A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Oral Ozanimod as Maintenance Therapy for Moderately to Severely Active Crohn's Disease
Phase: PHASE3
Conditions: Crohn Disease
Sponsor: Celgene

Official Title of Study:  
A Phase 3, Multicenter, Randomized, Double-blind, Placebo Controlled 
Study of Oral Ozanimod as Maintenance Therapy for 
Moderately to Severely Active Crohn’s disease 
 
 
NCT Number: NCT03464097 
Document Date (Date in which document was last revised): 06-Feb-2024 
 
 
 

Ozanimod 
Protocol RPC01-3203
Celgene International II Sàrl
RPC01-3203, Amendment 7.0
Final:06 Feb 2024
1
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-
CONTROLLED STUDYOF ORAL OZANIMOD ASMAINTENANCE THERAPYFOR 
MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE
INVESTIGATIONAL PRODUCT:
Ozanimod
PROTOCOL NUMBER:
RPC01-3203
DATE FINAL:
26 Sep 2017
AMENDMENT No. 1
19 Dec 2017
AMENDMENT No. 2
18 Jun 2018
AMENDMENT No. 3
10 June 2019
AMENDMENT No. 4
28 Aug 2020
AMENDMENT No. 5
14 Jun 2021
AMENDMENT No. 6
16 Mar 2023
AMENDMENT No. 7
06 Feb 2024
IND NUMBER:
126,740
EU CT NUMBER:
2023-510426-33
SPONSOR NAME/ADDRESS:
Celgene International II Sàrl
Route de Perreux 1
2017 Boudry
Switzerland
Tel: 
CONFIDENTIAL
This protocol is provided to you as an investigator, potential investigator, or 
consultant for review by you, your staff, and ethics committee/institutional 
review board. The information contained in this document is regarded as 
confidential and, except tothe extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by 
law or regulations. Persons to whom the information is disclosed must be 
informed that the information is confidential and may notbe further 
disclosed by them.
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Protocol RPC01-3203
Celgene International II Sàrl
RPC01-3203, Amendment 7.0
Final:06 Feb 2024
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MEDICAL MONITOR /EMERGENCY CONTACT INFORMATION 
Contact Information:
Name: 
Title: 
 Clinical Trial Physician, 
Address: 3033 Science Park Road, Suite 300
San Diego, California 92121,USA
Tel(office):
Tel (cell):
E-mail:
Note: The back-up 24-hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls.
Back-up 24-hour Global Emergency Contact Call Center: +1-877-501-7738
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Protocol RPC01-3203
Celgene International II Sàrl
RPC01-3203, Amendment 7.0
Final:06 Feb 2024
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SPONSORTHERAPEUTIC AREA LEADSIGNATURE PAGE
See Electronic Signature and Date on File in Electronic 
Document Management System.
Signature of Celgene Therapeutic Area Head
Date
Printed Name of Celgene Therapeutic Area Head and Title
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable. 
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Celgene International II Sàrl
RPC01-3203, Amendment 7.0
Final:06 Feb 2024
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SPONSOR: CELGENE INTERNATIONAL II SÀRL
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Celgene International II Sàrl
RPC01-3203, Amendment 7.0
Final:06 Feb 2024
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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
Date
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study 
site and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) procedures, 
instructions from Celgene representatives, the Declaration of Helsinki, International 
Council on Harmonisation (ICH) Good Clinical Practices Guidelines, and local 
regulations governing the conduct of clinical studies.
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Protocol RPC01-3203
Celgene International II Sàrl
RPC01-3203, Amendment 7.0
Final:06 Feb 2024
6
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 7.0:
The overall rationale for this protocol amendment is toadjust the order of secondary 
 
 endpoints 
, and to accommodate a 
greater number of subjects entering the Maintenance Study from the Induction Studies.
The Protocol Summary was updated with all relevant changes.
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 7.0
Section Number & 
Title
Description of Change
Brief Rationale
Section 2.2.2: Key 
Secondary Endpoints
Moved the following endpoint 
 
 toKey Secondary: 
“Proportion 
of subjects with SES-CD ≤ 4 points and SES-
CD decrease from baseline ≥ 2 points with no 
SES-CD subscore >1 pointat Week 52.”
Added a note that “Final ranking of key 
secondary endpoints may vary by region and 
will be defined in the SAP.”
To allow for differences in
regulatory requirements
between regions.
Section 2.2.2: Key 
Secondary Endpoints
Section 2.2.3: 
Additional Secondary 
Endpoints
Moved the following endpoints from Key 
Secondary to Additional Secondary:
“Proportion of subjects with CDAI score < 
150 at Week 52 and at ≥ 80% of visits 
between Week 8 and Week 52, inclusive, in 
subjects with CDAI score < 150 at 
Maintenance Day 1”
“Proportion of subjects with average daily 
abdominal pain score ≤ 1 point and 
average daily stool frequency score ≤ 3 
points with abdominal pain and stool 
frequency no worse than baseline and SES-
CD decrease from baseline ≥ 50% at Week 
52”
To consolidate the list of 
Key Secondary Endpoints 
which will be subject to 
hierarchical testing/ 
multiplicity adjustment.
Section 3.1: Study 
Design
Section 4.1: Number 
of Subjects
Addedlanguage to allow for additional
subjects to be enrolledbased on eligibility 
from the Induction Study.
Sample sizehas been revised 
to allow for flexibility based 
on the number of eligible 
subjects from Induction
Study.
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Protocol RPC01-3203
Celgene International II Sàrl
RPC01-3203, Amendment 7.0
Final:06 Feb 2024
7
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 7.0
Section Number & 
Title
Description of Change
Brief Rationale
Section9.1:
Overview
Section 9.3.2: Power 
Calculations
Section 3.3: End of 
Study
Added following sentence: “If the Sponsor 
discontinues the Maintenance Study prior to 
the planned end of study, active subjects will 
be considered completers of the study and may 
be eligible to enroll in the Open-Label 
Extension Study (RPC01-3204).”
To allowfor flexibility 
within the study program, 
and to provide access to the 
Open-Label Extension Study 
for all subjects in the 
Maintenance Study.
Section 6.4.1.2: 
Simple Endoscopic 
Score for Crohn’s 
Disease
Aligned scoringof SES-CD for endoscopic 
remissionwith endpoint.
To be aligned with 
regulatory interaction and 
updated scientific 
examination of measures of 
endoscopic remission.
Section 9.2: Study 
Population 
Definitions
Removed the per protocol (PP) population 
definition.
To align with International 
Council for Harmonisation 
(ICH)guideline E9 (R1) 
Section A.5.3.
Section 9.8: 
Treatment Failure 
Rules
Changed the discontinuationof investigational 
product (IP)from “for lack of therapeutic 
effect” to “due to any reason.”
To align with ICH E9 (R1) 
Section A.3.1.
All
Minor formatting and typographical 
corrections/edits.
Minor, therefore have not 
been summarized.
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Protocol RPC01-3203
Celgene International II Sàrl
RPC01-3203, Amendment 7.0
Final:06 Feb 2024
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PROTOCOL SUMMARY
Study Title
A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Studyof Oral Ozanimod 
as Maintenance Therapy for Moderately to Severely Active Crohn’s Disease
Indication
Crohn’s disease (CD) is an immune-mediated inflammatory disease of the gastrointestinal (GI) 
tract. Annual incidence varies geographically, with estimates ranging from 3.1 to 14.6 per 
100,000people in the United States and from 0.1 to 16 per 100,000 worldwide (Lakatos, 2006). 
Subjects with CD suffer from diarrhea, rectal bleeding, weight loss, abdominal pain, and fever. 
CDis characterized by a lifelong chronic course of remissions and exacerbations. The pathology 
of this disease is characterized by transmural infiltration of lymphocytes and macrophages, 
granulomas, fissuring ulceration, and submucosal fibrosis. The transmural inflammatory process 
of CD predisposes 
subjects 
to 
the 
formation 
of fistulas 
and it 
has been 
estimated 
that 
approximately 
35% of subjects will have at least 1fistula during the course of their disease (Schwartz, 2002). In 
a recent study, within 10 years of diagnosis, 50% of adults with CD had undergone bowel surgery 
(Peyrin-Biroulet, 2010).
The current standard of medical care for patients with moderately to severely active CD consists 
of anti-inflammatory approaches, such as corticosteroids, azathioprine (AZA)/6-mercaptopurine
(6-MP), methotrexate (MTX), and biologics such as anti-tumor necrosis factor (TNF)α, 
anti-interleukin (IL)-12/IL-23, or anti-integrins.
Immunomodulators aid in corticosteroid withdrawal and in preventing relapse, but also are 
associated with considerable side effects. Infliximab, an anti-TNFα-therapy, is able to reduce signs 
and symptoms and induce and maintain remission in the majority of subjects for which it is 
indicated. However, in a large Phase 3 maintenance trial of infliximab for CD (ACCENT I), only 
45% of subjects were considered in remission at Week 30 in the highest dose group (where 
remission was defined as the ability to achieve a Crohn’s Disease Activity Index [CDAI] of
<150points) (Hanauer, 2002). Similarly,the primary response rates in trials of adalimumab 
(Colombel, 2007) and certolizumab (Sandborn, 2007) were approximately 47% and 37%, 
respectively. Thus, a sizable proportion of the patientpopulation is unresponsive to both 
conventional therapy and TNF antagonists. Vedolizumab, a gut-specific anti-integrin therapy, is 
also indicated for achieving clinical response and clinical remission in this population. However, 
in a large clinical trialof vedolizumab, only 32% of subjects had a clinical response at Week6, 
and only 39% receiving vedolizumab every 8 weeks were in remission at Week 52 (Sandborn, 
2013). Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and 
interleukin-23, was approved for the treatment of patients who failed or were intolerant to 
treatment with immunomodulators, corticosteroids, or 1or more TNF antagonists. However, in 
the induction trials of ustekinumab, only 32% of subjects were responders at 6weeks (Feagan, 
2016), and about 40% were in remission at Week 52 of the maintenance trial.
Therefore, there remains a considerable unmet medical need for safeand effective oral treatments 
for patientswith CD.
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Protocol RPC01-3203
Celgene International II Sàrl
RPC01-3203, Amendment 7.0
Final:06 Feb 2024
9
Objectives
Primary Objective:
Demonstrate the efficacyof ozanimod compared toplacebo on the maintenance of clinical 
remission and endoscopic response
Secondary Objectives:
Demonstrate the efficacy of ozanimod compared to placebo on maintenance of clinical 
response
Demonstrate the efficacy of ozanimod compared to placebo on maintenance of endoscopic 
remission and mucosal healing
Demonstrate the efficacyof ozanimod, compared to placebo, in achieving corticosteroid-free 
clinical remission
Demonstrate the efficacyof ozanimod, compared to placebo, 
on healthcare resource utilization
(HRU), subject-reported outcomes, and quality of life
Demonstrate the safety and tolerability of ozanimod as maintenance therapy
Study Design
This is a Phase 3, randomized, double-blind, placebo-controlled studyto demonstrate the effect of 
oral ozanimod as maintenance therapy in adult subjects with moderatelyto severely activeCD, 
defined as CDAI score≥220 to ≤450. Subjects who complete theinitial 12 weeks of treatment 
(Induction Studies RPC01-3201 or RPC01-3202) and are in clinical response (CDAI reduction 
from baseline ≥100 points or CDAI score<150),clinical remission (CDAI score < 150),and/or 
have an average daily stool frequency score ≤ 3 and an average abdominal pain score ≤1with 
abdominal pain and stool frequency no worse than baselinewill be eligible to participate in the 
Maintenance Study.
The total number of subjects enrolled (estimated at 550) will be determined based on how many 
subjects are eligible from the Induction Studies and choose to continue to the Maintenance Study. 
Approximately410subjects allocated to receive ozanimodin either RPC01-3201 or RPC01-3202 
are expected to meet the clinical criteria described aboveby Week 12 and are expectedto enroll 
in this study. Subjects will be stratified by clinical remission at entry into the Maintenance Study
(yes/no)andcorticosteroid use at entry into the Maintenance Study(yes/no). Subjects who 
received ozanimod in the Induction Studies and met the clinical criteria to enter the Maintenance 
Study will be randomly assigned to receive ozanimod0.92mg or placebo in a 1:1 ratio. 
Subjects who meet the clinical criteria described aboveafter treatment with placebo in RPC01-
3201 or RPC01-3202 will continue to receive placebo in a double-blinded manner. 
Subjects will be assessed for disease activity through Week 52 of the RPC01-3203 study. Subjects 
who experiencedisease relapsein the RPC01-3203 study (see Section14.2) and allsubjects who 
complete the RPC01-3203 study will be eligibleto enter the Open-Label Extension (OLE) Study 
RPC01-3204.
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Protocol RPC01-3203
Celgene International II Sàrl
RPC01-3203, Amendment 7.0
Final:06 Feb 2024
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The study will be conducted in compliance with the International Councilon Harmonisation (ICH) 
of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical 
Practice (GCP) and applicable regulatory requirements.
Overall Study Design
Note: Subjects in clinical response and/or clinical remission at Week 12 of the Induction Studywho were randomized 
to placebo will continue to receive placebo in the Maintenance Studyin a double-blind manner. Only subjects in 
clinical response and/or clinical remission assigned to ozanimod in the Induction Studywill be randomized to either 
ozanimodor placebo when entering the Maintenance Study.
Study Population
Subjects who complete the initial 12 weeks of treatment (Induction Study, RPC01-3201 or 
RPC01-3202) and are in clinical response,clinical remission,and/or have an average daily stool 
frequency score ≤ 3 and an average abdominal pain score ≤ 1with abdominal pain and stool 
frequency no worse than baselinewill be eligible to participate in the Maintenance Study.
Length of Study
The duration of this study is 52 weeks. Subjects who complete the Maintenance Study are 
anticipated to receive 64 weeks of treatment (12-week Induction Study + 52-week Maintenance 
Study).Subjects not entering the OLEStudy will have 
 
