’s daily 
recollection of abdominal discomfort and general sense of well-being, and other observations, such 
as physical findings and the subject’s performance status.
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Phase 2, 12-Week Study in UC
Amendment 1.0
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16.4. 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 ulcerative colitis (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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Phase 2, 12-Week Study in UC
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16.5. APPENDIX 5: GUIDANCE FOR THE ASSESSMENT OF POTENTIAL 
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
If a participant exhibits signs and symptoms suspicious for progressive multifocal 
leukoencephalopathy (PML), the Investigator must interrupt study treatment and perform a targeted 
neurologic examination to assess for signs of PML, which are diverse, progress over days to weeks, 
and may include progressive weakness on one side of the body or clumsiness of limbs or difficulty 
with walking or writing or fine motor skills, disturbance of vision, changes in thinking, memory and 
orientation leading to confusion and personality changes, paresthesia/anesthesia (of any domain: 
peripheral to central), dysarthria (expressive aphasia), and/or agnosia (receptive aphasia). 
Consultation with a local neurologist may be warranted, as presented in the PML case evaluation 
algorithm in Figure 2.
The Medical Monitor should be informed of any suspected cases of PML and, if needed, will 
facilitate investigator/local neurologist consultation with PML medical experts on the independent 
adjudication committee.
Figure 2:
Progressive Multifocal Leukoencephalopathy Case Evaluation Algorithm
Note: IP dosing may resume, and no further evaluation is needed if the Investigator assessment reveals no objective signs of 
PML, the local neurologist confirms that the patient does not have PML, or the IAC’s review of the evidence concludes that 
PML is ruled out.
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
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Phase 2, 12-Week Study in UC
Amendment 1.0
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16.6. APPENDIX 6: LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury but adapt are 
termed “adaptors.” In some participants, transaminase elevations are a harbinger of a more serious 
potential outcome. These participants fail to adapt and therefore are “susceptible” to progressive and 
serious liver injury, commonly referred to as DILI. Participants who experience a transaminase 
elevation above 3 × ULN should be monitored more frequently to determine if they are “adaptors” or 
are “susceptible.”
In the majority of DILI cases, elevations in AST and/or ALT precede T bili elevations (>2 × ULN) by 
several days or weeks. The increase in T bili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and T bili values will be elevated within the same laboratory sample). 
In rare instances, by the time T bili elevations are detected, AST/ALT values might have decreased. 
This occurrence is still regarded as a potential DILI. Therefore, abnormal elevations in either AST 
OR ALT in addition to T bili that meet the criteria outlined below are considered potential DILI 
(assessed per Hy’s law criteria) cases and should always be considered important medical events, 
even before all other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the participant’s 
individual baseline values and underlying conditions. Participants who present with the following 
laboratory abnormalities should be evaluated further as potential DILI (Hy’s law) cases to definitively 
determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and T bili baseline values within the normal range who 
subsequently present with AST OR ALT values ≥3 × ULN AND a T bili value ≥2 × ULN 
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not available 
(refer to Section 5.1 for guidance on when to discontinue the participant).

For participants with baseline AST OR ALT OR T bili values above the ULN, the following 
threshold values are used in the definition mentioned above, as needed, depending on which 
values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT values 
≥2 times the baseline values AND ≥3 × ULN; or ≥8 × ULN (whichever is smaller).

Preexisting values of T bili above the normal range: T bili level increased from baseline 
value by an amount of ≥1 × ULN or if the value reaches ≥3 × ULN (whichever is 
smaller).
Rises in AST/ALT and T bili separated by more than a few weeks should be assessed individually 
based on clinical judgment; any case where uncertainty remains as to whether it represents a potential 
Hy’s law case should be reviewed with the sponsor.
The participant should return to the investigator site and be evaluated as soon as possible, preferably 
within 48 hours from awareness of the abnormal results. This evaluation should include laboratory 
tests, detailed history, and physical assessment. 
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Phase 2, 12-Week Study in UC
Amendment 1.0
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In addition to repeating measurements of AST and ALT and T bili for suspected Hy’s law cases, 
additional laboratory tests should include albumin, CK, direct and indirect bilirubin, GGT, PT/INR, 
total bile acids, and alkaline phosphatase. Consideration should also be given to drawing a separate 
tube of clotted blood and an anticoagulated tube of blood for further testing, as needed, for further 
contemporaneous analyses at the time of the recognized initial abnormalities to determine etiology. A 
detailed history, including relevant information, such as review of ethanol, 
acetaminophen/paracetamol (either by itself or as a coformulated product in prescription or 
over-the-counter medications), recreational drug, or supplement (herbal) use and consumption, family 
history, sexual history, travel history, history of contact with a jaundiced person, surgery, blood 
transfusion, history of liver or allergic disease, and potential occupational exposure to chemicals, 
should be collected. Further testing for acute hepatitis A, B, C, D, and E infection, liver imaging (eg, 
biliary tract), and collection of serum samples for acetaminophen/paracetamol drug and/or protein 
adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and T bili 
elevation defined above should be considered potential DILI (Hy’s law) cases if no other reason for 
the LFT abnormalities has yet been found. Such potential DILI (Hy’s law) cases are to be reported as 
SAEs, irrespective of availability of all the results of the investigations performed to determine 
etiology of the LFT abnormalities. 
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of reasonable 
investigations have been received and have excluded an alternative etiology.
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V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
T A B L E O F C O N T E N T S
1.
I N T R O D U C TI O N.................................................................................................................. 1 3
2.
S T U D Y O B J E C TI V E S A N D E S TI M A N D S...................................................................... 1 3
2. 1.
Pri m ar y O bjecti ve.......................................................................................................................................... 1 3
2. 2.
S ec o n d ar y O bjecti ve...................................................................................................................................... 1 3
2. 3.
S af et y O bjecti ve............................................................................................................................................. 1 3
2. 4.
Ot h er O bjecti ves............................................................................................................................................ 1 3
2. 5.
Esti m a n ds....................................................................................................................................................... 1 4
3.
S T U D Y D E SI G N.................................................................................................................... 1 6
3. 1.
Ge n er al Descri pti o n....................................................................................................................................... 1 6
3. 2.
S c h e d ul e of E ve nts......................................................................................................................................... 1 7
3. 3.
C h a n ges t o A n al ysis f r o m Pr ot oc ol.............................................................................................................. 1 7
4.
P L A N N E D A N A L Y S E S........................................................................................................ 1 8
4. 1.
I nteri m A n al ysis............................................................................................................................................. 1 8
4. 2.
Fi n al A n al ysis................................................................................................................................................. 1 8
5.
A N A L Y SI S S E T S................................................................................................................... 1 9
5. 1.
S cree n e d S et ................................................................................................................................................... 1 9
5. 2.
R a n d o mi ze d S et ............................................................................................................................................. 1 9
5. 3.
F ull A n al ysis S et ( F A S).................................................................................................................................. 1 9
5. 4.
Per Pr ot oc ol S et ( P P S)................................................................................................................................... 1 9
5. 5.
M o difi e d F ull A n al ysis S et ( m F A S).............................................................................................................. 2 0
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 5 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
5. 6.
S af et y S et ( S S)................................................................................................................................................ 2 0
5. 7.
P h ar m ac o ki n etic Set ( P K S)........................................................................................................................... 2 0
6.
G E N E R A L C O N SI D E R A TI O N S........................................................................................ 2 1
6. 1.
Ref ere n ce St art D ate a n d St u d y D a y............................................................................................................ 2 1
6. 2.
B as eli n e........................................................................................................................................................... 2 1
6. 3.
Retests, U nsc h e d ul e d Visits a n d E arl y Ter mi n ati o n D at a ......................................................................... 2 1
6. 4.
Wi n d o wi n g C o n ve nti o ns............................................................................................................................... 2 2
6. 5.
St atisti c al T ests............................................................................................................................................... 2 4
6. 6.
C o m m o n C alc ul ati o ns................................................................................................................................... 2 4
6. 7.
Ge n er al St u d y I nf or m ati o n........................................................................................................................... 2 4
7.
D E T E R MI N A TI O N O F S A M P L E SI Z E........................................................................... 2 4
8.
S T A TI S TI C A L C O N SI D E R A TI O N S................................................................................ 2 5
8. 1.
M ulti ce nter St u di es........................................................................................................................................ 2 5
8. 2.
A dj ust m e nts f or C o v ari ates a n d F act ors t o b e I n cl u de d i n A n al yses........................................................ 2 5
8. 3.
Missi n g D at a................................................................................................................................................... 2 5
8. 4.
M ulti pl e C o m p aris o ns/ M ulti pli cit y............................................................................................................. 2 5
8. 5.
S u b gr o u ps A n al ysis........................................................................................................................................ 2 6
9.
O U T P U T P R E S E N T A TI O N S.............................................................................................. 2 7
1 0.
DI S P O SI TI O N A N D P R O T O C O L D E VI A TI O N S ......................................................... 2 7
1 0. 1.
Dis p ositi o n.................................................................................................................................................. 2 7
1 0. 2.
Pr ot oc ol De vi ati o ns.................................................................................................................................... 2 7
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 6 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
1 1.
D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E RI S TI C S......................... 2 8
1 1. 1.
Deri v ati o ns.................................................................................................................................................. 3 0
1 2.
M E DI C A L HI S T O R Y........................................................................................................... 3 0
1 3.
M E DI C A TI O N S A N D N O N- D R U G T R E A T M E N T....................................................... 3 0
1 4.
S T U D Y T R E A T M E N T E X P O S U R E ................................................................................. 3 1
1 4. 1.
Deri v ati o ns.................................................................................................................................................. 3 1
1 5.
S T U D Y T R E A T M E N T C O M P LI A N C E ........................................................................... 3 1
1 5. 1.
Deri v ati o ns.................................................................................................................................................. 3 2
1 6.
E F FI C A C Y O U T C O M E S .................................................................................................... 3 3
1 6. 1.
Pri m ar y Effi c ac y........................................................................................................................................ 3 4
1 6. 1. 1.
Pri m ar y Effi cac y Varia bl e & Deri vati o n................................................................................................. 3 4
1 6. 1. 2.
Missi n g Dat a Met h o ds f or Pri m ar y Efficac y Vari a ble............................................................................. 3 4
1 6. 1. 3.
Pri m ar y A nal ysis of Pri m ar y Efficac y Vari a ble ...................................................................................... 3 5
1 6. 1. 4.
S u p ple m e ntar y A nal ysis of Pri mar y Effi cac y Vari a bl e........................................................................... 3 5
1 6. 2.
S ec o n d ar y Effic ac y.................................................................................................................................... 3 5
1 6. 2. 1.
S ec o n dar y Effi cac y V aria bl es & Deri vati o ns.......................................................................................... 3 6
1 6. 2. 2.
Missi n g Dat a Met h o ds f or S ec o n dar y Efficac y Vari a bles....................................................................... 3 6
1 6. 2. 3.
Pri m ar y A nal ysis of S ec o n dar y Effi cac y Varia bl es................................................................................. 3 6
1 6. 2. 4.
S u p ple m e ntar y A nal ysis of Sec o n dar y Effi cac y Varai bl es...................................................................... 3 6
1 6. 3.
E x pl or at or y Effi c ac y.................................................................................................................................. 3 7
1 6. 3. 1.
E x pl orat or y Efficac y Vari a bles a n d Deri vati o ns..................................................................................... 3 7
1 6. 3. 2.
Missi n g Dat a Met h o ds f or E x pl orat or y Efficac y Varia bl es..................................................................... 3 7
1 6. 3. 3.
A nal ysis of E x pl orat or y Efficac y Vari a bles ............................................................................................ 3 7
1 6. 4.
Effi c ac y- Rel ate d Bi o m ar k ers.................................................................................................................... 3 8
1 7.
H E A L T H- R E L A T E D Q U A LI T Y O F LI F E ( H R Q O L) A N D H E A L T H C A R E 
R E S O U R C E U TI LI Z A TI O N A N A L Y SI S................................................................................... 3 8
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 7 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
1 7. 1.
V ari a bles a n d Deri v ati o ns......................................................................................................................... 3 9
1 7. 1. 1.
Ul cerati ve C olitis Patie nt- R e p orte d O ut c o m es Si g ns a n d S y m pt o ms...................................................... 3 9
1 7. 1. 2.
3 6 Ite m S h ort F or m Healt h S ur ve y, versi o n 2......................................................................................... 3 9
1 7. 1. 3.
U C- R elat e d H os pitali zati o ns a n d S ur geries............................................................................................. 3 9
1 7. 2.
Missi n g D at a Met h o ds............................................................................................................................... 4 0
1 8.
S A F E T Y O U T C O M E S ......................................................................................................... 4 0
1 8. 1.
A d verse E ve nts........................................................................................................................................... 4 0
1 8. 1. 1.
All T E A Es............................................................................................................................................... 4 0
1 8. 1. 1. 1.
S e verit y............................................................................................................................................ 4 0
1 8. 1. 1. 2.
R elati o ns hi p t o St u d y Treat m e nt...................................................................................................... 4 1
1 8. 1. 2.
T E A Es Lea di n g t o Disc o nti n uati o n of St u d y Treat m e nt......................................................................... 4 1
1 8. 1. 3.
S eri o us a n d N o n- S eri o us T E A Es............................................................................................................. 4 1
1 8. 1. 4.
T E A Es Lea di n g t o Deat h......................................................................................................................... 4 2
1 8. 1. 5.
T E A Es of S peci al I nterest........................................................................................................................ 4 2
1 8. 1. 6.
O verall S u m mar y of A d verse E ve nt........................................................................................................ 4 3
1 8. 2.
De at hs ......................................................................................................................................................... 4 4
1 8. 3.
L a b or at or y E v al u ati o ns............................................................................................................................ 4 4
1 8. 3. 1.
S afet y La b orat or y E val uati o ns................................................................................................................. 4 4
1 8. 3. 2.
Pre g na nc y Tests....................................................................................................................................... 4 6
1 8. 3. 3.
Ot her S cree ni n g La b orat or y Assess me nts............................................................................................... 4 6
1 8. 4.
E C G E v al u ati o ns....................................................................................................................................... 4 6
1 8. 4. 1.
E C G Mar ke dl y A b n or mal Criteri a........................................................................................................... 4 7
1 8. 5.
Vit al Si g ns................................................................................................................................................... 4 8
1 8. 5. 1.
Vital Si g ns S pecific Deri vati o ns.............................................................................................................. 4 9
1 8. 5. 2.
Vital Si g ns Mar ke dl y A b n or m al Crit eria................................................................................................. 4 9
1 8. 6.
P h ysic al E x a mi n ati o n................................................................................................................................ 5 0
1 8. 7.
Ot h er S af et y Assess m e nts.......................................................................................................................... 5 0
1 8. 7. 1.
P ul m o nar y F u ncti o n Test......................................................................................................................... 5 0
1 8. 7. 1. 1.
P F T M ar ke dl y A b n or mal a n d P ot e nti all y I m p orta nt Criteri a.......................................................... 5 0
1 8. 7. 2.
O p ht hal m osc o p y a n d O pti cal C o here nce T o m o gra p h y........................................................................... 5 1
1 8. 7. 3.
T u berc ul osis S cree ni n g a n d C hest X- R a y ............................................................................................... 5 1
1 9.
P H A R M A C O KI N E TI C A N A L Y SI S.................................................................................. 5 1
2 0.
D A T A N O T S U M M A RI Z E D O R P R E S E N T E D.............................................................. 5 4
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 8 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
2 1.
R E F E R E N C E S....................................................................................................................... 5 5
A P P E N DI X 1.
P R O G R A M MI N G C O N V E N TI O N S F O R O U T P U T S................................ 5 6
I Q VI A O ut p ut C o n ve nti o ns...................................................................................................................................... 5 6
Deci m als, Perce nt a ges a n d CI................................................................................................................................... 5 6
C o n ve nti o ns Rel ate d t o P h ar m ac o ki n eti c D at a....................................................................................................... 5 6
D ates & Ti m es............................................................................................................................................................ 5 6
S p elli n g F or m at.......................................................................................................................................................... 5 7
Pres e nt ati o n of Tre at me nt G r o u ps .......................................................................................................................... 5 7
Pres e nt ati o n of Visits a n d St u d y Peri o d.................................................................................................................. 5 7
Listi n gs........................................................................................................................................................................ 5 7
A P P E N DI X 2.
P A R TI A L D A T E C O N V E N TI O N S................................................................. 5 9
I n c o m plete St art D ates f or A d verse E ve nts:........................................................................................................... 5 9
Al g orit h m f or T re at m e nt E mer ge nce of A d verse E ve nts:..................................................................................... 5 9
Al g orit h m f or Pri or / C o n c o mit a nt Me dic ati o ns:................................................................................................... 6 0
Al g orit h m f or St arti n g D ate of H os pit ali z ati o n a n d St art/ St o p D ates of C o n c o mit a nt Me dic ati o ns:................ 6 1
A P P E N DI X 3.
U C- P R O/ S S S C O RI N G R U L E S....................................................................... 6 2
A P P E N DI X 4.
S F- 3 6 S C O RI N G R U L E S.................................................................................. 6 5
A P P E N DI X 5.
C L A S SI FI C A TI O N O F R E S C U E T H E R A P Y.............................................. 6 6
L I S T O F T A B L E S 
Ta ble 1:
List of Pri m ar y a n d Sec o n dar y Esti m a n ds................................................................... 1 4
Ta ble 2:
Visit Wi n d o ws f or Effic ac y a n d Safet y A n al ys es ....................................................... 2 3
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 9 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
Ta ble 3:
Pla n n e d A n al ysis b y E n d p oi nt...................................................................................... 3 5
Ta ble 4:
Mar k e dl y A b n or m al Criteria f or Vital Si g ns ............................................................... 4 9
L I S T O F F I G U R E S
Fi g ure 1:
St u d y Desi g n.................................................................................................................. 1 7
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 1 0 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
L I S T O F A B B R E VI A TI O N S
A b b re vi ati o n
T er m
5- A S A
5-a mi n osali c yli c aci d
A E
a d vers e e ve nt
A E SI
a d vers e e ve nts of s peci al i nterest
A L C
a bs ol ut e l y m p h oc yt e c o u nt
A L P
al kali ne p h os p hatas e
A L T
al a ni ne a mi n otra nsferase
A P D 3 3 4
etrasi m o d
A N C O V A
a nal ysis of c o varia nce
Are na
Are na P har mace uticals, I nc.
A S T
as partat e a mi n otra nsferas e
A T C
A nat o mical T hera pe utic C he mi cal
A V
atri o ve ntri c ular
B L Q
bel o w t he li mit of q ua ntifi cati o n
B MI
b o d y m ass i n de x
b p m
beats per mi n ut e
CI
c o nfi de nce i nt er val
C M
c o nc o mit a nt m e dicati o n
C M H
C oc hra n- M a nt el- Hae nszel
C O VI D- 1 9
c or o na vir us disease 2 0 1 9
C R
c o p y refer e nce
C R F
case re p ort f or m
C R P
C-reacti ve pr ot ei n
C S
cli ni call y si g nifica nt
C S R
cli ni cal st u d y re p ort
C T C A E
C o m m o n Ter mi n ol o g y Criteri a f or A d vers e E ve nts
C tr ou gh,ss
a vera ge stea d y-stat e tr o u g h pl as ma c o nce ntrati o n
C V
c oeffi cie nt of vari ati o n
D B P
di ast oli c bl o o d press ure
D L C O
diff usi n g ca pacit y of t he l u n gs f or car b o n m o n o xi de
D M C
Data M o nit ori n g C o m mitt ee 
E AI R
e x p os ure-a dj ust e d i nci de nce rat e
E C G
el ectr ocar di o gra m
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 1 1 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
e C R F
el ectr o ni c cas e r e p ort f or m
e DI S H
e val uati o n of dr u g-i n d uce d s eri o us he pat ot o xicit y
EI M
e xtrai nt esti nal ma nifestati o n
E S
e n d os c o pi c sc ore
F A S
F ull A nal ysis S et
F C P
fecal c al pr otecti n
F C S
f ull y c o n diti o nal s pecificati o n
F D A
F o o d a n d Dr u g A d mi nistrati o n
F E F
f orce d e x pirat or y fl o w
F E V 1
f orce d e x pirat or y v ol u me i n 1 sec o n d
F V C
f orce d vit al ca pacit y
G G T
ga m ma- gl ut a m yl tra nsferase
H R
heart rate
H R Q o L
healt h-rel ate d q ualit y of life
hs- C R P
hi g h-se nsiti vit y C-reacti ve pr ot ei n
I C F
i nf or m e d c o nse nt f or m
I R T
I nteracti ve R es p o nse Tec h n ol o g y
J A K
J a n us ki nas e
L L Q
l o wer li mit of q ua ntificati o n
L S
l east s q uares
Me d D R A
M e dical Dicti o nar y f or R e g ul at or y Acti viti es
m F A S
M o difi e d F ull A nal ysis S et 
M M R M
mi xe d-effect m o del wit h re peat e d meas ures
M M S
m o difie d Ma y o s c ore
N C S
n ot cli ni call y si g nifi ca nt
N HI
Na nc y Hist ol o gi cal I n de x
N RI
n o nres p o n der i m p utati o n
N R S
n u m eri c rati n g scale
O C T
o pti cal c o here nce t o m o gra p h y
O L E
o pe n-l a bel e xt e nsi o n
P F T
p ul m o nar y f u ncti o n t est
P G A
P K
p har m ac o ki netics
P K S
P har mac o ki netic S et
P M D A
P har mace uti cals a n d M e di cal De vices A ge nc y
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 1 2 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
P P S
P er Pr ot oc ol Set 
P R E S
p osteri or re versi ble e nce p hal o pat h y s y n dr o m e
P T
preferre d t er m
R B
rect al bl ee di n g
R HI
R o barts Hist o pat h ol o g y I n de x
S A E
s eri o us a d vers e e ve nt
S S
S afet y S et 
S A P
statisti cal a nal ysis pla n
S B P
s yst oli c bl o o d press ure
S D
sta n dar d de vi ati o n
S D T M
St u d y Dat a Ta b ul ati o n M o del
S E
sta n dar d err or
S F
st o ol fre q ue nc y
S F- 3 6
M e dical O utc o m es St u d y 3 6-It e m S h ort F or m Healt h S ur ve y
SI
I nter nati o nal S yst e m of U nits
S O C
s yst e m or ga n class
ss
stea d y st ate
T B
t u berc ul osis
T E A E
treat m e nt-e m er ge nt a d vers e e v e nt
T L C
t ot al l u n g ca pacit y
T M E
t ar gete d m e dical e ve nt
T M S
t ot al Ma y o sc ore
t u m or necr osis fact or al p ha
U C
ul cerati ve c olitis
U C- P R O/ S S
Ulcerati ve C olitis Pati e nt- R e p orte d O utc o m es Si g ns a n d S y m pt o ms
U L N
u p per li mit of n or m al
U L Q
u p per li mit of q ua ntitati o n
W H O
W orl d Healt h Or ga nizati o n
- h C G
bet a- h u ma n c h ori o nic g o na d otr o pi n
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 1 3 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
1. I N T R O D U C TI O N
T his statistical a nal ysis pl a n ( S A P) descri bes t he r ul es a n d c o n ve nti o ns t o be us e d i n t he prese nt ati o n a n d a nal ysis of 
effi ca c y, safet y, p har mac o ki neti c ( P K), a n d effi c ac y-r elat e d bi o m ar ker data f or Pr ot oc ol A P D 3 3 4- 2 0 3. It descri bes
t he dat a t o be s u m m arize d a n d a nal yze d, i ncl u di n g s pecifi cs of t he st atisti cal a nal ys es t o be perf or m e d (I C H 1 9 9 8).
