Clinical trial NCT01647516
Conditions: Ulcerative Colitis
Sponsor: Celgene
Start date: 2012-12-26; Completion date: 2019-08-30
Enrollment: 199 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:

Arms: arm 1: Participants received 0.5 mg capsules of ozanimod hydrochloride daily during the induction period weeks 0-9 (an initial 8-day dose escalation regimen in the induction period that consisted of 4 days of ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg), followed by 3 days of ozanimod HCl 0.5 mg, (equivalent to ozanimod 0.46 mg) followed by the assigned treatment level for at least 8 weeks. Participants who completed the induction period and were responders at week 8, continued to receive the same dose of ozanimod during the maintenance period up to week 32. Participants who received ozanimod 0.5 mg capsules and completed the induction period and were non-responders at Week 8 and who completed the maintenance period or experienced a disease relapse, were given the option to enter the OLP and receive 1 mg ozaninod capsules daily up to 6 years. Participants who had not shown clinical improvement 8 weeks after initiation of the OLP were discontinued from the study. arm 2: Participants received 1 mg capsules of ozanimod hydrochloride daily during the induction period weeks 0-9 (an initial 8-day dose escalation regimen in the induction period that consisted of 4 days of ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg), followed by 3 days of ozanimod HCl 0.5 mg, (equivalent to ozanimod 0.46 mg) followed by the assigned treatment level for at least 8 weeks. Participants who completed the induction period and were responders at week 8, continued to receive the same dose of ozanimod during the maintenance period up to week 32. Participants who received ozanimod 1 mg capsules and completed the induction period and were non-responders at Week 8 and who completed the maintenance period or experienced a disease relapse, were given the option to enter the OLP and receive 1 mg ozaninod capsules daily up to 6 years. Participants who had not shown clinical improvement 8 weeks after initiation of the OLP were discontinued from the study. arm 3: Identically matching placebo capsules daily for 32 weeks followed by an optional open label treatment period.
Interventions: intervention 1: Ozanimod intervention 2: Placebo
Intervention descriptions: intervention 1: Ozanimod capsules by mouth daily. intervention 2: None

Protocol documents:
Prot_000.pdf: 
EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
03 May 2019 (Version 10.0) 
CONFIDENTIAL
1
A PHASE 2, MULTI-CENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED PARALLEL-GROUP STUDY TO EVALUATE THE 
CLINICAL EFFICACY AND SAFETY OF INDUCTION THERAPY WITH RPC1063 IN 
PATIENTS WITH MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS
Test Drug: RPC1063
Protocol Number: RPC01-202
Study Phase:  Phase 2
IND/EudraCT number:  115,243/2012-003123-38
Date and Version: 03 May 2019 (Version 10.0)
Replaces Version:  29 May 2018 (Version 9.0)
Sponsor:
Celgene International II Sàrl
Rue du Pré-Jorat 14
2108 Couvet Switzerland
Tel: + 41 32 864 69 01
Medical Monitor:
Ernesto Oviedo-Orta, MD, PhD, MBA
 
CONFIDENTIAL
This protocol is provided to you as an Investigator, potential Investigator, or 
consultant for review by you, your staff, and ethics committee/institutional 
review board. The information contained in this document is regarded as 
confidential and, except to the extent necessary to obtain informed consent, 
may not be disclosed to another party unless such disclosure is required by 
law or regulations. Persons to whom the information is disclosed must be 
informed that the information is confidential and may not be further 
disclosed by them.


EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
03 May 2019 (Version 10.0) 
CONFIDENTIAL
2
1.
SIGNATURES
Protocol RPC01-202, Version 10.0, was approved by:
Receptos Services LLC
{See appended electronic signature page}
Ernesto Oviedo-Orta, MD, PhD, MBA
Senior Director, Clinical Research & Development
Date




EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
03 May 2019 (Version 10.0)
CONFIDENTIAL
4
Declaration of Investigators
I have read and agree to the protocol RPC01-202 entitled ‘A Phase 2, multi-center, randomized, 
double-blind, placebo-controlled parallel-group study to evaluate the clinical efficacy and safety 
of induction therapy with RPC1063 in patients with moderately to severely active ulcerative 
colitis’ dated 03 May 2019 (Version 10.0). I am aware of my responsibilities as an Investigator 
under the guidelines of GCP, local regulations (as applicable) and the study protocol.  I agree to 
conduct the study according to these responsibilities and to appropriately direct and assist the 
staff under my control, who will be involved in the study.
Clinical Site: 
Site Number:
Site Principal Investigator:
Print Name
Title
Signature
Date


EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
03 May 2019 (Version 10.0)
CONFIDENTIAL
5
2.
SYNOPSIS 
NAME OF SPONSOR:
Celgene International II Sàrl
(CIS II)
PROTOCOL No.: RPC01-202
NAME OF STUDY TREATMENT: RPC1063
TITLE OF STUDY: A Phase 2, multi-center, randomized, double-blind, placebo-controlled parallel-group 
study to evaluate the clinical efficacy and safety of induction therapy with RPC1063 in patients with 
moderately to severely active ulcerative colitis
PLANNED NUMBER OF STUDY CENTERS: It is planned to initiate approximately 80 study centers to 
enroll patients in North America, Europe, and Asia Pacific.
PHASE OF DEVELOPMENT: 2
PLANNED STUDY DATES: The planned duration of the study is from October 2012 through December 
2019.
OBJECTIVES: 
Primary Objective: The primary objective of the study is to compare the efficacy of RPC1063 vs placebo 
for induction of clinical remission at Week 8 in patients with moderately to severely active ulcerative colitis 
(UC)
Secondary Objectives: The secondary objectives are to:

Compare the efficacy of RPC1063 vs placebo at weeks 8 and 32 as measured by clinical response, 
clinical remission, and mucosal healing

Compare the overall safety and tolerability of RPC1063 vs placebo for the duration of the study
 
STUDY DESIGN AND METHODOLOGY:  Study RPC01-202 is a Phase 2, multi-center, randomized, 
double-blind, placebo-controlled, parallel-group study in patients with moderately to severely active UC.
This study includes 3 periods (Screening, Induction, and Maintenance) and an optional Open-Label 
Treatment Period (OLP).  Following the 5-week Screening Period, eligible patients will be randomized and 
enter the 9-week placebo-controlled Induction Period (IP).  Patients who are responders at Week 8 will
continue on their assigned treatment in the 24-week Maintenance Period (MP).  Non-responders at Week 8 
have the option to enter the OLP.  Patients who complete the MP will be given the option to participate in 
the OLP. Patients that enter the MP and experience disease relapse will also have the option to enter the 
OLP.
The study will include both patients that have received anti-TNF therapy and those that have not. It is 
anticipated that approximately 50% of the patients included in the study will have received anti-TNF 
therapy.  
Induction Period (IP):  The IP will serve as a dose-finding study to assess the efficacy and safety of 
RPC1063 for the induction of clinical response, remission, and mucosal healing in patients with moderately
to severely active UC.  The IP will last 9 weeks and consists of dose escalation over 8 days followed by the 
full dose for 8-weeks.
Approximately 180 patients will be randomized in a 1:1:1 ratio to receive 1 of 3 treatment regimens:

RPC1063/ozanimod HCl 0.5 mg (equivalent to ozanimod 0.46 mg) daily oral capsule

RPC1063/ozanimod HCl 1 mg (equivalent to ozanimod 0.92 mg) daily oral capsule

Placebo daily oral capsule


EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
03 May 2019 (Version 10.0)
CONFIDENTIAL
6
The randomization will be stratified by prior anti-TNF therapy experience (yes versus no).
For patients randomized to one of the active treatment groups, there will be an 8-day dose escalation
regimen in the IP consisting of 4 days of treatment with RPC1063/ozanimod HCl 0.25 mg (equivalent to 
ozanimod 0.23 mg), followed by 3 days of treatment with RPC1063 0.5 mg, followed by the assigned 
treatment level.
Maintenance Period (MP):  All patients who complete the IP and are responders at Week 8 of the IP will 
enter the 24-week MP.  Patients will continue to receive the same investigational drug in the MP as
received during the IP, and individual patient treatment will remain blinded until all patients have reached 
Week 32.  The last visit in the MP will occur at Week 32.  Patients who complete the MP will be given the 
option to participate in the OLP. Patients that enter the MP and experience disease relapse will have the 
option to enter the OLP.
Disease relapse is defined as when all of the following criteria are met:

An increase in UC disease activity as defined by an increase in partial Mayo score of 2 points 
compared to the Week 8 partial Mayo score with an absolute partial Mayo score 4 points

An endoscopic subscore of 2 points

Exclusion of other causes of an increase in disease activity unrelated to underlying UC 
(e.g., infections, change in medication)
Open-Label Treatment Period (OLP):  Patients who complete the IP and are non-responders at Week 8
and those that complete the MP or experience disease relapse during the MP will have the option to enter 
the OLP.  All patients in the OLP will receive daily study treatment with RPC1063 1 mg.  There will be an
8-day dose escalation regimen consisting of 4 days of treatment with RPC1063 0.25 mg, followed by 
3 days of treatment with RPC1063 0.5 mg, followed by RPC1063 1 mg. Patients who have not shown 
clinical improvement 8 weeks after initiation of the OLP should discontinue from the study. Eligible 
patients will be transitioned into the Phase 3 open-label extension UC Study RPC01-3102 and will be able 
to immediately enter the study (without completing the 30-day or 90-day Safety Follow-up Visits).  The 
OLP will continue for up to 6 years or until marketing approval of RPC1063 for UC in the country of the 
clinical site (estimated to be in 2019), or completed transition of patients to Study RPC01-3102, or until the 
Sponsor discontinues the development program.
Safety Monitoring/Follow-up:  
Potential adverse events (AEs) of interest that may be a consequence of sphingosine 1-phosphate 1 
receptor 1 (S1P1) modulation will be closely monitored during the study. These AEs include bradycardia, 
heart conduction abnormalities, pulmonary toxicity, macular edema, cutaneous malignancy, serious or 


EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
03 May 2019 (Version 10.0)
CONFIDENTIAL
7
opportunistic infection and hepatotoxicity.  A Data Monitoring Committee (DMC) for the study will 
perform safety reviews periodically, approximately four times a year until the end of the Maintenance 
Period.
The safety of patients will be monitored by collection of treatment-emergent AEs, serious adverse events 
(SAEs), physical exams, vital signs, Holter monitoring, electrocardiograms (ECGs), pulmonary function 
tests, optical coherence tomography (OCT), blood chemistry and hematology panels, coagulation panels, 
and urinalysis at baseline and various time points during the study.  White blood cell (WBC) counts and 
lymphocyte counts will be monitored centrally (and will not be provided to the site) to prevent potential 
unblinding of the Investigator.  Patients who discontinue from treatment due to lack of response, AEs, or 
other reasons, even if alternative treatment is given, will be followed for 90 days for collection of safety 
data and for the assessment of their disease status.
STUDY POPULATION AND MAIN CRITERIA FOR INCLUSION/EXCLUSION: 
Inclusion Criteria: 
1.
Male or female patients aged 18 to 75 years, inclusive
2.
Have had UC diagnosed at least 2 months prior to screening.  The diagnosis of UC must be confirmed 
by endoscopic and histologic evidence
3.
Have active UC confirmed on endoscopy with ≥15 cm involvement 
4.
Have active UC defined as Mayo score of 6-12 inclusive with endoscopic subscore of ≥2  
5.
Have undergone colonoscopy or sigmoidoscopy within the past 2 years for extent of disease, and if 
the UC has been present for > 10 years, have had a colonoscopy with biopsy to rule out dysplasia
6.
Female patients of childbearing potential:
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 

placement of an intrauterine hormone-releasing system 

bilateral tubal occlusion

vasectomised partner

sexual abstinence 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods of 
contraception. 
7.
Must be currently receiving treatment with at least 1 of the following therapies:
a.
Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, balsalazide) for at least 6 
weeks with the dose stable for at least 3 weeks prior to screening endoscopy
b.
Prednisone (doses ≤30 mg) or equivalent for at least 4 weeks and receiving a stable dose for at 
least 2 weeks
8.
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
9.
All patients aged 45 or over must have had a colonoscopy to screen for adenomatous polyps within 
5 years prior to the first dose of investigational drug or must have had a colonoscopy at screening to 
assess for polyps.  The adenomatous polyps must be removed prior to their first dose of 
investigational drug.
10. Ability to provide written informed consent and to be compliant with the schedule of protocol 
assessments


EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
03 May 2019 (Version 10.0)
CONFIDENTIAL
8
11. Patients must have documentation of positive Varicella Zoster virus (VZV) IgG antibody status or 
complete VZV vaccination at least 30 days prior to randomization
12. Documentation of no evidence of chronic lung disease or tuberculosis (TB) on a chest X-ray 
completed within the 6 months prior to screening.  If a chest X-ray was not done in the 6 months 
preceding the Screening visit, it may be performed during the Screening visit
Exclusion Criteria: 
Exclusions Related to General Health:
1.
Have severe extensive colitis as evidenced by: 

Physician judgment that the patient is likely to require colectomy or ileostomy within 12 weeks of 
baseline

Current evidence of fulminant colitis, toxic megacolon or bowel perforation

Previous total colectomy

Have 4 or more of the following:  

Temp > 38°C

Heart rate (HR) > 110 (bpm)

Focal severe or rebound abdominal tenderness

Anemia (hemoglobin [Hgb] < 8.5 g/dL)

Transverse colon diameter > 5 cm on plain X-ray
2.
Diagnosis of Crohn’s disease or indeterminate colitis or the presence or history of a fistula consistent 
with Crohn’s disease
3.
Have positive stool culture for pathogens (O+P, bacteria) or positive test for C. difficile at screening.  
If C. difficile is positive, the patient may be treated and retested
4.
Have had treatment with cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) within 
16 weeks of screening
5.
Pregnancy, lactation, or a positive serum beta human chorionic gonadotropin (hCG) measured during 
screening
6.
Clinically relevant hepatic, neurological, pulmonary, ophthalmological, endocrine, psychiatric or 
other major systemic disease making implementation of the protocol or interpretation of the study 
difficult or that would put the patient at risk by participating in the study
7.
Clinically relevant cardiovascular conditions, including history or presence of:
i.
Recent (within the last 6 months) occurrence of myocardial infarction, unstable angina, 
stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, 
Class III/IV heart failure, sick sinus syndrome, or severe untreated sleep apnea
ii.
Prolonged QTcF interval (QTcF > 450 msec males, > 470 msec females), or at additional 
risk for QT prolongation (e.g., hypokalemia, hypomagnesemia, congenital long-QT 
syndrome)
iii.
Patients with other pre-existing stable cardiac conditions who have not been cleared for 
the study by an appropriate cardiac evaluation by a cardiologist
8.
Resting HR less than 55 beats per minute (bpm) when taking vitals as part of a physical exam at 
Screening
9.
History of diabetes mellitus type 1, or uncontrolled diabetes mellitus type 2 with hemoglobin 
A1c > 7% , or diabetic patients with significant co-morbid conditions such as retinopathy or 
nephropathy
10. History of uveitis
11. Known active bacterial, viral, fungal, mycobacterial infection or other infection (including TB or 
atypical mycobacterial disease [but excluding fungal infection of nail beds]) 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 prior to screening
12. History of recurrent or chronic infection (e.g., hepatitis B or C, human immunodeficiency virus 
[HIV], syphilis, TB); recurring urinary tract infections are allowed
13. History of cancer, including solid tumors and hematological malignancies (except basal cell and in 
situ squamous cell carcinomas of the skin that have been excised and resolved)
14. History of alcohol or drug abuse within 1 year prior to randomization


EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
03 May 2019 (Version 10.0)
CONFIDENTIAL
9
15. History of or currently active primary or secondary immunodeficiency
Exclusions Related to Medications:
16. History of treatment with a biologic agent within 5 half-lives of that agent prior to randomization
17. History of treatment with an investigational agent within 5 half-lives of that agent prior to 
randomization
18. History of treatment with topical rectal 5-ASA or steroids within 2 weeks of screening
19. Receipt of a live vaccine or attenuated live vaccine within 4 weeks prior to randomization
20. Previous treatment with lymphocyte-depleting therapies (e.g., Campath, anti-CD4, cladribine, 
rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, total body irradiation, bone marrow 
transplantation, alemtuzumab, daclizumab)
21. Previous treatment with D-penicillamine, leflunomide or thalidomide
22. Previous treatment with natalizumab or fingolimod
23. History of treatment with intravenous immune globulin (IVIg), plasmapheresis, within 3 months prior 
to randomization
24. Planned concurrent treatment with immunosuppressive agents (e.g., azathioprine, 6-MP, or 
methotrexate) after randomization.  Subjects receiving azathioprine, 6-MP or methotrexate at 
screening must discontinue treatment with these agents prior to dosing with investigational drug.
25. Treatment with Class Ia or Class III anti-arrhythmic drugs or treatment with two or more agents in 
combination known to prolong PR interval
26. Treatment with any of the following drugs or interventions within the corresponding timeframe:

At randomization

CYP2C8 inhibitors (eg, gemfibrozil or clopidogrel) or inducers (eg, rifampicin)

Two weeks prior to randomization

Monoamine oxidase inhibitors (eg, selegiline, phenelzine)
Exclusions Related to Laboratory Results:
27. Serum creatinine 1.4 mg/dL for women or 1.6 mg/dL for men
28. Liver function impairment or persisting elevations of aspartate aminotransferase (AST) or alanine 
aminotransferase (ALT) 2 times the upper limit of normal (ULN), or direct bilirubin 1.5 times the 
ULN
29. Platelet count 100,000/L
30. Hgb 8.5 g/dL
31. Neutrophils 1500 /L
32. Absolute WBC count  3500/L
33. Absolute lymphocyte count 800/L
34. ECG showing any clinically significant abnormality (e.g., acute ischemia, any significant heart 
conduction abnormality [e.g., left bundle branch block])
35. Forced expiratory volume at 1 second (FEV1) or forced vital capacity (FVC) < 70% of predicted 
values at screening
NUMBER OF PATIENTS:  Approximately 180 patients will be randomly assigned 1:1:1 on Day 1 to 1 of 3
treatment regimens (approximately 60 per treatment group)
STUDY TREATMENTS:  
IP 
On Day 1, patients will be randomly assigned 1:1:1 to 1 of 3 treatment regimens through Week 8:

RPC1063/ozanimod HCl 0.5 mg (equivalent to ozanimod 0.46 mg) oral capsule daily

RPC1063/ozanimod HCl 1 mg (equivalent to ozanimod 0.92 mg) oral capsule daily

Matching placebo oral capsule daily 
For patients randomized to one of the active treatment groups, there will be an 8-day dose escalation
regimen in the IP consisting of 4 days of treatment with RPC1063/ozanimod HCl 0.25 mg (equivalent to 
ozanimod 0.23 mg), followed by 3 days of treatment with RPC1063/ozanimod HCl 0.5 mg (equivalent to 
ozanimod 0.46 mg), followed by the assigned treatment level for at least 8 weeks.


EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
03 May 2019 (Version 10.0)
CONFIDENTIAL
10
MP
Patients will continue to receive the same investigational drug in the MP as received during the IP, and 
individual patient treatment will remain blinded until all patients have reached Week 32.
OLP
All patients in the OLP will receive daily oral study treatment with RPC1063/ozanimod HCl 1 mg
(equivalent to ozanimod 0.92 mg).  There will be an 8-day dose escalation regimen consisting of 4 days of 
treatment with RPC1063/ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg), followed by 3 days 
treatment with RPC1063/ozanimod HCl 0.5 mg (equivalent to ozanimod 0.46 mg), followed by 
RPC1063/ozanimod HCl 1 mg (equivalent to ozanimod 0.92 mg).
DURATION OF TREATMENT: 
IP: 9 weeks
MP: 24 weeks
OLP: Up to 6 years (or until marketing approval, or completed transition of patients to Study RPC01-3102, 
or discontinuation of the development program)
STUDY EVALUATIONS
Efficacy Endpoints: 
Primary Efficacy Endpoint: 

The primary endpoint is the proportion of patients in clinical remission at Week 8,  defined as a 
Mayo score of ≤2 points and with no individual subscore of > 1 point
Secondary Efficacy Endpoints:

Proportion of patients with a clinical response at Week 8, defined as a reduction from baseline in 
Mayo score of ≥3 points and ≥30%, and a decrease from baseline in the rectal bleeding subscore 
of ≥1 point or an absolute rectal bleeding subscore of ≤1 point

Change from baseline in Mayo score at Week 8 

Proportion of patients with mucosal healing at Week 8, defined by an endoscopy subscore of ≤1 
point  

Proportion of patients in clinical remission at Week 32 defined as Mayo score of ≤2 points with 
no individual subscore of > 1 point 

Proportion of patients with a clinical response at Week 32, defined as a reduction from baseline in 
Mayo score of ≥3 points and ≥30%, and a decrease from baseline in the rectal bleeding subscore 
of ≥1 point or an absolute rectal bleeding subscore of ≤1 point 

Proportion of patients with mucosal healing at Week 32, defined as an endoscopy subscore of 
≤1 point
 
 
 
 patients with histologic remission at Week 8 as determined by a Geboes index 
score < 2.0
Safety Endpoints:

The incidence and type of AEs, SAEs, AEs leading to discontinuation of investigational drug, 
target AEs of special interest, laboratory abnormalities, vital signs, ECG, and physical exam 
abnormalities 
Pharmacokinetic (PK) and Pharmacodynamic (PD) Endpoints: 

PK assessments will include PK sampling to determine plasma concentration of RPC1063 and 
active metabolites at scheduled assessments during the treatment period.