The end of study(MaintenanceStudyRPC01-3203) is defined as either the date of the last visit of 
the last subject to complete the 
, or the date of receipt of the last 
datapoint from the last subject that is required for primary orsecondary analysis, as pre-specified 
in the protocol, whichever is the later date.If the Sponsor discontinues the Maintenance Study 
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Celgene International II Sàrl
RPC01-3203, Amendment 7.0
Final:06 Feb 2024
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prior to the planned end of study, active subjectswill be considered completers of the study and 
may be eligible to enroll in the Open-Label ExtensionStudy (RPC01-3204).
Study Treatments
Subjectswho meet the criteria to enter the Maintenance Study (RPC01-3203) and were assigned 
to ozanimod in the Induction Study(RPC01-3201 or RPC01-3202) will be randomly assigned to 
receive ozanimod 0.92mg or placebo in a 1:1 ratio.
Subjects who were assigned to placebo in the Induction Study and met 
the clinical criteria for entry 
into the Maintenance Study will continue on placeboin a double-blind manner.
The possible treatments are as follows:
ozanimod: taken by mouth as a single 0.92 mg capsule (equivalent to ozanimod hydrochloride 
[HCl]1 mg) once daily x 52 weeks, or
placebo: taken by mouth as a single capsule once daily x 52 weeks
Overview of Key Efficacy Assessments
Note: All endpoints will evaluate subjects on ozanimod 0.92mg and placebo at Week 52 unless 
otherwise specified.Baseline is defined as Day 1 in the Induction Study.
Primary Endpoints:
Proportion of subjects with CDAI score <150at Week 52
Proportion of subjects with Simple Endoscopic Score for Crohn’s Disease(SES-CD)decrease 
from baseline ≥50% at Week 52
Key Secondary Endpoints:
Proportion of subjects with CDAI reduction from baseline ≥100 points or CDAI score <150 
at Week 52
Proportion of subjects with average daily abdominal pain score ≤ 1 point and average daily 
stool frequency ≤ 3 points with abdominal pain and stool frequency no worse than baseline at 
Week 52
Proportion of subjects with CDAI score < 150 at Week 52, while remaining corticosteroidfree 
in the 12 weeksprior to Week 52, among all subjects atMaintenance Day1
Proportion of subjects with CDAI score < 150 at Week 52 in subjects with CDAI score <150 
at Maintenance Day 1
Proportion of subjects with SES-CD ≤ 4 points and SES-CD decrease from baseline ≥ 2points 
with no SES-CD subscore > 1 point at Week 52
Note: Final ranking of key secondary endpoints may vary by region and will be defined in the 
SAP. 
AdditionalSecondary Endpoints:
Proportion of subjects with CDAI score < 150 and SES-CD decrease from baseline ≥50% at 
Week 52
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Proportion of subjects with average daily abdominal pain score ≤ 1 point, and average daily 
stool frequency score ≤ 3 points with abdominal pain and stool frequency no worse than 
baseline and SES-CD ≤ 4 points and SES-CD decrease ≥2 points with no SES-CD subscore 
>1 point at Week 52
Proportion of subjects with CDAI reduction from baseline ≥ 100 points or CDAI score <150 
and SES-CD decrease from baseline ≥ 50% at Week 52
Proportion of subjects with CDAI score < 150 at Maintenance Day 1 and SES-CD decrease 
from baseline ≥ 50% at Week 52
Proportion of subjects with CDAI reduction from baseline ≥ 70 points at Week 52
Proportion of subjects with CDAI score < 150 at Week 52, while remaining corticosteroid free 
in the 12 weeks prior to Week 52 among subjects using corticosteroids at Maintenance Day 1
Proportion of subjects with mucosal healing (SES-CD ≤ 4 points and SES-CD decrease 
≥2points with no SES-CD subscore > 1 point) and histologic improvement based on Robarts 
Histologic Index (RHI) at Week 52
Time to relapse (an increase in CDAI score from Maintenance Day 1 ≥100 points and CDAI 
score > 220, SES-CD ≥ 6 [or ≥4 if isolated ileal disease]), and exclusion of other causes of an 
increase in disease activity unrelated to underlying CD (eg, infections, change in medication)
Proportion of subjects with a Crohn’s Disease Endoscopic Index of Severity (CDEIS) decrease 
from baseline ≥ 50% at Week 52
Proportion of subjects with CDAI score < 150 at Week 52 and at ≥80% of visits between 
Week 8 and Week 52, inclusive, in subjects with CDAI score < 150 at Maintenance Day 1
Proportion of subjects with average daily abdominal pain score ≤ 1 point and average daily 
stool frequency score ≤ 3 points with abdominal pain and stool frequency no worse than
baseline and SES-CD decrease from baseline ≥ 50% at Week 52
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RPC01-3203, Amendment 7.0
Final:06 Feb 2024
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Celgene International II Sàrl
RPC01-3203, Amendment 7.0
Final:06 Feb 2024
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Overview of Safety Assessments
The incidence, severity, relationship, and type of treatment-emergent adverse events (TEAEs), 
serious adverse events (SAEs), adverse events (AEs)leading to discontinuation of IP, and AEs of 
special interest(AESIs)will be summarized, as well as clinically meaningful changes from 
baseline for clinical laboratory measures, vital signs, and electrocardiograms (ECGs).
Statistical Methods
Analysis Populations
This is a Phase 3, randomized, blinded, placebo-controlled studyto demonstratethe effect of oral 
ozanimod as maintenance therapy in subjects with moderately to severely active CD. The 
following analysis populations will be used in the statistical analysis:
Intent-to-Treat (ITT): 
The ITT analysis population will consist 
of all randomized subjects from 
theScreenedanalysis population that receive at least 1dose of IP. Subjects in the ITT analysis 
population will be analyzed according to 
the randomized treatment, regardless of the treatment 
actually given. The primary analysis population for all efficacy endpoints will be the ITT 
analysis population.
Safety: The safety analysis population is defined as all subjects who are randomized and 
receive at least one dose of study treatment, analyzed by actual treatment received.
Determination of Enrolled Sample Size
It is estimated that approximately 550adult subjects from RPC01-3201 and RPC01-3202 will be 
enrolled in the study, with approximately 410 subjects having received ozanimod in the Induction 
Studies. The subjects who had received ozanimod during the Induction Studieswill be randomly 
assigned 
to 
receiveozanimod 
0.92mg or placeboin 
a 
1:1ratio. 
Subjects in response 
after 
receiving 
placebo in either RPC01-3201 or RPC01-3202 will continue to receive placeboin a blinded 
fashion. Section9.3presents a detailed discussion of the needed sample size to properly power the 
randomized 
component 
of 
this 
study, 
and 
a 
comparison to 
the 
approximately410 
subjects available 
for randomization is made. 
Efficacy Analysis
For the primary analysis of responder/remitterendpoints, subjects who have insufficient data for 
response/remissiondetermination for the timepointunder consideration will be considered 
non-responders/non-remittersfor that timepoint. Sensitivity analyses, missing data imputation, 
and continuous endpoint efficacy analysis are discussed in the statistical analysis plan (SAP).
The primary analysis ofthe primary and key secondary endpoints with binary measure (eg,yes/no) 
such as clinical remission and clinical response at Week 52 will be carried out using the 
Cochran-Mantel-Haenszel (CMH) method. The stratifying factors of clinical remission at entry
into the Maintenance Study (yes/no)andcorticosteroid use at entry into the Maintenance Study 
(yes/no)will be accounted for in the CMH analyses. Details regarding risk differences, 
odds ratios, 
confidence limits, and considerations for sensitivity analyses will be provided in the separate SAP.
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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
OVERALL RATIONALE FOR PROTOCOL AMENDMENT7.0:............................................6
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 7.0.........................................6
PROTOCOL SUMMARY..........................................................................................................8
TABLE OF CONTENTS..........................................................................................................15
LIST OF TABLES....................................................................................................................19
LIST OF FIGURES..................................................................................................................20
1
INTRODUCTION..................................................................................................21
1.1
Disease Background...............................................................................................21
1.2
Compound Background..........................................................................................21
1.2.1
Summary of Nonclinical Studies..............................................................................22
1.2.2
Summary of Clinical Studies in Inflammatory Bowel Disease..................................22
1.2.2.1
Ulcerative Colitis....................................................................................................22
1.2.2.2
Crohn’s Disease.....................................................................................................23
1.2.3
Rationale for Dose Selection...................................................................................24
1.3
Study Rationale......................................................................................................24
1.4
Risk/Benefit Assessment........................................................................................25
25
1.4.2
Benefit Assessment..................................................................................................30
1.4.3
Overall Risk/Benefit Conclusion.............................................................................30
2
STUDY OBJECTIVES ANDENDPOINTS...........................................................31
2.1
Study Objectives.....................................................................................................31
2.1.1
Primary Objective:.................................................................................................31
2.1.2
Secondary Objectives:............................................................................................31
2.2
Study Endpoints.....................................................................................................31
2.2.1
Primary Endpoints:................................................................................................31
2.2.2
Key Secondary Endpoints:......................................................................................31
2.2.3
Additional Secondary Endpoints:............................................................................31
32
32
33
2.2.7
Overview of Safety Assessments..............................................................................34
3
OVERALL STUDY DESIGN................................................................................35
3.1
Study Design..........................................................................................................35
3.2
Study Duration for Subjects....................................................................................36
3.3
End of Study...........................................................................................................36
4
STUDY POPULATION.........................................................................................37
4.1
Number of Subjects................................................................................................37
4.2
Inclusion Criteria....................................................................................................37
4.3
Exclusion Criteria...................................................................................................38
4.3.1
Exclusions Related to General Health:...................................................................38
4.3.2
Exclusions Related to Medications:........................................................................38
4.3.3
Exclusions Related to Laboratory Results and Other Assessments:.........................40
41
6
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6.1
Pre-Randomization Procedures...............................................................................46
6.2
Treatment Period....................................................................................................46
7
6.2.2
Relapse Assessment Visit........................................................................................47
6.2.3
Study Stopping Rules..............................................................................................47
47
47
6.4
Efficacy Assessment...............................................................................................48
6.4.1
Primary Efficacy Assessments.................................................................................48
6.4.1.1
Crohn’s Disease Activity Index...............................................................................48
6.4.1.2
Simple Endoscopic Score for Crohn's Disease........................................................49
6.4.2
Other Efficacy Measures.........................................................................................50
6.4.2.1
Abdominal Pain and Stool Frequency.....................................................................50
6.4.2.2
Histology................................................................................................................50
6.5
Other Assessments..................................................................................................51
6.5.1
Physical Examination.............................................................................................51
6.5.2
Vital Signs..............................................................................................................52
6.5.3
Electrocardiogram..................................................................................................52
6.5.4
Pulmonary Function Test........................................................................................52
52
53
6.7
Health-related Quality of Life and Health Economics Assessments.........................53
54
54
54
55
55
55
7
DESCRIPTION OF STUDYTREATMENTS........................................................56
7.1
Description of Investigational Product(s)................................................................56
7.2
Treatment Administration and Schedule.................................................................56
7.2.1
Instructions for Missed Doses.................................................................................56
7.2.2
Guidelines for Monitoring Subjects at Risk for Cardiac Events During 
Re-Initiation of Treatment with Investigational Product..........................................57
7.3
Method of Treatment Assignment...........................................................................59
7.4
Packaging and Labeling..........................................................................................59
7.5
Investigational Product Accountability and Disposal..............................................59
7.6
Investigational Product Compliance........................................................................60
8
CONCOMITANT MEDICATIONS AND PROCEDURES....................................61
8.1
Permitted Concomitant Medications and Procedures...............................................61
8.1.1
Corticosteroids.......................................................................................................61
8.1.2
Aminosalicylates or Purified Medicinal Probiotics.................................................61
8.1.3
COVID-19 Vaccination...........................................................................................62
8.2
Prohibited Concomitant Medications and Procedures..............................................62
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62
63
8.3
Required Concomitant Medications and Procedures................................................63
9
STATISTICAL CONSIDERATIONS....................................................................64
9.1
Overview................................................................................................................64
9.2
Study Population Definitions..................................................................................64
9.3
Sample Size and Power Considerations...................................................................64
9.3.1
Primary Endpoints..................................................................................................64
9.3.2
Power Calculations................................................................................................65
9.3.3
Stratified Block Randomization...............................................................................65
9.4
Background and Demographic Characteristics........................................................65
9.5
Subject Disposition.................................................................................................66
9.6
Efficacy Analysis....................................................................................................66
9.6.1
Analysis of Primary and Key Secondary Endpoints.................................................66
9.6.2
Control of Family-wise Type IError Rate...............................................................66
9.7
Safety Analysis.......................................................................................................66
9.8
Treatment Failure Rules..........................................................................................67
9.9
Other Topics...........................................................................................................67
67
9.9.2
Data Monitoring Committee...................................................................................67
10
ADVERSE EVENTS..............................................................................................68
10.1
Monitoring, Recording, and Reporting of Adverse Events......................................68
10.1.1
Treatment of Overdose of Investigational Product..................................................69
10.1.2
Monitoring of Subjects with Adverse Events and Serious Adverse Events................69
10.2
Evaluation of Adverse Events.................................................................................69
10.2.1
Seriousness.............................................................................................................69
10.2.2
Severity...................................................................................................................71
10.2.3
Causality................................................................................................................71
10.2.4
Duration.................................................................................................................71
10.2.5
Action Taken...........................................................................................................72
10.2.6
Outcome.................................................................................................................72
10.2.7
Adverse Events of Special Interest..........................................................................72
11
CLINICAL LABORATORY EVALUATIONS......................................................74
11.1
Hematology............................................................................................................74
11.2
Chemistry...............................................................................................................75
12
PREGNANCY.......................................................................................................77
12.1
Female Subjects of Childbearing Potential..............................................................77
12.2
Male Subjects.........................................................................................................78
13
REPORTING OF SERIOUSADVERSE EVENTS................................................79
13.1
Safety Queries........................................................................................................79
13.2
Expedited Reporting of Adverse Events..................................................................79
13.3
Sponsor Drug Safety Contact Information..............................................................80
14
DISCONTINUATIONS.........................................................................................81
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14.1
Treatment Discontinuation......................................................................................81
14.2
Study Discontinuation............................................................................................81
15
EMERGENCY PROCEDURES.............................................................................84
15.1
Emergency Contact.................................................................................................84
15.2
Emergency Identification of Investigational Products.............................................84
16
REGULATORY CONSIDERATIONS...................................................................85
16.1
Good Clinical Practice............................................................................................85
16.2
Investigator Responsibilities...................................................................................85
16.3
Subject Information and Informed Consent.............................................................85
16.4
Confidentiality........................................................................................................86
16.5
Protocol Amendments.............................................................................................86
16.6
Institutional Review Board/Independent Ethics Committee Review and 
Approval................................................................................................................86
16.7
Ongoing Information for Institutional Review Board/Independent Ethics 
Committee..............................................................................................................87
16.8
Termination of the Study........................................................................................87
17
DATA HANDLING AND RECORDKEEPING.....................................................88
17.1
Data/Documents.....................................................................................................88
17.2
Data Management...................................................................................................88
17.3
Record Retention....................................................................................................88
18
QUALITY CONTROL AND QUALITY ASSURANCE........................................90
18.1
Study Monitoring and Source Data Verification......................................................90
18.2
Product Quality Complaint.....................................................................................90
18.3
Audits and Inspections............................................................................................90
19
PUBLICATIONS...................................................................................................92
20
REFERENCES.......................................................................................................93
21
APPENDICES........................................................................................................95
APPENDIX A
TABLE OF ABBREVIATIONS.............................................................95
99
APPENDIX C
SARS-COV-2 GUIDELINES...............................................................100
APPENDIX D
PROTOCOL AMENDMENT SUMMARY OF CHANGE 
HISTORY............................................................................................101
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LIST OF TABLES
41
Table2:
Crohn’s Disease Activity Index Assessment...........................................48
Table3:
Crohn'
s Disease Severity Definitions......................................................49
Table4:
Definitions of Simple Endoscopic Score for Crohn'
s Disease..................49
50
Table6:
Robarts Histological Index Grading System............................................51
63
Table8:
Sample Size Calculation.........................................................................65
Table9:
Abbreviations and Specialist Terms........................................................95
99
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LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................36
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1
INTRODUCTION
1.1
Disease Background
Crohn’s disease (CD) is an immune-mediated inflammatory disease of the gastrointestinal (GI) 
tract. Annual incidence varies geographically, with estimates ranging from 3.1 to 14.6 per 
100,000people in the United States and from 0.1 to 16 per 100,000 worldwide (Lakatos, 2006). 
Subjects with CD suffer from diarrhea, rectal bleeding, weight loss, abdominal pain, and fever. 
CDis characterized by a lifelong chronic course of remissions and exacerbations. The pathology 
of this disease is characterized by transmural infiltration of lymphocytes and macrophages, 
granulomas, fissuring ulceration, and submucosal fibrosis. The transmural inflammatory process 
of CD predisposes 
subjects 
to 
the 
formation 
of fistulas 
and it 
has been estimated 
that 
approximately 
35% of subjects will have at least 1fistula during the course of their disease (Schwartz, 2002). In 
a recent study, within 10 years of diagnosis, 50% of adults with CD had undergone bowel surgery 
(Peyrin-Biroulet, 2010).
The current standard of medical care for patients with moderately to severely active CD consists 
of anti-inflammatory approaches, such as corticosteroids, azathioprine (AZA)/6-mercaptopurine 
(6-MP), methotrexate (MTX), and biologics such as anti-tumor necrosis factor (TNF)α, 
anti-interleukin (IL)-12/IL-23, or anti-integrins.
Immunomodulators aid in corticosteroid withdrawal and in preventing relapse, but also are 
associated with considerable side effects. Infliximab, an anti-TNFα-therapy, is able to reduce signs 
and symptoms and induce and maintain remission in the majority of subjects for which it is 
indicated. However, in a large Phase 3 maintenance trial of infliximab for CD (ACCENT I), only 
45% of subjects were considered in remission at Week 30 in the highest dose group (where 
remission was defined as the ability to achieve a Crohn’s Disease Activity Index [CDAI] of
<150points) (Hanauer, 2002). Similarly, the primary response rates in trialsof adalimumab 
(Colombel, 2007) and certolizumab (Sandborn, 2007) were approximately 47% and 37%, 
respectively. Thus, a sizable proportion of the patient population is unresponsive to both 
conventional therapy and TNF antagonists. Vedolizumab, a gut-specific anti-integrin therapy, is 
also indicated for achieving clinical response and clinical remission in this population. However, 
in a large clinical trial of vedolizumab, only 32% of subjectshad a clinical response at Week 6, 
and only 39% receiving vedolizumab every 8 weeks were in remission at Week 52 (Sandborn, 
2013). Ustekinumab, a monoclonal antibody to the p40 subunit of IL-12 and IL-23, was approved 
for the treatment of patients who failed or were intolerant to treatment with immunomodulators, 
corticosteroids, or 1or more TNF antagonists. However, in the induction trials of ustekinumab, 
only 
32% of 
subjects 
were 
responders 
at 
6 
weeks (Feagan, 
2016), and 
about 
40% were 
in remission 
at Week 52 of the maintenance trial. 
Therefore, there remains a considerable unmet medical need for safeand effectiveoral treatments 
for patientswith CD.
1.2
Compound Background 
Ozanimod is a small molecule compound which selectively binds with high affinity to sphingosine 
1-phosphate receptors 1 and 5(S1P1and S1P5). In vitro, ozanimod has little activity on the other 
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sphingosine-1-phosphate (S1P) receptors, showing half maximal effective concentration (EC50) 
greater than 10,000 nM for S1P2, > 5000 nM for S1P3, and > 2000 nM for S1P4. Ozanimod is 
extensively metabolized in humans with up to 13 metabolites identified in plasma, 
urine, 
and feces, 
including 2 active selectivemajor metabolites and 1 inactive major metabolite found in human 
plasma at steady state. The 2 active metabolites (CC112273 and CC1084037) have similar 
structures to ozanimod and similar selectivity across the S1P receptor family. 
Many cell types expressS1P1, including vascular endothelial cells, brain cells, and lymphocytes. 
Stimulation (agonism) of this receptor results in biological activities that includes lymphocyte 
retention in peripheral lymphoid organs (eg, lymph nodes and GIPeyer’s patches), resulting in 
reversible systemic reduction in circulating lymphocytes (Mandala, 2002). Given the 
immune-mediated inflammation in CD, prevention of circulation of disease-exacerbating, 
self-reactive lymphocytes to the gut is likely to have salutary immunomodulatory effects with a 
consequent dampening of disease processes.
Please refer to the Investigator’s Brochure (IB) for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and adverse event(AE)profile of 
the investigational product (IP).
1.2.1
Summary of Nonclinical Studies
The nonclinical safety assessment for ozanimod included repeated dose toxicity (rodent and 
non-rodent), genotoxicity, carcinogenicity, reproductive and developmental toxicity, 
phototoxicity, and immunotoxicology studies. 
The majority of the findings in the chronic toxicology studies, the carcinogenicity studies, and the 
reproductive toxicology studies are considered target mediated effects of S1P1and S1P5agonists. 
These include peripheral blood lymphopenia, lymphoid depletion in the splenic periarteriolar 
lymphoid sheaths and decreased thymic cortical lymphocytes. The activity of ozanimod and the 
characterized metabolites was evaluated in in vitro and in vivo pharmacology assays. Two mouse 
models of IBD, naïve T-cell adoptive transfer and 2,4,6-trinitrobenzenesulfonic acid 
(TNBS)-induced 
colitis, 
demonstrated 
significant 
reduction in 
disease severity scores 
as 
evidenced 
by colon weight 
and length measurements, and 
histopathology. 
Improvement 
in disease 
parameters 
correlated with lymphocyte count reduction with statistically significant effects observed when 
lymphocyte counts were decreased by 
 or more.
Please refer to the IBfor detailed information concerning the available pharmacology, toxicology, 
drug metabolism, clinical studies, and AEprofile of the IP.
1.2.2
Summary of Clinical Studies in Inflammatory Bowel Disease
1.2.2.1
Ulcerative Colitis
Ozanimod has beenstudied in subjects with active ulcerative colitis (UC) in a Phase 2 study 
(RPC01-202)and a Phase 3 global study (RPC01-3101). Itis being studied in a Phase 2/3 study in 
Japan (RPC01-3103)and the global Phase 3open-label extension (OLE) (RPC01-3102).
At the conclusion of the Induction Phaseof RPC01-202, the proportion of patients achieving 
clinical response and clinical remission with ozanimod 0.92 mg was greater than placebo and the 
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difference was both clinically meaningful and statistically significant. In addition, all secondary 
endpoints at 
the 
conclusion 
of 
the Induction Phase, including 
clinical 
response, the 
change in Mayo 
score, and mucosal improvement on endoscopy, were also positive and statistically significant for 
the ozanimod 0.92 mg dose. The overall AEprofile in the induction and maintenance periods 
appeared comparable between the ozanimod dose groups and placebo, with no concerning safety 
signals observed. 
RPC01-202 also had amaintenance periodand an OLEperiod. Treatment with ozanimod0.92mg 
in the OLEperiod demonstrated efficacy in the endpoints of clinical remission, clinical response,
histological remission, and mucosal healingin a substantial proportion of subjects.Decreases in 
partial Mayo scores and complete Mayo scores during the induction and maintenanceperiodswere 
maintained throughout the OLE period. Correspondingly, individual Mayo subscores of stool 
frequency, rectal bleeding, physician’s global assessment score, and endoscopy showed 
improvement with ozanimod 0.92 mg treatment throughoutthe OLE period.The safety and 
tolerability results from the UC RPC01-202 Phase2 study suggest that ozanimod at doses of 
0.46and 0.92 mg daily for 32 weeks are well tolerated and have an acceptable safety profile in 
subjects with moderatelyto severely active UC(Sandborn, 2016).
RPC01-3101, aPhase 3 study in adult subjects with moderate to severe UCmet both primary 
endpoints, demonstrating highly statistically significant (p-value < 0.0001) results for clinical 
remission in induction at Week10 and in maintenance at Week 52(Sandborn, 2021). All 3 key 
secondary endpoints in the Induction Period (clinicalresponse, endoscopic improvement, and 
mucosal healing), and all 6 key secondary endpoints inthe Maintenance Period (clinical response, 
endoscopic improvement, maintenance of remission,corticosteroid-free remission, mucosal 
healing, and durable clinical remission) were achieved bya statistically significantly greater 
proportion of subjects in the ozanimod 0.92 mg treatmentgroup compared with placebo. The 
treatment effects for the primary and key secondaryendpoints consistently supported a favorable 
treatment effect for ozanimod in multipledemographics, prior and concomitant medication, 
disease characteristics, and geographicsubgroups.
1.2.2.2
Crohn’s Disease
RPC01-2201, aPhase 2 study wasconducted in CDto examine endoscopic and clinical outcomes 
following treatment with ozanimod 0.92 mg daily for 12 weeks. Simple Endoscopic Score for 
Crohn’s Disease (SES-CD) reductions of ≥50% from baseline were seen in 28.6% of subjects
(observed cases)as measured by paired segments,with greater endoscopic response in subjects 
with baseline SES-CD score ≤12 and a shorter disease duration.At Week 52, the proportion of 
subjects achieving reductions of ≥ 50% was maintained at 26.7%. Clinical response wasseen in 
68.5% and 93.8% of subjects (observed cases)at Week 12 andWeek 52, respectively. Clinical 
remission wasseen in 46.3% and 65.6% of subjects (observed cases) at Week12 and Week 52, 
respectively. 
 
