A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Oral RPC1063 as Induction and Maintenance Therapy for Moderate to Severe Ulcerative Colitis
Phase: PHASE3
Conditions: Ulcerative Colitis
Sponsor: Celgene



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histopathology report (note:  endoscopy and histopathology may be performed at Screening if no 
prior report is readily available)
3.
Evidence of UC extending ≥15 cm from the anal verge as determined by Baseline endoscopy 
(flexible sigmoidoscopy or colonoscopy)
4.
Have active UC defined as a complete Mayo score of 6 to 12 inclusive, with endoscopic subscore of 
≥2, a rectal bleeding score of ≥1, and a stool frequency score ≥1  
5.
Must be currently receiving treatment with at least 1 of the following therapies and must continue 
on these therapies during Induction:
Oral aminosalicylates at a therapeutic dose for their disease (eg, mesalamine, sulfasalazine, 
olsalazine, balsalazide), with the dose stable for at least 3 weeks prior to Screening endoscopy
Prednisone (doses ≤20 mg per day) or equivalent receiving a stable dose for at least 2 weeks
prior to Screening endoscopy
Budesonide MMX therapy receiving a stable dose for at least 2 weeks prior to Screening 
endoscopy
6.
Have undergone colonoscopy (or are willing to undergo colonoscopy during Screening):
within the past 2 years, to screen for dysplasia (unless otherwise recommended by local and 
national guidelines) if the patient has had left-sided colitis of > 12 years duration or 
total/extensive colitis of > 8 years duration 
within the past 5 years, to screen for polyps if the patient age is > 45 years
If oral aminosalicylates or corticosteroids have been recently discontinued, they must have 
been stopped for at least 2 weeks prior to the endoscopy used for Baseline Mayo score
7.
Females of childbearing potential (FCBP):
Must agree to practice a highly effective method of contraception throughout the trial until 
completion of the 90-day 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. Acceptable methods of birth control in the trial are the 
following:

combined hormonal (oestrogen and progestogen containing) 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. 
8.
Must provide written informed consent/assent and have the ability to be compliant with the schedule 
of protocol assessments. The parent/legal guardian of the adolescent must sign an informed consent 
form. In addition, adolescent patients must also agree to participate in the study by signing an 
assent.
9.
Patients must have documentation of positive Varicella zoster virus (VZV) immunoglobulin G 
(IgG) antibody status or complete VZV vaccination at least 30 days prior to randomization
Exclusion Criteria: 
Patients are not eligible for this trial if they fulfill any of the following:
Exclusions Related to General Health:
1.
Have severe extensive colitis as evidenced by: 

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12.1.8.
Monitoring of Adverse Events and Serious Adverse Events ................. 75
12.1.10.
Guidelines for Monitoring Patients Taking Their First Dose of 
RPC1063 ............................................................................................. 75
12.1.11.
Clinical Laboratory Evaluations........................................................... 76
12.2.
Adverse Events and Serious Adverse Events........................................ 79
12.2.1.
Definition of Adverse Events............................................................... 79
12.2.2.
Definition of Serious Adverse Events................................................... 79
12.2.3.
Assessment of Adverse Event Severity ................................................ 80
12.2.4.
Assessment of Adverse Event Relationship to Investigational Drug ..... 80
12.2.5.
Reporting of Serious Adverse Events................................................... 81
12.2.5.1.
Reporting of Serious Adverse Events to Regulatory Authorities and 
Investigators ........................................................................................ 82
12.2.6.
Adverse Events of Special Interest....................................................... 82
12.2.7.
Monitoring of Patients with Adverse Events, Serious Adverse Events, 
and Adverse Events of Special Interest................................................. 84
12.2.8.
Treatment of Overdose of Investigational Drug.................................... 84
12.2.9.
Procedures in Case of Pregnancy ......................................................... 84
12.2.10.
Data Safety Monitoring Board ............................................................. 85
12.4.
Appropriateness of Measurements ....................................................... 86
13.
PLANNED STATISTICAL METHODS ............................................. 87
13.1.
Determination of Sample Size.............................................................. 87
13.2.
Statistical Methods............................................................................... 89
13.2.1.
General Considerations........................................................................ 89
13.2.2.
Analysis Populations............................................................................ 89
13.3.
Disposition, Demographics and Baseline Characteristics...................... 90
13.4.
Efficacy ............................................................................................... 90
13.4.1.
Induction Period (Adult Patients)......................................................... 90
13.4.1.1.
Induction Period Primary Efficacy Analysis (Adult Patients) ............... 91
13.4.1.2.
Induction Period Secondary Efficacy Analysis (Adult Patients) ........... 91

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13.4.2.
Maintenance Period (Adult Patients).................................................... 92
13.4.2.1.
Maintenance Period Primary Efficacy Analysis.................................... 92
13.4.2.4.
Handling Missing Data ........................................................................ 93
13.6.
Interim Analyses.................................................................................. 94
13.7.
Induction Period Analysis .................................................................... 95
13.8.
End of Study Analysis.......................................................................... 95
13.9.
Treatment Failure Rules....................................................................... 95
14.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.................... 96
14.1.
Monitoring........................................................................................... 96
14.2.
Data Management/Coding.................................................................... 96
14.3.
Quality Assurance and Inspections....................................................... 97
15.
QUALITY CONTROL AND QUALITY ASSURANCE..................... 98
15.1.
Study Monitoring and Source Data Verification................................... 98
15.2.
Product Quality Complaint................................................................... 98
16.
ETHICS............................................................................................... 99
16.1.
Institutional Review Board or Independent Ethics Committee.............. 99
16.2.
Ethical Conduct of the Trial.................................................................99
16.3.
Patient Information and Informed Consent/Assent ............................... 99
16.4.
Patient Data Protection....................................................................... 100
16.5.
Investigator Obligations..................................................................... 100
16.6.
Protocol Signatures............................................................................ 100
17.
DATA HANDLING AND RECORD KEEPING............................... 101
17.1.
Inspection of Records ........................................................................ 101
17.2.
Retention of Records.......................................................................... 101
18.
PUBLICATION POLICY, FINANCING, AND INSURANCE ......... 102

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Appendix 2:  Investigator Responsibilities............................................................ 109
Appendix 3: BENEFIT RISK ASSESSMENT...................................................... 110

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List of Tables
Table 1:
Schedule of Events............................................................................... 42
Table 2:
Cardiac Monitoring During Dose Escalation........................................ 47
Table 3:
Examples of Prohibited Cardiac Medications (Systemic Use) .............. 64
Table 5:
Sample Size and Corresponding Precision............................................ 88
List of Figures
Figure 1:
Trial Schematic for Cohort 1 and Cohort 2........................................... 40

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4.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
5-ASA
5-aminosalicylic acid
6-MP
6-mercaptopurine
ADR
Adverse drug reaction
AE
Adverse event
ALC
Absolute lymphocyte count
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AV
Atrioventricular
AZA
Azathioprine
BCRP
Breast cancer resistance protein
β-hCG
Beta-human chorionic gonadotropin
CFR
Code of Federal Regulations
CI
Confidence interval
CL
Clearance
CMH
Cochran-Mantel-Haenszel
CMV
Cytomegalovirus
CRO
Contract research organization
CYP3A4
Cytochrome P450 3A4
DLCO
Diffusion capacity of the lung for carbon monoxide
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
ELISA
Enzyme-linked immunosorbent assay
FEV
Forced expiratory volume at 1 second
FVC
Forced vital capacity
GCP
Good Clinical Practice

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GGT
Gamma glutamyltransferase
HAV
Hepatitis A virus
Hb
Hemoglobin
HbA1c
Glycosylated hemoglobin
HBc
Hepatitis B core antigen
HBs
Surface antigen of the HBV
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Heart rate
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IP
Induction Period
IRB
Institutional Review Board
ITT
Intent-to-treat
IUD
Intrauterine device
IUS
Intrauterine-hormone releasing system
IV
Intravenous
IVIg
Intravenous immunoglobulin
IXRS
Interactive voice / web-based activated response system 
LFT
Liver function test
MedDRA
Medical Dictionary for Regulatory Activities
MMF
Mycophenolate mofetil
MP
Maintenance Period
NASH
Nonalcoholic steatohepatitis
NOAEL
No-observed-adverse-effect level
NRI
Non-responder imputation
NSAID
Non-steroidal anti-inflammatory drug

