Induction Study #2 - A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of Oral Ozanimod as Induction Therapy for Moderately to Severely Active Crohn's Disease
Phase: PHASE3
Conditions: Crohn Disease
Sponsor: Celgene

Official Title of Study: 
Induction Study #2 - A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of 
Oral Ozanimod as Induction Therapy for Moderately to Severely Active Crohn's Disease 
 
NCT Number: NCT03440385 
Document Date (Date in which document was last revised): 14 June 2021 
 
 
 

EDMS Doc. Number: 25662590 - 25662583
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Protocol RPC01-3202, Version 6.0
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TITLE PAGE
INDUCTION STUDY #2 - A PHASE 3, MULTICENTER, 
RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF ORAL 
OZANIMOD AS INDUCTION THERAPY FOR 
MODERATELY TO SEVERELY ACTIVE CROHN’S 
DISEASE
INVESTIGATIONAL PRODUCT:
Ozanimod
PROTOCOL NUMBER:
RPC01-3202
VERSION 5 DATE:
03 Sep 2020
VERSION NUMBER:
6.0
AMENDMENT NUMBER:
5.0
DATE FINAL:
14 Jun 2021
IND NUMBER:
126,740
EudraCT NUMBER:
2017-004293-33
SPONSOR NAME/ ADDRESS:
Celgene International II Sàrl
Rue du Pré-Jorat 14
2108 Couvet
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 to the 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 not be further 
disclosed by them.
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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: 
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SPONSOR THERAPEUTIC AREA LEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature
Date
By my signature, I indicate I have reviewed this protocol and find its content to be 
acceptable.
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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 SUMMARY
Study Title
Induction Study #2 - A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Study of Oral Ozanimod as Induction 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 
100,000 people 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.  
CD is 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 1 fistula 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 
< 150 points) (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 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 subjects had 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 interleukin-12 and 
interleukin-23, was most recently approved for the treatment of patients who failed or were 
intolerant to treatment with immunomodulators, corticosteroids, or 1 or more TNF antagonists.
However, in the recent 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 considerable unmet medical need for safe, effective, and oral treatments 
for patients with CD.
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Objectives
Primary objective:

Demonstrate the efficacy of ozanimod compared to placebo on the induction of 
clinical remission 
Secondary objectives:

Demonstrate the efficacy of ozanimod compared to placebo on induction of clinical 
response, endoscopic response, endoscopic remission, and histologic improvement 

Evaluate the efficacy of ozanimod compared to placebo, in subjects who had 
previously received biologic therapy (eg, anti-IL-12, anti-IL-23, anti-TNF, or 
anti-integrin therapy)

Characterize the population pharmacokinetics (PK) and PK/pharmacodynamics (PD) 
relationship of ozanimod

Demonstrate the safety and tolerability of ozanimod as induction therapy
Study Design
This is a Phase 3, randomized, double-blind, placebo-controlled study to determine the effect of 
oral ozanimod as an induction treatment for subjects with moderately to severely active CD, 
defined as a CDAI score ≥ 220 to ≤ 450. Approximately 600 subjects with active clinical 
symptoms and mucosal inflammation will be randomized in a 2:1 ratio to receive either 
ozanimod 0.92 mg or placebo. Subjects will be stratified 
 
. Approximately 50% of subjects with a history of 
treatment with marketed biologic agents (eg, TNF antagonists, anti-IL-12/23 and anti-integrin 
therapy) will be recruited. This limit will ensure the enrollment of subjects who have failed or 
been intolerant to corticosteroids or immunomodulators but never failed a biologic agent. A
futility analysis will be conducted when approximately 300 subjects have been enrolled, with a 
similar proportion of biologic naïve to biologic exposed population as that in the overall study 
population. 
 
 
 
The primary endpoint of the study is the proportion of subjects in clinical remission (CDAI 
score < 150) at Week 12. Key secondary endpoints are presented in Section 2. 
 
 
 
 
 
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 Those subjects
not meeting the criteria outlined above at the end of the Induction Study will be eligible to enter 
the Open-Label Extension (OLE) Study (RPC01-3204). Subjects receiving any medical or 
surgical intervention for the treatment of CD who meet the criteria for treatment failure will be 
discontinued from the study and will not be eligible for the Maintenance or OLE Studies.
The study will be conducted in compliance with International Council on Harmonisation (ICH) 
of Technical Requirements for Registration of Pharmaceuticals for Human Use/Good Clinical 
Practice (GCP) and applicable regulatory requirements.
Overall Study Design
Abbreviations:  OLE = Open-label Extension 
Study Population
Subjects with moderately to severely active CD will be qualified based on clinical symptoms 
(CDAI ≥220 to ≤450 with an average stool frequency score ≥4 and/or an average abdominal 
pain score of ≥2) and endoscopic findings (Simple Endoscopic Score for Crohn’s Disease [SES-
CD] ≥6 or ≥4 for isolated ileal disease).  
Length of Study
Subjects who complete the Induction Study are anticipated to receive 12 weeks of treatment 
(12-week Induction Study). Subjects not entering the Maintenance Study or Open-Label 
Extension Study will have 
 
The end of study (Induction Study RPC01-3202) is defined as either the date of the last visit of 
the last subject to complete the Safety Follow-up, or the date of receipt of the last data point from 
the last subject that is required for primary or secondary analysis, as pre-specified in the 
protocol, whichever is the later date.
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Study Treatments
Following a 7-day dose escalation, subjects will receive a single 0.92 mg oral dose of ozanimod 
(equivalent to ozanimod HCl 1 mg) or matching placebo administered daily. The dose escalation 
regime is as follows:
Day 1 through 4: Ozanimod 0.23 mg (equivalent to ozanimod HCl 0.25 mg) (or matched 
placebo)
Day 5 through 7: Ozanimod 0.46 mg daily (equivalent to ozanimod HCl 0.5 mg) (administered 
as two 0.23-mg capsules or 2 matched placebo capsules)
Day 8 through Week 12: Ozanimod 0.92 mg daily (equivalent to ozanimod HCl 1 mg) (or 
matched placebo)
Overview of Key Efficacy Assessments
Note: All endpoints will evaluate subjects at Week 12 unless otherwise specified.
Primary Endpoint:

Proportion of subjects with a CDAI score < 150 at Week 12
Major Secondary Endpoints:

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 at Week 12

Proportion of subjects with a Simple Endoscopic Score for Crohn’s Disease 
(SES-CD) score decrease from baseline of ≥50% at Week 12

Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI 
score < 150 at Week 12

Proportion of subjects with CDAI reduction from baseline of ≥100 points or CDAI 
score < 150 and SES-CD decrease from baseline of ≥50% at Week 12
Other Secondary Endpoints: 

Proportion of subjects with CDAI score < 150 at Week 12 and SES-CD decrease 
from baseline of ≥ 50% at Week 12 

Proportion of subjects with an 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 an SES-CD ≤ 4 points and decrease ≥2 points 
at Week 12

Proportion of subjects with an 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 an SES-CD decrease from baseline of ≥ 50% at 
Week 12

Histologic Improvement based on differences between ozanimod and placebo in 
histologic disease activity scores (ie, Global Histologic Activity Score (GHAS) 
changes (Geboes, 2000) at Week 12
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Proportion of subjects with CDAI reduction from baseline of ≥70 points at Week 12

Proportion of subjects with absence of ulcers ≥0.5 cm with no segment with any 
ulcerated surface ≥10% at Week 12

Proportion of subjects with a Crohn’s Disease Endoscopic Index of Severity (CDEIS) 
decrease from baseline of ≥ 50% at Week 12
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Overview of Key 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 
, clinical laboratory measures, vital signs, and 
electrocardiograms (ECGs).
Statistical Methods
This is a Phase 3, double-blind, randomized, placebo-controlled study to explore the effect of 
oral ozanimod as an induction treatment on clinical remission for 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 the Screened analysis population that receive at least 1 dose 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.
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
Per-protocol (PP): The PP population will consist of all subjects in the ITT population
who do not have protocol deviations that may substantially affect the primary efficacy 
assessment. This population will be used in a sensitivity analysis of the primary 
endpoint.
Determination of Sample Size for the Primary Endpoint
The primary endpoint is CDAI clinical remission at Week 12.  Subjects will be deemed a 
responder with respect to this endpoint if they meet the definition for CDAI clinical remission at 
Week 12.  This study is designed to have at least a 90% power to correctly detect a statistically 
significant difference between placebo and ozanimod with respect to this endpoint.  
Sample size determination was done separately for the two-group chi-square test of equal 
proportions with 2:1 unbalanced treatment arms.  This yields an overall sample size of 600 with 
the assumption of a type I error rate of 5%.  The overall type I error rate across all controlled 
endpoints will be maintained at 5%.
Efficacy Analyses
A futility analysis is planned to be performed when approximately 300 subjects (with a similar 
proportion of biologic naïve to biologic exposed subjects as that in the overall study population) 
from both Induction Studies, collectively, have completed the 12-week Induction Period. The 
analysis will occur after these subjects have completed the Induction Period and the data have
been cleaned. The primary endpoint, CDAI remission (CDAI < 150) at Week 12 be used in the 
analysis. 
 
 
The Induction Studies (RPC01-3201 and RPC01-3202) may be stopped for futility 
if the observed treatment effect size in CDAI remission is at a low probability to demonstrate 
superiority.  Additional efficacy endpoints including CDAI response, abdominal pain and stool 
frequency scores, SES-CD,
will be evaluated as supporting 
analyses. The futility boundary is “non-binding,” implying that the boundary can be overruled if 
desired without inflating the type-1 error. The “non-binding” boundary is intended to allow the 
Sponsor or the independent Data Monitoring Committee (DMC) to continue the study to gather 
additional information, despite crossing the futility boundary. 
The futility analysis will be conducted by the designated unblinded team (statistician and 
programmers) that supports the DMC and the results will be sent to the DMC and may also be 
sent to a Celgene internal review committee (IRC) for review. The Celgene IRC members will 
not play a role in the study conduct, and the blind will be maintained for persons responsible for 
the ongoing conduct and management of the study through the end of the Maintenance Study 
(RPC01-3203), until database lock.
For the primary analysis of remission and/or responder endpoints, subjects who have insufficient 
data for remission and/or response determination for the timepoint/study visit under 
consideration will be considered non-responders for that timepoint. Sensitivity analyses, missing 
data imputation, and continuous endpoint efficacy analyses are discussed in the statistical 
analytical plan (SAP).  
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The primary analysis of proportion of clinical remission (as well as clinical response) endpoints 
will be carried out using the Cochran-Mantel-Haenszel (CMH) test to account for 
 