 
The safety and tolerability results fromthe 12-week Induction Period of RPC01-2201 suggest that 
ozanimod0.92 mg daily is well tolerated and has an acceptable safety profile in subjects with 
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moderately toseverely active CD. In the open-label period (OLP), ozanimod 0.92 mg was well 
tolerated andthere were no new safety concerns. The AEs reported in the study were generally 
consistent with those seen in subjects with moderately to severely active UC. 
 
 
 
 
Please refer to the IBfor detailed information concerning the available pharmacology, toxicology, 
drug metabolism, clinical studies, and AEprofile of the IP.
1.2.3
Rationale for Dose Selection
Results from Phase 1 single-ascending dose and multiple ascending dose studies were utilized to 
select appropriate doses for Phase 2 studies. The Phase 2 trial of ozanimod in UC was conducted 
comparing 0.92 mg and 0.46 mg of ozanimod with placebo. Safety was comparable across both 
ozanimod arms, and the 0.92mg/day dose arm demonstrated better efficacy as compared to the 
0.46mg/day dose arm across various clinical and endoscopic endpoints (Sandborn, 2016). Results 
suggested a dose dependent efficacy response, making 0.92mg more favorable for future 
investigation. 
The favorable 
clinical 
results 
and the available 
safety 
data from 
the 
Phase 2 
and 
Phase 3 
UC studies 
as described above, as well assupportive clinical and safety data from the completed relapsing 
multiple sclerosis (RMS)program, provide additional data to support useof the 0.92mg dose of
ozanimod. Datafrom 52 weeks of treatment (RPC01-2201)demonstrated that subjects with active 
CD treated with ozanimod 0.92mg experienced efficacious clinical, endoscopic, histologic
 
 treatment responses with a comparable safety profile to subjects 
previously evaluated with ozanimod.The overall data supportedevaluating the 0.92 mg dose in 
the ozanimod Crohn’s disease program. 
A dose-escalation regimen over the first 7 days is being utilized to mitigate the magnitude of heart 
rate reduction as a result of supportive data from the Phase 1 study (RPCS 001) and preliminary 
results from the Phase2 UC study (RPC01-202). Preliminary evidence from these studies suggests 
a lower likelihood of profound decrease in heart rate or blood pressure in subjects who increase 
their dose progressively over the first week. A dose escalation starting with 0.23mgof ozanimod 
for the first 4 days of dosing followed by 0.46mg on Days5 through7 before progressing to the 
0.92mg/day dose will be used.
Please refer to the IBfor detailed information concerning the available pharmacology, toxicology, 
drug metabolism,clinical studies, and AEprofile of the IP.
1.3
Study Rationale
Given the mechanism of action of ozanimod, data from the preclinical animal model, the positive 
results from the Phase 2 UC study, RPC01-202, and preliminary results from the Induction Period 
of the Phase 2 studyin CD, RPC01-2201, a Phase 3 program with ozanimod in CD wasinitiated.
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The current study, designed as a randomized, double-blind, placebo-controlled study, will assess 
whetherongoing treatment with ozanimod is required and effective in maintaining clinical 
remission (CDAI score < 150) and clinical response(CDAI reduction from baseline ≥100points 
or CDAI score <150)in subjects who have previously responded to ozanimod. All subjectswho 
loseresponse will be offered treatment with ozanimod in an OLEStudy. Primary efficacy 
assessment of ozanimod 0.92mg per day for maintenance will be assessed at Week 52 in subjects 
who achieve clinical response after 12 weeks of treatment in the Induction Studies. Week 52 is 
selected based on the efficacy results seen in the RPC01-2201 after 12weeks of treatment with 
ozanimod 0.92mg dailyand the time needed to evaluate maintenance of clinical remission. Safety 
of treatment with ozanimod for 64weeks will beexamined in subjects who complete both the 
Induction and Maintenance Studies.
1.4
Risk/Benefit Assessment
The assessment of potential risks for identified safety findings, as well as the risk mitigations, are 
summarized in the table below. More detailed information about the known and expected benefits 
and risks and reasonably anticipated adverse events (AEs) of ozanimod may be found in the IB.
Individual risk/benefit considerations remain the responsibility of the investigator. Investigators 
should apply clinical judgment and these risks should be considered when managing a subject and 
when deciding if continuation of treatment with ozanimod is warranted.
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1.4.2
Benefit Assessment
The benefit in UC is established. See Section1.2.2.1for details. Preliminary results from a 
non-controlled Phase 2 trial in CD indicated that subjects derived clinical and endoscopic benefit 
from treatment with ozanimod. See Section1.2.2.2for details.
1.4.3
Overall Risk/Benefit Conclusion
Despite recent progress in CD treatment, there remains an unmet need for agents that are safe and 
convenient oral treatments and can provide effective induction and long-term maintenance of 
clinical remission. The risk/benefit profile for ozanimod has been evaluated for the indication of 
CD. Results from subjects with moderate 
to severe disease who previously failed prior 
therapy and 
were treated with ozanimod 0.92 mg daily for at least 12 weeks suggested clinical and endoscopic 
benefit. In addition, the safety results suggest that ozanimod is well tolerated in patients with CD 
and is consistent with that observed in other patient populations (UC and RMS). The overall data 
to date suggest that this ozanimod Maintenance Study (RPC01-3203) has a potential favorable 
risk/benefit profile for patients with active CD who have achieved clinical response after 12weeks 
of treatment.
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2
STUDY OBJECTIVESAND ENDPOINTS
2.1
Study Objectives
2.1.1
Primary Objective:
Demonstrate the efficacy of ozanimod compared to placebo on the maintenance of clinical 
remission and endoscopic response
2.1.2
Secondary Objectives:
Demonstrate the efficacy of ozanimod compared to placebo on maintenance of clinical 
response
Demonstrate the efficacy of ozanimod compared to placebo on maintenance of endoscopic 
remission and mucosal healing
Demonstrate the efficacy of ozanimod, compared to placebo, in achieving corticosteroid-free 
clinical remission
Demonstrate the efficacy of ozanimod, compared to placebo, 
on healthcare resource utilization
(HRU), subject-reported outcomes, and quality of life
Demonstrate the safety and tolerability of ozanimod as maintenance therapy
2.2
Study Endpoints
Note: All endpoints will evaluatesubjects on ozanimod 0.92mg and placebo at Week 52 unless 
otherwise specified.Baseline is defined as Day 1 in the Induction Study. 
2.2.1
Primary Endpoints:
Proportion of subjects with CDAI score < 150 at Week 52
Proportion of subjects with SES-CD decrease from baseline ≥ 50% at Week 52
2.2.2
Key Secondary Endpoints:
Proportion of subjects with CDAI reduction from baseline ≥ 100 points or CDAI score <150 
at Week 52
Proportion of subjects with average daily abdominal pain score ≤1point and average daily 
stool frequency ≤ 3pointswith abdominal pain and stool frequency no worse than baselineat 
Week52
Proportion of subjects with CDAI score < 150 at Week 52, while remaining corticosteroidfree 
in the 12 weeksprior to Week 52among all subjects at Maintenance Day 1
Proportion of subjects with CDAI score < 150 at Week 52 in subjects with CDAI score <150 
at Maintenance Day 1
Proportion of subjects with SES-CD ≤ 4 points and SES-CD decrease from baseline ≥ 2points 
with no SES-CD subscore > 1 point at Week 52
Note: Final ranking of key secondary endpoints may vary by region and will be defined in the 
SAP. 
2.2.3
Additional Secondary Endpoints:
Proportion of subjects with CDAI score < 150 and SES-CD decrease from baseline ≥50% at 
Week 52
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Proportion of subjects with average daily abdominal pain score ≤ 1 point, and average daily 
stool frequency score ≤ 3 points with abdominal pain andstool frequency no worse than 
baseline andSES-CD ≤ 4 points and SES-CD decrease ≥2 pointswith no SES-CD subscore 
>1 pointat Week 52
Proportion of subjects with CDAI reduction from baseline ≥ 100 points or CDAI score <150 
and SES-CD decrease from baseline ≥ 50% at Week 52
Proportion of subjects with CDAI score < 150 at Maintenance Day 1and SES-CD decrease
from baseline ≥ 50% at Week 52
Proportion of subjects with CDAI reduction from baseline ≥ 70 points at Week 52
Proportion of subjects with CDAI score < 150 at Week 52, while remaining corticosteroid free 
in the 12 weeks prior to Week 52 among subjects using corticosteroids at Maintenance Day 1
Proportion of subjects with mucosal healing (SES-CD ≤ 4 points and SES-CD decrease 
≥2pointswith no SES-CD subscore > 1 point)and histologic improvementbased on Robarts 
Histologic Index (RHI) at Week 52
Time to relapse (an increase in CDAI score from Maintenance Day 1 ≥100 points and CDAI 
score >220, SES-CD ≥ 6 [or ≥4 if isolated ileal disease]), and exclusion of other causes of an 
increase in disease activity unrelated to underlying CD (eg, infections, change in medication)
Proportion of subjects with a Crohn’s Disease Endoscopic Index of Severity (CDEIS) decrease 
from baseline ≥ 50% at Week 52
Proportion of subjects with CDAI score < 150at Week 52 and at ≥80% of visits between 
Week 8 and Week 52, inclusive, in subjects with CDAI score < 150 at Maintenance Day 1
Proportion of subjects with average daily abdominal pain score ≤1 pointand average daily 
stool frequency score ≤3 points with abdominal pain and stool frequency no worse than 
baseline and SES-CD decrease from baseline ≥50% at Week 52
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2.2.7
Overview of Safety Assessments
The incidence, severity, relationship, and type of treatment-emergent adverse events (TEAEs), 
serious adverse event (SAEs), AEs leading to discontinuation of IP(see Section14), and AESIs 
will be summarized, as well as clinically meaningful changes from baseline for clinical laboratory 
measures, vital signs, and electrocardiograms (ECGs).
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3
OVERALL STUDY DESIGN
3.1
Study Design
This is a Phase 3, randomized, double-blind, placebo-controlled study to demonstrate the effect of 
oral ozanimod as maintenance therapy in subjects with moderately to severely active CD. Subjects 
who complete the initial 12 weeks of treatment (Induction Studies RPC01-3201 or RPC01-3202) 
and are in clinical response (CDAI reduction from baseline ≥100 points or CDAI score <150),
and/or clinical remission (CDAI score < 150points),and/or have an average daily stool frequency 
score ≤ 3 and an average abdominal pain score ≤ 1 with abdominal pain andstool frequency no 
worse than baseline will be eligible to participate in the Maintenance Study.
The total number of subjects enrolled (estimated at 550)will be determined based on how many 
subjects are eligible from the Induction Studies and choose to continue to the Maintenance Study. 
Approximately 410subjects who receivedozanimod in either RPC01-3201 or RPC01-3202
(Induction Studies) and arein clinical remission,clinical response,and/or have an average daily 
stool frequency score ≤ 3 with an average abdominal pain score ≤ 1 andabdominal pain and stool 
frequency no worse than baseline by Week 12,are expectedto enroll in this study. For additional 
details see Section4.1.Subjects who received ozanimod in the Induction Studies will be randomly 
assigned to receive ozanimod or placeboin a 1:1 ratio.Subjects will be stratifiedby clinical 
remission at entry into the Maintenance Study (yes/no)andcorticosteroid use at entry into the 
Maintenance Study (yes/no).
In addition, subjects who meet the criteria for the Maintenance Study (RPC01-3203)after 
receiving placebo in either RPC01-3201 or RPC01-3202 will continue to receive placebo in a 
blinded fashion. 
Subjects will be assessed for disease activity through Week 52 of the RPC01-3203 study. Subjects 
who experience disease relapse in the RPC01-3203 study (see Section14.2)and all subjects who 
complete the RPC01-3203 study will be eligible to enter the OLEStudy (RPC01-3204).
The study will be conducted in compliance with International Councilon Harmonisation (ICH) of 
Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical 
Practice(GCP) and applicable regulatory requirements.
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Figure 1:
Overall Study Design
Note: Subjectswho meet the criteria for the Maintenance Study (RPC01-3203) atWeek 12of the Induction Study
who were randomized to placebo will continue to receive placebo in the Maintenance Studyin a double-blind manner. 
Only subjects assigned to ozanimod in the Induction Studywill be randomized into ozanimod or placebo when 
entering the Maintenance Study.Refer to Section3.1.
3.2
Study Duration for Subjects 
Subjects who complete the Maintenance Studyare anticipated to receive 64 weeks of treatment 
(12-week Induction Study+ 52-week Maintenance Study).Subjects not entering the OLEStudy 
will have 
.
3.3
End of Study
The end of study(Maintenance Study RPC01-3203) is defined as either the date of the last visit of 
the last subject 
to complete the 
, 
or 
the date 
of receipt of 
the last datapoint 
from the last subject that is required for primary or secondary analysis, as pre-specified in the 
protocol, whichever is the later date.If the Sponsordiscontinuesthe Maintenance Studyprior to 
theplanned end of study, active subjectswill be considered completers of the study and maybe 
eligible to enrollin the Open-Label Extension Study (RPC01-3204).
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4
STUDY POPULATION
4.1
Number of Subjects
The total number of subjects enrolled (estimated at 550) will be determined based on how many 
subjects are eligible from the Induction Studies and choose to continue to the Maintenance Study. 
Approximately410subjectswho wereallocated to receive ozanimod in either RPC01-3201 or 
RPC01-3202and arein clinical remission,clinical response,and/or have an average daily stool 
frequency score≤3 with an average abdominal pain score ≤ 1 withabdominal pain and stool 
frequency no worse 
than baseline by Week 12are estimated to be randomized to receive ozanimod
or placeboin a 1:1 ratio.Subjects inclinical remission and/or clinicalresponse after receiving 
placebo in either RPC01-3201 or RPC01-3202 will continue to receive placebo in a blinded 
fashion.
4.2
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1.Subject fulfilled the inclusion criteria at time of entry into the Induction Study
(RPC01-3201 or RPC01-3202) and has completed the Week12 efficacy assessments of
the Induction Study.
2.Subjectshould not have any constraints under local regulations,must provide written 
informed consentprior to any study-related procedures,and must have the ability to 
comply
.
3.Subject is in clinical response (a reduction from baseline in CDAI ≥100points or CDAI 
score <150 points) and/or clinical remission (CDAI score < 150 points)and/or has an 
averagedailystool frequency score ≤3 and an average abdominal pain score ≤ 1 with 
abdominal pain andstool frequencyno worse than baseline at Week 12 oftheInduction 
Study.
4.Female subjects of childbearing potential(FCBP):
Note: For the purposes of this study, a female subject is considered to be of childbearing 
potential if she 1) has not undergone a hysterectomy (the surgical removal of the uterus) or 
bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been 
postmenopausal for at least 24 consecutive months (that is, has had menses at any time 
during the preceding 24 consecutivemonths).
Must agree to practice a highly effective method of contraception throughout the study 
until completion of the 
. Highly effective methods of 
contraception are those that alone or in combination result in a failure rate of a Pearl Index 
of less than 1% per year when used consistently and correctly. Examples of acceptable 
methods of birth control in the study are the following:
combined hormonal (containing oestrogen and progestogen) contraception, which may 
be oral, intravaginal, or transdermal
progestogen-only hormonal contraception associated with inhibition of ovulation, 
which may be oral, injectable, or implantable
placement of an intrauterine device (IUD)
placement of an intrauterine hormone-releasing system (IUS)
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bilateral tubal occlusion
vasectomized partner
complete sexual abstinence
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method are not 
acceptable methodsof contraception.
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted for FCBP. 
 