Absolute lymphocyte count (ALC) derived from blinded hematology laboratory results


EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
03 May 2019 (Version 10.0)
CONFIDENTIAL
11

Plasma protein biomarkers (cytokines, chemokines, other inflammatory proteins)

Stool culture for fecal biomarkers – fecal lactoferrin and calprotectin

Total immunoglobulins (Igs) - IgA, IgG, IgM
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 


EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
03 May 2019 (Version 10.0)
CONFIDENTIAL
12
3.
TABLE OF CONTENTS
1.
SIGNATURES.........................................................................................................2
2.
SYNOPSIS...............................................................................................................5
3.
TABLE OF CONTENTS........................................................................................12
4.
LIST OF ABBREVIATIONS.................................................................................17
5.
ETHICS..................................................................................................................20
5.1.
Ethics Committee ...................................................................................................20
5.2.
Ethical Conduct of the Study ..................................................................................20
5.3.
Patient Information and Consent.............................................................................20
6.
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ................22
7.
INTRODUCTION..................................................................................................26
7.1.
Disease Review ......................................................................................................26
7.2.
Investigational Drug RPC1063 Overview ...............................................................27
7.3.
Nonclinical Pharmacology and Toxicology.............................................................27
7.4.
Clinical Studies.......................................................................................................27
7.5.
Clinical Study Rationale .........................................................................................27
8.
STUDY OBJECTIVES AND ENDPOINTS...........................................................29
8.1.
Study Objectives.....................................................................................................29
8.1.1.
Primary Study Objective.........................................................................................29
8.1.2.
Secondary Study Objectives ...................................................................................29
8.1.3.
Exploratory Study Objectives .................................................................................29
8.2.
Endpoints ...............................................................................................................29
8.2.1.
Efficacy Endpoints .................................................................................................29
8.2.2.
Safety Endpoints.....................................................................................................30
8.2.3.
PK and PD Endpoints .............................................................................................30
9.
INVESTIGATIONAL PLAN .................................................................................31
9.1.
Overall Study Design and Plan ...............................................................................31
9.1.1.
Study Schematic and Schedule of Events................................................................33
9.1.2.
Additional Information ...........................................................................................40
9.1.2.1.
Adverse Events of Special Interest..........................................................................40
9.2.
Dose Rationale .......................................................................................................40
9.3.
Study Design Rationale ..........................................................................................41


EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
03 May 2019 (Version 10.0)
CONFIDENTIAL
13
9.4.
Study Duration .......................................................................................................41
9.5.
Study Population ....................................................................................................41
9.5.1.
Inclusion Criteria....................................................................................................41
9.5.2.
Exclusion Criteria...................................................................................................43
9.6.
Treatment ...............................................................................................................45
9.6.1.
Treatments Administered........................................................................................45
9.6.2.
Study Treatment After Missed Dose(s) ...................................................................46
9.6.3.
Study Treatment Formulation .................................................................................46
9.6.4.
Study Treatment Labeling and Packaging ...............................................................46
9.6.5.
Blinding of Study Treatment...................................................................................47
9.6.6.
Study Treatment Storage and Accountability ..........................................................47
9.6.6.1.
Study Treatment Storage.........................................................................................47
9.6.6.2.
Study Treatment Accountability .............................................................................47
9.6.7.
Guidelines for Dose Escalation (Induction or OLP) ................................................48
9.6.7.1.
Overview of Dose Escalation Schedule...................................................................48
9.6.7.2.
Day 1/1OLP Dose...................................................................................................48
9.6.7.3.
Cardiac Monitoring During Dose Escalation...........................................................49
9.7.
Withdrawal of Patients from Study Treatment and/or the Study..............................50
9.7.1.
Discontinuation of Study Treatment........................................................................50
9.7.2.
Withdrawal of Patients from the Study....................................................................51
9.8.
Prior and Concomitant Therapy ..............................................................................51
9.8.1.
Concomitant Medications and Therapy Prohibited Through the 30-Day 
Safety Follow-up Visit............................................................................................52
9.8.2.
Concomitant Medications Between the 30-Day Safety Follow-up Visit and 
the 90-Day Safety Follow-up Visit..........................................................................53
9.9.
Concomitant Procedures.........................................................................................53
9.10.
Treatment Compliance............................................................................................53
9.11.
Assignment to Treatment........................................................................................54
9.12.
Unblinding Procedures for Individual Patients........................................................54
10.
STUDY SCHEDULE .............................................................................................55
10.1.
Screening Period.....................................................................................................55
10.2.
Screening Failures and Rescreening of Patients ......................................................55
10.3.
Induction Period (IP) and Maintenance Period (MP)...............................................55


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10.4.
Open-Label Period (OLP).......................................................................................55
10.5.
Early Termination...................................................................................................56
10.6.
Unscheduled Relapse Assessment Visit ..................................................................56
10.7.
Study Stopping Rules .............................................................................................56
11.
METHODS OF ASSESSMENT.............................................................................57
11.1.
Efficacy Assessments .............................................................................................57
11.1.1.
Flexible Sigmoidoscopy/Colonoscopy....................................................................57
11.1.2.
Mayo Score ............................................................................................................57
11.2.
Clinical Safety Assessments ...................................................................................58
11.3.
Laboratory Safety Assessments...............................................................................61
11.4.
PK and PD Assessments.........................................................................................62
11.5.
Monitoring of Patients With Adverse Events of Special Interest .............................63
12.
SAFETY DEFINITIONS, MONITORING, AND REPORTING............................66
12.1.
Adverse Events.......................................................................................................66
12.2.
Serious Adverse Events ..........................................................................................67
12.3.
Reporting of Serious Adverse Events......................................................................68
12.4.
Monitoring of Patients with Adverse Events ...........................................................68
12.5.
Procedures to be followed in the Event of Abnormal Laboratory Test Values .........69
12.6.
Clinical Laboratory Parameters and Abnormal Laboratory Test Results..................69
12.7.
Abnormal Clinical Safety Findings .........................................................................70
12.8.
Treatment of Overdose of Study Treatment ............................................................70
12.9.
Procedures in Case of Pregnancy ............................................................................70
13.
DATA MANAGEMENT AND STATISTICAL ANALYSIS.................................72
13.1.
Data Management...................................................................................................72
13.2.
Sample Size Estimation ..........................................................................................72
13.3.
Statistical Analysis Plan..........................................................................................72
13.4.
Randomization........................................................................................................72
13.5.
Analysis Populations ..............................................................................................73
13.6.
Demographic and Baseline Data .............................................................................73
13.7.
Patient Disposition..................................................................................................73
13.8.
Efficacy Analysis....................................................................................................73
13.8.1.
Endpoints ...............................................................................................................73
13.8.2.
Primary Efficacy Analysis ......................................................................................74


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13.8.3.
Key Secondary Analyses ........................................................................................74
13.8.4.
Exploratory and Sensitivity Analyses......................................................................75
13.9.
Pharmacokinetics....................................................................................................76
13.10.
Safety.....................................................................................................................76
13.11.
Missing Data ..........................................................................................................76
13.12.
Interim Analysis .....................................................................................................76
13.13.
Data Monitoring Committee ...................................................................................76
14.
MONITORING PROCEDURES (QUALITY ASSURANCE)................................78
14.1.
Routine Monitoring ................................................................................................78
14.2.
Inspections and Auditing Procedures ......................................................................78
14.3.
Product Quality Complaint .....................................................................................78
15.
STUDY MANAGEMENT AND MATERIALS .....................................................80
15.1.
Electronic Case Report Forms.................................................................................80
15.2.
Data Collection.......................................................................................................80
15.3.
Source Documents Maintenance.............................................................................80
15.4.
Record Maintenance ...............................................................................................81
15.5.
Confidentiality........................................................................................................81
16.
ADMINISTRATION PROCEDURES....................................................................83
16.1.
Regulatory Approval ..............................................................................................83
16.2.
Protocol Amendments.............................................................................................83
16.3.
Protocol Adherence and Deviations ........................................................................83
16.4.
Publication Policy...................................................................................................84
16.5.
Clinical Study Report .............................................................................................84
16.6.
Contractual and Financial Details ...........................................................................84
16.7.
Insurance, Indemnity and Compensation.................................................................84
16.8.
Discontinuation of the Study...................................................................................84
16.9.
Study Center File Management...............................................................................84
17.
REFERENCE LIST................................................................................................86
18.
APPENDIX............................................................................................................88
18.1.
Appendix 1: Elements of Informed Consent............................................................88


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LIST OF TABLES
Table 1:
Schedule of Assessments and Procedures for Induction and Maintenance 
Periods ...................................................................................................................34
Table 2:
Schedule of Assessments and Procedures for the Optional Open-Label 
(OLP) Period ..........................................................................................................37
Table 3:
Dose Escalation Schedule for the RPC1063 and Placebo Treatment Groups ...........48
Table 4:
Cardiac Monitoring During Dose Escalation...........................................................50
Table 5:
Examples of Prohibited Cardiac Medications (Systemic) ........................................53
LIST OF FIGURES
Figure 1:
Study Schematic .....................................................................................................33


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4.
LIST OF ABBREVIATIONS 
5-ASA
5-aminosalicylate
6-MP
6-mercaptopurine
ACLS
Advanced Cardiac Life Support
ADME
absorption, distribution, metabolism and excretion 
AE
adverse event 
ALC
absolute lymphocyte count
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase 
AUC0-24
area under the plasma concentration-versus-time curve from time 0 to 
24 hours
AV
Atrioventricular
AZA
Azathioprine
BCRP
Breast Cancer Resistance Protein
BP
blood pressure (systolic/diastolic)
CFR
Code of Federal Regulations
Cl/F
total clearance
Cmax
observed values for maximum concentration
CMH
Cochran-Mantel-Haenszel
CRO
clinical research organization
CRP
C-reactive protein
DDI
Drug-drug interaction
DLCO
diffusion capacity of the lung for carbon monoxide
DMC
Data Monitoring Committee
EAE
experimental autoimmune encephalomyelitis
ECG
electrocardiogram
eCRF
electronic case report form
ET
early termination
FDA
Food and Drug Administration
FEV1
forced expiratory volume at 1 second
FVC
forced vital capacity
GCP
Good Clinical Practice
GGT
gamma glutamyltransferase
GMP
Good Manufacturing Practice
HBcAg
hepatitis B core antigen
HBsAg
hepatitis B surface antigen
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
Hgb
Hemoglobin
HIV
human immunodeficiency virus
HR
heart rate
IBD
inflammatory bowel disease
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IFN β-1a
interferon beta-1a


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Ig
Immunoglobulin
IND
Investigational New Drug
IP
Induction Period
IRB
Independent Review Board
ITT
intent-to-treat 
IUD
Intrauterine device
IUS
Interuterine-hormone releasing system
IV
intravenous/ly
IVIg
intravenous immune globulin 
IVRS
Interactive Voice Response System
LFT
liver function test
MCH
mean corpuscular hemoglobin 
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MITT
modified intent-to-treat
MMF
mycophenolate mofetil
MP
Maintenance Period
MS
multiple sclerosis
OCT
optical coherence tomography
OLP
Open-Label Period
PD
pharmacodynamic(s)
PFTs
pulmonary function tests (FEV1, FVC and DLCO)
PK
pharmacokinetic(s)
PP
per protocol
PQC
Product Quality Complaint
PT
prothrombin time
PTT
partial thromboplastin time
PVG
pharmacovigilance
QTcF
QT interval corrected for heart rate according to Fridericia's formula
RBC
red blood cell
RDC
remote data capture
RPR
rapid plasma regain
S1P1
sphingosine 1-phosphate 1 receptor
SAE
serious adverse event
SAP
Statistical Analysis Plan
t½
terminal half-life
TB
Tuberculosis
Tmax
time of maximum concentration
TNBS
trinitrobenzene sulfonic acid
TNF
tumor necrosis factor
TQT
thorough QT
UC
ulcerative colitis
ULN
upper limit of normal
US/USA
United States/United States of America
VZV
varicella zoster virus
WBC
white blood cell


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WMA
World Medical Association
WOCBP
women of child-bearing potential


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5.
ETHICS
5.1.
Ethics Committee
In Europe, this study will be conducted in compliance with independent ethics committee (IEC) 
and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) E6 
Guidelines, in accordance with applicable regulations regarding clinical safety data management 
(E2A, E2B(R3)), European Community directives 2001/20, 2001/83, 2003/94 and 2005/28 as 
enacted into local law, and with ICH guidelines regarding scientific integrity (E4, E8, E9 and 
E10).  In addition this study will adhere to all local regulatory requirements, and requirements 
for data protection.
In the United States (US), this study will be conducted in compliance with institutional review 
board (IRB) and ICH GCP Guidelines - including Title 21 Part 56 of the United States of 
America (USA) Code of Federal Regulations (CFR) relating to IRBs and GCP as described in 
the United States Food and Drug Administration (FDA) CFR (21 CFR § 50, 56, 312) - in 
accordance with applicable ICH regulations regarding clinical safety data management (E2A, 
E2B(R3)), and with ICH regulations regarding scientific integrity (E4, E8, E9 and E10).  
In addition this study will adhere to all local regulatory requirements, and requirements for data 
protection.
Before initiating a trial/study, the Investigator/institution must have written and dated 
approval/favorable opinion from the IRB/IEC for the study protocol/amendment(s), written 
informed consent form, any consent form updates, patient recruitment procedures 
(e.g., advertisements), and any written information to be provided to patients and a statement 
from the IRB/IEC that they comply with GCP requirements.  The IRB/IEC approval must 
identify the protocol version as well as the documents reviewed.
5.2.
Ethical Conduct of the Study
This study will be conducted in accordance with the Note for Guidance on GCP (ICH 
Harmonised Tripartite Guideline E6 (R1); FDA CFR (21 CFR § 50, 56, 312)), applicable version 
of the Declaration of Helsinki and all applicable regulatory requirements.
5.3.
Patient Information and Consent
The Investigator will explain the benefits and risks of participation in the study to each patient, 
the impartial witness and obtain written informed consent.  Written informed consent must be 
obtained prior to the patient entering the study and before initiation of any study related 
procedure (including administration of investigational drug).  
The Sponsor or their designee will provide a sample informed consent form, based on the 
elements of informed consent in Section 18.1.  The final version-dated form must be agreed to by 
the IRB/IEC and will contain all elements in the sample form, in language readily understood by 
the patient.  In the event 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.  Each patient’s original consent form, 
personally signed and dated by the patient or witness, and by the person who conducted the 


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informed consent discussion, will be retained by the Investigator.  The Investigator will supply all 
enrolled patients with a copy of their signed informed consent.
The consent form may need to be revised during the study 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 (21CFR 
56.108(a)(4)).  Those patients who are presently enrolled and actively participating in the study 
should be informed of the change if it might relate to the patients’ willingness to continue their 
participation in the study (21CFR 50.25(b)(5)).  The FDA does not require re-consenting of 
patients that have completed their active participation in the study, or of patients who are still 
actively participating when the change will not affect their participation, for example when the 
change will be implemented only for subsequently enrolled patients.
The Investigator should, with the consent of the patient, inform the patient’s primary physician 
about participation in the clinical study.


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6.
INVESTIGATORS AND STUDY ADMINISTRATIVE 
STRUCTURE
Principal Investigator(s):
This is a multi-center study.  There will not be a leading/coordinating Investigator assigned.
Monitoring and Evaluation Committee(s):
This study will use an independent Data Monitoring Committee (DMC, see Section 13.13).  
Clinical Laboratories:
Central laboratories will be used for this study: 
PPD Global Central Labs
Kleine Kloosterstraat 19
B-1932 Zaventem – Belgium
Tel. +32 2 725 21 27
Fax. +32 2 725 21 02 
PPD Global Central Labs
Global Central Labs
2 Tesseneer Drive
Highland Heights, KY, USA 41076-9167
Tel: +1-859-781-8877
Fax: +1-859-781-9310
PPD Global Central Labs 
61 Science Park Road
#02-12/14, The Galen
Singapore Science Park II
Singapore 117525 
Tel: +6565946210
Fax: +65 65946201


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PK Laboratory:
ICON Development Solutions, LLC
8282 Halsey Road, Whitesboro, NY, USA 13492
Tel: +1-315-768-2540
Fax: +1-315-736-2460


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Central Colonoscopy Evaluation:
Independent central evaluation will be performed for this study by:
Robarts Clinical Trials 
Robarts Research Institute 
100 Perth Drive 
London, Ontario, Canada 
N6A 5K8
Central Electrocardiogram (ECG) Reading:
Central ECG reading will be performed for this study by:
BioClinica Inc. (formerly CoreLab Partners, Inc.)
100 Overlook Center
Princeton, NJ  08540, US
Clinical Research Organizations (CRO):
PPD Development, LLC.  
929 North Front Street 
Wilmington, NC 28401
Tel: 910-251-0081
Fax: 910-762-5820
ClinStar, a PRA Company
4130 ParkLake Avenue, Suite 400
Raleigh, NC 27612, USA
Tel.: 919-786-8200
Fax: 919-786-8201
Central IRB:
Quorum IRB
1601 Fifth Ave
Seattle, WA, 98101


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Study Medical Monitor/Medical Expert:
Ernesto Oviedo-Orta, MD, PhD, MBA
Clinical Study Supply Management:
For Europe:
Almac Clinical Service Ltd.
9 Charlestown Road 
Seagoe Industrial Estate 
Craigavon 
BT63 5PW 
United Kingdom
For the US:
Almac Clinical Services LLC
25 Fretz Road 
Souderton
PA 18964
Almac Clinical Services LLC
4204 Technology Drive
Durham, NC 27704








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8.
STUDY OBJECTIVES AND ENDPOINTS
8.1.
Study Objectives
8.1.1.
Primary Study Objective
The primary objective of the study is to compare the efficacy of RPC1063 vs placebo for 
induction of clinical remission at Week 8 in patients with moderately to severely active UC.
8.1.2.
Secondary Study Objectives
The secondary objectives are to:

Compare the efficacy of RPC1063 vs placebo at weeks 8 and 32 as measured by 
clinical response, clinical remission, and mucosal healing

Compare the overall safety and tolerability of RPC1063 vs placebo for the 
duration of the study
 
 
 
 
8.2.
Endpoints
8.2.1.
Efficacy Endpoints
Primary Efficacy Endpoint: 

The primary endpoint is the proportion of patients in clinical remission at Week 8,  
defined as a Mayo score of ≤2 points and with no individual subscore of > 1 
point
Secondary Efficacy Endpoints:

Proportion of patients with a clinical response at Week 8, defined as a reduction 
from baseline in Mayo score of ≥3 points and ≥30%, and a decrease from 
baseline in the rectal bleeding subscore of ≥1 point or an absolute rectal bleeding 
subscore of ≤1 point

Change from baseline in Mayo score at Week 8 

Proportion of patients with mucosal healing at Week 8, defined by an endoscopy 
subscore of ≤1 point


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
Proportion of patients in clinical remission at Week 32 defined as Mayo score of 
≤2 points with no individual subscore of > 1 point 

Proportion of patients with a clinical response at Week 32, defined as a reduction 
from baseline in Mayo score of ≥3 points and ≥30%, and a decrease from 
baseline in the rectal bleeding subscore of ≥1 point or an absolute rectal bleeding 
subscore of ≤1 point 

Proportion of patients with mucosal healing at Week 32, defined by an endoscopy 
subscore of ≤1 point
 
 
 
 at Week 8 as determined by a 
Geboes index score < 2.0 (Geboes 2000)
8.2.2.
Safety Endpoints

The incidence and type of AEs, SAEs, AEs leading to discontinuation of 
investigational drug, target AEs of special interest, laboratory abnormalities, vital 
signs, ECG, and physical exam abnormalities 
8.2.3.
PK and PD Endpoints

PK assessments will include PK sampling to determine plasma concentration of 
RPC1063 and active metabolites at scheduled assessments during the treatment 
period (see Table 1 [IP and MP] and Table 2 [OLP] Schedule of Events)

Absolute lymphocyte count (ALC) derived from blinded hematology laboratory 
results

Plasma protein biomarkers (cytokines, chemokines, other inflammatory proteins) 

Stool analysis for fecal biomarkers – fecal lactoferrin and calprotectin

Total immunoglobulins (Igs) - IgA, IgG, IgM


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9.
INVESTIGATIONAL PLAN
9.1.
Overall Study Design and Plan
Study RPC01-202 is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, 
parallel-group study in patients with moderately to severely active UC.
This study includes 3 periods (Screening, Induction, and Maintenance) and an optional 
Open-Label Treatment Period (OLP).  Following the 5-week Screening Period, eligible 
patients will be randomized and enter the 9 week placebo-controlled IP.  Patients who are 
responders at Week 8 will continue on their assigned treatment in the 24-week MP.  Non-
responders at Week 8 have the option to enter the OLP.  Patients who complete the MP will 
be given the option to participate in the OLP. Patients that enter the MP and experience 
disease relapse will also have the option to enter the OLP.
The study will include both anti-TNF patients as well as anti-TNF naïve patients. It is 
anticipated that approximately 50% of the patients enrolled will have had prior anti-TNF 
therapy experience.
The study design is shown in Figure 1.  Assessments and procedures are outlined in Table 1
for the IP and MP and Table 2 for the OLP.  Assessments are described in Section 11.
Induction Period (IP)
The IP will serve as a dose-finding study to assess the efficacy and safety of RPC1063 for the 
induction of clinical response, remission, and mucosal healing in patients with moderately to 
severely active UC.  The IP will last 9 weeks and consists of dose escalation over 8 days 
followed by the full dose for 8 weeks.
Approximately 180 patients will be randomized in a 1:1:1 ratio to receive 1 of 3 treatment 
regimens:

RPC1063/ozanimod HCl 0.5 mg (equivalent to ozanimod 0.46 mg) daily oral 
capsule

RPC1063/ozanimod HCl 1 mg (equivalent to ozanimod 0.92 mg) daily oral 
capsule

Placebo daily oral capsule
The randomization will be stratified by prior anti-TNF therapy experience (yes or no).  
For patients randomized to one of the active treatment groups, there will be an 8-day dose 
escalation regimen in the IP consisting of 4 days of treatment with RPC1063/ozanimod HCl 
0.25 mg (equivalent to ozanimod 0.23 mg), followed by 3 days of treatment with RPC1063
0.5 mg, followed by the assigned treatment level for at least 8 weeks.
Maintenance Period (MP)
All patients who complete the IP and are responders (see Section 13.8) at Week 8 of the IP
will enter the 24-week MP.  Patients will continue to receive the same investigational drug in 
the MP as received during the IP, and individual patient treatment will remain blinded until 
all patients have reached Week 32.  The last visit in the MP will occur at Week 32.  Patients 


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who complete the MP will be given the option to participate in the OLP. Patients that enter 
the MP and experience disease relapse will have the option to enter the OLP.
Optional Open-Label Treatment Period (OLP)
Patients who complete the IP and are non-responders at Week 8 and those that complete the 
MP or experience disease relapse during the MP will have the option to enter the OLP.  All 
patients in the OLP will receive daily study treatment with RPC1063 1 mg.  There will be an
8-day dose escalation regimen consisting of 4 days of treatment with RPC1063 0.25 mg, 
followed by 3 days of treatment with RPC1063 0.5 mg, followed by RPC1063 1 mg.
Patients who have not shown clinical improvement 8 weeks after initiation of the OLP should 
discontinue from the study.  Eligible patients will be transitioned into the Phase 3 open-label 
extension UC Study RPC01-3102 and will be able to immediately enter the study (without 
completing the 30-day or 90-day Safety Follow-up Visits).  The OLP will continue for up to 
6 years, or until marketing approval of RPC1063 for UC in the country of the clinical site 
(estimated to be in 2019), or completed transition of patients to Study RPC01-3102, or until 
the Sponsor discontinues the development program.
Safety Monitoring/Follow-up
Potential AEs of interest that may be a consequence of S1P1 modulation will be closely 
monitored during the study.  These AEs include bradycardia, heart conduction abnormalities, 
pulmonary toxicity, macular edema, cutaneous malignancy, serious or opportunistic 
infection, and hepatotoxicity.  A DMC for the study will perform safety reviews periodically, 
approximately 4 times a year until the end of the Maintenance Period.  
The safety of patients will be monitored by collection of treatment-emergent AEs, SAEs, 
physical exams, vital signs, Holter monitoring and ECGs, PFTs, optical coherence 
tomography (OCT), blood chemistry and hematology panels, coagulation panels, and 
urinalysis at baseline and at various time points during the study.  White blood cell (WBC)
counts and lymphocyte counts will be monitored centrally (and will not be provided to the 
site) to prevent potential unblinding of the Investigator.  
Patients who discontinue from treatment due to lack of response, AEs, or other reasons, even 
if alternative treatment is given, will be followed for 90 days for collection of safety data and 
for the assessment of their disease status.


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9.1.1.
Study Schematic and Schedule of Events
Figure 1:
Study Schematic


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Table 1:
Schedule of Assessments and Procedures for Induction and Maintenance Periods
Study Procedures
Screening
Induction Period (IP)
Maintenance Period (MP)
Safety Follow-up
Dose Escalation
Assigned 
Dose
Visit
1a,b,c
Visit
4b,d
Visit
5b,d
Relapse 
Visit
Visit
6b
End of 
Study 
Visit/ET
Dose Escalation
Day 1
Week
4
Week
8
Week
20
Week
32
Day
-35 to 0
Dose Escalation
Day 1
Day
36±3
Day
64±3
Day
1OLP
Day
148±3
Day
232±3
Last dose 
+ 30 days
± 7 days
Last dose 
+ 90 ± 
10 daysr
Informed consent
X
Patients not in response or who do not maintain response within 
this time period should follow the assessments and timings 
provided in the OLP table (Table 2)
Inclusion/exclusion criteria
X
X
Demographics
X
Medical historye
X
X
TB screeningf
X
Chest X-rayf
(if not done in previous 6 months)
X
Total immunoglobulins (Igs) - IgA, IgG, 
IgM
X
X
Viral serologyg
X
Stool cultureh
X
Randomization
X
Dispense investigational drug
X
X
X
X
Administer investigational drug at clinic
X
Review drug compliance
X
X
X
X
Prior and concomitant medications
X
X
X
X
X
X
X
X
SAFETY 
ASSESSMENTS
Adverse events
X
X
X
X
X
X
X
X
12-Lead ECG
X
Xa
X
X
Holter monitoring
X
Vital signs
X
Xa
X
X
X
X
Clinical laboratory tests
Hematologys
X
X
X
X
X
X
X
Blood chemistry
X
X
X
X
X
X
X


EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC Patients
03 May 2019 (Version 10.0)
CONFIDENTIAL
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Study Procedures
Screening
Induction Period (IP)
Maintenance Period (MP)
Safety Follow-up
Dose Escalation
Assigned 
Dose
Visit
1a,b,c
Visit
4b,d
Visit
5b,d
Relapse 
Visit
Visit
6b
End of 
Study 
Visit/ET
Dose Escalation
Day 1
Week
4
Week
8
Week
20
Week
32
Day
-35 to 0
Dose Escalation
Day 1
Day
36±3
Day
64±3
Day
1OLP
Day
148±3
Day
232±3
Last dose 
+ 30 days
± 7 days
Last dose 
+ 90 ± 
10 daysr
Pregnancy test 
(WOCBP only)i
X
X
X
X
X
X
X
X
Coagulation panel
X
X
Urinalysis
X
X
X
X
Physical examinationj
X
Xk
Xk
Xk
X
Xk
Pulmonary function testsl
Xl
Xl
X
Optical coherence tomography
X
X
PK AND PD
ASSESSMENTS
Stool collection for fecal biomarkers
X
X
X
X
Inflammatory biomarkers plasma
sampling
X
X
X
X
PK blood samplingm
X
X
X
X
X
X
X
EFFICACY 
ASSESSMENTS
Endoscopyn
X
Xo
X
Mayo scoring
Mayo diary
Xp
X
X
X
X
X
Mayo full clinical score 
X
X
X
Mayo partial clinical score
Xq
X
X
Patient diary to support
mayo clinical score
X
X
X
X
X
X
Colonic biopsy
X
X
X
Key: ALC = absolute lymphocyte count; ET = Early Termination; IP = Induction Period; MP = Maintenance Period; OCT = optical coherence tomography; OLP
= Open-Label Period;PD = pharmacodynamic; PK = pharmacokinetic; TB = tuberculosis; WOCBP = women of child-bearing potential.


EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC Patients
03 May 2019 (Version 10.0)
CONFIDENTIAL
36
Footnotes to Table 1
a.
The duration of Visit 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 (±10 minutes) postdose.  A further 12-lead ECG will be performed at the end of the observation period.
b.
Study visits should be scheduled in the morning, where possible, and on study visit days patients should be instructed to withhold the dose until the study visit 
and the dose should be administered during the visit.
c.
Just prior to dosing at Visit 1, patients will begin 24-hours of Holter monitoring.  Patients will not be expected to remain on site for the 24-hour duration as 
monitoring will continue at home.  
d.
IP Week 4 and IP Week 8 occur 4 and 8 weeks, respectively, following the completion of dose escalation, ensuring 8 weeks of dosing at the assigned dose.
e.
Medical history will include smoking history. The Day 1 medical history can be abbreviated, noting events that occurred between Screening and Day 1. 
f.
Screening for TB will include a review of past history, current physical exam, A chest X-ray will be obtained for those subjects who do not have a chest X-ray 
within  6 months prior to screening and either a tuberculin skin test or a QuantiFERON® gold test for TB.
g.
Serology testing will be performed at screening to determine the patient's immune status with respect to the following viruses: varicella zoster virus (VZV),
human immunodeficiency virus (HIV) antibodies, hepatitis B surface antigen (HBsAg) and anti-hepatitis B core antigen (HBcAg) IgM, anti-hepatitis C virus 
(HCV) IgG or IgM, should be assessed at screening in all patients.
h.
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.
i.
For females of childbearing potential only, serum beta human chorionic gonadotropin (hCG) at screening is required, and a urine beta hCG 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 RPC1063 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.
At screening includes height and weight, and Visits 1, 5, 6, End-of-Study, and 30-day Safety Follow-up Visit includes weight only.   A complete PE will be 
performed at screening and End-of-Study. The complete physical examination will include a full examination of the skin for lesions as well as a check for visual 
symptoms (i.e., blurred vision or decreased visual acuity).  
k.
An interim physical examination will be conducted at Visits 1, 5, 6, and 30-day Safety Follow-up Visit. The interim PE will include areas with previously noted 
abnormalities and/or that are associated with any new complaints from the patient.  The interim PE will also include a check for visual symptoms (i.e., blurred 
vision or decreased visual acuity).
l.
DLCO, if applicable, will be done at Screening and End of Study/ET.
m. Blood samples for PK evaluation are to be taken up to 15-30 minutes prior to investigational drug (pre-dose) and just prior to discharge from the clinic (6-8 
hours post dose) on Day 1.  Blood samples on Week 4 and 20 should be taken 2-6 hours after dosing.  Blood samples on Week 8 and 32 will be trough level, 
taken just prior to dose administration.  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 AE resulting in unblinding, discontinuation, or SAE.    
n.
At screening a colonoscopy will be required if the patient has had UC ≥10 years but has not had a colonoscopy within 1 year of the screening date.  If the 
patient has had a colonoscopy within 1 year of the screening date a flexible sigmoidoscopy may be used. Endoscopy must be completed within 21 days of 
randomization.  This procedure can also be used to determine the endoscopy subscore component of the Mayo Score.  
o.
At Visit 5, sigmoidoscopy should be performed either on day of visit or no more than 7 days prior to the visit date.
p.
At screening patients will be issued with a Mayo diary and will be trained in the completion of the diary.
q.
The Mayo partial clinical score on Day 1 should be combined with the Central endoscopic read in order to assess the patient for “Mayo Score” entrance criteria.
r.
The 90-day Safety Follow-up Visit should be conducted as a clinic visit.  However, if the patient is not available for a clinic visit, a telephone call follow-up 
should be performed (with at least 3 attempts within the visit window) to record the pregnancy test result, concomitant medications, and AEs, including 
information regarding relationship of the AE to RPC1063.
s.
If ALC is confirmed < 200 cells/μL, the Investigator will temporarily discontinue investigational drug and then consult the Medical Monitor. Laboratory testing will be 
repeated weekly until ALC is > 500 cells/µL.  For patients whose ALC level is confirmed < 200 cells/μL and has not reached the acceptable range (ALC > 500 cells/µL) 
during the study, laboratory testing will be repeated at the 90-day Safety Follow-up Visit.


EDMS Doc. Number: 23698993 - 23698906
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Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC Patients
03 May 2019 (Version 10.0)
CONFIDENTIAL
37
Table 2:
Schedule of Assessments and Procedures for the Optional Open-Label (OLP) Period 
Open-Label Period (OLP)
Safety Follow-upm
Study Procedures
Dose Escalation
Assigned Dose (1 mg)
Visit
1OLPa,b,c
Visit
4OLPb,d
Visit
5OLPb,d
Additional
OLP
Visitse
End of Open-
label 
Visit/ETe
Dose Escalation
Day 1 
Week
4OLP
Week
8OLP
12-week 
Intervals
End of Study
Dose Escalation
Day
1OLP
Day
36 ± 3 OLP
Day
64 ± 3 OLP
Day
(last visit 
calculated 
from Day 1 +
84) ± 14 OLP
Day of last dose
Last dose 
+ 30 ± 7
days
Last dose 
+ 90 ± 10 
daysn
Dispense investigational 
drug
X
X
X
X
Xm
Administer investigational 
drug at clinic
X
Review drug compliance
X
X
X
X
Prior and concomitant 
medications
X
X
X
X
X
X
X
SAFETY 
ASSESSMENTS
Total 
immunoglobulins 
(Igs) - IgA, IgG, IgM
X
Adverse events
X
X
X
X
X
X
X
12-Lead ECG
Xa
X
Holter monitoring
X
Vital signs
Xa
X
X
X
X
Clinical laboratory tests
Hematologyo
X
X
X
X
X
Blood chemistry
X
X
X
X
X
Pregnancy test 
(WOCBP only)f
X
X
X
X
X
X
Coagulation panel
X
Urinalysis
X
X
Physical examinationg
Xh
Xg
Xh
Pulmonary function testsi
X
Optical coherence 
X


EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC Patients
03 May 2019 (Version 10.0)
CONFIDENTIAL
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Open-Label Period (OLP)
Safety Follow-upm
Study Procedures
Dose Escalation
Assigned Dose (1 mg)
Visit
1OLPa,b,c
Visit
4OLPb,d
Visit
5OLPb,d
Additional
OLP
Visitse
End of Open-
label 
Visit/ETe
Dose Escalation
Day 1 
Week
4OLP
Week
8OLP
12-week 
Intervals
End of Study
Dose Escalation
Day
1OLP
Day
36 ± 3 OLP
Day
64 ± 3 OLP
Day
(last visit 
calculated 
from Day 1 +
84) ± 14 OLP
Day of last dose
Last dose 
+ 30 ± 7
days
Last dose 
+ 90 ± 10 
daysn
tomography 
PK AND PD
ASSESSMENTS
Stool collection for fecal 
biomarkers
X
X
X
Inflammatory biomarkers
plasma sampling
X
X
X
PK blood samplingj
X
X
X
X
EFFICACY 
ASSESSMENTS
Endoscopy
Xk
Xl
Mayo scoring
Mayo diary
X
X
X
X
Mayo full clinical score 
Xk
X
Mayo partial clinical 
score
X
X
X
Patient diary to support 
Mayo clinical score
X
X
X
X
Colonic biopsy
Xk
X
Key: ALC = absolute lymphocyte count; ET = Early Termination; OCT = optical coherence tomography; OLP = Open-label Period; PD = pharmacodynamic; PK
= pharmacokinetic; WOCBP = women of child-bearing potential.
Footnotes to Table 2
a.
The duration of Visit 1OLP 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 (±10 minutes) postdose.  Another 12-lead ECG will be performed at the end of the observation period.
b.
Study visits should be scheduled in the morning, where possible, and on study visit days patients should be instructed to withhold the dose until the study visit
and the dose should be administered during the visit.


EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC Patients
03 May 2019 (Version 10.0)
CONFIDENTIAL
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c.
Just prior to dosing at Visits 1OLP, patients will begin 24- hours of Holter monitoring.  Patients will not be expected to remain on site for the 24-hour duration as 
monitoring will continue at home.
d.
Visit 4OLP and Visit 5OLP occur 4 and 8 weeks, respectively, following the completion of dose escalation, ensuring 8 weeks of dosing at the assigned dose.
e.
Patients who continue past Week 8 in the OLP will have the Additional OLP Visit assessments performed at 12-week intervals throughout the OLP. The OLP 
will continue for up to 6 years, or until marketing approval of RPC1063 for UC in the country of the clinical site (estimated to be in 2019), or the completed 
transition of patients to Study RPC01-3102, or until the Sponsor discontinues the development program.  
f.
For females of childbearing potential only, serum beta human chorionic gonadotropin (hCG) at screening is required and a urine beta hCG is required at each 
visit.  Between scheduled visits, monthly urine pregnancy tests should be performed by the patient. If a urine pregnancy test is positive, the Investigator will 
instruct the patient to suspend further RPC1063 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.
g.
Includes weight.  The complete physical examination will include a full examination of the skin for lesions as well as a check for visual symptoms (i.e., blurred 
vision or decreased visual acuity).
h.
An interim physical examination will be conducted at Visit 5OLP and 30-day Safety Follow-up Visit. The interim PE will include areas with previously noted 
abnormalities and/or that are associated with any new complaints from the patient.  The interim PE will also include a check for visual symptoms (i.e., blurred 
vision or decreased visual acuity).
i.
DLCO, if applicable, will be done at End of Open-Label/ET.
j.
The PK blood sample on Week 8 should be trough level, taken just prior to dose administration. The blood sample on End of Open-label Visit/ET should be 
taken 2-6 hours after dosing. 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 AE resulting in unblinding, discontinuation, or SAE.
k.
For patients who continue past Week 8 in the OLP, an endoscopy will be performed at Week 56OLP and a full Mayo score will be calculated at that time.
l.
At End of Open-Label or ET Visit sigmoidoscopy should be performed either on day of visit or no more than 7 days prior to the visit date.
m. For patients who are entering the open-label extension UC Study RPC01-3102 at a date other than the End of Study visit, investigational drug will be dispensed
in this study. For patients who are immediately entering (at the End of Study visit) the open-label extension UC Study RPC01-3102, investigational drug will be 
dispensed in Study RPC01-3102.
n.
The 90-day Safety Follow-up Visit should be conducted as a clinic visit.  However, if the patient is not available for a clinic visit, a telephone call follow-up 
should be performed (with at least 3 attempts within the visit window) to record the pregnancy test result, concomitant medications, and AEs, including 
information regarding relationship of the AE to RPC1063.
o.
If the ALC is confirmed below 200 cells/µL, the Investigator will temporarily discontinue investigational drug and then consult the Medical Monitor.  Laboratory 
testing will be repeated weekly until ALC is > 500 cells/µL. For patients whose ALC level is confirmed < 200 cells/μL and has not reached the acceptable range 
(ALC > 500 cells/µL) during the study, laboratory testing will be repeated at the 90-day Safety Follow-up Visit.


EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
03 May 2019 (Version 10.0)
CONFIDENTIAL
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9.1.2.
Additional Information 
9.1.2.1.
Adverse Events of Special Interest
Investigators should identify AEs that are in the following categories for AESIs.  AESIs fall into 
a number of categories based on the safety observations from the potential pharmacologic effects 
of S1P modulators.  These target AEs of special interest will be closely monitored in the 
RPC01-202 study.  These AEs include serious or opportunistic infections, cardiac events 
(bradycardia and heart conduction abnormalities), pulmonary events (dyspnea and clinically 
significant wheezing) ophthalmic events (macular edema), dermatologic events (cutaneous 
malignancies), and hepatic events (liver function test [LFT] elevation).  Further details on 
monitoring of these AEs are provided in Section 11.5.
9.2.
Dose Rationale
 
  
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 


EDMS Doc. Number: 23698993 - 23698906
Sponsor: Celgene International II Sàrl
Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
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41
 
 
  
 
9.3.
Study Design Rationale
 
 
 
 
 
 
9.4.
Study Duration
The study duration from first patient enrolled to last patient last visit is estimated to be 
approximately 32 months.  The enrollment period is estimated to last approximately 18 months.  
Patients who complete the MP and then participate in the OLP of the study are anticipated to 
receive a minimum of 12 months of treatment.  
9.5.
Study Population
Eligible patients will be 18 to 65 years of age, inclusive, with a diagnosis of active UC (Mayo 
score 6-12).
9.5.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following inclusion criteria:
1. Males or female patients aged 18 to 75 years, inclusive 
2. Have had UC diagnosed at least 2 months prior to screening.  The diagnosis of UC must 
be confirmed by endoscopic and histologic evidence
3. Have active UC confirmed on endoscopy with ≥15 cm involvement 
4. Have active UC defined as Mayo score of 6-12 inclusive with endoscopic subscore of 
≥2
5. Have undergone colonoscopy or sigmoidoscopy within the past 2 years for extent of 
disease, and if the UC has been present for > 10 years, have had a colonoscopy with 
biopsy to rule out dysplasia


EDMS Doc. Number: 23698993 - 23698906
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Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
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6. Female patients of childbearing potential:
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

vasectomised partner

sexual abstinence 
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method are not 
acceptable methods of contraception. 
7. Must be currently receiving treatment with at least 1 of the following therapies:
a.
Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, balsalazide) for 
at least 6 weeks with the dose stable for at least 3 weeks prior to screening
endoscopy
b. Prednisone (doses ≤30 mg) or equivalent for at least 4 weeks and receiving a 
stable dose for at least 2 weeks
8. 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
9. All patients aged 45 years or over must have had a colonoscopy to screen for 
adenomatous polyps within 5 years of their first dose of investigational drug or must have 
had a colonoscopy at screening to assess for polyps.  The adenomatous polyps must be 
removed prior to their first dose of investigational drug.
10. Ability to provide written informed consent and to be compliant with the schedule of 
protocol assessments
11. Patients must have documentation of positive Varicella Zoster virus (VZV) IgG antibody 
status or complete VZV vaccination at least 30 days prior to randomization
12. Documentation of no evidence of chronic lung disease or tuberculosis (TB) on a chest 
X-ray completed within the 6 months prior to screening.  If a chest X-ray was not done in 


EDMS Doc. Number: 23698993 - 23698906
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Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
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the 6 months preceding the Screening visit, it may be performed during the Screening 
visit
9.5.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
time of randomization or at the time point specified in the individual criterion listed:
Exclusions Related to General Health:
1. Have severe extensive colitis as evidenced by: 

Physician judgment that the patient is likely to require colectomy or ileostomy within 
12 weeks of baseline

Current evidence of fulminant colitis, toxic megacolon or bowel perforation

Previous total colectomy

Have 4 or more of the following:
-
Temp > 38°C
-
HR > 110 (bpm)
-
Focal severe or rebound abdominal tenderness
-
Anemia (hemoglobin [Hgb] < 8.5 g/dL)
-
Transverse colon diameter > 5 cm on plain X-ray
2. Diagnosis of Crohn’s disease or indeterminate colitis or the presence or history of a 
fistula consistent with Crohn’s disease
3. Have positive stool culture for pathogens (O+P, bacteria) or positive test for C. difficile at 
screening.  If C. difficile is positive, the patient may be treated and retested
4. Have had treatment with cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil
(MMF) within 16 weeks of screening
5. Pregnancy, lactation, or a positive serum beta-hCG measured during screening
6. Clinically relevant, hepatic, neurological, pulmonary, ophthalmological, endocrine, 
psychiatric or other major systemic disease making implementation of the protocol or 
interpretation of the study difficult or that would put the patient at risk by participating in 
the study
7. Clinically relevant cardiovascular conditions, including history or presence of:
i.
Recent (within the last 6 months) occurrence of myocardial infarction, unstable 
angina, stroke, transient ischemic attack, decompensated heart failure requiring 
hospitalization, Class III/IV heart failure, sick sinus syndrome, or severe untreated 
sleep apnea
ii.
Prolonged QTcF interval (QTcF > 450 msec males, > 470 msec females), or at 
additional risk for QT prolongation (e.g., hypokalemia, hypomagnesemia, 
congenital long-QT syndrome)


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iii.
Patients with other pre-existing stable cardiac conditions who have not been 
cleared for the study by an appropriate cardiac evaluation by a cardiologist
8. Resting HR less than 55 beats per minute (bpm) when taking vitals as part of a physical 
exam at Screening
9. History of diabetes mellitus type 1, or uncontrolled diabetes mellitus type 2 with 
hemoglobin A1c > 7%, or diabetic patients with significant co-morbid conditions such as 
retinopathy or nephropathy
10. History of uveitis
11. Known active bacterial, viral, fungal, mycobacterial infection or other infection 
(including TB or atypical mycobacterial disease [but excluding fungal infection of nail 
beds]) 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 
prior to screening
12. History of recurrent or chronic infection (e.g., hepatitis B or C, HIV, syphilis, TB); 
recurring urinary tract infections are allowed
13. History of cancer, including solid tumors and hematological malignancies (except basal 
cell and in situ squamous cell carcinomas of the skin that have been excised and 
resolved)
14. History of alcohol or drug abuse within 1 year prior to randomization
15. History of or currently active primary or secondary immunodeficiency
Exclusions Related to Medications:
16. History of treatment with a biologic agent within 5 half-lives of that agent prior to 
randomization
17. History of treatment with an investigational agent within 5 half-lives of that agent prior to 
randomization
18. History of treatment with topical rectal 5-ASA or steroids within 2 weeks of screening
19. Receipt of a live vaccine or attenuated live vaccine within 4 weeks prior to randomization
20. Previous treatment with lymphocyte-depleting therapies (e.g., Campath, anti-CD4, 
cladribine, rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, total body 
irradiation, bone marrow transplantation, alemtuzumab, daclizumab)
21. Previous treatment with D-penicillamine, leflunomide or thalidomide
22. Previous treatment with natalizumab or fingolimod
23. History of treatment with intravenous immune globulin (IVIg), plasmapheresis, within 
3 months prior to randomization
24. Planned concurrent treatment with immunosuppressive agents (e.g., azathioprine, 6-MP, 
or methotrexate) after randomization.  Subjects receiving azathioprine, 6-MP or 
methotrexate at screening must discontinue treatment with these agents prior to dosing 
with investigational drug.


EDMS Doc. Number: 23698993 - 23698906
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Protocol No.  RPC01-202
Induction Therapy with RPC1063 in UC
03 May 2019 (Version 10.0)
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45
25. Treatment with Class Ia or Class III anti-arrhythmic drugs or treatment with two or more 
agents in combination known to prolong PR interval
26. Treatment with any of the following drugs or interventions within the corresponding 
timeframe:

At randomization

CYP2C8 inhibitors (eg, gemfibrozil or clopidogrel) or inducers (eg, rifampicin)

Two weeks prior to randomization

Monoamine oxidase inhibitors (eg, selegiline, phenelzine)
Exclusions Related to Laboratory Results:
27. Serum creatinine 1.4 mg/dL for women or 1.6 mg/dL for men
28. Liver function impairment or persisting elevations of aspartate aminotransferase (AST) or
alanine aminotransferase (ALT) 2 times the upper limit of normal (ULN), or direct 
bilirubin 1.5 times the ULN
29. Platelet count 100,000/L
30. Hgb 8.5 g/dL
31. Neutrophils 1500 /L
32. Absolute WBC count 3500/L
33. Absolute lymphocyte count 800/L
34. ECG showing any clinically significant abnormality (e.g., acute ischemia, any significant
heart conduction abnormality [e.g., left bundle branch block])
35. FEV1or FVC < 70% of predicted values at screening
9.6.
Treatment
9.6.1.
Treatments Administered
The Investigator must ensure that the investigational product will be used only in accordance 
with the protocol.
During the IP, patients will be randomly assigned in a 1:1:1 ratio on Day 1 to one of following 
3 treatment regimens as set out in Table 3:

RPC1063/ozanimod HCl 0.5 mg (equivalent to ozanimod 0.46 mg) daily oral capsule 

RPC1063/ozanimod HCl 1 mg (equivalent to ozanimod 0.92 mg) daily oral capsule 

Placebo daily oral capsule
Capsule dosing:  dosing will be once daily in the morning, if possible, with or without food.  
On days of study visits, patients should be instructed to withhold the dose until the office visit, 
and dose will be administered during the visit.  


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9.6.2.
Study Treatment After Missed Dose(s)
Patients should be instructed that if they forget to take a dose, they can take the dose within 
4 hours of the normal dosing time; otherwise they should take their next dose at the regular time 
on the following day.  If the patient vomits the capsule, he/she should be instructed not to take 
another capsule on the same day, but to take the next dose at the regular time on the following 
day.  If the patient is ill and unable to take a dose, 2 days without treatment is acceptable, 
otherwise the patient will contact the Investigator.  If the patient misses more than 7 consecutive 
doses for any reason, Day 1 cardiac monitoring procedures will be performed on the first day 
that the patient resumes dosing. Holter monitoring will not be performed. If the patient misses 
more than 14 consecutive doses for any reason, the Medical Monitor must be contacted to 
discuss procedures for resuming therapy, which may include an additional dose escalation
schedule if deemed appropriate.
Patients will continue to receive the same investigational drug in the MP as received during the 
IP, and individual patient treatment will remain blinded until all patients have reached Week 32.  
9.6.3.
Study Treatment Formulation
 
  
 
 
 
 
 
 
  
 
  
9.6.4.
Study Treatment Labeling and Packaging
 
 
 


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9.6.5.
Blinding of Study Treatment
Investigational medicinal product and placebo capsules will be identical in physical appearance.  
The treatment each patient will receive will not be disclosed to the Investigator, study center 
personnel, patient, Sponsor and their representatives.  The treatment codes will be held according 
to an Interactive Voice Response System (IVRS).  Further instructions will be provided in a 
separate IVRS manual.
For details of the emergency procedure for unblinding of individual patients see Section 9.12, 
below.
9.6.6.
Study Treatment Storage and Accountability
Study treatment should not be used for purposes other than as defined in this protocol.
9.6.6.1.
Study Treatment Storage
RPC1063 and placebo capsules should be stored at room temperature (approximately 25°C
[77°F], excursions permitted 15°C to 30°C [59°F to 86°F]) in a dry location.  The inactive 
ingredients used in the formulations are slightly hygroscopic; therefore, all bottles contain a 
½-gram desiccant canister and should be kept tightly sealed when drug product is not being 
dispensed.
9.6.6.2.
Study Treatment Accountability
All supplies of investigational drug and placebo will be accounted for in accordance with GCP.  
There will be an individual investigational drug accountability record for each patient and the 
Investigator should maintain accurate records relating to investigational drug supplies received 
during the study.  These records should include the amounts and dates clinical drug supplies 
were received, dispensed to the patient, returned by the patient and returned to the Sponsor.  If 
errors or damages in the clinical drug supply shipments occur, the Investigator should contact 
Almac and the Study Monitor immediately.  Copies of the investigational drug accountability 
records will be provided by each Investigator for inclusion in the Trial Master File after database 
lock.  The Study Monitor will periodically check the supplies of investigational drug held by the 
Investigator or pharmacist to verify accountability of all investigational drug used.
The Investigator will provide investigational drug only to the identified patients of this study, 
according to the procedures described in this study protocol.  After the end of the study, the 
Study Monitor will ensure that all unused investigational drug and all medication containers can 
be destroyed on-site as long as proper documentation is supplied.  The Study Monitor will 
perform final accountability, package, seal, and prepare for shipment.  If destruction on-site is 
not possible then medication and all medication containers will be returned to Almac 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 Study Center File.




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 During Dose Escalation
A summary of the cardiac monitoring during dose escalation is presented in Table 4.


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Table 4:
Cardiac Monitoring During Dose Escalation
Procedure
Cardiac Monitoring
Day 1/1OLP
Pre-dose
Hourly for 6 
hours
At Hour 6
Continuous Monitoring 
for 24 hours
Vital signs
X
X
12-lead ECG
X1
X
Holter monitoring2
X3
Assess Discharge Criteria4
X
1 Baseline or predose ECG should be provided by the site and be available for comparison to the postdose ECG in 
order to determine if discharge criteria are met.
2 Begin at least 15 minutes predose and continue for 24 hours after dose.
3 Holter monitoring will be performed on Day 1/1OLP.
4 See Section 9.6.7.2 for discharge criteria.  Additional observation should be instituted until the finding has 
resolved in the following situations: HR 6 hours post-dose is < 45 bpm; HR 6 hours post-dose is at the lowest 
value post-dose; ECG 6 hours post-dose shows new onset second degree or higher AV block; the ECG 6 hours 
post-dose shows a prolonged QTcF interval (> 450 msec males, > 470 msec females).
There is no provision for dose adjustments in this study.  Patients who cannot tolerate 
investigational drug must be withdrawn from the study.
9.7.
Withdrawal of Patients from Study Treatment and/or the Study
9.7.1.
Discontinuation of Study Treatment
Patients will be encouraged to complete the study; however, they may voluntarily withdraw at 
any time.  The Investigator will provide a written explanation in the source documentation to be 
entered on the appropriate electronic case report form (eCRF) page describing the reason for 
discontinuation.  If a patient withdraws before completion, every effort should be made to 
complete the assessments at the 30-day and 90-day Safety Follow-up Visits.  
A patient may discontinue the study for the following medical or administrative reasons:

Investigator decision
The Treating Investigator may discontinue investigational drug if it is determined that 
it is not in the patient’s best interest to receive further treatment.  The Medical 
Monitor should be promptly notified of the decision.

Adverse Event/Intercurrent illness
A patient may be discontinued from the study if, in the judgment of the Investigator, 
the patient develops an adverse event such as an intercurrent illness or complication 
that is not consistent with the protocol requirements or that, in any way, justifies
withdrawal from the study.

Lack of Efficacy/Worsening Disease

If the patient becomes pregnant


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
Noncompliance
After consultation between the Investigator, the Medical Monitor, and the Sponsor
when appropriate, a patient may be discontinued from the study for failure to comply 
with protocol requirements.

Patient chooses to discontinue investigational drug.
The patient may choose to discontinue investigational drug but has not withdrawn 
consent. In this case it is expected that the ET and 30-day and 90-day Safety Follow-
up Visits would be completed.

