A Phase 3, Multicenter, Open-Label Extension Study of Oral Ozanimod for Moderately to Severely Active Crohn's Disease
Phase: PHASE3
Conditions: Crohn Disease
Sponsor: Celgene

Official Title of Study: 
A Phase 3, Multicenter, Open-Label Extension Study of Oral Ozanimod for Moderately to Severely 
Active Crohn's Disease 
 
NCT Number: NCT03467958 
Document Date (Date in which document was last revised): 16 Mar 2023 
 
 
 

Ozanimod 
Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
1
TITLE PAGE
A PHASE 3, MULTICENTER, OPEN-LABEL EXTENSION STUDY OF ORAL 
OZANIMOD FOR MODERATELY TO SEVERELY ACTIVE CROHN’S DISEASE
INVESTIGATIONAL PRODUCT:
Ozanimod (BMS-986374)
PROTOCOL NUMBER:
RPC01-3204 
DATE FINAL:
26 Sep 2017
AMENDMENT No. 1.0 DATE:
19 Dec 2017
AMENDMENT No. 2.0 DATE:
18 Jun 2018
AMENDMENT No. 3.0 DATE:
10 Jun 2019
AMENDMENT No. 4.0 DATE:
03 Sep 2020
AMENDMENT No. 5.0 DATE:
14 Jun 2021
AMENDMENT No. 6.0 DATE:
16 Mar 2023
IND NUMBER:
126,740
EudraCT NUMBER:
2017-004295-55
SPONSOR NAME/ ADDRESS:
Celgene International II Sàrl
Route de Perreux 1
2017 Boudry
Switzerland
Tel:
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or 
consultant for review by you, your staff, and ethics committee/institutional 
review board.  The information contained in this document is regarded as 
confidential and, except 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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Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
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MEDICAL MONITOR / EMERGENCY CONTACT INFORMATION 
Contact Information:
Name:  
Title:  
Address:  3033 Science Park Road, Suite 300
San Diego, California 92121, USA
Tel (office):
Tel (cell):
E-mail:  
Note: The back-up 24-hour global emergency contact call center should only be used if you 
are not able to reach the Clinical Research Physician(s) or Medical Monitor or designee for 
emergency calls. 
Back-up 24-hour Global Emergency Contact Call Center: +1-877-501-7738
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RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
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SPONSOR THERAPEUTIC AREA LEAD SIGNATURE PAGE
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Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
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SPONSOR:  CELGENE INTERNATIONAL II SÀRL
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Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
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SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE
Signature of Site Principal Investigator
Date
Printed Name of Site Principal Investigator
Institution Name:_______________________________________
By my signature, I agree to personally supervise the conduct of this study at my study site 
and to ensure its conduct is in compliance with the protocol, informed consent, 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) procedures, 
instructions from Celgene representatives, the Declaration of Helsinki, International 
Council on Harmonisation (ICH) Good Clinical Practices Guidelines, and local 
regulations governing the conduct of clinical studies.
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Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
6
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 6.0:
The main reason for this amendment is to extend the study duration so that all subjects might 
complete 264 weeks (5 years) of treatment. Additionally, this amendment serves to consolidate the 
protocol with the European Union Clinical Trials Regulations (EU-CTR) requirements, addressing 
the removal of the France-specific protocol. Other changes include simplification of the 
 
after the first year; addition of benefit/risk assessment details; and updates to prohibited 
medications, discontinuation requirements, and ophthalmic monitoring language.
The Protocol Summary has been updated to align with the changes in the table below.
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 6.0
Section Number & 
Title
Description of Change
Brief Rationale
Title Page
Sponsor address updated.
Sponsor address change.
Medical 
Monitor/Emergency 
Contact Information
Medical Monitor and associated 
contact information updated.
Sponsor staff change.
Sponsor Therapeutic 
Area Lead Signature 
Page
Sponsor Therapeutic Area Lead 
updated.
Sponsor staff change.
Section 1.2.4: 
Benefit/Risk 
Assessment
Section removed (now 
Section 1.4.3: Overall Benefit/Risk 
Conclusion).
Integration of previously 
stand-alone Benefit/Risk
document into body of protocol.
Section 1.4: 
Benefit/Risk
Assessment
 
Section 1.4.2: Benefit 
Assessment
Section 1.4.3: Overall 
Benefit Risk 
Conclusion
Sections added.
Integration of previously 
stand-alone Benefit/Risk
document into body of protocol.
Section 2.2: Study 
Endpoints
Section 3.2: Study 
Duration for Subjects
Extended study duration from 
234 weeks to 264 weeks plus the 
Safety Follow-up Visits.
Study duration was extended to 
collect long-term safety and 
efficacy data for a full 5 years 
on study drug.
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RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 6.0
Section Number & 
Title
Description of Change
Brief Rationale
Section 2.2.1: Efficacy 
Endpoints
Section 2.2.3: 
Overview of Safety 
Assessments
Removed the word “key” from 
section headings (previously 
Section 2.2.1: Key Efficacy 
Endpoints and Section 2.2.3:
Overview of Key Safety 
Assessments).
Correction.
Section 3.1: Study 
Design
Section 14.2: Study 
Discontinuation
Updated language regarding 
Investigator discretion in 
discontinuation of subjects based 
on Crohn’s Disease Activity Index 
(CDAI) score for clinical response 
and/or clinical remission.
To enable Principal Investigator
discretion in terms of 
benefit/risk assessment and in 
alignment with real-world 
clinical practice.
Section 4.3.1: 
Exclusions Related to 
General Health
Added the following
France-specific language:
“In France, hypotension is 
exclusionary if it makes the 
implementation of the protocol or 
interpretation of the study difficult 
or would put the subject at risk by 
participating in the study.”
To align with EU-CTR 
consolidation and removal of 
the France-specific protocol.
Section 4.3.2: 
Exclusions Related to 
Medications
Updated Exclusion Criterion 7 to 
remove “within the corresponding 
timeframe.”
Correction.
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Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 6.0
Section Number & 
Title
Description of Change
Brief Rationale
Section 4.3.2: 
Exclusions Related to 
Medications
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RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 6.0
Section Number & 
Title
Description of Change
Brief Rationale
Section 6.4.3: 
Electrocardiogram
 
 
 
 
 
 
Clarification.
 
Section 6.3.2: Simple 
Endoscopic Score for 
Crohn’s Disease
 
 
 
 
 
Clarification.
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Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 6.0
Section Number & 
Title
Description of Change
Brief Rationale
Section 8.1.3: 
COVID-19 
Vaccination
Added language regarding 
non-live coronavirus disease 2019
(COVID-19) vaccination. 
Moved language from 
Benefit/Risk section.
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Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
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SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 6.0
Section Number & 
Title
Description of Change
Brief Rationale
Appendix B: 
SARS-CoV-2 
Guidelines
Updated language to indicate that 
testing for COVID-19 to inform 
decisions about clinical care 
during the study should follow 
local standard practice and to 
provide guidance on the evaluation 
and management of SARS-CoV-2 
infections. 
Moved language from 
Benefit/Risk section.
All
Minor formatting and 
typographical corrections.
Minor, therefore have not been 
summarized.
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Protocol RPC01-3204
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RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
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PROTOCOL SUMMARY
Study Title
A Phase 3, Multicenter, Open-Label Extension Study of Oral Ozanimod 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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RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
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Objectives
The objective of this study is to demonstrate the long-term safety and explore long-term efficacy 
of ozanimod (BMS-986374) for the treatment of subjects with moderately to severely active CD.
Study Design
This is a Phase 3, open-label, multicenter extension study to evaluate safety and explore the long-
term efficacy of ozanimod in subjects with moderately to severely active CD. It is anticipated that 
approximately
subjects who have participated in a prior study of ozanimod for CD will be 
eligible to participate in this study if they meet the eligibility criteria and have not met the 
discontinuation criteria as outlined in the prior studies (RPC01-3201, RPC01-3202, RPC01-3203,
and RPC01-2201).
Subjects entering the study from RPC01-2201 will continue to receive ozanimod 0.92 mg/day
(equivalent to ozanimod HCl 1 mg). Subjects entering the study from RPC01-3201, RPC01-3202, 
or RPC01-3203 will initiate ozanimod treatment in accordance with a 7-day dose escalation 
regimen as follows:

Days 1 through 4: Ozanimod 0.23 mg daily (equivalent to ozanimod HCl 0.25 mg)

Days 5 through 7: Ozanimod 0.46 mg daily (equivalent to ozanimod HCl 0.5 mg) 
(administered as two 0.23-mg capsules)

Day 8 through End of Study: Ozanimod 0.92 mg daily (equivalent to ozanimod HCl 1 mg) 
 