 
 
 
 
4.3
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
4.3.1
Exclusions Related to General Health:
1.Subject has any clinically relevant cardiovascular, hepatic, neurological, pulmonary
(severe respiratory disease [pulmonary fibrosis or chronic obstructive pulmonary disease]), 
ophthalmological, endocrine, psychiatric, or other major systemic disease making 
implementation of the protocol or interpretation of the studydifficult or that would put the 
subject at risk by participating in the study.In France, hypotension is exclusionary if it
makesthe implementation of the protocol or interpretation of the study difficult or would 
put thesubject at risk by participating in the study.
2.Subject is pregnant, lactating, or has a positive urine beta human chorionic gonadotropin 
(β-hCG)testmeasured prior to randomization.
3.Subject has suspected or diagnosed intra-abdominal or perianal abscess that has not been 
appropriately treated.
4.Subject has undergone a colectomy (partial or total), small bowel resection,or an ostomy 
(ie,temporary colostomy, permanent colostomy, ileostomy, or other enterostomy) since 
Day 1of the Induction Studiesor has developed symptomatic fistula (enterocutaneous or 
entero-enteral).
5.Subject has had cancerwithin 5 years including solid tumors and hematological 
malignancies (except basal cell and in situ squamous cell carcinomas of the skin or cervical 
dysplasia/cancer that have been excised and resolved);or colonic dysplasia that has not 
been completely removed.
4.3.2
Exclusions Related to Medications:
6.Hypersensitivity to active ingredients or excipients of ozanimod orplacebo
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19.Subjects who have met the discontinuation criteria in the Induction Period.
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4.3.3
Exclusions Related to Laboratory Resultsand Other Assessments:
20.Subject has any clinically significant abnormalresults (eg,labs or ECG) which,in the 
opinion of the investigator, may put the subjectat risk.
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6
6.1
Pre-Randomization Procedures
Written, signed, and dated informed consent from the subjectprior to the performance of any 
study-related procedures must be obtained by the investigator or designee (refer to Section16.3
for further details regarding obtaining subject’s informed consent). A copy of the signedInformed 
Consent Form(ICF)must be given to the subjectfor his/her records.
Assessments and procedures as per 
are to be performed by the investigator or a qualified 
designee.
 
See APPENDIXCfor further SARS-CoV-2 guidance.
6.2
Treatment Period
Eligible subjects will be randomized to treatment on Day 1. 
 
 Guidelines for dose escalationand 
instructions for missed doses are in Section7.2.
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6.2.2
Relapse Assessment Visit
If during the Maintenance Period, the investigator becomes aware of potential relapse outside the 
normal visit schedule, subjects should be evaluated for relapse as outlined in the 
 
(
;see Section14.2).
6.2.3
Study Stopping Rules
The sponsor has the right to terminate the studyfor safety reasons. In addition, the sponsor may 
terminate the studyfor administrative reasons. In all cases, all necessary measures mustbe taken 
to guarantee appropriate 
 of all subjects already included in the study.
The Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and the Regulatory 
Authorities will be informed in writing about any termination of the study.
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6.4
EfficacyAssessment 
See Section2for a description of study endpoints.
6.4.1
Primary Efficacy Assessments
The CDAI and SES-CDwill be used to evaluate the primary efficacy endpoints.
6.4.1.1
Crohn’s Disease Activity Index
The CDAI is a composite score that is used to measure the clinical activity of CD. The CDAI uses 
a questionnaire with responses scored numerically and weighted. Scores range from 0 to 
approximately 600, with higher scores indicating greater disease activity. The 8 components used 
to assess the CDAI and their weighting factors are noted in Table2. The definitions of mild, 
moderate, and severe CDare provided in Table3.
Clinical remission based on CDAI score is defined as CDAI score < 150. Clinical response is 
defined as CDAI reduction from baseline ≥ 100 points or CDAI score < 150. Clinical remission 
based on abdominal pain and stool frequency is defined an average daily stool frequencyscore ≤3 
and an average abdominal pain score ≤ 1 with abdominalpain and stool frequency no worse than 
baseline.
Subject-reported components of the CDAI (stool frequency and abdominal pain components and 
general well-being) will be collected in an electronic diary. Subjects will complete their electronic 
diary starting at Randomization visit and will continue throughout the study.
Subjects will be instructed on the use and completion of questions on the electronic diary.
The diary entries will be reviewed by site personnel during Randomization and throughout the 
study.
Table2:
Crohn’s Disease Activity Index Assessment
Clinical or Laboratory Variable
Weighting Factor, ×
Number of liquid or soft stools each dayfor 7 days
2
Abdominal pain (graded from 0-3 on severity) each day for 7 days
5
General well-being, assessed from 0 (well) to 4 (terrible) daily for 7 days
7
Presence of complications
20
Taking diphenoxylate/atropine, loperamide, or opiates for diarrhea
30
Presence of an abdominal mass (0 as none, 2 as questionable, 5 as definite)
10
Hematocrit 47-HCT in men and 42-HCT in women
6
Percentage deviation from standard weight
1
Total Score
b
Abbreviations: HCT = hematocrit.
b One point each is added for each set of complications: arthritis or arthralgia; iritis or uveitis; erythema nodosum, 
pyoderma gangrenosum, aphthous stomatitis; anal fissure, fistula or perirectal abscess; other bowel-related fistula; 
febrile (fever) episode over 100 degrees during the past week.
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Table3:
Crohn's Disease Severity Definitions
Severity
CDAI Score
Mild
150-219
Moderate
220-450
Severe
> 450
Abbreviations: CDAI = Crohn’s Disease Activity Index.
6.4.1.2
Simple Endoscopic Score for Crohn's Disease
The SES-CD assesses the degree of inflammation. The SES-CD assesses the following 
4components: size of ulcers, ulcerated surface, affected surface, and presence of narrowing. Each 
of these components are scored on a scale of 0 to 3 as outlined inTable4.
In the SES-CD, each of these 4 components are assessed in the 5segments of the ileum and colon: 
Ileum, right, transverse, left (descending and sigmoid), and rectum. The SES-CD is the sum of the 
individual scores of each of the components across the 5segments.
Endoscopic response has not yet been validatedand maybedefined as a 25%to 50% or greater 
decrease in SES-CD from baseline. Endoscopic remission may be defined as SES-CD ≤4 points 
and SES-CD decrease from baseline≥2 pointswith no SES-CD subscore > 1 point.
To ensure quality data and standardization, the same endoscopist and the same diameter 
colonoscope as used in screening should be used throughout the study wherever possible. During 
the colonoscopy, each subject will have 2 biopsies taken from the most affected areas of each 
accessible segment (maximum of 10 biopsies), or a minimum of 1 biopsy from each segment if 
restricted by national or local regulations. Details regarding the biopsies are provided in the biopsy 
manual and Histology Image Charter. Colonoscopies will be read at a centralized reading facility 
in a process outlined in the Endoscopy Image Charter. Centralized reading will be the primary 
assessment for endoscopy; local endoscopy scores will also be collected.
Table4:
Definitions of Simple Endoscopic Score for Crohn's Disease
Simple Endoscopic Score for Crohn's DiseaseValues
Variable
0
1
2
3
Size of ulcers
None
Aphthous ulcers 
(0.1to0.5cm)
Large ulcers 
(0.5 to 2 cm)
Very large ulcers
(>2 cm)
Ulcerated surface
None
<10%
10%-30%
> 30%
Affected surface
Unaffected segment
<50%
50%-75%
> 75%
Presence of 
narrowings
None
Single, can be 
passed
Multiple, can be 
passed
Cannot be passed
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6.4.2
Other Efficacy Measures
6.4.2.1
Abdominal Pain and Stool Frequency
The abdominal pain and stool frequency scores are based on 2 components of the CDAI (Khanna,
2015). See Section6.4.1.1above for more details.
Stool frequency and abdominal pain, as described in Section6.4.1.1, will be obtained and 
calculated without a weighting factor for use as part of the inclusion criteria. These unweighted 
subject-reported assessments will also be used as efficacy endpoints (Section2).
The 
 is an additional tool for the visual evaluation of diarrhea, 
and will be collected from all subjects in the electronic diary.
 
6.4.2.2
Histology
A central reader will evaluate biopsies taken during colonoscopy and determine the 
 
 RHI (Table6). Biopsies will be taken from the explored ileal and colonic segments. 
The 
 RHI scores provided from the central readerwill be used for histopathology 
endpoints.
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Table6:
Robarts Histological Index Grading System
RHI Descriptors and Levels
Chronic inflammatory infiltrate
0: No increase
1: Mild butunequivocal increase
2: Moderate increase
3: Marked increase
Lamina propria neutrophils
0: None
1: Mild but unequivocal increase
2: Moderate increase
3: Marked increase
Neutrophils in epithelium
0: None
1: < 5% crypts involved
2: < 50% crypts involved
3: > 50% crypts involved
Erosion or ulceration
0: No erosion, ulceration, or granulation tissue
1: Recovering epithelium + adjacent inflammationor probable erosion-
focally stripped
2: Unequivocal erosion
3: Ulcer or granulation tissue
6.5
Other Assessments
6.5.1
Physical Examination
A complete physical examination will be performed to evaluate the heart, lungs, head and neck, 
abdomen, skin and extremities, and weight as well as to check for visual symptoms (ie,blurred 
vision 
 as reported by the subject). A full examination of the skin should 
be repeated every 6 months. An interim physical examination will include weight, a check for 
visual symptoms, and an evaluation of body systems with previously noted abnormalities and/or 
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those body systems associated with any new complaints from the subject. 
 
6.5.2
Vital Signs
Systolic and diastolic blood pressure and pulse will be assessed in a supine and standing position. 
An automated validated device may be used, if available. In case the cuff sizes available are not
large enough for the subject’s arm circumference, a sphygmomanometer with an appropriately 
sized cuff may be used.
6.5.3
Electrocardiogram
The 12-lead digital ECG devices will be provided to each clinical site by the central ECG 
laboratory for the duration of the trial. Detailed instructions describing the process for recording 
and transmission of the digital ECGs will be outlined in the trial-specific manual and provided to 
the site before the start 
of the trial. Paper versions of ECG tracings will be printed and photocopied 
to preserve the ink if necessary, and kept at the site as source documentation. An ECG will be 
performed while resting. Only clinically significant abnormalities should be reported in the 
medical history/current medical conditions or the AE electronic case report form (eCRF).
6.5.4
Pulmonary Function Test
The pulmonary function test (PFT) refers to “pulmonary functiontest –no bronchodilator” 
(eg,spirometry which includes total and timed vital capacity, and expiratory flow rate 
measurement).
 
