Clinical trial NCT02531113
Conditions: Crohn's Disease
Sponsor: Celgene
Start date: 2015-10-09; Completion date: 2019-11-28
Enrollment: 69 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose is to determine whether RPC1063 is effective in the treatment of Crohn's disease.

Detailed description:
This open-label trial is composed of two periods: Induction and Extension. All eligible patients will be enrolled into the 12-Week Induction period and receive study medication. Patients who complete the Induction period may then be eligible to enter the 100-Week Extension period where they will continue to receive study medication.

Arms: arm 1: None
Interventions: intervention 1: RPC1063
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
Sponsor: Celgene International II Sàrl 
 
 
Protocol No. RPC01-2201 
Efficacy and Safety of RPC1063 in CD 
 
24 May 2019, Version 5.0 
 
Confidential 
1 
1. 
CLINICAL TRIAL PROTOCOL 
Protocol Title:  
A Phase 2, Multi-Center, Open-Label Induction Trial with 
Extension Period to Assess Endoscopic Improvement and 
Changes in Intestinal and Serum Biomarkers in Patients 
with Moderately to Severely Active Crohn's Disease 
Receiving Oral RPC1063 as Induction Therapy 
Protocol Number: 
RPC01-2201 
Version and Date: 
 
 
5.0 dated 24 May 2019 
Replaces Version: 
 
 
4.0 dated 29 May 2018 
Investigational Product: 
RPC1063 
IND No.: 
126,740 
EudraCT No.: 
2015-002025-19 
Trial Phase: 
2 
Sponsor: 
  
 
 
 
 
Sponsor Medical Monitor: 
W. Jerry Liu, MD 
  
 
 
 
 
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. 


Sponsor: Celgene International II Sàrl 
 
 
Protocol No. RPC01-2201 
Efficacy and Safety of RPC1063 in CD 
 
24 May 2019, Version 5.0 
 
Confidential 
2 
SIGNATURES 
PROTOCOL TITLE:  A Phase 2, Multi-Center, Open-Label Induction Trial with Extension 
Period to Assess Endoscopic Improvement and Changes in Intestinal and Serum Biomarkers in 
Patients with Moderately to Severely Active Crohn's Disease Receiving Oral RPC1063 as 
Induction Therapy  
PROTOCOL NO:  RPC01-2201 
 
 
{See appended electronic signature page} 
 
 
Signature 
 
Date 
 
 
 
 
 
 
 


Sponsor: Celgene International II Sàrl 
 
 
Protocol No. RPC01-2201 
Efficacy and Safety of RPC1063 in CD 
 
24 May 2019, Version 5.0 
 
Confidential 
3 
Sponsor:  Celgene International II Sàrl 
 
 
 
 
 
 
 
 
 
Signature of Celgene International II Sàrl 
Representative 
 
Date  
 
 
 
 
 
 
 
 
Printed Name of Celgene International II Sàrl Representative 
 
 
 
 


Sponsor: Celgene International II Sàrl 
 
 
Protocol No. RPC01-2201 
Efficacy and Safety of RPC1063 in CD 
 
24 May 2019, Version 5.0 
 
Confidential 
4 
2. 
SYNOPSIS 
Sponsor/Company: Celgene International II Sàrl  
Investigational Product: RPC1063 
Name of Active Ingredient: RPC1063 
Trial Title: 
A Phase 2, Multi-Center, Open-Label Induction Trial with Extension Period to Assess 
Endoscopic Improvement and Changes in Intestinal and Serum Biomarkers in Patients 
with Moderately to Severely Active Crohn's Disease Receiving Oral RPC1063 as 
Induction Therapy 
Brief Title: 
Open-Label  Endoscopic Improvement Trial of RPC1063 for Moderate to Severe 
Crohn’s Disease 
Protocol No: 
RPC01-2201 
Investigators: 
Approximately 60-80 
Regions: 
North America, Europe 
Trial Duration:  3 years  
Phase:  2 
Objectives: 
Induction Period 
Primary: 
 
To assess endoscopic improvement following treatment with RPC1063  
Secondary: 
 
To characterize clinical improvement, response, and remission following treatment with RPC1063  
 
To assess changes in intestinal and blood biomarkers following treatment with RPC1063 by 
characterizing the following: 
 