Patient withdrawal of consent
Every effort should be made within the bounds of safety and patient choice to have 
each patient complete the study.  If a patient withdraws consent, the only additional 
study data to be collected will be the follow-up of SAEs as mandated by the protocol.

Sponsor termination or suspension of the study.
All patients who discontinue investigational drug and who have not withdrawn consent should 
complete an Early Termination Visit and the 30-day and 90-day Safety Follow-up Visits for the 
collection of safety data and to assess their disease status (see Table 1 and Table 2).  For subjects 
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 it is above the lower limit of normal.
The reason for discontinuation of investigational drug will be recorded in the clinical records and 
the patient’s eCRF.  
9.7.2.
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any one of the following reasons:

The patient withdraws consent.  

The patient is unwilling or unable to comply with the protocol.

Patient’s safety is affected, assessed by the Treating Investigator and/or the Medical 
Monitor
The reason for the patient’s withdrawal from the study must be recorded in the clinical records 
and the patient’s eCRF.
9.8.
Prior and Concomitant Therapy
 
 
 
 




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9.10.
Treatment Compliance
It is the Investigator’s responsibility to ensure that patients are correctly instructed on how to 
take their investigational drug and that each patient is fully compliant with their assigned dosage 
regimen.  Records of investigational drug used and intervals between visits will be kept during 


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the study.  Drug accountability will be noted by the field monitor during site visits and at the 
completion of the study.  Patients will be asked to return all unused investigational drug at the 
end of the study.  The investigational drug should be dispensed by the Investigator, or by a 
qualified individual under the Investigator’s supervision.  An up-to-date treatment 
inventory/dispensing record must be maintained.
Overall study non-compliance is defined as taking less than 80% or more than 120% of 
investigational drug during the entire treatment period.
At each visit, previously dispensed investigational drug capsules will be collected by the 
Investigator and compliance assessed.  Patients will record missed doses in a diary that will be 
reviewed periodically by site staff and the Clinical Monitor.  Patients exhibiting poor compliance 
as assessed by medication counts (i.e., 2 or more missed medication days in 1 week) and 
response to the question “Did you take your medication regularly?” should be counseled on the 
importance of good compliance to the study dosing regimen.  Patients who are persistently 
non-compliant (< 80% or > 120%) should be discussed with the Medical Monitor to determine 
whether they should be withdrawn from the study. 
9.11.
Assignment to Treatment
Patients must provide proper informed consent before any study procedures are performed 
(refer to Section 5.3 for further details regarding obtaining patients informed consent).  At the 
time of consent, the patient is enrolled in the study.  Patients will be randomized into the IP of 
the study on Day 1 after all screening and baseline assessments have been completed and the 
Investigator has verified that the patient is eligible per the inclusion (Section 9.5.1) and exclusion 
criteria (Section 9.5.2).  
Randomization will be performed through an IVRS (further instructions will be provided in a 
separate IVRS manual).  Treatment groups are described in Section 9.6.1.  
Patients will be stratified by anti-TNF treatment (yes vs no) and will be randomized 1:1:1 to 
receive placebo, RPC1063 0.5 mg, or RPC1063 1 mg.  
9.12.
Unblinding Procedures for Individual Patients
A patient’s treatment group assignment blind will not be broken until the end of the study unless 
medical treatment of that patient depends upon knowing whether the patient is receiving active 
drug.  In the event that the blind needs to be broken because of a medical emergency, the 
investigator may unblind an individual patient’s treatment allocation. Prior to unblinding, the 
investigator should first attempt to contact the Medical Monitor to discuss the medical 
emergency and the reason for wanting to unblind.  The treatment assignment will be unblinded 
through an IVRS.  Reasons for treatment unblinding must be clearly explained and justified in 
the eCRF.  The date on which the code was broken, together with the identity of the person 
responsible, must also be documented.
A PK sample will be obtained whenever possible for patients with any AE or SAE resulting in 
unblinding, or discontinuation.


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10.
STUDY SCHEDULE
The study design is shown in Figure 1.  Assessments and procedures are outlined in Table 1 for 
the IP and MP and Table 2 for the OLP.  Assessments are described in Section 11.
It is recommended that the study visits are scheduled in the morning.  On days of study visits, 
patients should be instructed to withhold the dose until the office visit, and the dose will be 
administered during the visit.  
Whenever possible, the sequence of when assessments are done should remain constant and at 
approximately the same time of day throughout the study.
It is recommended that procedures are performed in the following order (note that not all 
procedures are performed at every visit):  

Spontaneous or solicited AE reporting

ECG

Vital signs

Clinical laboratory tests, including pre-dose PK sampling

Physical examination

Efficacy assessments
10.1.
Screening Period
Screening procedures must be completed within 35 days prior to receiving the first dose of 
investigational drug.  All screening assessments and procedures as per Table 1 (IP and MP) and
Table 2 (OLP) are to be performed by the Principal Investigator or a qualified designee.  
Written, signed, and dated informed consent from the patient prior to the performance of any 
study-related procedures must be obtained by the Principal Investigator or designee (refer to 
Section 5.3 for further details regarding obtaining patients informed consent).  A copy of the 
signed informed consent must be given to the patient for his/her records.
10.2.
Screening Failures and Rescreening of Patients
A screen failure is defined as a patient who has given informed consent, and failed to meet the 
inclusion and/or exclusion criteria.  Patients who fail to meet the inclusion/exclusion criteria can 
be rescreened.
10.3.
Induction Period (IP) and Maintenance Period (MP)
Eligible patients will be randomized to treatment group on Day 1.  Visits, assessments, and 
procedures will be performed as per the Schedule of Events in Table 1. Guidelines for dose 
escalation (Day 1) are provided in Section 9.6.7.
10.4.
Open-Label Period (OLP)
Patients who complete the IP and are non-responders at Week 8 and those that complete the MP 
or experience disease relapse during the MP will have the option to enter the OLP. Patients must 


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start the OLP within 2 weeks of their Week 8 Induction Visit, Disease Relapse visit in the MP or 
Week 32 MP visit.  Visits, assessments, and procedures will be performed as per the Schedule of 
Events in Table 2.  Guidelines for monitoring patients during dose escalation (Day 1OLP) are 
provided in Section 9.6.7.
The OLP will continue for up to 6 years or until marketing approval of RPC1063 for UC in the 
country of the clinical site (estimated to be in 2019), or completed transition of patients to Study 
RPC01-3102, or until the Sponsor discontinues the development program. 
10.5.
Early Termination
For patients who discontinue the study for any reason, every attempt should be made to complete 
the assessments detailed in the End of Period/Early Termination (ET) visit and the 30-day and 
90-day Safety Follow-up Visits for the collection of safety data and for the assessment of their 
disease status (Table 1 [IP and MP] and Table 2 [OLP]).  With the exception of patients who 
withdraw consent or are lost to follow-up, central laboratory testing of ALC will continue every 
14 days (± 3 days) after permanent discontinuation of RPC1063 until it is above the lower limit 
of normal for patients who discontinue treatment or complete the trial.
10.6.
Unscheduled Relapse Assessment Visit
If during the MP or OLP the Investigator becomes aware of a potential relapse outside the 
normal visit schedule, patients should be evaluated for relapse as outlined in the Schedule of 
Events (Table 1 [IP and MP] and Table 2 [OLP]).
10.7.
Study Stopping Rules
The Sponsor has the right to terminate the study prematurely for safety reasons.  In addition, the 
Sponsor may terminate the study prematurely for administrative reasons.  In all cases, all 
necessary measures have to be taken to guarantee appropriate safety follow-up of all patients 
already included in the study.
The IEC or IRB and the Regulatory Authorities will be informed in writing about any premature 
termination of the study.


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11.
METHODS OF ASSESSMENT
The study design is shown in Figure 1.  Assessments and procedures are outlined in Table 1 for 
the IP and MP and Table 2 for the OLP.
11.1.
Efficacy Assessments
11.1.1.
Flexible Sigmoidoscopy/Colonoscopy
To ensure quality data and standardization, the same endoscopist should be used throughout the 
study wherever possible.  Colonoscopies will be read blinded to treatment allocation at a 
centralized reading facility, Robarts Clinical Trials.
11.1.2.
Mayo Score
The Mayo score is a standardized, accepted, numerical scale used to evaluate disease severity in 
people with UC.
The Mayo score consists of four subscores, each ranging from (0-3) for a total score that ranges 
from 0 to 12:
1. Stool frequency a
0Normal number of stools for this patient
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 bleeding b
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, mild 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
1Mild disease
2Moderate disease


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3Severe disease
a
Each patient serves as his or her own control to establish the degree of abnormality of the stool frequency.
b
The daily bleeding score represents the most severe bleeding of the day.
c
The physician’s global assessment acknowledges the three other criteria, the patient’s daily recollection of 
abdominal discomfort and general sense of well-being, and other observations, such as physical findings and the 
patient’s performance status.
Partial Mayo scores are calculated using data from Items 1, 2 and 4 only.
Mayo scores are calculated using:
1. The Stool frequency and rectal bleeding data form the most recent consecutive 3-day 
period prior to the visit, excluding the following:
a.
The day medications for constipation, diarrhea, or bowel irregularity are taken
b. The day(s) of a procedure or preparation for a procedure (e.g., enemas, other 
laxative, clear liquid diet) that would affect bowel frequency or blood content of 
the stool
c.
The 48 hours following use of anti-motility agents (i.e., loperamide)
d. The 48 hours following endoscopy
Disease relapse is defined as when all of the following criteria are met:

An increase in UC disease activity as defined by an increase in partial Mayo score of 
2 points compared to the Week 8 partial Mayo score with an absolute partial Mayo 
score 4 points

An endoscopic subscore of 2 points

Exclusion of other causes of an increase in disease activity unrelated to underlying 
UC (e.g., infections, change in medication).
11.2.
Clinical Safety Assessments
Physical Examination 
A complete physical examination will include evaluation of heart, lung, head and neck, 
abdominal, neurological, full examination of the skin for lesions, and extremities.  An interim (or 
brief) physical examination will include areas with previously noted abnormalities and/or that are 
associated with any new complaints from the patient. In addition, patients will be questioned on 
visual symptoms (i.e., blurred vision or decreased visual acuity) during both the complete and 
interim physical examinations.  
All significant findings that are present at screening must be reported on the relevant medical 
history/current medical conditions eCRF.  Significant findings made after randomization that 
meet the definition of an AE must be recorded on the AEs eCRF.


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Height and Weight 
Height will be measured at screening.  Weight will be monitored throughout the study.
Vital Signs
Heart rate and blood pressure (systolic and diastolic) will be assessed per the Schedule of Events 
(Table 1 and Table 2).  
When obtaining the predose HR and BP during dose escalation (Day 1/1OLP), the patient should 
rest in the supine position for at least 15 minutes before measurement to establish an accurate 
baseline measurement.  After the patient has been supine for at least 15 minutes, HR and BP will 
be measured 3 times. An automated validated device can be used, if available.  In case the cuff 
sizes available are not large enough for the patient's arm circumference, a sphygmomanometer 
with an appropriately sized cuff may be used.  The repeat HR and BP measurements will be 
made at 2-minute intervals.  The lowest predose value of supine HR and BP (based on the 
systolic BP) should be taken as the baseline measure and used for comparison to postdose values.  
Orthostatic blood pressure will then be measured once with the patient in the standing position
(after standing for 2 minutes).  A sudden, significant fall in BP (> 20 mmHg) between 2 and 5 
minutes after standing from the supine position will be interpreted as orthostatic hypotension and 
will be documented in the patient chart and eCRF.  
Post-baseline HR and BP measurements should be taken after the patient has been supine for 
at least 5 minutes. HR and BP will be measured once using an automated validated device.  
Any clinically relevant change from baseline should be confirmed on repeat measures. 
Orthostatic blood pressure will then be measured in the same manner with the patient in the 
standing position (after standing for 2 minutes).  A sudden, significant fall in BP (> 20 mmHg) 
between 2 and 5 minutes after standing from the supine position will be interpreted as orthostatic 
hypotension and will be documented in the patient chart and eCRF.  
ECG
12-lead ECG to be performed after the patient has been resting quietly for at least 10-15 minutes.
Digital ECG devices will be provided to each clinical site by the central ECG laboratory for the 
duration of the study. The screening ECG report from the central reader must be available to 
confirm patient eligibility before randomization. A 12-lead ECG will be performed before and 
6 hours after the first dose of investigational drug administration, while the patient is at the 
clinic.
Detailed instructions describing the process for recording and transmission of the digital ECGs 
will be outlined in the study-specific manual and provided to the site before the start of the study. 
Stand-alone ECGs will be obtained, printed, photocopied to preserve the ink if necessary, and 
kept at the site as source documentation.


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ECG & Holter Monitoring
Dual function Digital ECG devices that are capable of capturing both stand-alone ECGs and 
Holter data will be provided to each clinical site by the central ECG laboratory for the duration 
of the study.  Detailed instructions describing the process for recording and transmission of the 
digital ECGs and Holter data will be outlined in the study-specific manual and provided to the 
site before the start of the study.  
Stand Alone/Static ECGs
Static ECGs will be captured at intervals as defined in the schedule of assessments 
(Section 9.1.1).  The 12-lead ECG will be performed after the patient has been resting quietly in 
a supine position for at least 10-15 minutes.  The screening 12-lead ECG report from the central 
reader must be available to confirm patient eligibility before randomization. Six hour post dose 
ECG will be evaluated by the treating physician or the central reader to confirm if extended 
monitoring is required. Simultaneously the ECGs will be printed out locally, photocopied to 
preserve the ink if necessary, and kept at the site as source documentation.
Each ECG tracing should be labeled with the study number, patient initials, patient number, date, 
and kept in the source documents at the study site.  Only clinically significant abnormalities 
should be reported in the medical history/current medical conditions or AE CRF.  Clinically 
significant findings must be discussed with the Medical Monitor before enrolling the patient in 
the study.  
Continuous 12-lead Holter Monitoring
24 hour continuous cardiac monitoring (12 lead digital Holter monitoring) will be captured at 
Day 1/1OLP.  Holter monitoring will start at least 15 minutes prior to dose and complete at least 
24 hours post dose administration.  Patients should be in the supine position prior to Holter 
application through the capture of the static pre-dose 12-lead ECG as well as for the acquisition 
of the 6 hour post dose 12-lead ECG.  Holter analysis parameters will be described in the 
operations document.
Pulmonary Function Tests
Pulmonary function tests including FEV1, FVC and DLCO, if applicable, measurements will be 
performed as scheduled Table 1 and Table 2. These tests will be performed at a qualified
pulmonary function laboratory or respiratory department. 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).  
Ophthalmological Examination
OCT will be performed at scheduled times as outlined in Table 1 and Table 2.  
Monitoring of AEs and SAEs
Throughout the course of the study, every effort must be made to remain alert to possible AEs or 
SAEs.  Refer to Section 12 for definitions of AEs/SAEs, monitoring, and reporting.  Refer to 
Section 11.5 for monitoring of AEs of special interest.


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Monitoring of Concomitant Therapy
The use of concomitant medication and procedures will be monitored throughout the study.  
Refer to Section 9.8 for prohibited concomitant therapies.
11.3.
Laboratory Safety Assessments
Analysis of samples will be conducted centrally by PPD Global Lab.  Wherever possible during 
the Induction and Maintenance Period, Investigators should not send laboratory samples to their 
local labs as this may lead to unblinding of the treatment assignment given RPC1063’s MoA 
(retention of systemic lymphocytes).  Further details of the procedures to be followed for sample 
collection, storage, and shipment will be documented in a laboratory manual.
Additional and repeat laboratory safety testing may be performed at the discretion of the 
Investigator.
The following laboratory tests will be performed to assess the safety profile of RPC1063, as 
outlined in Table 1 and Table 2:

Routine safety laboratory tests:  

Hematology – red blood cell (RBC) count, total and differential WBC count 
(basophils, eosinophils, lymphocytes, monocytes, and neutrophils), platelet count, 
Hgb, hematocrit, mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC).  
Total and differential WBC counts will not be provided to the Investigator to 
maintain the treatment blind during the Induction and Maintenance Period. These 
parameters and alerts for these parameters will be monitored by the PPD Safety 
Surveillance team.

Blood chemistry - sodium, potassium, chloride, calcium, magnesium, phosphate, 
blood urea nitrogen, random glucose, albumin, alkaline phosphatase, creatinine, 
ALT, AST, gamma glutamyltransferase (GGT), amylase, total bilirubin, 
conjugated bilirubin and CRP. CRP results will not be reported until completion 
of the study to maintain the treatment blind during the Induction and Maintenance 
Period.  Abnormal laboratory parameters inconsistent with clinical presentation of 
UC or suspicious of underlying medical condition should be repeated for 
accuracy.  If an increase of amylase above the clinically notable value 
(≥300 U/L) is observed at any post randomization visit, lipase should be tested to 
determine the origin of elevated amylase (pancreatic versus extra pancreatic).

Urinalysis - leukocytes, specific gravity, bilirubin, blood, glucose, ketones, pH, 
protein, and urobilinogen

Routine blood samples will be analyzed by the central laboratory.  Blood samples 
taken at the screening visit are to be in the fasting state.  Blood samples taken at 
subsequent visits are recommended to be in the fasting state.  Details regarding 
collection of samples, shipment of samples, reporting of results, laboratory reference 
ranges, and alerting abnormal values will be supplied to the site before site initiation 
in a study laboratory manual.  The results of the analysis will be made available to 


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each site by the central laboratory, at the earliest, 48 hours after receipt of the samples 
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.  Abnormal laboratory values should not be 
recorded on the AE eCRF; however, any diagnoses (or signs or symptoms if a 
diagnosis is not possible) associated with the abnormal findings should be recorded 
on the AE eCRF.

Pregnancy test: serum beta-hCG must be performed at screening in women of 
childbearing potential. Urine beta-hCG will be performed in women 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 RPC1063 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.

Coagulation panel: prothrombin time (PT) and partial thromboplastin time (PTT).  
To be performed as scheduled in Table 1 and Table 2.

Serology testing will be performed at screening to determine the patient's immune 
status with respect to several viruses; testing will be as follows: 

anti-VZV IgG

HIV antibodies

HBsAg and HBcAg IgM

anti-HCV IgG or IgM
Patients who are negative for VZV IgG antibodies at screening can undergo vaccination and be 
randomized 30 days after appropriate VZV vaccination has been completed.  Patients testing 
positive for HIV, or for serological markers of acute or chronic hepatitis B or C, will be excluded 
from the study unless they are indicative of prior hepatitis B vaccination or cured hepatitis B and 
accompanied by normal liver transaminase values.  

TB infection: to be assessed using review of the patients’ medical history, current 
physical exam, current screening chest X-ray (if past chest X-rays within 6 months
prior to screening is not available) and either a purified protein derivative skin test or 
a QuantiFERON® Gold test for TB.  Patients with a positive purified protein 
derivative may use a QuantiFERON® Gold test to confirm the absence of active or 
latent TB.  
11.4.
PK and PD Assessments
PK samples will be shipped to PPD Global Central Labs.  Details of the procedures to be 
followed for sample collection, storage, and shipment will be documented in a separate PK 
Laboratory Manual.


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The following PK and PD assessments will be performed on the visit days specified in Table 1
and Table 2 to determine the safety profile of RPC1063:

Standard PK sampling:  PK samples are to be taken predose and 6-8 hours after 
dosing on Day 1. Samples on study will either be trough samples, taken prior to dose 
administration or will be collected 2 to 6 hours after dose administration, as indicated 
in the Schedule of Events footnotes.

Stool culture for fecal biomarkers – fecal lactoferrin and calprotectin, which are tests 
sensitive to the identification of intestinal inflammation

Plasma protein biomarker analysis (cytokines, chemokines, other inflammatory 
proteins)

Total Igs: IgA, IgG, IgM
11.5.
Monitoring of Patients With Adverse Events of Special Interest
Several of the AEs noted in fingolimod clinical studies may be a consequence of S1P1 
stimulation and will therefore be closely monitored in the RPC01-202 study.  These AEs include: 
a.
Bradycardia and heart conduction abnormalities.  Dose-related transient, reversible 
bradycardia and first degree atrioventricular block were reported primarily as first 
dose effects in fingolimod studies.  The HR reduction observed with sphingosine-1-
receptor agonists is an expected effect of S1PR modulation and appears to be 
conducted through the same pathway as vagus nerve stimulation. In addition, these 
negative chronotropic effects of S1P1 agonists appear to attenuate over time 
secondary to S1PR desensitization and internalization on cardiac myocytes 
(Kovarik 2008). This effect appears to occur with increasing exposure to 
investigational drug; thus, gradual dose escalation of the dose of RPC1063 over 
several days may mitigate against larger reductions in HR.
b. Pulmonary toxicity.  An initial sharp decrease followed by a slow progressive decline 
over time in FEV1 was observed in fingolimod clinical studies.  Nonclinical toxicity 
studies with RPC1063 have revealed the potential for pulmonary toxicity at doses 
considerably higher than the pharmacologically active dose.  Pulmonary function 
tests including FEV1, FVC, and DLCO, if applicable, will be measured in all patients. 
All efforts should be made to obtain DLCO assessments and exceptions based on lack 
of equipment must be pre-approved by the Sponsor. Every patient whose PFTs are 
abnormal will be followed 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).
c.
Hepatotoxicity.  Fingolimod caused frequent, reversible liver enzyme elevations 
greater than 3-fold above the ULN in up to 12% of patients; this was a significant 
cause of cessation of therapy.  In this study, clinical blood chemistry analyses to 
assess LFTs will be performed.  Every patient whose LFTs are abnormal will be 
followed until values return to baseline.
d. Macular edema. Instances of serious macular edema were reported in fingolimod 
renal transplant studies, and a 0.8% incidence was reported as an SAE in fingolimod 


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(1.25 mg dose) MS clinical studies.  Nonclinical studies with RPC1063 have not 
revealed eye-related toxicities.  In this study, OCT will be performed in all patients at 
baseline and the end of study visits or early termination.  In addition, patients will be 
questioned about visual signs or symptoms at each study visit and instructed to 
inform the investigator if they develop symptoms between visits. For patients with 
symptoms of macular edema, OCT and ophthalmologic examination including dilated 
ophthalmoscopy will also be performed.  Every patient whose ophthalmic evaluations 
reveal abnormalities will be followed until values return to baseline.
e.
Opportunistic or serious infections.  TB, serious bacterial infections, systemic fungal 
infections, viral infections such as herpes infections (including herpes zoster and 
disseminated herpes simplex) and protozoal infections should be reported as adverse 
events of special interest.
Overall, the following procedures should be followed:

Vital signs will be assessed in supine and standing position at every visit.  A sudden, 
significant fall in BP (> 20 mmHg) between 2 and 5 minutes after standing from the 
supine position will be interpreted as orthostatic hypotension and will be documented 
in the patient chart and eCRF.

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.  ECGs will occur predose 
and at Hour 6 following dosing, with more frequent assessments as clinically 
indicated; vital signs, including orthostatic BP assessment, will be assessed predose 
and then hourly for 6 hours following dosing.  

Clinicians should be particularly mindful of patients who have a low HR at baseline 
(spontaneously or through drug induced ß-receptor blockade), 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.  Furthermore, the common 
guidelines for treatment of bradycardia (e.g., Advanced Cardiac Life Support-ACLS 
guidelines) should be followed as appropriate:

In case of clinical symptoms or hypotension, administration of atropine 1 mg, 
repeated administration in 3-5 minutes.

If HR and/or BP remain unresponsive, consider administration of dopamine drip 
5-20 g/kg/min or epinephrine drip 2-10 g/min.

Performance of transcutaneous pacing may also be considered

In the setting of decreased BP, isoproterenol should be avoided or used with 
caution.

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 should be discontinued.
If a patient discontinues due to respiratory AE, the Investigator should ensure that the 


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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).

If patients have elevations in LFTs (ALT or/and AST) greater than 3 times the ULN, 
a retest should be performed within 14 days whenever possible. Upon confirmation 
of the abnormality, retests should be performed weekly until the elevated LFT 
decreases below 3 times the ULN.  If the LFTs increase is confirmed to be above 
5 times the ULN the investigational drug must be permanently discontinued.  

Study drug must be discontinued in any patient who has a diagnosis of macular 
edema.  Patients with a diagnosis of macular edema must be followed up monthly or
more frequently if needed based on the ophthalmologist’s judgment.  Further 
ophthalmological evaluations will be conducted until such time as resolution is 
confirmed or no further improvement is expected by the ophthalmologist (based on a 
follow-up period of not less than 3 months).  If the patient does not show definite 
signs of improvement on examination 6 to 8 weeks after discontinuation of 
investigational drug, then therapy for macular edema in conjunction with an 
ophthalmologist experienced in the management of this condition should be initiated.

Examination of the skin for lesions will be performed as part of the physical 
examination at screening and at the end of study.  If skin lesions are noted, the patient 
will be referred to a dermatologist for evaluation and follow-up care.