Pulmonaryfuncti
on tests may be performed at a qualifiedpulmonaryfuncti
onl
aboratory,
respiratorydepartment,orattheclinical trial site. If being performed at the clinical trial site, the 
Principal Investigatormaydelegatethe performanceofthistesttoanystaffmemberthatis 
qualified to perform the pulmonary functi
ontest.If the pulmonary function test results are not 
within normal range and are considered clinically significant, the results must be verified by a 
pulmonologist, and potential confoundingfactors identified.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).
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6.7
Health-related Quality of Life and Health Economics Assessments
The health-related quality of life questionnaires will be provided to each subject via electronic 
device and completed by the subjects at those visits as described in 
.
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7
DESCRIPTION OF STUDY TREATMENTS
7.1
Description of Investigational Product(s)
Ozanimod capsules will be manufactured, quality control tested,and released in accordance with 
Good Manufacturing Practices (GMP).
Ozanimod and matching placebo will be provided as powder-filled capsules. Ozanimod drug 
substance is blended with microcrystalline cellulose, colloidal silicon dioxide, croscarmellose 
sodium and magnesium stearate in opaque hard-gelatin capsules. Two ozanimod dosage strengths 
have been prepared for the clinical investigations: 0.23 mg (size 4 capsule; equivalent to 0.25mg 
ozanimod HCl) and 0.92 mg (size 4 capsule; equivalent to 1 mg ozanimod HCl). For matching 
placebo, the same size 4 opaque hard-gelatin capsules will contain the same blended excipients 
described above. Alldoses of ozanimod and placebo capsules are identical in appearance.
The capsules will be orally administered singularly, or in varying combinations, to achieve the 
desired dose for clinical studies. There is no provision for dose adjustments in this study. Subjects 
who cannot tolerate IPmust be withdrawn from the study.
7.2
Treatment Administration and Schedule
Subjects will receive a single oral dose of ozanimod 0.92 mg(equivalent to ozanimod HCl 1mg) 
or matching placebo administered daily starting on Day 1.
Subjects should be instructed to take IP(either ozanimod or placebo) at approximately the same 
time each day with or without food.
An overdose is any dose of IPgiven to a subject or taken by a subject that exceeds the dose 
described in the protocol. There is no informationregarding overdose with ozanimod. Any 
overdose, with or without associated AEs, must be promptly reported to the Medical Monitor or 
other designated Drug Safety Center. The overdose should be recorded in the OverdoseeCRF.
Adverse Eventsassociated with anoverdose should be reported on the relevant AE/SAE sections 
in the eCRF.
Please refer to the IBfor more information.
7.2.1
Instructions for Missed Doses
Subjects 
should be instructed 
that 
if they forget 
to 
take 
a 
dose, 
they 
can 
take 
the 
dose 
within4hours 
ofthe normal dosing time; otherwise,they should take their next dose at the regular time on the 
following day. If the subject vomits the capsule, he/she should be instructed not to take another 
capsule on the same day, but to take the next dose at the regular time on the following day.
If the subject misses more than 14 consecutive doses for any reason, the Medical Monitor must be 
contacted to discuss procedures for resuming therapy, which may include cardiac monitoring 
procedures on the first day that the subject resumes dosing.If treatment is to be re-initiated after 
14 days, the subject will require a 7-day dose escalation regimen as follows:
Days 1 through 4: Ozanimod 0.23 mg (equivalent to ozanimod HCl 0.25mg) (or matched 
placebo)
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Days 5 through 7: Ozanimod 0.46 mg daily (equivalent to ozanimod HCl 0.5mg) 
(administered as two 0.23-mg capsules or 2 matched placebo capsules)
Days 8 through Week 52: Ozanimod 0.92 mg daily (equivalent to ozanimod HCl1mg) (or 
matched placebo)
 
If IP is re-initiatedand a singledose is missed duringthe first 14 days of treatment re-initiation 
(ie, the dose-escalation period and the following week), or if doses are missed for more than 
7consecutive days during the following 2 weeks (ie, 15-28days after treatment re-initiation), the 
Medical Monitor should be contacted to discuss completing the dose escalation and to again 
reinitiate treatment 
. The missed dose and extended days for dose 
escalation need to be documented as appropriate in the eCRF.
7.2.2
Guidelines for Monitoring Subjects at Risk for Cardiac Events During 
Re-Initiation of Treatment with Investigational Product
Due to the risk of transient decreases in heart rate with the initiation of ozanimod, 
 
 
 
 
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Subjects should be instructed not to drive on the same day after the first dose of IP administration.
7.3
Method of Treatment Assignment
Subjects will be assigned as follows:
ozanimod 0.92mg capsule orally
matching placebo capsule orally
7.4
Packaging and Labeling
Ozanimod capsules will be packaged in 30 cc white high-density polyethylene bottles (35capsules 
per bottle, apart from the dose escalation kits), closed with a 28-mm child-resistant screw-cap that 
is induction sealed. The ozanimod 0.23mg capsules (and matched placebo capsules) will be 
bottled in a 12-count bottle, intended to supply the dose-escalation period only. The ozanimod 
0.92mg capsules (and matched placebo capsules) will be bottled into a 35-count bottle, intended 
to supply daily treatment 
of the intended regimen following the dose-escalation period. To aid with 
visual identification of dosage strength, the cap on the 12-count dose-escalation bottles is blue, 
and the cap on the 35-count bottles is white.
The label(s) for 
IP will include sponsor name, address and telephone number, the protocol number, 
IP name, dosage form and strength (where applicable), amount of IP per container, lotnumber, 
expiry date (where applicable), medication identification/kit number, dosing instructions, storage 
conditions, and required caution statements and/or regulatory statements as applicable. Additional 
information may be included on the label as applicable per local regulations.
7.5
Investigational Product Accountability and Disposal 
Investigational product should not be used for purposes other than as defined in this protocol.
All supplies of IPwill be accounted for in accordance with GCP. There will bean individual IP
accountability record for each subjectand the investigator should maintain accurate records of the 
disposition of all IPsupplies received during the study. These records should include the amounts 
and dates that clinical drug supplies were received, dispensed to the subject, returned by the 
subject,and returned to the sponsor. If errors or damages in the clinical drug supply shipments 
occur, the investigator should contact the Clinical Monitor immediately. Each investigator will 
provide copies of the IPaccountability records for inclusion in the StudyMaster File after database 
lock. The Clinical Monitor will periodically check the supplies of IPheld by the investigator or 
pharmacist to verify accountability of all IPused.
The investigator will provide the IPonly to the identified subjects of this study, according to the 
procedures described in this studyprotocol. After the end of the study, the Clinical Monitor will 
perform final accountability, package, seal, and prepare for shipment. Investigational productand 
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all medication containers will be returned to the clinical supply distribution vendor and 
documentation will be returned to the contract research organization (CRO). The CRO will verify 
that a final report of IPaccountability is prepared and maintained in the investigator’s TrialCenter 
File.
The sponsor(or designee) will review with the investigator and relevant site personnel the process 
for IPreturn, disposal, and/or destruction including responsibilities for the site versus sponsor(or 
designee).
7.6
Investigational Product Compliance
It is the investigator’s responsibility to ensure that subjects are correctly instructed on how to take 
their IP,and that each subjectis fully compliant with his/herassigned dosage regimen. Records of 
IPused atintervals between visits will be kept during the study. Drug accountability will be noted 
by the Clinical Monitor during site visits and at the completionof the study. Subjects will be asked 
to return all unused IPat the end of the study. The IPshould be dispensed by the investigator, or 
by a qualified individual under the investigator’s supervision.
Overall studynoncompliance is defined as taking less than 80% or more than 120% of IPduring 
the entire treatment period.
At each visit, previously dispensed IPcapsules will be collected by the investigator, or by a 
qualified individual under the investigator’s supervision, and compliance assessed. Subjects 
exhibiting poor compliance (ie, 2 or more missed medication days in 1 week) as assessed by 
medication counts and their response to a medication compliance question at each visit should be 
counseled on the importance of good compliance to the studydosingregimen. Subjects who are 
persistently noncompliant (<80% or >120%) should be discussed with the Medical Monitor to 
determine whether they should be withdrawn from the study.
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8
CONCOMITANT MEDICATIONS AND PROCEDURES
All treatments,other than ozanimod, being taken by the subjects on entry into the studyor at any 
time during the study,including through the 
, are regarded as 
concomitant medications and must be documented on the appropriate section of the eCRF. 
Additionally, alldiagnostic, therapeutic, or surgical procedures relating to CD should be recorded.
Administration of concomitant medications must be reported along with dosage information, dates 
of administration, 
and 
reasons for 
use. For 
concomitant 
medications with a single 
active ingredient, 
generic names for concomitant medicationsshould be used if possible. For combination products, 
brand names should be used. The total daily dose should be filled in whenever possible.
8.1
Permitted Concomitant Medications and Procedures
Any medication that is considered necessary for the subject’s health and that is not expected to 
interfere with the evaluation of or interact with IPmay be continued during the study.
The decision to temporarily interrupt dosing for treatment of an intercurrent medical condition, or 
for major surgery that could present an unreasonable risk to the subject, remains the responsibility 
of the treating physician, which will not be delayed or refused by the Sponsor. Prior 
to interruption 
of dosing, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion. The Investigator will report the action taken with IP. The 
Medical Monitor should be contacted to discuss treatment re-initiation (Section7.2.1).See 
Section14for permanent discontinuation of IP.
8.1.1
Corticosteroids
Subjects who were taking baselinecorticosteroids during the Induction Study may continue 
receiving these medications.However,corticosteroids shouldbe tapered followingcompletion of 
the Induction Study. 
8.1.2
Aminosalicylatesor Purified Medicinal Probiotics
Subjects who are receiving oral 5-ASA, or purified medicinal probiotics prior to randomization 
should, if possible, keep their prescribed dosage steady through Week 52. Oral 5-ASAs or 
probiotics should only be discontinued or reduced in dose if required byan investigator’s 
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judgment. Oral 5-ASA or purified medicinal probiotics should not be started in subjects who are 
not receiving them. Ideally, subjects receiving 5-ASA or purified medicinal probiotics should 
maintain a stable dose throughout the study unless reduction or discontinuation is clinically 
indicated.
8.1.3
COVID-19Vaccination
COVID-19 vaccines that are NOT live are allowed and should be handled in the same manner as 
other vaccines. Administration may occur during the study, including during treatmentwith IP and 
after the last dose of IP.
Non-live COVID-19 vaccination is considered a simple concomitant medication within the study. 
However, the efficacy and safety of non-live vaccines (including non-live COVID-19 vaccines) in 
subjects receiving ozanimod is unknown. The individual risk/benefit assessment of a vaccine 
remains with the Investigator. If the assessment of the Investigator suggests the vaccine to be 
beneficial, it must be a non-live, replication-incompetent vaccine, and be approved or otherwise 
authorized (eg, Emergency Use Authorization [FDA] or equivalent) by national health authorities.
See APPENDIXCfor further SARS-CoV-2 guidance.
8.2
Prohibited Concomitant Medications and Procedures
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8.3
Required Concomitant Medications and Procedures
Not Applicable.
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9
STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan (SAP), which will be maintained by the sponsor. The 
SAP may modify the plans outlined in the protocol; however, any major modifications of the 
primary endpoint definition and/or its analysis will also be reflected in a protocol amendment.
9.1
Overview
This is a Phase 3, randomized, double-blind, placebo-controlled studyto demonstrate the effectof 
oral ozanimod as maintenance therapy in adult subjects with moderatelyto severely activeCD, 
defined as CDAI score ≥220 to ≤ 450which will enrollanestimate of 550subjects.
Approximately 410 subjects allocated to receive ozanimod in either RPC01-3201 or RPC01-3202 
are expected to bein clinical remission or clinical response at Week 12 and are expectedto enroll 
in this study. These subjects will be randomized to receive ozanimod0.92 mgor placeboin a 1:1 
ratio.Subjects will be stratified by clinical remission at entry into the Maintenance Study(yes/no)
andcorticosteroid 
use at 
entry into 
the 
Maintenance 
Study(yes/no). 
To 
maintain 
the blind, 
subjects 
in response after receiving placebo in either RPC01-3201 or RPC01-3202 will continue to receive 
placebo in a blinded fashion.
Interactive Response Technology (IRT) will be utilized to implement a centralized randomization. 
See Section9.3.3for more details. An independent Data Monitoring Committee (DMC) will be 
used to monitor the study conduct.
9.2
Study Population Definitions
The following analysis populations will beused in the statistical analysis:
Intent-to-Treat (ITT): 
The ITT analysis population will consist 
of all randomized subjects from 
the Screenedanalysis population receiving at least 1dose of IP. Subjects in the ITT analysis 
population will be analyzed according to 
the randomized treatment, regardless of the treatment 
actually given. The primary analysis population for all efficacy endpoints will be the ITT 
analysis population.
Safety: The safety analysis population is defined as all subjects who are randomized and 
receive at least one dose of study treatment, analyzed by actual treatment received.
Additional analysis populations are defined and their use described in the SAP.
9.3
Sample Size and Power Considerations
9.3.1
Primary Endpoints
This study has 2co-primary endpoints. The first primary endpoint is CDAI clinical remission at 
Week 52. Subjectswill be deemed responderswith respect to this endpoint if they meet the 
definition, CDAI score < 150 at Week 52.
The second primary endpoint is endoscopic response at Week 52. Subjects will be deemed 
responderswith respect to this endpoint if they meet the definition, SES-CD decrease from 
baseline ≥ 50% at Week 52.
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9.3.2
Power Calculations
It is assumed that the placebo remission rate at Week 52 (64 weeks total treatment) will be not 
more than 19% in a randomized withdrawal study in CD subjects. It is assumed that the ozanimod 
remission rate at Week 52 will be not less than 33%. This studyis therefore designed to have at 
least 90% power to reject the first co-primary endpointwhen these conditions are met. The two
group chi-square test of equal proportions for 1:1 balanced treatment arms was applied and the 
following sample size was obtained (Table8).
Table8:
Sample Size Calculation
Endpoint
Assumed 
Placebo 
Rate
Assumed 
Ozanimod 
Rate
Odds 
Ratio
Delta
Type I 
Error Rate
Power
Estimated 
Sample 
Size
Clinical Remission 
(CDAI <150) 
19%
33%
2.1
+14%
5%
90%
409
CDAI= Crohn’s Disease Activity Index.
The same effect size with a smaller placebo response rate is expected for the endoscopic response 
endpoint, implying that 
this estimated sample sizeof subjects receiving ozanimodwill be adequate 
for that endpoint as well. The power for both of these co-primary endpoints is bounded below by 
81%, and it is expected that these endpoints are strongly positively correlated so that the actual 
power to reject both null hypotheses will be greater than 81%. Therefore, asample size of 
approximately 410 subjects who received ozanimod in either RPC01-3201 or RPC01-3202 and 
enrolled in this study is a prioriestimated to be adequate for both co-primary endpoints.
Note: The overall type I error rate across all controlled endpoints will be maintained at 5% using 
methods discussed in Section9.6.
9.3.3
Stratified Block Randomization
Subjects 
enrolled in this 
studyfrom the ozanimod 
arms 
of 
the 
Induction 
Studies 
will be 
randomized 
using stratified block randomization in order to account for the study design. These subjects will 
be randomized with the following stratification factors: clinical remission at entry into the 
Maintenance Study(yes/no)andcorticosteroid use at entry into the Maintenance Study (yes/no). 
Each unique combination of the stratification factors will have an independent randomization list 
that will be used to assign subjects to either ozanimod or placebo in a 1:1 allocation ratio.
9.4
Background and Demographic Characteristics
Subject demographics and baseline characteristics from Studies RPC01-3201and RPC01-3202 
will define subject demographicsand baseline characteristicsfor RPC01-3203. Descriptive 
summaries will be presented for all collected baseline and demographic information. Continuous 
variables will be summarized using number of subjects (n), mean, SD, median, minimum, and 
maximum. Categorical variables will be summarized using frequency counts and percentages.
Baseline characteristics and subject demographics will include, at minimum, age at CD symptom 
onset, age at CD diagnosis,years since CD symptom onset, years since CD diagnosis, baseline 
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CDAI score, baseline SES-CD score, prior anti-TNFbiologic (anti-TNF and others)use, and prior 
corticosteroid use.
9.5
Subject Disposition
Subject disposition will be based on the following:
number of subjects randomized
number of subjects receiving blinded placebo
number of subjects dosed
number of subjects completing the Maintenance Study
number of subjects not completing the Maintenance Studyby reason for dropout
number of subjects entering the OLEStudy
9.6
Efficacy Analysis
Because most of the primary and secondary endpoints for this study, including both co-primary 
endpoints and all of the key secondary endpoints, are either remission or responder endpoints (ie, 
proportions of subjects meeting the criteria to be classified as remitters or responders for the two
treatment groups), 
the analysis of endpoints using a continuous measure will not be described here, 
but rather discussed in the SAP.
The ITT analysis population will be the primary analysis population for all efficacy endpoints. 
Furthermore, for the primary analysis of remission or responder endpoints and for a given time
pointor study visit, ITT subjects who have insufficient data for remission or response 
determination will be considered non-remitters/non-responders for that timepointor study visit. 
Sensitivity analyses and missing data imputation are discussed in the SAP.
9.6.1
Analysis of Primary and Key Secondary Endpoints
The primary analysis of the primary and key secondary endpoints with binary measure (ie,yes/no) 
such as clinical remission and clinical response at Week 52 will be each carried out using the 
Cochran-Mantel-Haenszel (CMH) method. The stratifying factors of clinical remission at entry 
into the Maintenance Study (yes/no) and corticosteroid use at entry into the Maintenance Study 
(yes/no)will be accounted for in the CMH analyses. Details regarding risk differences, 
odds ratios, 
confidence limits, and considerations for sensitivity analyses will be provided in the separate SAP.
9.6.2
Control of Family-wise Type I Error Rate
The primary endpoints and key secondary endpoints will be tested using a closed, hierarchical 
testing procedure in order to control the overall type I error rate for multiple endpoints. The details 
will be provided in the SAP.Only the primary and key secondary endpoints will have type I error 
rates controlled at the family-wise level. All other endpoints will be tested at a nominalα=0.05 
level.
9.7
Safety Analysis
All safety data will be listed and summarized by treatment group as appropriate. All TEAEswill 
be coded and tabulated by system organ class and preferred term. The incidence of AEs, SAEs, 
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and AEs leading to discontinuation will be summarized and presented in descending order of 
frequency. Associated laboratory parameters such as hepatic enzymes, renal function, and 
hematology values will be grouped and presented together. Individual subject values will be listed 
and values outside of the standard reference range will be flagged. Shift tables and analyses of 
changes from baseline willbe produced. The change from baseline for each of the vital signs and 
ECG parameters will be summarized. The incidence of abnormal vital signs parameters and outlier 
ECG results will be tabulated.Adverse events will be summarized by patient years of exposure 
(PYE).
9.8
Treatment Failure Rules
Treatment failure rules (TFR) will be applied to the primary analyses of all efficacy endpoints. 
Subjects will be considered to have failed treatment if any of the following occur:
Surgical resection of small intestine or colon as a treatment of CD related symptoms
Endoscopic dilation treatment for CD associated stricture(s)
Discontinuation of IP due to any reasonbefore the Week 52 efficacy evaluations
9.9
Other Topics
9.9.2
Data Monitoring Committee
An independent, externalData Monitoring Committee(DMC) will be charged with monitoring 
accumulating safetyand efficacydata from the study, as well as general aspects of studyconduct.
The 
committee 
will meet 
periodically 
during 
the 
study
 