T his S A P is base d o n pr ot oc ol versi o n A m e n d m e nt 1. 0, dat e d 1 2 J a n uar y 2 0 2 3.
A nal yses of e x pl orat or y efficac y r elat e d bi o m ar kers ( Cli nical St u d y Pr ot oc ol A P D 3 3 4- 2 0 3 S ecti o n 9. 8. 4. 1) data will 
be s pecifie d i n a s e parat e bi o m ar ker a n al ysis pla n.
2. S T U D Y O B J E C TI V E S A N D E S TI M A N D S
2. 1.
Pri m ar y O bjecti v e
T he pri m ar y o bjecti ve is t o assess t he effi cac y of etrasi m o d at 2 d oses ( 1 a n d 2 m g) o n cli nical re missi o n i n Ja pa nese 
partici p a nts wit h m o deratel y t o s e verel y acti ve ulcerati ve c olitis ( U C) w he n a d mi nistere d f or 1 2 wee ks.
2. 2.
Sec o n d a r y O bjecti v e
T he sec o n dar y o bjecti ve is t o ass ess t he efficac y of etrasi m o d at 2 d oses ( 1 a n d 2 m g) o n cli nical res p o nse, 
s y m pt o matic re missi o n, e n d osc o pi c i m pr o ve m e nts, a n d m uc osal heali n g i n J a pa nese parti ci pa nts wit h m o deratel y t o 
se verel y acti ve U C w he n a d mi nistere d f or 1 2 wee ks.
2. 3.
S afet y O bjecti v e
T he safet y o bj ecti ve is t o assess t he safet y of etrasi m o d at 2 d oses ( 1 a n d 2 m g) f or 1 2 wee ks i n Ja pa nes e 
partici pa nts wit h m o deratel y t o s e verel y acti ve U C.
2. 4.
Ot h er O bjecti v es
Ot her o bj ecti ves i ncl u de e val uati o n of etrasi m o d P K a n d t he effect of etrasi m o d o n healt h-relat e d s u bj ect re p ort e d 
o ut c o m es a n d bi o mar kers.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 1 4 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
2. 5.
Esti m a n ds
T he pri m ar y a n d t he sec o n dar y esti m a n ds t o s u p p ort re g ul at or y decisi o ns are des cri be d i n Ta bl e 1 bel o w. T he 
a nal ys es will be perf or m e d o n t he F ull A nal ysis S et ( F A S) wit h bas eli ne M M S 5- 9 as defi ne d i n S ecti o n 5. 3. 
S u p pl e me nt ar y a nal yses f or t he pri mar y esti ma n d will be perf or m e d o n t he m o difi e d F ull A nal ysis Set ( m F A S) a n d 
t he P er Pr ot oc ol p o p ul ati o ns, res pecti vel y (I C H 2 0 1 9). S u p ple m e nt ar y a nal ys es f or s ec o n dar y esti ma n ds will be 
perf or m e d o n t he m F A S o nl y. I nterc urre nt e ve nts i ncl u de: 1) disc o nti n ue t he st u d y f or l ac k of effica c y or a d vers e 
e ve nt rel ate d t o U C, 2) i niti ate a resc ue m e dicati o n f or U C, 3) ha ve a n i ncreas e i n d ose o ver B aseli ne l e vels i n t heir 
e xisti n g U C me di cati o n, or 4) ha ve a res c ue n o n- dr u g treat me nt (e g, c olect o m y, ile ost o m y, or si g m oi dect o m y) 
bef ore t he effi cac y ass ess m e nt. R efer t o A P P E N DI X 5 f or t he defi niti o n of resc ue t hera pi es ( m e dicati o n a n d m e di cal 
pr oce d ures).
T a bl e 1:
List of Pri m ar y a n d Sec o n d a r y Esti m a n ds
Esti m a n d
Defi niti o n
Attri b utes
P o p ul ati o n
V ari a ble/ E n d p oi nt
I nterc u rre nt e ve nt 
h a n dli n g str ate g y
P o p ul ati o n-l e vel 
s u m m ar y m e as u re
Pri mar y 
Esti m a n d
Effi cac y of 
etrasi m o d o n 
cli ni cal 
re missi o n at 
Wee k 1 2
R a n d o mi ze d 
Ja pa nese 
partici pa nts
w h o recei ve at 
l east 1 d ose of 
st u d y treat me nt
a n d wit h 
B aseli ne M M S 
5 t o 9
T he pr o p orti o n of 
partici pa nts wit h S F
s u bs c ore = 0 ( or = 1 
- p oi nt 
decreas e fr o m 
B aseli ne), R B 
s u bs c ore = 0, a n d E S 
fri a bilit y) at Wee k 
1 2
P artici pa nts wit h 
a n y of t he 4
i nterc urre nt e ve ntsa
bef ore t he effi cac y 
assess me nt will be 
treat e d as 
n o nres p o n ders. 
Differe nc e bet wee n 
eac h etrasi m o d
d ose ( 1 a n d 2 m g)
a n d place b o i n t he 
e n d p oi nt at Wee k 
1 2
S ec o n dar y 
Esti m a n d 
1
Effi cac y of 
etrasi m o d o n 
e n d osc o pi c 
i m pr o ve m e n
t at Wee k 1 2
R a n d o mi ze d 
Ja pa nese 
partici pa nts
w h o recei ve at 
l east 1 d ose of 
st u d y treat me nt
a n d wit h 
B aseli ne M M S 
5 t o 9
T he pr o p orti o n of 
partici pa nts wit h E S 
fri a bilit y) at Wee k 
1 2. 
S a m e as t he 
i nterc urre nt e ve nt 
ha n dli n g strate g y 
f or t he pri m ar y 
esti m a n d
Differe nc e bet wee n 
eac h etrasi m o d
d ose ( 1 a n d 2 m g)
a n d place b o i n t he 
e n d p oi nt at Wee k 
1 2
S ec o n dar y 
Esti m a n d 
2
Effi cac y of 
etrasi m o d o n 
s y m pt o matic 
R a n d o mi ze d 
Ja pa nese 
partici pa nts
w h o recei ve at 
T he pr o p orti o n of 
partici pa nts wit h S F
s u bs c ore = 0 ( or = 1 
1- p oi nt 
S a m e as t he 
i nterc urre nt e ve nt 
ha n dli n g strate g y 
Differe nc e bet wee n 
eac h etrasi m o d
d ose ( 1 a n d 2 m g)
a n d place b o i n t he 
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 1 5 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
Esti m a n d
Defi niti o n
Attri b utes
P o p ul ati o n
V ari a ble/ E n d p oi nt
I nterc u rre nt e ve nt 
h a n dli n g str ate g y
P o p ul ati o n-l e vel 
s u m m ar y m e as u re
re missi o n at 
Wee k 1 2
l east 1 d ose of 
st u d y treat me nt
a n d wit h 
B aseli ne M M S 
5 t o 9
decreas e fr o m 
B aseli ne) a n d 
R B s u bs c ore = 0 at 
Wee k 1 2.
f or t he pri m ar y 
esti m a n d
e n d p oi nt at Wee k 
1 2
S ec o n dar y 
Esti m a n d 
3
Effi cac y of 
etrasi m o d o n 
m uc os al 
heali n g at 
Wee k 1 2
R a n d o mi ze d 
Ja pa nese 
partici pa nts
w h o recei ve at 
l east 1 d ose of 
st u d y treat me nt
a n d wit h 
B aseli ne M M S 
5 t o 9
T he pr o p orti o n of 
partici pa nts wit h E S 
1 (e xcl u di n g 
fri a bilit y) wit h 
hist ol o gi c re missi o n 
m eas ure d b y a 
Ge b oes I n de x s c ore 
< 2. 0 at Wee k 1 2. 
S a m e as t he 
i nterc urre nt e ve nt 
ha n dli n g strate g y 
f or t he pri m ar y 
esti m a n d
Differe nc e bet wee n 
eac h etrasi m o d
d ose ( 1 a n d 2 m g)
a n d place b o i n t he 
e n d p oi nt at Wee k 
1 2
S ec o n dar y 
Esti m a n d 
4
Effi cac y of 
etrasi m o d o n 
cli ni cal 
res p o ns e at 
Wee k 1 2
R a n d o mi ze d 
Ja pa nese 
partici pa nts
w h o recei ve at 
l east 1 d ose of 
st u d y treat me nt
a n d wit h 
B aseli ne M M S 
5 t o 9
T he pr o p orti o n of 
partici pa nts wit h a
2-
decreas e fr o m 
baseli ne i n M M S, 
- p oi nt 
decreas e fr o m 
baseli ne i n R B 
s u bs c ore or a n 
a bs ol ute R B 
at 
wee k 1 2.
S a m e as t he 
i nterc urre nt e ve nt 
ha n dli n g strate g y 
f or t he pri m ar y 
esti m a n d
Differe nc e bet wee n 
eac h etrasi m o d
d ose ( 1 a n d 2 m g)
a n d place b o i n t he 
e n d p oi nt at Wee k 
1 2
S ec o n dar y 
Esti m a n d 
5
Effi cac y of 
etrasi m o d o n 
e n d osc o pic 
n or mali zati
o n at Wee k 
1 2
R a n d o mi ze d 
Ja pa nese 
partici pa nts
w h o recei ve at 
l east 1 d ose of 
st u d y treat me nt
a n d wit h 
B aseli ne M M S 
5 t o 9
T he pr o p orti o n of
partici pa nts wit h 
E S = 0 at wee k 1 2.
S a m e as t he 
i nterc urre nt e ve nt 
ha n dli n g strate g y 
f or t he pri m ar y 
esti m a n d
Differe nc e bet wee n 
eac h etrasi m o d
d ose ( 1 a n d 2 m g)
a n d place b o i n t he 
e n d p oi nt at Wee k 
1 2
a I nterc urre nt e v e nts i n cl u d e: 1) dis c o nti n u e t h e st u d y f or lac k of efficac y or a d v ers e e v e nt relate d t o U C, 2) i nitiate a res c u e 
me dicati o n f or U C, 3) h a v e a n i n creas e i n d os e o v er B as eli n e le v els i n t h eir e xisti n g U C me dicati o n, or 4) h a v e a res c ue n o n- dr u g 
treat me nt (e g, c olect o m y, ile ost o m y, or si g m oi d ect o m y) b ef ore t h e efficac y ass ess me nt. R efer t o A P P E N DI X 5 f or t h e d efi niti o n 
of res c u e t h era pies ( me dicati o n a n d me dical pr o ce d ures). 
E S, e n d os c o pic s c ore;
M M S, m o difie d Ma y o s c ore; R B, rectal blee di n g; S F, st o ol fre q u e n c y; U C, ulcerati v e c olitis.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 1 6 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
3. S T U D Y D E SI G N
3. 1.
G e ner al Descri pti o n
T his is a d os e ra n gi n g, m ultice nter, ra n d o mize d, d o u bl e- bli n d, place b o-c o ntr oll e d st u d y t o eval uate t he efficac y a n d 
safet y of etrasi m o d 1 a n d 2 m g i n Ja pa nese partici pa nts wit h m o derat el y t o se verel y acti ve U C. T he st u d y c o nsists of 
a 2 8 Da y S cree ni n g P eri o d, a 1 2 Wee k I n d ucti o n Treat m e nt P eri o d, a n d a 4 Wee k F oll o w Up P eri o d. Eli gi bl e 
partici pa nts will be ra n d o mi ze d ( 1: 1: 1 rati o) t o recei ve eit her etrasi m o d ( 1 m g o nce dail y), etrasi m o d ( 2 m g o nce 
dail y), or m atc hi n g place b o ( o nce dail y) i n a d o u bl e- bli n d fas hi o n f or 1 2 wee ks. R a n d o mizati o n will be stratifie d b y 
(a) naï ve t o bi ol o gi c or Ja n us ki nase (J A K) i n hi bit or t hera p y at st u d y e ntr y ( yes or n o), ( b) bas eli ne c orti c oster oi d 
use ( yes or n o), a n d (c) baseli ne dis eas e a cti vit y ( m o difie d M a y o s c ore [ M M S]: 4 t o 6 or 7 t o 9).
A t ot al of 9 6 partici pa nts are pl a n ne d t o be e nr olle d i n t he st u d y, wit h 3 2 partici pa nts e x pecte d i n eac h of t he 3 
treat m e nt gr o u ps. T he t ar get s u bj ect p o p ulati o n will i ncl u de t h ose w h o ha ve ha d a n i na de q uat e res p o nse t o, l oss of 
res p o ns e t o, or i nt ol era nce t o t he f oll o wi n g:
C o n ve nti o nal t hera p y, a n d are naï ve t o bi ol o gic or J A K i n hi bit or t hera p y 
Bi ol o gi c or J A K i n hi bit or ( partici pa nts i n t his cate g or y m a y ha ve recei ve d pri or c o n ve nti o nal t hera p y)
P artici pa nt eli gi bilit y will be det er mi ne d d uri n g a 4- Wee k ( 2 8- Da y) S cree ni n g P eri o d. E ntr y criteria will be base d o n 
c o nfir mati o n of m o deratel y t o se verel y acti ve U C, defi ne d b y a n M M S of 4 t o 9, w hi c h i ncl u des a n E S
2 a n d 
rectal blee di n g ( R B) s u bsc or
1.
At t he e n d of t he 1 2 Wee k I n d ucti o n Treat me nt P eri o d, parti ci pa nts will u n der g o Wee k 1 2 effica c y a n d s afet y 
assess me nts a n d be e val uat e d f or cli nical res p o nse/re missi o n. P arti ci pa nts will t he n ha ve t he o pti o n t o e nter a n o pe n 
l a bel e xte nsi o n ( O L E) st u d y ( St u d y A P D 3 3 4- 3 0 3) f oll o wi n g c o m pl eti o n of Wee k 1 2 st u d y pr oce d ures pr o vi de d t he y 
m eet all eli gi bilit y criteri a f or t he O L E. P arti ci pa nts m ust c o m plet e Wee k 1 2 t o be eli gi bl e f or t he O L E.
P artici pa nts w h o disc o nti n ue fr o m t he st u d y a n d d o n ot parti ci pate i n t he O L E st u d y will have 2 Wee k a n d 4 Wee k 
F oll o w U p visits aft er t he l ast o n treat me nt visit/ Earl y Ter mi nati o n ( E T) visit. T he st u d y desi g n is o utli ne d i n Fi g ure 
1 bel o w.
T his st u d y will be earl y dis c o nti n ue d i n a gree me nt wit h P har m ace uti cals a n d Me di cal De vices A ge nc y ( P M D A).
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 1 7 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
Fi g ure 1:
St u d y Desi g n
3. 2.
Sc he d ule of E v e nts
S c he d ule of e ve nts ca n be f o u n d i n A p pe n di x 1 of t he pr ot oc ol.
3. 3.
C h a n g es t o A n al ysis fr o m Pr ot o c ol
N o statistical t est will be c o n d ucte d d ue t o t he n u m ber of partici pa nts ra n d o mi ze d will be decre as e d. 
N o h y p ot hesis will be t este d a n d n o a dj ust m e nt f or m ulti pli cit y.
N o a dj ust me nts f or c o vari ates a n d fact ors t o be i ncl u de i n a nal ysis.
F or pri m ar y a n d 
-
C M H test stratifie d b y 3 stratificati o n fact ors ( naï ve t o bi ol o gic/J A K i n hi bit or t hera p y at st u d y e ntr y ( Yes/ N o), 
baseli ne c ortic ost er oi d us e ( Yes/ N o), a n d baseli ne disease acti vit y ( M M S: 4 t o 6 or 7 t o 9) will n ot be c o n d uct e d 
per s p o ns or re q uire m e nts.
C oc hra n Ar mit a ge test f or d os e tre n d is re m o ve d.
F or H R Q o L e n d p oi nts, c ha n ge t he missi n g dat a m et h o ds fr o m m ulti pl e i m p ut ati o n t o n ot i m p ut e per s p o ns or 
re q uire me nts.
R e m o ve t he fact ors ( naï ve t o bi ol o gi c or J A K i n hi bit or t hera p y at st u d y e ntr y ( Yes or N o), B as eli ne 
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 1 8 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
c ortic ost er oi d us e ( Yes or N o), B aseli ne dis ease acti vit y ( M M S: 4 t o 6 or 7 t o 9)) i n M M R M m o del.
T he pri m ar y a nal ysis s et f or t he efficac y e n d p oi nts is u p date d t o t he F ull A nal ysis S et ( F A S) wit h M M S 5 t o 9. 
S u b gr o u p defi niti o n rel at e d t o M M S is u p date d acc or di n gl y. T he F A S wit h baseli ne M M S 4 t o 9 will be use d i n 
s u p pl e me nt ar y a nal yses. 
T he P er Pr ot oc ol S et ( P P S) will be us e d i n s u p pl e me nt ar y a nal ysis i nst ea d of se nsiti vit y a nal ysis f or o nl y 
pri mar y e n d p oi nts.
T he f oll o wi n g defi niti o ns use d t o assess efficac y o ut c o m es i n S ecti o n 1 6 is c ha n ge d or a d de d as bel o w:
o
A d de d defi niti o n f or hist ol o gic i m pr o ve m e nt (as defi ne d b y R o barts Hist o pat h ol o g y I n de x, a n d 
Na nc y Hist ol o gic I n de x).
o
A d de d defi niti o n f or hist ol o gic re missi o n (as defi ne d b y R o barts Hist o pat h ol o g y I n de x, a n d Na nc y 
Hist ol o gic I n de x).
o
A d de d defi niti o n f or i m pr o ve m e nt i n e xtrai nt esti nal ma nifest ati o ns ( EI Ms).
N ot all i n di vi d ual s u bj ect dat a f or all ra n d o mi ze d parti ci pa nts is prese nt e d i n dat a listi n gs, e g, safet y dat a is 
prese nt e d i n safet y set.
4. P L A N N E D A N A L Y S E S
T he f oll o wi n g a nal yses will be perf or me d f or t his st u d y:
Fi nal A nal ysis 
4. 1.
I nteri m A n al ysis
T here is n o pl a n ne d or u n pla n ne d i nteri m a nal ysis f or t his st u d y.
4. 2.
Fi n al A n al ysis 
All fi nal, pl a n ne d a nal ys es i de ntifi e d i n t his S A P will be perf or me d b y I Q VI A Bi ostatistics f oll o wi n g S p o ns or 
( Are na P har mac e uticals, I nc., a w h oll y o w ne d s u bsi di ar y of Pfi zer I nc., hereafter referre d t o as Are na) a ut h ori zati o n 
of t he S A P, dat a bas e l oc k, a nal ysis sets, a n d u n bli n di n g of treat me nt. Aft er Are na has a ut h ori ze d brea ki n g of t he 
st u d y bli n d, t he fi nal a nal ysis will be perf or m e d. 
A n y, p ost h oc, e x pl orat or y a nal yses c o m plet e d t o s u p p ort pla n ne d st u d y a nal ys es, w hi c h were n ot i de ntifie d i n t his 
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 1 9 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S A P, will be d oc u m e nt e d a n d re p orte d i n t he cli nical st u d y re p ort ( C S R). A n y res ults fr o m t hese u n pla n ne d a nal ys es 
will als o be clearl y i de ntifi e d i n t he t e xt of t he C S R (I C H, 1 9 9 5).
5.
A N A L Y SI S S E T S
A gree m e nt a n d a ut h orizati o n of parti ci pa nts i ncl u de d/e xcl u de d fr o m eac h a nal ysis set will be c o n d uct e d pri or t o t he 
u n bli n di n g of t he st u d y. 
5. 1.
Scree ne d Set 
T he S cree ne d S et will c o nsist of all partici pa nts w h o si g n i nf or me d c o nse nt t o partici pat e i n t he st u d y.
5. 2.
R a n d o mize d S et
T he Ra n d o mize d S et will c o nsist of all parti ci pa nts w h o are ra n d o mi ze d t o st u d y treat m e nt.
F or a nal yses a n d dis pla ys base d o n R a n d o mize d S et, parti ci pa nts will be cl assifi e d acc or di n g t o ra n d o mize d 
treat m e nt. 
5. 3.
F ull A n al ysis Set ( F A S)
T he F A S will c o nsist of all ra n d o mi ze d partici pa nts w h o recei ve at least 1 d ose of st u d y treat me nt. P arti ci pa nts will 
be s u m mari ze d b y t he treat m e nt t o w hic h t he y were ra n d o mize d, re gar dless of treat m e nt act uall y recei ve d.
5. 4.
Per P r ot o c ol Set ( P P S)
T he P er Pr ot oc ol S et will c o nsist of all parti ci pa nts i n t he F A S w h o a d here t o t he pr ot oc ol. T his set will be use d i n 
s u p pl e me nt ar y a nal yses of t he pri mar y e n d p oi nts t o e val uate t he i nfl ue nce of m aj or pr ot oc ol vi ol at ors a n d pr ot oc ol 
de viat ors o n t he pri m ar y res ults. 
P artici pa nts ma y be e xcl u de d fr o m t he P P S if t he y vi olat e t he eli gi bilit y crit eria or si g nifica ntl y de vi ate fr o m t he 
st u d y pla n, i ncl u di n g, b ut n ot li mite d t o: 
O verall st u d y treat m e nt n o nc o m plia nce ( < 8 0 or > 1 2 0 %)
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 2 0 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
R ecei ve i nc orrect st u d y treat me nt f or > 7 da ys
Us e resc ue me di cati o n ( ne w or d ose i ncre ase fr o m t he hi g hest d ose of bac k gr o u n d treat me nt f or U C recei ve d 
d uri n g S cree ni n g) or u n der g o res c ue m e dical pr oce d ure t hat m a y affect effi cac y e n d p oi nt at Wee k 1 2 
Miss Wee k 1 2 e n d osc o pi c s c ore ( E S) i n pres pecifie d a nal ysis wi n d o w ( per S ecti o n 6. 4) f or reas o ns ot her t ha n 
U C fl are or disc o nti n ue d d ue t o disease w orse ni n g or lac k of effi ca c y  
R efer t o A P P E N DI X 5 f or t he defi niti o n of resc ue t hera pi es ( m e dicati o n a n d m e dical pr oce d ures). All pr ot oc ol 
de viati o ns will be re vi e we d i n a d diti o n t o t he pr o gra m m a bl e de viati o ns (e g, st u d y treat m e nt n o nc o m plia nce) t o 
deter mi ne if a n y de viati o n is si g nifi ca nt e n o u g h t o e xcl u de a s u bj ect fr o m t he P er Pr ot oc ol S et. All e xcl usi o n fl a gs 
will be fi nali ze d bef ore st u d y u n bli n di n g. P artici pa nts e xcl u de d fr o m P er Pr ot oc ol S et will be liste d al o n g wit h t he 
reas o n cate g or y a b o ve. P arti ci pa nts will be s u m m arize d b y treat me nt t o w hic h t he y were ra n d o mi ze d, re gar dless of 
treat m e nt act uall y recei ve d.
5. 5.
M o difie d F ull A n al ysis Set ( m F A S)
T he m F A S will c o nsist of all ra n d o mi ze d partici pa nts w h o recei ve at l east 1 d os e of st u d y treat m e nt a n d ha ve a 
B aseli ne a n d at l east 1 p ost-ra n d o mi zati o n meas ure m e nt. P arti ci pa nts will be s u m m arize d b y treat m e nt t o w hi c h 
t he y were ra n d o mi ze d, re gar dl ess of treat me nt act uall y recei ve d. N ot e t hat t he m F A S ca n var y wit h e n d p oi nts si nce 
s o m e parti ci pa nts m a y ha ve t he nee de d dat a f or i ncl usi o n i n t he m F A S f or s o m e e n d p oi nts b ut ot hers m a y n ot. 