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12.
SAFETY DEFINITIONS, MONITORING, AND REPORTING
Throughout the study, the Investigator will remain alert to possible AEs.  If an AE occurs, the 
first concern should be for the safety of the patient, and appropriate medical intervention should 
be provided if necessary.  
At the signing for the informed consent form, patients should be given names and telephone 
numbers of site staff for reporting AEs and medical emergencies.
12.1.
Adverse Events
The AE definitions and reporting procedures provided in this protocol comply with current CFR 
21 Part 312.32.  An AE is any untoward medical occurrence that does not necessarily have a 
causal relationship with the investigational medicinal product.  An AE can therefore be any 
unfavorable or unintended sign, including an abnormal laboratory finding, symptom or disease 
temporally associated with the use of an investigational medicinal product whether or not 
considered related to the investigational medicinal product.
UC disease relapse and related symptoms will be monitored as study endpoints, but will not be 
recorded as AEs.
AEs will be monitored throughout the entire study including the 90-day Safety Follow-up Visit.  
Investigators will ask the patient at each visit if they have experienced any untoward occurrence 
since the last study visit.  All AEs will be recorded on the eCRFs provided: a description of the 
event, severity, time of occurrence, duration, any action (e.g., treatment and follow-up tests), and 
the outcome should be provided along with the Investigator’s assessment of the relationship to 
the investigational drug.
AEs will be recorded from the time written informed consent is signed until 90 days following 
the last dose of treatment with the investigational drug.
If known, the event diagnosis should be recorded, in preference to the listing of individual signs 
or symptoms.  AEs must be graded as being mild, moderate, or severe and their approximate 
duration given.  Definitions of severity are as follows:
Mild: an AE usually transient in nature and generally not interfering with normal activities;
Moderate: an AE that is sufficiently discomforting to interfere with normal activities;
Severe: an AE that is incapacitating and prevents normal activities.
Even if the Investigator feels there is no relationship to the investigational drug, all AEs MUST 
be recorded in the eCRF.  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.


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
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.

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 (e.g., 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 (e.g., 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.
12.2.
Serious Adverse Events
A SAE is any untoward medical occurrence or effect that fulfills the following criteria:

Results in death

Is life-threatening (NOTE: the term "life-threatening" 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 hospitalization or prolongation of existing inpatient hospitalization


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
Results in persistent or significant disability or incapacity

Is a congenital abnormality/birth defect

Important medical events not captured by the above but which may, for example, 
require medical intervention to prevent one of the outcomes above.
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 may 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.  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.
12.3.
Reporting of Serious Adverse Events
Investigator reporting requirements for SAEs will be managed on behalf of the Sponsor by PPD.  
Full details of the procedures to be adopted will be documented in a safety management plan 
approved by responsible parties, in brief:
Any SAE which occurs to any patient from the time written informed consent is signed through 
the last visit must be reported by the Investigator.  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 product, must also be reported.  Any SAE that is ongoing when the patient
completes the study or discontinues from the study will be followed by the Investigator until the 
event has resolved, stabilized, or returned to baseline status or the patient is lost to follow-up.
Any AE considered serious by the Investigator or Sub-Investigator or that meets serious criteria 
should be reported to PPD Pharmacovigilance (PVG) using the remote data capture (RDC) 
system. Data entry must be completed within 24 hours from the time the study site personnel 
first learned of the event. 
In the event that RDC entry is not possible (e.g., system failure or access problems), the study 
site should complete the paper SAE report form and fax the form to PPD PVG within 24 hours of 
awareness of the event.  The RDC system should be updated as soon as it is available.
Contact information for the PPD Pharmacovigilance Center: 
SAE Hotline: +44 1223 374240 
SAE Fax line: +44 1223 374102 
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.
12.4.
Monitoring of Patients with Adverse Events
Investigators must carefully monitor each patient for AEs.  This includes clinical laboratory 
variables.  Assessments must be made of the seriousness, severity, and relationship to the 


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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 PPD on the 
patient’s condition.  During the study, all AE/SAEs should be followed up until resolved, 
stabilized, or returned to baseline status or patient is lost to follow-up, unless the event is 
considered by the Investigator to be unlikely to resolve due to the patient’s underlying disease.
12.5.
Procedures to be followed in the Event of Abnormal Laboratory Test 
Values
In the event of unexplained abnormal laboratory test values, the tests should be repeated 
immediately and followed up until they have returned to the normal range and/or an adequate 
explanation of the abnormality is found.  For abnormal laboratory test values related to AEs of 
special interest, refer to Section 11.5.
12.6.
Clinical Laboratory Parameters and Abnormal Laboratory Test 
Results
Clinically significant changes, in the judgment of the Investigator, in laboratory parameters 
(abnormalities) will be recorded as AEs.  
During the treatment period, all Total WBC and WBC differential results will be blinded.  
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 lymphocyte count [ALC] < 200 cells/µL

Absolute neutrophil count [ANC] < 1000 cells/µL

Total WBC > 20,000 cells/µL
If the repeat values also exceed these limits, the Investigator will be informed that the patient’s 
results for the abnormal parameter have fallen below the acceptable threshold.
If ANC or total WBC counts are confirmed below the acceptable limits, the Medical Monitor 
will contact the treating investigator to request close monitoring for risk of serious infection and 
appropriate follow-up, at the discretion of the investigator.
If the ALC is confirmed < 200 cells/µL, the Investigator will temporarily discontinue 
investigational drug and then consult with the Medical Monitor. Laboratory testing will be 
repeated weekly until ALC is > 500 cells/µL.
When ALC has returned to > 500 cells/µL, the treatment may be reinitiated at the Investigator’s 
discretion (Section 9.6.2 for instructions on resuming treatment after missing doses).  For 
patients whose ALC level is confirmed < 200 cells/μL and has not reached the acceptable range 
(ALC > 500 cells/µL) during the study, laboratory testing will be repeated at the 90-day Safety 
Follow-up Visit.
If patients have elevations in ALT and/or AST ≥3x the upper limit of normal (ULN), a retest 
should be performed as soon as possible but not later than 14 days after the original test.  If the 
abnormality is confirmed, weekly testing should continue until ALT and AST are < 3x ULN. If 
the ALT and/or AST stabilizes at a level > 3x ULN, the Medical Monitor may agree to less 


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frequent testing.  The Investigator should establish causality. In addition, the confirmed 
elevation > 3x ULN is an adverse event of special interest (see Section 11.5) and should be 
reported by the Investigator. 
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 INR > 1.5) 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.
12.7.
Abnormal Clinical Safety Findings
Clinically significant changes, in the judgment of the Investigator, will be recorded as AEs.
12.8.
Treatment of Overdose of Study Treatment
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 PPD 
Pharmacovigilance Center.  Overdoses do not need to be recorded as AEs in the eCRF; only in 
case of any AEs associated with the overdose, these should be reported on relevant AE/SAE 
sections in the eCRF.  
12.9.
Procedures in Case of Pregnancy
If a urine pregnancy test is positive, the Investigator will instruct the patient to suspend further 
RPC1063 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 for 
confirmation.
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, or 
congenital abnormality) must be followed up and documented even if the patient was 
discontinued from the study.
All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous miscarriages should 
also be reported and handled as SAEs.  Elective abortions without complications should not be 


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handled as AEs.  All outcomes of pregnancy must be reported to the Sponsor and/or its designee.
In cases of live birth, the infant will be followed for up to a year.


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13.
DATA MANAGEMENT AND STATISTICAL ANALYSIS
The data management and statistical analysis of this study will be performed by PPD.
13.1.
Data Management
An eCRF will be used for the current study, and a data management plan will be prepared by the 
CRO, PPD.  
13.2.
Sample Size Estimation
Approximately 300 patients will be screened to ensure that 180 patients are randomized in the IP, 
assuming a 40% screen failure rate.  Patients will be enrolled in a 1:1:1 randomization with 
approximately 60 patients assigned per treatment arm.
The sample size is justified with respect to the comparison of remission rates at the end of the IP
between an RPC1063 group and the placebo group.  Based on the use of a two-sided test at the 
alpha=0.05 level of significance, and assuming a placebo remission rate of 10%, a sample size of 
60 patients per group will provide 80% power to detect an improvement in the remission rate of 
21 percentage points or larger (i.e., an active group remission rate of 31% or larger).
A meaningful change or clinical improvement (defined in this study as the incremental increase 
in the proportion of patients obtaining remission in response to a medication compared to 
placebo), is dependent upon both the impact of the disease and the impact of the medication on 
the patient’s health and well-being.  Key factors that need to be considered include: the 
consequences of the disease, the efficacy and safety profile of the therapy, and the efficacy and 
safety profile of alternative treatments.
UC is a disease with a profound impact on the patient’s health and well-being with chronic 
diarrhea, blood loss, abdominal pain and loss of income. Current therapies for moderately to 
severely active UC have significant limitation related to their efficacy, safety, or convenience.
We have chosen remission as the primary endpoint of this study since to obtain remission 
requires patients to be free of symptoms and have significant resolution of their disease activity. 
Patients who obtain remission have a notable improvement in their health and quality of life.  
Obtaining remission, this clinically important endpoint, is a notable medical achievement; 
therefore, a moderate increase of 15-20% in the proportion of patients in remission would be 
meaningful for patients with moderate to severely active UC.  
13.3.
Statistical Analysis Plan
The Statistical Analysis Plan (SAP) will provide a detailed description of the statistical methods 
and expand on the details provided in the protocol.  Tables, listings, and figures shells will also 
be provided.
13.4.
Randomization
Patients will be randomized into the study on Day 1 using an IVRS provided by PPD.  
Patients will be randomized 1:1:1 to receive placebo, RPC1063 0.5 mg, or RPC1063 1 mg.  
The randomization will be stratified by anti-TNF therapy (yes vs no).


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Treatment groups are described in Section 9.6.1.  
13.5.
Analysis Populations
The following analysis populations will be used in the statistical analysis: 
Intent-to-Treat (ITT): The ITT population will consist of all randomized patients. The primary 
efficacy analysis will be carried out in the intent-to-treat population, with treatment assignment 
designated according to randomized treatment.
Modified Intent-to-Treat (MITT):  The MITT population will consist of all randomized patients
who received at least 1 dose of investigational drug, with treatment assignment designated 
according to randomized treatment.  
Per Protocol (PP): The PP population will consist of the subset of the ITT population, excluding
those patients who have had a major protocol violation.  These will be defined prospectively, in 
advance of data lock and primary analyses, in the final SAP, by the (aggregate results blinded) 
project statistician.
PK: The PK population will consist of patients who have at least one baseline and one post-
baseline PK assessment.
Safety: The Safety population will consist of all patients receiving any investigational drug and 
safety analyses will be carried out on this population according to treatment actually received.
13.6.
Demographic and Baseline Data
Demographic and baseline data will be summarized by treatment group.  Frequency distributions 
and summary statistics will be presented.
13.7.
Patient Disposition
Patient disposition will be summarized and summary statistics presented.
13.8.
Efficacy Analysis
13.8.1.
Endpoints
Efficacy analyses include clinical remission, clinical response, mucosal healing, and histological 
remission, which are defined as follows:

Clinical remission: Mayo score of ≤2 points and with no individual subscore of > 1 
point

Clinical response: a reduction from baseline in Mayo score of ≥3 points and ≥30%, 
and a decrease from baseline in the rectal bleeding subscore of ≥1 point or an 
absolute rectal bleeding subscore of ≤1 point

Mucosal healing: an endoscopy subscore of ≤1 point 

Histological remission: Geboes index score < 2.0


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Endoscopy images will be obtained during each endoscopy and will be sent to Robarts Clinical 
Trials for central reading and determination of the Mayo endoscopy score. The result of the 
central reading of the endoscopy will be used to ensure patient eligibility prior to enrollment and 
to calculate the Mayo Score at the times indicated in the schedule of events.  The Mayo score 
used for clinical endpoints in the study will utilize the Mayo endoscopy score derived from the 
central reader.
13.8.2.
Primary Efficacy Analysis
The primary efficacy analysis will be completed based on the ITT population for the IP.  
The primary analysis will be carried out when all patients have completed (or would have been 
eligible to complete) the IP of the study.
The primary endpoint of clinical remission at Week 8 will be analyzed using the Cochran-
Mantel-Haenszel (CMH) test, stratified by prior anti-TNF therapy experience. The primary 
analysis will use the data from the 1 mg dose and placebo groups and compare the remission 
rates in these 2 groups using a two-sided test at the alpha=0.05 level of significance.
13.8.3.
Key Secondary Analyses
If the primary efficacy analysis is statistically significant (p < 0.05), then additional confirmatory 
tests using the ITT population will be performed in the following prespecified order:

Proportion of patients in clinical remission at Week 8: 0.5 mg dose versus placebo

Proportion of patients in clinical response at Week 8: 1 mg dose versus placebo

Proportion of patients in clinical response at Week 8: 0.5 mg dose versus placebo

Change in Mayo score from baseline at Week 8: 1 mg dose versus placebo 

Change in Mayo score from baseline at Week 8: 0.5 mg dose versus placebo 

Proportion of patients with mucosal healing at Week 8: 1 mg dose versus placebo  

Proportion of patients with mucosal healing at Week 8: 0.5 mg dose versus placebo  

Proportion of patients in clinical remission at Week 32: 1 mg dose versus placebo 

Proportion of patients in clinical remission at Week 32: 0.5 mg dose versus placebo 

Proportion of patients in clinical response at Week 32: 1 mg dose versus placebo

Proportion of patients in clinical response at Week 32: 0.5 mg dose versus placebo

Change in Mayo score from baseline at Week 32: 1 mg dose versus placebo 

Change in Mayo score from baseline at Week 32: 0.5 mg dose versus placebo 

Proportion of patients with mucosal healing at Week 32: 1 mg dose versus placebo

Proportion of patients with mucosal healing at Week 32: 0.5 mg dose versus placebo
Provided that all previously specified tests are statistically significant (p < 0.05), each of these 
comparisons will be assessed using a two-sided test at the alpha = 0.05 level of significance.  


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However, if a comparison is not statistically significant, then all subsequent comparisons will be 
considered exploratory.
Secondary endpoints that are defined as proportions will be analyzed using the same type of 
methodology as described for the primary analysis.  Analyses of all proportion endpoints using 
the CMH test will be completed using the data from the two groups being compared.  
Quantitative secondary endpoints will be analyzed using analysis of covariance (ANCOVA) 
models with effects for treatment group (three levels) and prior anti-TNF therapy experience, and 
with the baseline value of the corresponding endpoint included as a covariate.  All secondary 
analyses will be carried out using two-sided test at the 5% level of significance.
13.8.4.
Exploratory and Sensitivity Analyses
 
 
  
 
 
 
 
 
   
 
 
 
 
 


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13.9.
Pharmacokinetics
PK analyses will be detailed in a separate plan.
13.10.
Safety
The incidence of treatment-emergent AEs will be summarized for each treatment group overall, 
by severity, and by relationship to investigational drug.  SAEs will be presented by treatment 
group and by relationship to investigational drug.  Summary tables will present incidence 
estimates and individual event rates by system organ class as well as within each system organ 
class.  Patients experiencing an event more than once with varying severity will be counted only 
once with the maximum severity within each system organ class/preferred term.  For incidence 
of relationship to investigational drug, patients will be counted only once, in the category of the 
strongest relationship to investigational drug within each system organ class/preferred term.
Laboratory values, vital signs, ECG, and PFT data will be presented in appropriate summary 
tables.
13.11.
Missing Data
For the primary analysis, as well as for the analyses of all key secondary efficacy endpoints that 
are defined as proportions, patients who do not provide data at the specified time point will be 
classified as nonresponders.
The Mayo score used for clinical endpoints in the study will utilize the Mayo endoscopy score 
derived from the central reader. In the case that a central endoscopic result is missing and the 
endoscopic subscore read by the Investigator will be utilized.
One of the key secondary efficacy endpoints (change in Mayo score) is a quantitative endpoint.  
For the key secondary analyses of this variable, missing values will be replaced by the least 
favorable observed change observed in the placebo group.
Sensitivity analyses of the primary and key secondary endpoints will be carried out to investigate 
the impact of missing data on the efficacy conclusions.  These will include analyses of completed 
cases, observed cases, and multiple imputation model-based methods.
13.12.
Interim Analysis
No interim analysis is planned for this study.
13.13.
Data Monitoring Committee
An independent DMC will be charged with monitoring accumulating data from the trial, as well 
as general aspects of trial conduct.  
The committee will meet periodically, approximately four times a year during the study, to 
review unblinded aggregate analyses by treatment group concerning enrollment, treatment 
compliance, adherence to follow-up schedule, and safety data from the trial until the end of the 


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Maintenance Period.  The DMC may recommend modifying or stopping the trial early due to 
safety concerns based on data reviews.  
The blinding plan to assure that all Sponsor personnel and all personnel involved in the conduct 
of the study remain blinded to the results of reviews will be specified in the DMC Charter.


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14.
MONITORING PROCEDURES (QUALITY ASSURANCE)
The Sponsor has ethical, legal, and scientific obligations to conduct this study in accordance with 
established research principles and ICH GCP guidelines.  As such, in order to fulfill these 
obligations and to maintain current of study progress, the Sponsor's monitors or representatives 
will visit the investigative sites during study conduct, in addition to maintaining telephone and 
written communication.  On-site visits, telephone calls, and regular inspection of the eCRFs will 
be conducted in order to assess patient enrolment, compliance with protocol procedures, 
completeness and accuracy of data entered on the eCRFs, verification of eCRF data against 
original source documents, and occurrence of AEs.  The Investigator must provide the monitor 
with full access to all source and study documents.
14.1.
Routine Monitoring
Sponsor assigned monitors will conduct regular site visits to the investigational facilities for the 
purpose of monitoring various aspects of the study.  The Investigator must agree to Sponsor-
authorized personnel having direct access to the clinical (or associated) files and clinical study 
supplies (dispensing and storage areas) for all study patients considered for study entry for the 
purpose of verifying entries made in the eCRF, and assist with their activities, if requested.  
Adequate time and space for monitoring visits should be made available by the Investigator.
The site must complete the eCRFs in a timely manner and on an ongoing basis to allow regular 
review by the Study Monitor.
Whenever a patient name is revealed on a document that is to be collected for the Sponsor the 
name must be blacked out permanently by the site personnel, leaving the initials visible, and 
annotated with the patient number as identification.
14.2.
Inspections and Auditing Procedures
The Sponsor or its representative may conduct audits at the investigative sites including, but not 
limited to, drug supply, presence of required documents, the informed consent process, and 
comparison of eCRFs with source documents.  All medical records (progress notes) must be 
available for audit.  The Investigator agrees to participate with audits conducted at a convenient 
time in a reasonable manner.
Government regulatory authorities may also inspect the Investigator during or after the study.  
The Investigator or designee should contact the Sponsor/CRO immediately if this occurs.  
He/she must cooperate fully with regulatory authorities or other audits conducted at a convenient 
time in a reasonable manner.
The purpose of an audit is to assess whether ethics, regulatory and quality requirements are 
fulfilled.
14.3.
Product Quality Complaint
A Product Quality Complaint (PQC) is any written, electronic, or oral communication that 
alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, 
purity, or performance of any drug product manufactured by or on behalf of Celgene after it is 
released for distribution. PQCs may reduce the usability of the product for its intended function 


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or affect performance of the product and therefore pose a significant risk to the patient. Examples 
of PQCs include (but are not limited to): mixed product, mislabeling, lack of effect, 
seal/packaging breach, product missing/short/overage, contamination, suspected falsified, 
tampered, diverted or stolen material, and general product/packaging damage. If you become 
aware of a suspected PQC, you are obligated to report the issue immediately. You can do so by 
emailing customercomplaints@celgene.com or by contacting the Celgene Customer Care Center 
(1-888-423-5436).


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15.
STUDY MANAGEMENT AND MATERIALS
15.1.
Electronic Case Report Forms
An eCRF will be used to store and transmit patient information.  The file structure and format for 
the eCRF will be provided by the Sponsor or their representative and should be handled in 
accordance with the instructions provided.
The eCRF must be reviewed and electronically signed, and dated by the Investigator.
Access to the eCRF will be strictly password protected and limited to personnel directly 
participating in the study.  Data should be entered into the eCRF completely by examining 
personnel or the study coordinator.  The eCRF must be completed as soon as possible after any 
patient evaluation or communication.  If data is to be changed due to erroneous input or other 
reason, an electronic audit trail will track these changes.  The eCRFs and computers that store 
them must be accessible to Study Monitors and other regulatory auditors.
15.2.
Data Collection
During each study visit, a physician participating in the study will maintain progress notes in the 
patient’s medical records to document all significant observations.  At a minimum, these notes 
will contain:  the date of the visit and the corresponding day or visit in the study schedule (e.g., 
screening, Day 1, Day 28, etc.); general condition and status remarks by the patient, including 
any significant medical findings; the severity, frequency, duration, and resolution of any reported 
AE, and the Investigator's assessment as to whether or not the reported AE is study drug-related; 
changes in concomitant medications or dosages; and a general reference to the procedures 
completed; and the signature or initials of all physicians making an entry in the medical record 
(progress notes).
In addition, any contact with the patient via telephone or other means that provides significant 
clinical information will also be documented in the medical record (progress notes), as described 
above.  
Information from the medical records (progress notes) and other source documents will be 
promptly transcribed to the appropriate section of the eCRF.
Changes to information in the medical record (progress notes), eCRF, and other source 
documents will be initialed and dated on the day the change is made by the Investigator or 
designee.  If the reason for the change is not apparent, a brief explanation for the change will be 
written adjacent to the change.
15.3.
Source Documents Maintenance
Source documents contain the results of original observations and activities of a clinical 
investigation.  Source documents include, but are not limited to, medical records (progress 
notes), computer printouts, screening logs and recorded data from automated instruments.  
All source documents from this study will be maintained by the Investigator and made available 
for inspection by authorized persons.  The original signed informed consent for each patient shall
be filed with records kept by the Investigator and a copy shall be given to the patient.


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15.4.
Record Maintenance
All data derived from the study will remain the property of the Sponsor.
Records must be retained in accordance with the current ICH Guidelines on GCP.  All essential 
study documents including records of patients, source documents, eCRFs and investigational 
drug inventory must be kept on file.
US FDA regulations (21 CFR 312.62[c]) require that records and documents pertaining to the 
conduct of this study and the distribution of investigational drug, including eCRFs, consent 
forms, laboratory test results, and medical inventory records, must be retained by the Principal 
Investigator for 2 years after marketing application approval.  If no application is filed, these 
records must be kept 2 years after the investigation is discontinued and the US FDA and the 
applicable national and local health authorities are notified.  The Sponsor or their representative 
will notify the Principal Investigator of these events.
Essential documents should be retained until at least two years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or until at least two years have elapsed since the formal 
discontinuation of clinical development of the investigational products.  However, essential 
documents may be retained for a longer period if required by the applicable regulatory 
requirements or by agreement with the Sponsor.  The Sponsor is responsible for informing the 
Investigator when these documents need no longer be retained.
The Investigator will not dispose of any records relevant to this study without written permission 
from the Sponsor, and will provide the Sponsor the opportunity to collect such records.  
The Investigator shall take responsibility for maintaining adequate and accurate hard copy source 
documents of all observations and data generated during this study.  Such documentation is 
subject to inspection by the Sponsor, its representatives and regulatory authorities.
If an Investigator moves, withdraws from an investigation or retires the responsibility for 
maintaining the records may be transferred to another person who will accept responsibility.  
Notice of transfer must be made to and agreed by the Sponsor.
15.5.
Confidentiality
All information obtained during the conduct of the study with respect to the patient’s state of 
health will be regarded as confidential.  For disclosure of any such information, an agreement 
will be obtained in writing.  
The Investigator must ensure that each patient’s anonymity is maintained.  On eCRFs and other 
documents submitted to the Sponsor or the CRO, patients must not be identified by name.  
Instead, patients will only be known by their initials and by the unique patient number allocated 
to them in order to ensure confidentiality on all study documentation.  Patients will retain this 
unique number throughout the study.  The Investigator will keep a separate log of these codes.
In order to comply with government regulatory guidelines and to ensure patient safety, it may be 
necessary for the Sponsor and its representative, the CRO personnel, the local research review 
board, or the US FDA to review patients’ medical records as they relate to this study.  Only the 
patient’s unique number on the eCRFs will identify him/her, but their full names may be made 


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known to a drug regulatory authority or other authorized government or health care officials, if 
necessary, and to personnel designated by the Sponsor.
Documents that are not for submission to the Sponsor or the CRO (e.g., consent forms) will be 
maintained by the Investigator in strict confidence, except to the extent necessary to allow 
monitoring by the Sponsor and the CRO, and auditing by regulatory authorities.  No documents 
identifying patients by name will leave the investigative site and patient identity will remain 
confidential in all publications related to the study.