to 
review 
aggregate analyses by treatment group concerning enrollment, treatment compliance, adherence 
to 
 schedule, and safety data from the study. The DMC may recommend modifying or 
stopping the studyearly dueto safety concerns based on data reviews.
The blinding plan to assure that all personnel involved in the conduct of the studyremain blinded 
to the results of interim reviews will be specified in the DMC Charter.
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10
ADVERSE EVENTS
10.1
Monitoring, Recording,and Reporting of Adverse Events
An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in 
a subject during the course of a study. It may be a new intercurrent illness, a worsening 
concomitant illness, an injury, or any concomitant impairment of the subject’s health, including 
laboratory test values (as specified by the criteria in Section11), regardless of etiology. Any 
worsening (ie, any clinically significant adverse change in the frequency or intensity of a 
preexisting condition) should be considered an AE. A diagnosis or syndrome should be recorded 
on the AE page of the eCRF rather than the individual signs or symptoms of the diagnosis or 
syndrome.
CDrelapse and related symptoms will be monitored as studyendpoints.These occurrences will 
not be recorded as AEsunlessthey are new or worse than baseline or if they meet the criteria for 
seriousness.
Reductions in ALC levels for subjects in this study is an expected primary 
 
effect. Reductions in ALC, in general, need not be reported as AEs unless there are clinical 
consequences. The protocol requirements in Section11.1should be followed for confirmed 
. The decision to report decreased ALC as an AE is at the investigator’s 
discretion.
In order to facilitate reporting of SARS-CoV-2 events that occur during the study, all AEs and 
SAEs related to SARS-CoV-2 should be reported from the time of consent until the final study 
visit.
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
An adverse drug reaction (ADR) is defined as all noxious and unintended responses to a medicinal 
product related to any dose (ICH E2A, II.A.2).
An unexpected ADR is defined as an adverse reaction, the nature of which is not consistent with 
the applicable product information (ICH E2A, II.A.3).
Each AE is to be evaluated for duration, severity, seriousness and causal relationship to 
the IP. The 
action taken and the outcome must also be recorded.
Abuse, withdrawal, sensitivity or toxicity to an IPshould be reported as an AE.Overdose, 
accidental or intentional, that areassociated with an AE should be reported on the eCRF.See 
Section 7.2for the definition of overdose.Any sequela of an accidental or intentional overdose of 
an IPshould be reported as an AE on the AE eCRF. If the sequela of an overdose is an SAE, then 
the sequela must be reported 
on an SAE Report Form and on the AE eCRF. The overdose resulting 
in the SAE should be identified as the cause of the event on the SAE Report Form and eCRF but 
should not be reportedas an SAE itself.
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10.1.1
Treatment of Overdose of Investigational Product
An overdose is any dose of IPgiven to a subject or taken by a subject that exceeds the dose 
described in the protocol. Any overdose, with or without associated AEs, must be promptly 
reported to the CRO’s Medical Monitor or other designated Drug Safety Center. Overdose should 
be recorded in theOverdoseeCRF.OnlyAEs associated with anoverdose should be reported on 
relevant AE/SAE sections in the eCRF.
10.1.2
Monitoring of Subjects with Adverse Events andSerious Adverse 
Events
Investigators must carefully monitor each subject for AEs. This includes clinical laboratory 
variables. Assessments must be made of the seriousness, severity, and relationship to the 
administration of the IP. 
 
 
 
 Safety reporting must comply with ICH E6, 
4.11.
All AEs will be recorded by the investigator from the time the subject signs informed consent until
 as well as those SAEs 
made known to the investigator at any time thereafter that are suspected of being related to IP. All 
SAEs that occur 
, whether or not 
considered related to the IP, must also be reported. Adverse events and SAEs will be recorded on 
the AE page of the eCRF and in the subject’s source documents. Refer to Section13for 
instructions on how to report SAEs to Drug Safety.
10.2
Evaluation of Adverse Events
A qualified investigator willevaluate all AEsbased on seriousness, severity, causality, duration, 
action taken, and outcome.
10.2.1
Seriousness
An SAE (experience) or reaction is any untoward medical occurrence that at any dose (ICH E2A, 
II.B):
results in death
is life-threatening
NOTE: The term “life-threatening” in the definition of “serious” refers to an event in which 
the subject was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.
requires inpatient hospitalization or prolongation of existing hospitalization
results in persistent or significant disability/incapacity
is a congenital abnormality/birth defect
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If an AE is considered serious, the AE page/screen of the eCRF must be completed. The SAE 
Report Form may alsoneed to be completed if requiredper the applicable reporting process.
For each SAE, the investigator will provide information on severity, start and stop dates, 
relationship to the IP, action taken regarding the IP, and outcome.
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10.2.2
Severity
For both AEs and SAEs, the investigator must assess the severity of the event. The severity of the 
AE will be characterized as “mild, moderate, or severe” according to the following definitions:
10.2.3
Causality
The causal relationship between the IP and the AE has to be characterized as Not Suspected or 
Suspected as defined below.
10.2.4
Duration
For both AEs and SAEs, the investigator will provide a record of the start and stop dates of the 
event.
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10.2.5
Action Taken
The decision to 
temporarily interrupt dosing as a result of an AE or SAE remains the responsibility 
of the treating physician, which will not be delayed or 
refused by the Sponsor. Prior 
to interruption, 
the Investigator may contact the Medical Monitor and forward appropriate supporting documents 
for review and discussion.
The investigator will report the action taken withIP as a result of an AE or SAE, as applicable (eg, 
discontinuation, interruption, or dose reduction of IP, as appropriate) and report if concomitant 
and/or additional treatments were given for the event.
If dosing is interrupted, the Investigator should contact the Medical Monitor to discuss treatment 
reinitiation (Section7.2.1). See Section14for permanent discontinuation of IP.
10.2.6
Outcome
The investigator will report the outcome of the event for both AEs and SAEs.
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered (returned to baseline), recovered with sequelae, or death (due to 
the SAE).
10.2.7
Adverse Events of Special Interest
Potential AEs that may be a consequence of S1P receptor modulation, AESIs, will be monitored 
during the study. 
 
 
 
 
. For AESIs, the Sponsor may request additional medical 
information concerning the AESIs that are non-serious.
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11
CLINICAL LABORATORY EVALUATIONS
The central laboratory will analyze clinical laboratory samples. Further detailsof the procedures 
to be followed for sample collection, storage, and shipment will be documented in a laboratory 
manual.
Repeat testing for protocol-required laboratory tests are to be analyzed by the central laboratory. 
Additional testing may be performed for significant variations in protocol-required tests at the 
discretion of the investigator and in consultation with the Medical Monitor or designee, or at the 
request of the Sponsor. Approval from the Medical Monitor or designee must be obtained if retest 
is required to be repeated > 2 times and is not already pre-specified in the protocol.
11.1
Hematology
Red blood cell count, total and differential white blood cell (WBC) count (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils), platelet count, hemoglobin, hematocrit, mean 
corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin 
concentration. Total WBC count and all differential WBC counts will be blinded information for 
the treating investigator after initiation of IP. Of note, WBC, basophil, eosinophil, lymphocyte, 
monocyte, and neutrophil counts will not be disclosed to preserve the blind.
Reductions in ALC levels is a known 
 effect of ozanimod. 
 
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11.2
Chemistry
Full chemistry panelprior to randomization: sodium, potassium, chloride, calcium, 
magnesium, phosphate, blood urea nitrogen, glucose, albumin, alkaline phosphatase, 
creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma 
glutamyltransferase (GGT), total bilirubin, conjugated bilirubin, total cholesterol, 
triglycerides, 
, and low-density lipoprotein, 
All other visits: sodium, potassium, chloride, calcium, magnesium, phosphate, blood urea 
nitrogen, albumin, alkaline phosphatase, creatinine, ALT, AST, GGT, total bilirubin, 
conjugated bilirubin, 
. Total cholesterol, triglycerides, 
 
, and low-density lipoprotein willalso be included at the Week52 or Early 
Termination Visits.
 

Urinalysis: Leukocytes, specific gravity, bilirubin, blood, glucose, ketones, pH, protein, and 
urobilinogen
The central laboratory will analyze routine blood samples. Details regarding collection of 
samples, shipment of samples, reporting of results, laboratory reference ranges, and alerting 
abnormal values will be supplied to the site before site initiation in a studylaboratory manual. 
The results of the analysis will be made available to each site by the central laboratory.
Investigators will be asked to comment on those abnormalities on the respective laboratory 
result page, including a notation of the clinical significance of each abnormal finding in the 
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subject’s source documents. The laboratory sheets will be filed with the subject’s source 
documents.

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12
PREGNANCY
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IPmay have 
interfered with the effectiveness of a contraceptive medication; however, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, normal birth, or congenital 
abnormality) must be followed up and documented even if the subject was discontinued from the 
study. In cases of live birth, with the consent of a parent, the infant maybe followed for up to a 
year.
All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should 
also be reported and handled as SAEs. Elective abortions without complications should not be 
handled as AEs. All outcomes of pregnancy must be reported to Sponsor’s Drug Safety or 
designee.
12.1
Female Subjects of Childbearing Potential
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted for FCBP. 
 
 
 
 
 
Pregnancies and suspected pregnancies (including 
 in a 
FCBPregardless of disease state) occurring while the subject ison IP, 
 
 are considered immediately reportable events. Investigational product 
is to be discontinued immediately,and the subject instructed to return any unused portion of the 
IP to the investigator. The pregnancy, suspected pregnancy, or positive pregnancy test must be 
reported to Sponsor’sDrug Safety or designee immediately using the Pregnancy Initial Report 
Form, or approved equivalent form.
The investigator will follow the female subject until completion of the pregnancy, and must notify 
Sponsor’sDrug Safety 
or designee immediately 
about 
the 
outcome 
of 
the pregnancy 
(either 
normal 
or abnormal outcome) using the Pregnancy Follow-up Report Form, or approved equivalent form.
If the outcome of the pregnancy was abnormal (eg, spontaneous abortion), the investigator should 
report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious criteria, 
it must be reported as an SAE to Sponsor’sDrug Safety or designee within 24 hours of the 
investigator’s knowledge of the event using the SAE Report Form, or approved equivalent form.
All neonatal deaths that occur within 
 of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 
 that the investigator suspects is 
related to the in utero exposure to the IP should also be reported to Sponsor’s Drug Safety or 
designee within 24 hours 
of the investigator’s knowledge of the event using the SAE Report Form, 
or approved equivalent form.
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Note: For the purposes of this study, a female subjectis considered to be of childbearing potential 
if she 1) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral 
oophorectomy (the surgical removal of both 
ovaries) 
or 2) has not been postmenopausal for at least 
24 consecutive months (that is, has had menses at any time during the preceding 24consecutive 
months).
12.2
Male Subjects
If a female partner of a male subject taking IP becomes pregnant, the pregnant female partner 
should be advised to call her healthcare provider immediately.
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13
REPORTING OF SERIOUSADVERSE EVENTS
Reporting requirements for SAEs will be managed on behalf of the sponsor by Sponsor’s Drug 
Safety or designee. Full details of the procedures to be adopted will be documented in a safety 
management plan approved by responsible parties, in brief:
The investigator will report any SAE that occurs to any subject from the time written informed 
consent is signed through the last visit. All SAEs that occur 
 
, whether or not considered related to the IP, must also be reported. Any 
SAE that is ongoing when the subject completes the studyor discontinues from the studywill be 
followed by the investigator until the event has resolved, stabilized, or returned to baseline status.
Any AE considered serious by the investigator or sub-investigator or that meets serious criteria 
should be reported 
to 
Sponsor’s Drug Safety or designee 
using the 
designated 
SAEreporting forms 
and procedures. Data entry must be completed within 24 hours from the time the studysite 
personnel first learned of the event.
The SAE contact information is as follows:
For Celgene Drug Safety contact information, please refer to the Serious Adverse Event 
Report Form Completion Guidelines or to the Pregnancy Report Form Completion 
Guidelines.
The initial report should be promptly followed by detailed, written reports, which will include 
copies of hospital case records, discharge summaries, autopsy reports, and other documents when 
requested and applicable. For unrelated cases, a full detailed case description may negate the need 
for additional hospital case records, discharge summaries, etc.
Investigators will be notified by the Sponsor’s Drug Safety or designee of all SAEs that require 
prompt submission to their IRB or IEC. Investigators should provide written documentation of 
IRB/IEC notification for each report to the CRO. The CRO will ensure that all SAEs are reported 
to 
the 
appropriateregulatory 
authorities 
as 
required. 
Reporting 
of 
SAEs must 
comply 
with 
ICHE6, 
4.11.1.
13.1
Safety Queries
Queries pertaining to SAEs will be communicated from Sponsor’sDrug Safety or designee to the 
site. 
 
13.2
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Sponsor’sDrug Safety will determine the expectedness of 
events suspected of being related toozanimodbased on the IB.
In the United States,expedited reports sent to the FDA by the sponsor based on the reasonable 
possibility threshold are known as ‘IND safety reports’and will be reported in accordance 
with21CFR312.32.For reporting to the FDA, events that are not suspected to be causally related 
to ozanimod by the sponsor will not be considered adverse reactions. As per FDA regulations, 
events that are anticipated in the study population (as per the Reference Safety Information section 
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in the IB), will not be considered adverse reactions on individual assessment and will be reviewed 
on an aggregate basis for assessment of frequency.
For countries within the European Economic Area (EEA), sponsoror its authorized representative 
will report in an expedited manner to Regulatory Authorities and IECs concerned, suspected 
unexpected serious adverse reactions (SUSARs)in accordance with Directive 2001/20/EC and the 
Detailed Guidance on collection, verification and presentation of adverse reaction reports arising 
from clinical studieson IPs for human use (ENTR/CT3) and also in accordance with 
country-specific requirements.
Sponsoror its authorized representative shall notify the investigator of the following information:
Any AE suspected of being related to the use of IP in this study or in other studies that is both 
serious and unexpected (ie, SUSAR);
Any finding fromtests in laboratory animals that suggests a significant risk for human subjects 
including reports of mutagenicity, teratogenicity, or carcinogenicity.
Where 
required by local legislation, 
the investigator 
shall notify his/her 
IRB/IEC 
promptly 
of these
newSUSARsor significant risks to subjects.
The investigator must keep copies of all pertinent safety information on file including 
correspondence withthesponsorand the IRB/IEC. See Section 17.3for record retention 
information.
13.3
SponsorDrug Safety ContactInformation
For Sponsor’sDrug Safety contact information, please refer to the Serious Adverse Event Report 
Form Completion Guidelines or to the Pregnancy Report Form Completion Guidelines.
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14
DISCONTINUATIONS
14.1
Treatment Discontinuation
The following events are considered sufficient reasons for discontinuing a subject from the IP:
adverse event
withdrawal by subject
death