5. 6.
S afet y S et ( S S)
T he safet y s et ( S S) will i ncl u de all ra n d o mize d partici pa nts w h o recei ve at l east 1 d ose of st u d y treat m e nt. 
P artici pa nts will be a nal yze d acc or di n g t o t he treat m e nt recei ve d, re gar dl ess of ra n d o mizati o n. T he S afet y S et will 
be use d f or all s afet y a nal ys es.
5. 7.
P h a r m a c o ki n eti c S et ( P K S)
T he P har mac o ki neti c S et will i ncl u de all s u bj ects i n t he S afet y S et wit h at l east 1 q ua ntifia bl e p ost d ose P K 
m eas ure me nt of etrasi m o d w hi c h is n ot i m pacte d b y pr ot oc ol vi ol ati o ns or e ve nts wit h p ot e nti al t o affect t he P K 
c o nce ntrati o n.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 2 1 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
6.
G E N E R A L C O N SI D E R A TI O N S
6. 1.
Refere n ce St a rt D ate a n d St u d y D a y
St u d y Da y will be cal c ulat e d fr o m t he refere n ce st art dat e a n d will be use d t o s h o w start/st o p da y of ass ess m e nts a n d 
e ve nts. It will a p pear i n listi n g w here a n assess me nt date or e ve nt dat e a p pears.
R efere nc e st art dat e is defi ne d as t he da y of t he first d ose of st u d y me dicati o n ( Da y 1 is t he da y of t he first d ose of 
st u d y me di cati o n). 
If t he date of t he e ve nt is o n or after t he ref ere nc e date, t he n: 
St u d y Da y = ( dat e of e ve nt 
refere nce st art dat e) + 1
If t he date of t he e ve nt is pri or t o t he refere nce date, t he n: 
St u d y Da y = ( dat e of e ve nt 
refere nce st art dat e)
I n t he sit uati o n w here t he e ve nt date is partial or missi n g, St u d y Da y, a n d a n y c orres p o n di n g d urati o ns will a p pear 
partial or missi n g i n t he listi n gs.
6. 2.
B aseli n e
U nl ess ot her wise s pecifie d, baseli ne is defi ne d as t he l ast n o n- missi n g m eas ure me nt ta ke n pri or t o t he first d ose 
a d mi nistrati o n (i ncl u di n g u ns c he d ul e d assess me nts). If meas ure m e nts i ncl u de ti me (e xce pt f or healt h-relat e d q ualit y 
of life [ H R Q o L] i nstr u m e nts), t he date/ti me will be use d t o defi ne B as eli ne. Ot her wise, o nl y dates will be c o m pare d. 
F or H R Q o L i nstr u me nts, o nl y t he date will be use d t o deri ve Bas eli ne. I n t he cas e w here t he l ast n o n- missi n g 
m eas ure me nt a n d t he date of first d ose a d mi nistrati o n c oi nci de a n d ti me is n ot c oll ecte d, if t he meas ure m e nt was 
pl a n ne d i n t he pr ot oc ol t o be d o ne pri or t o t he dat e of first d os e, t hat meas ure m e nt will be c o nsi dere d i n defi ni n g 
B aseli ne.
6. 3.
Retests, U nsc he d ule d Visits a n d E a rl y Ter mi n ati o n D at a
F or b y visit a nal yses a n d s u m m ari es, efficac y, safet y, H R Q o L, a n d bi o m ar ker data (i ncl u di n g sc he d ule d, ret ests, 
u nsc he d ul e d, a n d earl y ter mi nati o n) will be assi g ne d t o visits aft er t he a p plicati o n of t he wi n d o wi n g c o n ve nti o ns 
descri be d i n S ecti o n 6. 4. All m eas ure me nts will be c o nsi dere d i n s u m mari es of a b n or m alities or w orst-case val ues 
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 2 2 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
p ost- B aseli ne.
T he visit wi n d o wi n g will be a p plie d bef ore missi n g data are i m p ut e d.
Listi n gs will i ncl u de sc he d ule d, u nsc he d ul e d, retest, a n d earl y t er mi nati o n dat a.
6. 4.
Wi n d o wi n g C o n v e nti o ns
All sc he d ule d st u d y visits are defi ne d rel ati ve t o St u d y Da y 1, t he date of first d ose a d mi nistrati o n. S c he d ul e d visit 
wi n d o ws are defi ne d i n Cli ni cal St u d y Pr ot oc ol A P D 3 3 4- 2 0 3 A p pe n di x 1. A wi n d o wi n g c o n ve nti o n will be use d t o 
deter mi ne t he a nal ysis visit val ue f or a gi ve n m eas ure m e nt a n d will be a p plica bl e f or all b y- visit s u m mari es a n d 
a nal ys es f or effi c ac y a n d safet y dat a. R ef er t o Ta bl e 2 f or s pecific visit wi n d o ws.
F or car di ac re m o nit ori n g u p o n treat me nt rei nitiati o n aft er Da y 2, as e vi de nce d b y m ore t ha n 1 ti me d m eas ure me nt i n 
vital si g ns or el ectr ocar di o gra m ( E C G) para m eters o n t he sa m e c ollecti o n dat e of a n u nsc he d ule d visit, 
m eas ure me nts will be ma p pe d t o a nal ysis visit of C ar di ac Re m o nit ori n g 1, C ar di ac R e m o nit ori n g 2, etc. i n t he 
res pecti ve a nal ysis dat aset. F or a nal ysis, eac h ti me d meas ure m e nt will be pr o gra m maticall y assi g ne d t o t he nearest 
h o url y ti m e p oi nt (e g, Pre d ose, 1- h o ur P ost d os e) base d o n t heir relati o ns hi p t o t he d osi n g ti m e o n t he s a m e da y. If 
t he d osi n g dat e/ti me o n t he sa m e da y is missi n g, t he ti me p oi nt will re m ai n missi ng. O nce ma p pe d, t hese ti m e d 
m eas ure me nts fr o m car diac re m o nit ori n g visits will n ot be c o nsi dere d f or a n y ot her a nal ysis visit. 
Wi n d o wi n g will be a p pli e d pri or t o a n y missi n g data cal c ul ati o ns. T he last n o n- missi n g m eas ure m e nt t a ke n pri or t o 
ot her wise, dat a fr o m all 
visits i ncl u di n g sc he d ule d, u nsc he d ul e d a n d E T visits will be eli gi ble f or all ocati o n t o a n a nal ysis visit. T he 2- Wee k 
a n d 4- Wee k F oll o w- U p visits will n ot be i ncl u de d i n t he visit wi n d o ws a n d will be s u m m arize d se paratel y wit h o ut 
a n y wi n d o w a p plie d.
If o ne or m ore res ults f or a varia ble are assi g ne d t o t he sa me a nal ysis visit, t he res ult wit h t he date cl osest t o t he 
pr ot oc ol sc he d ul e d da y will be us e d i n t he a nal ysis, e xce pt f or c o m p o ne nt s u bs c ores of M M S or T M S, i n w hic h 
case, t he c o m p osite sc ore a n d c o m p o ne nt s u bs c ores fr o m t he sa m e dat e will be use d i n t he a nal ysis. If t w o 
m eas ure me nts i n t he sa m e a nal ysis visit wi n d o w are e q ui dist a nt fr o m t he pr ot oc ol sc he d ul ed st u d y da y, t he earliest 
m eas ure me nt will be use d i n t he a nal ysis. If m ulti ple ass ess m e nts are a vaila ble o n t he sa m e da y, t he n t he a vera ge of 
t he assess m e nt will be use d i n t he a nal ysis, e xce pt f or l a b orat or y a n d E C G data w here t he assess m e nt at t he earliest 
ti m e of t he sa m e da y will be use d. If b ot h ce ntral a n d l ocal assess me nts of t he sa m e E C G or l a b test are a vaila bl e o n 
t he s a me da y/ a nal ysis visit, t he ce ntral res ult will ta ke prece de nce o ver t he l ocal r es ult.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 2 3 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
F or t he o verla p pi n g visit wi n d o ws at Wee k 1 2 a n d Wee k 8, a hierarc hi cal al g orit h m will be a p plie d as f oll o wi n g: 
al wa ys m a p t o t he Wee k 1 2 st u d y visit if t he st u d y da y falls wit hi n t he visit wi n d o w of t he Wee k 1 2 st u d y visit, t he n 
assess t he ot her rec or ds f or t he Wee k 8 st u d y visit.
T a bl e 2:
Visit Wi n d o ws f o r Effi c a c y a n d S af et y A n al yses
F or All Effi c ac y ( E xce pt E n d os c o p y/ M M S/ Hist ol o g y), Effi c ac y- Rel ate d Bi o m ar k ers, S afet y L a bs a n d 
Vit al Si g ns
S c h e d ule d St u d y Visit
( Pr ot oc ol S c h e d ule d D a y)
A n al ysis Visit Wi n d o w ( St u d y D a y)
B aseli ne
1
Wee k 0 ( Da y 1)
1
Wee k 0 ( Da y 2)
a        
2
Wee k 2 ( Da y 1 5 ± 3)
2 t o 2 2, or 3 t o 2 2 a
Wee k 4 ( Da y 2 9 ± 3)
2 3 t o 4 3
Wee k 8 ( Da y 5 7 ± 3)
4 4 t o 7 1 
Wee k 1 2 ( Da y 8 5 ± 7)
> 7 1
F or E n d osc o p y/ M M S/ Hist ol o g y/ All C o m p osite E n d p oi nts T h at I n cl u d e a n E n d osc o p y C o m p o n e nt 
- Rel ate d Q u alit y of Lif e, E C Gs, O C T, 
a n d P F T
S c h e d ule d St u d y Visit
( Pr ot oc ol S c h e d ule d D a y)
A n al ysis Visit Wi n d o w ( St u d y D a y)
B aseli ne
1
Wee k 0 ( Da y 1)
1
Wee k 0 ( Da y 2)
a
2
Wee k 1 2 ( Da y 8 5 ± 7)
b, c        
6 6 t o 1 1 3 e ( 6 6 t o 1 4 1 f or ass ess m e nts i m pact e d b y C O VI D- 1 9 pa n de mi c)d
o r
5 7 t o 1 1 3 f ( 5 7 t o 1 4 1 f or assess m e nts i m pacte d b y C O VI D- 1 9 pa n de mi c)e
a A p pli ca bl e o nl y f or parti ci pa nts w h o re q uire d e xte n de d m o nit ori n g o n Da y 2 f or vital si g ns a n d E C Gs
b A p pli ca bl e t o all Wee k 1 2 effi cac y e n d p oi nts bas e d o n a n y c o m p o ne nt of M a y o cli nic sc ore, s uc h as cli nical 
re missi o n a n d s y m pt o m ati c re missi o n. Pr ot oc ol visit wi n d o w f or P F T a n d O C T at Wee k 1 2 is Da y 8 5 ± 7(F D A 
2 0 2 0 )
c D ue t o o verla p pi n g wi n d o ws at Wee k 1 2 a n d Wee k 8, a hierarc hi cal al g orit h m will be us e d f or t he ma p pi n g. Wee k 
1 2 will al wa ys be m a p pe d first, t he n assess rec or ds f or t he Wee k 8 m a p pi n g. If sc he d ule d Wee k 8 a n d 1 2 visits are 
b ot h prese nt i n t he s a m e visit wi n d o w, t he y will be ma p pe d t o se parat e visits (i e, Wee k 8 a n d Wee k 1 2)
d Assess m e nts i m pact e d b y t he C O VI D- 1 9 pa n de mic are re p ort e d i n t he Date of Visit e C R F
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 2 4 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
e N ot a p pli ca ble f or O C T/ P F T
f A p pli ca bl e f or O C T/ P F T
C O VI D- 1 9, C or o na vir us disease 2 0 1 9; E C G, el ectr ocar di o gra m; e C R F, el ectr o ni c case re p ort f or m; M M S, m o difie d 
Ma y o sc ore; O C T, o pti cal c o here nce t o m o gra p h y; P F T, p ul m o nar y f u ncti o n test; R B, rectal blee di n g; S F, st o ol 
fre q ue nc y
6. 5.
St atistic al Tests
N o statistical t est will be c o n d ucte d. P oi nt esti mat e wit h 9 5 % c o nfi de nce i nt er vals ( CI) will be re p orte d.
6. 6.
C o m m o n C alc ul ati o ns
F or q ua ntit ati ve m eas ure me nts:
C ha n ge fr o m B aseli ne = Test Val ue at Visit X 
B aseli ne Val ue
P erce nt c ha n ge fr o m B aseli ne = ( Test Val ue at Visit X 
B aseli ne Val ue) / B aseli ne Val ue × 1 0 0
Pr o p orti o n at Visit X = N u m ber of partici pa nts s atisf yi n g criteri a at Visit X / T otal n u m ber of parti ci pa nts at 
Visit X
6. 7.
G e ner al St u d y I nf o r m ati o n 
A ge neral ta bl e wit h s u m m ar y of st u d y i nf or mati o n will be ge nerat e d, i ncl u di n g t he dat e of first partici pa nt si g ne d 
i nf or me d c o nse nt f or m (I C F), t he l ast parti ci pa nt visit date a n d t he dat a base l oc k dat e. All a nal yses will be 
c o n d ucte d usi n g S A S ® ( v 9. 4 or lat er, S A S I nstit ut e I nc., C ar y, N C). 
7.
D E T E R MI N A TI O N O F S A M P L E S I Z E
B ase d o n a C hi s q uare test at 2-si de d si g nifi ca nce l e vel of 0. 0 5, a t otal of 9 6 partici pa nts ( 3 2 per treat m e nt gr o u p) 
will pr o vi de at l east 8 0 % p o wer t o s h o w pair wise s u peri orit y of etrasi m o d 2 m g t o place b o i n t he pri m ar y e n d p oi nt 
ass u mi n g 5 % re missi o n rat e i n t he pl ace b o gr o u p a n d a 3 1. 5 % re missi o n rate i n t he etrasi m o d 2 m g gr o u p. T he 
ass u m pti o ns are base d o n t he res ults fr o m t he c o m pl ete d P hase 2 St u d y A P D 3 3 4- 0 0 3. S a m pl e size is calc ul ate d 
usi n g t he E A S T ® s oft ware.
T he act ual s a m pl e size will be s m aller t ha n ori gi nal pl a n ne d beca use t his st u d y will be earl y disc o nti n ue d i n 
a gree me nt wit h P M D A c o ns ultati o n.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 2 5 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
8. S T A TI S TI C A L C O N SI D E R A TI O N S
8. 1.
M ultice nter St u dies
T his st u d y will be c o n d uct e d b y m ulti pl e i n vesti gat ors at m ulti pl e ce nt ers i n Ja pa n. 
R a n d o mi zati o n t o treat me nt gr o u ps is stratifi e d b y:
Naï ve t o bi ol o gi c or J A K i n hi bit or t hera p y at st u d y e ntr y ( Yes or N o)
B aseli ne c orti c ost er oi d us e ( Yes or N o)
B aseli ne dis eas e acti vit y ( M M S: 4 t o 6 or 7 t o 9)
Dat a fr o m all sit es will be p o ol e d a n d st atistical a nal yses will n ot be a dj uste d f or i n vesti gati o nal sit e.
8. 2.
A dj ust me nts f o r C o v a ri ates a n d F a ct o rs t o b e I n cl u de d i n A n al yses
N ot a p pli ca ble.
8. 3.
Missi n g D at a
Missi n g a d vers e e ve nt ( A E) relati o ns hi p t o st u d y treat m e nt a n d A E s eri o us ness will be i m p ut e d as des cri be d i n 
S ecti o n 1 8. 1. 1. 2 a n d S ecti o n 1 8. 1. 3, res pecti vel y. P arti al or missi n g A E start dates, c o nc o mita nt me di cati o n ( C M)
st art dat es, a n d h os pitali zati o n dates will als o be i m p ut e d as des cri be d i n A P P E N DI X 2. N o ot her missi n g s afet y 
data will be i m p ute d.
Missi n g efficac y data will be ha n dle d as descri be d i n S ecti o ns 1 6. 1. 2, 1 6. 2. 2, 1 6. 3. 2. I n t he pri mar y a nal ysis of t he 
pri mar y e n d p oi nt a n d m ai n a nal yses of all bi nar y res p o n der-t y pe e n d p oi nts, all partici pa nts wit h missi n g data, 
re gar dl ess of re as o n f or missi n g ness, will be c o nsi dere d as n o n-res p o n ders. I n t he m ai n a nal ysis of c o nti n u o us or 
sc ore e n d p oi nts, s uc h as bi o mar ker m eas ures a n d healt h-rel at e d q ualit y of life m eas ures, parti ci pa nts wit h missi n g 
data will be a nal yse d wit h t heir o bser ve d dat a o nl y, a mi xe d-effect m o del wit h re peat e d m eas ures or a nal ysis of 
c o varia nce ( A N C O V A).
8. 4.
M ulti ple C o m p a ris o ns/ M ulti plicit y
T here is n o h y p ot hesis t o be teste d a n d a dj ust m e nt f or m ulti pli cit y.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 2 6 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
8. 5.
S u b g r o u ps A n al ysis
T he f oll o wi n g s u b gr o u ps will be ass esse d f or t he pri m ar y a n d sec o n dar y e n d p oi nts usi n g pri m ar y met h o d des cri be d 
i n S ecti o n 1 6. 1. 3 o n F A S wit h B aseli ne M M S 5 t o 9:
S e x ( F e m ale or Mal e)
A ge (
or > M e di a n, < or 
6 5)
B aseli ne oral c orti c oster oi d usa ge ( Yes or N o)
Naï ve t o bi ol o gi c or J A K i n hi bit or t hera p y at st u d y e ntr y ( Yes or N o)
B aseli ne dis eas e acti vit y
Act ual
M M S ( 4 t o 6, 7 t o 9) 
Act ual B aseli ne M M S ( 5 t o 7, 8 t o 9)
B aseli ne fecal cal pr otecti n (
or > M e di a n)
B aseli ne hi g h-se nsiti vit y C reacti ve pr otei n (
or > M e di a n)
B aseli ne T otal Ma y o sc ore (
or > 8)
D urati o n of U C (
or > M e di a n)
E xte nt of dis eas e ( Pr oct osi g m oi ditis/ Left si de d c olitis, P a nc olitis, Pr octitis as re p ort e d o n t he e C R F) 
Pr octitis ( Yes or N o, base d o n ce ntral rea d)
Pri or U C treat m e nt of oral 5-a mi n osali c yli c aci d ( 5- A S A) o nl y ( Yes or N o)
Pri or U C treat m e nt fail ure of or al 5- A S A o nl y ( Yes or N o)
N u m ber of pri or bi ol o gi c or J A K i n hi bit or t hera pi es ( 1 or > 1)
Pri or U C treat m e nt fail ure of a ntit u m or necr osis fact or al p ha (a nti-
A d diti o nal s u b gr o u ps m a y be assesse d, if dee m e d necessar y. T he me di a ns will be deri ve d base d o n F A S wit h 
baseli ne M M S 5 t o 9 f or all s u b gr o u ps c ut at m e dia n. It s h o ul d be n ot e d t hat t he st u d y was n ot desi g ne d t o detect 
treat m e nt differe nces wit h hi g h st atistical p o wer wit hi n s u b gr o u ps. If a n y s u b gr o u p i ncl u des < 5 % of all partici pa nts,
n o i nfere nti al st atistics will be ge nerat e d.
Act ual strat u m at baseli ne will be use d f or all s u b gr o u p a nal yses. 
F orest pl ots of t he o verall a nal ysis set a n d all s u b gr o u ps will be pres e nt e d f or t he pri mar y e n d p oi nt. I nfere nce fr o m 
t he m o del des cri be d i n S ecti o n 1 6. 1. 3 will be use d a n d differe nces i n re missi o n perce nta ges al o n g wit h 9 5 % CIs will 
be dis pla ye d.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 2 7 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
9.
O U T P U T P R E S E N T A TI O N S
A P P E N DI X 1 s h o ws c o n ve nti o ns f or prese nt ati o n of data i n o ut p uts. 
1 0.
D I S P O SI TI O N A N D P R O T O C O L D E VI A TI O N S
All parti ci pa nts w h o pr o vi de i nf or m e d c o nse nt will be acc o u nt e d f or i n t his st u d y. 
1 0. 1.
Dis p ositi o n
I ncl usi o n crit eria n ot met a n d e xcl usi o n crit eri a m et will be list e d.
A m o n g t he ra n d o mi ze d parti ci pa nts, t he n u m ber a n d perce nt of parti ci pa nts w h o c o m plet e d/ dis c o nti n ue d treat me nt, 
reas o ns off treat me nt, t he n u m ber a n d perce nt of partici pa nts w h o c o m plet e d/ disc o nti n ue d t he st u d y, reas o ns off 
st u d y, a n d t he n u m ber of parti ci pa nts w h o c o nti n ue t o A P D 3 3 4- 3 0 3 will be s u m m arize d.
T he n u m ber a n d perce nt of parti ci pa nts i n eac h a nal ysis s et will be s u m m arize d f or all ra n d o mi ze d parti ci pa nts. A n 
a d diti o nal s u m m ar y of t he n u m ber of partici pa nts scree ne d, t he n u m ber of scree n-faile d parti ci pa nts, a n d reas o n f or 
scree n fail ure will be prese nt e d f or all s cree ne d partici pa nts. A listi n g of partici pa nts w h os e bli n d was br o ke n will be 
pr o vi de d. 
T he n u m ber of parti ci pa nts w h ose visit was i m pact e d b y t he c or o na vir us disease 2 0 1 9 ( C O VI D- 1 9) pa n de mic per 
e C R F will als o be s u m m arize d b y n o mi nal visit.
A d diti o nall y, a s u m mar y of missi n g e n d osc o p y re gar dl ess of reas o n a n d missi n g e n d osc o p y d ue t o visit i m pact e d b y 
t he C O VI D- 1 9 pa n de mi c will be prese nte d b y visit.
1 0. 2.
Pr ot o c ol De vi ati o ns
D uri n g sit e m o nit ori n g, pr ot oc ol de viati o ns are gra de d as Critical, Maj or or Mi n or. 
Acc or di n g t o I C H E 3 a n d I C H E 3( R 1), i m p ort a nt pr ot oc ol de viati o ns are a s u bset of pr ot oc ol de viati o ns t hat mi g ht 
si g nifica ntl y affect t he c o m pl ete ness, acc urac y, a n d/ or relia bilit y of t he st u d y data or t hat mi g ht si g nifi ca ntl y affect a 
s u bj ect's ri g hts, s afet y, or well- bei n g (I C H 1 9 9 5, I C H 2 0 1 2). F or e xa m ple, i m p ort a nt pr ot ocol de viati o ns mi g ht 
i ncl u de e nr olli n g parti ci pa nts i n vi ol ati o n of ke y eli gi bilit y criteri a desi g ne d t o e ns ure a s pecifi c s u bj ect p o p ul ati o n 
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 2 8 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
or faili n g t o c ollect data necessar y t o i nter pret pri m ar y e n d p oi nts, as t his m a y c o m pr o mise t he sci e ntific val ue of t he 
st u d y. 
