Clinical trial NCT02435992
Conditions: Ulcerative Colitis
Sponsor: Celgene
Start date: 2015-06-17; Completion date: 2020-06-17
Enrollment: 1012 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether RPC1063 is effective in the treatment of Ulcerative Colitis (UC).

Detailed description:
The trial is composed of 2 periods: Induction and Maintenance. In the Induction Period (IP), patients will be entered into the trial in 2 separate cohorts (Cohort 1 and Cohort 2).Patients from Cohort 1 and 2 in clinical response at the end of the IP will proceed through to the Maintenance Period (MP). Patients from Cohort 1 and 2 who participate in this trial may also qualify to participate in an optional Open-Label Extension (OLE) trial.

Arms: arm 1: 1mg, daily oral administration during Induction and Maintenance periods. arm 2: Daily oral administration during Induction and Maintenance periods.
Interventions: intervention 1: RPC1063 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 












EDMS Doc. Number: 23968946 - 23968295
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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: 


























EDMS Doc. Number: 23968946 - 23968295
Sponsor: Celgene International II Sàrl
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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


EDMS Doc. Number: 23968946 - 23968295
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Induction and Maintenance Therapy of RPC1063 in UC
26 Jul 2019, Version 7.1
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21
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


EDMS Doc. Number: 23968946 - 23968295
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Appendix 2:  Investigator Responsibilities............................................................ 109
Appendix 3: BENEFIT RISK ASSESSMENT...................................................... 110


EDMS Doc. Number: 23968946 - 23968295
Sponsor: Celgene International II Sàrl
Induction and Maintenance Therapy of RPC1063 in UC
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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


EDMS Doc. Number: 23968946 - 23968295
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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


EDMS Doc. Number: 23968946 - 23968295
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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


EDMS Doc. Number: 23968946 - 23968295
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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 




























EDMS Doc. Number: 23968946 - 23968295
Sponsor: Celgene International II Sàrl
Induction and Maintenance Therapy of RPC1063 in UC
26 Jul 2019, Version 7.1
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EDMS Doc. Number: 23968946 - 23968295
Sponsor: Celgene International II Sàrl
Induction and Maintenance Therapy of RPC1063 in UC
26 Jul 2019, Version 7.1
Confidential
42
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


EDMS Doc. Number: 23968946 - 23968295
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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




EDMS Doc. Number: 23968946 - 23968295
Sponsor: Celgene International II Sàrl
Induction and Maintenance Therapy of RPC1063 in UC
26 Jul 2019, Version 7.1
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45
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.














EDMS Doc. Number: 23968946 - 23968295
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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 
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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. 







SAP_001.pdf: 
EDMS Doc. Number: 23867102 - 23530353
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Statistical Analysis Plan (Induction Period, Cohorts 1 and 2), V4.0
Protocol: RPC01-3101
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STATISTICAL ANALYSISPLAN
A PHASE 3, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED TRIAL OF ORAL RPC1063 AS INDUCTION AND 
MAINTENANCE THERAPY FOR MODERATE TO SEVERE ULCERATIVE COLITIS
INVESTIGATIONAL PRODUCT:
RPC1063
PROTOCOL NUMBER:
RPC01-3101
PROTOCOL VERSION #1.0FINAL:
3/30/2015
PROTOCOL VERSION#2.0 FINAL:
6/7/2016
PROTOCOL VERSION#3.0 FINAL:
6/7/2017
PROTOCOL VERSION#4.0 FINAL:
12/7/2017
PROTOCOL VERSION#5.0 FINAL:
5/29/2018
PROTOCOL VERSION #6.0 FINAL:
11/26/2018
PROTOCOL VERSION #7.0 FINAL:
5/20/2019












EDMS Doc. Number: 23867102 - 23530353
Celgene Corporation
Statistical Analysis Plan (Induction Period, Cohorts 1 and 2), V4.0
Protocol: RPC01-3101
Date: 6/18/2019
Confidential and Proprietary
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TABLE OF CONTENTS
1.
LIST OF ABBREVIATIONS.................................................................................11
2.
INTRODUCTION..................................................................................................15
3.
STUDY OBJECTIVES...........................................................................................17
4.
INVESTIGATIONAL PLAN.................................................................................18
4.1.
Overall Study Design and Plan...............................................................................18
4.2.
Study Endpoints.....................................................................................................20
4.2.1.
Definitions..............................................................................................................20
4.2.2.
Endpoints...............................................................................................................22
5.
DEFINITION OF ANALYSIS POPULATIONS....................................................24
5.1.
Intent-to-Treat (ITT) Population.............................................................................24
5.2.
Per-Protocol (PP) Population..................................................................................24
5.3.
Safety Population....................................................................................................25
6.
STATISTICAL METHODOLOGY FOR EFFICACY............................................26
6.1.
Analysis of Primary Efficacy Endpoint...................................................................26
6.1.1.
Primary Analysis....................................................................................................27
6.1.2.
Sensitivity Analyses...............................................................................................27
6.2.
Analyses of Key Secondary Efficacy Endpoints......................................................29
6.2.1.
Control of Family-wise Type I Error Rate...............................................................30
6.2.2.
Primary Analysis of Key Secondary Efficacy Endpoints.........................................30
6.2.3.
Additional Analyses...............................................................................................30
6.3.1.
Primary Analysis....................................................................................................32
6.7.
Result Blinding.......................................................................................................36
6.8.
Interim Analysis.....................................................................................................36
7.
SUMMARY OF PATIENT DISPOSITION............................................................38
8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS................................39


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8.1.
Demographics.........................................................................................................39
8.2.
Ulcerative Colitis Disease Characteristics at Baseline.............................................39
8.3.
Medical History......................................................................................................40
9.
STUDY TREATMENTS ANDEXTENT OF EXPOSURE....................................42
9.1.
Treatment Duration.................................................................................................42
9.2.
Dose Modifications.................................................................................................42
9.3.
Treatment Compliance............................................................................................43
10.
PROTOCOLDEVIATIONS/VIOLATIONS..........................................................44
11.
SAFETY ANALYSIS............................................................................................45
11.1.
Adverse Events.......................................................................................................45
11.2.
Adverse Events of Special Interest..........................................................................46
11.3.
Deaths....................................................................................................................46
11.4.
Clinical Laboratory Evaluations..............................................................................46
11.5.
Vital Sign Measurements........................................................................................48
11.6.
Physical Examination.............................................................................................51
11.8.
Electrocardiograms.................................................................................................51
11.9.
Pulmonary Function Tests......................................................................................51




EDMS Doc. Number: 23867102 - 23530353
Celgene Corporation
Statistical Analysis Plan (Induction Period, Cohorts 1 and 2), V4.0
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Date: 6/18/2019
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LIST OF TABLES
Table 1:
Abbreviations and Specialist Terms........................................................................11
Table2:
Sensitivity Analyses for the Primary Endpoint........................................................29
Table3:
Additional Analyses for the Key Secondary Endpoints...........................................31
Table4:
WHO DD Medication Query for Treatment Failure Review....................................64
LIST OF FIGURES
Figure 1: Trial Schematic for Cohort 1 and Cohort 2..............................................................18


EDMS Doc. Number: 23867102 - 23530353
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Statistical Analysis Plan (Induction Period, Cohorts 1 and 2), V4.0
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1. 
LISTOFABBREVIATIONS
Table 1:
Abbreviations and Specialist Terms
Abbreviation
Term
5-ASA 
5-aminosalicylic acid
6-MP
6-mercaptopurine
aCRF
annotatedcase report form
ADaM
analysis data model
AE
adverse event 
AESI
adverse event of special interest
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ANCOVA
analysis of covariance
anti-HBc total
anti-hepatitis B core total antibodies
anti-TNF
anti-tumor necrosis factor
AST
aspartate aminotransferase
ATC
anatomic therapeutic classification
AV
atrioventricular
BMI
body mass index
BUN
blood urea nitrogen
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CRP
C-reactive protein
CRO
contract research organization
DBP
diastolic blood pressure
DLCO
diffusioncapacity of the lung for carbon monoxide
DM
data management
DNA
deoxyribonucleic acid