 as randomization stratification factors.
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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
PROTOCOL SUMMARY ..........................................................................................................6
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
1.2.4.
Benefit Risk Assessment.........................................................................................24
1.3.
Study Rationale ......................................................................................................25
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................26
2.1.
Study Objectives.....................................................................................................26
2.1.1.
Primary Objective:..................................................................................................26
2.1.2.
Secondary Objectives: ............................................................................................26
2.2.
Study Endpoints .....................................................................................................26
2.2.1.
Primary Endpoint: ..................................................................................................26
2.2.2.
Key Secondary Endpoints:......................................................................................26
2.2.3.
Other Secondary Endpoints: ...................................................................................26
27
27
28
2.2.7.
Overview of Key Safety Assessments.....................................................................28
3.
OVERALL STUDY DESIGN ................................................................................29
3.1.
Study Design ..........................................................................................................29
3.2.
Study Duration for Subjects....................................................................................30
3.3.
End of Study...........................................................................................................30
4.
STUDY POPULATION.........................................................................................31
4.1.
Number of Subjects ................................................................................................31
4.2.
Inclusion Criteria....................................................................................................31
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4.3.
Exclusion Criteria...................................................................................................33
5.
TABLE OF EVENTS.............................................................................................37
6.
PROCEDURES......................................................................................................42
6.1.
Screening Period.....................................................................................................42
6.2.
Treatment Period ....................................................................................................43
43
45
45
6.2.4.
Study Stopping Rules .............................................................................................45
6.3.
46
46
6.3.2.
Efficacy Assessments .............................................................................................46
6.3.2.1.
Primary Efficacy Assessment..................................................................................46
6.3.2.2.
Simple Endoscopic Score for Crohn's Disease ........................................................48
6.3.2.3.
Histology................................................................................................................49
6.3.3.
Other Assessments..................................................................................................50
6.3.3.1.
Physical Examination .............................................................................................50
6.3.3.2.
Vital Signs..............................................................................................................51
6.3.3.3.
Electrocardiogram ..................................................................................................51
6.3.3.4.
Pulmonary Function Test........................................................................................51
52
52
52
53
53
53
54
54
54
55
7.
DESCRIPTION OF STUDY TREATMENTS........................................................56
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7.1.
Description of Investigational Product ....................................................................56
7.2.
Treatment Administration and Schedule .................................................................56
7.2.1.
Instructions for Missed Doses.................................................................................57
7.3.
Method of Treatment Assignment...........................................................................57
7.4.
Packaging and Labeling..........................................................................................57
7.5.
Investigational Product Accountability and Disposal ..............................................58
7.6.
Investigational Product Compliance........................................................................58
8.
CONCOMITANT MEDICATIONS AND PROCEDURES....................................59
8.1.
Permitted Concomitant Medications and Procedures...............................................59
8.1.1.
Corticosteroids........................................................................................................59
8.1.2.
Aminosalicylates and Purified Medicinal Probiotics ...............................................59
8.1.3.
COVID-19 Vaccination ..........................................................................................59
8.2.
Prohibited Concomitant Medications and Procedures..............................................60
60
.61
8.3.
Required Concomitant Medications and Procedures................................................62
9.
STATISTICAL CONSIDERATIONS ....................................................................63
9.1.
Overview................................................................................................................63
9.2.
Study Population Definitions ..................................................................................63
9.3.
Sample Size and Power Considerations...................................................................63
9.3.1.
Primary Endpoint....................................................................................................63
9.3.2.
Placebo Response Rates for the Primary Endpoint ..................................................64
9.3.3.
Power Calculations.................................................................................................64
9.3.4.
Stratified Block Randomization..............................................................................65
9.4.
Background and Demographic Characteristics........................................................65
9.5.
Subject Disposition.................................................................................................66
9.6.
Efficacy Analysis....................................................................................................66
9.6.1.
Futility Analysis .....................................................................................................66
9.6.2.
Analysis of Primary and Key Secondary Endpoints ................................................67
9.6.3.
Control of Family-Wise Type I Error Rate and Data Pooling ..................................67
9.7.
Safety Analysis.......................................................................................................67
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9.8.
Treatment Failure Rules..........................................................................................68
9.9.
Other Topics...........................................................................................................68
9.9.1.
Population Pharmacokinetics and Pharmacokinetics/Pharmacodynamics 
Analyses.................................................................................................................68
9.9.2.
Data Monitoring Committee ...................................................................................68
10.
ADVERSE EVENTS..............................................................................................69
10.1.
Monitoring, Recording and Reporting of Adverse Events .......................................69
10.1.1.
Treatment of Overdose of Investigational Product ..................................................69
10.1.2.
Monitoring of Subjects with Adverse Events, Serious Adverse Events....................70
10.2.
Evaluation of Adverse Events.................................................................................70
10.2.1.
Seriousness.............................................................................................................70
10.2.2.
Severity ..................................................................................................................71
10.2.3.
Causality ................................................................................................................72
10.2.4.
Duration .................................................................................................................72
10.2.5.
Action Taken..........................................................................................................72
10.2.6.
Outcome.................................................................................................................73
10.2.7.
Adverse Events of Special Interest..........................................................................73
11.
CLINICAL LABORATORY EVALUATIONS......................................................75
11.1.
Hematology............................................................................................................75
11.2.
Chemistry...............................................................................................................76
11.3.
Serology.................................................................................................................77
12.
PREGNANCY .......................................................................................................79
12.1.
Female Subjects of Childbearing Potential..............................................................79
12.2.
Male Subjects.........................................................................................................80
13.
REPORTING OF SERIOUS ADVERSE EVENTS ................................................81
13.1.
Safety Queries ........................................................................................................81
13.2.
Expedited Reporting of Adverse Events..................................................................81
13.3.
Sponsor’s Drug Safety Contact Information............................................................82
14.
DISCONTINUATIONS .........................................................................................83
14.1.
Treatment Discontinuation......................................................................................83
14.2.
Study Discontinuation ............................................................................................83
15.
EMERGENCY PROCEDURES.............................................................................86
15.1.
Emergency Contact.................................................................................................86
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15.2.
Emergency Identification of Investigational Products .............................................86
16.
REGULATORY CONSIDERATIONS...................................................................87
16.1.
Good Clinical Practice............................................................................................87
16.2.
Investigator Responsibilities ...................................................................................87
16.3.
Subject Information and Informed Consent.............................................................88
16.4.
Confidentiality........................................................................................................88
16.5.
Protocol Amendments.............................................................................................88
16.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................88
16.7.
Ongoing Information for Institutional Review Board/Independent Ethics 
Committee..............................................................................................................89
16.8.
Termination of the Study ........................................................................................89
17.
DATA HANDLING AND RECORDKEEPING.....................................................90
17.1.
Data/Documents .....................................................................................................90
17.2.
Data Management...................................................................................................90
17.3.
Record Retention....................................................................................................90
18.
QUALITY CONTROL AND QUALITY ASSURANCE........................................92
18.1.
Study Monitoring and Source Data Verification......................................................92
18.2.
Product Quality Complaint .....................................................................................92
18.3.
Audits and Inspections............................................................................................92
19.
PUBLICATIONS ...................................................................................................94
20.
REFERENCES.......................................................................................................95
21.
APPENDICES........................................................................................................97
APPENDIX A.
TABLE OF ABBREVIATIONS....................................................................97
APPENDIX B.
INCLUSION CRITERIA DRUG SPECIFICATIONS..................................102
APPENDIX C.
SARS-COV-2 GUIDELINES ......................................................................103
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LIST OF TABLES
Table 1:
Table of Events.......................................................................................................37
 
44
Table 3:
Crohn’s Disease Activity Index Assessment ...........................................................47
Table 4:
Crohn's Disease Severity Definitions ......................................................................47
Table 5:
Definitions of Simple Endoscopic Score for Crohn's Disease (SES-CD).................49
Table 6:
GHAS Grading System...........................................................................................49
50
61
Table 9:
Placebo Response Rates from Selected Literature...................................................64
Table 10:
Sample Size Calculation for the Primary Endpoint (CDAI Remission)....................64
64
65
Table 13:
Abbreviations and Specialist Terms........................................................................97
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LIST OF FIGURES
Figure 1:
Overall Study Design..............................................................................................30
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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 
100,000 people 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.  
CD is 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 1 fistula 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 
< 150 points) (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 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 subjects had 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 interleukin-12 and 
interleukin-23, was most recently approved for the treatment of patients who failed or were 
intolerant to treatment with immunomodulators, corticosteroids, or 1 or more TNF antagonists.
However, in the recent 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 considerable unmet medical need for safe, effective, and oral treatments 
for patients with 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. In vitro, ozanimod has little activity on the other 
sphingosine-1-phosphate (S1P) receptors, showing half maximal effective concentration (EC50) 
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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 selective major 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 express S1P1, 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 GI Peyer’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 S1P1 and S1P5 
agonists.  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 inflammatory bowel disease, 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 Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and AE profile of the IP.
1.2.2.
Summary of Clinical Studies in Inflammatory Bowel Disease
1.2.2.1.
Ulcerative Colitis
Ozanimod has been studied in subjects with active ulcerative colitis (UC) in a Phase 2 study
(RPC01-202), and a Phase 3 global study (RPC01-3101). It is being studied in a Phase 2/3 study 
in Japan (RPC01-3103), and the global Phase 3 open-label extension (RPC01-3102).
At the conclusion of the Induction Phase of RPC01-202, the proportion of subjects achieving 
clinical response and clinical remission with ozanimod 0.92 mg was greater than placebo and the 
difference was both clinically meaningful and statistically significant. In addition, all secondary 
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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 AE profile in the Induction and 
Maintenance periods appeared comparable between the ozanimod dose groups and placebo, with 
no concerning safety signal observed. 
RPC01-202 also had a maintenance phase and an open-label extension (OLE) period. Treatment 
with ozanimod 0.92 mg in the OLE period demonstrated efficacy in the endpoints of clinical 
remission, clinical response, histological remission, and mucosal healing in a substantial 
proportion of subjects. Decreases in partial Mayo scores and complete Mayo scores during the 
Induction and Maintenance Periods were 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 
throughout the OLE period.  
The safety and tolerability results from the UC RPC01-202 Phase 2 study suggest that ozanimod 
at doses of 0.46 and 0.92 mg daily for 32 weeks are well tolerated and have an acceptable safety 
profile in subjects with moderately to severely active UC (Sandborn, 2016).
RPC01-3101, a Phase 3 study in adult subjects with moderate to severe UC, met both primary 
endpoints, demonstrating highly statistically significant (p-value < 0.0001) results for induction 
of clinical remission at Week 10 and in maintenance at Week 52 (Sandborn, 2020). All 3 key 
secondary endpoints in the Induction Period (clinical response, endoscopic improvement, and 
mucosal healing), and all 6 key secondary endpoints in the Maintenance Period (clinical 
response, endoscopic improvement, maintenance of remission, corticosteroid-free remission, 
mucosal healing, and durable clinical remission) were achieved by a statistically significantly 
greater proportion of subjects in the ozanimod 0.92 mg treatment group compared with placebo. 
The treatment effects for the primary and key secondary endpoints consistently supported a 
favorable treatment effect for ozanimod in multiple demographics, prior and concomitant 
medication, disease characteristics, and geographic subgroups.
1.2.2.2.
Crohn’s Disease
RPC01-2201, a Phase 2 study, was conducted in CD to examine endoscopic and clinical 
outcomes following treatment with ozanimod 0.92 mg daily for 12 weeks in the Induction Period 
and up to 148 weeks in the Extended Period. 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 was seen in 68.5% and 93.8% 
of subjects (observed cases) at Week 12 and Week 52, respectively. Clinical remission was seen 
in 46.3% and 65.6% of subjects (observed cases) at Week 12 and Week 52, respectively.
 
The safety and tolerability results from the 12-week Induction Period of RPC01-2201 suggest 
that ozanimod 0.92 mg daily is well tolerated and has an acceptable safety profile in subjects 
with moderately to severely active CD. In the open-label period (OLP), ozanimod 0.92 mg was 
well tolerated and there were no new safety concerns. The AEs reported in the study were 
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generally consistent with those seen in subjects with moderately to severely active UC.
 
 
 
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and AE profile of the IP.
1.2.3.
Rationale for Dose Selection
Results from single ascending dose and multiple ascending dose studies in Phase 1 were utilized 
to select appropriate doses for Phase 2 studies. The Phase 2 study 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 0.92 mg/day dose arm demonstrated better efficacy as 
compared to the 0.46 mg/day dose arm across various clinical and endoscopic endpoints 
(Sandborn, 2016). Results suggested a dose dependent efficacy response, making 0.92 mg 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 as supportive clinical and safety data from the completed 
Relapsing Multiple Sclerosis (RMS) program, provide additional data to support use of the 0.92 
mg dose of ozanimod. Data from 52 weeks of treatment (RPC01-2201) in subjects with active 
CD treated with ozanimod 0.92 mg suggest clinical benefit based on clinical, endoscopic, 
histologic 
 responses, with a comparable safety profile to 
subjects previously evaluated with ozanimod. The overall data supported evaluating the 0.92 mg 
dose in the ozanimod CD program. 
A dose escalation regimen over the first 7 days is being utilized
 
 
 
A dose escalation starting 
with 0.23 mg of Ozanimod for the first 4 days of dosing followed by 0.46 mg on Days 5 
through 7 before progressing to the 0.92 mg/day dose will be used.
Please refer to the Investigator’s Brochure for detailed information concerning the available 
pharmacology, toxicology, drug metabolism, clinical studies, and AE profile of the IP.
1.2.4.
Benefit Risk Assessment
Despite recent progress in CD treatment, there remains an unmet need for oral agents that are 
safe and convenient and that can provide effective induction and long term maintenance of 
clinical remission. The benefit risk profile for ozanimod has been evaluated for the indication of 
Crohn’s disease. 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 generally 
well tolerated in patients with Crohn’s disease and is consistent with that observed in other 
patient populations (UC and RMS). The overall data to date suggest that this ozanimod Induction 
Study (RPC01-3202) has a potential favorable benefit risk profile for patients with moderate to 
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severe Crohn’s disease who have inadequate response or intolerance to corticosteroids, 
immunomodulators, or biologic therapy.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) global health pandemic has 
been identified as a potential risk to clinical trial subjects in general and may particularly affect 
patients with underlying chronic disease. It is not known if taking ozanimod increases the risk of 
SARS-CoV-2 infection, or the duration or severity of coronavirus disease 2019 (COVID-19). 
The individual benefit risk considerations remain the responsibility of the Investigator. 
Investigators should apply clinical judgment and these risks should be considered when enrolling 
a subject.
The exclusion criteria (Section 4.3) have been designed to exclude people with current and 
recent infections. Testing to exclude asymptomatic SARS-CoV-2 prior to enrollment should 
follow local practice.
The study has been designed with study visits that allow for close monitoring of subjects’ safety 
throughout the clinical trial (Table 1), and subjects are encouraged to contact the investigator if 
an intercurrent illness develops between study visits. Testing for COVID-19 to inform decisions 
about clinical care during the study should follow local standard practice. 
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 Sponsor advises the Investigator to consider holding dosing of 
investigational product and to consult the Medical Monitor. 
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 benefit risk 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 authorized (ie, Emergency Use Authorization [FDA] or equivalent) by national health 
authorities.
1.3.
Study Rationale
Given the mechanism of action of ozanimod, data from the preclinical animal model, the positive 
results from the Phase 2 (RPC01-202) and Phase 3 (RPC01-3101) UC studies, and preliminary 
results from the Induction Period of the Phase 2 study in CD (RPC01-2201), a Phase 3 program
with ozanimod in CD is being initiated.
The current study is designed as a double-blind, placebo-controlled study to assess the efficacy 
and safety of ozanimod in inducing clinical remission and response in subjects with moderately 
to severely active CD. 
Primary efficacy assessment of ozanimod 0.92 mg per day will be assessed at Week 12 based on 
the efficacy results seen in the RPC01-2201 study after 12 weeks of treatment with ozanimod 
0.92 mg daily.
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2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Study Objectives
2.1.1.
Primary Objective:

Demonstrate the efficacy of ozanimod compared to placebo on the induction of 
clinical remission 
2.1.2.
Secondary Objectives:

Demonstrate the efficacy of ozanimod compared to placebo on induction of clinical 
response, endoscopic response, endoscopic remission, and histologic improvement 

Evaluate the efficacy of ozanimod compared to placebo, in subjects who had 
previously received biologic therapy (eg, anti-IL-12, anti-IL-23, anti-TNF, or 
anti-integrin therapy)

Characterize the population pharmacokinetics (PK) and PK/pharmacodynamics (PD) 
relationship of ozanimod

Demonstrate the safety and tolerability of ozanimod as induction therapy
2.2.
Study Endpoints
Note: All endpoints will evaluate subjects at Week 12 unless otherwise specified.
2.2.1.
Primary Endpoint:

Proportion of subjects with a CDAI score < 150 at Week 12
2.2.2.
Key Secondary Endpoints:

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 at Week 12

Proportion of subjects with a Simple Endoscopic Score for Crohn’s Disease 
(SES-CD) score decrease from baseline of ≥ 50% at Week 12

Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI 
score < 150 at Week 12

Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI 
score < 150 and SES-CD decrease from baseline of ≥ 50% at Week 12
2.2.3.
Other Secondary Endpoints: 

Proportion of subjects with CDAI score < 150 at Week 12 and SES-CD decrease 
from baseline of ≥ 50% at Week 12 

Proportion of subjects with an average daily abdominal pain score ≤ 1 point, and 
average daily stool frequency score ≤ 3 points with abdominal pain and stool 
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frequency no worse than baseline and an SES-CD ≤ 4 points and decrease ≥2 points 
at Week 12

Proportion of subjects with an average daily abdominal pain score ≤ 1 point, and 
average daily stool frequency score ≤ 3 points with abdominal pain and stool 
frequency score no worse than baseline and an SES-CD decrease from baseline of 
≥50% at Week 12

Histologic Improvement based on differences between ozanimod and placebo in 
histologic disease activity scores (ie, Global Histologic Activity Score (GHAS)
changes) (Geboes, 2000) at Week 12

Proportion of subjects with CDAI reduction from baseline of ≥ 70 points at Week 12

Proportion of subjects with absence of ulcers ≥0.5 cm with no segment with any
ulcerated surface ≥10% at Week 12

Proportion of subjects with a Crohn’s Disease Endoscopic Index of Severity (CDEIS) 
decrease from baseline of ≥ 50% at Week 12
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2.2.7.
Overview of Key Safety Assessments
The incidence, severity, relationship, and type of treatment-emergent adverse events (TEAEs), 
serious adverse events (SAEs), AEs leading to discontinuation of IP (see Section 14), and AESIs
will be summarized, as well as clinically meaningful changes from baseline 
 
, clinical laboratory measures, vital signs, and electrocardiograms.
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3.
OVERALL STUDY DESIGN
3.1.
Study Design
This is a Phase 3, randomized, double-blind, placebo-controlled study to explore the effect of 
oral ozanimod as an induction treatment for subjects with moderately to severely active CD, 
defined as a CDAI score ≥ 220 to ≤ 450. Approximately 600 subjects with active clinical 
symptoms and mucosal inflammation will be randomized in a 2:1 ratio to receive either 
ozanimod 0.92 mg or placebo.  Subjects will be stratified 
 
. A maximum of approximately 50% of subjects with a 
history of treatment with marketed biologic agents (eg, TNF antagonists, anti-IL-12/23, and anti-
integrin therapy) will be recruited. This limit will ensure the enrollment of subjects who have 
failed or been intolerant to corticosteroids or immunodulators but never failed a biologic agent.  
The primary endpoint of the study is the proportion of subjects in clinical remission (CDAI 
score < 150) at Week 12. Key secondary endpoints are provided in Section 2. A futility analysis 
will be conducted when approximately 300 subjects have been enrolled, with a similar 
proportion of biological naïve to biological exposed population as that in the overall study 
population.
 
 
 
 
 
 
 
 Subjects who received 
placebo and are in clinical response, clinical remission, and/or have an average daily stool 
frequency score ≤ 3 and an average abdominal pain score ≤ 1 with abdominal pain and stool 
frequency no worse than baseline at the end of this study will continue to receive placebo in a 
blinded fashion in the Maintenance Study.  Those subjects not meeting the criteria outlined 
above at the end of the Induction Study will be eligible to enter the OLE Study (RPC01-3204).
Subjects receiving any medical or surgical intervention for the treatment of CD that meet the 
criteria for treatment failure (Section 9.8) will be discontinued from the study and will not be 
eligible for the Maintenance or OLE Studies.
The study will be conducted in compliance with International Council on 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
Abbreviations:  OLE = Open-Label Extension.
3.2.
Study Duration for Subjects 
Subjects who complete the Induction Study are anticipated to receive 12 weeks of treatment 
(12-week Induction Study). Subjects not entering the Maintenance Study or Open-Label 
Extension Study will have 
 
3.3.
End of Study
The end of study (Induction Study RPC01-3202) is defined as either the date of the last visit of 
the last subject to complete the 
 date of receipt of the last data
point from the last subject that is required for primary or secondary analysis, as pre-specified in 
the protocol, whichever is the later date.
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4.
STUDY POPULATION
4.1.
Number of Subjects 
Approximately 600 subjects with moderately to severely active CD will be randomized in a 2:1 
ratio to receive either ozanimod 0.92 mg or placebo.  
4.2.
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Male or female subjects aged 18 to 75 years (at Screening)
2. Subject should not have any constraints under local regulations, must provide written 
informed consent prior to any study-related procedures, and must have the ability to 
comply with the Table of Events.
3. Subject has signs and symptoms consistent with a diagnosis of CD for at least 3 months 
(prior to first IP administration).  The diagnosis should be confirmed by clinical and 
endoscopic evidence and corroborated by a histology report. (Note: endoscopy and local 
histopathology confirmation may be obtained during Screening if no prior report is 
readily available).
4. Subject has met each of the following 2 criteria:

a CDAI score ≥ 220 and ≤ 450

an average daily stool frequency ≥ 4 points and/or an abdominal pain of ≥2 points
5. Subject has a SES-CD score of ≥ 6 (or SES-CD ≥ 4 in subjects with isolated ileal 
disease).
6. Subject has an inadequate response or loss of response to or is intolerant of at least 1 of 
the following systemic CD treatments (see Appendix B for additional details):

corticosteroids 

immunomodulators 

biologic therapies (eg, ustekinumab, TNFα antagonists, or vedolizumab)
7. If the subject is taking the following background therapies for CD, a stable dose must be 
maintained throughout the study beginning from the screening period as indicated below:

oral aminosalicylates (eg, mesalamine, sulfasalazine, olsalazine, balsalazide) with a 
stable dose for at least 
 prior to Screening endoscopy

prednisone (doses 
) or equivalent with a stable dose for at least 
 prior to Screening endoscopy

budesonide therapy (doses 
) or beclomethasone (doses
)
at a stable dose for at least 
 prior to the Screening endoscopy 
8. Subject at high risk (ie, family history, CD duration) for colonic malignancy has 
documented evidence of having had a surveillance colonoscopy within the last 2 years or 
according to local and national medical guidelines to evaluate for polyps, dysplasia, or 
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
32
RPC01-3202, v6.0: 14 Jun 2021
malignancy.  If there is no recent history of surveillance colonoscopy, this can be done as 
part of the colonoscopy performed during Screening.  Any visualized adenomatous 
polyps must be removed and any suspicious lesion confirmed free of cancer and/or
dysplasia prior to randomization.
9. Female subjects of childbearing potential (FCBP):
Note: For the purposes of this study, a female subject is considered to be of childbearing 
potential if 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 consecutive months). 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)

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 methods of contraception.
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted for FCBP. The Investigator will educate all FCBP about the different options 
of contraceptive methods or abstinence at Screening and Day 1, as appropriate. The 
subject will be re-educated every time her contraceptive measures/methods or ability to 
become pregnant changes. The female subject’s chosen form of contraception must be 
effective by the time the female subject is randomized into the study (for example, 
hormonal contraception should be initiated at least 28 days before randomization).
10. Subject must have documentation of positive varicella zoster virus (VZV) 
or complete VZV vaccination at least 30 days 
prior to randomization. See Section 11.3.
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
33
RPC01-3202, v6.0: 14 Jun 2021
4.3.
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment or at the timepoint 
specified in the following criteria:
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 study difficult or that 
would put the subject at risk by participating in the study.
2. Subject is likely to require, in the physician's judgment, bowel resection within 12 weeks 
of entry into the study.
3. Subject has a diagnosis of UC, indeterminate colitis, radiation colitis, or ischemic colitis,
or has strictures with prestenotic dilatation, requiring procedural intervention, or with 
obstructive symptoms. In addition, subjects with colonic or ileal strictures that are not 
passable with an age-appropriate colonoscope that the endoscopist normally uses in 
clinical practice, or strictures in the ileum or ileocecal valve that are fibrotic in nature, 
will be excluded. Any other modality used in addition to the colonoscopy to assess this 
criterion must be discussed with the Medical Monitor. 
4. Subject has current stoma, ileal-anal pouch anastomosis, fistula that is likely to require, in 
the physician’s judgement, surgical or medical intervention within 12 weeks of entry into 
the study or need for ileostomy or colostomy.
5. Subject has extensive small bowel resection (> 100 cm) or known diagnosis of short 
bowel syndrome, or subject requires total parenteral nutrition.
6. Subject has suspected or diagnosed intra-abdominal or perianal abscess that has not been 
appropriately treated.
7. Subject has documentation of positive test for toxin producing Clostridium difficile 
(C. difficile), or polymerase chain reaction (PCR) examination of the stool. If positive, 
subjects may be rescreened after appropriate treatment and retested no earlier than 7 days 
after completion of treatment. 
8. Subject has documentation of positive examination for pathogens (ova and parasites, and 
bacteria). If positive, subjects may be treated and rescreened.
9. Subject is pregnant, lactating, or has a positive serum beta human chorionic gonadotropin 
(β-hCG) test measured during Screening.
10. Subject has any condition that would make implementation of the protocol or 
interpretation of the study difficult or that would put the subject at risk by participating in 
the study, including history or presence of the following clinically relevant cardiovascular 
conditions:

Recent (within the last 6 months) occurrence of myocardial infarction, unstable 
angina, stroke, transient ischemic attack, symptomatic bradycardia, decompensated 
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
34
RPC01-3202, v6.0: 14 Jun 2021
heart failure requiring hospitalization, Class III/IV heart failure, or severe untreated 
sleep apnea

Second degree (Mobitz type II) atrioventricular (AV) block, third degree AV block, 
sick sinus syndrome or sino-atrial block in subjects without a pacemaker in place (for 
subjects with a pacemaker in place, 
); if second degree Type II or 
third degree AV block is due to concomitant medication, consult Medical Monitor 
prior to Screening

Prolonged QT interval corrected for heart rate using Fridericia's formula (QTcF)
(QTcF > 450 msec males, > 470 msec females) at either Screening or Day 1 Predose 
assessment.

Resting 
 when taking vitals as part of the physical 
examination at either Screening or Day 1 Predose assessment. One recheck is allowed 
for subjects with 
 per visit (ie, during the Screening and/or Day 1 
Predose assessment visit).
Note: Subjects with certain preexisting cardiac conditions, as detailed 
, 
may be considered for participation in the trial. 
11. Subject has a history of diabetes mellitus type 1, or uncontrolled diabetes mellitus type 2 
with hemoglobin A1c (HbA1c) > 9% or is a diabetic subject with significant comorbid 
conditions such as retinopathy or nephropathy.
12. Subject has a history of uveitis (within the last year prior to Screening) or a history of 
macular edema.
13. Subject has a known active bacterial, viral, fungal (excluding fungal infection of nail 
beds, minor upper respiratory tract infections, and minor skin infections), mycobacterial 
infection (including tuberculosis [TB] or atypical mycobacterial disease) or any major 
episode of infection that either required hospitalization, treatment with intravenous (IV) 
antibiotics within 30 days of Screening, or treatment with oral antibiotics within 14 days 
of Screening

Note: In the case of a known SARS-CoV-2 infection, symptoms must have 
completely resolved and based on Investigator assessment in consultation with the 
Clinical Trial Physician / Medical Monitor, there are no sequelae that would place the 
subject at a higher risk of receiving investigational treatment. 
 