 
 
 
 
 
 
Subjects who discontinue from treatment due to lack of response, adverse events (AEs), or other 
reasons, even if alternative treatment is given, will be followed for 
for collection of safety data, including lymphocyte recovery, and for assessment 
of their disease status. Refer to 
and Section 11.1 for further details on lymphocyte 
recovery monitoring.
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 
Practices (GCPs) and applicable regulatory requirements.
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RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
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Study Population
Adult subjects with CD who have previously participated in a study of ozanimod for CD may be 
eligible for entry in this study if they met the eligibility criteria and have not met the 
discontinuation criteria outlined in the prior studies (eg, RPC01-3201, RPC01-3202, RPC01-3203, 
and RPC01-2201).
Length of Study
This study is expected to continue for a subject for approximately 264 weeks (5 years) plus the 
Safety Follow-up Visits. Subjects who do not meet discontinuation criteria or withdraw from the 
study may continue until they complete 264 weeks (5 years) on study treatment or until the study 
is discontinued, whichever comes first. Where applicable, the sponsor will provide IP after study 
discontinuation as per local or national requirements. The study may be discontinued early if the 
sponsor determines that the primary study objectives of demonstration of long-term safety and 
efficacy have been met, a significant safety and/or efficacy concern is identified, or the sponsor 
discontinues the development program. 
Study Treatments
Subjects entering the study from RPC01-2201 will continue to receive ozanimod 0.92 mg/day 
(equivalent to ozanimod HCl 1 mg). Subjects entering the study from RPC01-3201, RPC01-3202, 
or RPC01-3203 will initiate ozanimod treatment in accordance with a 7-day dose escalation 
regimen as described above.
Overview of Efficacy Assessments
Note: Endpoints will be evaluated annually for up to 264 weeks.
Efficacy Endpoints:

Proportion of subjects with a CDAI score of < 150 

Proportion of subjects with a Simple Endoscopy Score for Crohn’s Disease (SES-CD) decrease 
from baseline of ≥ 50% 

Proportion of subjects with average daily abdominal pain score ≤ 1 point, and average daily 
stool frequency ≤ 3 points with abdominal pain and a stool frequency no worse than baseline

Proportion of subjects with CDAI reduction from baseline of ≥100 points or CDAI score of 
< 150

Proportion of subjects with absence of ulcers ≥0.5 cm with no segment with any ulcerated 
surface ≥10% 

Proportion of subjects with CDAI reduction from baseline of ≥70 points

Change from baseline in CDAI

Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI score of 
< 150 and SES-CD decrease from baseline of ≥ 50%

Proportion of subjects with CDAI score of < 150 and SES-CD ≤ 4 points and a SES-CD 
decrease ≥ 2 points 
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
Proportion of subjects with average daily abdominal pain score ≤1 point and average daily 
stool frequency ≤3 points with abdominal pain and stool frequency no worse than baseline 
and SES-CD ≤4 points and a SES-CD decrease ≥2 points 

Proportion of subjects with SES-CD ≤ 4 points and a SES-CD decrease ≥ 2 points

Proportion of subjects with a CDAI score < 150 in subjects off corticosteroids 

Proportion of subjects with a Crohn’s Disease Endoscopic Index of Severity (CDEIS) decrease 
from baseline of ≥ 50%
Overview of Safety Assessments
The incidence, severity, relationship, and type of treatment-emergent adverse events (TEAEs), 
serious adverse events (SAEs), AEs leading to discontinuation of IP, and AEs of special interest 
(AESIs) will be summarized, as well as clinically meaningful changes from baseline for clinical 
laboratory measures, vital signs, and electrocardiograms (ECGs).
Statistical Methods
All subjects who receive at least 1 dose of IP in this study will comprise both the Intent-to-Treat 
population (ITT) and the Safety Population. These populations will be used to summarize all safety 
and efficacy data.
Each efficacy endpoint will be summarized and 
 around the estimates 
may also be presented. Due to the open-label nature of the study and the lack of a control group, 
all data will be summarized, and no hypothesis testing will be performed. All efficacy data will be 
listed.
All safety data will be listed and summarized. All TEAEs will be coded and tabulated by system 
organ class and preferred term. Incidence of TEAEs, SAEs, and AEs leading to discontinuation 
will be summarized and presented in descending order of frequency. Associated clinical laboratory 
parameters such as hepatic profile, renal function, and hematology values will be grouped and 
presented together. For each laboratory test, individual subject values outside standard reference 
range will be flagged and listed. Shift tables and analyses of changes from baseline will be 
produced. The change from baseline for each of the vital signs and ECG parameters will be 
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summarized. Incidence of abnormal vital signs parameters will be tabulated, and an outlier analysis 
of ECG results will be conducted.
Determination of Sample Size
As this is an open-label extension study for subjects who previously participated in a study of 
ozanimod for CD, there is no statistical basis for the sample size. It is anticipated that 
approximately 
 subjects who participated in prior studies of ozanimod in CD will be eligible 
for treatment in this study.
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RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
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TABLE OF CONTENTS
TITLE PAGE..............................................................................................................................1
OVERALL RATIONALE FOR PROTOCOL AMENDMENT 6.0.............................................6
SUMMARY OF CHANGES FOR PROTOCOL AMENDMENT 6.0.........................................6
PROTOCOL SUMMARY ........................................................................................................12
TABLE OF CONTENTS..........................................................................................................17
LIST OF TABLES....................................................................................................................21
1
INTRODUCTION..................................................................................................22
1.1
Disease Background ...............................................................................................22
1.2
Compound Background ..........................................................................................22
1.2.1
Summary of Nonclinical Studies..............................................................................23
1.2.2
Summary of Clinical Studies in Inflammatory Bowel Disease..................................23
1.2.2.1
Ulcerative Colitis....................................................................................................23
1.2.2.2
Crohn’s Disease .....................................................................................................24
1.2.3
Rationale for Dose Selection...................................................................................25
1.3
Study Rationale ......................................................................................................25
1.4
Benefit/Risk Assessment ........................................................................................26
26
1.4.2
Benefit Assessment..................................................................................................30
1.4.3
Overall Benefit Risk Conclusion .............................................................................30
2
STUDY OBJECTIVES AND ENDPOINTS...........................................................31
2.1
Study Objective ......................................................................................................31
2.2
Study Endpoints .....................................................................................................31
2.2.1
Efficacy Endpoints:.................................................................................................31
..31
2.2.3
Overview of Safety Assessments..............................................................................32
3
OVERALL STUDY DESIGN ................................................................................33
3.1
Study Design ..........................................................................................................33
3.2
Study Duration for Subjects....................................................................................33
3.3
End of Study...........................................................................................................34
4
STUDY POPULATION.........................................................................................35
4.1
Number of Subjects ................................................................................................35
4.2
Inclusion Criteria....................................................................................................35
4.3
Exclusion Criteria...................................................................................................36
4.3.1
Exclusions Related to General Health: ...................................................................36
4.3.2
Exclusions Related to Medications: ........................................................................36
4.3.3
Exclusions Related to Laboratory Results and Other Assessments: .........................37
38
6
PROCEDURES......................................................................................................43
6.1
Treatment Period ....................................................................................................43
43
6.1.2
Pre-Baseline Assessments/Day 1 Visit.....................................................................46
6.1.3
Study Visits.............................................................................................................46
46
6.1.5
Study Stopping Rules ..............................................................................................46
46
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46
6.3
Efficacy Assessments .............................................................................................47
6.3.1
Crohn’s Disease Activity Index...............................................................................47
6.3.2
Simple Endoscopic Score for Crohn's Disease ........................................................48
6.3.3
Abdominal Pain and Stool Frequency.....................................................................49
6.4
Other Assessments..................................................................................................49
6.4.1
Physical Examination .............................................................................................49
6.4.2
Vital Signs ..............................................................................................................49
6.4.3
Electrocardiogram..................................................................................................50
6.4.4
Pulmonary Function Tests ......................................................................................50
.............................................................................50
51
7
DESCRIPTION OF STUDY TREATMENTS........................................................52
7.1
Description of Investigational Product(s)................................................................52
7.2
Treatment Administration and Schedule .................................................................52
7.2.1
Instructions for Missed Doses.................................................................................53
7.3
Method of Treatment Assignment...........................................................................53
7.4
Packaging and Labeling..........................................................................................53
7.5
Investigational Product Accountability and Disposal ..............................................53
7.6
Investigational Product Compliance........................................................................54
8
CONCOMITANT MEDICATIONS AND PROCEDURES....................................55
8.1
Permitted Concomitant Medications and Procedures...............................................55
8.1.1
Corticosteroid Taper ..............................................................................................55
8.1.2
Aminosalicylates or Purified Medicinal Probiotics .................................................56
8.1.3
COVID-19 Vaccination...........................................................................................56
..56
..56
..57
8.3
Required Concomitant Medications and Procedures................................................57
9
STATISTICAL CONSIDERATIONS ....................................................................58
9.1
Overview................................................................................................................58
9.2
Study Population Definitions ..................................................................................58
9.3
Sample Size and Power Considerations...................................................................58
9.4
Background and Demographic Characteristics........................................................58
9.5
Subject Disposition.................................................................................................59
9.6
Efficacy Analysis....................................................................................................59
9.7
Safety Analysis.......................................................................................................59
9.8
Interim Analysis .....................................................................................................60
9.9
Other Topics...........................................................................................................60
9.9.1
Population Pharmacokinetics and Pharmacokinetics-Pharmacodynamics 
Analyses .................................................................................................................60
9.9.2
Data Monitoring Committee ...................................................................................60
10
ADVERSE EVENTS..............................................................................................61
10.1
Monitoring, Recording and Reporting of Adverse Events .......................................61
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10.1.1
Treatment of Overdose of Investigational Product ..................................................61
10.1.2
Monitoring of Subjects with Adverse Events and Serious Adverse Events................62
10.2
Evaluation of Adverse Events.................................................................................62
10.2.1
Seriousness.............................................................................................................62
10.2.2
Severity...................................................................................................................63
10.2.3
Causality ................................................................................................................64
10.2.4
Duration.................................................................................................................64
10.2.5
Action Taken...........................................................................................................64
10.2.6
Outcome .................................................................................................................65
10.2.7
Adverse Events of Special Interest ..........................................................................65
11
CLINICAL LABORATORY EVALUATIONS......................................................67
11.1
Hematology............................................................................................................67
11.2
Chemistry...............................................................................................................68
12
PREGNANCY .......................................................................................................70
12.1
Female Subjects of Childbearing Potential..............................................................70
12.2
Male Subjects.........................................................................................................71
13
REPORTING OF SERIOUS ADVERSE EVENTS ................................................72
13.1
Safety Queries ........................................................................................................72
13.2
Expedited Reporting of Adverse Events..................................................................72
13.3
Sponsor’s Drug Safety Contact Information:...........................................................73
14
DISCONTINUATIONS .........................................................................................74
14.1
Treatment Discontinuation......................................................................................74
14.2
Study Discontinuation ............................................................................................74
15
EMERGENCY PROCEDURES.............................................................................77
15.1
Emergency Contact.................................................................................................77
15.2
Emergency Identification of Investigational Products .............................................77
16
REGULATORY CONSIDERATIONS...................................................................78
16.1
Good Clinical Practice............................................................................................78
16.2
Investigator Responsibilities ...................................................................................78
16.3
Subject Information and Informed Consent.............................................................78
16.4
Confidentiality........................................................................................................79
16.5
Protocol Amendments.............................................................................................79
16.6
Institutional Review Board/Independent Ethics Committee Review and 
Approval ................................................................................................................79
16.7
Ongoing Information for Institutional Review Board/ Ethics Committee ................80
16.8
Termination of the Study ........................................................................................80
17
DATA HANDLING AND RECORDKEEPING.....................................................81
17.1
Data/Documents .....................................................................................................81
17.2
Data Management...................................................................................................81
17.3
Record Retention....................................................................................................81
18
QUALITY CONTROL AND QUALITY ASSURANCE........................................83
18.1
Study Monitoring and Source Data Verification......................................................83
18.2
Product Quality Complaint .....................................................................................83
18.3
Audits and Inspections............................................................................................83
19
PUBLICATIONS ...................................................................................................85
20
REFERENCES.......................................................................................................86
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Final: 16 Mar 2023
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21
APPENDICES........................................................................................................88
APPENDIX A
TABLE OF ABBREVIATIONS.............................................................88
APPENDIX B
SARS-COV-2 GUIDELINES.................................................................91
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LIST OF TABLES
38
 