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DSMB
data safety monitoring board
ECG
electrocardiogram
eCRF
electronic case report form
EQ-5D
EuroQol quality of life scale
FDA
Food and Drug Administration
FEV1
forced expiratory volume in 1 second
FVC
forced vital capacity
GGT
gamma glutamyltransferase
hCG
human chorionic gonadotropin
HAV
hepatitis A virus
HBsAG
surface antigen of the hepatitis B virus
HBV
hepatitis B virus
HCV
hepatitis C virus
HDL
high-density lipoprotein
HIV
human immunodeficiency virus
HR
heart rate
IG
implementation guide
IgG
immunoglobulin G
IgM
immunoglobulin M
IP
induction period
ITT
intent-to-treat 
IXRS
interactive voice/web-based activated response system
LDL
low-density lipoprotein
LFT
liver function test
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
medical dictionary for regulatory activities


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MI
multiple imputation
MP
maintenance period
ms
milliseconds
NRI
non-responder imputation
OCT
optical coherence tomography
OLE
open-label extension
PD
pharmacodynamic(s)
PFT
pulmonary function test
PGA
physician’s global assessmentor physician’s global assessmentsubscore
PK
pharmacokinetic(s)
PP
per protocol
PT
preferred term
QOL
quality of life
RBC
red blood cell
RBS
rectal bleeding subscore
S1P
sphingosine-1-phosphate
S1P1R
sphingosine-1-phosphate1 receptor
S1P5R
sphingosine-1-phosphate5 receptor
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
SD
standard deviation
SDTM
study data tabulation model
SE
standard error
SF-36 
short form 36 health survey
SF-6D
health utility scorederived from the SF-36
SFS
stool frequencysubscore
SI
standard international


EDMS Doc. Number: 23867102 - 23530353
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Statistical Analysis Plan (Induction Period, Cohorts 1 and 2), V4.0
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SOC
system organ class
TEAE
treatment-emergent adverse event
TFR
treatment failure rules
TNF
tumor necrosis factor
TPA
tipping point analysis
UC
ulcerative colitis
UK
United Kingdom
ULN
upper limit of normal
US
United States
VAS
visual analogue scale
VZV
varicella-zoster virus
WBC
white blood cell
WHO DDE
World Health Organization drug classification dictionaryenhanced
WPAI:UC
work productivity and activity impairment questionnaire for UC


EDMS Doc. Number: 23867102 - 23530353
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Statistical Analysis Plan (Induction Period, Cohorts 1 and 2), V4.0
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Date: 6/18/2019
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2.
INTRODUCTION
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 
The overall goal of treatment for patients with active UCis 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 avoiding toxicity. 
There remains an unmet need for a UC treatment that is highly effective, well-tolerated, and 
orally activein both the adult and pediatric populations.
RPC1063 is a small molecule compound that selectively and potently activates the sphingosine-
1-phosphate1 receptor (S1P1) and the S1P5 receptor (S1P5), although it is more selective 
towards S1P
1over S1P5.
The induction phase of a Phase 2 trial in adult patients with moderate to severe UC (RPC01-202) 
was completed in October2014.  At the conclusion of the induction phase, the proportion of 
patients achieving clinical response and clinical remission with RPC1063 1 mg was greater than 
placebo and thedifference was bothclinically meaningful and statistically significant.In 
addition, all secondary endpoints at the conclusion of the induction phase, including clinical 
response, change in the Mayo score,andmucosal improvement on endoscopy,were also positive 
and statistically significant for the RPC1063 1mg dose. The maintenance phase of this trial 
ended March2015 and an open-label extension period is ongoing. 
The objective of the RPC1063 clinical development program in UC is to demonstrate that 
RPC1063 administered orally is safe and effective in inducing and maintaining remission in 
patients with moderate to severe UC. Positive Phase 2 results on remission rates during the 
Induction Periodof protocol RPC01-202 suggest that RPC1063 has the potential to be a 
clinicallymeaningful addition to the therapeutic armamentarium for the treatment of moderate to 
severe UC.
The results fromthis trial are meant to serve as the primary efficacy and safety data to support an 
application for marketing approval from regulatory authorities.
For the purposes of statistical analyses, the induction period (IP)and the maintenance period 
(MP)will be treated as two independent trialsthus each analysis will retain the full alpha. This 
statistical analysis plan (SAP) presents a detailed plan of the statistical methods to be used during 
the reporting and analysis of clinical data collected in the IP of this trialin adult patients only. 
Theadultpatientdata from the IP in Cohort 1 will be cleaned, unblinded and analyzed after the 
last Cohort 1 adult patient has had their last IP visit (I 3 Visit). The analysis of Cohort 1 


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induction data which is used for planning for future development will be carried out by 
designated un-blinded Biostatistics and Programming teams at PPD (a CRO), the sameteams 
already contracted to support the on-going DSMB meetings for this study. A limited number of 
Sponsor (i.e., Celgene) members who are not part of the study team will have access to the 
Cohort 1 induction analysis results. The review and conduct of the study will continue in a 
blinded manner by study team members that are blinded to all study data until all randomized 
subjects have completed 42 weeks of the Maintenance Phase (Week 52 of overall study 
duration). The process the Cohort 1 induction analysis will be documented in a charter in a 
separate document.  
Theadult patientdata from Cohort 2 will be cleaned, unblindedand summarized after the last 
Cohort 2 adult patient has had their last Cohort 2 visit.Analysis of all clinical data collected for
adultpatients who enter the MP will bedescribed in a separate SAP. Analysis of clinical data 
collected for pediatric 
This plan should be read in conjunction with the trial protocol, the annotatedcase report forms 
(aCRFs), and vendor data transfer specifications.


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3.
STUDY OBJECTIVES
Induction Therapy
The primary objective is to:
Demonstrate the efficacy of RPC1063 versus placebo on induction of clinical remission
in adults
The secondary objectives are to:
Demonstrate the efficacy of RPC1063 versus placebo on induction of clinical responsein 
adults
Demonstrate the efficacy of RPC1063 versus placebo on achieving endoscopic 
improvementin adults


EDMS Doc. Number: 23867102 - 23530353
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Statistical Analysis Plan (Induction Period, Cohorts 1 and 2), V4.0
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Date: 6/18/2019
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4.
INVESTIGATIONAL PLAN
4.1.
Overall Study Design and Plan
This is a multicenter, randomized, double-blind, placebo-controlled trial of RPC1063 as 
induction and maintenance therapy for moderate to severe UC. The trial will be conducted at 
approximately 325 sites in North America, Europe, Asia Pacific, South America, South Africa.
The trial is composed of 2 periods: Induction and Maintenance. Adult patients will enter into the 
trial through the Inducti
on period (IP) in 2 separate cohorts (see below). Adult patients who have 
previously received anti-TNF therapy may commence enrollment into Cohort 2 once the 
randomization limit of approximately 30% anti-TNF therapy adult patients has been reached in 
Cohort 1. Those adult patients who are anti-TNF therapy naïve will continue to enroll into 
Cohort 1 and can enroll into Cohort 2 only after Cohort 1 has been closed to enrollment. The 
proportion of adult patients who have previously received anti-TNF therapy will be limited to 
approximately 50% in Cohort 2.
Adult patients from Cohort 1 or Cohort 2 with clinical response at the end of the IP will proceed 
through to the MP.  Patients who participate in this trial may participate in an optional 
Open-Label Extension (OLE) trial as described below.
Approximately 900adultpatients will be entered into the trial
 in 2 separate cohorts through the 
IP, and may proceed through to the MP and/or the OLE trial.
Figure 1:
Trial Schematic for Cohort 1 and Cohort 2