Intestinal mucosa histopathologic disease activity 
 
Select cellular, protein, and molecular biomarkers in the intestinal mucosa and blood 
 
To assess the pharmacokinetics (PK) and pharmacodynamics (PD) of RPC1063 
 
To assess the safety of RPC1063  
Extension Period 
Primary: 
 
To characterize the longer term safety of continued dosing of RPC1063 
Secondary: 
 
To characterize endoscopic improvement at Week 52 
 
To characterize the histopathological changes of the intestinal mucosa at Week 52 
 
To characterize the effect of RPC1063 in maintaining clinical improvement over time 
Methodology:  
This is an open label trial comprised of 2 periods – a 12 week Induction Period and an Extension Period 
(148 weeks).  Eligible patients will enter into the trial through the Induction Period and those who complete 
the Induction Period will have the opportunity to enter into the Extension Period.  
Induction Period: 
Patient eligibility will be determined during a 5-week Screening Period prior to first dose of investigational 
drug.  All eligible patients will complete a 7-day dose escalation regimen consisting of 4 days of treatment 
with RPC1063/ozanimod HCl 0.25 mg (equivalent to ozanimod 0.23 mg) daily followed by 3 days of 
treatment with RPC1063/ozanimod HCl 0.5 mg (equivalent to ozanimod 0.46 mg) daily, with the final 


Sponsor: Celgene International II Sàrl 
 
 
Protocol No. RPC01-2201 
Efficacy and Safety of RPC1063 in CD 
 
24 May 2019, Version 5.0 
 
Confidential 
5 
RPC1063/ozanimod HCl 1 mg (equivalent to ozanimod 0.92 mg) daily dose to be reached on Day 8.  Patients 
will then continue on open label at RPC1063 1 mg/day during the Induction Period for 11 weeks.  At Week 
12 patients will be evaluated for endoscopic and clinical response/remission. 
Patients who complete the Induction Period will have the opportunity to receive continued treatment with 
RPC1063 in the Extension Period.  Investigators should assess patient’s clinical status at the end of the 
Induction Period and, using clinical judgment, determine if the patient should continue into the Extension 
Period or withdraw from the trial and receive alternative therapy. 
Extension Period: 
All patients will receive RPC1063 1 mg daily dose in the Extension Period and may receive treatment 
through Week 160.  During the Extension Period, the investigator should continue to assess the patient’s 
clinical status and based on clinical judgment determine if the patient should continue or withdraw from the 
trial and receive alternative therapy. 
Patients who complete the Week 160 visit may have the option to immediately enter (without completing the 
30-day and 90-day Safety Follow-up Visits) the open-label extension Phase 3 Crohn’s disease Study 
. 
Diagnosis and main criteria for inclusion:  
Inclusion Criteria: 
1. Male or female patients aged 18 to 75 years, inclusive  
2. Diagnosis of Crohn’s disease for at least 2 months (prior to Screening) by clinical endoscopic evidence 
and corroborated by a histology report (Note: histopathology may be performed during Screening if no 
prior report is readily available) 
3. Crohn’s disease Activity Index score of 220 to 450 inclusive with an SES-CD score of ≥ 6.  (If disease 
isolated to ileum, the requirement will be a SES-CD score ≥ 4) 
4. Average daily stool score ≥ 4 points and/or an average daily abdominal pain score of ≥ 2 points 
5. Patients must meet one of the following criteria: 
 
Have an inadequate response or loss of response to at least one of the following Crohn’s disease 
treatments: 
 
Aminosalicylates, oral aminosalicylates ≥2.4 g/day or ≥3 g/day sulfasalazine for at least 
4 weeks 
 
Corticosteroids, oral prednisone ≥ 30 mg or budesonide ≥ 9 mg for at least 2 weeks or an 
equivalent (to oral prednisone) of intravenous corticosteroid for 1 week 
 
Immunomodulators, oral azathioprine ≥ 1.5 mg/kg or 6-mercaptopurine 0.75 mg/kg 
(documentation of therapeutic level of 6-thioguanine is also acceptable) or methotrexate 
≥ 12.5 mg/week for at least 8 weeks 
 