See Appendix C for more details.
14. History or known presence of recurrent or chronic infection (eg, hepatitis B virus (HBV), 
hepatitis C virus (HCV), human immunodeficiency virus (HIV); recurrent urinary tract 
infections are allowed.
15. Subject has a history of cancer within 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.
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
35
RPC01-3202, v6.0: 14 Jun 2021
16. Subject has a history of alcohol or drug abuse within 1 year prior to initiation of 
Screening.
Exclusions Related to Medications:
17. Hypersensitivity to active ingredients or excipients of ozanimod or placebo
18. Prior participation in an ozanimod clinical study.
19. Subject has a history of primary nonresponse to 2 or more approved biologic agents or 
has been treated with 4 or more biologics for CD. Subjects who have received biologic 
therapy at sub-therapeutic doses, or durations, should be discussed with the Medical 
Monitor to assess eligibility. 
20. Subject has been treated with a biologic agent within 8 weeks or 5 elimination half-lives 
(whichever is shorter) prior to the first dose of IP.
21. Subject has a history of treatment with an investigational agent within 5 
elimination half-lives of that agent prior to the first dose of IP.
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
36
RPC01-3202, v6.0: 14 Jun 2021
Exclusions Related to Laboratory Results and Other Assessments:
Note: Approval from the Medical Monitor or designee must be obtained if retest is required to be 
repeated > 2 times for assessing the following criteria:
36. Subject has screening ECG results showing any clinically significant abnormality.
37. Subject has serum creatinine results > 1.4 mg/dL (128 μmol/L) for female or > 1.6 mg/dL
(145 μmol/L) for male.
38. Subject has liver function impairment or persisting elevations of aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) results > 2 x the upper limit 
of normal (ULN), or direct bilirubin > 1.5 x ULN.
39. Subject has a platelet count < 100,000/μL (100 GI/L).
40. Subject has hemoglobin < 7.5 g/dL (75 g/L).
41. Subject has neutrophils < 1500/μL (1.5 GI/L).
42. Subject has an absolute white blood cell (WBC) count < 3500/μL (3.5 GI/L).
43. Subject has an absolute lymphocyte count (ALC) < 800 cells/μL (0.80 GI/L).
44. Subject has a forced expiratory volume at 1 second (FEV1) or forced vital capacity 
(FVC) < 70% of predicted values at screening.
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
37
RPC01-3202, v6.0: 14 Jun 2021
5.
TABLE OF EVENTS
Table 1:
Table of Events
Study Procedures
Screening
Initiation of 
Dose 
Escalation
Treatment
Early 
Termination 
(ET)
Day 1a,b
Day 8
Week 4b
Week 8b
Week 12b
Day
-35 to 0
Day 1
(Baseline)
Day 8
Day 28
±3 aa
Day 56
±3 aa
Day 84
±3 aa
Day ET
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
38
RPC01-3202, v6.0: 14 Jun 2021
Table 1:
Table of Events (Continued)
Study Procedures
Screening
Initiation of 
Dose 
Escalation
Treatment
Early 
Termination 
(ET)
Day 1a,b
Day 8
Week 4b
Week 8b
Week 12b
Day
-35 to 0
Day 1
(Baseline)
Day 8
Day 28
±3 aa
Day 56
±3 aa
Day 84
±3 aa
Day ET
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
39
RPC01-3202, v6.0: 14 Jun 2021
Table 1:
Table of Events (Continued)
Abbreviations:  
 
CDAI = Crohn’s Disease Activity Index; CDEIS = Crohn’s Disease Endoscopic Index of Severity; 
 ET = early termination; 
 
 
 
 
 
a
 
 
 
Study Procedures
Screening
Initiation of 
Dose 
Escalation
Treatment
Early 
Termination 
(ET)
Day 1a,b
Day 8
Week 4b
Week 8b
Week 12b
Day
-35 to 0
Day 1
(Baseline)
Day 8
Day 28
±3 aa
Day 56
±3 aa
Day 84
±3 aa
Day ET
Efficacy Assessments
Electronic diaryw
X
X
X
X
X
X
CDAI
Xq
X
X
X
Xr
X
Colonoscopy/SES-CD/
CDEIS/colonic biopsys
X
X
X
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
40
RPC01-3202, v6.0: 14 Jun 2021
b Study visits should be scheduled in the morning, where possible, and on study visit days, subjects should be instructed to withhold the dose until the study visit and the dose 
should be administered during the visit after the PK draw.  
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
41
RPC01-3202, v6.0: 14 Jun 2021
s Colonoscopy should be performed upon confirmation of eligibility based on CDAI at Screening and other entry criteria, if possible. A subject’s colonoscopy from a previous 
screening in this study may be used if within 35 days of randomization. If early termination visit is less than 4 weeks after Baseline, no further colonoscopy is required. At 
Week 12, a colonoscopy should be performed either on day of visit or no more than 7 days prior to the visit date. Intestinal mucosal biopsies will be performed when the 
ileocolonoscopies are done as indicated in Table 1, except in countries or sites with local restrictions.
w The electronic daily diary will be provided to subjects at the Screening Visit. Subject compliance with the completion of the diary data should be assessed at each study visit.
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
42
RPC01-3202, v6.0: 14 Jun 2021
6.
PROCEDURES
6.1.
Screening Period
Written, signed, and dated informed consent from the subject prior to the performance of any 
study-related procedures must be obtained by the Investigator or designee (refer to Section 16.3
for further details regarding obtaining subject’s informed consent).  
Screening procedures must be completed within 35 days prior to receiving the first dose of IP.  
All screening assessments and procedures as per Table 1 are to be performed by the Investigator
or a qualified designee. During the screening period, 
 
 
 
 
See Appendix C for further SARS-CoV-2 guidance.
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
43
RPC01-3202, v6.0: 14 Jun 2021
A screen failure is defined as a subject who has given informed consent and failed to meet the 
inclusion and/or exclusion criteria.  Subjects who fail to meet the inclusion/exclusion criteria can 
be rescreened per Investigator discretion. Additional screening attempts beyond the first should 
be approved by the Medical Monitor prior to rescreening.
During Screening, the subject’s prior use of medications to treat CD and whether he/she
responded to adequate treatment with each medication will be assessed and documented.  
It will also be documented when the subject has been intolerant to 1 of these therapies (eg, 
unable to achieve doses as indicated in Appendix B, dose levels, or treatment durations because 
of treatment-related side effects and/or laboratory abnormalities).
Screening period schedule and procedures are provided in the Table of Events (Table 1).  Each 
subject must be re-consented prior to each screening attempt.  A subject’s colonoscopy from a 
previous screening in this study may be used if within 35 days of randomization.
6.2.
Treatment Period
Eligible subjects will be randomized to treatment on Day 1.  Visits, assessments, and procedures 
will be performed as per the Table of Events in Table 1. 
 
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
44
RPC01-3202, v6.0: 14 Jun 2021
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
45
RPC01-3202, v6.0: 14 Jun 2021
6.2.4.
Study Stopping Rules
The Sponsor has the right to terminate the study for safety reasons.  In addition, the Sponsor may 
terminate the study for administrative reasons.  In all cases, all necessary measures must be taken 
to guarantee appropriate safety follow-up 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.
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
46
RPC01-3202, v6.0: 14 Jun 2021
6.3.
6.3.2.
Efficacy Assessments
See Section 2 for a description of study endpoints.
6.3.2.1.
Primary Efficacy Assessment
The CDAI will be used to evaluate the primary efficacy endpoint.
6.3.2.1.1. 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 Table 3.  The definitions of 
mild, moderate, and severe CD are provided in Table 4.
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
47
RPC01-3202, v6.0: 14 Jun 2021
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 screening 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 Screening and throughout the study.  
Table 3:
Crohn’s Disease Activity Index Assessment
Clinical or Laboratory Variable
Weighting Factor, ×
Number of liquid or soft stools each day for 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 complicationsb
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 Scoreb
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.
Table 4:
Crohn's Disease Severity Definitions
Severity
CDAI Score
Mild
150-219
Moderate
220-450
Severe
> 450
Abbreviations:  CDAI = Crohn’s Disease Activity Index.
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
48
RPC01-3202, v6.0: 14 Jun 2021
6.3.2.1.2. Abdominal Pain and Stool Frequency 
The abdominal pain and stool frequency scores are based on 2 components of the CDAI (Khanna 
2015).  See Section 6.3.2.1 above for more details. 
Stool frequency and abdominal pain, as described in Section 6.3.2.1, will be obtained and 
calculated without a weighting factor for use as part of the inclusion criteria.  These un-weighted 
subject-reported assessments will also be used as efficacy endpoints (Section 2).
 is an additional tool for the visual evaluation of diarrhea, 
and will be collected from all subjects in the electronic diary.
 
6.3.2.2.
Simple Endoscopic Score for Crohn's Disease 
The SES-CD assesses the degree of inflammation.  The SES-CD assesses the following four 
components: 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 in Table 5.  
In the SES-CD, each of these 4 components are assessed in the 5 segments 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 5 segments.
Endoscopic response has not yet been validated and may be defined as a 25% to 50% or greater 
decrease in SES-CD from baseline. 
 
 
, the same endoscopist and the same diameter 
colonoscope as used in screening should be used throughout the study wherever possible.  
 
 
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. 
Local colonoscopy may be used for baseline assessments in the Induction Study if within 35 
days of baseline, consent was obtained from the subject for use in a clinical study, and video 
quality and format is considered adequate for evaluation by centralized reading facility.
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
49
RPC01-3202, v6.0: 14 Jun 2021
Table 5:
Definitions of Simple Endoscopic Score for Crohn's Disease (SES-CD)
SES-CD Values
Variable
0
1
2
3
Size of ulcers
None
Aphthous ulcers 
(0.1 to 0.5 cm)
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
6.3.2.3.
Histology
A central reader will evaluate biopsies taken during colonoscopy and determine the Global 
Histologic Disease Activity Score (GHAS) (Table 6) 
. Biopsies will be taken from the explored ileal and colonic segments.  The GHAS 
 
 scores provided 
 will be used for histopathology endpoints. 
Table 6:
GHAS Grading System
GHAS Descriptors and Levels
Epithelial damage
0: Normal
1: Focal Pathology
2: Extensive Pathology
Architectural changes
0: Normal
1: Moderately disturbed (< 50%)
2: Severely disturbed (> 50%)
Infiltration of mononuclear cells in the lamina 
propia
0: Normal
1: Moderate increase
2: Severe increase
Infiltration of polymorphonuclear cells in the 
lamina propria
0: Normal
1: Moderate increase
2: Severe increase
Polymorphonuclear cells in epithelium
0: Absent
1: In surface epithelium
2: Cryptitis
3: Crypt abscess
Presence of erosion and/or ulcers
0: No
1: Yes
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
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RPC01-3202, v6.0: 14 Jun 2021
Table 6:
GHAS Grading System (Continued)
GHAS Descriptors and Levels
Presence of granuloma
0: No
1: Yes
Number of biopsy specimens affecteda
0: None 
1: ≤33% 
2: > 33%-66% 
3: > 66%
Abbreviations:  GHAS = Global Histologic Activity Score
a For individual segments with only one biopsy segment available, determine if the sample is entirely involved or 
not.  If the fragment is not involved, score as ‘0 – None’.  If ≤ 33% of the fragment is involved, score as ‘1 - ≤
33%’.  If 34 to 66% of the fragment is involved, score as ‘2 - 34%-66%’.  If > 66% of the fragment is involved, 
score as ‘3 - > 66%’.
6.3.3.
Other Assessments
6.3.3.1.
Physical Examination
A complete physical examination will be performed to evaluate the heart, lungs, head and neck, 
abdomen, skin, extremities, weight, as well as to check for visual symptoms (eg, blurred vision 
or decreased visual acuity as reported by the patient). Height should be measured and recorded at 
1.0
Approved
930229740
3.0
v
Approved
1.0
v

EDMS Doc. Number: 25662590 - 25662583
Ozanimod
Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
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RPC01-3202, v6.0: 14 Jun 2021
screening. 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 those body systems associated with any new 
complaints from the patient. See Table 1 for additional details and assessment time points.
6.3.3.2.
Vital Signs
Systolic and diastolic blood pressure and pulse will be assessed in a supine and standing position
at every visit. An automated validated device may be used, if available. In case the cuff sizes 
available are not large enough for the patient’s arm circumference, a sphygmomanometer with an 
appropriately sized cuff may be used. Subjects will be carefully monitored after the first dose of 
investigational drug with a 6 hour post-dose monitoring period of hourly recording of pulse and 
blood pressure as described in 
.
6.3.3.3.
Electrocardiogram
The 12-lead digital ECG devices will be provided to each clinical site by the central ECG 
laboratory for the duration of the study. Detailed instructions describing the process for recording 
and transmission of the digital ECGs will be outlined in the study-specific manual and provided 
to the site before the start of the study. 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. Electrocardiograms will be performed before the first dose 
of IP in all subjects and 2, 4 and 6 hours after the first dose of investigational drug administration 
for at-risk subjects (as outlined 
), or in all subjects if deemed necessary by 
national and local requirements, on Day 1 while the subject is in the clinic. 
All ECGs will be evaluated by the treating physician, with input from a local cardiologist (upon 
approval from a Medical Monitor) or a central reader to confirm if additional monitoring is 
required. If a local cardiologist is not available upon discharge, discharge criteria were evaluated 
by the treating physician, and the central results are assessed as abnormal or unmeasureable then
the subject will need to return for further evaluation. 
 