D uri n g t he re vie w of all re p orte d de vi ati o ns, i m p ort a nt de vi ati o ns relat e d t o st u d y i ncl usi o n or e xcl usi o n crit eri a, 
c o n d uct of t he st u d y, pati e nt ma na ge me nt or pati e nt ass ess m e nt will be i de ntifie d. W here rele va nt t he i m p ort a nce of 
t e 
p ot e nti al i m pact. 
All i m p ort a nt pr ot oc ol de vi ati o ns will be s u m m arize d f or t he F A S i n t he f oll o wi n g cate g ories i n desce n di n g 
fre q ue nc y i n t he etrasi m o d 2 m g gr o u p.
All pr ot oc ol de viati o ns will be list e d, i ncl u di n g w het her a de vi ati o n was i m pact e d b y t h e C O VI D- 1 9 pa n de mi c ( Yes 
or N o). Pr ot oc ol de viati o n cat e g ories i ncl u de b ut are n ot li mit e d t o t he f oll o wi n g:
I nf or m e d C o nse nt 
Eli gi bilit y a n d E ntr y Criteri a
C o nc o mita nt M e di cati o n
La b orat or y Assess me nt
St u d y Pr oce d ures 
S eri o us A d vers e E ve nt
R a n d o mi zati o n
Visit S c he d ule
I n vesti gati o nal Pr o d uct C o m pli a nce
Effi cac y 
A d mi nistrati ve
S o urce D oc u m e nt
R e g ulat or y or Et hi cs A p pr o vals
Ot her
I m p orta nt pr ot oc ol de viati o ns will als o be s u m m ari ze d b y w het her t he y were i m pacte d b y t he C O VI D- 1 9 pa n de mic 
( Yes or N o). 
1 1.
D E M O G R A P HI C A N D O T H E R B A S E LI N E C H A R A C T E RI S TI C S
T he f oll o wi n g de m o gra p hi c a n d baseli ne c haract eristi cs will be s u m m arize d f or t he F A S.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 2 9 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
A ge o n c o nse nt ( years) 
S e x ( M al e or F e m al e)
W o ma n of c hil d beari n g p ote ntial ( Yes or N o)
R ace 
Et h ni cit y
Hei g ht (c m)
Wei g ht ( k g)
B o d y mass i n de x ( B MI) ( k g/ m 2)
Al c o h ol c o ns u m pti o n ( Yes or N o)
C affei ne c o ns u m pti o n ( Yes or N o)
T o bacc o us e ( Yes or N o)
T he f oll o wi n g B aseli ne c haracteristics rel ate d t o U C will be s u m m arize d:
E xte nt of dis eas e ( Pr oct osi g m oi ditis/ Left-si de d c olitis, P a nc olitis, Pr octitis re p orte d o n t he Ul cerati ve C olitis 
Hist or y el ectr o ni c case re p ort f or m [e C R F], a n d Pr octitis re p orte d fr o m ce ntral rea der re vi e w)
B aseli ne M M S 
B aseli ne rectal blee di n g ( R B) s u bsc ore
B aseli ne st o ol fre q ue nc y ( S F) s u bs c ore
B aseli n e e n d osc o pi c s c ore
B aseli ne T M S
D urati o n of U C ( years)
A n y ac ut e e xacer bati o ns wit hi n past 1 2 m o nt hs ( Yes or N o), i ncl u di n g t he n u m ber of ac ut e e xacer b ati o ns 
a m o n g t h ose wit h a n y ac ute e xacer b ati o n = Yes
C ol o n os c o p y wit hi n past 1 2 m o nt hs ( Yes or N o)
S ur ger y f or U C ( Yes or N o), i ncl u di n g t he n u m ber of s ur geries a m o n g t h os e wit h s ur ger y f or U C = Yes
H os pit ali zati o ns f or U C ( Yes or N o), i ncl u di n g t he n u m ber of h os pitalizati o ns
Naï ve t o bi ol o gi c or J A K i n hi bit or t hera p y ( Yes or N o) 
R e p orte d ( us e d f or stratificati o n at ra n d o mizati o n)
Naï ve t o bi ol o gi c or J A K i n hi bit or t hera p y ( Yes or N o) 
Act ual ( C at e g or y of Treat m e nt re p orte d o n t he Pri or 
Treat m e nt f or Ulcerati ve C olitis e C R F)
B aseli ne c orti c ost er oi d us e ( Yes or N o) 
R e p orte d ( us e d f or stratificati o n at ra n d o mi zati o n)
B aseli ne c orti c ost er oi d us e ( Yes or N o) 
Act ual ( C at e g or y of Treat m e nt re p ort e d o n t he Pri or Treat m e nt f or 
Ul cerati ve C olitis e C R F)
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 3 0 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
B aseli ne M M S gr o u p ( 4 t o 6, 7 t o 9) 
R e p orte d ( us e d f or stratifi cati o n at ra n d o mizati o n)
B aseli ne M M S gr o u p ( 4 t o 6, 7 t o 9, a n d 5 t o 9) 
Act ual (s c ores re p ort e d o n t he
Ma y o Cli ni c S c ore e C R F)
Naï ve t o bi ol o gi c or J A K i n hi bit or t hera p y 
Differe nce bet we e n t he R e p ort e d a n d t he Act ual
B aseli ne c ortic ost er oi d us e ( Yes or N o) 
Differe nce bet w ee n t he R e p ort e d a n d t he Act ual
B aseli ne M M S gr o u p ( 4 t o 6, 7 t o 9) 
Differe nce bet wee n t he R e p orte d a n d t he Act ual
Pri or fail ure of oral 5- A S A o nl y ( Yes or N o)
Pri or fail ure of a nti-
Pri or fail ure of a nti-
Pri or treat m e nt f or U C will be s u m m arize d, i ncl u di n g cat e g or y of treat m e nt, reas o n f or disc o nti n uati o n, a n d 
esti m ate d d urati o n ( wee ks) of c ortic ost er oi d us e o ver t he l ast 1 2 m o nt hs.
1 1. 1.
Deri v ati o ns
D urati o n of U C ( year) = (I nf or m e d c o ns e nt date 
Dat e of dia g n osis b y p h ysici a n + 1) / 3 6 5. 2 5
Wei g ht ( k g) = Wei g ht (l b) × 0. 4 5 3 6 
Hei g ht (c m) = Hei g ht (i n) × 2. 5 4
Hei g ht ( m) = Hei g ht (i n) × 0. 0 2 5 4 = Hei g ht (c m) × 0. 0 1
B MI ( k g/ m 2) = Wei g ht ( k g)/ Hei g ht ( m)2
F or dat e of dia g n osis b y p h ysi cia n, if da y is missi n g, t he n i m p ute t o 1 st of t he m o nt h, if da y a n d m o nt h is missi n g, 
t he n i m p ute t o 1st Ja n uar y.
1 2.
M E DI C A L H I S T O R Y
Me di cal hist or y will be c ollecte d o n t he me dical hist or y e C R F a n d c o de d usi n g Me dical Dicti o nar y f or R e g ul at or y 
Acti vities ( M e d D R A, v 2 4. 1 or hi g her). T he versi o n use d t o c o de m e di cal hist or y will be dis pla ye d i n t he o ut p uts. 
All me di cal hist or y will be s u m m arize d f or t he S afet y S et b y s yste m or ga n class ( S O C) a n d preferr e d t er m ( P T).
1 3.
M E DI C A TI O N S A N D N O N - DR U G T R E A T M E N T
Me di cati o ns will be ca pt ure d o n t he C o nc o mit a nt Me di cati o ns e C R F a n d c o de d usi n g t he W orl d Healt h 
Or ga ni zati o n ( W H O) Dr u g dicti o nar y ( W H O D D E 0 1 S E P 2 0 2 1 or hi g her). R efer t o A P P E N DI X 2 f or ha n dli n g of 
partial dat es f or m e dicati o ns. I n t he case w here it is n ot p ossi bl e t o defi ne a m e di cati o n as pri or or c o nc o mita nt, t he 
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 3 1 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
m e di cati o n will be cl assifie d b y t he w orst case (i e, c o nc o mit a nt). 
i cati o ns w hi c h st arte d a n d st o p pe d pri or t o t he first d ose of st u d y treat m e nt
A N D e n de d o n or aft er t he dat e of first d os e of st u d y treat m e nt or were o n g oi n g at t he e n d of t he st u d y
C o nc o mita nt m e dicati o ns will be s u m m arize d b y A nat o mical T hera pe utic C he mi cal ( A T C) Le vel 2 a n d Preferre d 
Dr u g na m e f or t he S afet y S et. C o nc o mita nt me di cati o ns bei n g us e d f or U C will be fl a g ge d as s uc h o n t he 
C o nc o mita nt M e di cati o ns e C R F a n d s u m mari ze d b y A T C Le vel 2 a n d Preferre d Dr u g na m e f or t he S afet y S et.
N o n- dr u g treat me nt will be ca pt ure d o n t he C o nc o mita nt N o n- Dr u g Treat me nt e C R F a n d c o de d usi n g M e d D R A 
versi o n 2 4. 1 or hi g her. A listi n g will be pr o vi de d f or S afet y S et.
1 4.
S T U D Y T R E A T M E N T E X P O S U R E
T he dat e of first a n d last st u d y treat m e nt a d mi nistrati o n will be t a ke n fr o m t he Da y 1 O n Site D osi n g A d mi nistrati o n 
e C R F a n d t he E n d of St u d y e C R F, res pecti vel y. I nt err u pti o ns, c o m pli a nce, a n d d ose c ha n ges are n ot ta ke n i nt o 
acc o u nt f or d urati o n of e x p os ure. E x p os ure t o st u d y treat m e nt i n wee ks will be s u m mari ze d f or t he S afet y Set.
D os e i nt err u pti o ns will be rec or de d o n t he D osi n g A d mi nistrati o n e C R F, a n d o ver d ose will be rec or de d o n t he 
O ver d os e e C R F. T he fre q ue nc y a n d perce nt a ge of parti ci pa nts w h o ha d at least 1 d ose i nterr u pti o n, w h o ha d at least 
1 d ose i nterr u pti o n of > 7 da ys, w h o ha d at l east 1 d ose i nt err u pti o n of > 1 4 da ys, w h o ha d 1 o ver d ose, a n d w h o ha d 
> 1 o ver d ose will be s u m mari ze d. 
1 4. 1.
Deri v ati o ns
D urati o n of e x p os ure ( wee ks) = ( date of l ast st u d y treat m e nt a d mi nistrati o n 
date of first st u d y treat me nt 
a d mi nistrati o n + 1) / 7. F or parti ci pa nts wit h missi n g Dat e of Last D ose o n t he E n d of St u d y e C R F, t heir date of l ast 
st u d y treat me nt a d mi nistrati o n will be i m p ut e d b y t he l ast dat e of all D osi n g A d mi nistrati o n start/ e n d dat es e C R F
rec or de d. 
1 5.
S T U D Y T R E A T M E N T C O M P LI A N C E 
T he ti me o n st u d y ( wee ks), t otal s u bject- years o n st u d y, t ot al treat m e nt e x p os ure ( wee ks), t otal s u bj ect- years of 
e x p os ure, t otal n u m ber of ta bl ets e x pecte d, t otal nu m ber of ta bl ets ta ke n, t otal n u m ber of tabl ets misse d, o verall 
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 3 2 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
c o m pli a nce wit h st u d y treat m e nt, a n d fre q ue nc y a n d perce nt a ge of st u d y treat me nt e x p os ure cate g or y ( < 4 wee ks, 
4 a n d < 8 wee ks, 
8 a n d < 1 2 wee ks a n d 
1 2 wee ks) a n d parti ci pa nts wit h o verall c o m plia nce of < 8 0 % or > 1 2 0 % 
will be s u m m arize d f or t he Safet y S et.
1 5. 1.
Deri v ati o ns
C o m pli a nce wit h st u d y treat me nt is base d o n t he Dr u g Acc o u nta bilit y e C R F a n d will be calc ul ate d as t he t ot al 
n u m ber of ta bl ets t a ke n (t ot al dis pe nse d 
t otal ret ur ne d) di vi de d b y t he n u m ber of t a blets e x pecte d d uri n g t he 
Treat m e nt P eri o d, e x presse d as a perce nta g e, ref er t o calc ulati o ns bel o w. 
T he t ot al n u m ber of ta bl ets e x pect e d is defi ne d as t he n u m ber of t a blets t hat a s u bject is e x pect e d t o ha ve t a ke n 
bet wee n
treat m e nt e x p os ure, si nce t he m e dicati o n is t o be ta ke n o nce dail y. O n a n y sit e visit da y, t he me di cati o n is t o be hel d 
a n d ta ke n at t he site, aft er all pre d ose ass ess m e nts ha ve bee n c o m pl ete d. F or e xa m pl e, if a s u bj ect t o o k t heir last 
d ose of st u d y treat m e nt o n Da y 6 0 a n d ret ur ne d t o t he sit e o n Da y 7 8 t o ret ur n t he st u d y treat m e nt b ottle, t he n t he 
t otal n u m ber of t a blets e x pecte d w o ul d be 6 0, n ot 7 7.
T otal n u m ber of t a blets e x pecte d = ( dat e of l ast st u d y treat me nt a d mi nistrati o n 
date of first st u d y treat me nt 
a d mi nistrati o n + 1) ( da ys) × 1 (t a blet / da y)
F or all b ottles n ot ret ur ne d, it will be ass u m e d t hat all dis pe nse d ta bl ets were ta ke n. F or eac h s u bject, if a hi g h 
perce nta ge ( > 2 5 %) of b ottles were n ot ret ur ne d b y a s u bj ect, a d diti o nal a nal yses ma y be d o ne w here b ottles n ot 
ret ur ne d are e xcl u de d fr o m t he o verall c o m pli a nce cal c ulati o n f or t hat s u bject. I n s uc h a nal ysis, t he date of l ast d ose
B ot h s c he d ul e d a n d u nsc he d ule d st u d y treat m e nt dis pe nsati o ns will be use d i n t he c o m pli a nce calc ul ati o n. O verall 
c o m pli a nce calc ul ati o ns will be perf or me d f or t he 1 2- Wee k Treat me nt P eri o d a n d will be use d i n det er mi ni n g 
i ncl usi o n/e xcl usi o n of partici pa nts i n t he res pecti ve P er Pr ot oc ol Set.
Ot her deri vati o ns are s h o w n bel o w:
Ti m e o n st u d y ( wee ks) is cal c ulat e d as (" Dat e of C o m pl eti o n/ Ter mi nati o n of St u d y" o n t he e C R F P a ge " E n d of 
St u d y"
i nf or me d c o nse nt dat e + 1)/ 7.
T otal s u bj ect- years o n st u d y is cal c ulat e d as t he s u m of d urati o n of ti me o n st u d y ( da ys) acr oss all s u bj ects 
di vi de d b y 3 6 5. 2 5.
E x p os ure ( wee ks) is cal c ulat e d as (e n d date of st u d y treat m e nt - start date of st u d y treat m e nt + 1)/ 7.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 3 3 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
T otal s u bj ect- years of e x p os ure is cal c ulat e d as t he s u m of d urati o n of treat m e nt e x p os ure (da ys) acr oss all 
s u bj ects di vi de d b y 3 6 5. 2 5.
Ta blets miss e d is cal c ulat e d as (t he n u m ber of t a bl ets e x pecte d 
t he n u m ber of t a blets ta ke n) a n d ca n be 
ne gati ve if s u bject has ta ke n m ore t ha n e x pecte d n u m ber of ta bl ets.
1 6.
E F FI C A C Y O U T C O M E S 
U nl ess ot her wise state d, t he pri mar y effi cac y a nal ys es will be base d o n t he F A S wit h B aseli ne M M S 5 t o 9. Pri m ar y 
a n d sec o n dar y effi c ac y a nal yses will be re peat e d f or all parti ci pa nts i n F A S wit h B aseli ne M M S 4 t o 9 as 
s u p pl e me nt ar y a nal ysis.
T he f oll o wi n g defi niti o ns will be us e d t o assess effi cac y o utc o m es:
Cli ni cal re missi o n: S F s u bs c ore = 0 ( or =
1- p oi nt decrease fr o m baseli ne), R B s u bs c ore = 0, a n d 
E S
1 (e xcl u di n g fri a bilit y)
1 (e xcl u di n g fria bilit y) 
S y m pt o matic re missi o n: S F s u bsc ore = 0 ( or =
1- p oi nt decrease fr o m baseli ne) a n d R B s u bsc ore = 0
1 (e xcl u di n g fri a bilit y) wit h hist ol o gic re missi o n m eas ure d b y a Ge b oes I n de x sc ore 
< 2. 0
2-
3 0 % decrease fr o m baseli ne i n M M S, a n d a
1- p oi nt decreas e fr o m 
1
E n d osc o pic n or m ali zati o n: E S = 0
C o m pl ete s y m pt o matic re missi o n: S F s u bsc ore = 0 a n d R B s u bsc ore = 0
3 0 % decr
1- p oi nt 
1
3 0 % i n c o m p osit e R B a n d S F s u bsc ores
Cli ni cal re missi o n usi n g T M S: T M S
2 p oi nts wit h n o i n di vi d ual s u bsc ore of > 1 p oi nt
Cli ni cal res p o nse usi n g T M S
3-
3 0 % decrease fr o m baseli ne i n T M S
1- p oi nt decrease 
fr o m baseli ne i n R B s u bsc ore or a n a bs ol ute R B s u bs c ore
1
Hist ol o gi c i m pr o ve me nt usi n g Ge b oes I n de x: Ge b oes I n de x s c ore < 3. 1
Hist ol o gic re missi o n usi n g Ge b oes I n de x: Ge b oes I n de x sc ore < 2. 0
Hist ol o gic i m pr o ve me nt usi n g R o barts Hist o pat h ol o g y I n de x ( R HI): 
5 0 % re d ucti o n fr o m B aseli ne i n R HI or 
R HI 
3
Hist ol o gic re missi o n usi n g R HI: R HI 
3, wit h sc ores of 0 (zer o) f or b ot h Ge b oes Gra de 2 B (la mi na pr o pri a 
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 3 4 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
ne utr o p hils) a n d Gra de 3 ( ne utr o p hils i n e pit heli u m)
Hist ol o gic i m pr o ve me nt usi n g Na nc y Hist ol o gic I n de x ( N HI): 
1 p oi nt re d ucti o n fr o m B aseli ne N HI
Hist ol o gic re missi o n usi n g N HI: 
1
I m pr o ve m e nt i n e xtrai nt esti nal m a nifest ati o ns ( EI Ms): a n y cate g or y i m pr o ve d at p ost- bas eli ne
1 6. 1.
Pri m ar y Effic a c y
1 6. 1. 1.
Pri m a r y Effic a c y V a ri a ble & Deri v ati o n
T he pri m ar y effi ca c y e n d p oi nt will c o m pare eac h etr asi m o d d ose ( 1 a n d 2 m g) t o place b o f or: 
T he pr o p orti o n of partici pa nts ac hi e vi n g cli nical re missi o n at Wee k 1 2
Cli ni cal re missi o n is defi ne d i n S ecti o n 1 6. T he S F, R B, a n d E S s u bs c ores will be base d o n t he Ma y o Cli ni c s c ore 
e C R F, b ut o nl y if a s u bsc ore at baseli ne i n e C R F is missi n g it will be i m p ut e d b y c orres p o n di n g dat a i n I nt eracti ve 
R es p o nse Tec h n ol o g y (I R T). P arti ci pa nts w h o ac hi e ve cli nical re missi o n will be referre d t o as res p o n ders. 
P artici pa nts w h o d o n ot ac hie ve cli ni cal re missi on will be referr e d t o as n o nres p o n ders.
1 6. 1. 2.
Missi n g D at a Met h o ds f o r Pri m a r y Effic a c y V a ri a ble
P artici pa nts w h o: 1) disc o nti n ue t he st u d y f or lac k of effi cac y or a d vers e e ve nt relat e d t o U C ( dat a c oll ect e d f or 
Pri mar y R eas o n off St u d y fr o m E n d of st u d y e C R F a n d A d verse E ve nts e C R F), 2) i nitiat e a resc ue me di cati o n f or 
U C, 3) ha ve a n i ncreas e i n d ose o ver B aseli ne l e vels i n t heir e xisti n g U C me di cati o n, or 4) ha ve resc ue n o n- dr u g 
treat m e nt (e g, c ol ect o m y, il e ost o m y, or si g m oi dect o m y) d uri n g t he st u d y as c o nfir m e d after bli n de d re vi e w b y 
cli ni cal a n d me di cal t ea m me m bers bef ore st u d y u n bli n di n g will be c o nsi dere d t o ha ve a k n o w n (ie, n o n- missi n g) 
o ut c o m e of n o nres p o ns e a n d n ot as ha vi n g missi n g data i n t he a nal ysis of all efficac y e n d p oi nts at a n y s u bs e q ue nt 
ti m e p oi nts, i ncl u di n g t he pri mar y e n d p oi nt. T he resc ue t hera pi es will be i de ntifi e d b y t he Are na cli ni cal tea m d uri n g 
bli n de d data re vi e w. R efer t o A P P E N DI X 5 f or t he defi niti o n of resc ue t hera pies ( me dicati o n a n d m e di cal 
pr oce d ures). I n sc e nari os 2 a n d 3 a b o ve, if a s u bj ect has a n effi cac y m eas ure me nt c oll ect e d aft er t he i niti ati o n or 
d ose i ncreas e fr o m B aseli ne of U C me dicati o n, t he o bser ve d data will be ce ns ore d at t he ti m e of i nitiati o n or d os e 
i ncreas e a n d t he y will be c o nsi dere d as ha vi n g a n o nres p o nse. S u bjects i n all 4 s ce nari os a b o ve ma y still be i ncl u de d 
i n t he res pecti ve P er Pr ot oc ol S et, pr o vi de d t he y d o n ot vi ol ate ot her crit eria f or P er Pr ot oc ol S et. F or e xa m pl e, t he y 
will be e xcl u de d fr o m t he P er Pr ot oc ol S et if t he y i niti ate a pr o hi bit e d m e dicati o n bef ore t he Wee k 1 2 efficac y 
assess me nt t hat ca n affect effi cac y of t he st u d y treat m e nt a n d t he i n di cati o n is u nrelat e d t o U C.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 3 5 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
A nal ysis visits will be m a p pe d as per S ecti o n 6. 4 bef ore a n y missi n g data i m p ut ati o n m et h o d is a p pli e d.
P artici pa nts wit h a missi n g effi cac y o ut c o me will be i ncl u de d i n t he pri m ar y a nal ysis usi n g si n gl e i m p ut ati o n as 
n o n-res p o n der.
1 6. 1. 3.
Pri m a r y A n al ysis of Pri m a r y Effic a c y V a ri a ble
T he pri m ar y effi ca c y a nal ysis will be perf or m e d f or t he F A S wit h B aseli ne M M S 5 t o 9. R es ults will be e x presse d 
as t he n u m ber a n d perce nta ge of parti ci pa nts i n cli ni cal re missi o n, differe nce i n cli ni cal re missi o n perce nt a ges a n d 
9 5 % CI, o d ds rati o a n d ass ociat e d 9 5 % CI.
1 6. 1. 4.
S u p ple m e nt a r y A n al ysis of Pri m a r y Effic a c y V a ri a ble
T he pri m ar y a nal ysis as des cri be d i n S ecti o n 1 6. 1. 3 usi n g n o n-res p o n der i m p utati o n will be re peate d usi n g t he 
m F A S a n d P er Pr ot oc ol S et as s u p ple m e ntar y a nal ys es i n partici pa nts wit h act ual B aseli ne M M S 5 t o 9. 