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16.
ADMINISTRATION PROCEDURES
16.1.
Regulatory Approval
The Sponsor or their appointed agents will be responsible for ensuring that appropriate 
regulatory authority approvals are obtained, according to local country requirements.
No patient may enter the study until this approval has been obtained.  A copy of the approval 
(where one is provided, according to local country requirements) will be provided to the 
Investigator and to the IRB(s)/IEC(s).
16.2.
Protocol Amendments
In accordance with ICH Topic E 6 (R1) Guideline for GCP the Investigator should not 
implement any deviation from, or changes of the protocol without agreement by the Sponsor and 
documented approval from the IRB/IECs of a protocol amendment, except where necessary to 
eliminate an immediate hazard(s) to study patients, or when the change(s) involves only 
logistical or administrative aspects of the study (e.g., change in monitor(s), change of telephone 
number(s)).  
Any change to the protocol must be handled as a protocol amendment.  Any potential 
amendment must be approved by the Sponsor.  A written amendment must be submitted to 
the appropriate regulatory authorities and to the IRB/IECs assuming this responsibility.  
The Investigator must await IRB/IEC approval of protocol amendments before implementing 
the changes, except where necessary to eliminate apparent immediate hazard to patients.  In these 
cases, the IRB/IEC must be notified within 5 days of the change.
All amendments to the protocol must be approved in writing by both the appropriate regulatory 
authorities and the IRB/IEC, except for administrative amendments, which require notification 
but not written approval.  Once approved, the protocol amendment will be distributed to all 
recipients of the original protocol, with instructions to append the amendment to the protocol.
If, in the judgment of the local IRB/IEC, the Investigator, and/or Sponsor, the protocol 
amendment alters the study design, procedures and/or increases the potential risk to the patient, 
the currently approved written informed consent form will require modification.  The modified 
informed consent form must also be reviewed and approved by the Sponsor, appropriate 
regulatory authorities, and the IRB/IEC.  In such cases, repeat informed consent must be 
obtained from patients enrolled in the study before participation continues.
16.3.
Protocol Adherence and Deviations
The protocol must be read thoroughly and the instructions must be followed.  However, 
exceptions will be made in emergency situations when the protection, safety, and well-being of 
the patient requires immediate intervention based on the judgment of the Investigator or a 
responsible, appropriately trained, and credentialed professional(s) designated by the Investigator 
as a sub-Investigator.  
In the event of a significant protocol deviation due to an emergency, accident, or error, the 
Investigator or designee must contact the Medical Monitor at the earliest possible time by 
telephone.  This allows for an early joint decision to be made as to whether or not the patient


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should continue in the study.  The Investigator, the Sponsor, and the Medical Monitor will 
document this decision.
16.4.
Publication Policy
After completion of the study, the Investigator(s) may prepare a joint publication with the 
Sponsor.  The Investigator(s) must undertake not to submit any part of the data from this 
protocol for publication without the prior consent of the Sponsor.
16.5.
Clinical Study Report
A final clinical study report will be prepared according to the ICH guideline on Structure and 
Contents of Clinical Study Reports.  A final clinical study report will be prepared regardless of 
whether the study is completed or prematurely terminated.  
16.6.
Contractual and Financial Details
The Investigator (and/or, as appropriate, the hospital administrative representative) and the 
Sponsor will sign a clinical study agreement prior to the start of the study, outlining overall 
Sponsor and Investigator responsibilities in relation to the study.  The contract should describe 
whether costs for pharmacy, laboratory, and other protocol-required services are being paid 
directly or indirectly.  Financial Disclosure Statements will need to be completed, as requested 
by FDA CFR 21 part 54.
16.7.
Insurance, Indemnity and Compensation
The Sponsor undertakes to maintain an appropriate clinical study insurance policy.
Deviations from the study protocol - especially the prescription of a dose other than that 
scheduled in the study protocol, other modes of administration, other indications, and longer 
treatment periods - are not permitted and shall not be covered by the statutory patient insurance 
scheme.
16.8.
Discontinuation of the Study
This study may be terminated by the Sponsor.  The study may also be terminated prematurely at 
any time when agreed to by both the Investigators and the Sponsor as being in the best interests 
of patients, and justified on either medical or ethical grounds.  In terminating the study, the 
Sponsor, the CRO (PPD) and the Investigator will ensure that adequate consideration is given to 
the protection of the patients’ interests.
16.9.
Study Center File Management
The Investigator is responsible for assuring that the Study Center File is maintained.  The Study 
Center File will contain, but will not be limited to, the information listed below:
1. Investigator’s Brochure;
2. Current, signed version of the protocol and any previous versions of the protocol;
3. Protocol amendments (if applicable);


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4. Operations Manual (if applicable);
5. Current informed consent form (blank) and any previous versions of the informed 
consent form;
6. Curricula Vitae of Investigator(s) and sub-Investigator(s) and photocopy of their 
respective license(s) where required by law; Original US FDA Form 1572 (for all studies 
conducted under US Investigational New Drug [IND] regulations), signed by all Principal 
Investigators.  The names of any sub-Investigators must appear on this form.  
Investigators must also complete all regulatory documentation as required the ICH GCP 
and by local or national regulations;
7. Documentation of IRB/IEC approval of the protocol, the informed consent form, any 
protocol amendments, and any informed consent form revisions;
8. All correspondence between the Investigator, IRB/IEC, and the Sponsor/CRO relating to 
study conduct;
9. Lab certification(s);
10. Monitoring log;
11. Study drug invoices;
12. Signature list of all staff completing eCRFs; and
13. Signature list of all staff completing drug accountability summaries.






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18.
APPENDIX
18.1.
Appendix 1: Elements of Informed Consent
ELEMENTS OF INFORMED CONSENT
Both the informed consent discussion and the written informed consent form and any other written 
information to be provided to patients should include explanations of the following:

That the study involves research.

The purpose of the study.

The study treatment(s) and the probability for random assignment to each treatment.

The study procedures to be followed including all invasive procedures.

The patient’s responsibilities.

Those aspects of the study that are experimental.

The reasonably foreseeable risks or inconveniences to the patient and, when applicable, to an 
embryo, fetus, or nursing infant.

The reasonably expected benefits.  When there is no intended clinical benefit to the patient, the 
patient should be made aware of this.

The alternative procedure(s) or course(s) of treatment that may be available to the patient, and 
their important potential benefits and risks.

The compensation and/or treatment available to the patient in the event of study-related injury.

The anticipated prorated payment, if any, to the patient for participating in the study.

The anticipated expenses, if any, to the patient for participating in the study.

That the patient’s participation in the study is voluntary and that the patient may refuse to 
participate or withdraw from the study, at any time, without penalty or loss of benefits to which 
the patient is otherwise entitled.

That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be 
granted direct access to the patient’s original medical records for verification of clinical study 
procedures and/or data, without violating the confidentiality of the patient, to the extent 
permitted by the applicable laws and regulations and that, by signing a written informed 
consent form, the patient or the patient’s legally acceptable representative is authorizing such 
access.

That records identifying the patient will be kept confidential and, to the extent permitted by 
the applicable laws and/or regulations, will not be made publicly available.  If the results of 
the study are published, the patient’s identity will remain confidential.

That the patient or the patient’s legally acceptable representative will be informed in a timely 
manner if information becomes available that may be relevant to the patient’s willingness to 
continue participation in the study.

The person(s) to contact for further information regarding the study and the rights of study 
patients, and whom to contact in the event of study-related injury.

The foreseeable circumstances and/or reasons under which the patient’s participation in the 
study may be terminated.


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
The expected duration of the patient’s participation in the study.

The approximate number of patients involved in the study.


EDMS Doc. Number: 23698993 - 23698906
Celgene Signing Page
This is a representation of an electronic record that was signed electronically in Livelink.
This page is the manifestation of the electronic signature(s) used in compliance with
the organizations electronic signature policies and procedures.
UserName: Oviedo-Orta, Ernesto (eoviedoorta)
Title:  Sr Director, Clinical R&D, I&I
Date: Sunday, 05 May 2019, 02:39 PM   Eastern Daylight Time
Meaning: Approved, no changes necessary.
 ================================================

SAP_001.pdf: 
SAP for Protocol No.  RPC01-202  
 
Receptos, Inc 
 
 
Page 1 of 37 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
Title: 
 
 
A Phase 2, multi-center, randomized, double-blind, placebo-
controlled parallel-group study to evaluate the clinical efficacy and 
safety of induction therapy with RPC1063 in patients with 
moderately to severely active ulcerative colitis 
 
 
Protocol: 
RPC01-202 
 
 
Sponsor: 
Receptos, Inc. 
10835 Road to the Cure, Suite 205 
San Diego, CA 92121 
USA 
Tel: 858-652-5700 
Fax: 858-587-2659 
 
 
Date: 
 
September 23, 2014 
 
 
Status: 
 
Version 2.0 
 
 
 
 
 
CONFIDENTIAL 
 
 
This document is a confidential communication of Receptos.  Acceptance of this document constitutes agreement by the 
recipient that no unpublished information contained herein shall be published or disclosed without prior written approval, 
except that this document may be disclosed to the appropriate Institutional Review Board(s)/Independent Ethics 
Committee(s) under the condition that they keep it confidential. 




Sponsor: Receptos, Inc. 
 
Statistical Analysis Plan for Protocol No.  RPC01-202 
Page 3 of 37 
 
TABLE OF CONTENTS 
SIGNATURES.................................................................................................................................2 
TABLE OF CONTENTS.................................................................................................................3 
LIST OF ABBREVIATIONS..........................................................................................................6 
1. 
INTRODUCTION........................................................................................................8 
2. 
PURPOSE OF ANALYSES.........................................................................................8 
3. 
STUDY OBJECTIVES AND ENDPOINTS................................................................8 
3.1. 
Study Objectives...........................................................................................................8 
3.1.1. 
Primary Objective.........................................................................................................8 
3.1.2. 
Secondary Objectives ...................................................................................................8 
3.1.3. 
Exploratory Objectives.................................................................................................8 
3.2. 
Endpoints......................................................................................................................9 
3.2.1. 
Efficacy Endpoints........................................................................................................9 
3.2.2. 
Safety Endpoints...........................................................................................................9 
3.2.3. 
PK and PD Endpoints.................................................................................................10 
4. 
STUDY DESIGN .......................................................................................................10 
5. 
DEFINITIONS ...........................................................................................................13 
5.1. 
Time Point Definitions ...............................................................................................13 
5.2. 
Efficacy Assessments .................................................................................................14 
5.2.1. 
Flexible Sigmoidoscopy/Colonoscopy.......................................................................14 
5.2.2. 
Mayo Score.................................................................................................................14 
5.3. 
Safety Definitions.......................................................................................................16 
5.4. 
Other Definitions ........................................................................................................17 
6. 
STATISTICAL METHODS.......................................................................................17 
6.1. 
General Analysis Approach........................................................................................17 
6.2. 
Coding Dictionaries....................................................................................................18 
6.3. 
Data Management.......................................................................................................18 
6.4. 
Missing values ............................................................................................................18 
6.5. 
Sample Size ................................................................................................................18 
6.6. 
Study Blinding, Patient Identification and Replacement of Patients..........................19 
6.7. 
Enrollment and Randomization Procedures ...............................................................19 


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6.8. 
Analysis Populations ..................................................................................................19 
6.9. 
DMC ...........................................................................................................................20 
6.10. 
Final Analyses and Reporting.....................................................................................20 
6.11. 
Patient Disposition......................................................................................................21 
6.12. 
Demographics and Baseline Characteristics...............................................................21 
6.13. 
General Medical History.............................................................................................21 
6.14. 
Ulcerative Colitis Disease History..............................................................................21 
6.15. 
Protocol Deviations ....................................................................................................22 
6.16. 
Dosing Compliance ....................................................................................................22 
6.17. 
Treatment Compliance................................................................................................23 
6.18. 
Prior and Concomitant Medications...........................................................................23 
6.19. 
Efficacy Analyses.......................................................................................................23 
6.19.1. 
Endpoints....................................................................................................................24 
6.19.2. 
Primary Efficacy Analysis..........................................................................................24 
6.19.3. 
Secondary Efficacy Analyses .....................................................................................24 
6.19.4. 
Exploratory Efficacy Analyses...................................................................................25 
6.19.5. 
Sensitivity Analyses....................................................................................................25 
6.19.6. 
Other Efficacy Analyses.............................................................................................26 
6.19.6.1. 
Mayo Score at Week 32..............................................................................................26 
6.19.6.2. 
Mayo Score at the End of OLP...................................................................................26 
6.19.6.3. 
Partial Mayo Score .....................................................................................................26 
6.19.6.4. 
Endoscopy Data Availability......................................................................................27 
6.20. 
Safety Analysis...........................................................................................................27 
6.20.1. 
Adverse Events...........................................................................................................27 
6.20.2. 
Physical Examinations................................................................................................29 
6.20.3. 
Height and Weight......................................................................................................29 
6.20.4. 
Vital Signs ..................................................................................................................29 
6.20.5. 
Electrocardiograms (ECGs) and Holter Monitoring...................................................31 
6.20.6. 
Laboratory Assessments .............................................................................................31 
6.20.7. 
Pulmonary Function Tests..........................................................................................32 
6.20.8. 
Ophthalmological Examination..................................................................................33 
6.20.9. 
Dermatological Examination......................................................................................33 
6.21. 
PD Analysis ................................................................................................................33 


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7. 
REPORTING CONVENTIONS ................................................................................34 
8. 
DEVIATIONS FROM PROTOCOL..........................................................................36 
9. 
REFERENCES ...........................................................................................................37 
 


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LIST OF ABBREVIATIONS  
AE 
adverse event 
ALC 
absolute lymphocyte count 
ANCOVA 
analysis of covariance 
BP 
blood pressure (systolic/diastolic) 
CI 
confidence interval 
CMH 
Cochran-Mantel-Haenszel 
CRO 
clinical research organization 
CSR 
clinical study report 
DBP 
diastolic blood pressure 
DLCO 
Diffusing capacity of the lung for carbon monoxide 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
FEV1 
forced expiratory volume at 1 second 
FVC 
forced vital capacity 
HBcAg 
hepatitis B core antigen 
HBsAg 
hepatitis B surface antigen 
hCG 
human chorionic gonadotrophin 
HCV 
hepatitis C virus 
Hgb 
hemoglobin 
HIV 
human immunodeficiency virus 
HR 
heart rate 
ICH 
International Conference on Harmonisation 
Ig 
immunoglobulin 
IP 
Induction Period 
ITT 
intent-to-treat  
IV 
intravenous/ly 
IVRS 
interactive voice response system 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCH 
mean corpuscular hemoglobin  
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MITT 
modified intent-to-treat 
MP 
Maintenance Period 
OCT 
optical coherence tomography 
OLP 
Open-Label Period 
PD 
pharmacodynamic(s) 
PFTs 
pulmonary function tests (includes FEV1,  FVC, DLCO) 
PK 
pharmacokinetic(s) 
PP 
per protocol 
RBC 
red blood cell 
SAE 
serious adverse event 
SAP 
statistical analysis plan 


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SBP 
systolic blood pressure 
SD 
standard deviation 
UC 
ulcerative colitis 
ULN 
upper limit of normal 
VZV 
varicella zoster virus 
WBC 
white blood cell 
WOCBP 
women of child bearing potential 


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1. 
INTRODUCTION 
 
 
 
 
 
 
  
 
 2014 
• ICH Guidance on Statistical Principles for Clinical Trials (E9) 
2. 
PURPOSE OF ANALYSES 
 
 
 
 
 
analysis plan will be developed to guide analyses of heart rate data collected from the 
Holter monitors. 
3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Study Objectives 
3.1.1. 
Primary Objective 
The primary objective of the study is to compare the efficacy of RPC1063 vs. placebo for induction of 
clinical remission at Week 8 in patients with moderately to severely active ulcerative colitis (UC). 
3.1.2. 
Secondary Objectives 
The secondary objectives are to: 
• Compare the efficacy of RPC1063 vs. placebo at weeks 8 and 32 as measured by clinical response, 
clinical remission, and mucosal healing 
• Compare the overall safety and tolerability of RPC1063 vs. placebo for the duration of the study 
3.1.3. 
Exploratory Objectives 
 


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3.2. 
Endpoints 
3.2.1. 
Efficacy Endpoints 
Primary Efficacy Endpoint:  
• The primary endpoint is the proportion of patients in clinical remission at Week 8,  defined as a 
Mayo score of ≤ 2 points and with no individual subscore of > 1 point 
Key Secondary Efficacy Endpoints (rank ordered): 
• Proportion of patients with a clinical response at Week 8, defined as a reduction from baseline in 
Mayo score of ≥ 3 points and ≥ 30%, and a decrease from baseline in the rectal bleeding subscore 
of ≥ 1 point or an absolute rectal bleeding subscore of ≤ 1 point 
• Change from baseline in Mayo score at Week 8  
• Proportion of patients with mucosal healing at Week 8, defined by an endoscopy subscore of ≤ 1 
point 
Other Secondary Efficacy Endpoints: 
• Proportion of patients in clinical remission at Week 32 defined as Mayo score of ≤ 2 points with no 
individual subscore of > 1 point  
• Proportion of patients with a clinical response at Week 32, defined as a reduction from baseline in 
Mayo score of ≥ 3 points and ≥ 30%, and a decrease from baseline in the rectal bleeding subscore 
of ≥ 1 point or an absolute rectal bleeding subscore of ≤ 1 point  
• Proportion of patients with mucosal healing at Week 32, defined by an endoscopy subscore of ≤ 1 
point 
 
 
 
 
 
  
  
with histologic remission at Week 8 as determined by a Geboes index score 
< 2.0 (Geboes 2000) 
3.2.2. 
Safety Endpoints 
• The incidence and type of Adverse Events (AEs), Serious Adverse Events (SAEs), AEs leading to 
discontinuation of study treatment, target AEs of special interest, laboratory abnormalities, vital 
signs, electrocardiograms (ECG), and physical exam abnormalities  


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3.2.3. 
PK and PD Endpoints 
• PK assessments will include PK sampling to determine plasma concentration of RPC1063 and 
active metabolites at scheduled assessments during the treatment period  
• Absolute lymphocyte count (ALC) derived from blinded hematology laboratory results 
• Plasma protein biomarkers (cytokines, chemokines, other inflammatory proteins)  
• Stool analysis for fecal biomarkers – fecal lactoferrin and calprotectin  
• Total immunoglobulins (Igs) - IgA, IgG, IgM 
4. 
STUDY DESIGN  
Study RPC01-202 is a Phase 2, multi-center, randomized, double-blind, placebo-controlled, parallel-
group study in patients with moderately to severely active UC. 
This study includes 3 periods (Screening, Induction, and Maintenance) and an optional Open-Label 
Treatment Period (OLP).  Following the 5-week Screening Period, eligible patients will be randomized 
and enter the 8-week placebo-controlled Induction Period (IP).  Patients who are responders at Week 8 
will continue on their assigned treatment in the 24-week Maintenance Period (MP).  Non-responders at 
Week 8 have the option to enter the OLP.  Patients who complete the MP will be given the option to 
participate in the OLP. Patients that enter the MP and experience disease relapse will also have the option 
to enter the OLP.  
The study will include both patients that have received anti-TNF therapy and those that have not.  It is 
anticipated that approximately 50% of the patients included in the study will have received anti-TNF 
therapy.   
The study design is shown in Figure 1.   
Induction Period (IP) 
The 8-week IP will serve as a dose-finding study to assess the efficacy and safety of RPC1063 for the 
induction of clinical response, remission, and mucosal healing in patients with moderately to severely 
active UC. The IP will actually last for 9 weeks and consists of dose titration over 8 days followed by the 
full dose for 8-weeks. 
 Approximately 180 patients will be randomized in a 1:1:1 ratio to receive 1 of 3 treatment regimens: 
• 
RPC1063 0.5 mg oral capsule daily 
• 
RPC1063 1.0 mg oral capsule daily 
• 
Placebo oral capsule daily 
The randomization will be stratified by prior anti-TNF therapy experience (yes or no).   
For patients randomized to one of the active treatment groups, there will be an 8 day dose titration 
regimen in the IP consisting of 4 days of treatment with RPC1063 0.25 mg, followed by 3 days treatment 
with RPC1063 0.5 mg, followed by the assigned treatment level for approximately 8 weeks. 
Maintenance Period (MP) 
All patients who complete the IP and are responders at Week 8 of the IP will enter the 24-week MP.  
Patients will continue to receive the same study treatment in the MP as received during the IP, and 
individual patient treatment will remain blinded until all patients have reached Week 32.  The last visit in 


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the MP will occur at Week 32.  Patients who complete the MP will be given the option to participate in 
the OLP.  Patients that enter the MP and experience disease relapse will have the option to enter the OLP. 
Optional Open-Label Treatment Period (OLP) 
Patients who complete the IP and are non-responders at Week 8 and those that complete the MP or 
experience disease relapse during the MP will have the option to enter the OLP.  All patients in the OLP 
will receive daily study treatment with RPC1063 1.0 mg.  There will be an 8 day dose titration regimen 
consisting of 4 days of treatment with 0.25 mg RPC1063, followed by 3 days treatment with RPC1063 
0.5 mg, followed by RPC1063 1.0 mg. Patients who are non-responders 8 weeks after initiation of the 
OLP should discontinue from the study.  The OLP will continue until the last patient who enters the OLP 
portion of the study has completed 20 weeks of treatment in the OLP.  
Safety Monitoring/Follow-up 
Potential adverse events (AEs) of interest that may be a consequence of sphingosine 1-phosphate 1 
receptor 1 (S1P1R) modulation will be closely monitored during the study.  These AEs include 
bradycardia and heart conduction abnormalities, pulmonary toxicity, macular edema, cutaneous 
malignancy, serious or opportunistic infection and hepatotoxicity.  A Data Monitoring Committee (DMC) 
for the study will perform safety reviews periodically, approximately four times a year. 
The safety of patients will be monitored by collection of treatment-emergent AEs, SAEs, physical exams, 
vital signs, Holter monitoring and ECGs, Pulmonary Function Tests (PFTs) , optical coherence 
tomography (OCT), dermatologic exams, blood chemistry and hematology panels, coagulation panels, 
and urinalysis at baseline and at various time points during the study.  White blood cell (WBC) counts 
and lymphocyte counts will be monitored centrally (and will not be provided to the site) to prevent 
potential unblinding of the Investigator.   
Patients who discontinue from treatment due to lack of response, AEs, or other reasons, even if alternative 
treatment is given, will be followed for 30 days for collection of safety data, including lymphocyte 
recovery, and for the assessment of their disease status. 


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Figure 1: Study Schematic 
 
 
  
Placebo (N=60) 
0.5 mg (N=60) 
9Weeks 
Disease 
Relapse 
I 
I 
I 
I y 


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5. 
DEFINITIONS 
5.1. 
Time Point Definitions 
 
Study Day for Induction and Maintenance Periods 
All visit data will be assigned a study day, from the Visit 1 in the Induction Period according to the 
following rules: 
• 
Visit 1 Day will be designated as Day 1 
• 
All other days after Day 1: Study Day = (Visit Date − Visit 1 Date + 1) 
• 
All other days before Day 1: Study Day = (Visit Date − Visit 1 Date) 
Study days for evaluations occurring during the Screening visit will be negative numbers (e.g., “–7”), no 
Day 0 is defined for this study. 
Study Day for the Open Label Period 
All visit data will be assigned a study day, from the Visit 1 in the Open Label Period according to the 
following rules: 
• 
OLP Day 1 will be designated as Day 1 
• 
All other days after OLP Day 1: Open Label Day = (Visit Date − Open Label Visit 1 Date + 1) 
• 
All other days before OLP Day 1: Open Label Day = (Visit Date – Open Label Visit 1 Date) 
Baseline Measurement 
There will be two baseline definitions: 
Baseline: The latest assessments completed prior to initial study drug administration will be used as the 
Baseline measurement for all analyses for the IP and MP. It will also be used as the Baseline 
measurement for efficacy analyses for the OLP. 
Treatment Baseline: The last assessment prior to initial administration of RPC1063 will be used as the 
Baseline measurement for safety analyses for the OLP. 
Visits 
Visits identifiers on the study electronic case report forms (eCRFs) will be used.    