Only clinically significant abnormalities should be reported in the medical history/current 
medical conditions or the AE eCRF.
6.3.3.4.
Pulmonary Function Test
The pulmonary function test (PFT) refers to “pulmonary function test – no bronchodilator” 
(eg, spirometry which includes total and timed vital capacity, and expiratory flow rate 
measurement). 
 
 
Pulmonary function tests may be performed at a qualified pulmonary function laboratory, 
respiratory department, or at the clinical trial site. If being performed at the clinical trial site, the 
Principal Investigator may delegate the performance of this test to any staff member that is 
qualified to perform the pulmonary function test. 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 confounding factors identified. Please refer to the American 
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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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7.
DESCRIPTION OF STUDY TREATMENTS
7.1.
Description of Investigational Product
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 0.25 mg 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. Both doses 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 IP must be 
withdrawn from the study.
7.2.
Treatment Administration and Schedule
Following the 7-day dose escalation, subjects will receive a single 0.92 mg oral dose of 
ozanimod (equivalent to ozanimod HCl 1 mg) or matching placebo administered daily. The dose 
escalation regime is as follows:

Day 1 through 4: Ozanimod 0.23 mg (equivalent to ozanimod HCl 0.25 mg) (or 
matched placebo)

Day 5 through 7: Ozanimod 0.46 mg daily (equivalent to ozanimod HCl 0.5 mg) 
(administered as two 0.23-mg capsules or 2 matched placebo capsules)

Day 8 through Week 12: Ozanimod 0.92 mg daily (equivalent to ozanimod HCl 1 
mg) (or matched placebo)
 
 
If subjects miss dosing for more than 14 days, they are required to complete the 7-day dose 
escalation regimen as outlined above, including 
.  
An overdose is any dose of IP given 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 Medical Monitor or other designated Drug Safety Center. The overdose should be 
recorded in the study exposure eCRF. AEs associated with an overdose should be reported on 
relevant AE/SAE sections in the eCRF.
Please refer to the Investigator’s Brochure for more information.
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7.2.1.
Instructions for Missed Doses
Subjects should be instructed that if they forget to take a dose, they can take the dose within
4 hours of the normal dosing time. 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 a single dose is missed during the first 2 weeks of treatment, or for more than 7 consecutive
days during Days 15 to 28, treatment must be reinitiated using the
 
 If a subject misses a dose during dose escalation, the
Medical Monitor should be contacted to discuss completing the dose escalation schedule. The 
missed dose and extended days for escalation need to be documented as appropriate in the 
eCRFs.
If a subject misses more than 14 consecutive doses for any reason, the Medical Monitor must be 
contacted to discuss procedures for resuming therapy,
 
. 
7.3.
Method of Treatment Assignment
Subjects will be assigned as follows:

ozanimod 0.92 mg capsule orally starting with a 7-day dose escalation

matching placebo capsule orally starting with a 7-day dose escalation
7.4.
Packaging and Labeling
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, lot 
number, 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.
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7.5.
Investigational Product Accountability and Disposal 
IP should not be used for purposes other than as defined in this protocol.
All supplies of IP will be accounted for in accordance with GCP.  There will be an individual IP
accountability record for each subject, and the Investigator should maintain accurate records of 
the disposition of all IP supplies received during the study.  These records should include the 
amounts and dates that the 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 IP accountability records for inclusion in the Trial Master 
File after database lock.  The Clinical Monitor will periodically check the supplies of IP held by 
the Investigator or pharmacist to verify accountability of all IP used.
The Investigator will provide the IP only to the identified subjects of this study, according to the 
procedures described in this study protocol.  After the end of the study, the Clinical Monitor will 
perform final accountability, package, seal, and prepare for shipment.  IP and all medication 
containers will be returned to the clinical supply distribution vendor and documentation will be 
returned to the Clinical Research Organization.  The CRO will verify that a final report of IP
accountability is prepared and maintained in the Investigator’s Trial Center File.
The Sponsor (or designee) will review with the Investigator and relevant site personnel the 
process for IP return, 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 subject is fully compliant with his/her assigned dosage regimen.  
Records of IP used at intervals between visits will be kept during the study.  Drug accountability 
will be noted by the Clinical Monitor during site visits and at the completion of the study.  
Subjects will be asked to return all unused IP at the end of the study.  The IP should be dispensed 
by the Investigator, or by a qualified individual under the Investigator’s supervision.  
Overall study noncompliance is defined as taking less than 80% or more than 120% of IP during 
the entire treatment period.
At each visit, previously dispensed IP capsules 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 study dosing regimen.  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 to the study or 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. A 
complete history of all previous treatments for CD must be documented. All diagnostic, 
therapeutic, or surgical procedures and/or past biologic exposure relating to CD should be 
recorded. Histories of all other prior medications taken during the 30 days prior to the date of 
informed consent, must also be documented. 
Administration of concomitant medications must be reported along with dosage information, 
dates of administration, and reasons for use. For medications with a single active ingredient, 
generic names for concomitant medications should 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 IP may be continued during the study.
 
 
 
 
 
 
8.1.1.
Corticosteroids
During the Induction Study, subjects are to maintain their stable baseline corticosteroid dose, if 
applicable.  Corticosteroids may be tapered starting after completion of the Induction Study at 
Week 12 for subjects after entering either the Maintenance Study or the OLE Study.  Please see 
protocols RPC01-3203 and RPC01-3204 for details on the tapering regimen in these studies.  
8.1.2.
Aminosalicylates and 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 12 unless reduction or 
discontinuation is clinically indicated. Oral 5-ASAs or probiotics should only be discontinued or 
reduced in dose if required based on Investigator’s judgment. Oral 5-ASA or purified medicinal 
probiotics should not be started in subjects who are not receiving them.
8.1.3.
COVID-19 Vaccination
COVID-19 vaccines that are NOT live are allowed and should be handled in the same manner as 
other vaccines. Administration may occur prior to or during the study, including during treatment 
with IP and after the last dose of IP. In the instance of COVID-19 vaccination given during the 
screening period, both doses (if applicable) should be given prior to randomization.
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See Appendix C for 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 multicenter, double-blind, randomized, Phase 3, placebo-controlled study to determine 
the effect of oral ozanimod as induction therapy on clinical remission in subjects with 
moderately to severely active CD. Approximately 600 subjects with active clinical symptoms 
and mucosal inflammation will be randomized in a 2:1 ratio to receive either ozanimod 0.92 mg 
or placebo. Subjects will be stratified 
 
.  
Interactive response technology (IRT) will be utilized to ensure a central randomization based on 
a stratified block randomization. See Section 9.3.4 for 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 be used in the statistical analysis: 

Intent-to-Treat (ITT): The ITT analysis population will consist of all randomized 
subjects from the Screened analysis population receiving at least 1 dose 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.

Per-protocol (PP): The PP population will consist of all subjects in the ITT population 
who do not have protocol deviations that may substantially affect the primary efficacy 
assessment. This population will be used in a sensitivity analysis of the primary 
endpoint.
Additional analysis populations are defined and their use described in the SAP.
9.3.
Sample Size and Power Considerations
9.3.1.
Primary Endpoint 
The primary endpoint is CDAI clinical remission at Week 12.  Subjects will be deemed 
responders with respect to this endpoint if they meet the definition for CDAI clinical remission at 
Week 12.  Rejection of the null hypothesis associated with the primary endpoint will lead to the 
conclusion that the proportion of Week 12 CDAI clinical remission responders in the ozanimod 
arm is statistically significantly different from the proportion of Week 12 CDAI clinical 
remission responders in the placebo arm.
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9.3.2.
Placebo Response Rates for the Primary Endpoint 
The Week 12 placebo response rate(s) were developed from a literature search (Jairath, 2017; 
Vermeire, 2016; Sandborn, 2013).  The Week 12 ozanimod response rate for the primary 
endpoint
was derived from data obtained from Protocol RPC01-2201 (see Section 1.2.2
for a summary of the RPC01-2201 study).  Table 9 summarizes this information:
Table 9:
Placebo Response Rates from Selected Literature
Placebo Rates from Literature
CDAI < 150
18% (95% confidence interval: 16% - 21%)
23%
6.80%
Abbreviations: CDAI = Crohn’s Disease Activity Index.
9.3.3.
Power Calculations
For the primary endpoint (CDAI < 150 clinical remission) the ozanimod remission rate is 
assumed to be 
 and the placebo remission rate is assumed to be 
  Using nQuery 
Advisor® 7.0, the two-group chi-square test of equal proportions for 2:1 unbalanced treatment 
arms was applied, and the following sample sizes were obtained (Table 10):
Table 10:
Sample Size Calculation for the Primary Endpoint (CDAI Remission)
Abbreviations: CDAI = Crohn’s Disease Activity Index.
To account for subject drop-out during the study, we plan to enroll approximately 600 subjects in 
each study (RPC01-3201 and RPC01-3202) separately.
 the following is known from 
Study RPC01-2201 (ozanimod rate) and also from the published FITZROY study (placebo rate; 
Vermeire, 2016):
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It is often true that response rates in randomized blinded studies are smaller than in open-label 
studies.  To provide a conservative sample size estimate, the assumed ozanimod and placebo 
rates for endoscopic response are therefore 
 and 
 respectively.  This yields the 
following sample size calculations:
In order to provide at least 
 power to detect a difference of at least 
 between the 
ozanimod and placebo arms with respect to the endoscopic response endpoints (proportion of 
subjects with 
 at Week 12 and proportion of subjects 
with CDAI reduction from baseline of ≥ 100 points 
 
 at Week 12), the data from RPC01-3201 and RPC01-3202 will be 
pooled for those endpoints
Additional power and sample size details regarding the endoscopic response major secondary 
endpoints, as well as a discussion around the power associated with the collection of primary and 
major secondary endpoints, are provided in the SAP.
Note: The overall type I error rate across all controlled endpoints will be maintained at 5% using 
methods discussed in Section 9.6.3.
9.3.4.
Stratified Block Randomization
Subjects enrolled in this protocol will be randomized using stratified block randomization in 
order to account for the study design.  Subjects will be stratified 
 
 and then randomized to either ozanimod 0.92 mg or placebo in a 
2:1 allocation ratio.  
9.4.
Background and Demographic Characteristics
Descriptive summaries will be presented for all collected baseline and demographic information. 
Continuous variables will be summarized using number of subjects (n), mean, standard deviation 
(SD), median, minimum, and maximum. Categorical variables will be summarized using 
frequency counts and percentages.
Baseline characteristics subject demographics will include, at minimum, age, sex, race, ethnicity, 
height, weight, body mass index, age at CD symptom onset, age at CD diagnosis, years since CD 
symptom onset, years since CD diagnosis, baseline CDAI score, baseline SES-CD score, 
baseline stool frequency and abdominal pain score
 
 
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EDMS Doc. Number: 25662590 - 25662583
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9.5.
Subject Disposition
Subject disposition will be based on the following:

number of subjects screened

number of subjects randomized

number of subjects dosed

number of subjects completing the Induction Study

number of subjects not completing the Induction Study by reason for dropout 

number of subjects entering the OLE Study

number of subjects entering the Maintenance Study
9.6.
Efficacy Analysis
Because all primary and secondary endpoints for this study are either remission or responder 
endpoints (ie, proportions of subjects meeting the criteria to be classified as remitters or 
responders for the 2 treatment groups), the analysis of endpoints using a continuous measure will 
not be described here, but rather discussed in the SAP. For the primary analysis of remission or 
responder endpoints, the ITT analysis population will be used. Furthermore, for the primary 
analysis of remission or responder endpoints and for a given timepoint or study visit, ITT 
subjects who have insufficient data for remission or response determination will be considered 
non-remitters/non-responders for that timepoint or study visit. Sensitivity analyses, missing data 
imputation and continuous endpoint efficacy analyses are discussed in the SAP.
9.6.1.
Futility Analysis
A futility analysis is planned to be performed when approximately 300 subjects (with a similar 
proportion of biologic naïve to biologic exposed subjects as that in the overall study population) 
from both Induction studies, collectively, have completed the 12-week Induction Period. The 
analysis will occur after these subjects have completed the Induction Period and the data have 
been cleaned. The primary endpoint, CDAI remission (CDAI < 150) at Week 12 will be used in 
the analysis. 
 