T he pri m ar y a nal ysis as des cri be d i n Secti o n 1 6. 1. 3 will be re peat e d f or t he pri m ar y e n d p oi nt usi n g t he F A S wit h 
B aseli ne M M S 4 t o 9. 
1 6. 2.
Sec o n d a r y Effic a c y
T here is n o statistical h y p ot hetical t esti n g of t he s ec o n dar y e n d p oi nts.
S ec o n dar y effi ca c y e n d p oi nts are defi ne d i n S ecti o n 1 6. I n ge neral, t he pri mar y a nal ysis a n d s u p pl e me nt ar y a nal ys es
i n m F A S pl a n ne d f or t he pri m ar y e n d p oi nts i n Secti o ns 1 6. 1. 3 a n d 1 6. 1. 4 will be re peate d f or eac h sec o n dar y 
effi ca c y e n d p oi nt ( Ta ble 3). 
T a bl e 3:
Pl a n ne d A n al ysis b y E n d p oi nt
E n d p oi nt
Pri m ar y A n al ysis
S u p pl e m e nt ar y A n al yses 
i n m F A S 
S u p pl e m e nt ar y A n al yses 
i n P P S
Pri mar y e n d p oi nts
X
X
X
S ec o n dar y e n d p oi nts
  E n d osc o pic i m pr o ve m e nt
X
X
  S y m pt o matic re missi o n
X
X
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 3 6 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
E n d p oi nt
Pri m ar y A n al ysis
S u p pl e m e nt ar y A n al yses 
i n m F A S 
S u p pl e m e nt ar y A n al yses 
i n P P S
  M uc osal heali n g
X
X
  Cli ni cal res p o nse
X
X
  E n d osc o pic n or m ali zati o n
X
X
A nal yses i n t he t a ble will be re peat e d f or partici pa nts i n t he F A S wit h B aseli ne M M S 4 t o 9. 
m F A S, m o difi e d F ull A nal ysis S et.
1 6. 2. 1.
Sec o n d a r y Effic a c y V a ri a bles & Deri v ati o ns
E n d osc o pic i m pr o ve m e nt at Wee k 1 2
S y m pt o matic re missi o n at Wee k 1 2
M uc osal heali n g at Wee k 1 2
Cli ni cal res p o nse at Wee k 1 2
E n d osc o pic n or m ali zati o n at Wee k 1 2
1 6. 2. 2.
Missi n g D at a Met h o ds f o r Se c o n d a r y Effic a c y V a ri a bles
T he sa me missi n g data m et h o ds use d f or t he pri m ar y e n d p oi nt descri be d i n S ecti o n 1 6. 1. 1 a n d S ecti o n 1 6. 1. 2 will be 
use d f or t he sec o n dar y e n d p oi nts.
1 6. 2. 3.
Pri m a r y A n al ysis of Sec o n d a r y Effic a c y V a ri a bles
T he pri m ar y a nal ysis of all t he sec o n dar y effi cac y e n d p oi nts will be perf or me d f or t he F A S wit h Bas eli ne M M S 5 t o 
9. F or all s ec o n dar y e n d p oi nts, t he s a me a nal ysis t hat was des cri be d i n S ecti o n 1 6. 1. 3 will be perf or me d.
1 6. 2. 4.
S u p ple m e nt a r y A n al ysis of Sec o n d a r y Effic a c y V a r ai bles
F or all s ec o n dar y e n d p oi nts, t he pri m ar y a nal ysis as des cri be d i n S ecti o n 1 6. 1. 3 usi n g n o n-res p o n der i m p utati o n will 
be re peate d usi n g t he m F A S wit h act ual B aseli ne M M S 5 t o 9 as s u p ple m e nt ar y a nal ys es.
F or all t he sec o n dar y e n d p oi nts, pri m ar y a nal yses list e d i n Ta bl e 3 will be re peate d i n parti ci pa nts usi n g F A S wit h 
B aseli ne M M S 4 t o 9.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 3 7 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
1 6. 3.
E x pl o r at o r y Effic a c y 
E x pl orat or y effi cac y e n d p oi nts are defi ne d i n S ecti o n 1 6.
1 6. 3. 1.
E x pl o r at o r y Effic a c y V a ri a bles a n d De ri v ati o ns
E x pl orat or y effi cac y e n d p oi nts are:
T he pr o p orti o n of partici pa nts ac hi e vi n g s y m pt o matic re missi o n at Wee ks 2, 4, 8
T he pr o p orti o n of partici pa nts ac hi e vi n g c o m pl ete s y m pt o matic re missi o n at eac h st u d y visit ( Wee ks 2, 4, 8, 1 2)
T he pr o p orti o n of partici pa nts ac hi e vi n g n o ni n vasi ve cli ni cal res p o ns e at eac h st u d y visit ( Wee ks 2, 4, 8, 1 2)
T he pr o p orti o n of partici pa nts ac hi e vi n g s y m pt o matic res p o nse at eac h st u d y visit ( Wee ks 2, 4, 8, 1 2)
T he pr o p orti o n of partici pa nts wit h re missi o n a n d res p o ns e usi n g T M S at Wee k 1 2
T he pr o p orti o n of partici pa nts wit h hist ol o gi c i m pr o ve me nt at Wee k 1 2 (as defi ne d b y t he Ge b oes I n de x, 
R o barts Hist o pat h ol o g y I n de x, a n d Na nc y Hist ol o gic I n de x)
T he pr o p orti o n of partici pa nts wit h hist ol o gi c re missi o n at Wee k 1 2 (as defi ne d b y t he Ge b oes I n de x, R o barts 
Hist o pat h ol o g y I n de x, a n d Na nc y Hist ol o gic I n de x)
T he pr o p orti o n of partici pa nts wit h i m pr o ve m e nt i n e xtrai nt esti nal ma nifest ati o ns ( EI Ms) at Wee k 1 2 i n 
partici pa nts wit h EI Ms at baseli ne
1 6. 3. 2.
Missi n g D at a Met h o ds f o r E x pl o r at o r y Effic a c y V a ri a bles
All parti ci pa nts wit h missi n g dat a, re gar dless of reas o n f or missi n g ness, will be c o nsi dere d as n o n-res p o n ders. T he 
i nterc urre nt e ve nts t hat are c o nsi dere d i n t he pri m ar y effi c ac y a nal ysis will be ha n dl e d si milarl y f or t he e x pl orat or y 
effi ca c y e n d p oi nts, as s pecifi e d i n S ecti o n 1 6. 1. 2.
1 6. 3. 3.
A n al ysis of E x pl o r at o r y Effic a c y V a ri a bles
All pr o p orti o n- base d e n d p oi nts will be a nal yse d as descri be d i n S ecti o n 1 6. 1. 3 f or t he m F A S wit h Baseli ne M M S 5 
hist ol o gi cal s c ori n g i n di ces will als o be 
prese nt e d b y treat me nt gr o u p.
N o m ulti plicit y a dj ust me nts will be m a de.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 3 8 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
1 6. 4.
Effic a c y- Rel ate d Bi o m a r kers
Val ue a n d c ha n ge fr o m B aseli ne i n l e vel of fecal cal pr ot e cti n ( F C P), hs- C R P, a n d l y m p h ocyte c o u nts at pr ot oc ol-
s pecifie d visits will be s u m m arize d b y visit a n d treat m e nt f or t he F A S wit h B as eli ne M M S 5 t o 9. A d diti o nall y, 
perce nt c ha n ge fr o m B aseli ne i n l y m p h oc yt e c o u nts will als o be s u m mari ze d. C ha n ge fr o m B aseli ne i n t hese 
bi o mar kers will als o be a nal yse d usi n g a mi xe d-effect m o del wit h re peate d m eas ures ( M M R M), wit h fact ors f or 
treat m e nt, visit, treat me nt b y visit i nt eracti o n, a n d a c o vari at e of t he c orres p o n di n g B aseli ne val ue. U nstr uct ure d 
c o varia nce will be use d. If t here is a c o n ver g e nce iss ue i n fitti n g t he u nstr uct ure d c o varia nc e, a heter o ge ne o us 
T oe plitz, het er o ge ne o us a ut ore gressi ve ( 1), a ut ore gressi ve ( 1), or c o m p o u n d s y m metr y c o vari a nce str uct ure will be 
use d. T he sa me m o del will be fit t o t he perce nt c ha n ge fr o m B aseli ne i n l y m p h oc yt es. L S mea ns, S Es, a n d CIs b y 
visit will be re p orte d.
A d diti o nall y, t he f oll o wi n g s u m mari es will be pr o vi de d f or bi o m ar ker data:
Li ne pl ots o ver ti m e f or L S mea n a n d S E f or t he f oll o wi n g l a b orat or y assess m e nts:
o
C ha n ge fr o m B aseli ne i n l y m p h oc yt es
o
P erce nt c ha n ge fr o m B aseli ne i n l y m p h oc yt es
o
C ha n ge fr o m B aseli ne i n hs- C R P
o
C ha n ge fr o m B aseli ne i n F C P
T he e x pl orat or y effica c y-relat e d bi o m ar ker a nal yses f or i m m u n o p he n ot y pi n g a n d pr ot e o mics will be descri be d i n a 
se parat e bi o m ar ker a n al ysis pla n.
1 7.
H E A L T H - RE L A T E D Q U A LI T Y O F L I F E ( H R QO L) A N D 
H E A L T H C A R E R E S O U R C E U TI LI Z A TI O N A N A L Y SI S 
S u bj ect-re p ort e d H R Q o L i nstr u m e nts will be electr o nicall y ca pt ure d a n d us e d i n s u p p ort of t he effi cac y o ut c o mes. 
All H R Q o L are a d mi nist ere d at B aseli ne a n d Wee k 1 2. T he H R Q o L a nal yses will be perf or m e d usi n g t he m F A S 
wit h Bas eli ne M M S 5 t o 9. 
All H R Q o L e n d p oi nts will be a nal yze d usi n g a n A N C O V A f or t he c ha n ge fr o m B aseli ne, wit h a fact or f or treat m e nt 
a n d a c o variat e of t he c orres p o n di n g H R Q o L B aseli ne val ue. 
Healt hcare r es o urce utili zati o n e n d p oi nts, i e, t he pr o p orti o n of c o nc o mit a nt U C-rel ate d h os pit ali zati o ns a n d t he 
pr o p orti o n of c o nc o mita nt U C-rel ate d s ur geries, i ncl u di n g c olect o m y, will be a nal yze d as descri be d i n S ecti o n
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 3 9 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
1 6. 1. 3 f or t he F A S wit h B aseli ne M M S 5 t o 9.
1 7. 1.
V a ri a bles a n d Deri v ati o ns
1 7. 1. 1.
Ulc er ati v e C olitis P atie nt- Re p o rte d O utc o m es Si g ns a n d S y m pt o ms
T he Ul cerati ve C olitis Patie nt- R e p orte d O utc o mes Si g ns a n d S y m pt o ms ( U C- P R O/ S S) is a 9-ite m dail y diar y 
desi g ne d t o q ua ntif y t he effects of treat me nt o n pati e nt-re p orte d si g ns a n d s y m pt o ms of U C. T w o se parate wee kl y 
a vera ge sc ores will be cal c ulat e d, o ne f or b o wel si g ns a n d s y m pt o ms sc ore ( 6 it e ms), a n d t he ot her f or a b d o mi nal 
s y m pt o ms ( 3 ite ms). T he hi g her t he sc ore, t he w orse t he s y m pt o ms. T he U C- P R O/ S S sc ores a n d c ha n ge fr o m 
B aseli ne at Wee k 1 2 will be e val uat e d. Details a b o ut sc ori n g r ul es ca n be f o u n d i n A P P E N DI X 3.
1 7. 1. 2.
3 6 Ite m S h o rt F o r m H e alt h S ur v e y, v e rsi o n 2
T he 3 6-It e m S h ort F or m Healt h S ur ve y ( S F- 3 6) is a 3 6-ite m, s u bject-re p ort e d s ur ve y of s u bject healt h. T he S F- 3 6 
c o nsists of 3 6 q uesti o ns m eas uri n g 8 healt h d o mai ns: p h ysi cal f u ncti o ni n g, b o dil y pai n, r ol e li mitati o ns d ue t o 
p h ysi cal pr o bl e ms, r ole li mitati o ns d ue t o e m oti o nal pr o ble ms, ge neral healt h perce pti o ns, me nt al healt h, s oci al 
res p o ns e o pti o ns per it e m. T he S F- 3 6 will be s c ore d usi n g 2 o verall s u m m ar y sc ores: p h ysical c o m p o ne nt s u m m ar y 
a n d me nt al c o m p o ne nt s u m m ar y sc ores. A hi g her s c ore i n di cat es bett er healt h st at us. 
T he P h ysi cal C o m p o ne nt S u m mar y S c ore ( n or m- bas e d), t he Me nt al C o m p o ne nt S u m m ar y S c ore ( n or m- base d), 8 
d o m ai n s u bs c ores ( 0 t o 1 0 0 base d), a n d t he S F- 6 D healt h utilit y i n de x sc ore are deri ve d b y O pt u m a n d i nt e grat e d 
i nt o t he S F- 3 6 e C R F. Det ails a b o ut sc ori n g r ules a n d deri vati o ns of d o m ai n/ c o m p o ne nt sc ores ca n be f o u n d i n 
A P P E N DI X 4.  
1 7. 1. 3.
U C- Rel ate d H os pit aliz ati o ns a n d S ur g eries
T he U C-rel ate d h os pitalizati o ns are ca pt ure d o n t he A d verse E ve nts e C R F. T he U C-relat e d s ur geries, i ncl u di n g 
c olect o m y, are ca pt ure d o n t he C o nc o mita nt N o n- Dr u g Treat m e nt e C R F. Bli n de d re vie w of A E preferre d ter ms will 
be perf or m e d t o det er mi ne U C-rel ate d h os pitalizati o ns.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 4 0 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
1 7. 2.
Missi n g D at a Met h o ds
Missi n g dat a will n ot be i m p ut e d f or H R Q o L e n d p oi nts.
1 8.
S A F E T Y O U T C O M E S
All o ut p uts f or safet y o ut c o mes will be base d o n t he S S. T here will be n o statisti cal c o m paris o ns bet wee n t he 
treat m e nt gr o u ps f or safet y dat a, u nless ot her wise s pecifi e d.
1 8. 1.
A d v erse E v e nts
A Es will be c o de d usi n g M e d D R A ( v 2 4. 1 or hi g her). T he versi o n us e d t o c o de A Es will be dis pla ye d i n t he 
a nal ys es. Treat me nt e mer ge nt a d verse e v e nts ( T E A Es) are defi ne d as A Es t hat start e d or w ors e ne d i n se verit y o n or 
aft er t he first d ose of st u d y treat me nt. 
R efer t o A P P E N DI X 2 f or ha n dli n g of parti al dat es f or A Es f or t he p ur p os e of assi g ni n g treat m e nt-e mer ge nt fla gs. 
I n t he cas e w her e it is n ot p ossi ble t o defi ne a n A E as treat m e nt e m er ge nt or n ot, t he A E will be classifie d as 
treat m e nt e mer ge nt.
1 8. 1. 1.
All T E A Es
All T E A Es will be s u m m arize d b y S O C a n d P T. T his s u m mar y t a ble a n d all ot her T E A E s u m mari es b y S O C a n d P T 
will be prese nt e d b y des ce n di n g fre q ue nc y i n t he etrasi m o d t ot al gr o u p. All A Es, re gar dless of treat me nt e m er ge nt 
st at us, will be i ncl u de d i n a n A E listi n g. A d diti o nall y, a listi n g of ot her A E details, as c oll ecte d o n t he e C R F, will be 
prese nt e d.
E x p os ure-a dj ust e d i nci de nce rat e ( E AI R) of T E A Es will be s u m mari ze d b y S O C a n d P T. E x p os ure is defi ne d as t he 
s u m of eit her ti m e ( year) fr o m first d ose t o t he o nset of first s uc h e ve nt f or t h ose w h o e x perie nce d t his A E, or ti m e 
( year) fr o m first d ose t o last partici pati o n dat e i n t he st u d y f or t h ose w h o di d n ot e x perie nce t his A E. T he E AI R is 
calc ul ate d as t he n u m ber of parti ci pa nts wit h t he A E di vi de d b y t he t otal e x p os ure i n s u bj ect- years.
1 8. 1. 1. 1.
S E V E RI T Y
S e verit y is classifi e d as Gra de 1: Mil d, Gra de 2: M o derate, Gra de 3: S e vere, Gra de 4: Life t hreat e ni n g, Gra de 5: 
Deat h relat e d t o A E, usi n g t he C o m m o n Ter mi n ol o g y Criteri a f or A d vers e E ve nts, v 5. 0 ( C T C A E v 5. 0).
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 4 1 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
All T E A Es will be s u m marize d b y S O C, P T, a n d ma xi m u m se verit y, wit h S O C a n d P T pres e nte d b y desce n di n g 
fre q ue nc y of etr asi m o d t ot al gr o u p. If a s u bject re p orts a T E A E m ore t ha n o nce wit hi n a S O C/ P T, t he A E wit h t he 
w orst-cas e s e verit y will be use d i n t his s u m m ar y.
T E A Es wit h a missi n g se verit y will be classifi e d as Gra de 3: S e vere t o st u d y treat me nt f or s u m m ar y ta b ul ati o n 
p ur p ose o nl y.
1 8. 1. 1. 2.
R E L A TI O N S HI P T O S T U D Y T R E A T M E N T
. 
All T E A Es will be s u m marize d b y S O C, P T, a n d hi g hest rel ati o ns hi p (as re p ort e d o n t he e C R F, n ot gr o u pe d), wit h 
S O C a n d P T prese nte d b y desce n di n g fre q ue nc y of etrasi m o d t ot al gr o u p. If a s u bj ect re p orts a T E A E m ore t ha n 
o nce wit hi n a S O C/ P T, t he A E wit h t he w orst-case rel ati o ns hi p t o st u d y treat me nt will be use d i n t his s u m m ar y. 
t a b ul ati o n p ur p ose o nl y. 
1 8. 1. 2.
T E A Es Le a di n g t o Dis c o nti n u ati o n of St u d y Tr e at m e nt
T E A Es lea di n g t o dis c o nti n uati o n of st u d y treat me nt will be i de ntifie d b y acti o n t a ke n wit h st u d y treat me nt bei n g 
All T E A Es l ea di n g t o disc o nti n uati o n of st u d y treat m e nt will be s u m mari ze d b y S O C a n d P T. A listi n g of all 
T E A Es lea di n g t o dis c o nti n uati o n of st u d y treat m e nt will als o be pres e nte d.
Li ver-rel ate d A Es ar e defi ne d b y eit her S O C of he pat o bili ar y dis or ders or P T of ala ni ne a mi n otra nsferase a b n or m al, 
ala ni ne a mi n otra nsferase i ncre ase d, as partate a mi n otra nsfer as e a b n or m al, as partate a mi n otra nsferase i ncr ease d, 
he pati c e nz y m e a b n or mal, he pati c e nz y m e i ncreas e d, li ver f u ncti o n t est a b n or m al, li ver f u ncti o n test i ncreas e d, 
tra nsa mi nases a b n or m al, or tra nsa mi nases i ncrease d.
1 8. 1. 3.
Seri o us a n d N o n- Se ri o us T E A Es
S eri o us a d verse e ve nts ( S A Es) are t h ose e ve nts rec or de d as 
e C R F.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 4 2 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
All seri o us T E A Es will be s u m m arize d b y S O C a n d P T. If t he s eri o us ness is missi n g, t he A E will be c o nsi dere d as 
y. A s eri o us T E A E listi n g will als o be prese nt e d. All n o n-seri o us 
T E A Es will be s u m marize d b y S O C a n d P T.
1 8. 1. 4.
T E A Es Le a di n g t o De at h
or A E S e verit y is e q ual t o 
Gra de 5 o n t he A d vers e E ve nts e C R F. All T E A Es l ea di n g t o deat h will be list e d.
1 8. 1. 5.
T E A Es of S peci al I nte rest 
C ate g ori es of Tar gete d Me di cal E ve nts ( T M Es) a n d a list of preferre d ter ms ass oci ate d wit h t hes e T M E cate g ories 
were de vel o pe d bas e d o n t he mec ha nis m of acti o n of etrasi m o d, pri or e x peri e nce wit h ot her a ge nts acti n g via a 
si mil ar mec ha nis m, a n d disease s pecific cli ni cal j u d g me nt. I n a d diti o n, w here sta n dar d t esti n g has bee n i m ple me nte d 
t o scree n f or p ote ntial A E SI (e g, electr ocar di o gra ms, s pir o m etr y, s er u m tra nsa mi nases, etc.), t he rele va nt data will 
be re vie we d t o i de ntif y p ote ntial cases of A E SI t hat i n vesti gat ors m a y n ot ha ve i de ntifie d a n d t o pr o vi de q ua ntitati ve 
data f or A E SIs. T he pr o p ose d ca n di dat e ter ms will be re vi e we d t o i de ntif y w hic h e ve nts refl ect A E SI.  
Treat m e nt-e m er ge nt A E SIs will be s u m m arize d b y cate g or y, s u bcat e g or y, a n d P T b y des ce n di n g fre q ue nc y b y 
treat m e nt gr o u p. C ate g ori es a n d s u bcat e g ories of T E A Es of s peci al i nterest are t he f oll o wi n g:
C ar di o vas c ul ar E ve nts
o
Bra d ycar dia
o
A V c o n d ucti o n dela y
o
H y pert e nsi o n
Mac ul ar E de m a
P ul m o nar y Dis or ders
o
Airfl o w o bstr ucti o n (f orce d e x pirat or y v ol u m e i n 1 s ec o n d [ F E V 1], f orce d vital ca pacit y [ F V C])
o
Decre ase gas e xc ha n g e ( diff usi n g ca pacit y of t he l u n gs f or car b o n m o n o xi de [ D L C O])
I nfecti o ns
o
S e vere i nfecti o ns
o
O p p ort u nisti c i nfecti o ns ( Narr o w) 
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 4 3 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
o
Her pes si m pl e x a n d her pes z oster
Li ver I nj ur y
o
Li ver tra nsa mi nases el e vati o n
o
Bilir u bi n ele vati o n
P ost eri or R e versi ble E nce p hal o pat h y S y n dr o me ( P R E S)
Mali g na nci es
1 8. 1. 6.
O v er all S u m m a r y of A d v erse E v e nt
I n a d diti o n t o t he s u m m ari es a b o ve, a n o ver vi e w of T E A Es will be s u m m arize d ( n ot br o ke n d o w n b y S O C or P T) b y 
n u m ber a n d perce nt a ge of partici pa nts a n d b y n u m ber of A Es:
A n y T E A Es
A n y rel ate d T E A Es *
A n y s eri o us T E A Es
A n y rel ate d s eri o us T E A Es *
T E A Es lea di n g t o deat h
o
Li ver rel ate d T E A Es l ea di n g t o deat h
T E A Es lea di n g t o st u d y treat me nt dis c o nti n uati o n
o
R elat e d T E A Es l ea di n g t o st u d y treat me nt disc o nti n uati o n *
o
Li ver rel ate d T E A Es l ea di n g t o st u d y treat me nt disc o nti n uati o n
T E A Es lea di n g t o st u d y treat me nt i nterr u pti o n (e ve nts rec or de d wit h a n acti o n ta ke n wit h st u d y treat m e nt as 
)
o
R elat e d T E A Es l ea di n g t o st u d y treat me nt i nt err u pti o n *
T E A Es b y ma xi m u m s e verit y
R elat e d T E A Es b y m a xi m u m se verit y *
T E A Es b y m a xi m u m relati o ns hi p t o st u d y treat me nt
rel at e d or pr o ba bl y relat e d
t o st u d y treat m e nt or ar e missi n g rel ati o ns hi p.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 4 4 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
1 8. 2.