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Induction Period
The IPof the trial is composed of 2 cohorts that will be treated for 10 weeks and evaluated for 
clinical response/remission:
Cohort 1: Approximately 600 adult patients will be randomized in a 2:1 ratio to receive 
either RPC1063 1 mg (400 patients) or placebo (200 patients) once daily in a double-
blind fashion, stratified by corticosteroid use at Screening (yes or no), and prior anti-TNF 
use (yes or no)
Cohort 2:Approximately 300 adult patients*will receive open-label RPC1063 1 mg once 
daily
*The number of adult patients in Cohort 2 maybe increased if necessary to ensure approximately 
400 patients who have received RPC1063 will be randomized in the MP.
Patient eligibility for the IP will be determined during a 5-week Screening Period prior to entry.
The trial will include both patients that have received anti-TNF therapy and those who have not.  
The proportion ofadultpatients who have previously received anti-TNF therapy will be limited 
to approximately 30% in Cohort 1. The proportion of adult patients who have previously 
received anti TNF therapy will be limited to approximately
 50% in Cohort 2. 
All adult patients will initiate investigational drug in accordance with a 7-day dose escalation 
regimen starting with RPC1063/ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg) or 
matching placebo (matching placebo for Cohort 1 only) on Days 1 to 4 and RPC1063/ozanimod 
HCl 0.5 mg (equivalent to ozanimod 0.46 mg) once daily or matching placebo on Days 5 to 7. 
On Day 8, patients will receive the final dose level RPC1063/ozanimod HCl 1 mg (equivalent to 
ozanimod 0.92 mg) once daily or matching placebo for 9 weeks.
The total duration of the IP is 10 weeks.
Maintenance Period
It is anticipated that approximately 400 adult patients treated with RPC1063 during the IP and 
who complete the IP (both Cohort 1 and Cohort 2) will be in clinical response (by either 
definition in Section4.2.1) at Week 10and will be eligible to enter the randomized, 
double-blind, placebo-controlled MP. These adult patients in clinical response at Week 10 of the 
IP will be randomized to receiveeither RPC1063 1 mg or matching placebo in a 1:1 ratio. who 
received RPC1063 during Induction will be randomized to receive either RPC1063 1 mg or 
matching placebo in a 1:1 ratio. Adult patients in clinical response at Week 10 of the IP who 
were randomized to placebo (Cohort 1) will continue to receive placebo in the MP in a 
double-blind manner. Adult patients from Cohort1 or Cohort 2who do not show a clinical


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response at Week 10 or who lose response at any time during the MP may enter the optional 
OLEtrial, if appropriate.
Adult patients randomized in the MP will be stratified by clinical remission status (by either 
definition in Section4.2.1) at Week 10 (yes or no) and corticosteroids use at Week 10 (yes or 
no). Adult patients will be evaluated for disease activity/efficacy at Week 42 of the MP (52 
weeks total treatment). 
Adult patients who complete the IP and are non-responders at Week 10, orthose who complete 
the MP, or those who experience disease relapse during the MP, will have the option to enter a 
separate OLE trial (RPC01-3102).
4.2.
Study Endpoints
4.2.1.
Definitions
Complete Mayo score:the sum of the Rectal Bleeding subscore, Stool Frequency subscore, 
Physician Global Assessment subscore, and the Endoscopy subscore.  Each subscore has a range 
of 0-3 points and the complete Mayo score has a range of 0-12 points
The Mayo endoscopic subscore will be determined both at the investigator site and centrally 
 
 
 
 
Clinical Remission
Three-component Mayo: Rectal Bleeding subscore = 0 and Stool Frequency subscore ≤ 1 (and a 
decrease of ≥ 1 point from the Baseline Stool Frequency subscore) and Endoscopy
 subscore ≤1
Four-component Mayo:Complete Mayo score of ≤ 2 points with no individual subscore of > 1 
point
Clinical Response
Three-component Mayo: A reduction from Baseline in the 9-point Mayo score of ≥ 2 points and 
≥35%, and a reduction from Baseline in the Rectal Bleeding subscore of ≥ 1 point or an absolute 
Rectal Bleeding subscore of ≤ 1 point


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DurableClinicalRemission: Clinical remission at Week 10 and at 52 weeksin all patients who 
entered the MP
Maintenance of Remission: Clinical remission at 52 weeks in the subset of patients who are in 
remission at Week 10
Corticosteroid-free Remission: Clinical remission at 52 weeks while off corticosteroids for ≥ 
12 weeks
Endoscopic Improvement:Endoscopy subscore of ≤ 1 point
Mucosal Healing: Endoscopy subscore of ≤ 1 point and a Geboes index score <2.0
 
 
 
Treatment Failure:
Adultpatients will be considered to have failed treatment if any of the following occur:

Any protocol-prohibited change in medications including:
o Post-Baseline initiation of, or increase intotal daily dose level higher than the 
maximum dose taken between the Screening and Baseline visitsin:
Corticosteroids or 5-ASAdose to treat UC 
Prolonged course of systemic corticosteroids >7daysfor treatment of disease 
other than UC
o Initiation of an immune suppressing therapy including 6-mercaptopurine (6-MP), 
azathioprine, anti-TNF agents, or vedolizumab

A colectomy (partial or total) or an ostomy

Discontinuation of investigational drug for lack of therapeutic effect before the Week 
10or 52 week efficacy evaluations


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Treatment failure will be confirmed via a blinded clinical data review process as per 
Appendix1.3.
4.2.2.
Endpoints
Efficacy -Cohort 1
The primary efficacy endpoint is:
The proportion of adult patients in clinical remission at Week 10
The keysecondary efficacy endpoints are: 
The proportion ofadult patients with a clinical response at Week 10
The proportion of adult patients with endoscopic improvement at Week 10
The proportionof adult patients with mucosal healing at Week 10
 
 
 
 
 
Cohort 2
Cohort 2 is open-label; therefore no formal analysis of efficacy endpoints will be conducted. All 
efficacy endpoints listed under Cohort 2 will be summarized and described without hypothesis 
testingand reported using descriptive statistics.


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5.
DEFINITION OF ANALYSIS POPULATIONS
Unless specified otherwise, patients refer to adult patients from Cohort 1 and/or Cohort 2 only.
5.1.
Intent-to-Treat (ITT) Population
The ITT population will consist of:
Cohort 1: All randomized patients from Cohort 1 of the IPof the trial who received at 
least 1 dose of investigational drug (RPC1063 or placebo)
Cohort 2: All enrolled patients from Cohort 2 of the IPof the trial who received at least 1 
dose of investigational drug (RPC1063)
The ITT population will be used as the primary population for all efficacyparameters. Patients 
who prematurely withdrew from the trial for any reason and for whom an assessment was not 
performed for any reason will still be included in the ITT analyses. Patients in Cohort 1 who 
receivedan incorrect investigational drug from that which was randomized will be summarized 
in the treatment group according to the intended randomization. Patients in Cohort 1 who were 
randomized with a misreported stratum will be analyzed according to their original[misreported]
stratum.
Patients receiving RPC1063 in Cohort 2 will be reported in either a separate column from 
patients randomized to RPC1063 in Cohort 1 or in a separate table and will not be subject to 
statistical hypothesis testing.
5.2.
Per-Protocol (PP) Population
The PPpopulation will consist of all patients in the ITT population who adheredto the protocol
withno major protocol deviation that potentially affects efficacy in the induction period.This 
population will be used in the sensitivity analysis of clinical remissionand additional analysis of 
clinical responseto evaluate the influence of major protocol violators and protocol deviators on 
the primary results. Patients will be excluded from this population if they meet any of the 
following reasons, which will be documented prior to database snapshot:
Investigational drug noncompliance > 20%(i.e., overall IP drug compliance not in [80%, 
120%])
Receiving incorrect investigational drug leading to a treatment change for more than 1 
weekin the IP
Prolonged concomitant use of systemic corticosteroids (excepttopical use) > 7 days 
before Week 10, for treatment of disease other than UC, at a total daily dose higher than 
the maximum dose taken between the Screening and Baseline


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Concomitant use of protocol-specified excluded medication that potentially affects 
efficacyfor unrelated comorbid condition
 
Violation of key entry criteria (i.e., inclusion criterion #4 [Have active UC defined as 
Mayo score of 6 to 12 inclusive, with endoscopic subscore of ≥ 2, a rectal bleeding score 
of ≥ 1, and a stool frequency score ≥ 1], exclusion criterion #2 [Diagnosis of Crohn’s 
disease or indeterminate colitis or the presence or history of a fistula consistent with 
Crohn’s disease or microscopic colitis or radiation colitis or ischemic colitis], and 
primary non-responders to 2 or more biologic agents approved for the treatment of UC)
The PP population will be fully identified and documented prior to induction treatment is 
unblinded.Patients excluded from PP population and the reason for exclusion will be listed.
Similar to the ITT population, PP patients in Cohort 1 who received an incorrect investigational 
drug from that which was randomized will be summarized in the treatment group according to 
the intended randomization. Patients in Cohort 1 who were randomized with a misreported 
stratum will be analyzed according to their original[misreported]stratum.
5.3.
Safety Population
The Safety populationwill consist of all patients who receivedat least 1 dose of investigational 
drug. This population will be used for all summaries of safety data. Patients randomized to 
placebo who receive any amount of RPC1063 will be summarized in the RPC1063 1 mg group.  
Patients randomized to RPC1063 who receive only placebo for all doses will be summarized in 
the placebo group, otherwise they will be summarized in the RPC1063 1 mg group.