45
Table 3:
Crohn’s Disease Activity Index Assessment ...........................................48
Table 4:
Crohn's Disease Severity Definitions ......................................................48
Table 5:
Definitions of Simple Endoscopic Score (SES-CD) for Crohn's 
Disease...................................................................................................49
57
Table 7:
Abbreviations and Specialist Terms........................................................88
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Final: 16 Mar 2023
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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 (BMS-986374) 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 
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Protocol RPC01-3204
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RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
23
other sphingosine-1-phosphate (S1P) receptors, showing half maximal effective concentration 
(EC50) greater than 10,000 nM for S1P2, > 5000 nM for S1P3, and > 2000 nM for S1P4. 
Ozanimod is extensively metabolized in humans with up to 13 metabolites identified in plasma, 
urine, and feces, including 2 active 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 include 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 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 50% 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 
(RPC01-202) study 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). 
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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 
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 
signals 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 sub-scores 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, 2021). 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. 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 52, respectively. 
 
 
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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 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 trial of ozanimod in UC was conducted 
comparing 0.92 mg and 0.46 mg of ozanimod with placebo. Safety was comparable across both 
ozanimod arms, and the 0.92 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 the 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 and 
 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. 
 
 
 
 
 
 
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.
1.3
Study Rationale
Given the mechanism of action of ozanimod, data from the preclinical animal model, the positive 
results from the Phase 2 UC study, RPC01-202, and preliminary results from the Induction Period
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Final: 16 Mar 2023
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of the Phase 2 study in CD, RPC01-2201, a Phase 3 program with ozanimod in CD is being 
conducted.
The current study is designed to assess the long-term safety and explore long-term efficacy of 
ozanimod in subjects with moderately to severely active CD. This study will allow subjects who 
are receiving clinical benefit from ozanimod the opportunity to continue to receive IP and 
experience potential long-term endoscopic benefit. For subjects who are not in clinical response 
and/or clinical remission after completing 12 weeks in the Induction Studies, this study provides 
an opportunity for potential delayed clinical benefit.
1.4
Benefit/Risk Assessment
The assessment of potential risks for identified safety findings, as well as the risk mitigations, are 
summarized in the table below. More detailed information about the known and expected benefits 
and risks and reasonably anticipated adverse events (AEs) of ozanimod may be found in the IB.
Individual benefit/risk considerations remain the responsibility of the investigator. Investigators 
should apply clinical judgment, and these risks should be considered when managing a patient and 
when deciding if continuation of treatment with ozanimod is warranted.
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Final: 16 Mar 2023
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1.4.2
Benefit Assessment
The benefit of ozanimod for the treatment of UC is established. See Section 1.2.2.1 for details. 
Preliminary results from a non-controlled Phase 2 trial in CD indicated that subjects derived 
clinical and endoscopic benefit from treatment with ozanimod. See Section 1.2.2.2 for details.
1.4.3
Overall Benefit Risk Conclusion
Despite recent progress in CD treatment, there remains an unmet need for agents that are safe and 
convenient oral treatments and can provide effective induction and long-term maintenance of 
clinical remission. The benefit/risk profile for ozanimod has been evaluated for the indication of 
CD. Results from subjects with moderate to severe disease who previously failed prior therapy and 
were treated with ozanimod 0.92 mg daily for at least 12 weeks suggested clinical and endoscopic 
benefit. In addition, the safety results suggest that ozanimod is well tolerated in patients with CD 
and is consistent with that observed in other patient populations (UC and RMS). The overall data 
to date suggest that this ozanimod Open-Label Extension Study (RPC01-3204) has a potential 
favorable benefit/risk profile for patients with active CD.
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2
STUDY OBJECTIVES AND ENDPOINTS
2.1
Study Objective

Demonstrate the long-term safety and explore long-term efficacy of ozanimod for the treatment 
of subjects with moderate to severely active CD.
2.2
Study Endpoints
Note: Endpoints will be evaluated annually for up to 264 weeks. 
2.2.1
Efficacy Endpoints:

Proportion of subjects with a CDAI score of < 150 

Proportion of subjects with a SES-CD decrease from baseline of ≥ 50% 

Proportion of subjects with average daily abdominal pain score ≤ 1 point, and average daily 
stool frequency ≤ 3 points with abdominal pain and stool frequency no worse than baseline

Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI score of 
< 150

Proportion of subjects with absence of ulcers ≥0.5 cm with no segment with any ulcerated 
surface ≥ 10% 

Proportion of subjects with CDAI reduction from baseline of ≥ 70 points

Change from baseline in CDAI

Proportion of subjects with CDAI reduction from baseline of ≥ 100 points or CDAI score of 
< 150 and SES-CD decrease from baseline of ≥ 50%

Proportion of subjects with CDAI score of < 150 and SES-CD ≤ 4 points and a SES-CD 
decrease ≥ 2 points 

Proportion of subjects with average daily abdominal pain score ≤ 1 point and average daily 
stool frequency ≤ 3 points with abdominal pain and stool frequency no worse than baseline 
and SES-CD ≤ 4 points and a SES-CD decrease ≥ 2 points 

Proportion of subjects with SES-CD ≤ 4 points and a SES-CD decrease ≥ 2 points

Proportion of subjects with a CDAI score < 150 in subjects off corticosteroids 

Proportion of subjects with a Crohn’s Disease Endoscopic Index of Severity (CDEIS) decrease 
from baseline of ≥ 50%
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2.2.3
Overview of Safety Assessments
The incidence, severity, relationship, and type of treatment-emergent adverse events (TEAEs), 
serious adverse events (SAEs), and AEs leading to discontinuation of IP will be summarized (see 
Section 14), as well as clinically meaningful changes from baseline for clinical laboratory 
measures, vital signs, and electrocardiograms (ECGs).
 