De at hs
I nf or m ati o n c oll ecte d a b o ut deat hs (e g, dat e of deat h, pri mar y ca use of deat h) will be pres e nt e d i n a dat a listi n g, as 
descri be d i n S ecti o n 1 8. 1. 4.
1 8. 3.
L a b o r at o r y E v al u ati o ns
N o l ocal l a b orat or y assess m e nts will be use d i n a n y s u m mari es e xce pt f or li pi d pa nel a n d t h yr oi d pa nel t ests. N o 
l ocal la b orat or y assess me nts will be us e d t o deri ve ma xi m u m/ mi ni m u m/ w orst val ue. L ocal la b orat or y assess m e nts 
will be liste d.
1 8. 3. 1.
S afet y L a b o r at or y E v al u ati o ns
He m at ol o g y, ser u m c he mistr y, c oa g ulati o n, a n d uri nal ysis are a nal ys e d a n d re p orte d b y ce ntral l a b orat or y a n d 
s o m eti mes b y l ocal la b orat or y. R es ults o ut of refere n ce ra n g e are fl a g ge d b y t he perf or mi n g l a b orat or y ( e g, l o w, 
hi g h). A f ull list of la b orat or y assess me nts t o be i ncl u de d i n t he o ut p uts is i ncl u de d i n Cli nical St u d y Pr ot oc ol 
A P D 3 3 4- 2 0 3 Ta ble 6. 
I n ge neral, pres e ntati o ns will use 
SI u nits). Q ua ntitati ve la b orat or y m eas ure me nts 
q ua ntit ati o n
( U L Q), res pecti vel y, will be c o n vert e d t o X f or t he p ur p ose of q ua ntit ati ve s u m mari es, b ut will be prese nt e d as 
q ua ntit ati ve t ests. If l ocal a n d ce ntral l a b orat or y assess me nts are a vaila bl e fr o m t he sa m e da y, ce ntral la b orat or y 
assess me nts will be use d i n t he s u m mar y as per S ecti o n 6. 4. 
T he f oll o wi n g s u m m aries will be pr o vi de d f or la b orat or y data:
Val ue a n d c ha n ge fr o m B aseli ne b y visit (f or he mat ol o g y, ser u m c he mistr y, q ua ntit ati ve uri nal ysis [ p H a n d 
s pecific gra vit y], c oa g ul ati o n, a n d hi g h-s e nsiti vit y C-reacti ve pr otei n [ hs- C R P])
I nci de nce of a b n or m al val ues ac c or di n g t o l a b orat or y refere n ce ra n ges b y visit
I nci de nce of l y m p h oc yt es < 0. 2 × 1 09/ L, 0. 5 × 1 09/ L, or ne utr o p hils < 0. 5 × 1 09/ L, 1 × 1 09/ L at e n d of treat m e nt 
a n d a n yti me i n t he st u d y
S hift fr o m e n d of treat m e nt t o eac h f oll o w- u p visit i n i nci de nce of l y m p h oc yt es i n n or mal ra n ge a n d i n 
i nci de nce of l y m p h oc ytes of at l east 8 0 % perce nt of B aseli ne, b y visit ( 2- Wee k F oll o w- U p, 4- Wee k F oll o w- U p, 
a n d Last F oll o w- U p)
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 4 5 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S hift fr o m B aseli ne t o e n d of treat m e nt acc or di n g t o l a b orat or y refere nce r a n ge (f or q u a ntitati ve meas ure m e nts 
a n d cate g ori cal m eas ure me nts)
E val uati o n of dr u g-i n d uce d seri o us he pat ot o xi cit y (e DI S H) pl ots f or t he f oll o wi n g la b orat or y assess me nts
( usi n g val ues after t he first a d mi nistrati o n of st u d y tr eat m e nt):
o
Ma xi m u m as part at e a mi n otra nsferase ( A S T) vers us sa me- da y t otal bilir u bi n
o
Ma xi m u m ala ni ne a mi n otra nsferase ( A L T) vers us sa m e- da y t ot al bilir u bi n
o
Ma xi m u m ga m ma- gl uta m yl tra nsferase ( G G T) vers us sa m e- da y t ot al bilir u bi n
o
Ma xi m u m al kali ne p h os p hatase ( A L P) vers us sa me- da y t otal bilir u bi n
T he e DI S H pl ots a b o ve will be re peate d wit h a dj ust m e nt f or el e vat e d baseli ne.
I nci de nce of he patic e n z y m e ele vati o ns b y visit
o
> 1 ×, 2 ×, 3 ×, 5 ×, 8 ×, 1 0 ×, 2 0 × u p per li mit of n or mal ( U L N) ele vati o n i n A L T
o
> 1 ×, 2 ×, 3 ×, 5 ×, 8 ×, 1 0 ×, 2 0 × U L N el e vati o n i n A S T
o
> 3 ×, 5 ×, 1 0 ×, 2 0 × U L N el e vati o n i n eit her A L T or A S T
o
> 1 ×, 1. 5 ×, 2 ×, 3 × U L N el e vati o n i n t ot al bilir u bi n
o
> 1 ×, 1. 5 ×, 2 ×, 3 ×, 5 ×, 8 × U L N ele vati o n i n A L P
o
> 1 ×, 2 ×, 3 ×, 5 ×, 8 × U L N el e vati o n i n G G T
o
> 3 × U L N ele vati o n i n eit her A L T or A S T a n d > 1. 5 × U L N ele vati o n i n t ot al bilir u bi n 
o
> 3 × U L N ele vati o n i n eit her A L T or A S T a n d > 2 × U L N ele vati o n i n t otal bilir u bi n 
o
> 3 × U L N ele vati o n i n eit her A L T or A S T a n d > 1. 5 × U L N ele vati o n i n A L P
o
> 3 × U L N ele vati o n i n eit her A L T or A S T i n t e m p oral ass ociati o n wit h treat m e nt-e m er ge nt 
na usea, v o miti n g, a n ore xi a, a b d o mi nal pai n, or fati g ue i de ntifi e d b y P T, w here t e m p oral 
ass oci ati o n is defi ne d as ± 1 4 da ys of o nset dat e fr o m t he ti m e of ele vati o n.
If b ot h ce ntral a n d l ocal assess m e nts of t ot al bilir u bi n are a vaila bl e o n t he sa m e da y, t he ce ntral res ult will t a ke 
prece de n ce o ver t he l ocal res ult i n t he e DI S H pl ot. If t he ma xi m u m A S T, A L T, G G T, or A L P assess m e nt occ urs at 
2 differe nt dat es, t he ass ess m e nt wit h t he hi g her acc o m pa n yi n g Bilir u bi n val ue will be use d. T w o versi o ns of t he 
e DI S H pl ots will be prese nt e d, wit h o ne s h o wi n g val ues as m ulti pl es of U L N, a n d t he ot her o ne s h o wi n g val ues as 
m ulti ples of U L N
All la b orat or y tests will be list e d.
or der. Val ues o utsi de of t he l a b orat or y refere n ce r a n ge will be fl a g ge d. Val ues o bt ai ne d fr o m l ocal la b orat or y will 
be fl a g ge d. Listi n g of l y m p h oc ytes a n d ne utr o p hils o ver ti m e i n parti ci pa nts w h o e ver ha d l y m p h oc yt es < 0. 5 ×
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 4 6 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
1 0 9/ L or ne utr o p hils < 1 × 1 09/ L will als o be pr o vi de d.
1 8. 3. 2.
Pre g n a nc y Tests
Uri ne beta-
-
- h C G pre g na nc y t ests are perf or m e d t hr o u g h o ut 
t he st u d y i n fe mal e parti ci pa nts of c hil d beari n g p ot e nti al. All pre g na nc y test res ults ( p ositi ve or ne gati ve) will be 
list e d i n c hr o n ol o gi cal or der.
1 8. 3. 3.
Ot her Scre e ni n g L a b o r at o r y Assess me nts
S cree ni n g l a b orat or y assess me nts f or vir ol o g y, dr u g scree n/t o xic ol o g y, Q ua nti F E R O N T u berc ul osis ( T B) G ol d, 
st o ol pat h o ge ns, a n d Cl ostri di oi des diffi cil e (f or m erl y k n o w n as Cl ostri di u m difficile) will be list e d. A nal yses of 
e x pl orat or y effi cac y-rel ate d bi o mar kers dat a bas e d o n s a m pl es c oll ecte d at Scree ni n g i n parti ci pa nts w h o pr o vi de d 
c o nse nt will be des cri be d i n a se parate pl a n.
1 8. 4.
E C G E v al u ati o ns
Electr ocar di o gra ms ( E C G) are r ec or de d o n a 1 2-le a d E C G mac hi ne a n d rea d ce ntr all y. T he f oll o wi n g E C G 
para met ers will be re p ort e d f or t his st u d y:
H R ( beats per mi n ut e [ b p m])
P R i nt er val ( ms)
R R i nter val ( ms)
Q R S i nt er val ( ms)
Q T i nter val ( ms)
Q Tc F i nter val ( ms) 
O verall i nt er preta
o
N or mal
o
A b n or mal, N ot Cli ni call y Si g nifica nt ( A b n or m al n ot cli ni call y si g nifica nt [ N C S])
o
A b n or mal, Cli ni call y Si g nifi ca nt ( A b n or mal C S)
O verall i nt er pretati o n of E C G (ce ntral rea der):
o
N or mal
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 4 7 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
o
A b n or mal N C S
o
A b n or mal C S
A V c o n d ucti o n a b n or maliti es
o
First de gree A V bl oc k
o
S ec o n d de gree A V bl oc k t y pe 1
o
S ec o n d de gree A V bl oc k t y pe 2 
o
T hir d- de gree A V bl oc k 
T he f oll o wi n g s u m m aries will be pr o vi de d f or E C G dat a:
Val ue a n d c ha n ge fr o m B aseli ne b y visit (f or q ua ntit ati ve m eas ure me nts)
I nci de nce of m ar ke dl y a b n or m al val ues ( defi ne d i n S ecti o n 1 8. 4. 1) a n d A V bl oc ks b y visit
S hift i n n or mal/a b n or m al N C S/ a b n or mal C S i n t he o verall i nt er pretati o n ( b y i n vesti gat or) fr o m B aseli ne t o e n d 
of treat m e nt a n d t o t he w orst-cas e p ost- Bas eli ne
S hift i n mar ke dl y a b n or mal cat e g ories fr o m B aseli ne t o p ost- Bas eli ne b y visit
Listi n gs of E C G res ults, i ncl u di n g first d os e car di ac m o nit ori n g, a n d disc har ge crit eri a f or first d ose car di ac 
m o nit ori n g will be pr o vi de d. 
A listi n g of all E C G assess me nts o ver ti me i n parti ci pa nts meeti n g mar ke dl y a b n or mal crit eria will als o be pr o vi de d. 
F or eac h s u bj ect, o nl y E C G para m eters e ver meeti n g mar ke dl y a b n or mal crit eri a will be i ncl u de d.
1 8. 4. 1.
E C G M a r ke dl y A b n o r m al Criteri a
Mar ke dl y a b n or mal q ua ntitati ve E C G meas ure m e nts will be i de ntifi e d i n acc or da nce wit h t he f oll o wi n g pre defi ne d 
m ar ke dl y a b n or m al criteri a:
A bs ol ut e val ues i n Q T a n d Q Tc F:
o
4 5 0 ms ( m al e) or 
4 7 0 ms (fe m al e) i n Q Tc F
o
> 5 0 0 ms i n Q T
C ha n ge fr o m B aseli ne i n Q T a n d Q Tc F:
o
> 3 0 ms i ncrease fr o m B aseli ne
o
> 6 0 ms i ncrease fr o m B as eli ne
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 4 8 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
I n s hift ta bl es, partici pa nts will be classifi e d acc or di n g t o t he bi nar y cate g or y f or eac h para m et er a n d t he pre defi ne d 
m ar ke dl y a b n or m al criteri o n (ie, M ar ke dl y a b n or mal vers us N ot m ar ke dl y a b n or m al, wit h Mar ke dl y a b n or mal 
defi ne d i n t he f o ot n ot e).
1 8. 5.
Vit al Si g ns
T he f oll o wi n g vital si g ns m eas ure me nts will be re p orte d f or t his st u d y:
S yst oli c Bl o o d Press ure ( m m H g)
Di ast oli c Bl o o d Press ure ( m m H g)
Heart R ate ( b p m)
R es pirat or y R at e (res p/ mi n)
Te m perat ure (° C)
Wei g ht ( k g)
Hei g ht (c m) ( S cree ni n g o nl y)
T he f oll o wi n g s u m m aries will be pr o vi de d f or vit al si g ns data:
Val ue a n d c ha n ge fr o m B aseli ne b y visit 
Val ue a n d c ha n ge fr o m pre d ose o n Da y 1 (as r e p ort e d o n t he e C R F) b y ti me p oi nt 
o
Val ue a n d c ha n ge fr o m pre d ose t o mi ni m u m p ost d ose heart rat e o n Da y 1 will be i ncl u de d i n t he 
sa m e ta bl e
I nci de nce of m ar ke dl y a b n or m al val ues ( defi ne d i n Ta ble 4) b y visit
Listi n g of partici pa nts meeti n g mar ke dl y a b n or mal crit eria 
I nci de nce of mi ni m u m heart rate o n Da y 1 b y p ost d ose ti me p oi nt ( 1, 2, 3, 4, a n d > 4 h o urs p ost d ose, a n d Da y 1 
o verall) a n
6 5, 6 0 t o 6 4, 5 5 t o 5 9, 5 0 t o 5 4, 4 5 t o 4 9, 4 0 t o 4 4, < 4 0 b p m)
o
If mi ni m u m heart rat e is attai ne d at m ulti ple p ost d os e ti m e p oi nts, o nl y t he earli est ti m e p oi nt will 
be c o u nte d i n t his i nci de nce s u m m ar y.
Ti m e t o mi ni m u m heart rate o n Da y 1 b y pl a n ne d h o url y ti me p oi nt (if mi ni m u m heart rate is att ai ne d at 
m ulti ple p ost d ose ti me p oi nts, o nl y t he earliest ti me p oi nt will be c o u nt e d). 
o
Act ual ti m e ela pse d fr o m first d ose t o mi ni m u m heart rat e o n Da y 1 will als o be s u m marize d usi n g 
descri pti ve st atistics ( n, mea n, S D, me di a n, mi ni m u m, a n d m a xi m u m) i n t he s a me t a bl e.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 4 9 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
Li ne pl ots f or mea n val ue a n d m ea n c ha n ge fr o m pre d ose o n Da y 1, u p t o 4 h o urs p ost d ose b y para met er a n d 
ti m e p oi nt (s yst oli c bl o o d press ure, diast oli c bl o o d press ure, a n d heart r at e)
Li ne pl ots f or mea n val ue a n d m ea n c ha n ge fr o m B aseli ne b y para met er a n d visit (s yst olic bl o o d press ure, 
di ast olic bl o o d press ure, heart rate)
Listi n gs of all vital si g ns, i ncl u di n g first d ose car diac m o nit ori n g, a n d disc har ge criteri a f or first d ose car di ac 
m o nit ori n g will be pr o vi de d. A listi n g of vital si g ns assess me nts o ver ti me i n parti ci pa nts meeti n g a mar ke dl y 
a b n or m al criteri o n will als o be pr o vi de d. F or eac h s u bject, o nl y t he para m eters wit h at l east o ne mar ke dl y a b n or mal 
criteri o n satisfie d will be i ncl u de d. 
F or partici pa nts wit h e xte n de d m o nit ori n g or re- m o nit ori n g, a listi n g of s yst olic bl o o d press ure, diast oli c bl o o d 
press ure, heart rat e v al ues, a n d c ha n ge fr o m pre d ose i n all para met ers o n Da y 1, Da y 2, a n d a n y re- m o nit ori n g visit
will be pr o vi de d.
1 8. 5. 1.
Vit al Si g ns S pe cific De ri v ati o ns
Te m perat ure (° C) = ( 5/ 9) ( Te m perat ur e (° F) 
3 2)
1 8. 5. 2.
Vit al Si g ns M a r k e dl y A b n o r m al Crite ri a
Mar ke dl y a b n or mal q ua ntitati ve Vital Si g ns meas ure m e nts will be i de ntifi e d i n acc or da nce wit h t he f oll o wi n g 
pre defi n e d mar ke dl y a b n or mal crit eria:
T a bl e 4:
M a r ke dl y A b n or m al Crite ri a f or Vit al Si g ns
V ari a bl e
U nit
L o w
Hi g h
S B P
m m H g
> 1 5 0 m m H g
D B P
m m H g
> 9 0 m m H g
Heart rate
b p m
< 4 0 b p m
< 5 0 b p m
< 5 0 b p m a n d decrease fr o m pre d ose ( B aseli ne) of > 1 0 b p m 
at 4 h o urs o n Da y 1 or Da y 2 or re m o nit ori n g visit
> 1 0 0 b p m 
b p m, beats per mi n ute; D B P, diast oli c bl o o d press ure; S B P, s yst olic bl o o d press ure. 
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 5 0 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
1 8. 6.
P h ysic al E x a mi n ati o n
A listi n g of all p h ysical e xa mi nati o n assess m e nts i n partici pa nts w h o ha d at l east 1 a b n or mal p h ysical e xa mi nati o n 
fi n di n g will be pr o vi de d.
1 8. 7.
Ot h er S afet y Assess me nts
1 8. 7. 1.
P ul m o n a r y F u ncti o n Test
T he f oll o wi n g p ul m o nar y f u ncti o n test ( P F T) meas ure m e nts (act ual a n d % Pre dict e d) will be re p ort e d f or t his st u d y:
F orce d E x pirat or y V ol u m e at 1 sec o n d ( F E V 1)
F orce d Vit al C a pacit y ( F V C)
T otal L u n g C a pacit y ( T L C) 
F E V 1/ F V C
F orce d E x pirat or y Fl o w ( F E F) 2 5- 7 5
Diff usi n g C a pacit y of t he L u n gs f or C ar b o n M o n o xi de ( D L C O) (if a vaila bl e)
T he f oll o wi n g s u m m aries will be pr o vi de d f or P F T dat a: 
Val ue a n d c ha n ge fr o m B aseli ne b y visit
I nci de nce of m ar ke dl y a b n or m al val ues b y visit ( S ecti o n 1 8. 7. 1. 1)
All P F T data will be list e d. A listi n g i n partici pa nts w h o e ver re p ort e d a n a b n or malit y i n P F T will als o be pr o vi de d, 
i ncl u di n g a fla g f or w het her m ar ke dl y a b n or m al criteri o n is als o met.
1 8. 7. 1. 1.
P F T M A R K E D L Y A B N O R M A L A N D P O T E N TI A L L Y IM P O R T A N T C RI T E RI A
Mar ke dl y a b n or mal q ua ntitati ve P F T meas ure m e nts will be i de ntifie d i n acc or da nce wit h t he f oll o wi n g pre defi ne d 
m ar ke dl y a b n or m al criteri a:
% Pre di cte d F E V
1 < 5 0 %
% Pre di cte d F V C < 5 0 %
% Pre di cte d F E V
1/ F V C rati o < 5 0 %
P ot e nti all y i m p orta nt P F T m eas ure me nts will als o be i de ntifi e d usi n g t he crit eria bel o w:
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 5 1 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
Decre ase fr o m Bas eli ne > 2 0 % i n F E V 1, i e, perce nt c ha n ge fr o m Bas eli ne < - 2 0 % 
Decre ase fr o m Bas eli ne > 2 0 % i n F V C, i e, perce nt c ha n ge fr o m B aseli ne < - 2 0 %
Decre ase fr o m Bas eli ne > 2 0 % i n D L C O, i e, perce nt c ha n ge fr o m B aseli ne < - 2 0 %
1 8. 7. 2.
O p ht h al m os c o p y a n d O ptic al C o her e nce T o m o g r a p h y
T he f oll o wi n g s u m m aries will be pr o vi de d f or o p ht hal m osc o p y a n d o ptical c o here nce t o m o gra p h y ( O C T) dat a:
Val ues a n d c ha n ge fr o m B aseli ne i n i ntra oc ular press ure b y visit
C ate g ori cal res ult i n o p ht hal m osc o p y wit h O C T para m eters b y visit (t he cat e g ories are liste d o n t he
O p ht hal m osc o p y wit h O C T e C R F)
A listi n g of all o p ht hal m os c o p y a n d O C T assess me nts will be pr o vi de d. A listi n g of parti ci pa nts w h o e ver re p orte d 
a n a b n or malit y i n O C T will als o be pr o vi de d. A d diti o nall y, a listi n g of reti nal p h ot o gra p h a n d e ye press ure 
assess me nts will be pr o vi de d f or parti ci pa nts w h o e x peri e nce d a n A E rel ate d t o e ye dis or ders.
1 8. 7. 3.
T u ber c ul osis Scre e ni n g a n d C hest X- R a y
S cree ni n g t u berc ul osis res ults a n d c hest X-ra ys will be list e d. R es ults of t u berc ul osis q uesti o n naires will als o be 
list e d.
1 9.
P H A R M A C O KI N E TI C A N A L Y SI S
Pl as ma c o nce ntrati o ns of etrasi m o d will be ass esse d fr o m sa m ples c oll ect e d pri or t o d osi n g a n d 4 h o urs 
( ± 1 5 mi n utes) p ost- d os e (after 1 2-l ea d E C G) o n Wee k 0/ Da y 1, sa m ples c oll ect e d pri or t o d osi n g (tr o u g h; wit hi n 
6 0 mi n ut es pri or t o d osi n g) at Wee ks 2, 4, 8, a n d 1 2. A d diti o nall y, s a m ples are bei n g c ollecte d at 2- Wee k a n d 4-
Wee k S afet y F oll o w- u p visits (f or s u bjects n ot e nr olli n g i nt o t he O L E st u d y), a n d if p ossi ble, at t he ti me of a n y S A E 
or a d verse e ve nt l ea di n g t o st u d y treat me nt disc o nti n uati o n are bei n g c oll ect e d. C o nce ntrati o ns bel o w t he li mit of 
q ua ntifi cati o n ( B L Q) will be assi g n e d a n u m erical val ue of zer o f or t he cal c ulati o n of des cri pti ve statistics i n 
c o nce ntrati o ns (e xce pt f or ge o m etri c mea n a n d ge o metric % C V) a n d pl otti n g of c o nce ntrati o ns. F or ge o metric m ea n 
a n d ge o metric % C V, t he zer o val ues will be e xcl u de d.