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OCT
Optical coherence tomography
OLE
Open-Label Extension
PCR
Polymerase chain reaction
PD
Pharmacodynamic(s)
PFT
Pulmonary function tests
PK
Pharmacokinetic(s)
PML
Progressive multifocal leukoencephalopathy
PP
Per protocol
PQC
Product Quality Complaint
QTcF
Fridericia’s corrected QT interval
RMS
Relapsing multiple sclerosis
S1P
Sphingosine 1-phosphate
S1P1
Sphingosine 1-phosphate 1 receptor
S1P5
Sphingosine 1-phosphate 5 receptor
SAE
Serious adverse event
SD
Standard deviation
SE
Standard error
SOP
Standard operating procedures
TB
Tuberculosis 
TEAE
Treatment-emergent adverse event
TFR
Treatment failure rules
TNF
Tumor necrosis factor
UC
Ulcerative colitis
ULN
Upper limit of normal
VZV
Varicella zoster virus
WBC
White blood cell
WHO
World Health Organization

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5.
INTRODUCTION
5.1.
Ulcerative Colitis
Ulcerative colitis (UC) is a chronic gastrointestinal inflammatory disorder that involves the 
surface mucosa, the crypt epithelium, and the submucosa of the colon 
 
The etiology of UC is multifactorial, but likely includes a dysregulated 
mucosal immune response against commensal non-pathogenic bacteria of the colon, resulting 
in bowel inflammation
Patients with UC suffer from diarrhea, rectal bleeding, weight loss, abdominal pain, and 
fever 
  The pathology of ulcerative 
colitis is characterized by a life-long chronic course of remissions and exacerbations.  In 
severe UC, the bowel wall may become thinned, the mucosa denuded, and the inflammation 
may extend to the serosa, leading to dilation, toxic megacolon, and perforation 
  Toxic megacolon commonly requires an urgent colectomy to avoid 
perforation, peritonitis, and sepsis.  Within 10 years of diagnosis, 19.9% of adults with UC 
had undergone colectomy. 
In addition, patients with UC have an increased risk of carcinoma when compared with the 
general population.  The estimated risk of colorectal carcinoma increases as the duration and 
extent of disease increases from 2% of patients with UC for 10 years, to 8% of patients with 
UC for 20 years, and to 18% of patients with UC for 30 years 
The overall goal of treatment for patients with active UC is to induce and maintain remission 
and to induce and maintain mucosal healing
 
  Treatment of UC consists of anti-inflammatory and immunosuppressive therapies 
that are chosen to maximize efficacy while minimizing toxicity.  The therapy chosen is 
therefore dependent on the patient’s disease severity and their response to therapy 
 
  While agents used to treat mild to moderate 
UC are generally well tolerated, as the severity of UC disease increases, so do the potential 
toxicities of the medications required to manage the disease.  Treatment for mild to moderate 
UC typically starts with topical agents (5-aminosalicylate [5-ASA] or corticosteroids 
administered via suppository or enema).  In patients unresponsive to local therapy or in 
patients with more severe or more extensive disease, systemic treatment with an oral 5-ASA, 
such as mesalamine, olsalazine, sulfasalazine, and balsalazide, with or without antibiotics, is 
commonly required
  Initially, up 
to 90% of patients with mild to moderate UC can be maintained in remission using once-
daily oral administration of 5-ASA, and treatment with 5-ASA is generally safe and well 
tolerated 
For those patients who do not respond or lose response to treatment with 5-ASA or those 
with more severe, extensive disease at presentation, corticosteroids are generally the first-line 
treatment for inducing disease remission.  Although effective in inducing disease remission, 
treatment with corticosteroids is associated with multiple adverse effects including the 
following: weight gain, insomnia, mood swings, osteoporosis, scalp hair loss or facial hair 

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Table 1:
Schedule of Events
Trial Procedures
Induction
Maintenance
Early 
Termq
Safety Follow-ups
Dose 
Escalation
Assigned Dose
Treatment
(Visit Label)
Screening
Visit
I 1a,b
(Week 0)
Visit
I 2w
(Week 5)
(EoT)
Visit
Visit
I 3b
(Week 10)
Visit
M 1b,c
(Week 0)
Visit
M 2
(Week 8)
Visit
M 3
(Week 18)
Visit
M 4
(Week 30)
Relapse 
Visit
(When 
Indicated)
(EoT)
Visit
M 5b
(Week 
42)
(Visit Day and Window)
Day 
-35 to 0
Day 1
Day 35±5
Day 70±10
Day 1
Day 
56±10
Day 
126±10
Day 
210±10
Day 
294±1
0
Day of 
Early 
Term
Last 
dose + 
30 to 
60 
days
Last 
dose + 
90 day
s ± 10 
dayst
(Overall Duration)
0 weeks
5 weeks
10 weeks
10 weeks
18 weeks
28 weeks
40 weeks
52 
weeks
Informed consent/assent
X
Inclusion/exclusion 
criteria
X
X
X
Demographics
X
Medical historyd,e
X
X
Viral serologyf
X
Stool cultureg
X
Randomization
X
X
Dispense investigational
drug
X
X
Xh
X
X
X
X
X
Xr
Administer 
investigational drug at 
clinic
X
X
X
X
Review drug compliance
X
X
X
X
X
X
X
X
X
Prior and concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical procedures (non-
trial)
X
X
X
X
X
X
X
X
X
X

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Trial Procedures
Induction
Maintenance
Early 
Termq
Safety Follow-ups
Dose 
Escalation
Assigned Dose
Treatment
(Visit Label)
Screening
Visit
I 1a,b
(Week 0)
Visit
I 2w
(Week 5)
(EoT)
Visit
Visit
I 3b
(Week 10)
Visit
M 1b,c
(Week 0)
Visit
M 2
(Week 8)
Visit
M 3
(Week 18)
Visit
M 4
(Week 30)
Relapse 
Visit
(When 
Indicated)
(EoT)
Visit
M 5b
(Week 
42)
(Visit Day and Window)
Day 
-35 to 0
Day 1
Day 35±5
Day 70±10
Day 1
Day 
56±10
Day 
126±10
Day 
210±10
Day 
294±1
0
Day of 
Early 
Term
Last 
dose + 
30 to 
60 
days
Last 
dose + 
90 day
s ± 10 
dayst
(Overall Duration)
0 weeks
5 weeks
10 weeks
10 weeks
18 weeks
28 weeks
40 weeks
52 
weeks
Safety 
Assessments
Adverse eventsz
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
Xy
Vital signs
X
X
X
X
X
X
X
X
X
X
X
Xy
Hematologyv
X
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry x
X
X
X
X
X
X
X
X
X
X
X
Xy
Pregnancy testi
X
X
X
X
X
X
X
X
X
X
X
X
Contraception education
X
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
Xy
Pulmonary function testsp
X
X
X
X
X
Xy
Complete Physical 
examinationj
X
X
X
Xy
Interim Physical 
examinationj
X
X
X
X
X
X
X
X
Xy
Height and Weight 
(adults)
X
Xy
Height (adolescents)
X
X
X
Xy
Weight (adolescents)
X
X
X
X
X
X
X
Xy
Optical coherence
tomography
X
X
X
X
Xy