 
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3
OVERALL STUDY DESIGN
3.1
Study Design
This is a Phase 3, open-label, multicenter extension study to evaluate safety and explore the 
long-term efficacy of ozanimod 0.92 mg in subjects with moderately to severely active CD. It is 
anticipated that approximately 
subjects who have participated in a prior study of ozanimod 
for CD will be eligible to participate in this study if they meet the eligibility criteria and have not 
met the discontinuation criteria as outlined in the prior studies (eg, RPC01-3201, RPC01-3202, 
RPC01-3203, and RPC01-2201).
Subjects entering the study from RPC01-2201 will continue to receive ozanimod 0.92 mg/day 
(equivalent to ozanimod HCl 1 mg). Subjects entering the study from RPC01-3201, RPC01-3202, 
or RPC01-3203 will initiate ozanimod treatment in accordance with a 7-day dose escalation 
regimen as follows:

Days 1 through 4: Ozanimod 0.23 mg daily (equivalent to ozanimod HCl 0.25 mg)

Days 5 through 7: Ozanimod 0.46 mg daily (equivalent to ozanimod HCl 0.5 mg) 
(administered as two 0.23-mg capsules)

Day 8 through End of Study: Ozanimod 0.92 mg daily (equivalent to ozanimod HCl 1 mg) 
 
 
 
 
 
 
 
Subjects who discontinue from treatment due to lack of response, AEs, or other reasons, even if 
alternative treatment is given, will be followed for 
 for 
collection of safety data, including lymphocyte recovery, and for assessment of their disease status.
Refer to 
and Section 11.1 for further details on lymphocyte recovery monitoring.
The study will be conducted in compliance with the International Council on Harmonisation (ICH) 
of Technical Requirements for Registration of Pharmaceuticals for Human Use/GCP and 
applicable regulatory requirements.
3.2
Study Duration for Subjects 
This study is expected to continue for a subject for approximately 264 weeks (5 years) plus the 
Safety Follow-up Visits. Subjects who do not meet discontinuation criteria or withdraw from the 
study may continue until they complete 264 weeks (5 years) on study treatment, or until the study 
is discontinued, whichever comes first. Where applicable, the sponsor will provide IP after study 
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Final: 16 Mar 2023
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discontinuation as per local or national requirements. The study may be discontinued early if the 
Sponsor determines that the primary study objectives of demonstration of long-term safety and 
efficacy have been met, a significant safety and/or efficacy concern is identified, or the sponsor 
discontinues the development program. 
3.3
End of Study
The end of study 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 and is subject to 
provisions in Section 3.2, whichever is the later date.
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Final: 16 Mar 2023
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4
STUDY POPULATION
4.1
Number of Subjects 
It is anticipated that approximately 
subjects who participated in prior studies of ozanimod in 
CD (RPC01-2201, RPC01-3201, RPC01-3202, RPC01-3203) will be eligible for treatment in this 
study.
4.2
Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subjects who are not in clinical response and/or clinical remission after completing 12 weeks 
in the Induction Studies RPC01-3201 or RPC01-3202, subjects who experience relapse in the 
Maintenance Study RPC01-3203, subjects who complete the Maintenance Study RPC01-3203, 
subjects who complete at least 1 year of RPC01-2201.
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 
3. Female subjects of childbearing potential (FCBP):
Note: For the purposes of this study, a female subject is considered to be of childbearing 
potential if she 1) has not undergone a hysterectomy (the surgical removal of the uterus) or 
bilateral oophorectomy (the surgical removal of both ovaries) or 2) has not been 
postmenopausal for at least 24 consecutive months (that is, has had menses at any time during 
the preceding 24 consecutive months).
Must agree to practice a highly effective method of contraception throughout the study until 
completion of the 
 Safety Follow-up Visit. 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. Female condom and male condom should not be used together.
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4.3
Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
4.3.1
Exclusions Related to General Health:
1. Subject has any clinically relevant cardiovascular (See 
 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. In France, hypotension is exclusionary if it makes 
the implementation of the protocol or interpretation of the study difficult or would put the 
subject at risk by participating in the study.
2. Subject is pregnant, lactating, or has a positive urine beta human chorionic gonadotropin 
(β-hCG) test.
3. Subject has suspected or diagnosed intra-abdominal or perianal abscess that has not been 
appropriately treated.
4.3.2
Exclusions Related to Medications:
4. Hypersensitivity to active ingredients or excipients of ozanimod 
 
 
 
 
 
 
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4.3.3
Exclusions Related to Laboratory Results and Other Assessments:
8. Subject has any clinically significant abnormal results (eg, labs or ECG) which, in the opinion 
of the Investigator, may put the subject at risk.
9. Subjects has a pre-dose resting 
. One recheck is allowed at the Day 1 visit. If 
 
remains
 at Day 1, one additional recheck is allowed at a later date within the available 
window for roll-over from the previous study.
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Final: 16 Mar 2023
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Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
42
1.0
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1.0
v
Approved
1.0
v

Ozanimod 
Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
43
6
PROCEDURES
6.1
Treatment Period
Visits, assessments, and procedures will be performed as per the 
 
 instructions for missed doses are in Section 7.2.
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Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
44
1.0
Approved
930201755
1.0
v
Approved
1.0
v

Ozanimod 
Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
45
1.0
Approved
930201755
1.0
v
Approved
1.0
v

Ozanimod 
Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
46
6.1.2
Pre-Baseline Assessments/Day 1 Visit
 
 
 
 
 
 
 
For these at-risk subjects, the duration of the visit on Day 1 will be approximately 7 hours.
 
 
 
 
See APPENDIX B for further SARS-CoV-2 guidance.
6.1.3
Study Visits
Visits, assessments, and procedures will be performed according to 
Subjects who have previously received ozanimod for at least 1 year in an open-label study such as 
RPC01-2201 do not return for visits at 
. 
6.1.5
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 have to 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.
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Ozanimod 
Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
47
6.3
Efficacy Assessments
See Section 2 for a description of study endpoints.
6.3.1
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.
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 Pre-baseline 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 pre-baseline and throughout the study. 
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Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
48
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 Score
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.
6.3.2
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. Endoscopic remission has not yet been validated and may be 
defined as SES-CD ≤4 points and a SES-CD decrease ≥2 points, an absence of large ulcers, 
absence of ulcers, or SES-CD = ≤ 2.
To ensure quality data and standardization, the same endoscopist and the same diameter 
colonoscope as used in screening should be used throughout the study wherever possible. 
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Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
49
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. Biopsies are not required in this study.
Table 5:
Definitions of Simple Endoscopic Score (SES-CD) for Crohn's 
Disease
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
6.3.3
Abdominal Pain and Stool Frequency
The abdominal pain and stool frequency scores are based on 2 components of the CDAI (Khanna,
2015). See Section 6.3.1 above for more details. 
Stool frequency and abdominal pain, as described in Section 6.3.1, will be obtained and calculated 
without a weighting factor for use as part of the inclusion criteria. These unweighted 
subject-reported assessments will also be used as efficacy endpoints (Section 2).
6.4
Other Assessments
6.4.1
Physical Examination
A complete physical examination will be performed to evaluate the heart, lungs, head and neck, 
abdomen, skin, extremities, and weight as well as to check for visual symptoms (eg, blurred vision
or decreased visual acuity as reported by the subject). A full examination of the skin should be 
repeated every 24 weeks. An interim physical examination will include weight and 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 subject. See 
for additional 
details and 
6.4.2
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 subject’s arm circumference, a sphygmomanometer with an 
appropriately sized cuff may be used. Subjects entering from a blinded study and deemed as high 
risk due to cardiac conditions 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 
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Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
50
6.4.3
Electrocardiogram
The 12-lead digital ECG devices will be provided to each clinical site by the central ECG 
laboratory for the duration of the trial. Detailed instructions describing the process for recording 
and transmission of the digital ECGs will be outlined in the trial-specific manual and provided to 
the site before the start of the trial. Paper versions of ECG tracings will be printed and photocopied 
to preserve the ink if necessary and kept at the site as source documentation. An ECG will be 
performed while resting. 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 in 
 or in all subjects if deemed necessary by national or 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 was evaluated 
by the treating physician, and the central results are assessed as abnormal or unmeasurable 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 electronic case report form (eCRF).
At the 
 Safety Follow-up Visit, an ECG should be repeated if the ECG at the ET/EoT visit
shows a new abnormal result.
6.4.4
Pulmonary Function Tests
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 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).
1.0
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930201755
1.0
v
Approved
1.0
v