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5.2. 
Efficacy Assessments 
5.2.1. 
Flexible Sigmoidoscopy/Colonoscopy 
To ensure quality data and standardization, the same endoscopist should be used throughout the study 
wherever possible.  Colonoscopies will be read blinded to treatment allocation at a centralized reading 
facility, Robarts Clinical Trials. 
5.2.2. 
Mayo Score 
The Mayo score is a standardized, accepted, numerical scale used to evaluate disease severity in people 
with UC. 
The Mayo score consists of four subscores, each ranging from (0-3) for a total score that ranges from 0 to 
12: 
1. Stool frequencya 
0 = Normal number of stools for this patient 
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, mild 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 
1 = Mild disease 
2 = Moderate disease 
3 = Severe disease 


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a Each patient serves as his or her own control to establish the degree of abnormality of the stool 
frequency. 
b The daily bleeding score represents the most severe bleeding of the day. 
c The physician’s global assessment acknowledges the three other criteria, the patient’s daily 
recollection of abdominal discomfort and general sense of well-being, and other observations, 
such as physical findings and the patient’s performance status. 
The Mayo score will be derived at all visits when an endoscopy is performed. For these visits, the Mayo 
score will be derived using the endoscopy subscore and the non-endoscopy subscores performed at the 
same nominal visits, even if the assessments have different dates. The baseline Mayo score will be 
derived from the most recent endoscopy subscore (Item 3) completed during Screening and the last non-
missing non-endoscopy subscores (i.e., Items 1, 2, and 4) prior to initial study drug administration.  
Partial Mayo scores are calculated using data from Items 1, 2, and 4 only. 
Mayo scores are calculated using: 
1. The stool frequency and rectal bleeding data form the most recent consecutive 3-day period prior 
to the visit, excluding the following: 
a. The day medications for constipation, diarrhea, or bowel irregularity are taken 
b. The day(s) of a procedure or preparation for a procedure (e.g., enemas,  other laxative, 
clear liquid diet) that would affect bowel frequency or blood content of the stool 
c. The 48 hours following use of anti-motility agents (i.e., loperamide)  
d. The 48 hours following endoscopy 
Disease relapse is defined as when all of the following criteria are met: 
• 
An increase in UC disease activity as defined by an increase in partial Mayo score of ≥2 
points compared to the Week 8 partial Mayo score with an absolute partial Mayo score ≥4 
points 
• 
An endoscopic subscore of ≥ 2 points 
• 
Exclusion of other causes of an increase in disease activity unrelated to underlying UC (e.g., 
infections, change in medication). 
Using the full Mayo score: 
Clinical Remission is defined as a Mayo score of ≤ 2 points and no individual subscore > 1 point 
Clinical Response is defined when all of the following criteria are met: 
• 
Reduction in Mayo score of ≥ 3 points 
• 
Reduction in Mayo score of ≥ 30% 
• 
Reduction in Rectal Bleeding subscore of ≥ 1 point OR a Rectal Bleeding subscore of ≤ 1 
point 
Mucosal Healing is defined as an Endoscopic subscore of ≤ 1 point 


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Using the partial Mayo score: 
Clinical Remission is defined as a partial Mayo score of ≤ 2 points and no individual subscore > 1 point 
Clinical Response is defined when all of the following criteria are met: 
• 
Reduction in partial Mayo score of ≥ 2 points 
• 
Reduction in partial Mayo score of ≥ 30% 
• 
Reduction in Rectal Bleeding subscore of ≥ 1 point OR a Rectal Bleeding subscore of ≤ 1 
point 
5.3. 
Safety Definitions 
AE or SAE Onset Date 
AE and SAE onset or start dates are reported in the AE eCRFs.   
AE or SAE End Date 
AE and SAE end dates are reported in the AE eCRFs. 
AEs and SAEs 
AEs will be recorded from the time written informed consent is signed through the Follow-up visit (last 
dose + 30 days). 
An AE or SAE will be regarded as treatment-emergent if it has a start date during or after the first study 
drug administration or if it worsened or if the relationship to study drug changed from unrelated to related 
after the first study drug administration.  UC disease relapse and related symptoms will be monitored as 
study endpoints, but will not be recorded as AEs unless they meet the definition of an SAE. 
All AEs or SAEs meeting these criteria with a start date up to and including 30 days following the last 
dose of treatment with the study drug will be considered treatment-emergent.   
Treatment Related AEs 
For summary purposes, all AEs classified by the Investigator on the AE eCRF as “possible”, “probable” 
or “related” will be considered treatment related AEs.  If the relationship to study drug is unknown or 
missing, the AE will be considered to be treatment related. 
Duration of AEs 
 The duration of an AE will be calculated as:  
Duration = (AE End Date – AE Onset Date) + 1 


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5.4. 
Other Definitions 
Age 
Age (in years) will be calculated from the date of birth to the date of informed consent.  Age will be 
reported as an integer. 
Study Drug 
Study drug refers to RPC1063 0.5 mg, RPC1063 1.0 mg, or Placebo oral capsules as well as the titration 
doses. 
6. 
STATISTICAL METHODS 
This section presents the statistical approaches that are anticipated for the analysis of study data.  These 
approaches may at times require modifications due to unanticipated features of the data.  Any 
modifications that are not in the final SAP are considered to be post-hoc and will be detailed in the CSR. 
6.1. 
General Analysis Approach 
Unless otherwise noted, all summaries of data by treatment group during the IP/MP and the OLP will 
include the following three groups: 
1) Placebo 
2) RPC1063 0.5 mg 
3) RPC1063 1.0 mg 
The following conventions will be used for all data presentations and analyses unless otherwise specified. 
• Appropriate descriptive statistics will be computed and displayed (by time point and other key 
variables as appropriate) for both continuous and categorical variables.  For continuous variables, 
descriptive statistics will include n (the number of patients with non-missing data), mean, 
standard deviation (SD), median, and minimum and maximum values.  For categorical data, the 
number and percentage of patients within each category will be presented.  The denominator for 
percentages will be based on the number of patients with non-missing data appropriate for 
summary purposes.  Unless otherwise noted, all percentages will be presented to one decimal 
place.  
• Individual data listings of all data represented on the eCRF and from the clinical laboratory will be 
presented.  Sort order for data listings will be treatment, site-patient number, visit, and assessment 
period where appropriate. 
• Version 9.1 (or higher) of the SAS® statistical software package will be used to provide all tables, 
figures, data listings, and analyses. 


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• There are approximately 70 study sites in this study.  Due to the large number of study sites and the 
small numbers of patients per site, the analysis of efficacy endpoints will not include adjustments 
for study site.   
Further analysis and reporting conventions are described in Section 7. 
6.2. 
Coding Dictionaries 
Adverse events will be coded using version 15.0 or later of the Medical Dictionary for Regulatory 
Activities (MedDRA).  Prior and concomitant medications will be coded according to the World Health 
Organization Drug Dictionary, Enhanced, September 1, 2012 or later.   
6.3. 
Data Management 
An eCRF will be used for the current study, and a data management plan will be prepared by the contract 
research organization (CRO), PPD.   
6.4. 
Missing values 
The Mayo score used for clinical endpoints in the study will utilize the Mayo endoscopy score derived 
from the central reader.  In the case that a central endoscopic result is missing the endoscopic subscore 
read by the Investigator will be utilized. 
For calculation of the Mayo score for the efficacy endpoints, at least 2 of the 4 subscores must be 
available to calculate the total Mayo score.  A missing subscore(s) will be carried forward from the most 
recent previous visit for which the subscore is available.  The endoscopy subscore is not considered 
missing if the Investigator endoscopic subscore is available.  If more than 2 subscores are missing, then 
the Mayo score will be considered missing.   
 
For calculation of the partial Mayo score for the efficacy endpoints, at least 2 of the 3 subscores must be 
available to calculate the partial Mayo score.  The missing subscore will be carried forward from the 
previous visit.  If more than 1 subscore is missing, then the partial Mayo score will be considered missing. 
For the primary analysis, as well as for the analyses of all key secondary efficacy endpoints that are 
defined as proportions, patients who have missing Mayo or partial Mayo scores at the specified time point 
will be classified as nonresponders. 
One of the key secondary efficacy endpoints (change in Mayo score) is a quantitative endpoint.  For the 
key secondary analysis of this variable, missing values will be replaced by the last observation carried 
forward (LOCF).  If no post-Baseline observation is available to carry forward, then the average score for 
the observed values within the same treatment group will be used, rounded to the nearest integer. 
6.5. 
Sample Size 
Approximately 300 patients will be screened to ensure that 180 patients are randomized in the IP, 
assuming a 40% screen failure rate.  Patients will be enrolled in a 1:1:1 randomization with approximately 
60 patients assigned per treatment arm. 
The sample size is justified with respect to the comparison of remission rates at the end of the IP between 
an RPC1063 group and the placebo group.  Based on the use of a two-sided test at the alpha=0.05 level of 


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significance, and assuming a placebo remission rate of 10%, a sample size of 60 patients per group will 
provide 80% power to detect an improvement in the remission rate of 21 percentage points or larger (i.e., 
an active group remission rate of 31% or larger). 
6.6. 
Study Blinding, Patient Identification and Replacement of Patients 
Investigational medicinal product and placebo capsules will be identical in physical appearance.  The 
treatment each patient will receive will not be disclosed to the Investigator, study center personnel, 
patient, Sponsor and their representatives.  The treatment codes will be held according to an Interactive 
Voice Response System (IVRS).  Further instructions will be provided in a separate IVRS manual. 
Patients will be assigned a unique patient number and will only be identified by their patient number and 
their initials on all study documentation.  
Patients who discontinue from the study following randomization will not be replaced. 
6.7. 
Enrollment and Randomization Procedures 
A patient is considered enrolled in the study when the informed consent form is signed at the screening 
visit. 
Patients will be randomized into the study on Day 1 using the IVRS system.   
Patients will be randomized 1:1:1 to receive placebo, RPC1063 0.5 mg, or RPC1063 1 mg.  The 
randomization will be stratified by prior anti-TNF therapy (yes vs. no). 
6.8. 
Analysis Populations 
The following analysis populations will be used in the statistical analysis.  Analysis population 
membership will be determined prior to unblinding.  
Intent-to-Treat (ITT) Population:  The ITT population will consist of all randomized patients who 
received at least 1 dose of study treatment, with treatment assignment designated according to 
randomized treatment.  This will be the primary population for the analysis of efficacy endpoints.   
Per Protocol (PP) Population: The PP population will consist of the subset of the ITT population, 
excluding those patients who have had a major protocol violation.  Major protocol violations will include 
all violations that would significantly impact assessment of safety and efficacy of the compound and will 
be finalized in advance of data lock and primary analyses. Violation of any of the following three 
inclusion criteria related to UC specific disease activity would exclude a patient from the PP population:   
• Must have a confirmed diagnosis of UC by endoscopic and histologic evidence  
• Must have a baseline Mayo score of 6-12 inclusive with endoscopic subscore of >=2 
• Must have a baseline endoscopy with >= 15 cm involvement 
Poor study drug compliance will also exclude the patient from the PP population. Poor study drug 
compliance is defined as taking less than 80% or more than 120% of study treatment during the entire 
treatment period. 


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The patients excluded from the PP population will be fully defined and documented with reasons for 
exclusion prior to database lock. 
Safety Population: The Safety population will consist of all patients receiving any study treatment.  All 
patients in the Safety population will be analyzed according to the highest dose of RPC1063 actually 
received and not according to the treatment they are randomized to receive, in the event there is a 
discrepancy. 
6.9. 
DMC 
An independent DMC will be charged with monitoring accumulating data from the trial, as well as 
general aspects of trial conduct.   
The committee will meet periodically, approximately four times a year during the study, to review 
unblinded aggregate analyses by treatment group concerning enrollment, treatment compliance, 
adherence to follow-up schedule, and safety data from the trial.  The DMC may recommend modifying or 
stopping the trial early due to safety concerns based on data reviews.  The DMC will also review the 
Primary Endpoint (Week 8 Induction) and make recommendations taking into account both the efficacy 
results and the safety profile. 
The blinding plan to assure that all personnel at Receptos and all personnel involved in the conduct of the 
study remain blinded to the results of reviews will be specified in the DMC Charter. 
6.10. 
Final Analyses and Reporting 
The primary analysis will be carried out when all patients have completed (or would have been eligible to 
complete) the IP of the study.  The randomized treatment groups will be unblinded for both the IP and 
MP for the primary analysis.  At the time of the primary analysis, the database will be locked for all visits 
through Week 8 and the available Mayo score data will be cleaned for all visits beyond Week 8. Data will 
continue to accrue for the MP and OLP visits. For this primary analysis, the safety analyses will be 
summarized for the IP only. 
Final database lock will occur when all patients have completed the study and all data during the 
assessment periods has been monitored.  In addition, no database may be locked, randomization code 
unblinded, or analyses completed (other than analyses for the DMC) until this SAP has been approved.  
All analyses outlined in the protocol and in this SAP (other than analyses conducted for the DMC) will be 
carried out after: 
• 
The SAP has been approved 
• 
All analysis populations are determined 
Further exploratory analyses not necessarily identified in this SAP may be performed to support the CSR.  
Any post-hoc or unplanned analyses performed and not identified in this SAP will be clearly identified in 
the CSR. 


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6.11. 
Patient Disposition 
The number and percentage of patients who signed the informed consent form, who were randomized, in 
each analysis population, who completed the study, who completed the IP, MP, and OLP will be 
summarized by treatment group.  The number and percentage of patients who withdrew from the study 
and their reasons for withdrawal in each period will be tabulated by treatment group. All percentages will 
be based on the number of subjects in the ITT population.  Disposition data will also be presented in a 
listing. 
6.12. 
Demographics and Baseline Characteristics 
The demographics and baseline characteristics will be presented in a table.  The demographic 
characteristics consist of age, age category, sex, race, ethnicity, weight, height, body mass index (BMI), 
smoking history, and stratification factors.  Age, weight, height, BMI, years as a smoker, and numbers of 
cigarettes, cigars, and pipes smoked per week will be summarized using the descriptive statistics.  The 
number and percentage of patients in each age category (18-29, 30-39, 40-49, 50-59, 60-69, and 70-75, 
and < median, ≥ median) and in each race category (White, Black, Asian, American Indian or Alaska 
Native, Native Hawaiian or Other Pacific Islander, and Other) will be reported. The number and 
percentage of patients who have ever smoked, are current smokers, and who smoke each type of tobacco 
product will be reported.  The summaries will be presented for the ITT population. Listings will be 
provided for demographic and baseline characteristic data. 
6.13. 
General Medical History 
Medical history information will be collected at the Screening Visit and on Day 1 (Visit 1).   
Medical history will be summarized for the ITT population and will display the number and percentages 
of subjects with a significant history for each body system. Significant medical history included specific 
details will also be listed 
6.14. 
Ulcerative Colitis Disease History 
The following UC disease history parameters will be summarized using descriptive statistics: 
• Age at UC diagnosis 
• Years since UC diagnosis 
• Mayo score at Baseline (using the central endoscopy score) 
• Mayo score subgroup proportions using the central endoscopy score (< 8 vs. ≥ 8) 
• Mayo score at Baseline (using the investigator endoscopy score) 
• Mayo component scores at Baseline (stool frequency, rectal bleeding, physician’s global 
assessment, investigator endoscopy score, central endoscopy score) 
• Extent of disease (limited to left side of colon or extensive). 
For partial UC diagnosis dates, the following imputation methods will be applied: 


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• If month and year are present but day is missing, then the day will be set to the 15th 
• If year is present but not month and day, month and day will be set to July 1st 
• If either imputation above results is a date >= the date of informed consent, then impute the date as 
informed consent date – 1. 
UC disease history will also be listed. 
6.15. 
Protocol Deviations 
Deviations and violations from the protocol will be recorded appropriately.  If a patient was allowed to 
continue in the study, this will be recorded.  According to the recommendations in the ICH guidelines, the 
protocol deviations will be classified into, but not necessarily limited to, the following categories: 
• Inclusion/exclusion criteria deviation 
• Prohibited medication use 
• Incorrect treatment or dose 
• Treatment non-compliance 
• Procedure non-compliance 
• Safety observation 
Classification of deviations as major protocol violations, and decisions regarding exclusion of patients 
and/or patient data from the statistical analyses, will be decided on a case-by-case basis without 
knowledge of the treatment assigned and before database lock by the project statistician with input from 
the clinical study team.  All protocol deviations will be presented in a summary table by protocol 
deviation category and treatment.  Major protocol violations will be summarized separately.  A listing of 
protocol deviations will also be presented that identifies those patients excluded from analyses. 
6.16. 
Dosing Compliance 
 
 
 
  
 
   
 
 


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6.17. 
Treatment Compliance 
 
 
 
 
 
6.18. 
Prior and Concomitant Medications 
 
All treatments being taken by the subjects on entry to the study or at any time during the study in addition 
 
 
 
 
 
 
 
 
 
 
 
6.19. 
Efficacy Analyses 
Analysis of all efficacy endpoints will primarily be based on the ITT population with treatment failure 
rules applied.  Patients will be considered to have failed treatment if they have protocol-prohibited 
changes in concomitant UC medications, including an increase in corticosteroid dose from baseline to 
treat UC or a prolonged course of systemic corticosteroids >7 days for treatment of disease other than 
UC; initiation of an immune suppressing therapy including 6-MP or azathioprine or anti-TNF agents; a 
colectomy (partial or total) or an ostomy; or have discontinued study agent for lack of therapeutic effect 
before the week 8 evaluations.  Patients with a treatment failure will be considered not to have achieved 
the dichotomous end points; and for continuous end points, their last values will be carried forward for all 


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visits subsequent to the time of treatment failure.  Treatment failure rules will supersede other data 
handling rules. 
The efficacy endpoints will also be analyzed in the PP population. 
6.19.1. 
Endpoints 
Efficacy analyses include clinical remission, clinical response, mucosal healing, and changes in Mayo 
score. 
Endoscopy images will be obtained during each endoscopy and will be sent to Robarts Clinical Trials for 
central reading and determination of the Mayo endoscopy score.  The result of the central reading of the 
endoscopy will be used to ensure patient eligibility prior to randomization and to calculate the Mayo score 
at the times indicated in the schedule of events.  The Mayo score used for clinical endpoints in the study 
will utilize the Mayo endoscopy score derived from the central reader.  Sensitivity analyses of clinical 
endpoints using the Mayo score derived from the investigator interpretation will be performed. 
6.19.2. 
Primary Efficacy Analysis 
The primary analysis will be carried out when all patients have completed (or would have been eligible to 
complete) the IP of the study (Week 8). 
The primary endpoint of proportion of patients in clinical remission at Week 8 will be analyzed using the 
Cochran-Mantel-Haenszel (CMH) test, stratified by prior anti-TNF therapy experience (yes or no).  The 
primary analysis will use the data from the 1 mg dose and placebo groups and compare the remission 
rates in these two groups using a two-sided test at the 0.05 level of significance.  The second comparison 
for the primary endpoint will be the comparison of remission rates between the 0.5 mg group and the 
placebo group. The CMH p-value and the relative risk along with its 95% CI will be provided for each 
treatment group. In addition, the treatment difference and associated 95% CI will also be provided. 
6.19.3. 
Secondary Efficacy Analyses 
If the primary efficacy analysis is statistically significant (p < 0.05), then additional confirmatory tests 
using the ITT population will be performed in the following prespecified order: 
• Proportion of patients in clinical response at Week 8: 1 mg dose versus placebo 
• Proportion of patients in clinical response at Week 8: 0.5 mg dose versus placebo 
• Change in Mayo score from baseline at Week 8: 1 mg dose versus placebo  
• Change in Mayo score from baseline at Week 8: 0.5 mg dose versus placebo  
• Proportion of patients with mucosal healing at Week 8: 1 mg dose versus placebo   
• Proportion of patients with mucosal healing at Week 8: 0.5 mg dose versus placebo   
Provided that all previously specified tests are statistically significant (p < 0.05), each of these 
comparisons will be assessed using a two-sided test at the 0.05 level of significance.  However, if a 
comparison is not statistically significant, then all subsequent comparisons will be considered 
exploratory. 


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Secondary endpoints that are defined as proportions will be analyzed using the same type of methodology 
as described for the primary analysis.  Analyses of all proportion endpoints using the CMH test will be 
completed using the data from the two groups being compared.  Quantitative secondary endpoints such as 
change in Mayo score will be analyzed using analysis of covariance (ANCOVA) models with effects for 
treatment group and prior anti-TNF therapy experience, and with the baseline value of the corresponding 
endpoint included as a covariate.  All secondary analyses will be carried out using two-sided test at the 
5% level of significance. 
Actual and change from baseline in Mayo scores over time will be plotted. 
6.19.4. 
Exploratory Efficacy Analyses 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.19.5. 
Sensitivity Analyses 
Sensitivity analyses will be carried out to assess homogeneity of the results for the primary and key 
secondary endpoints across geographical regions.  In these analyses, geographic region will be 
categorized as North America, Europe, and Asia Pacific.  For proportion endpoints, these analyses will be 
carried out using logistic regression models including effects for treatment group, prior anti-TNF therapy 
experience, geographic region, and the interaction between treatment group and geographic region.  If 
interactions cannot be excluded, results will be summarized by geographic region.  Similarly, quantitative 
endpoints will be analyzed using ANCOVA models as described previously, with the addition of effects 
for geographic region and the interaction between treatment group and geographic region. 
Sensitivity analyses of the primary and key secondary endpoints will be carried out to investigate the 
impact of missing data on the efficacy conclusions.  All sensitivity analyses will be conducted in the ITT 
population.  The primary and secondary efficacy analyses will be repeated using the following missing 
data methods: 


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• Analyses using LOCF (except change in Mayo score) 
• Analyses of observed cases (i.e., using only observed data, with no imputation for missing data) 
• Multiple imputation model-based methods 
Finally, each of the primary and key secondary endpoint analyses will be repeated using clinical 
endpoints derived from the Mayo score using the investigator endoscopy interpretation. 
6.19.6. 
Other Efficacy Analyses 
6.19.6.1. Mayo Score at Week 32 
The analyses will be performed for all available Week32 data at the time of database lock as described in 
Section 6.10. 
• Proportion of patients in clinical remission at Week 32 
• Proportion of patients in clinical response at Week 32 
• Change in Mayo score from baseline at Week 32 
• Proportion of patients with mucosal healing at Week 32 
The endpoints that are defined as proportions will be analyzed using the same type of methodology as 
described for the primary analysis.  Analyses of all proportion endpoints using the CMH test will be 
completed using the data from the two groups being compared.  Quantitative secondary endpoints such as 
change in Mayo score will be analyzed using ANCOVA models with effects for treatment group and prior 
anti-TNF therapy experience, and with the baseline value of the corresponding endpoint included as a 
covariate.  All analyses will be carried out using two-sided test at the 5% level of significance. 
Actual and change from baseline in partial Mayo scores over time will be plotted. 
6.19.6.2. Mayo Score at the End of OLP 
The analyses will be carried out when all patients have completed (or would have been eligible to 
complete) the OLP of the study. The mayo score will be summarized using descriptive statistics. 
6.19.6.3. Partial Mayo Score  
Partial Mayo score at all visits will be analyzed as follows: 
• Proportion of subjects in clinical remission based on the partial Mayo score at each visit through 
last available 
• Proportion of subjects in clinical response based on the partial Mayo score at each visit through last 
available 
• Change in partial Mayo score from baseline at each visit through last available 
The endpoints that are defined as proportions will be analyzed using the same type of methodology as 
described for the primary analysis.  Analyses of all proportion endpoints using the CMH test will be 


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completed using the data from the two groups being compared.  Quantitative secondary endpoints such as 
change in Mayo score will be analyzed using ANCOVA models with effects for treatment group and prior 
anti-TNF therapy experience, and with the baseline value of the corresponding endpoint included as a 
covariate.  All analyses will be carried out using two-sided test at the 5% level of significance. 
6.19.6.4. Endoscopy Data Availability 
The counts and percentages of available endoscopy data from both Central reader and Investigator 
interpretation will be summarized at each visit (Baseline, Week 8, Week 32, and End of Study/ET). 
 
6.20. 
Safety Analysis 
All summaries of Safety data will use the Safety population.  All data collected during the IP, MP and 
OLP will be summarized by treatment group.  Statistical hypothesis testing will not be performed on any 
safety results.   
6.20.1. 
Adverse Events 
For presentation, adverse event verbatim text will be coded into MedDRA System Organ Class (SOC) 
and preferred term.  For all AE summaries, if a patient has more than one AE within a preferred term, the 
patient is counted once in that preferred term at the maximum severity and closest relationship to study 
material or dosing procedure.  If a patient has more than one AE within a system organ class, the patient 
is similarly counted once in that system organ class. 
All AE safety summaries by treatment group will separately summarize the incidence of events 
in the placebo group, each RPC1063 dose group, and RPC1063 dose groups combined. 


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An overview of AEs will be tabulated by treatment group.  The number and percentage of patients in each 
treatment group will be summarized for the following categories: 
• any treatment-emergent AEs 
• any SAEs 
• treatment-related AEs 
• treatment-related SAEs 
• mild, moderate and severe AEs 
• AEs with a start date during IP 
• AEs with a start date during MP 
• AEs with a start date during OLP 
• AEs leading to study discontinuation  
• AEs leading to study drug discontinuation 
The following AE tables refer to AEs that are reported at any time during the study.  The number and 
percentage of unique patients reporting each treatment-emergent AEs will be summarized by SOC, 
preferred term, and treatment group.  A similar table will also be prepared separately for SAEs.  Further, 
the number of treatment-emergent AEs and SAEs, categorized by SOC, preferred term, maximum 
severity (mild, moderate, or severe), and treatment group will be summarized.  In addition, the number of 
treatment-emergent AEs and SAEs, categorized by system organ class, preferred term, relationship to 
study drug, and treatment group will be summarized.  Finally, the incidence of AEs by preferred term 
only will be summarized, sorted by descending frequency in the combined RPC1063 group.  All AE 
tables with both SOC and preferred term will be sorted by SOC alphabetically and then by preferred term 
in descending AE frequency in the combined RPC1063 treatment group.  All of these AE and SAE tables 
will also be repeated for AEs that are reported with start dates during the IP, during the MP, and during 
the OLP. 
AEs with start dates during a follow-up period will be categorized with the previous study phase.   
For AE and SAE tables summarizing maximum severity, patients reporting an event more than once with 
varying severity will be counted only once with the maximum severity within each system organ 
class/preferred term.  For AE and SAE tables summarizing AEs by drug relationship patients will be 
counted only once, in the category of the strongest relationship to study drug within each system organ 
class/preferred term. 