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6. 
STATISTICAL METHODOLOGY FOR EFFICACY
Generalconventions on datareporting andanalysis regarding reportingformats, definitionsof 
Baseline, change, percent change, analysis visit window,methods forhandling missing data 
(e.g., missing Mayo subscore), and methods for handling treatment failuresin analysiscan be 
found in Appendix1.
Unless stated otherwise, the stool frequency and rectal bleeding subscores and associated Mayo 
composite scores using the 7-day scoring algorithmdescribed in Appendix 3.2will be used as 
the primary analysis for the primary and key secondary efficacy endpoints: clinical remission 
and clinical response.
The 14-day scoring algorithm(A and B)describedin Appendix 3.1will also be used for the 
analysis of these two endpoints servingasa sensitivityanalyses. 
For statistical analysis purposes, clinical remission and clinical response will be calculated using 
the Three-component Mayo definition 
Cohort 1 (double-blind RPC1063 1 mg once daily or placebo) will be used to formally assess the 
efficacy endpoints in the IPof the trial.
As Cohort 2 (open-label RPC1063 1 mg once daily) does not have a placebo control, no efficacy 
endpoints will be formally examined for the IP; however, the efficacy measures shown in 
Section4.2.2will be summarized and described.
As detailed in Section6.2.1, the primary and 3 key secondary endpoints will be subject to a 
closed, hierarchical testing procedure in order to control the overall Type I error rate 
(family-wise error rate or FWER) for testing of these multiple endpoints. 
 
 
 
6.1.
Analysis of Primary Efficacy Endpoint
The primary efficacy endpoint is the proportion of adult patients in clinical remission 
(Three-component Mayo definition)at Week 10. Thenull and alternativehypotheses for the 
primary efficacy endpoint are:
Null hypothesis H0: Clinical remission RPC1063= Clinical remission Placebo


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Alternative hypothesis Ha: Clinical remission RPC1063≠ Clinical remission Placebo
6.1.1.
Primary Analysis
The primary analysis of the primary endpoint of proportion ofpatients in clinical remission 
(Three-component Mayo definitionusing 7-day scoring algorithm, see Appendix 3.2) atWeek 
10will be carried outin the ITT populationusing Cochran-Mantel-Haenszel (CMH) testat two-
sided5% level of significance, stratified bycorticosteroid use at screening (yes or no),and prior 
anti-TNF use(yes or no). Results will be expressed as number of patients in remission, remission 
percentages, weighted difference in remission percentages, odds ratio, and associated two-sided 
95% confidence intervals (CIs) and p-values.A bar graph showing the percentagesof patients in 
clinical remission by treatment/cohort with the weighted treatment difference and CMH p-value 
will be produced.SeeAppendix6for some sample SAS codes.
For patients whose clinical remission (Three-component Mayo definition)at Week 10cannot be 
adequately determined (including missing data, discontinuation or lost to follow-up), their 
clinical remissionwill be imputed using a non-responder imputation (NRI)approachas 
described inAppendix1.3. Patients meeting the TFRcriteriaprior to the Week 10 visit, their 
clinical remission at Week 10will be imputed using NRI as described inAppendix 1.3.
6.1.2.
Sensitivity Analyses
Sensitivity analyses will be performed to support the primary analysis(Table2).These analyses 
use missing data handling methods including multiple imputation (MI)
 all 
observed data and tipping point analysis 
 
Tipping Point Analysis
A tipping point (TP) sensitivity analysis for the primary endpoint, clinical remission 
(Three-component Mayo definition) at Week 10, will be performed. The TP method is 
considered as an alternative strategy for handling missing data
 and the analysis 
for clinical remission (Three-component Mayo definition)at Week 10will follow the algorithm 
for a binary variable provided in the 
This analysis will include all observed data 
and then vary assumptions about the missing outcomes, by assigning remitters to some missing 
data and non-remitters to other missing data in the two treatment arms. Tipping point is defined 
here as the difference in the number of remitters (for clinical remission at Week 10) between the 
two treatment groups in the missing part at which the study conclusion changes. Unlike the non-
responder imputation (NRI) which assigns all missing data to a non-responder for the Week 10
clinical remission, a TPanalysis replaces the missing value with either remitteror non-remitter
so that the resulting treatment comparison, or level of significancebetween the two arms, varies. 
Analysis of each of the imputed dataset will be carried out using the same method for the 
primary analysis as described in Section6.1.1. Conducting these sensitivity analyses using the 
proposed missing data handling methods (NRI,tipping pointand multiple imputation), will 


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support that the comparison of the two treatment groups in clinical remissionat Week 10is 
robust under different missing data imputation methods.  
Multiple Imputation (MI)
Amultiple imputation procedure replaces each missing value with a set of plausible values that 
represent theuncertainty about the right value to impute. These multiply imputed data sets are 
thenanalyzed by using standard procedures for complete data and combining the results from
these analyses 
 
The following process will becarriedout MI for the primary endpoint, clinical remission (3 
component Mayo definition) at Week 10. Because clinical remission and response are 
determined using a 3-component subscores: Rectal Bleeding (RB), Stool Frequency (SF) and 
Endoscopy subscore, MI will be applied to each of the 3 component subscoresfollowed by 
applying the definition to determine clinicalremission and/or response at Week 10. 
Themissing datapatternwill beexamined first. Themissing dataforRB, SF and Endoscopy 
subscoresis expectedto followeither monotonepattern or arbitrary (non-monotone)for each of 
the three subscores.
• When asubscore(e.g., RB)is considered to follow amonotonemissing pattern fora
particularindividual at a given timepoint (e.g. Week 5), it implies that all subsequent 
visits (Weeks 5and 10)aremissing for that individual. Fordatasets with monotone
missing patterns, thevariableswith missing values can beimputed sequentially, with data
from the2visits (Weeks 5 and 10)usealogistic regression method(adjusting for the two 
stratification factors and other baseline covariates deemed appropriate). 
• A full conditional method (FCM) will be applied when a subscore(RB or SF)is 
considered to follow an arbitrary missing pattern. 
Combining inferences from imputed datasetsinvolves the following three steps:
• The missing data are filled in m=20times to generate m complete data sets.
• The m=20complete data sets after MI are analyzed using the primary analysis method 
outlinein Section 6.1.1.
• The results from the m=20complete data sets are combined for the inference.
The above MIprocess results in valid statistical inferences that properly reflect the uncertainty 
due to missing values; for example, valid confidence intervals for parameters.
The inference of the tipping point analysis will be made based on several factors including 
missing data pattern, reasons of subject discontinuation/drop-out, results from all observed (non-
missing) data and clinical remission results in the published historical studies.
All these analyses (sensitivity and tipping point) will be performed using SAS.