T he p har mac o ki neti cist will deter mi ne t he strat e g y f or deali n g wit h dat a affecte d b y pr ot oc ol de viati o ns or e ve nts 
w hi c h ma y i m pact t he q ualit y of P K c o nce ntrati o n data o n a case- b y-case basis wit h i n p ut fr o m t he Pfi zer st u d y 
p h ysi cia n a n d Pfi zer cli nical p har mac ol o gist, as nee de d. E xa m pl es f or pr ot oc ol de vi ati o ns or e ve nts i ncl u de, b ut 
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 5 2 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
m a y n ot be li mite d t o, v o miti n g o n t he da y pri or t o tr o u g h sa m ple c oll ecti o n, s a m pl e pr ocessi n g err ors t hat l ea d t o 
i nacc urat e bi oa nal yti cal res ults, a n d/ or i nacc urat e d osi n g pri or t o P K s a m pli n g. I n t he case of a n i m p ort a nt pr ot oc ol 
de viati o n or e ve nt, t he affect e d P K dat a c ollect e d ma y be e xcl u de d fr o m t he s u m m aries, cal c ul ati o n of t he a vera ge 
st ea d y stat e tr o u g h pl as m a c o nce ntrati o n ( Ctr ou gh) base d o n a vaila bl e Wee k 2 t o Wee k 1 2 tr o u g h c o nce ntrati o ns 
( Ctr ou gh,ss, W 2- W 1 2), e x p os ure-res p o nse a nal ysis, a n d/ or p o p ul ati o n P K a nal ysis, b ut will still be re p ort e d i n t he st u d y 
res ult listi n gs.  T he ti m e wi n d o w of 2 4 h o urs ± 8 h o urs after t he last d ose pri or t o P K sa m ple is re q uire d f or i ncl usi o n 
i n cal c ulati n g Ctr ou gh,ss, W 2- W 1 2 a n d s u m m arizi n g tr o u g h.
U nl ess ot her wise s pecifie d, P K s u m m aries will use t he P har mac o ki netic Set. E x p os ure-res p o ns e a nal ysis will use 
t he S afet y S et.
I n di vi d ual s u bj ect etrasi m o d pl as ma c o nce ntrati o ns will be prese nt e d i n t he data listi n gs, i ncl u di n g s u bj ect I D, 
treat m e nt recei ve d, se x, a ge, wei g ht, n o mi nal ti me p oi nt, act ual bl o o d c oll ecti o n dat e/ti m e, c o nce ntrati o n, a n d ti m e 
si nce last d ose, a n d als o s u m mari ze d usi n g des cri pti ve statistics ( n, mea n, S D, % C V, ge o metric m ea n, ge o metri c % 
C V, m e dia n, mi ni m u m, a n d ma xi m u m) b y n o mi nal ti me p oi nt a n d treat me nt. S u m mar y t a ble will be re peat e d b y: 
, T o bacc o us e ( Yes/ N o), a n d w
Me di a n).
All s u bjects are e x pect e d t o ac hi e ve stea d y-stat e pl as m a c o nce ntrati o n b y Wee k 2. F or eac h s u bj ect, t he a vera ge 
st ea d y stat e tr o u g h ( pre- d ose) pl as ma c o nce ntrati o n ( C tr ou gh) base d o n Wee k 2 t o Wee k 1 2 tr o u g h c o nce ntrati o ns 
( Ctr ou gh,ss, W 2- W 1 2) per s u bj ect will als o be cal c ulat e d a n d pres e nt e d i n a dat a listi n g a n d s u m mari ze d usi n g descri pti ve 
st atistics b y treat me nt. 
Mea n ( ± S D) etrasi m o d c o nce ntrati o n vers us n o mi nal ti m e will be pl otte d b y treat m e nt o n li near scale. S u m mar y 
fi g ure will be re peat e d b y: S e x ( mal e/fe male), a ge at c o
, T o bacc o us e ( Yes/ N o), a n d 
w
.
B o x pl ots of etrasi m o d c o nce ntrati o ns at Da y 1, 4 h o ur p ost- d os e ti me p oi nt ( C 4 hr) a n d a vera ge stea d y-st ate C tr ou gh 
( Wee ks 2 t hr o u g h 1 2 [ Ctr ou g h,ss, W 2- W 1 2]) will be pl ott e d vers us n o mi nal ti me p oi nt o n or di nal scal e, se par at el y b y 
treat m e nt. B o x pl ots f
, T o bacc o 
use ( Yes/ N o), a n d w
.
I n di vi d ual s u bj ect pl as m a c o nce ntrati o ns vers us act ual ti me will be pl otte d si nce st art of treat me nt o n li near s cal e. 
S catt er pl ots of i n di vi d ual s u bject a vera ge st ea d y-st ate C tr ou gh ss, W 2- W 1 2 vers us Bas eli ne b o d y wei g ht a n d vers us 
B aseli ne a ge as c o nti n u o us vari a bles will be ge nerat e d b y treat me nt f or t he P har mac o ki netic S et, w hic h will als o 
i ncl u de t he S pear m a n's ra n k c orrelati o n c oeffi cie nt, p- val ue, a n d L O E S S tre n d li ne.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 5 3 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
T o e x pl ore p ot e nti al etrasi m o d plas m a e x p os ure-res p o ns e rel ati o ns hi ps, t he f oll o wi n g scatter pl ots will be ge nerate d 
t he pl ace b o s u bjects will be a n n otat e d wit h a differe nt c ol or or s y m b ol. All scatt er pl ots will i ncl u de t he S pear m a n's 
ra n k c orrel ati o n c oeffi cie nt, p- val ue, a n d L O E S S tre n d li ne ( base d o n s ubj ects t hat recei ve d acti ve treat m e nt o nl y).
I n di vi d ual s u bj ect a bs ol ut e c ha n ge fr o m Baseli ne i n M M S vers us etrasi m o d st ea d y st ate Ctro u gh at 
t he c o m m o n visit w here b ot h M M S a n d Ctr ou gh are meas ure d ( Wee k 1 2). Fi g ure will be re pe at e d 
, T o bacc o us e ( Yes/ N o), a n d w
Me di a n or > Me di a n).
I n di vi d ual s u bj ect a bs ol ut e c ha n ge fr o m Baseli ne i n M M S vers us a vera ge st ea d y-stat e Ctr ou gh ss, W 2-
W 1 2 . 
, T o bacc o 
use ( Yes/ N o), a n d w
.
I n di vi d ual s u bj ect l y m p h oc yt es vers us etrasi m o d st ea d y-st ate Ctr ou gh b y Visit ( Wee k 2 t o Wee k 
1 2). 
.
I n di vi d ual s u bj ect a bs ol ut e c ha n ges fr o m B aseli ne i n l y m p h oc yt es vers us etrasi m o d st ea d y-st ate 
C tr ou gh b y Visit ( Wee k 2 t o Wee k 1 2). Fi g ure will be re peat e d b y: S e x ( mal e/fe m al e), a n d a ge at 
.
I n di vi d ual s u bj ect perce nt c ha n ges fr o m B aseli ne i n l y m p h oc ytes vers us etrasi m o d st ea d y-st ate 
C tr ou gh b y Visit ( Wee k 2 t o Wee k 1 2). Fi g ure will be re peat e d b y: S e x ( male/fe mal e), a n d a ge at 
.
F urt her m ore, t he f oll o wi n g o verl a y pl ots will be ge nerat e d i n t he P har m ac o ki neti c S et wit hi n t he etrasi m o d gr o u p 
o nl y:
Mea n ( S D) a bs ol ute l y m p h oc ytes a n d mea n ( S D) etrasi m o d c o nce ntrati o n vers us n o mi nal ti me p oi nt ( Wee ks 0
t hr o u g h 1 2). T his f
.
Mea n ( S D) a bs ol ute c ha n ge fr o m B aseli ne i n l y m p h oc yt es a n d mea n ( S D) etrasi m o d c o nce ntrati o n vers us 
n o mi nal ti m e p oi nt ( Wee ks 0 t hr o u g h 1 2). T his fi g ure will be re peate d b y: S e x ( mal e/fe male), a n d a ge at c o nse nt 
.
Mea n ( S D) perce nt c ha n ge fr o m B aseli ne i n l y m p h oc ytes a n d m ea n ( S D) etrasi m o d c o nce ntrati o n vers us 
n o mi nal ti m e p oi nt ( Wee ks 0 t hr o u g h 1 2). T his fi g ure will be re peate d b y: S e x ( m al e/fe m ale), a n d a ge at c o ns e nt 
.
Mea n ( S D) heart rat e a n d mea n ( S D) etrasi m o d c o nce ntrati o n vers us n o mi nal ti m e p oi nt ( Wee ks 0 t hr o u g h 1 2). 
T his fi g ure will be re peat e d b y: S e x ( m ale/fe male), a n d a ge at c o nse nt ( < 1 8, 1 8 t o < 6
.
Mea n ( S D) a bs ol ute c ha n ge fr o m B aseli ne i n heart rat e a n d m ea n ( S D) etrasi m o d c o nce ntrati o n vers us n o mi nal 
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 5 4 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
ti m e p oi nt ( Wee ks 0 t hr o u g h 1 2). T his fi g ure will be re peate d b y: S e x ( mal e/fe m ale), a n d a ge at c o nse nt ( < 1 8, 1 8 
).
2 0.
D A T A N O T S U M M A RI Z E D O R P R E S E N T E D
T he ot her vari a bles a n d/ or d o mai ns n ot s u m mari ze d are:
C o m m e nts
T hese d o mai ns a n d/ or varia bl es will n ot be s u m mari ze d b ut will be a vail a bl e i n t he cli nical st u d y data base a n d 
St u d y Dat a Ta b ul ati o n M o del ( S D T M) dat as ets.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 5 5 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
2 1.
R E F E R E N C E S 
C a o D, He X. St atistical a nal ysis of a d verse e ve nts i n ra n d o mize d cli nical tri als usi n g S A S. C a o D, He X. Statistical 
a nal ysis of a d vers e e ve nts i n ra n d o mi ze d cli nical tri als usi n g S A S. P har m a S U G C o nfere nce Pr ocee di n gs; 2 0 1 1. 
F D A. M ulti pl e e n d p oi nts i n cli ni cal tri als. U. S. De part m e nt of Healt h a n d H u ma n Ser vices, F o o d a n d Dr u g 
A d mi nistrati o n. G ui da nce f or I n d ustr y We b sit e. htt ps:// w w w.f da. g o v/ me di a/ 10 2 6 5 7/ d o w nl oa d. P u blis he d 2 0 1 7. 
Access e d F e br uar y 1 9, 2 0 2 1.
F D A. F D A g ui da nce o n c o n d uct of cli ni cal tri als of me di cal pr o d ucts d uri n g C O VI D- 1 9 p u bli c healt h e m er ge nc y. 
U. S. De part m e nt of Healt h a n d H u m a n Ser vices, F o o d a n d Dr u g A d mi nistrati o n. G ui da nce f or I n d ustr y, 
I n vesti gat ors, a n d I nstit uti o nal Re vi e w B oar ds
We b sit e. htt ps:// w w w.f da. g o v/ m e dia/ 1 3 6 2 3 8/ d o w nl oa d. P u blis he d 
2 0 2 0. Access e d J ul y 8, 2 0 2 0.
I C H. Str uct ure a n d c o nt e nt of cli nical st u d y re p orts, E 3. I nt er nati o nal C o nfere nce o n Har m o nisati o n of Tec h nical 
R e q uire m e nts f or R e gistrati o n of P har mace uti cals f or H u ma n Us e. 
htt ps:// dat a base.ic h. or g/sites/ defa ult/files/ E 3 _ G ui deli ne. p df. P u blis he d 1 9 9 5. Access e d M arc h 1 0, 2 0 2 1.
I C H. Statistical pri nci pl es f or cli nical tri als, E 9. I nt er nati o nal C o u ncil f or Har m o nisati o n of Tec h ni cal R e q uire m e nts 
f or R e gistrati o n of P har m ace uti cals f or H u ma n Use. htt ps:// dat a base.ic h. or g/sites/ defa ult/files/ E 9 _ G ui deli ne. p df. 
P u blis he d 1 9 9 8. Accesse d M arc h 1 9, 2 0 2 1.
I C H. Str uct ure a n d c o nt e nt of cli nical st u d y re p orts q uesti o ns & a ns wers ( R 1). 
htt ps:// dat a base.ic h. or g/sites/ defa ult/files/ E 3 _ Q % 2 6 As _ R 1 _ Q % 2 6 As. p df. P u blis he d 2 0 1 2. Accesse d Dec 1 4, 2 0 2 1.
I C H. A d de n d u m o n esti m a n ds a n d se nsiti vit y a nal ysis i n cli nical tri als t o t he g ui deli ne o n statistical pri nci ples f or 
cli ni cal trials, E 9( R 1). I nter nati o nal C o u ncil f or Har m o nis ati o n of Tec h ni cal R e q uire m e nts f or R e gistrati o n of 
P har m ace uticals f or H u ma n Use. htt ps:// dat a base.ic h. or g/sites/ defa ult/files/ E 9- R 1 _ St e p 4 _ G ui deli ne _ 2 0 1 9 _ 1 2 0 3. p df. 
P u blis he d 2 0 1 9. Accesse d M arc h 1 9, 2 0 2 1.
R u bi n D B. M ulti pl e i m p ut ati o n f or n o nr es p o nse i n s ur veys.
Ne w Y or k, N Y: J o h n Wil e y a n d S o ns; 1 9 8 7. O n fil e at 
Are na.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 5 6 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
A P P E N DI X 1.
P R O G R A M MI N G C O N V E N TI O N S F O R O U T P U T S
I Q VI A O ut p ut C o n v e nti o ns
O ut p uts will be pres e nt e d as s h o w n i n t he O ut p ut s hells.
Deci m als, Perce nt a g es a n d CI
If t he ori gi nal dat a has N deci mal places, t he n t he s u m m ar y statistics s h o ul d ha ve t he f oll o wi n g deci mal places:
o
Mi ni m u m a n d ma xi m u m: N
o
Mea n (a n d L S Mea ns), m e dia n: N + 1
o
S D or S E: N + 2
o
CI: 2
P erce nta ges will be re p orte d t o o ne deci mal place. W here c o u nts are zer o, perce nta ges will n ot a p pear i n t he 
o ut p ut. 
C o n v e nti o ns Rel ate d t o P h a r m a c o ki n etic D at a
All etrasi m o d c o nce ntrati o ns will be re p ort e d a n d a n al yze d wit h t he sa m e precisi o n as t he s o urce data pr o vi de d b y 
t he bi oa nal ytical la b orat or y re gar dless of h o w m a n y si g nifica nt fi g ures or deci m als t he data carr y. T he deri ve d P K 
data (etrasi m o d c o nce ntrati o n) will be r o u n de d t o carr y 3 si g nifica nt di gits a n d c o nsi dere d t he s o urce data f or t he 
calc ul ati o n of descri pti ve statistics a n d t he statistical a nal ysis s o urce dat a.
F or t he re p orti n g of descri pti ve st atistics, t he m ea n, ge o metric m ea n, m e dia n, S D, % C V, an d ge o metric % C V will 
be prese nt e d wit h 4 si g nifi ca nt di gits. T he mi ni m u m a n d ma xi m u m will be pres e nte d wit h 3 si g nifica nt di gits.
D ates & Ti mes
De pe n di n g o n data a vail a ble, dat es a n d ti mes will t a ke t he f or m D D M M M Y Y Y Y or D D M M M Y Y Y Y: h h: m m.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 5 7 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
S p elli n g F o r m at
E n glis h U S.
P rese nt ati o n of Tre at m e nt Gr o u ps
F or o ut p uts, treat m e nt gr o u ps will be re prese nt e d as f oll o ws a n d i n t he gi ve n or der:
T re at m e nt Gr o u p
F or T a bl es, G r a p hs a n d Listi n gs
Etrasi m o d T ot al a
Etrasi m o d 2 m g a n d Etrasi m o d 1 m g
Etrasi m o d 2 m g
Etrasi m o d 2 m g
Etrasi m o d 1 m g
Etrasi m o d 1 m g
Pl ace b o
Place b o
S cree n F ail ure
S cree n F ail ure
N ot Treate d a         
N ot Treate d
a T o be o nl y us e d f or A E ta bl es.
P rese nt ati o n of Visits a n d St u d y Peri o d
F or o ut p uts, visits a n d st u d y peri o ds will be re pres e nt e d as f oll o ws a n d i n t hat or der:
Visit N a m e
St u d y Peri o d 
S cree ni n g
S cree ni n g
B aseli ne, Da y 1, Da y 2, Wee k 2, Wee k 4, 
Wee k 8, Wee k 1 2
Treat m e nt
E n d of St u d y/ Earl y Ter mi nati o n
De pe n d o n A nal ysis Visit assi g ne d, des cri be d i n S ecti o n 6. 4
2- Wee k F oll o w- U p, 4- Wee k F oll o w- U p
F oll o w- U p
Listi n gs
All listi n gs will be or dere d b y t h e f oll o wi n g ( u nless ot her wise i n di cate d i n t he t e m pl ate):
R a n d o mi ze d treat me nt gr o u p ( or treat m e nt recei ve d if it is a safet y o ut p ut), first b y Etrasi m o d 2 m g, Etrasi m o d
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 5 8 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
1 m g, t he n Place b o, t he n S cree n F ail ure)
S u bj ect n u m ber ( w hi c h is e x pect e d t o i nc or p orat e st u d y sit e/ce nt er)
Dat e ( w here a p pli ca bl e)
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 5 9 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
A P P E N DI X 2.
P A R TI A L D A T E C O N V E N TI O N S
I m p ute d dat es will N O T be pres e nte d i n t he listi n gs.
I n c o m plete St a rt D ates f o r A d v erse E v e nts:
I n case t he start date of a n A E is c o m plet el y missi n g, or t he start date is i n t he sa m e year as t he date of st u d y dr u g 
a d mi nistrati o n ( w he n o nl y year is rec or de d), or t he st art dat e is i n t he sa me m o nt h a n d year (if o nl y t he da y is 
missi n g) as t he dat e of first st u d y dr u g a d mi nistrati o n, t he n t he start date of t he A E will be i m p ute d b y t he mi ni m u m 
of t he dat e of first st u d y dr u g a d mi nistrati o n a n d t he A E e n d date. I n all ot her cases t he missi n g start da y will be 
i m p ut e d b y t he 1st a n d t he missi n g start m o nt h will be re pl ace d b y Ja n uar y.
Al g o rit h m f o r Tre at m e nt E mer g e nce of A d v erse E v e nts:
A E St art D ate
A E St o p 
D ate
Acti o n
K n o w n
K n o w n, 
P artial or 
Missi n g
If A E start date < st u d y treat m e nt first d ose dat e, t he n n ot T E A E
P artial, b ut k n o w n 
c o m p o ne nts s h o w t hat 
it ca n n ot be o n or after 
date of first d ose of 
st u d y treat me nt
K n o w n, 
P artial or 
Missi n g
N ot T E A E
P artial, c o ul d be o n or 
aft er dat e of first d ose 
of st u d y treat m e nt
O R 
Missi n g
K n o w n
If A E st o p dat e < st u d y treat me nt first d os e dat e, t he n n ot T E A E
t u d y treat me nt first d ose date, t he n T E A E
P artial
I m p ute A E st o p dat e as lat est p ossi bl e dat e (i e, l ast da y of m o nt h if 
da y u n k n o w n or 3 1st Dece m ber if da y a n d m o nt h are u n k n o w n), t he n:
If A E st o p dat e < st u d y treat me nt first d ose date, t he n n ot T E A E
Missi n g
Ass u me d T E A E
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 6 0 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
Al g o rit h m f o r P ri o r / C o nc o mit a nt Me di c ati o ns:
St art D ate
St o p D ate
Acti o n
K n o w n
K n o w n
If m e di cati o n st o p date < st u d y treat m e nt first d os e dat e, assi g n as pri or 
c o nc o mita nt 
P artial
I m p ute st o p date as l atest p ossi bl e dat e (ie, l ast da y of m o nt h if da y 
u n k n o w n or 3 1st Dece m ber if da y a n d m o nt h are u n k n o w n), t he n:
If m e dicati o n st o p date < st u d y treat me nt first d ose date, assi g n as pri or
c o nc o mita nt
Missi n g
If m e dicati o n st o p date is missi n g c o ul d ne ver be ass u m e d a pri or 
m e di cati o n, assi g n as c o nc o mit a nt
P artial
K n o w n
I m p ute st art dat e as earli est p ossi bl e dat e (i e, first da y of m o nt h if da y 
u n k n o w n or 1st J a n uar y if da y a n d m o nt h are u n k n o w n), t he n:
If m e dicati o n st o p date < st u d y treat me nt first d ose date, assi g n as pri or
c o nc o mita nt
P artial
I m p ute st art dat e as earli est p ossi bl e dat e (i e, first da y of m o nt h if da y 
u n k n o w n or 1st J a n uar y if da y a n d m o nt h are u n k n o w n) a n d i m p ute st o p 
date as l atest p ossi bl e date (ie, last da y of m o nt h if da y u n k n o w n or 3 1st 
Dece m ber if da y a n d m o nt h are u n k n o w n), t he n:
If m e dicati o n st o p date < st u d y treat me nt first d ose date, assi g n as pri or
treat m e nt first d ose date, assi g n as 
c o nc o mita nt
Missi n g
I m p ute st art dat e as earli est p ossi bl e dat e (i e, first da y of m o nt h if da y 
u n k n o w n or 1st J a n uar y if da y a n d m o nt h are u n k n o w n), t he n:
If m e dicati o n st o p date is missi n g c o ul d ne ver be ass u me d a pri or 
m e di cati o n, assi g n as c o nc o mit a nt
Missi n g
K n o w n
If m e di cati o n st o p date < st u d y treat m e nt first d os e dat e, assi g n as pri or
Els e assi g n as c o nc o mit a nt
P artial
I m p ute st o p date as l atest p ossi bl e dat e (ie, l ast da y of m o nt h if da y 
u n k n o w n or 3 1st Dece m ber if da y a n d m o nt h are u n k n o w n), t he n:
If m e dicati o n st o p date < st u d y treat me nt first d ose date, assi g n as pri or
c o nc o mita nt
Missi n g
Assi g n as c o nc o mit a nt
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 6 1 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
Al g o rit h m f o r St a rti n g D ate of H os pit aliz ati o n a n d St a rt/ St o p D ates of 
C o nc o mit a nt Me di c ati o ns:
St art D ate
St o p D ate
Acti o n
P artial
P arti al
I m p ute st art dat e as earli est p ossi bl e dat e (i e, first da y of m o nt h if da y u n k n o w n or 
1st Ja n uar y if da y a n d m o nt h are u n k n o w n). I m p ut e st o p dat e t o lat est p ossi bl e dat e 
(i e, last da y of m o nt h if da y u n k n o w n or 3 1st Dece m ber if da y a n d m o nt h are 
u n k n o w n).
N o parti al st o p date i m p utati o n f or h os pitali zati o n.
Missi n g
Missi n g
I m p ute st art dat e as i nf or me d c o nse nt date. I m p ut e st o p date as l ast visit date w he n 
t he c o nc o mit a nt m e dicati o n ti m e p oi nt is n ot o n g oi n g.
N o missi n g st o p dat e i m p utati o n f or h os pit ali zati o n.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 6 2 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
A P P E N DI X 3.
U C- P R O/ S S S C O RI N G R U L E S
T he Ul cerati ve C olitis Patie nt- R e p orte d O utc o mes Si g ns a n d S y m pt o ms ( U C- P R O/ S S) is a 9-ite m dail y diar y, 
desi g ne d f or electr o nic a d mi nistrati o n. P atie nts/res p o n de nts are i nstr uct e d t o c o m pl et e t he diar y eac h e ve ni n g, 
- P R O/ S S ta kes a p pr o xi matel y t hree 
mi n ut es t o c o m pl ete.
T he U C- P R O/ S S yiel ds t w o se parate wee kl y a ver a ge s c ores: B o wel si g ns a n d s y m pt o ms ( 6 it e ms) a n d f u ncti o nal 
s y m pt o ms ( 3 ite ms). T here is n o si n gle t otal sc ore. T he wee kl y s c ores ca n be us e d al o ne or as part of a pr ofil e.