lack of efficacy
pregnancy
The reason for discontinuation of treatment should be recorded in the eCRF and in the source 
documents.
The decision to discontinue a subject from treatment remains the responsibility of the treating 
physician, which will not be delayed or refused by the sponsor. However, prior to discontinuing a 
subject, the investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion.
14.2
Study Discontinuation
Subjects may voluntarily withdraw from the studyat any time. The investigator will provide a 
written explanation in the source documentation to be entered on the appropriateeCRF page 
describing the reason for discontinuation.
The criteria for enrollment are to be followed explicitly. If a subject who does not meet enrollment 
criteria is inadvertently enrolled, the Medical Monitor must be contacted, and that subject will be 
withdrawn from the studyif continuation is determined to be a safety risk.
Reasons for discontinuation include, but are not limitedto,the following:
Physician decision: The investigator must discontinue IPif it is determined that it is not safe 
or in the subject’s best interest to receive further treatment. The Medical Monitor should be 
promptly notified of the decision.
Noncompliance with IP: After consultation between the investigator, the Medical Monitor, and 
the sponsor when appropriate, a subject may be discontinued from the studyfor failure to 
comply with dosing regimen as specified by the protocol.
Noncompliance with protocol/protocol deviation: After consultation between the investigator, 
the Medical Monitor, and the sponsor when appropriate, a subject may be discontinued from 
the study for failure to follow protocol procedures, or other event or decision that stands in 
contrast to the guidelines set in the protocol.
Adverse event: A subject must be discontinued from IPif, in the judgment of the investigator 
or if specified in the protocol, the subject develops an AE such as an intercurrent illness or 
complication that justifies discontinuation of IP.
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1International Normalized Ratio (INR) is part of the coagulation panel and may be obtained at the discretion ofthe 
investigator via central or local laboratory testing.
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Lack of efficacy: Decision by the subject and/or 
the investigator 
to discontinue IP due to a lack 
of expected or desired effect related to a therapy.
Withdrawal by subject: The subject may choose to discontinue IPat any time. Every effort 
should be made within the bounds of safety and subjectchoiceto have each subject complete 
the Early Termination Visit 
. If a subject withdraws consent, the only 
additional investigational data to be collected will be the
 of SAEs as mandated by 
the protocol.
Pregnancy: If a femalesubject becomes pregnant,IPmust be discontinued (see Section12).
Studytermination by sponsor
Other
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15
EMERGENCY PROCEDURES
15.1
Emergency Contact
In emergency situations, the investigator should contact the responsible Clinical Research 
Physician/Medical Monitor or designee by telephone at the number(s) listed on the Emergency 
Contact Information page of the protocol (after title page).
In the unlikely event that the Clinical Research Physician/Medical Monitor or designee cannot be 
reached, please contact the global Emergency Call Center by telephone at the number listed on the 
Emergency 
Contact 
Information page of the protocol 
(after 
title 
page).This 
global 
Emergency 
Call 
Center is available 24 hours a day and 7 days a week. The representatives are responsible for 
obtaining your call-back information and contacting the on-call sponsor/designeeMedical 
Monitor, who will then contact you promptly.
Note: The back-up 24-hour global emergency contact call center should only be used if you are 
not able to 
reach the Clinical Research Physician(s) 
or Medical Monitor 
or designee for emergency 
calls.
15.2
Emergency Identification of Investigational Products
The blind must not be broken during the course of the study unlessin the opinion of the 
investigator, it is absolutely necessary to safely treat the subject. If it is medically imperative to 
know what IP the subject is receiving, IP should be temporarily discontinued if, in the opinion of 
the investigator, continuing IP can negatively affect the outcome of the subject’s treatment.
The decision to break the blind in emergency situations remains the responsibility of the treating 
physician, which will notbe delayed or refused by the sponsor. However, the investigator may 
contact 
the 
Medical 
Monitor 
prior 
to 
breaking 
the blind 
to 
discuss 
unblinding, 
mainly in the interest 
of the subject.
The investigator should ensure that the code is broken only in accordance with the protocol. The 
investigator should promptly notify the Medical Monitor of the emergency unblinding and the 
reason for breaking the blind, which should be clearly documented by the investigator in the 
subject’s source documentation.
Emergency unblinding should only be performed by the investigator through the IRT by using an 
emergency unblinding personal identification number (PIN). The investigator should log into IRT 
for unblinded dose information.
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16
REGULATORY CONSIDERATIONS
16.1
Good Clinical Practice
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study are designed toensure that sponsor, its authorized representative, and 
investigator abide by GCP, as described in ICH Guideline E6 and in accordance with the general 
ethical principles outlined in the Declaration of Helsinki. The study will receive approval from an 
IRB/IEC prior to commencement. The investigator will conduct all aspects of this study in 
accordance with applicable national, state, and local laws of the pertinent regulatory authorities.
16.2
Investigator Responsibilities
Investigator responsibilities are set out in the ICH Guideline for GCPand in the local regulations. 
The sponsor’sstaff or an authorized representative will evaluate and approve all investigators who 
in turn will select their staff.
The investigator should ensure that all persons assisting withthe study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of sponsorinformation. The investigator should maintain 
a list of sub-investigators and other appropriately qualified persons to whom he or she has 
delegated significant study-related duties.
The investigator is responsible for keeping a record of all subjects who sign an ICFforthe study.
The investigator, or a designated member of the investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records 
(eg,medical records, office charts, hospital charts, and study-related charts) for source data 
verification. The investigator must ensure timely and accurate completion of eCRFs and queries.
The information contained in the protocol and amendments (with the exception of the information 
provided bythesponsoron public registry websites) is considered sponsorconfidential 
information. Only information that is previously disclosed by sponsoron a public registry website 
may be freely disclosed by the investigator or its institution, or as outlined in the Clinical Study
Agreement. Sponsor’sprotocol,amendment,and IBinformation is not to be made publicly 
available (for example on the investigator’s or their institution’s website) without express written 
approval from thesponsor. Information proposed for posting on the investigator’s or their 
institution’s website must be submitted to the sponsorfor review and approval, providing at least 
5 business days for review.
At the time results of this study are made available to 
the public, sponsorwill provide investigators 
with a summary of the results that is written for the lay person. The investigator is responsible for 
sharing these results with the subjectand/or his/hercaregiver as agreed by the subject.
16.3
Subject Information and Informed Consent
The investigator must obtain informed consent from asubject and/or a subject’slegal 
representative prior to any study-related procedures.
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Documentation that informed consent occurred prior 
to 
the study subject’s entry into 
the study and 
of the informed consent process should be recorded in the study subject’s source documents 
including the date. The original ICF signed and dated by the study subject and by the person 
consenting the study subject prior to the study subject’s entry into the study, must be maintained 
in the investigator’s study files and a copy given to the study subject. In addition, if a protocol is 
amended and it impacts the content of the informed consent, the ICF must be revised. Study 
subjects participating in the study when the amended protocol is implemented must be 
re-consented with the revised version of the ICF. The revised ICF signed and dated by the study 
subject and by the person consenting the study subject must be maintained in the investigator’s 
study files and a copy given to the study subject.
16.4
Confidentiality
Sponsoraffirms 
the 
subject'
s 
right 
to 
protection 
against invasion of privacy 
and 
to 
be in compliance 
with ICH and other local regulations (whichever is most stringent). Sponsorrequires the 
investigator to permit sponsor'
s representatives and, when necessary, representatives from 
regulatory authorities, to review and/or copy any medical records relevant to the study in 
accordance with local laws.
Should direct access to medical records require a waiver or authorization separate from the 
subject’s signed ICF, it is the responsibility of the investigator 
to 
obtain such permission in writing 
from the appropriate individual.
16.5
Protocol Amendments
Any amendment to this protocol must be approved by the sponsor’sClinical Research 
Physician/Medical Monitor. Amendments will be submitted to the IRB/IEC for written approval. 
Written approval must be obtained before implementation of the amended version occurs. The 
written signed approval from the IRB/IEC should specifically reference the investigator name, 
protocol number, study title,and amendment number(s) that is applicable. Amendments that are 
administrativein nature do not require IRB/IEC approval but will be submitted to the IRB/IEC for 
information purposes.
16.6
Institutional Review Board/Independent Ethics Committee Review and
Approval
Before the start of the study, the study protocol, ICF, and any other appropriate documents will be 
submitted to the IRB/IEC with a cover letter or a form listing the documents submitted, their dates 
of issue, and the site (or region or area of jurisdiction, as applicable) for which approval is sought. 
If applicable, the documents will also be submitted to 
the authorities in accordance with local legal 
requirements.
IP can only be supplied to an investigator by sponsoror its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
sponsoror its authorized representative. This documentation must also include a list of the 
members of the IRB/IEC and their occupation,and qualifications. If the IRB/IEC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
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a statement confirming that the composition of the committee is in accordance with GCP. For 
example, the IRB General Assurance Number may be accepted as a substitute for this list. Formal 
approval by the IRB/IEC should mention the protocol title, number, amendment number (if 
applicable), study site (or region or area of jurisdiction, as applicable), and any other documents 
reviewed. The formal approval must mention the date on which the decision was made and must 
be officially signed by a committee member. Before the first subject is enrolled in the study, all 
ethical and legal requirements must be met.
The IRB/IEC and, if applicable, the authorities, must be informed of all subsequent protocol 
amendments in accordance with local legal requirements. Amendments must be evaluated to 
determine whether formal approval must be sought and whether the ICFshould also be revised.
The investigator must keep a record of all communicationswith the IRB/IECand, if applicable, 
between a coordinating investigator and the IRB/IEC. This statement also applies to any 
communication between the investigator (or coordinating investigator, if applicable) and 
regulatory authorities.
Any advertisements used to recruit subjects for the study must be reviewed by sponsorand the 
IRB/IEC prior to use.
16.7
Ongoing Information for Institutional Review Board/Independent Ethics 
Committee
If required by legislation or the IRB/IEC, the investigator must submit to the IRB/IEC:
Information on serious or unexpected AEsas soon as possible;
Periodic reports on the progress of the study;
Deviations from the protocol or anything that may involve added risk to subjects.
16.8
Termination of the Study
The sponsor has the right to terminate the studyfor safety reasons. In addition, the sponsor may 
terminate 
the studyfor administrative reasons. In all cases, all necessary measures have to be taken 
to guarantee appropriate safety 
 of all subjects already included in the study.
The IRB/IECand the Regulatory Authorities will be informed in writing about any termination of 
the study.
In addition, the investigator or the sponsor has the right to discontinue a single site at any time 
during the study for medical or administrative reasons such asthe following:
unsatisfactory enrollment
GCP noncompliance
inaccurate or incomplete data collection
falsification of records
failure to adhere to the study protocol
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17
DATA HANDLING AND RECORDKEEPING
17.1
Data/Documents
The investigator must ensure that the records and documents pertaining to 
the conduct 
of the study 
and the distribution of the IPare complete, accurate, filed,and retained. Examples of source 
documents include: hospital records; clinic and office charts; laboratory notes; memoranda; 
subject’s diaries or evaluation checklists; dispensing records; recorded data from automated 
instruments; copies or transcriptions certified after verification as being accurate copies; 
microfiche; X-ray film and reports; and records kept at the pharmacy, and the laboratories, as well 
as copies of eCRFs or CD-ROM.
17.2
Data Management
Data will be collected via eCRF and entered into the clinical database. This data will be 
electronically verified through use of edit checks and manual review. Discrepancies in the data 
will be brought 
to 
the attention of the clinical team, and investigational site personnel, if necessary. 
Resolutions to these issues will be reflected in the database. An audit trail within the system will 
track all changes made to the data.
17.3
Record Retention
Essential documents must be retained by the investigator according to the period of time outlined 
in the clinical studyagreement. The investigator must retain these documents for the time period 
described above or according to local laws or requirements, whichever is longer. Essential 
documents include, but are not limited to, the following:
signed ICFs for all subjects
subject identification code list and enrollment log
record of all communications between the investigator and the IRB/IEC
composition of the IRB/IEC
record of all communications between the investigator, Sponsor, and their authorized 
representative(s)
list of sub-investigators and other appropriately qualified persons to whom the investigator has 
delegated significantstudy-related duties, together with their roles in the study, curriculum 
vitae, and their signatures
IP accountability records
record of any body fluids or tissue samples retained
all other source documents (subject records, hospital records, laboratory records, etc.)
all other documents as listed in Section 8 of the ICH consolidated guideline on GCP (Essential 
Documents for the Conduct of a Clinical Trial)
The investigator must notify the sponsorif he/she wishes to assign the essential documents to 
someone else, remove them to another location,or is unable to retain them for a specified period. 
The investigator must obtain approval in writing from the sponsorprior to destruction of any 
records. If the investigator is unable to meet this obligation, he or she must ask the sponsorfor 
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permission to make alternative arrangements. Details of these arrangements should be 
documented.
All study documents should be made available if required by relevant health authorities. The 
investigator or institution should take measures to prevent accidental or premature destruction of 
these documents.
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18
QUALITY CONTROL AND QUALITY ASSURANCE
All aspects of the study will be carefully monitored by sponsoror its authorized representative for 
compliance with applicable government regulations with respect to current GCP andstandard 
operating procedures(SOPs).
18.1
Study Monitoring and Source Data Verification
The sponsorensures that appropriate monitoring procedures are performed before, during,and 
after the study. All aspects of the study are reviewed with the investigator and the staff at a study 
initiation visit and/or at an investigator’s meeting. Prior to enrolling subjects into the study, a 
sponsorrepresentative will review the protocol, eCRFs, procedures for obtaining informed 
consent, record keeping, and reporting of AEs/SAEs with the investigator. Monitoring details 
describing strategy, including definition of study critical data items and processes (eg, risk-based 
initiatives in operations and quality such as risk management and mitigation strategies and 
analytical risk-based monitoring), methods, responsibilities, and requirements, including handling 
of noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) are 
provided in the monitoring plan.
Accuracy will be checked by performing source data verification that is a direct comparison of the 
entries made onto the eCRFs against the appropriate source documentation. Any resulting 
discrepancies 
will be 
reviewed 
with 
the investigator 
and/or his/her 
staff. Any necessary 
corrections 
will be made directly to the eCRFs or via queries by the investigator and/or his/her staff. 
Monitoring procedures require that informed consents, adherence to inclusion/exclusion criteria 
and documentation of SAEs and their proper recording be verified. Additional monitoring 
activities may be outlined in a study-specific monitoring plan.
18.2
Product Quality Complaint
Issues that call into question IP safety, purity, potency, quality,and identity (eg, evidence of 
suspected tampering of product) must be reported as soon as possible to your study Clinical Trial 
Monitor and/or Clinical Trial Manager or designee. Report an issue or concern with all 
Sponsor-supplied IP suspected to have occurred before the product was transferred to the 
responsibility of the investigational site (eg, during manufacturing, packaging and labeling, 
storage, and/or distribution).
This includes suspected quality issues of components co-packaged with the drug and labeling.
In the event of a suspected product quality issue, the immediate action to be taken by site is to 
quarantine the affected product. Do not dispose of the product unless retention presents a risk to 
personnel. Whenreporting, provide as much product information as possible. Suspected IPquality 
issues will be investigated,and a response will be provided back to the investigational site.
18.3
Audits and Inspections
In addition to the routine monitoring procedures, a GCP Quality Assurance unit existwithin 
sponsor. Representatives of this unit will conduct audits of clinical research activities in 
accordance withthesponsorSOPs to evaluate compliance with GCPguidelines and regulations.
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The investigator is required to permit direct access to the facilities where the study took place, 
source documents, eCRFs,and applicable supporting records of study subject participation for 
audits and inspections by IRB/IECs, Regulatory Authorities (eg, Food and Drug Administration 
[FDA], European Medicines Agency [EMA], and Health Canada) and company authorized 
representatives. The investigator should make every effort to be available for the audits and/or 
inspections. If the investigator is contacted by any regulatory authority regarding an inspection, he 
or she should contactthesponsorimmediately.
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19
PUBLICATIONS
As described in Section 16.2, all protocol-and amendment-related information, with the exception 
of the information provided by sponsoron public registry websites, is considered sponsor’s
confidential information and is not to be used in any publications. Sponsor’sprotocol-related 
information proposed for use in a publication must be submitted to sponsorfor review and 
approval, and should not be utilized in a publication without express written approval from 
sponsor, or as described in the Clinical TrialAgreement.
Sponsorwill ensure sponsor-sponsored studies are considered for publication in the scientific 
literature in a peer-reviewed journal, irrespective of the results. At a minimum,this applies to 
results from all Phase 3 clinical studies,and any other study results of significant medical 
importance. This also includes results relating to investigational medicines whose development 
programs have been discontinued.
Study results mayalso 
be presented 
at 
1or more 
medical 
congresses, 
and may be used for 
scientific 
exchange and teaching purposes. Additionally, this study and its results may be submitted for 
inclusion in all appropriate health authority study registries, as well as publication on health 
authority study registry websites, as required by local health authority regulations.
Eligibility for external authorship, as well as selection of first authorship, will be based on several 
considerations, including, but not limited to, contribution to protocol development, study 
recruitment, data quality, participation in data analysis, participation in study steering committee 
(when applicable) and contribution to abstract, presentation,and/or publication development.
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20
REFERENCES
Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al. Adalimumab 
for maintenance of clinical response and remission in patients with Crohn'
s disease: the CHARM 
trial. Gastroenterology. 2007;132:52-65.
Feagan BG, Sandborn WJ, GasinkC, Jacobstein D, Lang Y, Friedman JR, et al. Ustekinumab as 
induction and maintenance therapy for Crohn'
s disease. N Engl J Med. 2016;375:1946-1960.
Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Löfberg R. A reproducible grading scale for 
histological assessment of inflammation in ulcerative colitis. Gut. 2000;47:404-409.
Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. 
Maintenance infliximab for Crohn'
s disease: the ACCENT I randomised trial. Lancet. 
2002;359:1541-1549.
Khanna R, Zou G, D'
Haens G, Feagan BG, Sandborn WJ, Vandervoort MK, et al. A retrospective 
analysis: the development of patient reported outcome measures for the assessment of Crohn'
s 
disease activity. Aliment Pharmacol Ther. 2015;41:77-86.
Lakatos PL. Recent trends in the epidemiology of inflammatory bowel diseases: Up or down? 
World J Gastroenterol. 2006;12:6102-8.
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;26:720-735.
Mandala S, Hajdu R, Bergstrom J, Quackenbush E, et al. Alteration of lymphocyte trafficking by 
sphingosine-1-phosphate receptor agonists. Science. 2002 Apr 12;296(5566):346-9.
Miller MR, Crapo R, Hankinson J, et al. General considerations for lung function testing.Eur 
Respir J 2005a;26:153-161.
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 
2005b;26:319-38.
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Peyrin-Biroulet L, Loftus EV Jr, Colombel JF, Sandborn WJ. The natural history of adult Crohn'
s 
disease in population-based cohorts. Am J Gastroenterol. 2010;105:289-97.
Sandborn W, FeaganB, D’Haens G, et al. Ozanimod Induction and Maintenance Treatment for 
Ulcerative Colitis.N Engl J Med 2021;385:1280-91.
Sandborn WJ, Feagan BG, Wolf D, et al. Ozanimod Induction and Maintenance Treatment for 
Ulcerative Colitis. N Engl J Med 2016;374:1754-62.
Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. Vedolizumab 
as induction and maintenance therapy for Crohn'
s disease. N Engl J Med. 2013;369:711-721.
Sandborn WJ, Feagan BG,Stoinov S, Honiball PJ, Rutgeerts P, Mason D, et al. Certolizumab 
pegol for the treatment of Crohn'
s disease. N Engl J Med. 2007;357:228-238.
Schwartz DA, Loftus EV Jr, Tremaine WJ, Panaccione R, Harmsen WS, Zinsmeister AR, et al. 
The natural history of fistulizing Crohn'
s disease in Olmsted County, Minnesota. 
Gastroenterology. 2002;122:875-80.
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21
APPENDICES
APPENDIX A
TABLE OF ABBREVIATIONS
Table9:
Abbreviations and Specialist Terms
Abbreviation or Specialist Term
Explanation
6-MP
6-mercaptopurine
AE
Adverse event
ALC
Absolute lymphocyte count
ALT
Alanine aminotransferase (SGPT)
AP
Abdominal pain
AST
Aspartate aminotransferase (SGOT)
AZA
Azathioprine
β-hCG
β-subunit of human chorionic gonadotropin
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
CDEIS
Crohn’s Disease Endoscopic Index of Severity
CMH
Cochran-Mantel-Haenszel
COVID-19
Coronavirus disease 2019
CRO
Contract research organization
CYP
Cytochrome P450
DMC
Data Monitoring Committee
EC
European Committees
eCRF
Electronic case report form
EMA
European Medicines Agency
IEC
Independent Ethics Committee
ECG
Electrocardiogram
EEA
European Economic Area
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Table9:
Abbreviations and Specialist Terms
Abbreviation or Specialist Term
Explanation
ELISA
Enzyme linked immunosorbent assay
EMA
European Medicines Agency
FDA
Food and Drug Administration
FCBP
Female of childbearing potential
GCP
Good Clinical Practice
GGT
Gamma glutamyltransferase
GI
Gastrointestinal
HBV
Hepatitis B virus
HCl
Hydrochloride
HIV
Human immunodeficiency virus
HRU
Healthcare resource utilization
IB
Investigator’s Brochure
IBD
Inflammatory bowel disease
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IL
Interleukin
IND
Investigational New Drug
IP
Investigational Product
IRB
Institutional Review Board
IRT
Interactive Response Technology 
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Table9:
Abbreviations and Specialist Terms
Abbreviation or Specialist Term
Explanation
ITT
Intent-to-treat
IV
Intravenous
ME
Macular edema
MERS-CoV
Middle East respiratory syndrome coronavirus
MTX
Methotrexate
OLE
Open-Label Extension
PFT
Pulmonary function test
PP
Per protocol
PYE
Patient years of exposure
QoL
Quality of life
RHI
Robarts Histologic Index
RMS
Relapsing multiple sclerosis
SAE
Serious adverseevent
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2
SD
Standard deviation
SES-CD
Simple Endoscopic Score for Crohn'
s Disease
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Table9:
Abbreviations and Specialist Terms
Abbreviation or Specialist Term
Explanation
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
TNF
Tumor necrosis factor
TFR
Treatment failure rules
TRT
Treatment
UC
Ulcerative colitis
WBC
White blood cell 
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APPENDIX C
SARS-COV-2 GUIDELINES
 