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a The duration of Visit I 1 will be approximately 7 hours.  Prior to dosing a 12-lead ECG will be performed and following dosing patients will have hourly vital signs recorded at 
1, 2, 3, 4, 5, and 6 hours postdose.  A second 12-lead ECG will be performed at the end of the observation period.
b Visit I 1, Visit I 3, Visit M 1, and Visit M 5 should be scheduled in the morning, where possible. On Visits I 1, I 3, M 1, and M 5, since trough PK samples are to be drawn,
patients should be instructed to withhold the dose until the trial visit and the dose should be administered during the visit.  
c In general, for patients completing the IP and entering the MP, Visit 3 of the IP (Visit I 3) will serve as Visit 1 of the MP (Visit M 1). Patients should enter the MP within 21 
days of the Visit I 3 endoscopy. Procedures completed during Visit I 3 do not need to be repeated if Visit M 1 occurs within 14 days of I 3 visit. Patients may complete the M 1 
visit prior to completing the OCT and PFT scheduled for the I 3 visit. OCT and PFT must be completed within 14 days of the I 3 visit.
d Medical history will include smoking history. The Visit I 1 medical history can be abbreviated, noting events that occurred between Screening and Visit I 1.
e TB must be ruled out according to local medical practices, such as a TB skin test, QuantiFERON Gold test, or other interferon gamma release assay (eg, T-SPOT). Subjects with 
a positive test result using a TB skin test or QuantiFERON Gold test must have documentation of completed TB treatment by local standard of care.
f Serology testing will be performed at Screening to determine the patient's immune status with respect to the following viruses (see Section 12.1.11): Human immunodeficiency 
virus antibodies, anti-hepatitis A virus IgM, hepatitis B surface antigen, anti-hepatitis B core antigen, hepatitis B DNA, anti-hepatitis C virus IgG or IgM. In addition, patients 
must have documentation of positive Varicella Zoster Virus IgG antibody status or complete Varicella Zoster Virus vaccination at least 30 days prior to first dose of 
investigational drug.
g At Screening, the stool sample should be used to rule out serious infection and should include evaluation for C. difficile toxin as well as ova and parasitic examination.
h Investigational drug will only be dispensed for patients that could not complete the M1 Visit on the same day as the I 3 Visit.
i For females of childbearing potential only, a serum β-hCG pregnancy test at Screening is required and a urine β-hCG pregnancy test is required at each visit. Between scheduled 
visits up until the 90-day Safety Follow-up Visit, monthly home urine pregnancy tests should be performed by the patient. If a urine pregnancy test result is positive, the 
investigator will instruct the patient to suspend further study dosing, if applicable, and schedule a follow-up appointment as soon as possible. A serum pregnancy test will be 
performed for confirmation, including after the 90-day Safety Follow-up Visit, if needed.
j For all patients, a complete physical examination (which includes height and weight) will be performed at Screening.  For adult patients, the complete physical examination at  
M 5/EoT/Early Term visit does not include height and weight. Patients who enter the trial as adolescents should continue to be assessed as adolescents throughout the trial, 
regardless of an age change. The complete physical examination consists of a full examination of the skin for lesions as well as a check for visual symptoms (ie, blurred vision or 
decreased visual acuity).  A check for visual symptoms and a full examination of the skin should be repeated every 6 months. At all other visits following Screening (except M 
5/EoT/Early Term), an interim physical examination will be performed.  The interim physical examination will include body systems with previously noted abnormalities and/or 
those body systems associated with any new complaints from the patient.  
k At Visit I 1, blood samples for PK evaluation are to be taken prior to the administration of investigational drug (predose) and just prior to discharge from the clinic (6 to 8 hours 
postdose).  At Visit I 2, blood samples should be taken 2 to 6 hours after dosing; therefore, patients should be instructed to take investigational drug at home prior to arriving for 
this visit. At Visits I 1, I 3, M 1, and M 5, blood samples will be used to determine trough level, therefore patients should be instructed to withhold the dose until the trial visit, 
where the dose will be administered after the PK blood draw is done.   The actual time of investigational drug administration for all visits with PK evaluation will be recorded on 
the dosing log.  The blood sample at the 30-day and 90-day Safety Follow-up Visits can be collected at any point during the visit.  An additional PK sample will be obtained for 
patients with any adverse event resulting in unblinding, discontinuation, or serious adverse event.
l At Screening, a flexible sigmoidoscopy may be used if a colonoscopy is not required.  A colonoscopy will be required if the patient has had left-sided colitis of > 12 years 
duration or total/extensive colitis of > 8 years duration and has not had a colonoscopy within 2 years (unless otherwise recommended by local and national guidelines) of the 
screening date to rule out dysplasia, or if the patient’s age is > 45 years and the patient has not had a colonoscopy within 5 years to screen for polyps.  The screening endoscopy 
must be completed no more than 21 days prior to randomization.  A flexible rectosigmoidoscopy will be performed at Week 5 or later for adolescent patients who meet clinical 
symptom criteria for early discontinuation, with the understanding that the procedure may occur within approximately 7 days from the last visit prior to entering the OLE, to 
allow for preparation.  The final decision to discontinue the patient early for entry into the OLE will be left to the discretion of the Investigator based on the Partial Mayo score 
and the endoscopy score.
m Sigmoidoscopy should be performed no more than 10 days prior to the I 3 visit date in Induction and no more than 10 days prior to the M 5 visit date in Maintenance.
n At Screening, patients will be issued with a Mayo diary and will be trained in the completion of the diary.
o The Mayo partial clinical score on Visit I 1 should be combined with the central endoscopic read in order to assess the patient for "Mayo Score" entrance criteria.
p DLCO, if locally available, will be done at Screening, Visit I 3, Visit M 3, and M 5/Early Term visit.
q Early Term procedures performed at the Relapse Visit do not need to be repeated for patients who are early terminating due to relapse.

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
If oral aminosalicylates or corticosteroids have been recently discontinued, they 
must have been stopped for at least 2 weeks prior to the endoscopy used for 
Baseline Mayo score
7. Females of childbearing potential (FCBP):
Must agree to practice a highly effective method of contraception£ throughout the trial
until completion of the 90-day 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. Acceptable methods 
of birth control in the trial are the following:

combined hormonal (oestrogen and progestogen containing) 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. 
8. Must provide written informed consent/assent and have the ability to be compliant 
with the schedule of protocol assessments. The parent/legal guardian of the 
adolescent must sign an informed consent form. In addition, adolescent patients must 
also agree to participate in the study by signing an assent. 
9. Patients must have documentation of positive Varicella zoster virus (VZV) 
immunoglobulin G (IgG) antibody status or complete VZV vaccination at least
30 days prior to randomization
                                               
For the purposes of this study, a female patient is considered to be of childbearing potential if she is ≥ 12 years of age or 
has reached menarche, whichever occurred first, and 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)
£ Contraception Education: Counselling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted for FCBP.  The Investigator will educate all FCBP about the different options of contraceptive methods or 
abstinence at the Screening and Baseline visits, as appropriate. The patient will be re-educated every time her 
contraceptive measures/methods or ability to become pregnant changes.  The female patient’s chosen form of 
contraception must be effective by the time the female patient is randomized into the study (for example, hormonal 
contraception should be initiated at least 28 days before baseline). 

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7. History of diabetes mellitus type 1, or uncontrolled diabetes mellitus type 2 with 
glycosylated Hb (HbA1c) > 9%, or diabetic patients with significant comorbid 
conditions such as retinopathy or nephropathy
8. History of uveitis (within the last year) or macular edema
9. Subject has a known active bacterial, viral, or fungal infection [excluding fungal 
infection of nail beds, minor upper respiratory tract infections, and minor skin 
infections], a mycobacterial infection (including tuberculosis [TB] or atypical 
mycobacterial disease), or any major episode of infection that required hospitalization 
or treatment with intravenous (IV) antibiotics within 30 days of Screening or oral 
antibiotics within 14 days of Screening
10. Recurrent or chronic infection (eg, hepatitis A, B, or C, human immunodeficiency 
virus [HIV]); recurrent urinary tract infections are allowed. 
11. History of cancer, including solid tumors and hematological malignancies (except 
basal cell and in situ squamous cell carcinomas of the skin or uterine cervix that have 
been excised and resolved) or colonic mucosal dysplasia
12. History of alcohol or drug abuse within 1 year prior to randomization
13. History of or currently active primary or secondary immunodeficiency
Exclusions Related to Medications:
14. History of treatment with a biologic agent within 8 weeks or 5 elimination half-lives
(whichever is less) of that agent prior to randomization
15. History of treatment with an investigational agent within 5 elimination half-lives of 
that agent prior to randomization
16. History of treatment with topical rectal 5-aminosalicylic acid or topical rectal steroids 
within 2 weeks of Screening endoscopy or anti-motility medications (such as 
diphenoxylate/atropine) during Screening
17. Receipt of a live vaccine or live attenuated vaccine within 4 weeks prior to 
randomization
18. Previous treatment with lymphocyte-depleting therapies (eg, Campath, anti-CD4, 
cladribine, rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, total body 
irradiation, bone marrow transplantation, alemtuzumab, daclizumab)
19. Have had treatment with cyclosporine, tacrolimus, sirolimus, or mycophenolate 
mofetil (MMF) within 16 weeks of Screening or tofacitinib within 2 weeks of 
Screening
20. Previous treatment with D-penicillamine, leflunomide, or thalidomide
21. Previous treatment with natalizumab, fingolimod or etrasimod
22. History of treatment with intravenous immunoglobulin (IVIg) or plasmapheresis 
within 3 months prior to randomization

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8.3.
Considerations for Patients with Comorbid Conditions
8.3.1.
Patients with Type 2 Diabetes Mellitus
Patients with type 2 diabetes mellitus are permitted in the trial if their HbA1c is ≤9% at 
Screening. Such patients should receive appropriate diabetes management and treatment 
during the trial. 
Gestational diabetes and steroid-induced diabetes occurring in the past and resolved prior to 
Screening are not exclusionary.
The Investigator should ensure that diabetic patients who are included in the trial are closely 
monitored for signs or symptoms of macular edema (See Section 12.2.6).  Patients with 
diabetic uveitis or diabetic patients with significant comorbid conditions such as retinopathy 
or nephropathy are excluded.
Duration of disease and medication history for 3 months prior to randomization and 
throughout the trial will be recorded in source documents and in the electronic case report 
form (eCRF).
8.3.2.
Patients with History of Cardiac Disease
Patients with some pre-existing cardiac conditions, who have stable disease and would not 
be placed at significant safety risk by participating in the trial, may be considered for 
participation in the trial. Please refer to Section 8.2 for a list of cardiac exclusion criteria. 
These patients should have a cardiology consultation to determine whether it is appropriate 
for them to participate in the trial and whether they need additional cardiac monitoring. 
The results and recommendations of this consultation should be discussed with the medical 
monitor before patient enrollment.
If more intensive monitoring is not deemed necessary by the consulting cardiologist, 
these patients will follow the detailed first dose monitoring procedures as outlined in 
Section 12.1.10. The Investigator should ensure these patients included in the trial are 
closely monitored for signs of any bradycardia or other rhythm disturbances after the first 
dose of RPC1063, as these patients may be at higher risk for cardiac AEs.
8.4.
Trial Discontinuation
Patients may voluntarily withdraw from the trial 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 patient who does not meet
enrollment criteria is inadvertently enrolled, the Medical Monitor must be contacted, and that 
patient will be withdrawn from the trial 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 investigational drug if it is 
determined that it is not safe or in the patient’s best interest to receive further 
treatment. The Medical Monitor should be promptly notified of the decision.