Ozanimod 
Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
51
1.0
Approved
930201755
1.0
v
Approved
1.0
v

Ozanimod 
Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
52
7
DESCRIPTION OF STUDY TREATMENTS
7.1
Description of Investigational Product(s)
Ozanimod capsules will be manufactured, quality control tested, and released in accordance with 
Good Manufacturing Practices (GMP). 
Ozanimod 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. Ozanimod doses and strengths are expressed as the HCl 
salt form of ozanimod. Two ozanimod dosage strengths have been prepared for the clinical 
investigations: 0.23 mg (size 4 capsule; equivalent to ozanimod HCl 0.25 mg) and 0.92 mg (size 
4 capsule; equivalent to ozanimod HCl 1 mg).
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
Subjects entering the study from RPC01-2201 will continue to receive ozanimod 0.92 mg/day 
(equivalent to ozanimod HCl 1 mg). Subjects entering the study from RPC01-3201, RPC01-3202, 
or RPC01-3203 will initiate ozanimod treatment in accordance with a 7-day dose escalation as 
follows: 

Days 1 through 4: Ozanimod 0.23 mg daily (equivalent to ozanimod HCl 0.25 mg)

Days 5 through 7: Ozanimod 0.46 mg daily (equivalent to ozanimod HCl 0.5 mg) 
(administered as two 0.23-mg capsules)

Day 8 through End of Study: Ozanimod 0.92 mg daily (equivalent to ozanimod HCl 1 mg)
 
 
 Subjects should be instructed to take IP at approximately the 
same time each day with or without food.
If subjects miss dosing for more than 14 days, they are required to complete the 
 
 
An overdose is any dose of IP given to a subject or taken by a subject that exceeds the dose 
described in the protocol. There is no information regarding overdose with ozanimod. Any 
overdose, with or without associated AEs, must be promptly reported to the Medical Monitor or 
other designated Drug Safety Center. The overdose should be recorded in the Overdose eCRF. 
Any 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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Ozanimod 
Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
53
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 7-day titration regimen (4 days of 
dosing at 0.23 mg daily [ozanimod HCl 0.25 mg] and 3 days of dosing at ozanimod 0.46 mg daily 
[ozanimod HCl 0.5 mg]). 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 doses 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
A single 0.92 mg oral daily dose of ozanimod will be administered.
7.4
Packaging and Labeling
Ozanimod capsules will be packaged in 30 cc white high-density polyethylene bottles (35 capsules 
per bottle, apart from the dose escalation kits), closed with a 28-mm child-resistant screw-cap that 
is induction sealed. The ozanimod 0.23 mg capsules will be bottled in a 12-count bottle, intended 
to supply the dose-escalation period only. The ozanimod 0.92 mg capsules will be bottled into a 
35-count bottle, intended to supply daily treatment of the intended regimen following the dose-
escalation period. To aid with visual identification of dosage strength, the cap on the 12-count 
dose-escalation bottles is blue, and the cap on the 35-count bottles is white.
The label(s) for IP will include sponsor name, address and telephone number, the protocol number, 
IP name, dosage form and strength (where applicable), amount of IP per container, 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.
7.5
Investigational Product Accountability and Disposal 
Investigational product should not be used for purposes other than as defined in this protocol.
All supplies of 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 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 Study Master File after database 
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Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
54
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. Investigational product and 
all medication containers will be returned to the clinical supply distribution vendor and 
documentation will be returned to the contract research organization (CRO). The CRO will verify 
that a final report of 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 and 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 medication 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 as assessed by medication counts (ie, 2 or more missed medication 
days in 1 week) 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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1.0
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Approved
1.0
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Ozanimod 
Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
55
8
CONCOMITANT MEDICATIONS AND PROCEDURES
All treatments, other than ozanimod, being taken by the subjects on entry into the study or at any 
time during the study, including through the 
 Safety Follow-up Visit, are regarded as 
concomitant treatments and must be documented on the appropriate section of the eCRF. 
Additionally, all diagnostic, therapeutic, or surgical procedures relating to CD should be recorded.
Administration of concomitant medications must be reported along with dosage information, dates 
of administration, and reasons for use. For medications with a single active ingredient, generic 
names for concomitant medication 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. All 
treatments being taken in addition to the IP by the subjects on entry to the study or at any time 
during the study are regarded as concomitant treatments and must be documented on the 
appropriate section of the eCRF. All prior medications that were continuing at the time of study 
discontinuation in the prior study or any new medications that started between the prior study 
discontinuation and enrollment in RPC01-3204 need to be documented.
The decision to temporarily interrupt dosing for treatment of an intercurrent medical condition, or 
for major surgery that could present an unreasonable risk to the subject, remains the responsibility 
of the treating physician, which will not be delayed or refused by the Sponsor. Prior to interruption 
of dosing, the Investigator may contact the Medical Monitor and forward appropriate supporting 
documents for review and discussion. The Investigator will report the action taken with IP. The 
Medical Monitor should be contacted to discuss treatment re-initiation (Section 7.2.1). See 
Section 14 for permanent discontinuation of IP.
8.1.1
Corticosteroid Taper
If subjects are still receiving corticosteroids in the Open-label Extension Study, subjects should 
begin tapering corticosteroids once clinical response or clinical remission has been achieved. 
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Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
56
8.1.2
Aminosalicylates or Purified Medicinal Probiotics
Subjects receiving 5-aminosalicylic acid (ASA) or purified medicinal probiotics should maintain 
a stable dose throughout the study unless reduction or discontinuation is clinically indicated.
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 during the study, including during treatment with IP and 
after the last dose of IP. 
Non-live COVID-19 vaccination is considered a simple concomitant medication within the study. 
However, the efficacy and safety of non-live vaccines (including non-live COVID-19 vaccines) in 
subjects receiving ozanimod is unknown. The individual 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 otherwise 
authorized (eg, Emergency Use Authorization [FDA] or equivalent) by national health authorities.
See APPENDIX B for further SARS-CoV-2 guidance.
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1.0
v
Approved
1.0
v

Ozanimod 
Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
57
8.3
Required Concomitant Medications and Procedures
Not applicable.
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Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
58
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 key
endpoint definitions and/or its analysis will also be reflected in a protocol amendment.
9.1
Overview
This is a Phase 3, open-label, multicenter extension study to evaluate the safety and efficacy of 
ozanimod in subjects with moderately to severely active CD, defined as a CDAI score of ≥220 to
≤ 450. It is anticipated that approximately 
subjects who participated in prior studies of 
ozanimod in CD will be eligible for treatment in this study
9.2
Study Population Definitions
All subjects who receive at least 1 dose of IP will comprise both the Intent-to-Treat (ITT) 
population and the Safety population. These populations will be used to summarize all safety and 
efficacy data, respectively.
9.3
Sample Size and Power Considerations
As this is an Open-label Extension Study for subjects who participated in a prior study of ozanimod 
for CD, there is no statistical basis for the sample size. It is anticipated that approximately 
subjects who participated in prior studies of ozanimod in CD will be eligible for treatment in 
this study.
9.4
Background and Demographic Characteristics
Subject demographics and baseline characteristics from RPC01-3201, RPC01-3202, and 
RPC01-2201 will define subject demographics and baseline characteristics for RPC01-3204. 
Descriptive summaries will be presented for the safety and efficacy variables collected. 
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.
Subject demographics and baseline characteristics will include 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 abdominal 
pain and stool frequency, prior anti-TNF use, and prior corticosteroid use.
Subject baseline for a given assessment is defined as the most recent non-missing measurement 
for that assessment immediately prior to administration of the first dose of IP (or ozanimod for 
safety analysis) for that subject across all of the following studies: RPC01-3201, RPC01-3202, 
RPC01-3203, RPC01-3204, and RPC01-2201. Additional details are provided in the SAP.
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Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
59
9.5
Subject Disposition
Subject disposition will include, at the minimum, the following:

the number of subjects enrolled

the number of subjects dosed

subject status including completion of prior study

the number of subjects completing the RPC01-3204 Study

the number of subjects not completing the RPC01-3204 Study by reason for dropout 
9.6
Efficacy Analysis
Due to the open-label nature of the study and the lack of a control group, all data will be 
summarized, and no hypothesis testing will be performed. Each efficacy endpoint will be 
summarized and 
 around the estimates may also be presented. 
All efficacy data will be listed.
For all proportion-based efficacy endpoints, subjects with missing efficacy data will be considered 
non-responders.
For continuous efficacy endpoints, subjects with missing data will have their last post-baseline 
value carried forward. 
Observed-cases analyses will also be presented for all efficacy endpoints.
9.7
Safety Analysis
Adverse events will be monitored during the study and the data analyzed with respect to incidence 
within each parent study treatment group as well as severity and potential relationship of the AEs 
to IP. 
All AEs with a start date before the first open-label dose date, and that are ongoing from a previous 
study to this Open-label Extension Study, will be listed in the AE data listing and labeled as “Prior 
Adverse Event.” 
Adverse events with an onset date on or after the first dose of drug in this study, or with an onset 
prior to the first dose of IP that increase in severity on or after the first dose of IP, will be considered 
treatment emergent. Treatment-emergent AEs will be summarized for the Safety population by 
system organ class and preferred term and presented in descending order of frequency within each 
System Organ Class. Serious AEs and AEs leading to discontinuation will be summarized 
similarly. Adverse events will be summarized by patient years of exposure (PYE).
Associated laboratory parameters such as hepatic profile, 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 will be produced showing the 
frequency of shifts from baseline to the highest and to the lowest on-study value in and out of the 
normal range as well as by visit. Changes from Baseline to each visit for each laboratory parameter 
will also be summarized. 
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Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
60
The change from baseline to each visit for each of the vital sign variables will be summarized. 
Abnormal vital sign values will be flagged and listed.
The change from baseline to each visit for each of the ECG parameters will be summarized. An 
outlier analysis of ECG results will be conducted.
9.8
Interim Analysis
Not applicable.
9.9
Other Topics
9.9.1
Population Pharmacokinetics and Pharmacokinetics-
Pharmacodynamics Analyses
Population PK and PK/PD analyses will be performed using data from Phase 1 through 3 studies. 
Results will be reported in a separate independent report.
9.9.2
Data Monitoring Committee
An independent Data Monitoring Committee (DMC) will be charged with monitoring 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 analyses 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.
1.0
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Protocol RPC01-3204
Celgene International II Sàrl 
RPC01-3204 Amendment 6.0
Final: 16 Mar 2023
61
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.
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, whether or not it is associated with an AE should be reported on the 
overdose 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 on an SAE Report Form and on the AE 
eCRF. The overdose resulting in the SAE should be identified as the cause of the event on the SAE 
Report Form and eCRF but should not be 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 
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reported to the CRO’s Medical Monitor or other designated Drug Safety Center. Cases of overdose 
should be recorded in the overdose eCRF and AEs associated with the overdose should be reported 
on relevant AE/SAE sections in the eCRF.
10.1.2
Monitoring of Subjects with Adverse Events and 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 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 
the end of Safety Follow-up 
 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 within 
 days of the last dose of treatment with the IP, whether or 
not considered related to the IP, must also be reported. Adverse events and SAEs will be recorded 
on the AE page of the eCRF and in the subject’s source documents. Refer to 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
The decision to temporarily interrupt dosing as a result of an AE or SAE remains the responsibility 
of the treating physician, which will not be delayed or refused by the Sponsor. Prior to interruption, 
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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 study. 
 
 
 
 
 The sponsor may request additional medical information 
concerning the AESIs that are non-serious. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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11
CLINICAL LABORATORY EVALUATIONS
The central laboratory will analyze clinical laboratory samples. Further 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 in consultation with the Medical Monitor or designee, or at the 
request of the Sponsor. Approval from the Medical Monitor or designee must be obtained if retest 
is required to be repeated > 2 times and is not already pre-specified in the protocol. 
11.1
Hematology
Red blood cell count, total and differential white blood cell (WBC) count (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils), platelet count, hemoglobin, hematocrit, mean 
corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin 
concentration. 
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11.2
Chemistry

Full chemistry panel at Day 1 visit: sodium, potassium, chloride, calcium, magnesium, 
phosphate, blood urea nitrogen, glucose, albumin, alkaline phosphatase, creatinine, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyltransferase 
(GGT), total bilirubin, conjugated bilirubin, total cholesterol, triglycerides, 
 
 and low-density lipoprotein, 

All other visits: sodium, potassium, chloride, calcium, magnesium, phosphate, blood urea 
nitrogen, albumin, alkaline phosphatase, creatinine, ALT, AST, GGT, total bilirubin, 
conjugated bilirubin, 
; Total cholesterol, triglycerides, 
 
 and low-density lipoprotein will also be included 
and at ET/EoT.
.

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.

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.
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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 consent from the 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
 
 
 
 
 
 
Pregnancies and suspected pregnancies (including elevated β-hCG or positive pregnancy test in a 
FCBP regardless of disease state) occurring while the subject is on IP, or within 
 days of 
the subject’s last dose of IP, are considered immediately reportable events. Investigational product 
is to be discontinued immediately, and the subject instructed to return any unused portion of the IP 
to the Investigator. The pregnancy, suspected pregnancy, or positive pregnancy test must be 
reported to Sponsor’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 within 
 days of the last dose 
of treatment with the IP, 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 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 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 Reference Safety Information section 
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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), sponsor or its 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 investigational products 
for human use (ENTR/CT3) and also in accordance with country-specific requirements. 
Sponsor or its authorized representative shall notify the Investigator of the following information:

any AE suspected of being related to the use of IP in this study or in other studies that is both 
serious and unexpected (ie, SUSAR);

any finding 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 serious and unexpected AE(s) 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 IP(s):

AE

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.

AE: 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.
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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.
 
 
 
 
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.

Withdrawal by subject:  The subject may choose to discontinue IP at any time. Every effort 
should be made within the bounds of safety and subject choice to have each subject complete 
the End of Treatment Visit and
 If a subject 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 (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/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
This is an Open-label Extension Study; however, to maintain the blind from the parent study from 
which a subject may be entering, certain procedures such as 
and 
 
for all subjects entering from a blinded parent study will be conducted as outlined in this protocol.
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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. 
The 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 informed consent 
form (ICF) for the study. 
The Investigator, or a designated member of the Investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records 
(eg, medical records, office charts, hospital charts, and study-related charts) for source data 
verification. The Investigator must ensure timely and accurate completion of eCRFs and queries.
The information contained in the protocol and amendments (with the exception of the information 
provided by the sponsor on public registry websites) is considered sponsor confidential 
information. Only information that is previously disclosed by 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’s protocol, amendment, and Investigator’s Brochure information is not to be 
made publicly available (for example 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.
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 
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occurred prior to the study subject’s entry into the study and of the informed consent process 
should be recorded in the study subject’s source documents including the date. The original ICF 
signed and dated by the study subject and by the person consenting the study subject prior to the 
study subject’s entry into the study, must be maintained in the Investigator’s study files and a copy 
given to the study subject. In addition, if a protocol is amended and it impacts the content of the 
informed consent, the ICF must be revised. Study subjects participating in the study when the 
amended protocol is implemented must be re-consented with the revised version of the ICF. The 
revised ICF signed and dated by the study subject and by the person consenting the study subject 
must be maintained in the Investigator’s study files and a copy given to the study subject.
16.4
Confidentiality
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 the sponsor or its authorized representative after 
documentation on all ethical and legal requirements for starting the study has been received by the 
sponsor or its authorized representative. This documentation must also include a list of the 
members of the IRB/IEC and their occupation, and qualifications. If the IRB/IEC will not disclose 
the names, occupations and qualifications of the committee members, it should be asked to issue 
a statement confirming that the composition of the committee is in accordance with GCP. For 
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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/ 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 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/EC

composition of the IRB/EC

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 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. The 
Investigator must obtain approval in writing from sponsor prior to destruction of any records. If 
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the Investigator is unable to meet this obligation, the Investigator must ask 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 (SOPs).
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, and 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 unless retention presents a risk to 
personnel. 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 exists within 
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 16.2, 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 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.
Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. 
Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 
2002;359:1541-1549.
Khanna R, Zou G, D'Haens G, Feagan BG, Sandborn WJ, Vandervoort MK, et al. A retrospective 
analysis: the development of patient reported outcome measures for the assessment of Crohn's 
disease activity. Aliment Pharmacol Ther. 2015;41:77-86.
Lakatos PL. Recent trends in the epidemiology of inflammatory bowel diseases: Up or down? 
World J Gastroenterol. 2006;12:6102-8.
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.
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.
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.
 