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AEs of special interest will also be summarized by treatment group.  The MedDRA SOC and preferred 
terms that refer to these AEs will be identified by the clinical study team and the project statistician prior 
to study unblinding and database lock.  Treatment-emergent AEs of special interest are defined as AEs 
related to the following abnormalities:   
• Infections 
• Bradycardia and heart conduction abnormalities. 
• Pulmonary toxicity as measured by the following Pulmonary Function Test (PFT) parameters: 
FEV1, FVC, and DLCO. 
• Hepatotoxicity which will be assessed by clinical blood chemistry liver function tests. 
• Macular edema 
• Cutaneous malignancy.  
Complete listings of all AEs will be provided.  For each AE, the corresponding severity, relationship to 
study drug, seriousness (yes/no), and available start and stop dates of the event will be specified.   
In addition, data listings of all SAEs, AEs leading to discontinuation, and a listings of deaths will also be 
provided, displaying details of the death captured on the eCRF.  Serious adverse event narratives will be 
provided for the CSR.  
6.20.2. 
Physical Examinations 
A complete physical examination will include evaluation of heart, lung, head and neck, abdominal, 
neurological, skin, and extremities.  An interim (or brief) physical examination will include areas with 
previously noted abnormalities and/or that are associated with any new complaints from the patient.  
Abnormal physical examination findings at each visit will be listed. 
6.20.3. 
Height and Weight  
Height will be measured at screening.  Weight will be monitored throughout the study.  
6.20.4. 
Vital Signs 
Heart rate (HR) and systolic/diastolic blood pressure (BP) will be assessed at scheduled times as outlined 
in protocol.   
After the patient has been supine for at least 15 minutes, HR and BP will be measured 3 times using an 
automated validated device.  The repeat HR and BP measurements will be made at 2-minute intervals.  
The lowest predose HR and BP (based on Systolic BP) will be taken as the baseline measure and used as 
comparison to postdose values.  BP will then be measured in the same manner with the patient in the 
standing position.  A sudden, significant fall in BP (> 20 mmHg) between 2 and 5 minutes after standing 
from the supine position will be interpreted as orthostatic hypotension and will be documented in the 
patient chart and eCRF.   


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After the first dose of study treatment, patients will be carefully monitored during a 6-hour post-dose 
monitoring period of hourly recording of HR (supine) and BP (supine and orthostatic).  During the 6-hour 
post-dose monitoring on Day 1, after the patient has been supine for at least 5 minutes, HR and BP will be 
measured once using an automated validated device.  Any clinically relevant change from baseline should 
be confirmed on repeat measures.  Blood pressure will then be measured in the same manner with the 
patient in the standing position.  The same orthostatic hypotension criteria stated above will be applied. 
Heart rate and systolic and diastolic blood pressure will be summarized using descriptive statistics at each 
timepoint by treatment group.  BP measurements will be summarized separately in the supine and 
orthostatic positions.  Any clinically significant changes will be recorded as AEs or SAEs.  
For patients participating in cardiac monitoring on Day 5, a summary table will be provided that 
summarizes the hourly change from pre-dose assessment through hour 6 at each of the baseline and Day 
5,  visits by treatment group for heart rate and blood pressure.   
 
Box plots will be provided to display the distribution of HR and BP. In addition, line plots will be created 
to display the change from baseline over the entire study period and change from pre-dose in HR and BP 
for the baseline and Day 5visits. 
 
The number and percentage of subjects with clinically relevant abnormalities will be presented by 
treatment group. The criteria for clinically relevant abnormalities are shown in the following table. 
 
Table 1. Criteria to Determine Clinically Relevant Abnormalities in Vital Signs 
Vital Sign 
Criteria for Abnormalities 
Temperature 
>38oC and an increase from pre-dosing of at least 1oC 
Heart Rate  
>120 beats per minute post-baseline, or 
an increase from pre-dosing of more than 20 beats per minute, or 
<45 beats per minute post-baseline, or 
a decrease from pre-dosing of more than 20 beats per minute 
Systolic Blood Pressure 
>180 mmHg post-baseline, or  
an increase from pre-dosing of more than 40 mmHg, or  
<90 mmHg post-baseline, or  
a decrease from pre-dosing of more than 30 mmHg 
Diastolic Blood Pressure 
>105 mmHg post-baseline, or  
an increase from pre-dosing of more than 30 mmHg, or 
<50 mmHg post-baseline, or  
a decrease from pre-dosing of more than 30 mmHg 
 
All vital sign measurements will also be listed. 


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6.20.5. 
Electrocardiograms (ECGs) and Holter Monitoring 
Stand Alone/Static ECGs 
Static ECGs will be captured at intervals as defined in the schedule of assessments.   The 12-lead ECG 
will be performed after the patient has been resting quietly in a supine position for at least 15 minutes.  
ECGs will be captured at scheduled times as outlined in the protocol.   
Summary tables including actual values and change from baseline values will be presented for ECG 
results. Any clinically significant changes will be recorded as AEs or SAEs.  
ECG results including morphology parameters will also be listed. 
Continuous 12-lead Holter Monitoring 
Continuous 24-hour cardiac monitoring (12-lead digital Holter monitoring) will be captured.  Holter 
monitoring will start at least 15 minutes prior to dose and complete at least 24 hours postdose 
administration.  Patients should be in the supine position prior to Holter application through the capture of 
the static predose 12-lead ECG as well as for the acquisition of the 6 hour post dose 12-lead ECG.  Holter 
analysis parameters will be described in the operations document. 
Any clinically significant changes will be recorded as AEs or SAEs. 
6.20.6. 
Laboratory Assessments 
Laboratory tests include the following:   
• Hematology – red blood cell (RBC) count, total and differential 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).  Total and differential WBC counts will not be 
provided to the Investigator to maintain the treatment blind.  These parameters and alerts for these 
parameters will be monitored by the PPD Safety Surveillance team. 
• Blood chemistry - sodium, potassium, chloride, calcium, magnesium, phosphate, blood urea 
nitrogen, random glucose, albumin, alkaline phosphatase, creatinine, alanine aminotransferase, 
aspartate transaminase, gamma glutamyltransferase, amylase, total bilirubin, conjugated bilirubin.   
• Urinalysis - leukocytes, specific gravity, bilirubin, blood, glucose, ketones, pH, protein, and 
urobilinogen 
• Pregnancy test: serum beta-hCG must be performed at screening in women of childbearing 
potential; urine beta-hCG will be performed at each visit, and if positive, do not dose, and 
confirm with a serum pregnancy test. 
• Coagulation panel: prothrombin time and partial thromboplastin time.   
• Serology testing will be performed at screening to determine the patient's immune status with 
respect to several viruses; testing will be as follows:  
o anti-VZV IgG 


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o HIV antibodies 
o anti-hepatitis A virus IgM 
o HBsAg and HBcAg IgM 
o anti-HCV IgG or IgM 
Hematology, blood chemistry, and coagulation test results will be summarized at each study visit by 
treatment group for visits during the IP and MP and for all patients during the OLP.  Changes from Visit 1 
to the End of Study Visit will be summarized by treatment group. 
Subjects with abnormalities in hematology assessments, defined as absolute lymphocyte count (ALC) 
<200 cells/uL, absolute neutrophil count (ANC) < 500 cells/uL as well as ANC <1000 cells/uL and total 
WBC >20,000 cells/uL will be summarized for each treatment group. 
 
In addition, the change and percent change from baseline in CBC with Differential will be summarized 
for each treatment group. 
The incidence of subjects with abnormalities in Liver Function Tests (SGPT/ALT, SGOT/AST, and 
GGT)  will be summarized overall and at each visit for each treatment group for the following categories:  
• > 1 x upper limit of normal (ULN)  
• ≥ 2 x ULN 
• ≥ 3 x ULN 
• ≥ 4 x ULN 
• ≥ 5 x ULN  
Shift tables will summarize changes from relevant Baseline by treatment group for visits during the IP, 
MP, and the OLP.  Changes from Day 1 to visits during the OLP will be summarized for all patients. 
All clinical laboratory results will also be listed.  Laboratory values that are outside the normal range will 
be flagged high (H) or low (L).  All out of range values will be identified in the listing. 
Plasma protein biomarker results (cytokines, chemokines, other inflammatory proteins) may not be 
available at the time of database lock and thus may be analyzed at a later time. 
6.20.7. 
Pulmonary Function Tests 
Pulmonary function tests (PFTs) including FEV1, FVC, and DLCO, if applicable, measurements will be 
performed as scheduled in the protocol. These tests will be performed at a high qualified pulmonary 
function laboratory or respiratory department.  
A minimum of 3 acceptable maneuvers will be performed at each visit.  The acceptability criteria are a 
satisfactory start of test and a satisfactory end of test.  The largest FVC and the largest FEV1 will be 
recorded, after examining the data from all of the acceptable curves, even if the 2 values do not come 
from the same curve.   
For FEV1 and FVC, summary tables for actual value, change, percent change, percent predicted, change 
in percent predicted, and percent change in percent predicted will be produced.  For DLCO summary 
tables for actual value, change, and percent change will be produced.  DLCO is collected at the local lab 


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for each site, so results may be collected in domestic or SI units.  DLCO results in domestic units 
(mL/min/mmHg) will be converted to SI units (mmol/min/kPa) prior to analysis using the following 
conversion factor: DLCO in SI units = (DLCO in domestic units) / 2.986. 
Line plots of FEV1, FVC, and DLCO results over time will be presented.  PFT test results will also be 
listed.   
6.20.8. 
Ophthalmological Examination 
Optical Coherence Tomography (OCT) will be performed at scheduled times as outlined in protocol.   
Any clinically significant changes will be recorded as AEs or SAEs.  OCT details will also be listed. 
6.20.9. 
Dermatological Examination 
Dermatological evaluations will be performed Screening, the End of Study Visit, Visit 1OLP, and the End 
of OLP Visit as part of the physical examination.   
A certified dermatologist will perform dermatological evaluations if abnormal results are found on the 
physical examination.  Any clinically significant changes will be recorded as AEs or SAEs. 
Dermatological examination abnormalities by visit will be presented and dermatological examination 
details will be listed. 
6.21. 
PD Analysis 
In addition to summarizing the actual values and change from baseline in Absolute lymphocyte count 
(ALC) specified as part of the Hematology analysis, percent change in ALC will also be summarized by 
treatment group.  Actual value, change, and percent change in ALC over time will also be plotted. 


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7. 
REPORTING CONVENTIONS 
The following reporting conventions will be adopted for the tables, listings, and figures.  These 
conventions will enhance the review process and help to standardize presentation with common notations. 
• All tables and data listings will be presented in Landscape Orientation, unless presented as part 
of the text in a CSR, in Courier New, 10 point font. 
• Figures will be presented in Landscape Orientation, unless Portrait Orientation suggests that the 
information presented is easier to interpret. 
• Legends will be used for all figures with more than one variable or item displayed. 
• Lines should be wide enough to see the line after being copied.  
• Specialized text styles, such as bolding, italics, borders, shading text will not be used in tables, 
figures, and data listings unless they add significant value to the table, figure, or data listing.  
• Only standard keyboard characters should be used in tables and data listings.  Special 
characters, such as non-printable control characters, printer specific, or font specific 
characters, will not be used on a table, figure, or data listing.  Hexadecimal characters are 
allowed (e.g., µ,α,β). 
• Capital letters will be used throughout all tables, figures, and data listings.  
• A standard header on each page will contain information to include the sponsor name 
(“Receptos, Inc.”) and study identifier (“Protocol RPC01-202”). 
• The ICH numbering convention will be used for all tables, listings, and figures. 
• All footnotes will be left justified and at the bottom of a page.   
• Missing values (other than date values) for both numeric and character variables will be 
presented as blanks in a table or data listing.  Missing date/month/year will be presented as 
dash (‘-‘) for each space.  
• All date values will be presented as DDMMMYYYY (e.g., 29AUG2009) format.  A four-digit 
year is preferred for all dates.  
• All observed time values will be presented using a 24-hour clock HH:MM format (e.g., 01:35).  
Seconds should only be reported if they were measured as part of the study.  
• Time durations will be reported in mixed HHh MMm notation (e.g., 5h 32m).  The use of 
decimal notation to present time durations should be avoided (e.g., 0.083h = 5m) unless it is 
necessary to show the computation of time differences in a table, figure, or data listing, in 
which case both notations may be used to display the time duration.  
• All tables, figures, and data listings will have the name of the program and a date/time stamp on 
the bottom of each output.  
• Each table, figure, and data listing will have “Page x of y” presented on the top right-hand side 
of each page. 
• Additional rounding rules as follows:  


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o If the original value has 0 decimal places: mean, median, and CIs will have one 
decimal place and SD will have 2 decimal places 
o If the original value has 1 decimal place: mean, median, and CIs will have 2 decimal 
places and SD will have 3 decimal places 
o If the original value has 2 or more decimal places: mean, median, CIs, and SD will all 
have 3 decimal places 
• All calculated percentages between 1% and 99% will be rounded to one decimal place.  A 
percentage of 100% will be reported as 100%.  Any computation of percentage that results in 
0% will be reported as 0 as the number of responses and no percentage will be reported.  All 
categories whose counts are zero will be displayed for the sake of completeness. 
• P-values will be rounded to four decimal places.  If a p-value is less than 0.0001, it will be 
reported as “<0.0001”.  If a p-value is greater than 0.9999, it will be reported as “>0.9999”. 
 


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8. 
DEVIATIONS FROM PROTOCOL 
The analyses of the following endpoints specified in the protocol are not performed due to collected 
samples have not been analyzed at the time of database lock. 
• Proportion of patients with histologic Remission at Week 8 for exploratory objectives and 
exploratory efficacy endpoints. 
• Plasma protein biomarkers (cytokines, chemokines, other inflammatory proteins) as PD endpoint. 




SAP Addendum for Protocol No.  RPC01-202  
 
Celgene Corporation 
 
 
Page 1 of 9 
 
 
STATISTICAL ANALYSIS PLAN – OPEN LABEL PERIOD ADDENDUM 
 
 
 
Title: 
 
 
A Phase 2, multi-center, randomized, double-blind, placebo-
controlled parallel-group study to evaluate the clinical efficacy and 
safety of induction therapy with RPC1063 in patients with 
moderately to severely active ulcerative colitis 
 
 
Protocol: 
RPC01-202 
 
 
Sponsor: 
Celgene International II Sàrl (see appended signature page) 
Rue du Pré-Jorat 14 
2108 Couvet Switzerland 
Tel: + 41 32 864 69 01 
 
 
 
Date: 
 
October 15, 2019 
 
 
Status: 
 
Addendum to Version 2.0 
 
 
 
 
 
CONFIDENTIAL 
 
 
This document is a confidential communication of Receptos.  Acceptance of this document constitutes agreement by the 
recipient that no unpublished information contained herein shall be published or disclosed without prior written approval, 
except that this document may be disclosed to the appropriate Institutional Review Board(s)/Independent Ethics 
Committee(s) under the condition that they keep it confidential. 




Sponsor:  Celgene International II Sàrl                                  Statistical Analysis Plan Addendum for Protocol No. RPC01-202 
Page 3 of 9 
 
TABLE OF CONTENTS 
SIGNATURES .................................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................4 
1. 
Introduction ...................................................................................................................5 
2. 
Study Design .................................................................................................................5 
3. 
Analysis Cohorts ...........................................................................................................5 
4. 
DMC .............................................................................................................................5 
5. 
Patient Disposition ........................................................................................................5 
6. 
OLP Baseline ................................................................................................................5 
7. 
Efficacy Analyses .........................................................................................................6 
7.1. 
Endpoints ......................................................................................................................6 
7.2. 
Mayo Score at the End of OLP .....................................................................................6 
7.3. 
Visit Windows ..............................................................................................................7 
8. 
Safety Analyses ............................................................................................................8 
9. 
Guideline on Missing Date Imputation .........................................................................8 
 


Sponsor:  Celgene International II Sàrl                                  Statistical Analysis Plan Addendum for Protocol No. RPC01-202 
Page 4 of 9 
 
LIST OF ABBREVIATIONS 
AE 
adverse event 
DEF 
definition 
DMC 
data monitoring committee
IP 
Induction Period
ITT 
intent-to-treat  
MP 
Maintenance Period
NRI 
Non-responder imputation
OLP 
Open-Label Treatment Period
SAE 
serious adverse event
SAP 
statistical analysis plan
UC 
ulcerative colitis
 
 
 
 
 
 
 
 


Sponsor:  Celgene International II Sàrl                                  Statistical Analysis Plan Addendum for Protocol No. RPC01-202 
Page 5 of 9 
1. 
Introduction  
 
 
  
 
  
 
 
 Label Treatment 
Period (OLP) as in the Core Period and are detailed in SAP Version 2.0.  
2. 
Study Design  
 
 
 
 
 
  
3. 
Analysis Cohorts 
 
Intent-to-Treat (ITT) Analysis Cohorts will be labeled by randomized treatment in the parent 
study for all subjects who received at least one dose of RPC1063 1mg in OLP.  
 
Safety Analysis Cohorts will be labeled by actually received treatment in the parent study for all 
subjects who received east one dose of RPC1063 1mg in OLP.  
4. 
DMC  
There were no DMC reviews planned for the OLP.  
5. 
Patient Disposition  
Patient disposition information will only include subjects who participated the OLP.  
6. 
OLP Baseline  
Baseline for efficacy analyses:  
 Core baseline: The last assessment prior to/on first dose date in Core Period. 
The full set of the efficacy endpoints will be derived based on Core baseline. 
Baseline for safety analyses:  
The adverse events (AEs) will be summarized per Section 8. 
For non-AE safety endpoints, definition of Baseline will not change (SAP v2.0 Section 5.1)  


Sponsor:  Celgene International II Sàrl                                  Statistical Analysis Plan Addendum for Protocol No. RPC01-202 
Page 6 of 9 
7. 
Efficacy Analyses 
The efficacy measurements will be summarized by parent study treatment group at each OLP visit in the 
OLP ITT population. Non-responder imputation (NRI) will be used as the primary method for addressing 
missing binary outcomes. No treatment failure rule will be applied in the OLP, as per its defined in 
Section 6.19 (SAP v2.0).   
7.1. 
Endpoints 
Complete Mayo score: The Full Mayo score in SAP v2.0.  
The 9-point Mayo score: The sum of the Rectal Bleeding subscore, Stool Frequency subscore, and the 
Endoscopy subscore. The 9-point Mayo score has a range of 0-9 points. 
OLP Efficacy Endpoints 
Clinical Remission 
 
Four-component Mayo clinical remission: Complete Mayo score of <=2 points with no individual 
subscore of >1 point 
 
 Three-component Mayo clinical remission: 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 
Clinical Response 
 
 Four-component Mayo clinical response: Reduction from baseline in complete Mayo score of 
>=3 points and reduction from baseline in complete Mayo score of >=30%, and (reduction in 
rectal bleeding subscore of >=1 point or a rectal bleeding subscore of <=1 point) 
 
 Three-component Mayo clinical response: Reduction from baseline in the 9-point Mayo score of 
>=2 points and Reduction from baseline in the 9-point Mayo score >=35%, and (reduction from 
baseline in the rectal bleeding subscore of >=1 point or a rectal bleeding subscore of <=1 point).  
Mucosal Healing  
 
Mucosal Healing is defined as an Endoscopic subscore of ≤ 1 point 
 
Mucosal healing (alternative definition): Endoscopy subscore of <=1 point and a Geboes index 
score <2.0 
Histological remission 
 
Histological remission is defined as Geboes index score < 2.0. 
Analysis visit windows defined in Section 7.3 will be applied on all efficacy analyses.  
7.2. 
Mayo Score at the End of OLP 
The analyses will be carried out when all patients have completed (or would have been eligible to 
complete) the OLP of the study. The mayo score will be summarized using descriptive statistics. 
The proportion of patients in clinical remission, clinical response, and with mucosal healing will be 
descriptively summarized at each visit window defined in Section 7.3 in the OLP ITT population.  


Sponsor:  Celgene International II Sàrl                                  Statistical Analysis Plan Addendum for Protocol No. RPC01-202 
Page 7 of 9 
The proportion of patients in partial Mayo clinical remission and in partial Mayo clinical response will be 
descriptively summarized for each OLP visit in the OLP ITT population.  
The proportion of patients in clinical remission (for all bullet definitions listed in Section 7.1), in clinical 
response (for all bullet definitions listed in Section 7.1), and with mucosal healing will also be 
descriptively summarized as described above in the same subgroups as the Core period in the OLP ITT 
population. 
 
Prior anti-TNFα use (yes vs. no) 
 
Age (< median vs. ≥ median) 
 
Sex (Female vs. Male) 
 
Disease localization (Left side vs. Extensive) 
 
Baseline disease activity (Mayo score using the central endoscopy read ≤ 8 vs. > 8) 
The proportion of patients in clinical remission (for all definitions), in clinical response (for all 
definitions), and with mucosal healing will be descriptively summarized as described above in the OLP 
ITT population using: 
 
Observed cases  
 
NRI  
7.3. 
Visit Windows 
Post-OLP-Baseline visits (scheduled or unscheduled) during OLP will be mapped to an analysis visit 
based on the windowing algorithm below. If a visit cannot be mapped to any analysis visit, then the 
analysis visit will be set to missing and the data of interest will be excluded from summaries. If multiple 
visits containing the same data of interest can be mapped to the same analysis visit, the visit closest to the 
target day will be used in the analysis. In the event that two or more visits are equidistant to the target 
day, the later visit will be used in the analysis.  If the two visits are on the same day, then the visit with 
the worst result will be used in the analysis. 
Visit 
Target Day 
Analysis Visit Window for 
partial Mayo score  
 
Analysis Visit Window for Complete Mayo 
Score, 9-point Mayo Score and Geboes Index
 
 
 
(+/- 6 weeks) 
(+/- 24 weeks) 
Day 1OLP 
1 
N/A 
N/A 
Week 4OLP 
36 
(19-50) 
N/A 
Week 8OLP 
64 
(51 - 106) 
N/A 
Week 20OLP 
148 
(107 - 190) 
N/A 
Week 32OLP 
232 
(191 - 274) 
N/A 
Week 44OLP 
316 
(275 - 358) 
N/A 
Week 56OLP 
400 
(359 - 442) 
(232 - 568) 
Week 68OLP 
484 
(443 - 526) 
N/A 
Week 80OLP 
568 
(527 - 610) 
N/A 
Week 92OLP 
652 
(611 - 694) 
N/A 


Sponsor:  Celgene International II Sàrl                                  Statistical Analysis Plan Addendum for Protocol No. RPC01-202 
Page 8 of 9 
Week 104OLP 
736 
(695 - 778) 
(569 - 904) 
Week 116OLP 
820 
(779 - 862) 
N/A 
Week 128OLP 
904 
(863 - 946) 
N/A 
Week 140OLP 
988 
(947 - 1030) 
N/A 
Week 152OLP 
1072 
(1031 - 1114) 
(905 - 1240) 
Week 164OLP 
1156 
(1115 - 1198) 
N/A 
Week 176OLP 
1240 
(1199 - 1282) 
N/A 
Week 188OLP 
1324 
(1283 - 1366) 
N/A 
Week 200OLP 
1408 
(1367 - 1450) 
(1241 - 1576) 
Week 212OLP 
1492 
(1451 - 1534) 
N/A 
Week 224OLP 
1576 
(1535 - 1618) 
N/A 
Week 236OLP 
1660 
(1619 - 1702) 
N/A 
Week 248OLP 
1744 
(1703 - 1786) 
(1577 - 1912) 
Week 260OLP 
1828 
(1787 - 1870) 
N/A 
Week 272OLP 
1912 
(1871 - 1954) 
N/A 
Week 284OLP 
1996 
(1955 - 2038) 
N/A 
Week 296OLP 
2080 
(2039 - 2122) 
(1913 - 2248) 
Week 308OLP 
2164 
(2123 - 2206) 
N/A 
Week 320OLP 
2248 
(2207 - 2290) 
N/A 
 
8. 
Safety Analyses 
AEs will be recorded from the time written informed consent is signed through the 90-day safety Follow-
up visit to ensure adequate collection of adverse events that could be associated with investigational drug.  
Treatment-emergent adverse events include adverse events that started between the date of first dose of 
OLP and 90-day safety Follow-up visit after the date of last dose.  
9. 
Guideline on Missing Date Imputation 
The following missing data imputation rules will be applied to the OLP analyses.  
Medication Dates: 
If the start date of medication is completely missing in which the day, month, and year are all unknown or 
only the day is known, then the start date will not be imputed. 
For the partial start date of medication, 
 
If the year is present and the month and day are missing or the year and day are present and the 
month is missing, set month and day to January 1. 
 
If the year and month are present and the day is missing, set day to 1st day of month. 
 
If the imputed start date of medication is after the non-imputed end date of medication, then the 
start date will be set to the end date of medication. 


Sponsor:  Celgene International II Sàrl                                  Statistical Analysis Plan Addendum for Protocol No. RPC01-202 
Page 9 of 9 
If the end date of medication is completely missing which the day, month, and year are all unknown or 
only the day is known, then the end date will not be imputed. 
For the partial end date of medication, 
 
If the year is present and the month and day are missing or the year and day are present and the 
month is missing, set month and day to December 31. 
 
If the year and month are present and the day is missing, set day to last day of the month. 
Adverse Event Dates: 
If the adverse event onset date is completely missing, is set to date of first dose. 
If year is missing, set it as the year of first dose. 
If year is present but (month and/or day) are missing: 
 
If year = year of first dose, then set missing month and/or day to month and/or day of first dose 
 
If year < year of first dose, then set missing month and/or day to December and/or 31. 
 
If year > year of first dose, then set missing month and/or day to January and/or 1. 
If month and year are present but day is missing: 
 
If year = year of first dose and if month = month of first dose, then set day of first dose 
 
If month < month of first dose, then set day to last day of the month 
 
If month > month of first dose, then set day to first day of the month 
 
If year < year of first dose, then set day to last day of the month 
 
If year > year of first dose, then set day to first day of the month 
For all other cases, set to date of first dose.