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
Non-compliance with investigational drug:  After consultation between the 
Investigator, the Medical Monitor, and the Sponsor when appropriate, a patient 
may be discontinued from the trial for failure to comply with dosing regimen as 
specified by the protocol.

Non-compliance with protocol/protocol deviation:  A patient fails to follow 
protocol procedures, or other event or decision that stands in contrast to the 
guidelines set in the protocol.

Adverse event:  A patient must be discontinued from investigational drug if, in the 
judgment of the Investigator or if specified in the protocol, the patient develops an 
AE such as an intercurrent illness or complication that justifies discontinuation of 
investigational drug.

Lack of efficacy: Decision by the patient and/or the Investigator to discontinue 
investigational drug due to a lack of expected or desired effect related to a 
therapy.

Withdrawal by Patient (or Patient’s Parent/ Legal Guardian):  The patient (or 
patient’s parent/legal guardian) may choose to discontinue investigational drug at 
any time. Patients who discontinue investigational drug will be withdrawn from 
the study.  Every effort should be made within the bounds of safety and patient (or 
patient’s parent/legal guardian) choice to have each patient complete the Early 
Termination Visit and 30-day and 90-day Safety Follow-up Visits.  If a patient (or 
patient’s parent/legal guardian) withdraws consent/assent, the only additional 
investigational data to be collected will be the follow up of SAEs as mandated by 
the protocol.

Pregnancy: If the patient becomes pregnant investigational drug must be 
discontinued (see Section 12.2.9).

Trial termination by Sponsor

Other
All patients who discontinue the trial should complete an End of Treatment/Early 
Termination Visit (see Table 1). For patients who have a confirmed ALC below the 
200 cells/μL limit and permanently discontinue from participation in the study, central 
laboratory testing will continue every 14 days (± 3 days) after the Early Termination Visit 
until the ALC is above the lower limit of normal.  With the exception of patients who 
withdraw consent/assent or are lost to follow-up, patients should complete the 30-day and 90-
day Safety Follow-up Visits for the collection of safety data and to assess their disease status.  
For patients who have a confirmed ALC below the 200 cells/μL limit at the 30-day or 90-day
Safety Follow-up Visit, central laboratory testing will continue every 14 days (± 3 days) after 
these visits until the ALC is above the lower limit of normal. Alternative treatment for UC
can be started, if needed, after the 30-day Safety Follow-up visit.
The reason for discontinuation of investigational drug will be recorded in the clinical records 
and the patient’s eCRF.  For those patients whose status is unclear because they fail to appear 
for trial visits without stating an intention to discontinue trial participation, the Investigator 
should document in the source documents the steps taken to contact the patient or patient’s 

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9.
TRIAL TREATMENTS
9.1.
Treatments Administered
The Investigator must ensure that the investigational product will be used only in accordance 
with the protocol.
Patients should be instructed to take investigational drug (either RPC1063 or placebo) at 
approximately the same time each day with or without food.
9.1.1.
Induction Period
Cohort 1 (adults)
 On Induction Day 1, patients will be randomly 
assigned in a 2:1 ratio to initiate investigational drug in accordance with a 7-day dose 
escalation regimen starting with:

On Days 1 to 4, RPC1063/ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg)
or matching placebo once daily (one 0.25 mg capsule)

On Days 5 to 7, RPC1063/ozanimod HCl 0.5 mg (equivalent to ozanimod 0.46 mg) 
or matching placebo once daily (two 0.25 mg capsules)

On Day 8, patients will receive the final dose RPC1063/ozanimod HCl 1 mg 
(equivalent to ozanimod 0.92 mg) or matching placebo once daily for 9 weeks (one 1 
mg capsule)
Cohort 2 (adults): On Induction Day 1, all patients will initiate investigational drug in 
accordance with a 7-day dose escalation regimen starting with:

On Days 1 to 4, RPC1063/ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg)
once daily (one 0.25 mg capsule)

On Days 5 to 7, RPC1063/ozanimod HCl 0.5 mg (equivalent to ozanimod 0.46 mg) 
once daily (two 0.25 mg capsules)

On Day 8, patients will receive the final dose RPC1063/ozanimod HCl 1 mg 
(equivalent to ozanimod 0.92 mg) once daily for 9 weeks (one 1 mg capsule)
9.1.2.
Maintenance Period
On Maintenance Day 1, patients from Cohort 1, Cohort 2
with clinical response 
to RPC1063 during the IP will be randomly assigned 1:1 to:

RPC1063/ozanimod HCl 1 mg (equivalent to ozanimod 0.92 mg) once daily 
for 42 weeks (one 1 mg capsule), or

Matching placebo; a single capsule once daily for 42 weeks
Patients from Cohort 1 
 who had been randomized to receive placebo and showed 
a clinical response at Week 10 will continue to receive placebo in the MP in a double-blind 
manner.  

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The Investigator will provide the investigational drug only to the identified patients of this 
trial, according to the procedures described in this trial protocol. After the end of the trial, 
the Site Monitor will perform final accountability, package, seal, and prepare for shipment. 
Investigational drug and all investigational drug containers will be returned to the clinical 
supply distribution vendor and documentation will be returned to the CRO. The CRO will 
verify that a final report of drug accountability is prepared and maintained in the 
Investigator’s Trial Master File.

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11.
ASSESSMENT OF EFFICACY
Unless stated otherwise, all efficacy assessments will be performed for all patients (adults 
and adolescents).
11.1.
Efficacy Assessments
11.1.1.
Key Efficacy Measure: The Mayo Score
The Complete Mayo score is a composite of four assessments, each rated from 0 to 3:  
stool frequency, rectal bleeding, endoscopy, and Physicians Global Assessment 
(Schroeder et al. 1987).  The endoscopy subscore of the complete Mayo score is derived 
from an evaluation of findings on endoscopy based on central reading by a qualified central 
laboratory.  The 9-Point Mayo score eliminates the Physicians Global Assessment subscore, 
resulting in a composite of the rectal bleeding, stool frequency, and endoscopy subscores.
The partial Mayo score eliminates the endoscopy subscore, resulting in a composite of the 
rectal bleeding, stool frequency, and Physicians Global Assessment subscores. The complete 
Mayo score has a range of 0 to 12 and the 9-point Mayo score and partial Mayo score each
has a range of 0 to 9.
The complete Mayo score consists of four subscores, each ranging from (0-3) for a complete 
Mayo score that ranges from 0 to 12:
1. Stool frequencya
0 = Normal number of stools for this patient, prior to the onset of UC disease, or 
while in remission 
1 = 1 to 2 stools more than normal
2 = 3 to 4 stools more than normal
3 = 5 or more stools more than normal
2. Rectal bleedingb
0 = No blood seen
1 = Streaks of blood with stool less than half the time
2 = Obvious blood with stool most of the time
3 = Blood alone passes
3. Findings on endoscopy
0 = Normal or inactive disease
1 = Mild disease (erythema, decreased vascular pattern, does not include friability)
2 = Moderate disease (marked erythema, lack of vascular pattern, friability, erosions)
3 = Severe disease (spontaneous bleeding, ulceration)
4. Physician’s Global Assessmentc
0 = Normal