 Testing for COVID-19 to inform decisions about clinical care during the 
study should follow local standard practice.
If the subjectreceives a positive SARS-CoV-2 test result and is asymptomaticduring the 
pre-randomization period, the subject may be considered eligible for the study after meeting all 
inclusion/exclusion criteria related to active infection, and after meeting the following criteria:
1.At least 10 days have passed since positive test result, and
2.In the opinion of the investigator, there are no COVID-19 sequelae that may confound the 
assessment of safety or efficacy within the study and place the subject at a higher risk of 
receiving investigational treatment
If the subject receives a positive SARS-CoV-2 test result and is symptomaticduring the 
pre-randomization period, the subject may be considered eligible for the study after meeting all 
inclusion/exclusion criteria related to active infection, and after meeting the following criteria:
1.At least 10 days (7 days if initial test was performed 5 days after symptom onset, 20 days for 
severe/critical illness) have passed since symptoms first appeared or positive test result, and
2.At least 24 hours have passed since last fever without the use of fever-reducing medications, 
and
3.Symptoms (eg,cough, shortness of breath) have resolved,and
4.In the opinion of the investigator or in consultation with sponsor, there are no COVID-19 
sequelae that may confound the assessment of safety or efficacy within the study and place the 
subject at a higher risk of receiving investigational treatment.
Each study visit will include an assessment for AEs including SARS-CoV-2 and other infections. 
In order to facilitate reporting of SARS-CoV-2 events that occur during the study, all AEs and 
SAEs related to SARS CoV-2 should be reported from the time of consent until the final study 
visit(Section10).
Procedures related to COVID-19 identification (eg,MERS-CoV test, SARS-CoV-2 antibody test, 
SARS-CoV-2 ELISA test), and treatment (eg,intubation, dialysis) must be reported on the 
appropriate section of the eCRF.
Evaluation and management of SARS-CoV-2 infections arising during the course of the trial are 
left to the discretion and expertise of the Investigator. For subjects who are exhibiting symptoms 
consistent with SARS-CoV-2, 
the 
Sponsoradvises 
the 
Investigator 
to 
consult 
the 
Medical Monitor.
COVID-19 vaccines that are NOT live are allowed and should be handled in the same manner as 
other vaccines. Administration may occur during the study, including during treatment with IP and 
after the last dose of IP. Administration of vaccinations must be reported along with dosage 
information, dates of administration and vaccine name/trade name on the appropriate section of 
the eCRF. A separate logline should be entered for each vaccine administeredwith the dose 
number following the vaccine name/trade name.
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APPENDIX D
PROTOCOL AMENDMENT SUMMARY OF CHANGE HISTORY
Overall Rationale for Protocol Amendment 6.0, 16-Mar-2023:
The overall rationale for this protocol amendment is to consolidate the protocol with theEuropean 
Union (EU)/Clinical Trials Regulations (CTR) requirements, particularly to address the removal 
of the France-specific protocol. Other changes include the addition of risk/benefit assessment 
details, correction of Exclusion Criteria timeframes andupdates to prohibited medications, as well 
as updates to cardiac and ophthalmic monitoring language.
The Protocol Summary was updated with all relevant changes.
Summary of Changes For Protocol Amendment 6.0
Section Number & Title
Description of Change
Brief Rationale
Title Page
Sponsor address updated.
Sponsor address change.
Medical Monitor/Emergency 
Contact Information
Medical Monitor and associated 
contact information updated.
Sponsor staff change.
Sponsor Therapeutic Area 
Lead Signature Page
Sponsor Therapeutic Area Lead 
information updated.
Sponsor staff change.
Section 1.2.4: Risk/Benefit 
Assessment
Section removed (now 
Section1.4.3: Overall Risk/Benefit 
Conclusion).
Integration of previously stand-
alone Risk/Benefit document 
into body of protocol.
Section 1.4: Risk/Benefit 
Assessment;
 
Section 1.4.2: Benefit 
Assessment;
Section 1.4.3: Overall 
Risk/Benefit Conclusion
Sections added.
Integration of previously stand-
alone Risk/Benefit document 
into body of protocol.
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Summary of Changes For Protocol Amendment 6.0
Section Number & Title
Description of Change
Brief Rationale
Section 4.3.1: Exclusions 
Related to General Health
Added France-specific language to 
indicate that hypotension is 
mentioned as being exclusionary if 
it makes the implementation of the 
protocol or interpretation of the 
study difficult or would put the 
subject at risk by participating in the 
study.
To align with EU/CTR 
consolidation and removal of the 
France-specific protocol.
Section 4.3.2: Exclusions 
Related to Medications
Corrected to align with 
timeframe as stated in Induction 
protocol.
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Summary of Changes For Protocol Amendment 6.0
Section Number & Title
Description of Change
Brief Rationale
Section 4.3.2: Exclusions 
Related to Medications;
 
 
 
 
 
 
Section 7.2.2: Guidelines for 
Monitoring Subjects at Risk 
for Cardiac Events During 
Re-Initiation of Treatment 
with Investigational Product;
 
Cardiac monitoring language 
updated.
Correction/clarification.
Section 8.1.3: COVID-19 
Vaccination
Non-live coronavirus disease 2019 
(COVID-19) vaccination language 
added.
Moved language from 
Risk/Benefit section.
 
 
 
 
 
 
Clarification.
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Summary of Changes For Protocol Amendment 6.0
Section Number & Title
Description of Change
Brief Rationale
 
 
Appendix C: SARS-CoV-2 
Guidelines
Language updated to indicate that 
testing for COVID-19 to inform 
decisions about clinical care during 
the study should follow local 
standard practice and to provide 
guidance on the evaluation and 
management of SARS-CoV-2 
infections.
Moved language from 
Risk/Benefit section.
All
Minor formatting and typographical 
corrections/edits.
Minor, therefore have not been 
summarized
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1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
Update of Summary of Clinical Studies in Inflammatory Bowel Disease(IBD)
The Summary of Clinical Studies in IBD has been revised to align with the updated 
Investigator’s Brochure and the recent results from the phase 3RPC01-3101 study in ulcerative 
colitis.
Revised sections: Section 1.2.2,Summary of Clinical Studies in Inflammatory Bowel Disease;
and Section 1.2.3, Rationale for Dose Selection
Refinement of Per-Protocol Population
To ensure data integrity, the per-protocol population has been further defined to ensure subjects
included in analysis of primary endpoints are compliant with study treatments and protocol 
requirements.  
Revised sections: Protocol Summary and Section 9.2, Study Population Definitions
Update and Re-ordering of Endpoints
Key secondary 
 endpoints were revised 
 
 to align with the clinical relevance for evaluating 
the efficacy in the Crohn’s Disease (CD)population.
The endoscopic remission endpoints at Week 52 were previously defined as the proportion of 
subjectswith Simple Endoscopic Score for Crohn’s Disease (SES-CD) = 0. 
 
The proportion of subjects with a Crohn’s Disease Activity Index (CDAI)reduction from 
baseline of ≥ 100 points or CDAI score<150 at Week52 was elevated to the position of the first
major secondary endpoint, given its high clinical relevance in evaluating efficacy in the CD 
population. 
Revised sections: Protocol Summary;Section 2.2.2, Major Secondary Endpoints; 
 and Section 6.4.1.2,Simple Endoscopic Score for Crohn’s Disease
Update of Secondary Objective
The corticosteroid-free remission objective was revised to align with the corresponding endpoint. 
It is important to demonstrate that patients on corticosteroids at baseline are able to achieve 
clinical remission off CSs,as well as demonstrate that the use of corticosteroids was prevented 
when achieving clinical remission.
Revised sections: Protocol Summary; Section 2.1.2, Secondary Objectives
Removal of0.46mgTreatment Arm from the Maintenance Study
The results from previous trials to date support thebenefit risk profile ofa 0.92 mg dose in both 
CDand ulcerative colitis. Therefore,in an effort to simplify the protocol and complete the 
evaluation of ozanimod for CD patients in as efficient a manner as possible, the 0.46mg 
treatment arm was removed.In addition, the randomization scheme and sample size were
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readjustedto reflect the number of subjects needed based on the estimated treatment effects of 
ozanimod and placebo.
Revised sections: Protocol Summary;Section 1.2.3, Rationale for Dose Selection;Section2.2.9, 
Dose-Ranging Substudy Endpoints(now removed);Section 3.1, Study Design; Section4.1, 
Number of Subjects; Section 7.1, Description of Investigational Product(s); Section7.2, 
Treatment Administration and Schedule; Section 7.3, Method of Treatment Assignment; 
Section7.4, Packaging and Labeling; Section9.1, Overview;Section 9.3.2, Power Calculations; 
Section9.3.3, Sample Size Consideration for the Ozanimod 0.46mg Group(now removed); and 
Section9.3.3(previously Section 9.3.4), Stratified Block Randomization
CDAI Calculation
Details on CDAI calculation were removed and will be specified in the Statistical Analysis 
Plan(SAP). 
Revisedsections: Section 6.4.1.1, Crohn’s Disease Activity Index

Pulmonary Function Tests Will Only Be Required 
in Subjects Identified as AtRisk
 
 Baseline and subsequent pulmonary function tests (PFTs) will be 
conducted in subjects with a history of respiratory diseasenot considered to be severe.
Additional guidance isalso provided for subjects without preexisting respiratory disease who 
experience a decline in pulmonary function during the study. These revisions are aligned with 
the prescribing information for ozanimod.
Revisedsections: 
Section 6.5.4, Pulmonary Function Test;and 
Treatment Re-initiation MonitoringWill Be Required Only inSubjects 
Identified as at Risk forCardiac Events
The criteria for cardiac monitoring during re-initiation of treatment havebeen revised to align 
with the prescribing information for ozanimod.
Revised sections: Section 7.2.2
, Guidelines for Monitoring Subjects at 
Risk for Cardiac Events During Re-Initiation of Treatment with Investigational Product;and
Instructions for Missed Doses
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Additional instructions for missed doses were included in accordance with the prescribing 
information for ozanimod.The instructions for dose escalation upon treatment re-initiation were 
updated to account for the removal of the 0.46mgtreatment arm.
Revised sections: Section 7.2, Treatment Administration and Schedule and Section 7.2.1, 
Instructions for Missed Doses
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Minor editorial changes to enhance clarity of the protocol, and update study 
personnel names, abbreviations, and references.
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RPC01-3203, v4.0:  10 June2019
This document summarizesthe changes toProtocol RPC01-3203 from Version 3.0(dated18Jun 
2018)to Version4.0(dated 10 June2019).
1.
OVERVIEW OF KEY CHANGES
The following bulleted list identifies the key changes to the protocol and provides the rationale 
for each change:
Revisions to reflect the addition of adolescent subjects
Addition of a dose ranging sub-study with a 0.46mg dose arm
Minor editorial changes to enhance clarity of the protocol, and update study personnel 
names.
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Summary of Changes: Protocol Number: RPC01-3203  
18 June 2018 
Drug Name: Ozanimod 
Version 3 
CONFIDENTIAL  
Page 3 of 28 
This document summarizes the changes that were made between Protocol RPC01-3203 
Version 3 (dated 18 June 2018) and Version 2 (dated19 December 2017). 
1. 
OVERVIEW OF KEY CHANGES 
The following bulleted list identifies the key changes to the protocol and provides the rationale 
for each key change: 
 A change has been made to provide further guidance to investigators on the management of 
patients with symptomatic bradycardia, including a reference to local guidelines. 
 The protocol was updated to add new protocol template language regarding handling of 
product quality complaints for any drug product manufactured by or on behalf of Celgene 
Corporation. 
The following bulleted list identifies global changes to the protocol: 
 The term “patient” was changed to “subject” throughout the document in order to maintain 
consistency throughout the protocol. 
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CONFIDENTIAL  
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 The terms “investigational drug” and “study drug” were changed to “investigational product” 
throughout the document to comply with regulatory guidances and maintain consistency 
throughout the protocol 
 The term “Screening” was changed to “Randomization” throughout the document to 
maintain consistency and correctness with the study design 
 Abbreviations lists in footnotes were updated. 
 The list of references has been updated based on changes in this amendment. 
 Minor typographical corrections have been made.  
 Minor editorial changes and changes for clarification were made. 
 
 
 
 
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Summary of Changes: Protocol Number: RPC01-3203  
19 December 2017 
Drug Name: Ozanimod 
Version 2.0 
CONFIDENTIAL 
  
Page 3 of 15  
This document summarizes the changes that were made between Protocol RPC01-3203 Version 
1.0 (dated 26 September 2017) and Version 2.0 (dated 19 December 2017). 
1. 
OVERVIEW OF KEY CHANGES 
The following bulleted list identifies the key changes to the protocol and provides the rationale 
for each change: 
 The CDEIS is being introduced as an additional secondary endpoint because it is an 
established endoscopic measure. 
 A change has been made to provide further guidance to investigators on the management of 
patients with symptomatic bradycardia, including a reference to local guidelines.  
 Changes have been made to provide further guidance to investigators on cardiac monitoring. 
 The section on the evaluation of adverse events was modified since the investigator will not 
determine whether an adverse event is an adverse event of special interest (AESI). This 
change was made to better align with the planned designation of AESIs by the sponsor and to 
align with the Medical Monitoring plan. 
The following bulleted list identifies global changes to the protocol: 
 A general statement was made to note that additional detailed statistical information can be 
found in the study Statistical Analysis Plan. Therefore, details were removed from Section 9 
(Statistical Considerations). 
 Abbreviations lists in footnotes were updated. 
 The list of references has been updated based on changes in this amendment. 
 Edits were made throughout the document for the purposes of clarity and protocol 
consistency. 
 Minor typographical corrections have been made.
 
 
 
 
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