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6.2.1.
Control of Family-wise Type I Error Rate
The primary and 3key secondary endpoints will be tested in order in a closed, hierarchical 
testing procedure in order to control the overall Type I error rate for multiple endpoints. If the 
primary endpoint(Three-component Mayo definition) at Week 10 is statistically significant, the 
proportion of patients with a clinical response(Three-component Mayo definition)at Week 10 
will be tested at the 5% level of significance. If that endpoint is significant, then the proportion 
of patients with endoscopic improvement at Week 10 will be tested at the 5% level of 
significance. This testing procedure will continue through each of the 3 key secondary endpoints 
in the order listed in Section4.2.2until an endpoint fails to reach statistical significance, after 
which all subsequent key secondary endpoints will be considered exploratory. Endpoints listed 
as other secondary endpoints (Section4.2.2) will be tested in a nonhierarchical fashion without 
adjustments for multiplicity.
6.2.2.
Primary Analysisof Key Secondary Efficacy Endpoints
The clinical response determinedusing the 7-day scoring algorithm(Appendix 3.2) and the other 
two key secondary endpoints (endoscopic improvementand mucosal healing)will be tested
usingthe same type ofCMH testas specified for the primary endpoint.For each key secondary 
endpoint, the same summary and inferential statistics will be reported as specified for the
primary analysis of theprimary endpointin Section6.1.1, including a bar graph showing the 
percentagesby treatment/cohort with the weighted treatment difference, associated two-sided 
95% CIand CMH p-value.
Patients without sufficient data to determine clinical response at Week 10 will be analyzed using 
NRI as described in Appendix1.3. Patients withoutcentral read endoscopy results to determine
endoscopic improvement at Week 10 will be analyzed using NRI.Patients without endoscopy or 
Geboes index results to determinemucosal healing at Week 10 will be analyzed using NRI.
For all key secondary endpoints, patients meeting the TFR prior to the Week 10 efficacy 
evaluation will be analyzed using NRI as described in Appendix1.3.
The analysis of each key secondary endpointwill be repeated on each of the subgroups listed in 
Section6.4. In addition to reporting the subgroup analyses out in a table, a forest plot showing 
the weighted treatment differences with associated 95% CI and p-values will be produced.
 
 
 




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6.3.1.
Main Analysis
Change in Mayo score (complete, 
 from Baseline to Week 10 will be analyzed 
using an analysis of covariance (ANCOVA) model adjusted for corticosteroid use at screening 
(yes or no), prior anti-TNF use (yes or no), and the Baseline Mayo score, using observed cases. 
Actual values and changes from Baseline will be descriptively summarized. The adjusted least-
squares means and standard errors (SEs) with 95% CI for the difference in mean changes from 
Baseline and p-values will be reported. The Week 5 visit, when applicable,will also be included 
in the same table.For example, there will be an analysis for partial Mayo score at Week 5but not 
for complete or 9-point Mayo scores. 
Proportion ofadultpatients with histologic remissionat Week 10 will each be analyzed and
reported using the same stratified CMH test as specified forthe primary analysis ofthe primary 
endpointin Section6.1.1, using NRI described in Appendix1.3, including a bar graph showing 
the percentagesby treatment/cohort with the weighted treatment difference, associated 95% CI 
and CMH p-value.
 
Proportion of adult patients with clinical response, remission, or endoscopic improvement at
Week 10 in patients who previously received anti-TNF therapywill be analyzed and reported 
using the same stratified CMH test as specified for the primary analysis of the primary endpoint
in Section6.1.1, except prior anti-TNF use stratification factorwill not be used,using NRI
described in Appendix1.3.
 
 
 


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6.4.
Subgroup Analysis
Subgroup analyses will be performed for the endpoints of clinical remission and clinical 
response onlyusing the three-component Mayo score based on a 7-day scoring algorithm
(Appendix 3.2). Foreach specific subgroup, if there are not enough patients (i.e., <5% ITT 
population), the corresponding analyses will not be performed. The following are the pre-defined 
subgroups:
1. Corticosteroid use at screening (yes vs.no)
2. Prior anti-TNF use (yes vs. no)
3. Baseline complete Mayo score (≤ 9 vs. > 9)
4. Extent of colitis (left-sided vs. extensive)
5. Sex (female vs. male)
6. Age at screening (≤ medianvs. > median)  
7. Baseline fecal calprotectin (≤ 250 vs. > 250 mg/kg)
8. Baseline ALC (≤ 1,500vs. > 1,50010^6/L)
9. Years since initial UC diagnosis (≤ 4 vs. > 4 years)
10.Region (North America, Eastern Europe, Western Europe, Asia Pacific)
11.Baseline partial Mayo score (<=median vs. >median)


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12.Baseline partial Mayo score (<=7 vs. >7)
13.Baseline endoscopy subscore (2 vs. 3)
Other subgroups such as race (white vs. non-white), weight (≤ median vs. > median), 5-
aminosalicylic acid (5-ASA) use at screening (yes vs. no), and corticosteroid and 5-ASA use at 
screening (yes vs. no), and moderate UC at screeningmay also be explored.


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6.7.
Result Blinding
Before unblinding Cohort 1 treatment codes, results ofPK,total and differential white blood cell 
(WBC) count (basophils, eosinophils, lymphocytes, monocytes, and neutrophils), fecal 
calprotectin, and C-reactive proteinbeyond first dose will not be disclosed topreserve the blind.
6.8.
Interim Analysis
No interim analyses for efficacy are planned during the conduct of the IP. 
The data from the IPin Cohort 1 will be cleaned, unblinded, and analyzed after the last Cohort 1 
patient has had their last IPvisit(I 3 Visit). The analysis of Cohort 1 induction data which is 


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used for planning for future development will be carried out by designated un-blinded 
Biostatistics and Programming teams at PPD (a CRO), the same teams already contracted to 
support the on-going DSMB meetings for this study. A limited number of Sponsor (i.e., Celgene) 
members who arenot part of the study team will have access to the Cohort 1 induction analysis 
results. The review and conduct of the study will continue in a blinded manner by study team 
members that are blinded to all study data until all randomized subjects have completed 42 
weeks of the Maintenance Phase (Week 52 of overall study duration). The process the Cohort 1 
induction analysis will be documented in a charter in a separate document.
The data from Cohort 2 will be cleaned, locked, and analyzed after the last Cohort 2 patient has 
had their last Cohort 2 visit. The treatment blind for the Maintenance Period will not be broken 
until the end of the study. 
An independent data safety monitoring board(DSMB)will be charged with monitoring 
accumulating safety data from the trial, as well as general aspects of trial conduct. 
The committee will meet periodically during the trial (approximately 4 times each year) to 
review aggregate analyses bytreatment group concerning enrollment, treatment compliance, 
adherence to follow-up schedule, and safety data from the trial.  The DSMB may recommend 
modifying or stopping the trial early due to safety concerns based on data reviews. The 
unblinded data will be prepared by an independent team at the CROs.
The blinding plan to assure that all personnel involved in the conduct of the trial remain blinded 
to the results of interim reviews will be specified in the DSMB Charter.


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7. 
SUMMARY OF PATIENTDISPOSITION
The disposition of patientswill be summarized with numbers and percentagesby 
treatment/cohort and in Total Cohort 1 forall randomized subjects(Cohort 1) and all enrolled 
subjects(Cohort 2). Summaries will include the number and percentage of patients in the 
following
Never dosed, Dosed, Completedthe IP, and Discontinuedfrom the IP.
Primary reasons for discontinuation from the IP.
Patients who were randomized to Cohort 1 or enrolled to Cohort 2 will be summarized with
number and percentage by region, country, and site for all randomized subjects(Cohort 1) and 
all enrolled subjects(Cohort 2). Patientswho were dosed and who completed the induction 
period will be summarized with number and percentageby region, country,and sitefor the ITT 
population.
Patients in each analysis population as defined inSection5will be summarized with number and 
percentage.
Patients who were screened and who failed screening will be summarizedwith number and 
percentageby reasonfor All Consented population.
Patient dispositionwill be listedforthe ITTpopulation. Patienteligibility will be listed forAll 
Consented population.