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12.1.4.
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 recorded
at the times specified in the Schedule of Events (Section 7.1) 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. The screening ECG report from the central reader 
must be available to confirm patient eligibility before randomization. Electrocardiograms 
will be performed before and 6 hours after the first dose of investigational drug 
administration for all patients on Induction Day 1 while the patient is in the clinic. The 
6 hour postdose ECG will be evaluated by the treating physician, with input if needed from a 
local cardiologist or a central reader to confirm if extended monitoring is required.
Additional ECG monitoring will be performed on Days 5 and 8 if cardiac issues are 
identified on the prior day of dose escalation, as described in Section 12.1.10.
Only clinically significant abnormalities should be reported in the medical history/current 
medical conditions or the AE eCRF. Clinically significant findings must be discussed with 
the Medical Monitor before enrolling the patient in the trial. 
12.1.5.
Ophthalmological Examination
Optical coherence tomography (OCT) will be performed as scheduled in Table 1. All original 
OCT images are considered source documents that should be made available to the site upon 
request, or otherwise at the end of the study. If there is a suspicion of new onset macular 
edema, then general retinal exams, including eye history, visual acuity, and dilated 
ophthalmoscopy will be obtained. A general ophthalmologist can do the examination, 
although a retinal specialist would be preferred to do the exams wherever possible. OCT 
images may be reviewed by an independent panel of ophthalmologists assigned to this trial.
12.1.6.
Pulmonary Function Tests
Pulmonary function tests including FEV1 and FVC measurements will be performed as 
scheduled in Table 1. In addition, DLCO measurements will be performed at Screening, 
Visit I 3, Visit M 3, and at the End of Trial or Early Termination visit (see Table 1, footnote 
p) where locally available.  DLCO will not be required at sites where there is no local testing 
facility. 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, the results must be verified by a 
pulmonologist, and potential confounding factors identified. If the patient has a decline in 
PFT values, the patient should have adequate evaluation as clinically indicated by a 
pulmonologist as described in Section 12.2.6.  Please refer to the American Thoracic 
Society/European Respiratory Society guidelines for standardization of spirometry and single 
breath determination of carbon monoxide uptake in the lung (MacIntyre 2005; Miller 2005a; 
Miller 2005b).  

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12.1.7.
Dermatological Examination
Dermatological evaluations will be performed by the treating Investigator or designee as part 
of the physical exam, as scheduled in Table 1. Patients with any suspicious finding noted 
during the examination will be referred to an appropriately qualified dermatologist for 
evaluation and treatment, if warranted.
12.1.8.
Monitoring of Adverse Events and Serious Adverse Events
Throughout the course of the trial, every effort must be made to remain alert to possible AEs 
or SAEs. Refer to Section 12.2 for definitions of AEs/SAEs, monitoring and reporting. Refer 
to Section 12.2.6 for AEs of special interest.
12.1.9.
Monitoring of Concomitant Therapy
The use of concomitant medication and procedures will be monitored throughout the trial. 
Refer to Section 9.5.3 for prohibited concomitant therapies.
12.1.10.
Guidelines for Monitoring Patients Taking Their First Dose of RPC1063
On Day 1 of treatment for the IP, careful cardiac monitoring of the patients is required. The 
Investigator is responsible for monitoring the patient following the first intake of the 
investigational drug, as well as managing bradycardia symptoms should they occur.  The 
Investigator must review the Baseline predose ECG, pulse, and blood pressure during the    
6-hour monitoring period, postdose ECG, and assess discharge status at 6 hours after dosing.  
Baseline predose ECG should be provided by the site and be available for comparison to the 
postdose ECG in order to determine if criteria requiring extended monitoring are met. 
Resting pulse and blood pressure in the sitting position will be measured before the first dose 
of investigational drug and every hour for at least 6 hours thereafter (by the Investigator, an 
assisting nurse, or other medically qualified staff member). When obtaining the pulse and 
blood pressure before the first dose, the patient should be allowed to rest in a seated position 
at least 10 minutes before taking measurements. The HR and sitting blood pressure 
measurements should be repeated 2 additional times (only before the first dose of 
investigational drug) and the lowest HR and blood pressure will be recorded in the eCRF. 
The repeat measurements will be made at approximately 2-minute intervals. For the hourly 
measurements after investigational drug administration, HR and sitting blood pressure will be 
measured once and recorded in the eCRF. The lowest predose value of sitting heart rate and 
blood pressure (based on systolic blood pressure) will be recorded in the case report form and 
serve as baseline for comparison to postdose values.
If possible, patients should receive the first dose of investigational drug before 12:00 pm 
(noon) in the clinic with or without food. The first dose of investigational drug must be 
administered in a setting in which resources to appropriately manage symptomatic 
bradycardia are available. A member of the Investigator team should be available to monitor 
the patient for the 6-hour monitoring period and will need to report any abnormalities to the 
Investigator. Atropine and epinephrine or isoproterenol need to be readily available to the 
site personnel.

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During the treatment period, WBC differential results will be available to an unblinded 
medical reviewer not directly participating in study conduct.  Reductions in ALC levels is a 
known pharmacodynamic effect of RPC1063.  If any of the following results are observed, 
the Investigator will be notified and asked to repeat the laboratory tests within approximately 
7 days:

Absolute neutrophil count (ANC) < 1000 cells/µL

Absolute lymphocyte count (ALC) < 200 cells/µL
If the ANC is confirmed below the 1000 cells/µL limit, the Investigator will be requested to 
closely monitor for risk of serious infection and institute appropriate follow-up, at the 
discretion of the Investigator.
If the ALC is confirmed below the 200 cells/µL limit, the Investigator will temporarily 
discontinue investigational drug and then consult with the Medical Monitor. Laboratory 
testing will be repeated weekly during the treatment period until the ALC > 500 cells/µL.
When ALC has returned to > 500 cells/μL, the treatment may be reinitiated at the 
Investigator’s discretion (see Section 9.1.3 for instructions on resuming treatment after 
missing doses).
For patients who have a confirmed ALC below the 200 cells/μL limit and permanently 
discontinue from participation in the study, central laboratory testing will continue every 14 
days (± 3 days) after the Early Termination Visit until the ALC is above the lower limit of 
normal.

Chemistry:  
Full chemistry panel at Screening: sodium, potassium, chloride, calcium, 
magnesium, phosphate, blood urea nitrogen, glucose, HbA1c, albumin, alkaline 
phosphatase, creatinine, ALT, AST, gamma glutamyltransferase (GGT), total 
bilirubin, conjugated bilirubin, total cholesterol, triglycerides, high-density 
lipoprotein, and low-density lipoprotein, C-reactive protein
All other visits: blood urea nitrogen, albumin, alkaline phosphatase, 
creatinine, ALT, AST, GGT, total bilirubin, conjugated bilirubin, C-reactive 
protein.  Of note, C-reactive protein will not be disclosed to preserve the 
blind.

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 trial 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 patient’s source documents. The laboratory sheets will be 
filed with the patient’s source documents.

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
Pregnancy test:  Serum β-hCG must be performed at Screening in females of 
childbearing potential. Urine β-hCG will be performed in females of childbearing 
potential at each scheduled visit. Between scheduled visits up until the 90-day
Safety Follow-up Visit, monthly home urine pregnancy tests should be performed 
by the patient.  If a urine pregnancy test result is positive, the Investigator will 
instruct the patient to suspend further study dosing, if applicable, and schedule a 
follow-up appointment as soon as possible. A serum pregnancy test will be 
performed for confirmation, including after the 90-day Safety Follow-up visit, if 
needed.

Serology testing will be performed at Screening to determine the patient’s immune 
status with respect to the following viral infections: 
VZV 
A VZV titer will be performed to determine if the patient has immunity 
(positive IgG result to Varicella Zoster virus). If VZV antibody titer is 
negative, the patient may choose to receive VZV vaccination in order to 
qualify for the study. If the patient receives a VZV vaccination, 
randomization can occur at a minimum of 30 days after vaccination has 
been completed. 
HIV
A HIV antibody test will be performed. Patients testing positive for HIV
(ELISA test result, confirmed by Western blot) will be excluded from the 
trial.
HAV
An anti-hepatitis A virus (HAV) antibody (anti-HAV IgM) test will be 
performed. Patients testing positive will be excluded from the trial, unless 
they are indicative of prior hepatitis A that is considered cured and 
accompanied by normal liver transaminase values.  
HBV 
Anti-hepatitis surface (HBs) antigen and anti-hepatitis B core (HBc) antigen 
test will be performed 
Patients who test positive for HBs antigen will be excluded from the trial.
For patients who test positive only for antibody to HBc antigen, an HBV 
DNA test must be performed.
If the HBV DNA test is negative (without anti-viral therapy) and the liver 
function tests (LFTs) are normal, the patient will be eligible for this trial. 
These patients will undergo periodic monitoring for HBV DNA during the 
trial.
HCV
A HCV antibody (anti-HCV IgG or IgM test) will be performed.