 The Induction studies (RPC01-3201 and RPC01-
3202) may be stopped for futility if the observed treatment effect size in CDAI remission is at a 
low probability to demonstrate superiority. Additional efficacy endpoints including CDAI 
response, abdominal pain and stool frequency scores, SES-CD,
 will be evaluated as 
supporting analyses. The futility boundary is “non-binding,” implying that the boundary can be 
overruled if desired without inflating the type-1 error. The “non-binding” boundary is intended to 
allow the Sponsor or the independent DMC to continue the study to gather additional 
information, despite crossing the futility boundary. 
The futility analysis will be conducted by the designated unblinded team (statistician and 
programmers) that supports the DMC and the results will be sent to the DMC for review, and 
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may also be sent to a Celgene internal review committee (IRC) for review. The Celgene IRC 
members will not play a role in the study conduct, and the blind will be maintained for persons 
responsible for the ongoing conduct and management of the study through the end of the 
Maintenance Study (RPC01-3203), until database lock.
9.6.2.
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 12 will be each carried out using 
the Cochran-Mantel-Haenszel (CMH) method. The stratifying factors of 
 
 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. 
The primary analysis of the primary and key secondary endpoints will be performed with the 
missing data imputed using non-responder imputation (NRI) method. Sensitivity analyses will 
also be performed using other missing data handling rules.
9.6.3.
Control of Family-Wise Type I Error Rate and Data Pooling
The primary endpoint and major secondary endpoints of this study (RPC01-3202) will be tested 
statistically using a closed, hierarchical testing procedure in order to control the overall type I 
error rate for multiple endpoints in the current study.  In parallel, this procedure is also applied to 
RPC01-3202 trial.
If an endpoint in this pre-specified hierarchy fails to reach statistical significance, all subsequent 
major secondary endpoints will be considered exploratory.  Only the primary and major 
secondary endpoints will have type I error rates controlled at the family-wise level.  All other 
endpoints will be tested at a nominal α=0.05 level.
9.7.
Safety Analysis
All safety analysis will be carried out on the Safety Population.  No inferential testing for 
statistical significance is planned. 
All safety data will be listed and summarized by treatment group as appropriate. All TEAEs will 
be coded and tabulated by system organ class and preferred term.  The incidence of AEs, SAEs, 
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 will be produced.  The change from baseline 
 
, 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. AEs will 
be summarized by patient years of exposure (PYE).
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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 for lack of therapeutic effect before the Week 12 efficacy 
evaluations
9.9.
Other Topics
9.9.1.
Population Pharmacokinetics and Pharmacokinetics/Pharmacodynamics 
Analyses
  
9.9.2.
Data Monitoring Committee
An independent, external DMC will be charged with monitoring accumulating safety and 
efficacy data from the study, as well as general aspects of study conduct.  
The committee will meet periodically during the study 
 to 
review aggregate analyses by treatment group concerning enrollment, treatment compliance, 
adherence to follow-up schedule, and safety data, etc. from the study. The DMC may 
recommend modifying or stopping the study early due to safety concerns based on data reviews.
The blinding plan to assure that all personnel involved in the conduct of the study remain 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 Section 11), 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 CRF rather than the individual signs or symptoms of the diagnosis or 
syndrome.
CD relapse and related symptoms will be monitored as study endpoints. These occurrences will 
not be recorded as AEs unless they are new or worse than baseline or if they meet the criteria for 
seriousness.
Reductions in ALC levels for subjects in this study are an expected primary 
effect. 
Reductions in ALC, in general, need not be reported as AEs unless there are clinical 
consequences. The protocol requirements in Section 11 should 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 IP should be reported as an AE. Overdose, 
accidental or intentional, that are associated with an AE should be reported on the eCRF. See 
Section 10.1.1 for the definition of overdose. Any sequela of an accidental or intentional 
overdose of an IP should be reported as an AE on the AE eCRF. If the sequela of an overdose is 
an SAE, then the sequela must be reported as an SAE 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 reported as an SAE itself.
10.1.1.
Treatment of Overdose of Investigational Product
An overdose is any dose of IP given 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. The overdose 
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should be recorded in the Overdose eCRF. Only AEs associated with an overdose should be 
reported on relevant AE/SAE sections in the eCRF.
10.1.2.
Monitoring of Subjects with Adverse Events, Serious 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.  After the initial AE/SAE report, the Investigator is required to follow 
up proactively with each subject and provide further information to the Sponsor’s Drug Safety or 
designee on the subject’s condition.  During the study, all AE/SAEs should be followed up to 
resolution unless the event is considered by the Investigator to be unlikely to resolve due to the 
subject’s underlying disease, or the subject is lost to follow-up. 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.  AEs and SAEs will be 
recorded on the AE page of the eCRF and in the subject’s source documents.  Refer to 
Section 13 for instructions on how to report SAEs to Drug Safety.
10.2.
Evaluation of Adverse Events
A qualified Investigator will evaluate all AEs based 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 also need to be completed if required per 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.
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:
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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.
10.2.5.
Action Taken
 
 
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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 with IP 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 (Section 7.2.1). See Section 14 for 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 trial. 
 
 
 The Sponsor may request additional medical information 
concerning AESIs that are non-serious.
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11.
CLINICAL LABORATORY EVALUATIONS
The central laboratory will analyze clinical laboratory samples.  Further details of 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 the Medical Monitor or designee must be informed.  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 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 panel at Screening: sodium, potassium, chloride, calcium, magnesium, 
phosphate, blood urea nitrogen, glucose, HbA1c, albumin, alkaline phosphatase, 
creatinine, ALT, 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 will also be included at the 
Week 12 or early termination (ET) visit.
 

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 study laboratory manual. The results of the analysis will be made available to 
each site by the central laboratory.
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
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 subject’s source documents.  The laboratory sheets will be 
filed with the subject’s source documents.

Pregnancy test: Serum β-hCG must be performed at screening in FCBP; urine β-hCG 
will be performed monthly in FCBP potential at each subsequent visit up until the 
, and if positive, the subject’s dose should be held, and 
pregnancy status should be confirmed with a serum pregnancy test, including after the 
, if needed.
11.3.
Serology
Serology testing will be performed at Screening to determine the subject’s immune status with 
respect to the following viral infections: 

VZV 

A VZV titer will be performed to determine if the subject has immunity (positive 
IgG result to varicella zoster virus). If the titer is negative, and there are no 
antibodies detected against VZV, the subject should therefore be offered to 
receive VZV vaccination. If the subject receives a VZV vaccination, 
randomization can only occur at a minimum of 30 days after vaccination has been 
completed. Note: Should the treating physician decide to vaccinate, the Sponsor 
will reimburse for the vaccine (and office visit if necessary), regardless of choice 
of vaccine. However, it is the responsibility of the treating physician to treat each 
patient in accordance with the approved prescribing information (package insert)
and local and national guidelines. The Sponsor will not be involved in the supply 
of the vaccine.

HIV 

An HIV antibody test will be performed. Subjects testing positive for HIV 
(enzyme-linked immunosorbent assay [ELISA] test result, confirmed by Western 
blot) will be excluded from the study. 

HAV

An anti-hepatitis A virus (HAV) antibody (anti-HAV IgM) test will be performed. 
Subjects testing positive will be excluded from the study, unless they are 
indicative of prior hepatitis A that is considered cured and accompanied by 
normal liver function tests.  

HBV 

Hepatitis B surface antigen (HBsAg) screening test and Hepatitis B core antigen 
(HBcAg) test will be performed.

Subjects who test positive for HBsAg will be excluded from the study.  For 
subjects who test positive only for HBc antigen, an HBV DNA test must be 
performed. If the HBV DNA test is positive, the subject will be excluded from 
the study.  If the HBV DNA test is negative (without anti-viral therapy) and the 
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LFTs are normal, the subject will be eligible for this trial. These subjects will 
undergo periodic monitoring for HBV DNA during the trial.  

HCV

A HCV antibody (anti-HCV IgG or IgM test) will be performed.

Subjects testing positive for HCV antibody and a positive confirmatory test will 
be excluded from the study.
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12.
PREGNANCY
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an IP may 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 may be 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 female subjects of childbearing potential (FCBP).  The Investigator will educate 
all FCBP about the different options of contraceptive methods or abstinence at Screening and 
Day 1, as appropriate. The subject will be re-educated every time her contraceptive 
measures/methods or ability to become pregnant changes.  The female subject’s chosen form of 
contraception must be effective by the time the female subject is randomized into the study (for 
example, hormonal contraception should be initiated at least 28 days before randomization).
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
female subject of childbearing potential regardless of disease state) occurring while the subject is 
on IP, 
 are considered immediately 
reportable events.  IP 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’s Drug 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’s Drug 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’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.
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 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 consecutive 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 SERIOUS ADVERSE 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 study or discontinues from the study
will 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 the Sponsor’s Drug Safety or designee using the designated SAE reporting 
forms and procedures.  Data entry must be completed within 24 hours from the time the study
site 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 appropriate regulatory authorities as required.  Reporting of SAEs must comply with 
ICH E6, 4.11.1.
13.1.
Safety Queries
Queries pertaining to SAEs will be communicated from Sponsor’s Drug Safety or designee to the 
site. 
 
13.2.
Expedited Reporting of Adverse Events
For the purpose of regulatory reporting, Sponsor’s Drug Safety will determine the expectedness 
of events suspected of being related to ozanimod based on the Investigator’s Brochure.
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 an expedited 
manner in accordance with 21 CFR 312.32. 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 
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Reference Safety Information section in the Investigator’s Brochure), 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), the Sponsor or authorized 
representative will report in an expedited manner to Regulatory Authorities and IECs concerned, 
SUSARs in accordance with Directive 2001/20/EC and the Detailed Guidance on collection, 
verification and presentation of adverse reaction reports arising from clinical studies on IPs for 
human use (ENTR/CT3) and also in accordance with country-specific requirements.  
The Sponsor or 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 from tests 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 new SUSARs or significant risks to subjects.
The Investigator must keep copies of all pertinent safety information on file including 
correspondence with the Sponsor and the IRB/IEC.  See Section 17.3 for record retention 
information.
13.3.
Sponsor’s Drug Safety Contact Information
For Sponsor’s Drug 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 
investigational product(s):

adverse event

withdrawal by subject

death

lost to follow-up

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 study at any time. The Investigator will provide a 
written explanation in the source documentation to be entered on the appropriate eCRF 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 study if continuation is determined to be a safety risk. 
Reasons for discontinuation include, but are not limited to, the following:

Physician decision:  The Investigator must discontinue IP if 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 
study for 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.
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
Adverse event: A subject must be discontinued from IP if, 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.
                                               
1 International Normalized Ratio (INR) is part of the coagulation panel and may be obtained at the discretion of
the 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. Subjects receiving any 
medical or surgical intervention for the treatment of CD that meet the criteria for 
treatment failure will be discontinued from the study and will not be eligible for the 
Maintenance or OLE studies. See Section 9.8.

Withdrawal by subject (or subject’s parent/guardian): The subject (or subject’s 
parent/guardian) may choose to discontinue IP at any time. Every effort should be 
made within the bounds of safety and subject (or subject’s parent/guardian) choice to 
have each subject complete the Early Termination Visit 
 
. If a subject (or subject’s parent/guardian) withdraws consent, the only 
additional investigational data to be collected will be the follow-up of SAEs as 
mandated by the protocol.

Pregnancy: If a female subject becomes pregnant, IP must be discontinued (see
Section 12).