Q uesti o ns :
1. I n t he past 2 4 h o urs, h o w ma n y b o wel m o ve me nts di d y o u ha ve? 
0 = 0
1 = 1- 2 
2 = 3- 4 
3 = 5- 6 
4 = 7- 9 
5 = 1 0- 1 2 
6 = 1 3- 1 7 
7 = 1 8 or m ore 
2. I n t he past 2 4 h o urs, h o w ofte n were y o ur b o wel m o ve me nts m ostl y or c o m pl etel y li q ui d? 
0 = Ne ver 
1 = R arel y 
2 = S o meti m es 
3 = Ofte n 
4 = Al wa ys 
3. I n t he past 2 4 h o urs, di d y o u ha ve bl o o d i n y o ur b o wel m o ve m e nts? 
0 = N o 
1 = R arel y 
2 = S o meti m es 
3 = Ofte n 
4 = Al wa ys 
4. I n t he past 2 4 h o urs, di d y o u ha ve m uc us ( w hite materi al) i n y o ur b o wel m o ve me nts? 
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 6 3 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
0 = N o 
1 = R arel y 
2 = S o meti m es 
3 = Ofte n 
4 = Al wa ys 
5. I n t he past 2 4 h o urs, di d st ool, bl o o d, or li q ui d lea k o ut bef ore y o u reac he d a t oil et? 
0 = N o 
1 = R arel y 
2 = S o meti m es 
3 = Ofte n 
4 = Al wa ys 
6. I n t he past 2 4 h o urs, di d y o u pass gas? 
0 = N o 
1 = R arel y 
2 = S o meti m es 
3 = Ofte n 
4 = Ver y ofte n 
7. I n t he past 2 4 h o urs, di d y o u feel t he nee d t o ha ve a b o wel m o ve me nt ri g ht a wa y? 
0 = N o 
1 = Mil d 
2 = M o derat e 
3 = S e vere 
4 = Ver y S e vere 
8. I n t he past 2 4 h o urs, di d y o u feel pai n i n y o ur bell y? 
0 = N o 
1 = Mil d 
2 = M o derat e 
3 = S e vere 
4 = Ver y S e vere 
9. I n t he past 2 4 h o urs, di d y o u feel bl oati n g i n y o ur bell y? 
0 = N o 
1 = Mil d 
2 = M o derat e 
3 = S e vere 
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 6 4 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
4 = Ver y S e vere 
Deriv ati o n :
A dail y s c ore is t he mea n of res p o nses t o it e ms f or eac h scale: B o wel si g ns a n d s y m pt o ms ( Q uesti o ns 1- 5 a n d 7), 
a n d f u ncti o nal s y m pt o ms ( Q uesti o ns 6, 8 a n d 9). A wee kl y a vera ge s c ore f or e ac h scale is t he n cal c ulat e d wit h n o 
i m p ut ati o n usi n g t he mea n of at least f o ur o ut of t he se ve n dail y sc ores. If f o ur or m ore da ys of dat a are missi n g f or 
a n y wee k, t he wee kl y a ver a ge s c ore f or ea c h scale is set t o missi n g f or t hat wee k.
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 6 5 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
A P P E N DI X 4.
S F- 3 6 S C O RI N G R U L E S
T he Me dical O ut c o m es St u d y 3 6 Ite m S h ort F or m Healt h S ur ve y ( S F- 3 6) is a 3 6-ite m self-a d mi nistere d 
q uesti o n naire w hi c h has 8 scales: P h ysical f u ncti o ni n g ( 1 0 it e ms), r ol e li mit ati o ns d ue t o p h ysi cal pr o bl e ms ( 4 
ite ms), r ol e li mitati o ns d ue t o e m oti o nal pr o ble ms ( 3 ite ms), vitalit y ( 4 it e ms), m e ntal healt h ( 5 ite ms), s oci al 
f u ncti o n ( 2 ite ms), b o dil y pai n ( 2 it e ms), a n d ge neral healt h perce pti o ns ( 5 ite ms). Eac h it e m res p o ns e is s c ore d fr o m 
0 t o 1 0 0 a n d it e ms i n t he sa m e scale are a vera ge d t o get her t o cre ate 8 s u bsc ores. S c ores ra n ge fr o m 0 t o 1 0 0. A 
hi g her sc ore i n di cates a m ore fa v ora ble he alt h stat e.
T he 8 di m e nsi o ns are defi ne d as:
P h ysi cal f u ncti o ni n g: Q uesti o ns 3 t o 1 2
R ole li mit ati o ns d ue t o p h ysi cal pr o bl e ms: Q uesti o ns 1 3 t o 1 6
R ole li mit ati o ns d ue t o e m oti o nal pr o ble ms: Q uesti o ns 1 7 t o 1 9
Vit alit y: Q uesti o ns 2 3, 2 7, 2 9, 3 1
Me nt al healt h: Q uesti o ns 2 4 t o 2 6, 2 8, 3 0
S oci al f u ncti o n: Q uesti o ns 2 0, 3 2
B o dil y pai n: Q uesti o ns 2 1, 2 2
Ge neral healt h perc e pti o ns: Q uesti o ns 1, 3 3 t o 3 6
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 6 6 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
A P P E N DI X 5.
C L A S SI FI C A TI O N O F R E S C U E T H E R A P Y
T his a p pe n di x o utli nes t he al g orit h m f or t he Are na cli ni cal t ea m/ m e dical re vie wers t o cl assif y res c ue t hera pies f or 
ul cerati ve c olitis ( U C) i n a bli n de d m a n ner. T his will hel p est a blis h 1) i nt erc urre nt e ve nts f or t he efficac y esti m a n ds, 
a n d 2) w het her a s u bj ect will be e xcl u de d fr o m t he Per Pr ot oc ol S et(s). All resc ue t hera pi es i de ntifi e d b y t he m e di cal 
re vi e wers per t he al g orit h m bel o w will be i m p ort e d i n pr o gra m mi n g. T his pr ocess will be re peate d u ntil dat a base 
l oc k a n d t he list of all res c ue t hera pies i de ntifi e d will be fi nalize d bef ore st u d y u n bli n di n g.
O nl y m e di cati o ns a n d m e dical pr oce d ures re p ort e d o n t he el ectr o ni c cas e re p ort f or ms (e C R Fs) ca n be ass esse d 
w het her t he y are r esc ue t hera p y f or U C. If t he e x p os ure ha p pe ns i n t he f oll o w- u p peri o d ( be gi n ni n g o n or after t he 
date of l ast st u d y treat me nt a d mi nistrati o n), t he n it w o ul d n ot be c o nsi dere d as a res c ue t her a p y. 
Bi ol o gi cs wit h i m m u n o m o d ul at or y pr o perti es
R ule: 
o
A n y e x p os ure after first d ose
List of m e dicati o ns
o
A nti-
a nti b o di es: 
A D A LI M U M A B
C E R T O LI Z U M A B
C E R T O LI Z U M A B P E G O L
G O LI M U M A B
I N F LI XI M A B
o
Ot her Bi ol o gi cs:
U S T E KI N U M A B
V E D O LI Z U M A B
N o n- bi ol o gics wit h i m m u n o m o d ul at or y pr o perties
I m m u n os u p pressa nts
o
R ules:
After first d ose a n d u p t o a n d i ncl u di n g Wee k 8: a n y i ncrease fr o m bas eli ne f or m ore t ha n 
5 da ys 
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 6 7 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
After Wee k 8: A n y d ose a b o ve bas eli ne 
o
List of m e dicati o ns 
M E R C A P T O P U RI N E
A Z A T HI O P RI N E
TI O G U A NI N E
M E T H O T R E X A T E
M E T H O T R E X A T E S O DI U M
5- A S A c o m p o u n ds
o
R ules:
After first d ose a n d u p t o a n d i ncl u di n g Wee k 8: A n y i ncrease fr o m baseli ne f or m ore 
t ha n 5 da ys 
After Wee k 8: A n y d ose a b o ve bas eli ne 
o
List of m e dicati o ns 
M E S A L A ZI N E
B A L S A L A ZI D E
B A L S A L A ZI D E DI S O DI U M DI H Y D R A T E
B A L S A L A ZI D E S O DI U M
O L S A L A ZI N E S O DI U M
S U L F A S A L A ZI N E
B E C L O M E T A S O N E W/ M E S A L A ZI N E
o
R o utes
O R A L
R E C T A L
Ot her s m all m ol ec ule i m m u n o m o d ul at or y acti ve a ge nts 
o
R ules: 
After first d ose a n d u p t o a n d i ncl u di n g Wee k 8: A n y i ncrease fr o m baseli ne (i ncl u di n g 
ne w us e) f or m ore t ha n 5 da ys 
After Wee k 8: A n y d ose a b o ve bas eli ne
o
List of m e dicati o ns 
CI C L O S P O RI N 
T A C R O LI M U S
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 6 8 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
T O F A CI TI NI B 
T O F A CI TI NI B CI T R A T E 
S yst e mi c gl uc oc orti c oi ds
o
S yst e mi c gl uc oc orti c oi ds gi ve n vi a oral or rect al r o utes of a d mi nistrati o n 
R ules: 
After first d ose a n d u p t o a n d i ncl u di n g Wee k 8: A n y i ncrease fr o m baseli ne f or 
m ore t ha n 7 da ys
After Wee k 8: A n y d ose a b o ve bas eli ne
List of m e dicati o ns 
B E T A M E T H A S O N E
B E T A M E T H A S O N E DI P R O PI O N A T E
B E T A M E T H A S O N E S O DI U M P H O S P H A T E
D E X A M E T H A S O N E
D E X A M E T H A S O N E S O DI U M P H O S P H A T E
D E X A M E T H A S O N E V A L E R A T E
M E T H Y L P R E D NI S O L O N E
M E T H Y L P R E D NI S O L O N E S O DI U M S U C CI N A T E
P R E D NI S O L O N E
P R E D NI S O L O N E S O DI U M P H O S P H A T E
P R E D NI S O L O N E M E T A S U L F O B E N Z O A T E S O DI U M
P R E D NI S O N E
T RI A M CI N O L O N E
H Y D R O C O R TI S O N E
H Y D R O C O R TI S O N E A C E T A T E
H Y D R O C O R TI S O N E B U T Y R A T E
H Y D R O C O R TI S O N E S O DI U M S U C CI N A T E
R o utes
O R A L
R E C T A L
o
S yst e mi c gl uc oc orti c oi ds gi ve n vi a pare nteral r o utes of a d mi nistrati o n 
R ule: 
A n y e x p os ure after first d ose
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 6 9 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
List of m e dicati o ns 
B E T A M E T H A S O N E
B E T A M E T H A S O N E DI P R O PI O N A T E
B E T A M E T H A S O N E S O DI U M P H O S P H A T E
D E X A M E T H A S O N E
D E X A M E T H A S O N E S O DI U M P H O S P H A T E
D E X A M E T H A S O N E V A L E R A T E
M E T H Y L P R E D NI S O L O N E
M E T H Y L P R E D NI S O L O N E S O DI U M S U C CI N A T E
P R E D NI S O L O N E
P R E D NI S O L O N E S O DI U M P H O S P H A T E
P R E D NI S O L O N E M E T A S U L F O B E N Z O A T E S O DI U M
P R E D NI S O N E
T RI A M CI N O L O N E
H Y D R O C O R TI S O N E
H Y D R O C O R TI S O N E A C E T A T E
H Y D R O C O R TI S O N E B U T Y R A T E
H Y D R O C O R TI S O N E S O DI U M S U C CI N A T E
R o utes
I N T R A V E N O U S
I N T R A M U S C U L A R
T o pical Gl uc oc orti c oi ds
o
R ules
After first d ose a n d u p t o a n d i ncl u di n g Wee k 8: A n y e x p os ure a b o ve baseli ne ( or ne w 
use) f or m ore t ha n 5 da ys
After Wee k 8: A n y d ose a b o ve bas eli ne
o
List of m e dicati o ns 
B U D E S O NI D E
o
R o utes
O R A L
R E C T A L
B ecl o m et has o ne
P P D


P R O T O C O L A P D 3 3 4- 2 0 3
St ati sti c al A n al y si s Pl a n 
P a g e 7 0 of 7 0
D o c u m e nt:
\\ q ui ntil e s. n et\ e nt er pri s e\ A p p s\ s a s d at a\ S A S b\ S A S\ Ar e n a\ A P D 3 3 4\ R Z A 2 8 1 1 6\ Bi o st ati sti c s\ D o c u m e nt a
ti o n\ S A P\ 5 0 3- Fi n al S A P v 2. 0\ A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. d o c x
A ut h or:
V er si o n N u m b er:
2. 0
V er si o n D at e: 
2 0 N o v 2 0 2 3
T e m pl at e N o.:  C S _ T P _ B S 0 1 6 R e vi si o n 7
R ef er e n c e:  C S _ WI _ B S 0 0 5
Eff e cti v e D at e: 0 1 N o v 2 0 2 1
C o p yri g ht © 2 0 0 9, 2 0 1 0, 2 0 1 2, 2 0 1 6, 2 0 1 8, 2 0 1 9, 2 0 2 1 I Q VI A. All ri g ht s r e s er v e d. T h e c o nt e nt s of t hi s d o c u m e nt ar e c o nfi d e nti al 
a n d pr o pri et ar y t o I Q VI A H ol di n g s I n c. a n d it s s u b si di ari e s. U n a ut h ori z e d u s e, di s cl o s ur e or r e pr o d u cti o n i s stri ctl y pr o hi bit e d.
o
R ules
After first d ose a n d u p t o a n d i ncl u di n g Wee k 8: A n y i ncrease a b o ve baseli ne f or m ore 
t ha n 5 da ys
After Wee k 8: A n y d ose a b o ve bas eli ne
o
List of m e dicati o ns 
B E C L O M E T A S O N E
B E C L O M E T A S O N E DI P R O PI O N A T E
B E C L O M E T A S O N E W/ M E S A L A ZI N E
o
R o utes
O R A L
R E C T A L
Me di cal pr oce d ures
Le u k oc yt e a p heresis, ot her a p heresis, a n d pl as ma e xc ha n ge 
o
R ule: 
A n y e x p os ure after first d ose
o
List of m e dical pr oce d ures 
A P H E R E SI S
L E U K A P H E R E SI S
C O L E C T O M Y ( parti al or t ot al)
SI G M OI D E C T O M Y
C O L O S T O M Y
I L E O S T O M Y
P P D


C ertifi c at e Of C o m pl eti o n
E n v el o p e I d: 
St at u s: C o m pl et e d
S u bj e ct: C o m pl et e wit h D o c u Si g n: A P D 3 3 4- 2 0 3 _ S A P _ Fi n al v 2. 0- 2 0 2 3 1 1 2 0 _ cl e a n. p df
Pr oj e ct C o d e ( E nt er 0 f or n o n- bill a bl e pr oj e ct s): R Z A 2 8 1 1 6
I Q VI A I D ( L o gi n I D): 
B u si n e s s U nit: 
D S S R
S o ur c e E n v el o p e: 
D o c u m e nt P a g e s: 7 0
Si g n at ur e s: 3
E n v el o p e Ori gi n at or: 
C ertifi c at e P a g e s: 5
I niti al s: 0
 
A ut o N a v: E n a bl e d
E n v el o p eI d St a m pi n g: Di s a bl e d
Ti m e Z o n e: ( U T C- 0 8: 0 0) P a cifi c Ti m e ( U S & C a n a d a)
O n e I M S W a y
Pl y m o ut h M e eti n g,   1 9 4 6 2
I P A d dr e s s: 
R e c or d Tr a c ki n g
St at u s: Ori gi n al
             1 1/ 2 7/ 2 0 2 3 1: 2 8: 2 4 A M
H ol d er: 
            
L o c ati o n: D o c u Si g n
Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 1 1/ 2 7/ 2 0 2 3 1: 3 9: 3 6 A M
Vi e w e d: 1 1/ 2 7/ 2 0 2 3 1: 4 5: 5 2 A M 
Si g n e d: 1 1/ 2 7/ 2 0 2 3 1: 4 6: 3 4 A M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 4/ 1/ 2 0 2 2 1 2: 4 6: 0 2 A M
      I D: 
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 1 1/ 2 7/ 2 0 2 3 1: 3 9: 3 7 A M
Vi e w e d: 1 1/ 2 7/ 2 0 2 3 5: 0 0: 4 8 P M 
Si g n e d: 1 1/ 2 7/ 2 0 2 3 5: 0 2: 0 9 P M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 7/ 3 0/ 2 0 2 3 1 0: 3 7: 2 0 P M
      I D: 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
S e c urit y L e v el: E m ail, A c c o u nt A ut h e nti c ati o n 
( R e q uir e d)
Si g n at ur e A d o pti o n: Pr e- s el e ct e d St yl e
Si g n at ur e I D: 
U si n g I P A d dr e s s: 
Wit h Si g ni n g A ut h e nti c ati o n vi a D o c u Si g n p a s s w or d
Wit h Si g ni n g R e a s o n s ( o n e a c h t a b): 
   I a p pr o v e t hi s d o c u m e nt
S e nt: 1 1/ 2 7/ 2 0 2 3 1: 3 9: 3 7 A M
Vi e w e d: 1 1/ 2 7/ 2 0 2 3 9: 0 6: 5 9 P M 
Si g n e d: 1 1/ 2 7/ 2 0 2 3 1 0: 0 7: 0 9 P M
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e: 
      A c c e pt e d: 2/ 9/ 2 0 2 1 8: 1 7: 4 7 P M
      I D: 
I n P er s o n Si g n er E v e nt s
Si g n at ur e
Ti m e st a m p
E dit or D eli v er y E v e nt s
St at u s
Ti m e st a m p
A g e nt D eli v er y E v e nt s
St at u s
Ti m e st a m p
I nt er m e di ar y D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ertifi e d D eli v er y E v e nt s
St at u s
Ti m e st a m p
C ar b o n C o p y E v e nt s
St at u s
Ti m e st a m p
Wit n e s s E v e nt s
Si g n at ur e
Ti m e st a m p
N ot ar y E v e nt s
Si g n at ur e
Ti m e st a m p
E n v el o p e S u m m ar y E v e nt s
St at u s
Ti m e st a m p s
E n v el o p e S e nt
H a s h e d/ E n cr y pt e d
1 1/ 2 7/ 2 0 2 3 1: 3 9: 3 7 A M
C ertifi e d D eli v er e d
S e c urit y C h e c k e d
1 1/ 2 7/ 2 0 2 3 9: 0 6: 5 9 P M
Si g ni n g C o m pl et e
S e c urit y C h e c k e d
1 1/ 2 7/ 2 0 2 3 1 0: 0 7: 0 9 P M
C o m pl et e d
S e c urit y C h e c k e d
1 1/ 2 7/ 2 0 2 3 1 0: 0 7: 0 9 P M
P a y m e nt E v e nt s
St at u s
Ti m e st a m p s
El e ctr o ni c R e c or d a n d Si g n at ur e Di s cl o s ur e
P P D
P P D
P P D
P P D
P P D


C O N S E N T T O E L E C T R O NI C D E LI V E R Y A N D E X E C U TI O N O F D O C U M E N T S   
discl os ures, a ut h orizati o ns, ac k n o wle d ge me nts or ot her d oc u me nts (c oll ecti vel y, t he 
" D oc u m e nts") electr o nicall y. Please rea d t his c o nse nt f or m caref ull y. It e x plai ns t he ter ms a n d 
c o n diti o ns u n der w hic h s uc h D oc u me nts are pr o vi de d b y us a n d e x ec ute d b y y o u el ectr o nicall y 
e x ec uti o n of s uc h D oc u me nts electr o nicall y, ple ase clic k t he "I A gree" b utt o n.  
D oc u me nts will be se nt t o y o u electr o nic all y  
If y o u c o nse nt t o ele ctr o nic deli ver y, D oc u m e nts will be se nt t o y o ur D o c u Si g n user acc o u nt. 
Y o u ma y re q u est a pa per c o p y of d oc u me nts pre vi o usl y ma de a vaila ble t hr o u g h y o ur D oc u Si g n 
user acc o u nt, b ut a n a d diti o nal c har ge ma y b e i nc urre d. Alter n ati vel y, y o u ca n d o w nl oa d a n d 
pri nt d oc u me nts se nt t o y o ur D oc u Si g n us er acc o u nt. U nless ot her wise n ote d, y o u ca n access a 
D oc u me nt u p t o 3 0 da ys fr o m t he date we first se nt t he D oc u me nt t o y o u.  
Wit h h ol d C o ns e nt or Wit h dr a wi n g C o nse nt t o Electr o nic Deli ver y  
If y o u wit h h ol d c o nse nt t o electr o nic deli ver y or e x ec uti o n, or wit h dra w y o ur c o nse nt at a l ater 
date, all D oc u me nts will be se nt t o y o ur maili n g a d dress f oll o wi n g o ur recei pt of n otice of s uc h 
acti o n. T he f oll o wi n g secti o ns e x plai n t he c o nse q ue nces of wit h h ol di n g or wit h dra wi n g y o ur 
c o nse nt t o electr o ni c deli ver y a n d e xec uti o n of D oc u me nts, a n d als o t he pr o ce d ures y o u m ust 
f oll o w i n or der t o effect u ate deli ver y t o y o ur maili n g a d dress.  
C o nse q ue nces of Wit h dr a wi n g C o nse nt   
B y electi n g t o o nl y recei ve a n d e x ec ute D o c u me nts se nt t o y o ur maili n g a d dress, we will n ot be 
a ble t o carr y o ut tra nsacti o ns or ser vices as efficie ntl y. F or i nsta nce, s o me tra nsacti o ns or 
ser vices re q uire y o ur e x press c o nse nt. We ca n perf or m t hese tra nsacti o n or ser vices o nl y if we 
first recei ve a n ac k n o wle d ge m e nt t hat i n dicates y o u recei v e d a n d c o ns e nt t o t he D oc u me nt 
relate d t o t he pr o p os e d tra nsacti o n or ser vice.  
T o wit h h ol d c o nse nt n o w or wit h dra w c o ns e nt at a later date, please si g n D oc u Si g n's " Wit h dra w 
C o nse nt" f or m o n t he si g ni n g pa ge of y o ur D o c u Si g n user acc o u nt. T his will i n dicate t hat y o u 
ha ve wit h dra w n y o ur c o nse nt t o recei v e D oc u me nts electr o nicall y. O n ce y o u si g n t he " Wit h dra w 
C o nse nt" f or m, y o u will n o l o n ger be a ble t o us e y o ur D oc u Si g n us er acc o u nt t o e x ec ute 
D oc u me nts electr o nicall y a n d we will se n d D oc u me nts t o y o ur maili n g a d dress. Wit h dra wal of 
c o nse nt d oes n ot affect t h e vali dit y of a n y D oc u me nts pre vi o usl y e x ec ute d electr o nicall y pri or t o 
s uc h wit h dra wal of C o nse nt. I n a d diti o n, s h o ul d y o u e x ec ute a n y D oc u m e nts electr o nicall y, y o ur 
e x ec uti o n of s uc h D oc u me nts s hall i n dicate y o ur c o nti n ue d c o nse nt t o e x ec ute s uc h D oc u me nts 
electr o nicall y.  
H o w t o c o nt act I Q VI A:  
If y o u w o ul d li ke us t o se n d t he D oc u me nts t o a differe nt e- mail a d dress, re q uest pa per c o pies of 
D oc u me nts y o u ha ve pre vi o usl y recei ve d electr o nicall y, or wit h dra w y o ur c o nse nt t o recei ve 
electr o nic d o c u me nts, please f oll o w t he i nstr u cti o ns bel o w. If y o u ha v e a n y ot her q uesti o ns, 
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P P D


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