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Patients testing positive for HCV antibody and a positive confirmatory test 
will be excluded from the trial.
12.2.
Adverse Events and Serious Adverse Events
12.2.1.
Definition of Adverse Events
An AE is any untoward medical occurrence in a patient or clinical investigation patient
administered a pharmaceutical product, which does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a medicinal product, whether or not considered related to the medicinal product
(ICH E2A, II.A.1). 
Ulcerative colitis disease relapse and related symptoms will be monitored as trial endpoints 
and thus will not be recorded as AEs, unless it qualifies as a serious AE to trigger safety 
reporting as described in Section 12.2.7.
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 
investigational drug.  The action taken and the outcome must also be recorded.
12.2.2.
Definition of Serious Adverse Events
Definition of Serious Adverse Event (SAE):  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 patient 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, or

Is a congenital abnormality/birth defect
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but jeopardize the patient or 
may require intervention to prevent one of the other outcomes listed in the definition above.  
These should also usually be considered serious.

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Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
In case of a fatality, the cause of death is considered as the SAE, and the death is considered
as its OUTCOME.
12.2.3.
Assessment of Adverse Event Severity
The severity of the AE will be characterized as “mild, moderate, or severe” according to the 
following definitions:

Mild events are usually transient and do not interfere with the patient’s daily 
activities.

Moderate events introduce a low level of inconvenience or concern to the patient
and may interfere with daily activities.

Severe events are incapacitating and interrupt the patient’s usual daily activity.
12.2.4.
Assessment of Adverse Event Relationship to Investigational Drug
The causal relationship between the investigational drug and the AE has to be characterized 
as unrelated, unlikely, possible, probable, or related.  This medical assessment should be 
made as soon as feasible when reporting an SAE.
The Investigator is requested to assess the relationship of any AEs to treatment using the 
following definitions:
Unrelated: Those AEs which are clearly and incontrovertibly due to extraneous causes 
(concurrent drugs, environment, etc.) and do not meet the criteria for drug relationship listed 
under Unlikely, Possible, Probable, or Related.
Unlikely:  An AE may be considered unlikely if it includes at least the first two features:

It does not follow a reasonable temporal sequence from administration of the drug

It could readily have been produced by the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient

It does not follow a known pattern to the suspected drug

It does not reappear or worsen when the drug is re-administered
Possible: an AE may be considered possible if it includes at least the first two features:

It follows a reasonable temporal sequence from administration of the drug

It could readily have been produced by the patient’s clinical state, environment 
or toxic factors, or other modes of therapy administered to the patient

It follows a known response pattern to the suspected drug
Probable: an AE may be considered probable if it includes at least the first three features:

It follows a reasonable temporal sequence from administration of the drug

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
It could not be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors or other modes of therapy administered 
to the patient

It disappears or decreased on cessation or reduction in dose. There are exceptions 
when an AE does not disappear upon discontinuation of the drug (eg, bone marrow 
depression, fixed drug eruptions, tardive dyskinesia, etc.)

It follows a known pattern of response to the suspected drug
Related: an AE may be considered related if it includes all of the following features:

It follows a reasonable temporal sequence from administration of the drug

It could not be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors or other modes of therapy administered 
to the patient

It disappears or decreased on cessation or reduction in dose. There are exceptions 
when an AE does not disappear upon discontinuation of the drug (eg, bone marrow 
depression, fixed drug eruptions, tardive dyskinesia, etc.)

It follows a known pattern of response to the suspected drug

It reappears or worsens if the drug is re-administered
All efforts should be made to classify the AE according to the above categories.
After initiation of investigational drug, all AEs, regardless of relationship to investigational 
drug, will be recorded until the patient completes his or her last trial visit.
12.2.5.
Reporting of Serious Adverse Events
Reporting requirements for SAEs will be managed on behalf of the Sponsor by the CRO. 
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 patient from the time written 
informed consent/assent is signed through the last visit. All SAEs that occur within 90 days 
of the last dose of treatment with the investigational drug, whether or not considered related 
to the investigational drug, must also be reported. Any SAE that is ongoing when the patient 
completes the trial or discontinues from the trial will be followed by the Investigator until 
the event has resolved, stabilized, or returned to Baseline status.
Any AE considered serious by the Investigator or Sub-investigator or that meets serious 
criteria should be reported to the CRO’s Pharmacovigilance group using the designated 
SAE reporting forms and procedures. Data entry must be completed within 24 hours from 
the time the trial site personnel first learned of the event.

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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.
12.2.5.1.
Reporting of Serious Adverse Events to Regulatory Authorities and 
Investigators
Investigators will be notified by the CRO 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.
12.2.6.
Adverse Events of Special Interest
Potential AEs that may be a consequence of S1P1 modulation will be closely monitored 
during the trial.  These AEs include bradycardia, heart conduction abnormalities (2nd degree 
and higher AV block), macular edema, malignancy, serious or opportunistic infection, 
pulmonary effects, and hepatic effects.  An independent DSMB for the trial will perform 
quarterly safety reviews starting after the first patient is dosed.
Special considerations regarding monitoring for these events are as follows:

Bradycardia and heart conduction abnormalities (eg, symptomatic bradycardia, 
2nd degree AV block, QT prolongation):

Patients will be closely monitored in the clinic after their first dose of the initial 
dose escalation regimen for a period of 6 hours after treatment.  
Electrocardiograms will occur predose and at Hour 6 following dosing, with 
more frequent assessments if clinically indicated. Resting pulse and blood 
pressure in the sitting position will be assessed predose and then hourly for 
6 hours following dosing. See the monitoring guidelines in Section 12.1.10
for further details.

Investigators should be particularly cautious with patients who have a pulse 
rate < 55 bpm prior to administration of the investigational drug. Atropine IV 
is recommended as the first line treatment of bradycardia, up to a maximum 
daily dose of 3 mg. In general, the common guidelines for treatment of 
bradycardia (eg, Advanced Cardiac Life Support guidelines) should be followed 
as appropriate.

Pulmonary effects

Any condition that might affect the outcome of pulmonary function testing 
including infection, respiratory symptoms, occupational exposures (including 
asbestos) and cigarette smoking needs to be collected before PFT testing and 
transcribed to the pulmonary function tests eCRF page. If patients have decline 
in PFT values (FEV1 and/or FVC) below 50% of the predicted values, treatment 

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should be discontinued.  If a patient discontinues due to respiratory AE, the 
Investigator should ensure that the patient has adequate evaluations as clinically 
indicated by a pulmonologist (consider PFTs, chest X-ray or high resolution 
computed tomography, based on findings of the other exams) at the time of the 
AE.  For patients with pulmonary nodules, lung biopsy should be considered 
(Cryptococcus pneumonia and pulmonary TB have been reported with 
fingolimod).  Further evaluations will be conducted until such time as resolution 
is confirmed or no further improvement is expected by the Investigator (based 
on a follow-up period of not less than 3 months).

Hepatic effects

If patients have elevations in the LFTs (ALT or/and AST) ≥3 times the ULN, a 
retest should be performed as soon as possible but not later than 14 days after 
the original test.  Upon confirmation of the abnormality, retests should be 
performed weekly until the elevated LFT decreases to below 3 times the ULN.  
At any time, if any of the following occur and there are no apparent alternative 
causes for the finding, the investigational drug must be permanently 
discontinued:

ALT or AST > 8x ULN or

ALT or AST > 5x ULN with confirmation, within 2 weeks or

ALT or AST > 3x ULN and (total bilirubin > 2x ULN) or

ALT or AST > 3x ULN with the appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%).
The Investigator should establish causality
After discontinuation due to elevation of ALT or AST > 5x ULN or concurrent 
elevations of ALT or AST > 3x ULN and bilirubin > 2x ULN, further liver function 
evaluation should be performed (for example, coagulation panel and alkaline 
phosphatase) in consultation with the Medical Monitor.