Study termination 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 or 
designee/contract research organization Medical 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 unless in 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 not be 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 to ensure 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 GCP and in the local 
regulations.  Sponsor’s staff 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 with the study are adequately informed 
about the protocol, amendments, study treatments, as well as study-related duties and functions, 
including obligations of confidentiality of Sponsor information. 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 ICF and are 
screened for entry into the study.  Subjects who fail screening must have the reason(s) recorded 
in the subject’s source documents.
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 by Sponsor on public registry websites) is considered Sponsor confidential 
information.  Only information that is previously disclosed by the Sponsor on a public registry 
website may be freely disclosed by the Investigator or its institution, or as outlined in the Clinical 
Study Agreement.  Sponsor protocol, amendment, and Investigator’s Brochure information is not 
to be made publicly available (eg, on the Investigator’s or their institution’s website) without 
express written approval from the Sponsor.  Information proposed for posting on the 
Investigator’s or their institution’s website must be submitted to the Sponsor for review and 
approval, providing at least 5 business days for review.
At the time results of this study are made available to the public, Sponsor will 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 subject and/or his/her caregiver as agreed by the 
subject.
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16.3.
Subject Information and Informed Consent
The Investigator must obtain informed consent from a subject and/or a subject’s legal 
representative prior to any study-related procedures.
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/assent 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/assent 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/assent. The revised ICF/assent 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
Sponsor affirms 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). Sponsor requires 
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’s Clinical 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 administrative in 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 Sponsor or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by 
Sponsor or its authorized representative. This documentation must also include a list of the 
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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 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 ICF should also be revised.
The Investigator must keep a record of all communications with the IRB/IEC and, 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 Sponsor and 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 AEs as 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 study for safety reasons.  In addition, the Sponsor may 
terminate the study for administrative reasons.  In all cases, all necessary measures have to be 
taken to guarantee appropriate safety follow-up of all subjects already included in the study.
The IRB/IEC and 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 as the 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 IP are complete, accurate, filed, and retained.  Examples of 
source documents may 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 study agreement. 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 significant study-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 Sponsor if 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.  
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The Investigator must obtain approval in writing from the Sponsor prior to destruction of any 
records. If the Investigator is unable to meet this obligation, he or she must ask the Sponsor for 
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 Sponsor or its authorized representative 
for compliance with applicable government regulations with respect to current GCP and standard 
operating procedures.
18.1.
Study Monitoring and Source Data Verification
The Sponsor ensures 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 Investigators’ Meeting. Prior to enrolling subjects into the 
study, a Sponsor representative 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, labeling. 
In the event of a suspected product quality issue, the immediate action to be taken by the site is 
to quarantine the affected product. Do not dispose of the product. When reporting, provide as 
much product information as possible. Suspected IP quality 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 or other 
representatives exist within the Sponsor.  Representatives of this unit will conduct audits of 
clinical research activities in accordance with Sponsor SOPs to evaluate compliance with GCP 
guidelines 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], 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/she should contact the Sponsor immediately.
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19.
PUBLICATIONS
As described in Section 16.4, all protocol- and amendment-related information, with the 
exception of the information provided by Sponsor on public registry websites, is considered 
Sponsor confidential information and is not to be used in any publications.  Sponsor
protocol-related information proposed for use in a publication must be submitted to Sponsor for 
review and approval, and should not be utilized in a publication without express written approval 
from Sponsor, or as described in the Clinical Trial Agreement.  
Sponsor will ensure that 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 may also be presented at 1 or 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, Gasink C, 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.
 
Jairath V, Zou G, Parker CE, et al. Systematic review with meta-analysis: placebo rates in 
induction and maintenance trials of Crohn’s disease. Aliment Pharmacol Ther. 2017; 
vermdoi:10.1111/apt.13973.
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, D’Haens GR, Wolf DC, et al. Ozanimod as Induction Therapy in Moderate-to 
Severe Ulcerative Colitis: Results from the Phase III, Randomized, Double-Blind, Placebo-
Controlled True North Study 2020; 8(10): 1258-1275.
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.
The EuroQol Group. EuroQol - a new facility for the measurement of health-related quality of 
life. Health Policy 1990; 16:199-208.
Vermeire S, Schreiber S, Petryka R, et al. Clinical remission in with moderate-to-severe Crohn’s 
disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, 
randomised, placebo-controlled trial. Lancet 2016;S0140-6736(16):32537-5.
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21.
APPENDICES
APPENDIX A. TABLE OF ABBREVIATIONS
Table 13:
Abbreviations and Specialist Terms
Abbreviation or 
Specialist Term
Explanation
6-MP
Mercaptopurine
ADR
Adverse drug reaction
AE
Adverse event
AESI
Adverse event of special interest
ALC
Absolute lymphocyte count
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
AP
Abdominal pain
AST
Aspartate aminotransferase (SGOT)
AV
Atrioventricular
AZA
Azathioprine
β-hCG
β-subunit of human chorionic gonadotropin
BMI
Body Mass Index
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
DMC
Data Monitoring Committee
eCRF
Electronic case report form
ECG
Electrocardiogram
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Table 13:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
EEA
European Economic Area
EEN
Exclusive Enteral Nutrition
ELISA
Enzyme linked immunosorbent assay
EMA
European Medicines Agency
ET
Early termination
FCBP
Female subject of childbearing potential
FDA
Food and Drug Administration
FEV1
Forced expiratory volume 1
FVC
Forced vital capacity
GCP
Good Clinical Practice
GGT
Gamma glutamyltransferase
GHAS
Global Histologic Activity Score
GI
Gastrointestinal 
GMP
Good Manufacturing Practices
HAV
Anti-hepatitis A virus
HbA1c
Hemoglobin A1c
HBcAg
Anti-hepatitis B core antigen
HBV
Hepatitis B virus
HBsAg
Hepatitis B surface antigen 
HCV
Hepatitis C vaccine
HIV
Human immunodeficiency virus
ICF
Informed consent form
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Table 13:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IL
Interleukin
INR
International Normalised Ratio
IP
Investigational product
IRB
Institutional Review Board
IRT
Interactive response technology
ITT
Intent to treat
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
LFT
Liver function test
MERS-CoV
Middle East respiratory syndrome coronavirus
MTX
Methotrexate
NRI
Non-responder imputation
OLE
Open-Label Extension
PCR
Polymerase chain reaction
PD
Pharmacodynamics
PFT
Pulmonary function test
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Table 13:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
PIN
Personal identification number
PK
Pharmacokinetics
PP
Per protocol
PYE
Patient years of exposure
QTcF
Fridericia's Correction Formula
SAE
Serious adverse event
SAP
Statistical analysis plan
SARS-CoV-2
Severe acute respiratory syndrome coronavirus 2 
SES-CD
Simple Endoscopic Score for Crohn's Disease
SGOT
Serum glutamic oxaloacetic transaminase 
SGPT
Serum glutamic pyruvic transaminase
SOP
Standard operating procedure
SUSAR
Suspected unexpected serious adverse reaction
TB
Tuberculosis
TEAE
Treatment-emergent adverse event
TFR
Treatment failure rules
TNBS
Trinitrobenzenesulfonic acid
TNF
Tumor necrosis factor
TRT
Treatment 
UC
Ulcerative colitis
ULN
Upper limit of normal
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Table 13:
Abbreviations and Specialist Terms (Continued)
Abbreviation or 
Specialist Term
Explanation
VZV
Varicella zoster vaccine
WBC
White blood cell  
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APPENDIX B. INCLUSION CRITERIA DRUG SPECIFICATIONS
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APPENDIX C. SARS-COV-2 GUIDELINES
If the subject receives a positive SARS-CoV-2 test result and is asymptomatic during the 
screening 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 symptomatic during the 
screening 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.
Procedures related to COVID-19 identification (eg, MERS-CoV test, SARS-CoV-2 antibody 
test, SARS-CoV-2 ELISA test, etc.), and treatment (eg, intubation, dialysis, etc.) must be 
reported on the appropriate section of the eCRF. 
COVID-19 vaccines that are NOT live are allowed and should be handled in the same manner as 
other vaccines. Administration may occur prior to and during the study, including during 
treatment with IP and after the last dose of IP. In the instance of COVID-19 vaccination given 
during the screening period, both doses (if applicable) should be given prior to randomization. 
Administration of vaccinations must be reported along with dosage information, dates of 
administration and vaccine name/trade name on the appropriate sections of the eCRF. A separate 
logline should be entered for each vaccine administered with the dose number following the 
vaccine name/trade name.
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This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName: 
Title:  
Date: Thursday, 24 June 2021, 11:12 AM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
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EDMS Doc. Number: 25662590 - 25661592
Ozanimod
Summary of Changes Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
1
RPC01-3202, v6.0: 14 Jun 2021
TITLE PAGE
– SUMMARY OF CHANGES –
AMENDMENT NO. 5
INDUCTION STUDY #2: A PHASE 3, MULTICENTER, 
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLED
STUDY OF ORAL OZANIMOD AS INDUCTION THERAPY
FOR MODERATELY TO SEVERELY ACTIVE CROHN’S 
DISEASE
INVESTIGATIONAL PRODUCT (IP):
Ozanimod
PROTOCOL NUMBER:
RPC01-3202
PREVIOUS VERSION DATE:
03 Sep 2020
AMENDMENT No. 5 DATE:
14 Jun 2021
EudraCT NUMBER:
2017-004293-33
IND NUMBER: 
126,740
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:
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 to the 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 not be further disclosed by them.
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EDMS Doc. Number: 25662590 - 25661592
Ozanimod
Summary of Changes Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
2
RPC01-3202, v6.0: 14 Jun 2021
SPONSOR THERAPEUTIC AREA LEAD SIGNATURE PAGE
{See appended electronic signature page}
Signature
Date
Name and Title
By my signature, I indicate I have reviewed this summary of changes and find its 
content to be acceptable. 
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EDMS Doc. Number: 25662590 - 25661592
Ozanimod
Summary of Changes Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
3
RPC01-3202, v6.0: 14 Jun 2021
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
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EDMS Doc. Number: 25662590 - 25661592
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Summary of Changes Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
4
RPC01-3202, v6.0: 14 Jun 2021
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EDMS Doc. Number: 25662590 - 25661592
Ozanimod
Summary of Changes Protocol RPC01-3202, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
5
RPC01-3202, v6.0: 14 Jun 2021
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EDMS Doc. Number: 24997002 - 24977275
Ozanimod
Summary of Changes RPC01-3202, Version 5.0
Celgene International II Sàrl
Confidential and Proprietary
1
RPC01-3202, v5.0: 03 Sep 2020
TITLE PAGE
SUMMARY OF CHANGES
INDUCTION STUDY #2 - A PHASE 3, MULTICENTER, 
RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED 
STUDY OF ORAL OZANIMOD AS INDUCTION THERAPY 
FOR MODERATELY TO SEVERELY ACTIVE CROHN’S 
DISEASE
INVESTIGATIONAL PRODUCT (IP):
OZANIMOD
PROTOCOL NUMBER:
RPC01-3202
VERSION & DATE:
5.0 03 Sep 2020
REPLACES VERSION:
4.0 10 Jul 2019
EudraCT NUMBER:
2017-004293-33
IND NUMBER: 
126,740 
Contact Information: 
Name:
Title:
 Clinical Trial Physician, 
Address: 
3033 Science Park Road, Suite 300, San Diego, California 92121 USA
Phone:
Tel (office):  
 Tel (cell):  
E-mail:
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 to the 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 not be further disclosed by them.
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EDMS Doc. Number: 24997002 - 24977275
Ozanimod
Summary of Changes RPC01-3202, Version 5.0
Celgene International II Sàrl
Confidential and Proprietary
2
RPC01-3202, v5.0: 03 Sep 2020
This document summarizes the changes that were made between Protocol RPC01-3202
Version 5 (27 Aug 2020) and Version 4 (dated 10 June 2019).
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:
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EDMS Doc. Number: 24997002 - 24977275
Ozanimod
Summary of Changes RPC01-3202, Version 5.0
Celgene International II Sàrl
Confidential and Proprietary
3
RPC01-3202, v5.0: 03 Sep 2020
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EDMS Doc. Number: 24997002 - 24977275
Ozanimod
Summary of Changes RPC01-3202, Version 5.0
Celgene International II Sàrl
Confidential and Proprietary
4
RPC01-3202, v5.0: 03 Sep 2020
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EDMS Doc. Number: 23934175 - 23732425
Ozanimod
Summary of Changes RPC01-3202, Version 4.0
Celgene International II Sàrl
Confidential and Proprietary
1
RPC01-3202,v4.0: 10 July 2019
TITLE PAGE
SUMMARY OF CHANGES
INDUCTION STUDY #2 - A PHASE 3, MULTICENTER, 
RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED STUDY OF ORAL 
OZANIMOD AS INDUCTION THERAPY FOR 
MODERATELY TO SEVERELY ACTIVE CROHN’S 
DISEASE
Test Drug:
Ozanimod
Protocol Number:
RPC01-3202
Study Phase:
Phase 3
IND/EudraCT number:
126,740/2017-004293-33
Version and Date:
4 dated 10 July 2019
Replaces Version:
3 dated 18 June 2018
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EDMS Doc. Number: 23934175 - 23732425
Ozanimod
Summary of Changes RPC01-3202, Version 4.0
Celgene International II Sàrl
Confidential and Proprietary
2
RPC01-3202,v4.0: 10 July 2019
TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
1.
OVERVIEW OF KEY CHANGES...........................................................................8
2.
DETAILS OF CHANGES FROM THE PRIOR PROTOCOL VERSION.................9
TITLE PAGE............................................................................................................................46
PROTOCOL SUMMARY ........................................................................................................51
1.
INTRODUCTION..................................................................................................68
1.1.
Disease Background ...............................................................................................68
1.2.
Compound Background ..........................................................................................69
1.2.1.
Summary of nonclinical studies ..............................................................................69
1.2.2.
Summary of clinical studies in inflammatory bowel disease....................................70
1.2.3.
Rationale for Dose Selection...................................................................................70
1.2.4.
Benefit Risk Assessment.........................................................................................71
1.3.
Study Rationale ......................................................................................................71
2.
STUDY OBJECTIVES AND ENDPOINTS...........................................................73
2.1.
Study Objectives.....................................................................................................73
2.1.1.
Primary Objective:..................................................................................................73
2.1.2.
Secondary Objectives: ............................................................................................73
2.2.
Study Endpoints .....................................................................................................73
2.2.1.
Primary Endpoint: ..................................................................................................73
2.2.2.
Major Secondary Endpoints:...................................................................................73
2.2.3.
Other Secondary Endpoints: ...................................................................................74
2.2.4.
Other Secondary Endpoints (adolescents): ..............................................................74
74
75
76
76
2.2.9.
Overview of Key Safety Assessments.....................................................................76
3.
OVERALL STUDY DESIGN ................................................................................77
3.1.
Study Design ..........................................................................................................77
3.2.
Study Duration for Subjects....................................................................................78
3.3.
End of Study...........................................................................................................78
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EDMS Doc. Number: 23934175 - 23732425
Ozanimod
Summary of Changes RPC01-3202, Version 4.0
Celgene International II Sàrl
Confidential and Proprietary
3
RPC01-3202,v4.0: 10 July 2019
4.
STUDY POPULATION.........................................................................................79
4.1.
Number of Subjects ................................................................................................79
4.2.
Inclusion Criteria....................................................................................................79
4.3.
Exclusion Criteria...................................................................................................81
5.
TABLE OF EVENTS.............................................................................................86
6.
PROCEDURES......................................................................................................93
6.1.
Screening Period.....................................................................................................93
6.2.
Treatment Period ....................................................................................................94
94
96
96
6.2.34.
Study Stopping Rules .............................................................................................96
6.3.
96
96
6.43.2.
Efficacy Assessments .............................................................................................97
6.43.2.1.
Primary Efficacy Assessment..................................................................................97
6.4.3.2.2.
Simple Endoscopic Score for Crohn's Disease ........................................................99
6.4.3.12.3. Histology................................................................................................................99
6.3.2.4.
Pediatric Crohn’s Disease Activity Index (PCDAI)...............................................101
6.3.2.5.
Erythrocyte Sedimentation Rate............................................................................102
6.3.3.
Other Assessments................................................................................................102
6.3.3.1.
Physical Examination ...........................................................................................102
6.3.3.2.
Vital Signs............................................................................................................102
6.3.3.3.
Electrocardiogram ................................................................................................103
6.3.3.4.
Pulmonary Function Test......................................................................................103
103
6.6.6.3.3.6. Weight and BMI (Adolescent Subjects) ................................................................103
6.3.3.7.
Bone Age Determination (Adolescent Subjects Only)...........................................103
104
104
104
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Summary of Changes RPC01-3202, Version 4.0
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Confidential and Proprietary
4
RPC01-3202,v4.0: 10 July 2019
105
105
105
106
106
106
7.
DESCRIPTION OF STUDY TREATMENTS......................................................107
7.1.
Description of Investigational Product ..................................................................107
7.2.
Treatment Administration and Schedule ...............................................................107
7.2.1.
Instructions for Missed Doses...............................................................................108
7.3.
Method of Treatment Assignment.........................................................................108
7.4.
Packaging and Labeling........................................................................................108
7.5.
Investigational Product Accountability and Disposal ............................................109
7.6.
Investigational Product Compliance......................................................................109
8.
CONCOMITANT MEDICATIONS AND PROCEDURES..................................110
8.1.
Permitted Concomitant Medications and Procedures.............................................110
8.1.1.
Corticosteroids......................................................................................................110
8.1.2.
Aminosalicylates and Purified Medicinal Probiotics .............................................110
8.1.3.
Treatment for Adolescents....................................................................................110
8.2.
Prohibited Concomitant Medications and Procedures............................................111
111
112
8.3.
Required Concomitant Medications and Procedures..............................................113
9.
STATISTICAL CONSIDERATIONS ..................................................................114
9.1.
Overview..............................................................................................................114
9.2.
Study Population Definitions ................................................................................114
9.3.
Sample Size and Power Considerations.................................................................114
9.3.1.
Primary Endpoint..................................................................................................114
9.3.2.
Placebo Response Rates for the Primary Endpoint ................................................115
9.3.3.
Power Calculations...............................................................................................115
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Summary of Changes RPC01-3202, Version 4.0
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Confidential and Proprietary
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RPC01-3202,v4.0: 10 July 2019
9.3.4.
Stratified Block Randomization............................................................................116
9.4.
Background and Demographic Characteristics......................................................116
9.5.
Subject Disposition...............................................................................................117
9.6.
Efficacy Analysis..................................................................................................117
9.6.1.
Futility Analysis ...................................................................................................117
9.6.2.
Analysis of Primary and Key Secondary Endpoints ..............................................118
9.6.23.
Control of Family-wise Type I Error Rate and Data Pooling .................................118
9.7.
Safety Analysis.....................................................................................................120
9.8.
Treatment Failure Rules........................................................................................120
9.9.
Other Topics.........................................................................................................121
9.9.1.
Population Pharmacokinetics and Pharmacokinetics/Pharmacodynamics 
Analyses...............................................................................................................121
9.9.2.
Data Safety Monitoring BoardCommittee.............................................................121
10.
ADVERSE EVENTS............................................................................................122
10.1.
Monitoring, Recording and Reporting of Adverse Events .....................................122
10.1.1.
Treatment of Overdose of Investigational Product ................................................123
10.1.2.
Monitoring of Subjects with Adverse Events, Serious Adverse Events..................123
10.2.
Evaluation of Adverse Events...............................................................................123
10.2.1.
Seriousness...........................................................................................................123
10.2.2.
Severity ................................................................................................................125
10.2.3.
Causality ..............................................................................................................125
10.2.4.
Duration ...............................................................................................................127
10.2.5.
Action Taken........................................................................................................127
10.2.6.
Outcome...............................................................................................................127
10.2.7.
Adverse Events of Special Interest........................................................................127
10.3.
ABNORMAL11. CLINICAL LABORATORY VALUESEVALUATIONS.........128