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8.
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Summaries for the demographics, baseline characteristics, medical history, prior medication, and 
protocol deviations will be presented for the ITT population by treatment/cohort and in Total 
Cohort 1unless specified otherwise. Concomitantmedications will be presented for the Safety
populationby treatment/cohort and in Total RPC1063 1 mg. Individual listings will also be 
provided, including concomitant medical proceduresfor the Safety population.
8.1.
Demographics
Demographic characteristics includingage, age category(18-29, 30-39, 40-49, 50-59, 60-69, 70-
75, < 65, ≥ 65, ≤ Cohort 1 median, and >Cohort 1 median), sex, race, ethnicity, weight, height, 
body mass index (BMI),region (North America, Eastern Europe, Western Europe, Asia Pacific, 
South America, South Africa), country, and tobacco/nicotine usage (never, former, current)will 
be summarizedfor the ITT population and the PP population. Demographic characteristics will 
also be summarized for All Screen Failures, except weight, height, and BMI, which are not 
collected for screen failure patients.See reporting convention in Appendix 1.1.
8.2.
Ulcerative ColitisDiseaseCharacteristicsat Baseline
Ulcerative colitis disease characteristics at baseline includingcorticosteroid use at screening and 
prior anti-TNF use as entered in IXRS, actual corticosteroid use at screening and prior anti-TNF 
use as derivedby concomitant medication and prior UC medication eCRFs (corticosteroid and 
TNF-alpha antagonist, respectively), prior corticosteroid use, prior immunomodulator use, prior 
biologics use except TNF-alpha antagonist, and prior oral 5-ASA usewill be summarizedfor the 
ITT population andthePP population.See reporting convention in Appendix 1.1.
The following UC disease historyparameters will be summarizedin the same table.
Age at UC symptom onset
Age at UC diagnosis
Years since UC symptom onset
Years since UC diagnosis
Years since UC diagnosis category (0 to <1, 1 to <2, 2 to <5, 5 to <10, 10 to <15, ≥15, 
≤4, >4)
Extent of colitis (left-sided vs. extensive)
Complete Mayo score at Baseline using the central endoscopy subscore


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Complete Mayo score at Baseline category using the central endoscopy subscore (≤ 9vs. 
> 9)
 
 
 
8.3.
Medical History
A summary of medical history, excluding datacollected on the UC history and disease status 
eCRF, will be presented by system organ class (SOC) and preferred term (PT) according to the 
Medical Dictionary for Regulatory Affairs (MedDRA) version 18.1, or higher, using number and 
percentage of patients. 
 
 
 
 
 
 
 
 
 
 


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9.
STUDY TREATMENTS ANDEXTENT OF EXPOSURE
All patients will initiate investigational drug via a 7 day dose escalation regimen starting with 
RPC1063/ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg) or matching placebo 
(matching placebo for Cohort 1 only) on Days 1 to 4 and RPC1063/ozanimod HCl 0.5 mg 
(equivalent to ozanimod 0.46 mg) once daily or matching placebo on Days 5 to 7. On Day 8, 
patients will receive the final dose level (1 mg once daily or matching placebo) for 9 weeks.
Patients will record whether they took the daily dose of medication in a diary that will be 
reviewed periodically by site staff and the Site Monitor.
There will be an individual investigational drug accountability record for each patient and the 
Investigator should maintain accurate records of the disposition of all investigational drug 
supplies received during the trial. The number of capsules and date investigational drug supplies 
are dispensed to the patient and returned by the patient are reported on the Drug Log eCRFs. 
Overdoses are reported on the Overdose Log eCRF and drug interruptions are reported on the 
Drug Interruption Log eCRF.
A summary of extent of exposure to IP treatment for the Safety populationwill include overall 
treatment duration,dose modifications, and treatment compliance,asdefined inSection9.1,
Section9.2, andSection9.3.The summary will be presented by treatment/cohort and in Total 
RPC1063 1 mg. Individual datalistings will also be provided.
9.1.
TreatmentDuration
Additional investigational drug maybe dispensed topatients at Week 10visit(I3) who will 
continue with maintenance period but could not complete the first maintenance visit (M1)on the 
same day as I3. To account for this possibility of extended IP treatment, overall IP treatment 
duration (TDUR_IP) will be defined as:
the total number of days from the date of first dose to the date of last dose as reported on 
the End of Study eCRFfor patients who do not enter MP,or 
the total number of days from the date of first dose to the date beforeonsite dosing for 
MP for patients who enterMP.  
If the date of last IP dose is incomplete, see imputation method in Appendix2before calculating 
treatment duration.Overall IP treatment duration will be summarized descriptively.
9.2.
Dose Modifications
Dose modifications as reported on the Drug Log, Drug Interruption Log, and Drug Overdose Log 
eCRFs will be used in summaries. Patientswith any IP drug overdose, anyIP druginterruption, 
anyIP drug interruption of at least 14 dayswill be summarized by numberand percentage, 
respectively. The total number of drug overdoses and total number and percentage of AEs as a 


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result of overdose will be summarized. Duration of drug interruption will be summarized 
descriptively. The number and percentage of patients will be summarized by duration of drug 
interruption category (<7 days, 7-<14 days, ≥14 days). The total number of drug interruptions 
and reasons for interruptionwill be summarized.
9.3.
Treatment Compliance 
Treatmentcompliancefor IPwill be calculated for each patientby taking into account whether a 
patienttakes all doses of investigational drugas instructed. 
For subjects undergoing dose escalation, the total number of capsules expected to be taken by a 
patient is calculated as follows:
Last dose date –first dose date + 4 (+ 1 to account for the number of days between those dates 
inclusive and +3 to account for 3 extra capsules taken during dose escalation on Study Days 5-7)
If a patient discontinues trial during or prior to Study Days 5-7 during which2 capsules per day 
are taken, then the number of capsules expected will be adjusted accordingly.For example, if 
discontinuing on Day 5, then +1; on Day 6, then +2; on Day 7 or after, then +3.
The total number of IP capsules actually takenbya patient is defined as the total number of 
capsules dispensed –total number of capsules returned during IP, as reported on the Drug Log 
eCRFs.The overallIPtreatment compliance (%)will be calculated as the total number of IP 
capsules taken divided bythe total number of IP capsules expected and multipliedby 100.If the 
bottle is not returned by the patientat a visit, thenthe subject is considered to have returned zero 
pill from the unreturned bottle in the treatment compliance calculation.
The total number of IP capsules expected,actually takenand overall IP treatment compliance 
will be calculatedand summarizedafter taking into account all such visits at which the bottle is 
not returned.
Additionally, the number and percentage of patients will be summarized by category (<50%, 
50% to <60%, 60% to <70%, 70% to <80%, 80% to 100%, and >100%). Two additional 
categories (<80% and >120%) will also be included.


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10.
PROTOCOL DEVIATIONS/VIOLATIONS
Deviations and violations from the protocol will be recorded appropriately. Protocol deviations 
will be classified into, but not necessarily limited to, the following categories:
Excludedconcomitant medication
Informed consent
Other/GCP issue
Randomization procedure
Selection criteria not met (i.e., violation of inclusion/exclusion criteria)
Serious adverse event reporting
Study procedure
Treatment deviation
Visit scheduling
Classification of deviations as major protocol deviations/violations and decisions regarding 
exclusion of patients from the PP will be decided ona case-by-case basis without knowledge of 
the treatment assigned and before database lock or Cohort 1 unblinding. Major protocol 
deviations will be presented in a summary table by protocol deviation category. All protocol 
deviations will belisted. Major protocol deviations that exclude patients from the PP population 
will be summarized separately.
Besides the listing for patients excluded from the PP population with reason as specified in
Section5.2, a separatelisting will be created for patients who have met TFR during IPand thus 
excluded from PP population. This listing willincludethe date and study day of their first 
occurrence ofconfirmed TFR, andrelevant description (e.g.,medication name, indication, 
dose/frequency, Baseline dose/frequency, duration of use, or medical procedure name). This 
listing will also include the date and study day of their first IP dose, and the date and study day 
of their W10 endoscopy (if available). This listingwill bereviewed, confirmed, andfinalized 
before database lockor Cohort 1 unblinding. See detail about treatment failure rules data review 
in Appendix1.3.