Biologic therapy (TNFα antagonist or vedolizumab only) at an approved labeled dose used 
for induction therapy for at least 4 weeks or recurrence of disease activity despite 
scheduled maintenance therapy.  (Biologic therapy exposed patients will be capped at 50% 
of total enrolled patients) 
 
And/or have been intolerant to any of the above mentioned therapies (e.g., unable to achieve 
doses, dose levels, or treatment durations because of treatment related side effects and/or 
laboratory abnormalities) 
6. The following background therapies for Crohn’s disease will be permitted on a stable dose: 
 
Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, balsalazide) at a stable dose 
for at least 3 weeks prior to Screening endoscopy 


Sponsor: Celgene International II Sàrl 
 
 
Protocol No. RPC01-2201 
Efficacy and Safety of RPC1063 in CD 
 
24 May 2019, Version 5.0 
 
Confidential 
6 
 
Prednisone (doses ≤ 20 mg per day) or equivalent at a stable dose for at least 2 weeks prior to 
Screening endoscopy 
 
Budesonide therapy at a stable dose (dose ≤ 9 mg per day) for at least 2 weeks prior to 
Screening endoscopy 
 
Antibiotics used for the treatment of Crohn’s disease (i.e., ciprofloxacin, metronidazole) at a 
stable dose for at least 2 weeks prior to Screening endoscopy 
7. 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 endoscopy score 
8. 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 
 
complete sexual abstinence  
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of 
contraception. Female condom and male condom should not be used together. 
Counseling about pregnancy precautions and the potential risks of fetal exposure must be conducted for 
female subjects of childbearing potential. The Investigator will educate all FCBP about the different 
options of contraceptive methods or abstinence as appropriate. The subject will be re-educated every 
time her contraceptive measures/methods or ability to become pregnant changes. The female subject’s 
chosen form of contraception must be effective by the time the female subject is randomized into the 
study (for example, hormonal contraception should be initiated at least 28 days before randomization). 
9. Ability to provide written informed consent and to be compliant with the schedule of protocol 
assessments 
10. Must have documentation of positive Varicella zoster virus (VZV) immunoglobulin G (IgG) antibody 
status or complete VZV vaccination at least 30 days prior to first dose of investigational drug 
11. For patients at high risk (i.e., family history, disease duration) for colonic malignancy, documented 
evidence of having had a surveillance colonoscopy within the last 2 years or according to local medical 
guidelines to evaluate for polyps, dysplasia, or malignancy.  If no recent history of surveillance 
colonoscopy, this can be done as part of colonoscopy performed during Screening 
Diagnosis and Main Criteria for Exclusion: 
Exclusions Related to General Health: 
1. 
Diagnosis of ulcerative colitis or indeterminate colitis 
2. 
Crohn’s disease isolated to the stomach, duodenum, jejunum, or peri-anal region, without colonic or 
ileal involvement 
3. 
Known strictures or stenosis leading to symptoms of obstruction 
4. 
Current stoma or need for ileostomy or colostomy 
5. 
Extensive small bowel resection (>100 cm) or known diagnosis of short bowel syndrome 


Sponsor: Celgene International II Sàrl 
 
 
Protocol No. RPC01-2201 
Efficacy and Safety of RPC1063 in CD 
 
24 May 2019, Version 5.0 
 
Confidential 
7 
6. 
Suspected or diagnosed intra-abdominal or perianal abscess that has not been appropriately treated 
7. 
Currently require or are anticipated to require surgical intervention for Crohn’s disease during the 
Induction Period 
8. 
Currently receiving total parenteral nutrition 
9. 
Positive stool culture for pathogens (ova and parasites, bacteria) or positive test for Clostridium 
difficile (C. difficile) at Screening.  Patients may be treated and retested but must have negative stool 
culture for pathogens (ova and parasites, bacteria) within 30 days prior to first dose of investigational 
drug and 60 days prior to first dose of investigational drug for C. difficile 
10. Pregnancy, lactation, or a positive serum beta human chorionic gonadotropin (hCG) measured during 
Screening  
11. Clinically relevant hepatic, neurological, pulmonary, ophthalmological, endocrine, psychiatric or other 
major systemic disease making implementation of the protocol or interpretation of the trial difficult or 
that would put the patient at risk by participating in the trial 
12. Clinically relevant cardiovascular conditions, including history or presence of: 
 
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 
 
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) 
 