11.1. Hematology .................................................................................................128
11.2.
Chemistry:............................................................................................................129

11.3. Serology ......................................................................................................130
1011.4.
Pregnancy.............................................................................................................132
1011.4.1.
WomenFemale Subjects of Childbearing Potential................................................132
11.4.2.
Male Subjects.......................................................................................................133
12.
REPORTING OF SERIOUS ADVERSE EVENTS ..............................................134
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EDMS Doc. Number: 23934175 - 23732425
Ozanimod
Summary of Changes RPC01-3202, Version 4.0
Celgene International II Sàrl
Confidential and Proprietary
6
RPC01-3202,v4.0: 10 July 2019
10.512.1.
Safety Queries ......................................................................................................134
10.612.2.
Expedited Reporting of Adverse Events................................................................135
1113.
DISCONTINUATIONS .......................................................................................136
1113.1.
Treatment Discontinuation....................................................................................136
1113.2.
Study Discontinuation ..........................................................................................136
1214.
EMERGENCY PROCEDURES...........................................................................139
1214.1.
Emergency Contact...............................................................................................139
1214.2.
Emergency Identification of Investigational Products ...........................................139
1315.
REGULATORY CONSIDERATIONS.................................................................140
1315.1.
Good Clinical Practice..........................................................................................140
1315.2.
Investigator Responsibilities .................................................................................140
1315.3.
Subject Information and Informed Consent/Assent ...............................................141
15.4.
Confidentiality......................................................................................................141
1315.5.
Protocol Amendments...........................................................................................142
1315.6.
Institutional Review Board/Independent Ethics Committee Review and 
Approval ..............................................................................................................142
1315.7.
Ongoing Information for Institutional Review Board/Independent Ethics 
Committee............................................................................................................142
1315.8.
Termination of the Study ......................................................................................143
1416.
DATA HANDLING AND RECORDKEEPING...................................................144
1416.1.
Data/Documents ...................................................................................................144
1416.2.
Data Management.................................................................................................144
1416.3.
Record Retention..................................................................................................144
1517.
QUALITY CONTROL AND QUALITY ASSURANCE......................................146
1517.1.
Study Monitoring and Source Data Verification....................................................146
1517.2.
Product Quality Complaint ...................................................................................146
1517.3.
Audits and Inspections..........................................................................................146
1618.
PUBLICATIONS .................................................................................................148
1719.
REFERENCES.....................................................................................................149
20.
APPENDICES......................................................................................................152
Appendix A:
Table of Abbreviations ....................................................................................152
Appendix B:
Inclusion Criteria Drug Specifications..............................................................156
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EDMS Doc. Number: 23934175 - 23732425
Ozanimod
Summary of Changes RPC01-3202, Version 4.0
Celgene International II Sàrl
Confidential and Proprietary
7
RPC01-3202,v4.0: 10 July 2019
LIST OF TABLES
Table 1:
Specific Changes to Protocol RPC01-3201 from Version 3 (18 June 2018) to 
Version 4 (10 July 2019).........................................................................................10
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EDMS Doc. Number: 23934175 - 23732425
Ozanimod
Summary of Changes RPC01-3202, Version 4.0
Celgene International II Sàrl
Confidential and Proprietary
8
RPC01-3202,v4.0: 10 July 2019
This document summarizes the changes that were made between Protocol RPC01-3201
Version 4 (dated 10 July 2019) and Version 3 (dated 18 June 2018).
1.
OVERVIEW OF KEY CHANGES
The following bulleted list identifies the key changes to the protocol and provides the rationale 
for each key change:
The following bulleted list identifies the key changes to the protocol and provides the rationale 
for each change:
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Celgene International II Sàrl  
 
Summary of Changes: Protocol Number: RPC01-3202 
 
18 June 2018 
Drug Name: Ozanimod 
Version 3 
Page 1 of 28 
CONFIDENTIAL 
 
 
 
 
 
 
SUMMARY OF CHANGES 
 
INDUCTION STUDY #2 - A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study of Oral Ozanimod as Induction Therapy for Moderately to Severely Active 
Crohn’s Disease 
 
 
 
 
 
 
 
Test Drug: 
Ozanimod 
 
 
 
Protocol Number: 
RPC01-3202 
 
 
Study Phase: 
Phase 3 
 
 
IND/EudraCT number: 
126,740/2017-004293-33 
 
 
Version and Date: 
3 dated 18 June 2018 
 
 
Replaces Version: 
2 dated 19 December 2017 
 
 
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Celgene International II Sàrl  
 
Summary of Changes: Protocol Number: RPC01-3202 
 
18 June 2018 
Drug Name: Ozanimod 
Version 3 
Page 2 of 28 
CONFIDENTIAL 
TABLE OF CONTENTS 
1. 
OVERVIEW OF KEY CHANGES ..............................................................................3 
2. 
DETAILS OF CHANGES FROM THE PRIOR PROTOCOL VERSION .................5 
 
LIST OF TABLES 
Table 1: 
Specific Changes to Protocol RPC01-3202 from Version 2 (19 December 
2017) to Version 3 (18 June 2018) ...............................................................................5 
 
 
 
 
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Celgene International II Sàrl  
 
Summary of Changes: Protocol Number: RPC01-3202 
 
18 June 2018 
Drug Name: Ozanimod 
Version 3 
Page 3 of 28 
CONFIDENTIAL 
This document summarizes the changes that were made between Protocol RPC01-3202 
Version 3 (dated 18 June 2018) and Version 2 (dated 20 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: 
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Celgene International II Sàrl  
 
Summary of Changes: Protocol Number: RPC01-3202 
 
18 June 2018 
Drug Name: Ozanimod 
Version 3 
Page 4 of 28 
CONFIDENTIAL 
 
 
 
 
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Celgene International II Sàrl  
 
Summary of Changes: Protocol Number: RPC01-3202 
 
19 December 2017 
Drug Name: Ozanimod 
Version 2 
Page 1 of 13 
CONFIDENTIAL 
 
 
 
 
 
 
SUMMARY OF CHANGES 
 
INDUCTION STUDY #2 - A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-
Controlled Study of Oral Ozanimod as Induction Therapy for Moderately to Severely Active 
Crohn’s Disease 
 
 
 
 
 
Test Drug: 
Ozanimod 
 
 
 
Protocol Number: 
RPC01-3202 
 
 
Study Phase: 
Phase 3 
 
 
IND/EudraCT number: 
126,740/2017-004293-33 
 
 
Version and Date: 
2 dated 19 December 2017 
 
 
Replaces Version: 
1 dated 26 September 2017 
 
 
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Celgene International II Sàrl  
 
Summary of Changes: Protocol Number: RPC01-3202 
 
19 December 2017 
Drug Name: Ozanimod 
Version 2 
Page 2 of 13 
CONFIDENTIAL 
TABLE OF CONTENTS 
1. 
OVERVIEW OF KEY CHANGES ..............................................................................3 
2. 
DETAILS OF CHANGES FROM THE PRIOR PROTOCOL VERSION .................4 
 
LIST OF TABLES 
Table 1: 
Specific Changes to Protocol RPC01-3201 from Version 1 
(26 September 2017) to Version 2 (19 December 2017) ..............................................4 
 
 
 
 
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Celgene International II Sàrl  
 
Summary of Changes: Protocol Number: RPC01-3202 
 
19 December 2017 
Drug Name: Ozanimod 
Version 2 
Page 3 of 13 
CONFIDENTIAL 
This document summarizes the changes that were made between Protocol RPC01-3202 
Version 2 (dated 19 December 2017) and Version 1 (dated 26 September 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 following bulleted list identifies global changes to the protocol: 
 
 
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