Macular edema

For patients with abnormal OCT findings or with visual signs or symptoms 
of new onset macular edema that develop following initiation of treatment, 
a general ophthalmologic examination including eye history, visual acuity, 
and dilated ophthalmoscopy will also be performed

Investigational drug must be discontinued in any patient who has a confirmed 
diagnosis of macular edema that is of new onset since Baseline 

Patients with a diagnosis of macular edema must be followed up monthly and 
more frequently if needed based on the ophthalmologist’s judgment

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
Malignancies

Because RPC1063 is an immunomodulator, patients should be carefully 
monitored for malignancies (including dermatologic malignancy)

The Investigator will complete a dermatological examination for monitoring 
of the potential development of new cutaneous malignancies during the trial. 
Patients with any suspicious finding noted during the examination will be 
referred to an appropriately qualified dermatologist for evaluation and 
treatment, if warranted

Serious or opportunistic infections

TB, serious bacterial infections, systemic fungal infections, viral infections such 
as herpes infections (including herpes zoster and disseminated herpes simplex) 
and protozoan infections will be considered AEs of special interest
12.2.7.
Monitoring of Patients with Adverse Events, Serious Adverse Events, and 
Adverse Events of Special Interest
Investigators must carefully monitor each patient for AEs. This includes clinical laboratory 
variables. The reporting of AEs will begin at Induction Day 1 post first dose for all 
randomized patients. The reporting of SAEs for any patient will begin from the time written 
informed consent/assent is signed through the last visit, as detailed in Section 12.2.5.
Assessments must be made of the seriousness, severity, and relationship to the administration 
of the investigational drug. After the initial AE/SAE report, the Investigator is required to 
follow up proactively each patient and provide further information to the CRO on the 
patient’s condition. During the trial, all AEs/SAEs should be followed up to resolution 
unless the event is considered by the Investigator to be unlikely to resolve due to the patient’s 
underlying disease, or the patient is lost to follow-up.  Safety reporting must comply with 
ICH E6, 4.11.
12.2.8.
Treatment of Overdose of Investigational Drug
An overdose is any dose of investigational drug given to a patient or taken by a patient that 
exceeds the dose described in the protocol. There is no information regarding overdose with 
RPC1063. Any overdose, with or without associated AEs, must be promptly reported to the 
CRO’s Medical Monitor or other designated Drug Safety Center. Overdoses do not need to 
be recorded as AEs in the eCRF; only in the case of any AEs associated with the overdose 
should these be reported on relevant AE/SAE sections in the eCRF.
12.2.9.
Procedures in Case of Pregnancy
If a urine pregnancy test is positive, the patient will be instructed to suspend further study
dosing. If the test was performed by the patient between scheduled visits, a follow-up 
appointment will be scheduled as soon as possible. A serum pregnancy test will be performed 
to confirm the result.
Pregnancy in itself is not regarded as an AE unless there is a suspicion that an investigational 
product may have interfered with the effectiveness of a contraceptive medication; however, 
the outcome of all pregnancies (spontaneous miscarriage, elective termination, normal birth,

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imputation (NRI).  Sensitivity analyses around missing data may include tipping-point 
analysis, missing data imputed using multiple imputation (MI) and analyzing observed cases 
with no imputation.
For continuous efficacy endpoints, missing data analysis may be performed using a multiple 
imputation (MI) method and observed cases with no imputation. 
13.4.3.
Safety Analyses
All safety analyses will be carried out on the Safety population.
Adverse events will be monitored during the trial and the data analyzed with respect to 
incidence within each treatment group as well as severity and potential relationship of the 
AEs to investigational drug. Adverse events with onset on, or after the first dose of 
investigational drug or with onset prior to the first dose of investigational drug that increase 
in severity on, or after the first dose of investigational drug 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.
Associated laboratory parameters such as hepatic profile, renal function, and hematology 
values will be grouped and presented together. For each laboratory test, individual patient 
values outside the standard reference range will be flagged and listed. Shift tables will be 
produced showing the frequency of shifts from Baseline to the lowest and to the highest
on-trial 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.
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.
The change from Baseline for each of the PFT parameters will be summarized.  An outlier 
analysis of PFT results will be conducted.
OCT parameters will be summarized.
 
13.5.
Pharmacokinetic Analyses
Population PK analyses will use the PK data from this trial combined with data from other 
Phase 2 and Phase 3 trials to assess the influence of patient covariates on the exposure of 
RPC1063 and other relevant active metabolites. Exposure-response analysis may also be 
performed as appropriate. Results on population PK and exposure-response will be reported 
in separate, stand-alone reports.
13.6.
Interim Analyses
No interim analyses for efficacy are planned during the conduct of either trial period.

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14.3.
Quality Assurance and Inspections
Sites, the trial database, and trial documentation may be subject to Quality Assurance audit 
during the course of the trial by the Sponsor or CRO on behalf of the Sponsor.  In addition, 
inspections may be conducted by regulatory bodies at their discretion.  

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16.
ETHICS
16.1.
Institutional Review Board or Independent Ethics Committee
An Independent Ethics Committee should approve the final protocol, including the final 
version of the ICF, assent form, and any other written information and/or materials to be 
provided to the patients.  The Investigator will provide the Sponsor or CRO with 
documentation of IRB/IEC approval of the protocol and informed consent and/or assent 
before the trial may begin at the site(s).  The Investigator should submit the written approval 
to the Sponsor or representative before enrollment of any patient into the trial.
The Sponsor or representative should approve any modifications to the ICF and/or assent 
form that are needed to meet local requirements.
The Investigator will supply documentation to the Sponsor or CRO of required IRB/IEC’s 
annual renewal of the protocol, and any approvals of revisions to the informed consent/assent
document or amendments to the protocol.
The Investigator will report promptly to the IRB/IEC, any new information that may 
adversely affect the safety of patients or the conduct of the trial.  Similarly, the Investigator
will submit written summaries of the trial status to the IRB/IEC annually, or more frequently 
if requested by the IRB/IEC.  Upon completion of the trial, the Investigator will provide the 
Ethics Committee with a brief report of the outcome of the trial, if required.
16.2.
Ethical Conduct of the Trial
This trial will be conducted and the informed consent and/or assent will be obtained 
according to the ethical principles stated in the applicable version of the Declaration of 
Helsinki, the applicable guidelines for Good Clinical Practice (GCP; CPMP/ICH/135/95), or 
the applicable drug and data protection laws and regulations of the countries where the trial
will be conducted.
Good Clinical Practice is an international ethical and scientific quality standard for 
designing, conducting, recording and reporting studies that involve the participation of 
human patients.  The trial will be conducted in compliance with GCP and the applicable 
national regulations so as to assure that the rights, safety and well-being of the participating 
trial patients are protected consistent with the ethical principles that have their origin in the 
Declaration of Helsinki.
16.3.
Patient Information and Informed Consent/Assent
The Investigator will explain the benefits and risks of participation in the trial to each patient
(or patient’s parent/legal guardian), and/or the impartial witness and obtain written informed 
consent/assent. Written informed consent/assent must be obtained prior to the patient 
entering the trial and before initiation of any trial-related procedure. The final, version dated 
form must be agreed to by the IRB/IEC and must be provided in language readily understood 
by the patient. In case the patient is unable to read or write, an impartial witness should be 
present during the entire informed consent discussion. After the patient has orally consented 
to participation in the trial, the witness’ signature on the form will attest that the information 
in the consent form was accurately explained and understood. The Investigator or designee 

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will retain an original consent form/assent form for each patient, signed and dated by the 
patient, patient’s parent/legal guardian, or witness, and by the person who conducted the 
informed consent/assent discussion. The Investigator will supply all enrolled patients with 
either a copy of their signed informed consent/assent or, depending upon local requirements, 
a second original informed consent/assent, signed by both parties.
The consent form/assent form may need to be revised during the trial due to a protocol 
amendment or should important new information become available that may be relevant to 
the safety of the patient. In this instance, approval should always be given by the IRB/IEC 
and existing patients informed of the changes and re-consented, as directed by the IRB/IEC 
and in accordance with its policies and procedures; however, in some instances where an 
immediate change is necessary to eliminate an apparent hazard to patients, then it would not 
be necessary for a protocol amendment to receive IRB/IEC review and approval before being 
implemented. Those patients who are presently enrolled and actively participating in the trial
should be informed of the change if it might relate to the patients’ willingness to continue 
their participation in the trial.
With the consent/assent of the patient, the Investigator should inform the patient’s primary 
physician about participation in the clinical trial.
16.4.
Patient Data Protection
The ICF/assent form will incorporate (or, in some cases, be accompanied by a separate 
document incorporating) wording that complies with relevant data protection and privacy 
legislation.
16.5.
Investigator Obligations
This trial will be conducted in accordance with the ICH Harmonized Tripartite Guideline for 
GCP (GCP, 1997); the US Code of Federal Regulations (CFR) Title 21 parts 50, 56, and 312; 
and European Legislation; and the ethical principles that have their origin in the Declaration 
of Helsinki.  
A summary of Investigator Obligations is provided in Appendix 2.
The Investigator agrees to conduct the clinical trial in compliance with this protocol after the 
approval of the protocol by the IEC/IRB in compliance with local regulatory requirements.  
The Investigator and the Sponsor will sign the protocol to confirm this agreement.
16.6.
Protocol Signatures
After reading the protocol, each Investigator will sign the protocol signature page and send 
a copy of the signed page to the Sponsor or representative (Appendix 1).  By signing the
protocol, the Investigator confirms in writing that he/she has read, understands and will 
strictly adhere to the trial protocol and will conduct the trial in accordance with ICH 
Tripartite Guidelines for Good Clinical Practice and applicable regulatory requirements.  The 
trial will not be able to start at any center where the Investigator has not signed the protocol.