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11.
SAFETY ANALYSIS
All analyses of safety data will be conducted using the Safety population by treatment/cohort and 
in Total RPC1063 1 mgunless specified otherwise. Individual data listings will also be provided.
General conventions on data reporting and analysis regarding reporting formats, definitions of 
Baseline, change, percent change, analysis visit window, and treatment failure rules can be found 
in Appendix1. Analysis visits will be assigned for laboratory, vital signs, ECG, and pulmonary 
function test (PFT) dataas per Appendix1.3. 
No imputation of missing safety data will be performed except in the case of incomplete 
onset/stopdatesfor AEs, prior and concomitant medications(Appendix2).
11.1.
Adverse Events
AEswill 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.
Aserious adverse event (SAE)is any untoward medical occurrence that at any dose results in 
death, is life-threatening, requires inpatient hospitalization or prolongation of existing inpatient 
hospitalization, results in persistent or significant disability/incapacity, is a congenital 
abnormality/birth defector is an important medical event that may not beimmediately 
life-threatening or result in death or hospitalization but jeopardize the patient ormay require 
intervention to prevent one of the other outcomes listed in the definition above.
A treatment-emergent adverse event (TEAE) is any AEthat emerges during treatment having 
been absent pre-treatment, or worsens relative to the pre-treatment state, excluding those with 
onset after first MP dose.
An overall summary of TEAEs during IP will include the number andpercentage of patients 
with
  ≥ 1 TEAE   
  ≥ 1 Moderate or Severe TEAE
  ≥ 1 Severe TEAE
  ≥ 1 Possible, Probable or Related TEAE
  ≥ 1 Related TEAE
  ≥ 1 Serious TEAE
  ≥ 1 Possible, Probable or Related Serious TEAE
  ≥ 1 Related Serious TEAE


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  ≥ 1 TEAE Leading to Discontinuation of Study Drug
  ≥ 1 TEAE Leading to Interruption of Study Drug
  Death 
  Death Related to Study Drug
TEAEswill also be summarized and presented by decreasing frequency in the sort keys belowin 
theCohort 1 RPC10631 mg group:
by system organ class andpreferred term: all TEAEs, related TEAEs, severe TEAEs, 
serious TEAEs, possible, probable or relatedserious TEAEs, TEAEs leading to 
interruptionof study drug, TEAEs leading to discontinuation of study drug
by preferred term: all TEAEs, TEAEs with ≥2% higher incidence rate in RPC 1 mg than 
placebo, TEAEs with incidence rate ≥5%, TEAEs with incidence rate ≥2%
by systemorgan class, preferred term, and maximum severity: all TEAEs
Patients with multiple events reported for the same summary level will be counted onlyonce.
11.2.
Adverse Events of Special Interest
Potential AEs that may be a consequence of S1P1R modulation will be closely monitored during 
the trial. These AEs includebradycardia, heart conduction abnormalities (2nd degree and higher 
AV block), macular edema, malignancy, serious or opportunistic infection, pulmonary effects, 
and hepatic effects.TEAEs of special interest (AESI)adjudicated by the safety review teamper 
the safety management planwill be summarized by criterion(cardiac, pulmonary, elevated ALT, 
macular edema, infection, and malignancy)asreported on the Adverse Events eCRFand
preferred term.Patients with multiple events reported for the same summary level will be 
counted onlyonce.
11.3.
Deaths
All patient deaths during this trial will be collected and presented in a listing. The listing will 
includetreatment group, period of death, date and study day of last IP dose, date and study day 
of death, days from last dose, system organ class, preferred term and verbatim of the fatal AE.
11.4.
Clinical Laboratory Evaluations
Laboratory assessments will be performed by a central laboratory. All summaries will be based 
on the standard international (SI) units provided by the central lab.Each patient’s hematology, 
blood chemistry, and urinalysis values will be flagged as “low”, “normal”, or “high” relative to 
the normal ranges of the central laboratory. Results from certain laboratory assessments are 
blinded as perSection6.7.


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47
Summary statistics of observed values, changeandpercentchanges from Baseline in numeric 
laboratory parameters will be provided by visit (Baseline, Week 5
[hematology/chemistry/pregnancy only], Week 10, highest value post-baseline during IP, lowest 
valuepost-baseline during IP, last available measurement while on treatmentduring IP). For 
each laboratory parameter, frequency summaries of categorical shiftsfrom Baseline to each post-
Baselinetime point(Week 5[hematology/chemistry/pregnancy only], Week 10,and last 
available measurement while on treatmentduring IP)will be provided.For select laboratory 
parameters (ALC, ANC, WBC, AST, ALT), frequency summaries of patients with abnormalities
will be summarized by visit (Baseline, Week 5[hematology/chemistry/pregnancy only], Week 
10, last available measurement while on treatment during IP)and overall.
All laboratory data will be listed, including unscheduled/repeat visits. Unscheduled visitswill be 
included in the calculation of Baseline, highest/lowest/last availableon treatment/anytimepost-
Baselinevalue. 
For each laboratory test, individual patientswith any values outside the standard reference range 
will have all their test results listed.
Hematology
The following laboratory parameters will be included inhematology summary tables: red blood 
cell (RBC) count, total and differential white blood cell (WBC) count (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils), platelet count, hemoglobin (HGB), hematocrit, mean 
corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular 
hemoglobin concentration (MCHC). 
The number and percentage of patients with abnormalities in hematology assessments, defined as 
ALC < 200 cells/µL, ALC < 500 cells/µL, ANC < 1,000 cells/µL, and total WBC > 20,000 
cells/µL will be summarizedoverall and by visit post-Baseline.Patients with at least one 
abnormalityin ALC, ANC or total WBC defined above will be listed. 
Blood Chemistry
The following laboratory parameters will be included in thebloodchemistry summary tablesat 
the screening visit: sodium, potassium, chloride, calcium, magnesium, phosphate, blood urea 
nitrogen(BUN), glucose, hemoglobin A1c, albumin, alkaline phosphatase, creatinine, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyltransferase (GGT), 
total bilirubin, conjugated bilirubin, total cholesterol, triglycerides, high-density lipoprotein 
(HDL), low-density lipoprotein (LDL), and C-reactive protein (CRP). For all other visits the tests 
will include BUN, hemoglobin A1c, albumin, alkaline phosphatase, creatinine, ALT, AST, GGT, 
total bilirubin, conjugated bilirubin, and CRP.  


EDMS Doc. Number: 23867102 - 23530353
Celgene Corporation
Statistical Analysis Plan (Induction Period, Cohorts 1 and 2), V4.0
Protocol: RPC01-3101
Date: 6/18/2019
Confidential and Proprietary
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The number and percentage of patients with abnormalities in ALT and AST, defined as > 1 x 
ULN, ≥2 x ULN, ≥3 x ULN, ≥4 x ULN, ≥5 x ULN, ≥8 x ULN, and ≥10 x ULN will be 
summarizedby overall and by visit post-Baseline.
Patients with at least one ALT or AST that is ≥ 3 x ULN will be listed showing all LFTs (ALT, 
AST, total bilirubin, direct bilirubin, alkaline phosphatase, and GGT) observed across all visits.
Evaluation of drug-induced serious hepatotoxicity (eDISH) plots of maximum ALT/AST values 
versus Total Bilirubin will be presented for assessment of potential Drug Induced Liver Injury 
(DILI).Total bilirubin value will be taken from the same visit at which maximum ALT/AST is 
observed.If maximum ALT/AST is reached at multiple visits, then the highest total bilirubin 
value from those visits will be plotted.
Urinalysis
The following laboratory parameters will be included for urinalysis: leukocytes, specific gravity, 
bilirubin, blood, glucose, ketones, pH, protein, and urobilinogen.
Serum pregnancy and serology testing
Serum β-human chorionic gonadotropin (hCG) will be collected at Screening for females of 
childbearing potential. Serology testing will also be collected at Screening and will include 
immunoglobulin G (IgG) antibodies tovaricella-zoster virus (VZV), human immunodeficiency 
virus (HIV), immunoglobulin M (IgM) antibodies to hepatitis A virus (HAV), surface antigen of 
the hepatitis B virus (HBsAG), anti-hepatitis B core total antibodies (anti-HBc total), hepatitis B 
virus deoxyribonucleic acid (HBV DNA), and anti-hepatitis C virus (HCV) IgG/IgM.  
Serum pregnancy results and serology testing results at Screening will be listed only.
11.5.
Vital Sign Measurements
Systolic and diastolic blood pressure (SBP and DBP) and pulse (HR) will be assessed in a sitting 
position and collected at each visit.On Day 1 of treatment for the IP, careful cardiac monitoring 
of the patients is required. 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. For the hourly measurements after investigational drug administration, HR and sitting 
blood pressure will be measured once and recorded in the eCRF.The first dose monitoring 
strategy should also be repeated at Day 5 or at Day 8 if any cardiac safety issues were observed 
on the previous Day of dose escalation.
Summary statistics of actualvalues and changes from Baseline in vital signswill be provided by 
visit(Baseline, Week 5, Week 10, highest value post-baseline during IP, lowest valuepost-
baseline during IP, last available measurement while on treatment during IP).On Day 1, hourly 