 
 
 
 
 
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, Feagan B, D’Haens G, et al. Ozanimod Induction and Maintenance Treatment for 
Ulcerative Colitis. N Engl J Med 2021;385:1280-91.
Sandborn WJ, Feagan BG, Wolf D, et al. Ozanimod Induction and Maintenance Treatment for 
Ulcerative Colitis. N Engl J Med 2016;374:1754-62.
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Sandborn WJ, Feagan BG, Rutgeerts P, 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, et al. Certolizumab pegol for the treatment of Crohn's 
disease. N Engl J Med. 2007;357:228-238.
Schwartz DA, Loftus EV Jr, Tremaine WJ, Panaccione R, Harmsen WS, Zinsmeister AR, et al. 
The natural history of fistulizing Crohn's disease in Olmsted County, Minnesota. 
Gastroenterology. 2002;122:875-80.
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21
APPENDICES
APPENDIX A
TABLE OF ABBREVIATIONS
Table 7:
Abbreviations and Specialist Terms
Abbreviation or Specialist 
Term
Explanation
6-MP
6-mercaptopurine
ADR
Adverse drug reaction
AE
Adverse event
AESI
Adverse event of special interest
ALC
Absolute lymphocyte count
ALT
Alanine aminotransferase (SGPT)
ASA
Aminosalicylic acid
AST
Aspartate aminotransferase (SGOT)
AZA
azathioprine
 
β-hCG
β-subunit of human chorionic gonadotropin
CBC
Complete blood count
CD
Crohn’s disease
CDAI
Crohn’s Disease Activity Index
CDEIS
Crohn’s Disease Endoscopic Index of Severity 
COVID-19
Coronavirus disease 2019
CRO
Contract research organization
 
DMC
Data Monitoring Committee
EC
Ethics Committees
EC50
Effective concentration-50
ECG
Electrocardiogram
eCRF
Case report form
EEA
European Economic Area
ELISA
Enzyme linked immunosorbent assay
EMA
European Medicines Agency
EoT
End of treatment
ET
Early termination
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Table 7:
Abbreviations and Specialist Terms
Abbreviation or Specialist 
Term
Explanation
FCBP
Female of Childbearing Potential
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
Gamma glutamyltransferase
GI
Gastrointestinal
GMP
Good Manufacturing Practices
HR
Heart rate
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
ICF
Informed consent form
ICH
International Council on Harmonisation
IND
Investigational New Drug
INR
International normalized ratio
IP
Investigational Product
IRB
Institutional Review Board
ITT
Intent-to-treat
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
LFT
Liver function test
MERS-CoV
Middle East respiratory syndrome coronavirus
MTX
Methotrexate
PD
Pharmacodynamic
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Table 7:
Abbreviations and Specialist Terms
Abbreviation or Specialist 
Term
Explanation
PFT
Pulmonary function test
PK
Pharmacokinetics
PYE
Patient years of exposure
RMS
Relapsing multiple sclerosis
S1P
Sphingosine-1-phosphate
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
TEAE
Treatment-emergent adverse event
TNF
Tumor necrosis factor
UC
Ulcerative colitis 
WBC
White blood cell
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APPENDIX B
SARS-COV-2 GUIDELINES
 
. Testing for COVID-19 to inform decisions about clinical care during the 
study should follow local standard practice.
If the subject receives a positive SARS-CoV-2 test result and is asymptomatic during the 
pre-baseline 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 participant at a higher risk of 
receiving investigational treatment
If the subject receives a positive SARS-CoV-2 test result and is symptomatic during the 
pre-baseline 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 
participant 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 (Section 10.1).
Procedures related to COVID-19 identification (eg, MERS-CoV test, SARS-CoV-2 antibody test,
SARS-CoV-2 ELISA test), and treatment (eg, intubation, dialysis) must be reported on the 
appropriate section of the eCRF. 
Evaluation and management of SARS-CoV-2 infections arising during the course of the trial are 
left to the discretion and expertise of the Investigator. For subjects who are exhibiting symptoms 
consistent with COVID-19, the Sponsor advises the Investigator to consult the Medical Monitor.
COVID-19 vaccines that are NOT live are allowed and should be handled in the same manner as 
other vaccines. Administration may occur during the study, including during treatment with IP and 
after the last dose of IP. Administration of vaccinations must be reported along with dosage 
information, dates of administration and vaccine name/trade name on the appropriate section of 
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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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Summary of Changes RPC01-3204, Version 6.0
Celgene International II Sàrl
Confidential and Proprietary
3
RPC01-3204, v6.0: 14 Jun 2021
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:

Removal of Adolescent Subjects
The study design has been updated to reflect the development of a comprehensive pediatric 
program. Adolescents have been removed as potential subjects. The minimum age to enter the 
study has been adjusted to 18 years. No adolescent has been randomized into the study under any 
previous version of the protocol.
Revised sections: Protocol Summary; Section 1.1, Disease Background; Section 2.2, Study 
Endpoints; Section 4.2, Inclusion Criteria; 
; Section 6, Procedures; 
 Section 9.4, Background and 
Demographic Characteristics; Section 12.1, Female Subjects of Childbearing Potential; Section 
14.2, Study Discontinuation; Section 16.3, Subject Information and Informed Consent; and
Section 20, References

Update Summary of Clinical Studies in Inflammatory Bowel Disease (IBD)
The Summary of Clinical Studies in IBD has been updated to align with information in the latest 
Investigator Brochure and the recent results from the Phase 3 RPC01-3101 study in ulcerative 
colitis.
Revised sections: Section 1.2.2, Summary of Clinical Studies in Inflammatory Bowel Disease; 
and Section 1.2.3, Rationale for Dose Selection

Addition of SARS-CoV-2 Guidance
Due to the global SARS-CoV-2 pandemic, new considerations and requirements have been 
included to address the following: 
 
 
-
Adverse event reporting of COVID-19 cases, including an assessment for AEs at each 
study visit, and reporting requirements for testing-related and treatment-related 
procedures.
-
Guidance for the management of a positive SARS-CoV-2 test result prior to enrollment, 
including the assessment of symptoms, the presence of sequelae, and the effect on 
eligibility.
-
Drug Interruption due to COVID-19, including the decision to interrupt remaining the 
physician’s decision, and including the request to contact the Medical Monitor to discuss 
treatment re-initiation.
-
Vaccine considerations and reporting, including the requirement that it must be a 
non-live, replication incompetent vaccine.
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Summary of Changes RPC01-3204, Version 6.0
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RPC01-3204, v6.0: 14 Jun 2021
Revised sections: Protocol Summary; Section 1.2.4, Benefit Risk Assessment; 
 
Section 6, Procedures; Section 6.1.2, Pre-Baseline Assessments/Day 1 Visit; Section 
8.1.3, COVID-19 Vaccination; Section 10.1, Monitoring, Recording, and Reporting of Adverse 
Events; and Appendix B, SARS-CoV-2 Guidelines.

Modification of First Dose Monitoring Requirements
To ensure complete cardiac evaluation for subjects identified as at risk, the 
 
 and 
 have been enhanced as follows:
-
Added study exclusion criterion for subjects with resting 
.
-
Additional ECGs have been inserted at Hour 2 and Hour 4 postdose.
-
 
-
 
Revised sections: Section 4.3.3, Exclusions Related to Laboratory Results and Other 
Assessments; 
 
 and Section 6.4.3, Electrocardiogram

Pulmonary Function Tests for all Subjects
To ensure adequate characterization of ozanimod’s safety profile and to facilitate a robust dataset 
of pulmonary function in patients with CD, baseline and subsequent pulmonary function tests 
(PFTs) are being re-introduced in all subjects.
Revised sections: 
 Section 6.4.4, Pulmonary Function Test
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Summary of Changes RPC01-3204, Version 6.0
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RPC01-3204, v6.0: 14 Jun 2021

Product Quality Complaint Notification Update
Updated the guidelines on when and how to report a Product Quality Complaint to the current 
procedure.
Revised sections: Section 18.2, Product Quality Complaint

Minor editorial changes were made to enhance clarity of the protocol, as well as
an update to sponsor address, abbreviations, and references.
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EDMS Doc. Number: 24985144 - 23721215
Ozanimod
Summary of Changes Protocol RPC01-3204, Version 5.0
Celgene International II Sàrl
Confidential and Proprietary
2
RPC01-3204, v5.0 03 Sep 2020
1.
JUSTIFICATION FOR AMENDMENT
Significant changes included in this amendment are summarized below:

Sample Size Adjustment
The sample size was adjusted to 
 to account for the removal of the 0.46 mg treatment arm in 
3203.  This is sufficient for statistical considerations using the estimated treatment difference 
between ozanimod and placebo for the primary and first key secondary endpoints.
Revised sections: Protocol Summary; Section 3.1, Study Design; Section 4.1, Number of 
Subjects; Section 9.1, Overview; and Section 9.3, Sample Size and Power Considerations .