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17.
DATA HANDLING AND RECORD KEEPING
17.1.
Inspection of Records
The Investigator will prepare and maintain adequate and accurate source documents to record 
all observations and other pertinent data for each patient enrolled in the trial.
The Investigator will allow the Sponsor, CRO, and authorized regulatory authorities to have 
direct access to all documents pertaining to the trial, including individual patient medical 
records, as appropriate.
17.2.
Retention of Records
It is the Investigator’s responsibility to maintain essential trial documents (protocol and 
protocol amendments, completed eCRFs, signed ICFs/assent forms, relevant correspondence, 
and all other supporting documentation).  The trial site should plan on retaining such 
documents for approximately 15 years after trial completion.  The trial site should retain such 
documents until at least 2 years after the last approval of a marketing application in an 
International Conference on Harmonisation (ICH) region and until there are no pending or 
contemplated marketing applications in an ICH region or at least 2 years after the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period if required by the applicable regulatory requirements or 
the hospital, institution, or private practice in which the trial is being conducted.  Patient 
identification codes (patient names and corresponding trial numbers) will be retained for this 
same period of time.  These documents may be transferred to another responsible party, 
acceptable to Sponsor, who agrees to abide by the retention policies.  Written notification of 
transfer must be submitted to Sponsor.  The Investigator must contact Sponsor prior to 
disposing of any trial records.
No records should be disposed of without the written approval of the Sponsor.

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18.
PUBLICATION POLICY, FINANCING, AND INSURANCE
The data generated by this trial are confidential information of the Sponsor.  The Sponsor 
will make the results of the trial publicly available.  The publication policy, financing and 
insurance information with respect to the Investigator and site will be set forth in the Clinical 
Trial Agreement.

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Appendix 2:  Investigator Responsibilities
Per Good Clinical Practices 21 CFR 312.53
The Investigator:

Will conduct the study in accordance with the relevant, current protocol and will only 
make changes in the protocol after notifying the Sponsor, except when necessary to 
protect the safety, the rights, or welfare of patients;

Will comply with all requirements regarding the obligations of clinical Investigators 
and all other pertinent requirements;

Will personally conduct or supervise the described investigation;

Will inform any potential patients that the drugs are being used for investigational 
purposes and will ensure that the requirements relating to obtaining informed 
consent/assent and IEC review and approval are met;

Will report to the Sponsor adverse experiences that occur in the course of the 
investigation in accordance with Section 312.64;

Has read and understands the information in the Investigator’s Brochure, including 
the potential risks and side effects of the drug; and

Will ensure that all associates, colleagues, and employees assisting in the conduct of
the study are informed about their obligations in meeting the above commitments.
Per Good Clinical Practices 21 CFR 312.60
General Responsibilities of Investigators:
An Investigator is responsible for ensuring that an investigation is conducted according to the 
signed Investigator statement, the investigational plan, and applicable regulations; for 
protecting the rights, safety, and welfare of patients under the Investigator’s care; and for the 
control of drugs under investigation.  An Investigator shall, in accordance with the provisions 
of part 50, obtain the informed consent/assent of each human patient to whom the drug is 
administered, except as provided in 21 CFR 50.23.

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No important risks have been identified associated with ozanimod treatment.  Important 
potential risks based on experience with non-selective sphingosine 1-phosphate (S1P)
agonists include symptomatic bradycardia, atrioventricular conduction disorder, liver injury,
macular edema, Progressive Multifocal Leukoencephalopathy (PML), Posterior Reversible
Encephalopathy Syndrome (PRES), embryofetal toxicity in exposed pregnant females, 
malignancies, infections, and pulmonary effects.
ptomatic Bradycardia, Atrioventricular Conduction disorder:
Initiation of ozanimod may result in transient reductions in heart rate. In active-controlled 
MS clinical trials, after the initial dose of ozanimod 0.23 mg, the greatest mean reduction 
from baseline in heart rate of 1.2 beats per minute (bpm) occurred at Hour 5 on Day 1, 
returning to near baseline at Hour 6. Heart rates below 40 bpm were not observed. Initiation 
of ozanimod without dose escalation may result in greater reductions in heart rate. 
Ozanimod studies exclude subjects with severe untreated sleep apnea or recent myocardial 
infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure 
requiring hospitalization or Class III/IV heart failure or have a history or presence of second-
degree atrioventricular block Type II or third-degree AV block or sick sinus syndrome unless 
the subject has a functioning pacemaker. Subjects will be excluded from the study if they are 
being treated with Class Ia or Class III anti-arrhythmic drugs or with 2 or more agents in 
combination known to prolong PR interval.
On Day 1 of treatment, the protocol requires cardiac monitoring of the subjects for 6 hours 
after the first dose of investigational product and provides guidelines for extended monitoring 
and treatment if bradycardia. Subjects will be discontinued for clinically important 
bradycardia or AV conduction block as described in the protocol.
Liver Injury:
Elevations of aminotransaminases, primarily ALT and GGT, may occur in subjects receiving 
ozanimod. 
In active-controlled multiple sclerosis (MS) clinical trials, elevations of ALT to 5-fold the 
upper limit of normal (ULN) or greater occurred in 1.6% of subjects treated with ozanimod 
0.92 mg and 1.3% of subjects on interferon (IFN) β-1a. Elevations of 3-fold the ULN or 
greater occurred in 5.5% of subjects on ozanimod and 3.1% of subjects on IFN β-1a. The 
median time to elevation 3-fold the ULN was 6 months. The majority (79%) continued 
treatment with ozanimod with values returning to < 3 times the ULN within approximately 2-
4 weeks. 
A similar pattern of ALT elevations has been seen in UC and CD studies.  As of 20Dec2018, 
no cases of severe drug-induced liver injury were reported with ozanimod in RMS, UC, or 
CD clinical trials. 
Liver function tests and hepatobiliary AEs will be closely monitored within the clinical trials, 
including for patients who develop symptoms suggestive of hepatic disease. Repeat testing, 
stopping, and drug discontinuation rules have been provided to address elevations in liver 
enzymes.

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Macular Edema:
In the active-controlled MS clinical trials with ozanimod, macular edema was observed in 
one (0.1%) subject with ozanimod 0.92 mg and 3 (0.3%) subjects with ozanimod 0.46 mg, all 
of whom had preexisting risk factors.  
Subjects with a history of uveitis, Type 1 diabetes mellitus, and uncontrolled Type 2 diabetes 
mellitus were excluded from clinical trials with ozanimod. During the study, OCT will be 
used to screen for macular edema.  Subjects who present with visual symptoms of macular 
edema should be evaluated by the investigator and, if confirmed, treatment with ozanimod 
should be discontinued. Study drug must be discontinued in any subject who has a confirmed 
diagnosis of macular edema that is of new onset.
Progressive Multifocal Leukoencephalopathy (PML):
PML is an opportunistic viral infection of the brain caused by the John Cunningham virus 
(JCV) that typically only occurs in subjects who are immunocompromised, and that usually 
leads to death or severe disability.
JCV infection resulting in PML has been observed in subjects treated with MS therapies and 
has been associated with some risk factors (eg, polytherapy with immunosuppressants, 
severely immunocompromised subjects). No cases of PML were identified in clinical trials 
with ozanimod. Should symptoms present that are suggestive of PML, investigators should 
hold ozanimod and perform appropriate diagnostic evaluation. If confirmed, treatment with 
ozanimod should be discontinued.
Posterior Reversible Encephalopathy Syndrome (PRES):
In controlled clinical trials with ozanimod, one case of PRES was reported in a subject with 
Guillain-Barré syndrome. A relationship of PRES to ozanimod is uncertain. It has been 
observed with other S1P receptor modulators. If PRES is suspected, treatment with ozanimod 
should be discontinued by the investigator.
Embryofetal Toxicity in Exposed Pregnant Females:
There are no adequate and well-controlled studies in pregnant women. In animals, findings at 
similar exposure levels included embryo- fetal death, abnormal/delayed ossification, and 
abnormalities of the viscera and large blood vessels. There have been no reports of 
teratogenicity in the ozanimod clinical trials.
The use of ozanimod is not recommended during pregnancy and in women of childbearing 
potential not using contraception. Women of child-bearing potential should use effective 
contraception during treatment and for a minimum of 90 days after stopping treatment and 
must stop study treatment in the event of a diagnosis of pregnancy.
Malignancy:
Nonclinical testing found no carcinogenic effect through extensive genetic toxicology 
testing, in vivo carcinogenicity studies, and assessment of proliferative lesions in the general 
toxicology studies. The overall incidence of malignancies observed for patients on ozanimod 
is generally comparable to rates reported in the literature and health authority medical 
reviews for an age-matched population. The malignancies reported do not demonstrate any 
particular pattern and are not typical of those observed in an immunosuppressed population.