EDMS Doc. Number: 23867102 - 23530353
Celgene Corporation
Statistical Analysis Plan (Induction Period, Cohorts 1 and 2), V4.0
Protocol: RPC01-3101
Date: 6/18/2019
Confidential and Proprietary
49
changes from predose up to hour 6 in blood pressures and HRs will be summarized for all 
patients.
Patient’s lowest heartrate during 6-hour cardiac monitoring on Day 1 will be summarized by 
number and percentage bycategory: ≥65, 60-64, 55-59, 50-54, 45-49, 40-44, 35-39, <35 bpm, as 
well as <40 bpm and <45 bpm.
The number and percentage of patients requiring extended cardiac monitoring beyond hour 6 on 
Day 1 or requiring monitoring on Study Days 5 and/or 8 will be summarized by Day: Day1, 
Day5, and Day8.A listing of these patients will be presentedthat shows the hourly change from 
the pre-dose assessment at each of the available Baseline, Study Day 5, and Study Day 8 visits 
by patient for HR and blood pressures. 
The number and percentage of patients with clinically relevant abnormalities defined below will 
be summarized overall and by visit (Week 5, Week 10, last available while on treatmentduring 
IP) and overall.The denominator will be the number of patients with observed data at both 
Baseline and respective post-Baselinevisit, unless specified otherwise.
SBP: 
o >140 mmHg post-Baseline
o >160 mmHg post-Baseline
o >180 mmHg post-Baselineoran increase from baselineof >40 mmHg
>180 mmHg post-Baseline(denominator will be the number of patients 
with Baseline SBP ≤180)
an increase from Baseline of >40 mmHg
o <90 mmHg post-Baselineora decrease from Baseline of >30 mmHg
<90 mmHg post-Baseline 
<90 mmHg post-Baseline(denominator will be the number of patients 
with Baseline SBP ≥90)
a decrease from Baseline of >30 mmHg
DBP:
o >90 mmHg post-Baseline
o >100 mmHg post-Baseline
o >105 mmHg post-Baselineoran increase from Baseline of >30 mmHg


EDMS Doc. Number: 23867102 - 23530353
Celgene Corporation
Statistical Analysis Plan (Induction Period, Cohorts 1 and 2), V4.0
Protocol: RPC01-3101
Date: 6/18/2019
Confidential and Proprietary
50
>105 mmHg post-Baseline(denominator will be the number of patients 
with Baseline DBP ≤105)
an increase from Baseline of >30 mmHg
o <50 mmHg post-Baselineora decrease from Baseline of >30 mmHg
<50 mmHg post-Baseline
<50 mmHg post-Baseline(denominator will be the number of patients 
with Baseline SBP ≥50)
a decrease from baseline of >30 mmHg
HR:
o >100 bpm post-Baseline
o >120 bpm post-Baselineoran increase from baseline of >20 bpm
>120 bpm post-Baseline(denominator will be the number of patients with 
Baseline HR ≤120)
an increase from Baseline of > 20 bpm
o <60 bpm post-Baseline
o <45 bpm post-Baselineor a decrease from Baselineof >20 bpm
<45 bpm post-Baseline(denominator will be the number of patients with 
Baseline HR ≥45)
a decrease from Baseline of > 20 bpm
The number and percentage of patients with clinically relevant abnormalities during cardiac 
monitoring, including those beyond hour 6 on Day 1, will be summarized overalland by hour 
during pre-defined 6-hour monitoring window on Day 1, as well as overall during cardiac 
monitoring (Days 1/5/8),. The denominator will bethenumber of patients with observed data at 
both Baseline and respective post-Baselinetimepoint.
Discharge Status eCRF data after receiving extended cardiac monitoring after 6 hours will be 
summarized by number and percentageof patients.All data reported on the Discharge Status 
eCRF will be listed, including the reason for extended monitoring.
Box plots will be provided to display the distribution of vital signs results by timepoint on Day 1
up to hour 6, or byvisit. In addition, line plots of means and SEs will be created to display the


EDMS Doc. Number: 23867102 - 23530353
Celgene Corporation
Statistical Analysis Plan (Induction Period, Cohorts 1 and 2), V4.0
Protocol: RPC01-3101
Date: 6/18/2019
Confidential and Proprietary
51
actual valuesandchange from pre-dose by timepoint on Day 1up to hour 6. Line plots of means 
and SEs will also be created to display the actual values and change from Baseline by visit.
11.6.
Physical Examination
Physical examination results will be listed only.Patients with at least one dermatological 
abnormality will be listed.
 
 
 
11.8. 
Electrocardiograms
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.
Summary tables including actual values and change from Baseline will be presented for ECG 
resultsby visit (Baseline, Day 1 Hour 6, Week 10, last available measurement while on treatment 
during IP). An ECG outlier analysis will be performedby visit (Baseline, Day 1 Hour 6, Week 
10, last available measurement while on treatment during IP) and overallshowing the proportion 
of patients with QT >450 milliseconds (ms), QT > 480 ms, QT > 500 ms, QTcF > 450 ms, 
QTcF > 480 ms, QTcF > 500 ms, change from Baseline in QT of >30 ms, change from Baseline 
in QT of >60 ms, change from Baseline in QTcF of >30 ms, and change from Baseline in QTcF 
of >60 ms. The overall interpretation of the ECG results (normal; abnormal,probably non-
significant; and abnormal, possiblysignificant) will be summarizedin the same table.The 
denominator will be the number of patients with result (actual value or change)at the respective 
visit.
11.9.
Pulmonary Function Tests
The following pulmonary function tests (PFT) are performed at screening and Week 10: forced 
expiratory volume in 1 second (FEV1),forced vital capacity(FVC), percent of predicted FEV1, 
percent of predicted FVC, and if locally available, diffusioncapacity of the lung for carbon 
monoxide(DLCO). Summarytables including actual values, change, and percent changefrom 
Baseline will be presented for PFT resultsby visit (Baseline, Week 10, last available 


EDMS Doc. Number: 23867102 - 23530353
Celgene Corporation
Statistical Analysis Plan (Induction Period, Cohorts 1 and 2), V4.0
Protocol: RPC01-3101
Date: 6/18/2019
Confidential and Proprietary
52
measurement while on treatment during IP). DLCO results in domestic unit (mL/min/mmHg) 
will be converted to SI unit (mmol/min/kPa) prior to analysis using the following conversion 
factor:
DLCO in SIunit = (DLCO in domestic unit) / 2.986
Patients with at least one FEV
1or FVC < 70% predicted will be listed showing all PFTs 
observed across all visits.Data collected on the DLCO eCRF will be listed separately. 
 
 
 


EDMS Doc. Number: 23867102 - 23530353
Celgene Corporation
Statistical Analysis Plan (Induction Period, Cohorts 1 and 2), V4.0
Protocol: RPC01-3101
Date: 6/18/2019
Confidential and Proprietary
53
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


EDMS Doc. Number: 23867102 - 23530353
Celgene Corporation
Statistical Analysis Plan (Induction Period, Cohorts 1 and 2), V4.0
Protocol: RPC01-3101
Date: 6/18/2019
Confidential and Proprietary
54