Update Summary of Clinical Studies in Inflammatory Bowel Disease (IBD)
The Summary of Clinical Studies in IBD has been updated to align with information in the latest 
Investigator Brochure and the recent results from the Phase 3 RPC01-3101 study in ulcerative 
colitis.
Revised sections: Section 1.2.2, Summary of Clinical Studies in Inflammatory Bowel Disease

Inclusion of 
 
  as Adverse Events of Special 
Interest and Study Discontinuation Criteria
Adverse events of special interest will include monitoring criteria for 
 and 
confirmed diagnosis will require discontinuation from the study. This guidance is aligned with 
the company core data sheet and the prescribing information for ozanimod.
Revised section: Section 10.2.7, Adverse Events of Special Interest and Section 14.2, Study 
Discontinuation

 Pulmonary Function Tests Will Only Be Required 
in Subjects Identified as At Risk
 
 Baseline and subsequent pulmonary function tests (PFTs) will be 
conducted in subjects with with a history of respiratory disease not considered to be severe. 
Additional guidance was also provided for subjects without preexisting respiratory disease and 
who experience a decline in pulmonary function during the study. These revisions are aligned 
with the prescribing information for ozanimod.
Revised sections: 
; Section 6.4.4, Pulmonary Function Test; and 

 
The 
 and 
 has been revised to align with 
the prescribing information for ozanimod (Zeposia).
Revised sections: 
;
 
 and Section 6.4.3, Electrocardiogram
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Summary of Changes Protocol RPC01-3204, Version 5.0
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RPC01-3204, v5.0 03 Sep 2020

CDAI Calculation
Details on CDAI calculation were removed and will be specified in the Statistical Analysis Plan 
(SAP). 
Revised section: Section 6.3.1 Crohn’s Disease Activity Index

Instructions for Missed Doses
Additional instructions for missed doses were included in accordance with the prescribing 
information for ozanimod.
Revised section: Section 7.2.1, Instructions for Missed Doses

Update to Liver Function Testing and Discontinuation Criteria
 
 
 
 
 This 
guidance is aligned with the Food and Drug Administration (FDA) guidance on liver injury 
evaluation and balances the call for immediate action with the technical limitations around 
central laboratory processing. 
In addition, confirmation is not required to discontinue a subject based on the liver function test 
criteria outlined in Section 14.2.
Revised sections: Section 11.2, Chemistry and Section 14, Discontinuations
Revised sections: Protocol Summary; Section 2.2.4, Overview of Key Safety Assessments; 
 
and Section 9.7: Safety Analysis
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Summary of Changes Protocol RPC01-3204, Version 5.0
Celgene International II Sàrl
Confidential and Proprietary
4
RPC01-3204, v5.0 03 Sep 2020
Revised sections: Protocol Summary;
 

Minor editorial changes were made to enhance clarity of the protocol, as well as 
an update to study personnel names, abbreviations, and references.
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Sponsor: Celgene International II Sàrl
Protocol No. RPC01-3204
Efficacy and Safety of Ozanimod in CD—Summary of Changes 10 June 2019
Version 4.0 (replaces Version 3.0)
CONFIDENTIAL
Page 3 of 125
This document summarizes the changes that were made between Protocol RPC01-3204
Version 4 (dated 10 June 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:

Revisions to reflect the addition of adolescent subjects

Changed to Safety Follow-up from 
 to 
 Safety Follow-up 
Visit to ensure adequate collection of adverse events that could be associated with 
investigational product.  The timing of the visit is based on the estimated time needed 
to clear the major active metabolites of RPC1063 in the vast majority of patients (ie, 5 
half-lives of CC112273 and CC1084037 and accounting for variation of half-life 
duration in a human population).

Extended the requirements for contraception in females after treatment 
discontinuation from the 
 Safety Follow-up Visit to the 
 Safety Follow-
up Visit.

Addition of withdrawal/dependence questionnaires

Minor editorial changes to enhance clarity of the protocol, and update study personnel 
names 
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Celgene International II Sàrl  
 
Summary of Changes: Protocol Number: RPC01-3204 
 
18 June 2018 
Drug Name: Ozanimod 
Version 3 
Page 3 of 21 
CONFIDENTIAL 
This document summarizes the changes that were made between Protocol RPC01-3204 
Version 3 (dated 18 June 2018) and Version 2 (dated 19 December 2017). 
1. 
OVERVIEW OF KEY CHANGES 
The following bulleted list identifies the key changes to the protocol and provides the rationale 
for each key change: 
 
 
 because in vitro data 
show that the major active metabolite CC112273 is formed by and inhibits MAO-B.  The 
potential for clinical interaction with MAO inhibitors has not been studied.   
 Added 
 inhibitors to the list of medications that are 
prohibited during the trial until the 
 Safety Follow-up Visit. In a Phase 1 drug-drug 
interaction study, a strong inhibitor of 
, had no effect on ozanimod 
exposure, while it approximately doubled the exposure of its active metabolites, RP101988 
and RP101075. While the major active metabolite CC112273 is not a substrate of drug 
transporters, it is unknown if the increase in RP101075 (via RP101988) may also lead to a 
similar increase in CC112273, which is formed directly from RP101075. 
 
 
 
 
 was added to the list of medications that cannot or should not 
be used during the trial or after investigational product discontinuation because in vitro data 
show that the major active metabolite CC112273 is further metabolized by 
 
. The potential for clinical interactions with 
 
 has not been studied and therefore co-administration is not recommended. 
 
 
 
. 
 The protocol was updated to add new protocol template language regarding handling of 
product quality complaints for any drug product manufactured by or on behalf of Celgene 
Corporation. 
The following bulleted list identifies global changes to the protocol: 
 Language has been changed to indicate that subjects from Study RPC01-1201 are now 
eligible to participate in this study if they meet the eligibility criteria. 
 Language has been changed to indicate the scientific and medical rationale for the length of 
study and study duration for subjects.  
 A 
 Safety Follow-up Visit was added throughout the document and to the 
 to ensure adequate collection of adverse events that could be associated with 
investigational product. The timing of the visit is based on the estimated time needed to clear 
the major active metabolite of ozanimod (RPC1063, which is 5 half-lives of CC112273). 
 The term “patient” was changed to “subject” throughout the document in order to maintain 
consistency throughout the protocol. 
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Celgene International II Sàrl  
Summary of Changes: Protocol Number: RPC01-3204 
18 June 2018 
Drug Name: Ozanimod 
Version 3 
Page 4 of 21 
CONFIDENTIAL 

The term “investigational drug” was changed to “investigational product” throughout the
document to comply with regulatory guidances and maintain consistency throughout the
protocol

Abbreviations lists in footnotes were updated.

The list of references has been updated based on changes in this amendment.

Minor typographical corrections have been made.

Minor editorial changes and changes for clarification were made.
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Celgene International II Sàrl  
Summary of Changes: Protocol Number: RPC01-3204 
19 December 2017 
Drug Name: Ozanimod 
Version 2.0 
CONFIDENTIAL 
Page 3 of 11 
This document summarizes the changes that were made between Protocol RPC01-3204 Version 
1.0 (dated 26 September 2017) and Version 2.0 (dated 19 December 2017). 
1.
OVERVIEW OF KEY CHANGES
The following bulleted list identifies the key changes to the protocol and provides the rationale 
for each change: 

The CDEIS is being introduced as a key efficacy endpoint because it is an established
endoscopic measure.

The section on the evaluation of adverse events was modified since the investigator will not
determine whether an adverse event is an adverse event of special interest (AESI). This
change was made to better align with the planned designation of AESIs by the sponsor and to
align with the Medical Monitoring plan.

The criteria for discontinuation, including subjects with liver function test abnormalities and
subjects with clinically significant 
, was updated to provide further guidance to
investigators on monitoring the study.

Text on a Data Safety Monitoring Board (DSMB) was added to align with our current plan
for DSMB review.
The following bulleted list identifies global changes to the protocol: 

Abbreviations lists in footnotes and Appendix A: Table of Abbreviations were updated.

The list of references has been updated based on changes in this amendment.

Edits were made throughout the document for the purposes of clarity and protocol
consistency.

Minor typographical corrections have been made.
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