Resting HR < 55 beats per minute (bpm) when taking vitals as part of a physical examination at 
Screening 
 
Mobitz type 2nd degree or 3rd degree AV block 
13. History of diabetes mellitus type 1, or uncontrolled diabetes mellitus type 2 with hemoglobin 
A1c > 9%, or diabetic patients with significant co-morbid conditions such as retinopathy or 
nephropathy 
14. History of uveitis or known macular edema 
15. Known active bacterial, viral, fungal, mycobacterial infection, or other infection (including 
tuberculosis [TB] or atypical mycobacterial disease [but excluding fungal infection of nail beds, minor 
upper respiratory tract infections and minor skin infections]) or any major episode of infection that 
required hospitalization or treatment with intravenous antibiotics within 30 days of Screening or oral 
antibiotics within 14 days of Screening.   
16. History or known presence of recurrent or chronic infection (e.g., hepatitis A, B, or C, human 
immunodeficiency virus (HIV); recurrent urinary tract infections are permitted. 
17. 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) 
18. Past or current evidence of colonic dysplasia 
19. History of alcohol or drug abuse within 1 year prior to first dose of investigational drug 
20. History of or currently active primary or secondary immunodeficiency 
Exclusions Related to Medications: 
21. History of treatment with a biologic agent within 5 elimination half-lives of that agent prior to first 
dose of investigational drug 
22. History of treatment with an investigational agent within 5 elimination half-lives of that agent prior to 
first dose of investigational drug 
23. History of treatment with topical rectal 5-ASA or steroids within 2 weeks of Screening  
24. History of primary non-response to two approved biologic therapies used for the treatment of Crohn’s 
disease 


Sponsor: Celgene International II Sàrl 
 
 
Protocol No. RPC01-2201 
Efficacy and Safety of RPC1063 in CD 
 
24 May 2019, Version 5.0 
 
Confidential 
8 
25. Receipt of a live vaccine or live attenuated vaccine within 4 weeks prior to Screening 
26. Previous treatment with lymphocyte-depleting therapies (e.g., Campath, anti-CD4, cladribine, 
rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, total body irradiation, bone marrow 
transplantation, alemtuzumab, daclizumab) 
27. Treatment with cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil within 16 weeks of 
Screening 
28. Previous treatment with D-penicillamine, leflunomide, or thalidomide  
29. Previous treatment with natalizumab or fingolimod 
30. History of treatment with intravenous immune globulin (IVIg), plasmapheresis, within 3 months prior 
to first dose of investigational drug 
31. Planned concurrent treatment with immunosuppressive agents (e.g., azathioprine, 6-MP, or 
methotrexate) after enrollment.  Patients receiving azathioprine, 6-MP or methotrexate at Screening 
must discontinue treatment with these agents prior to first dose of investigational drug. 
32. Chronic non-steroidal anti-inflammatory drug (NSAID) use (Note: occasional use of NSAIDs and 
acetaminophen [eg, headache, arthritis, myalgias, or menstrual cramps] and aspirin up to 325 mg/day 
is permitted) 
33. Treatment with Class Ia or Class III anti-arrhythmic drugs, or treatment with two or more agents in 
combination known to prolong PR interval 
34. Treatment with any of the following drugs or interventions within the corresponding timeframe: 
 
At Day 1  
 
 
CYP2C8 inhibitors (eg, gemfibrozil or clopidogrel) or inducers (eg, rifampicin) 
 
Two weeks prior to Day 1 
 
Monoamine oxidase inhibitors (eg, selegiline, phenelzine) 
Exclusions Related to Laboratory Results: 
35. Serum creatinine  1.4 mg/dL for women or  1.6 mg/dL for men 
36. 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 
37. Platelet count  100,000/μL 
38. Hgb  8.5 g/dL 
39. Neutrophils < 1500/μL 
40. Absolute WBC count < 3500/μL 
41. Absolute lymphocyte count < 800/μL 
42. Electrocardiogram (ECG) showing any clinically significant abnormality (e.g., acute ischemia, any 
significant heart conduction abnormality [e.g., left bundle branch block]) 
43. Forced expiratory volume at 1 second (FEV1) or forced vital capacity (FVC) < 70% of predicted 
values at Screening 
Test Product, Dose, and Mode of Administration: 
Induction Period: 
All patients will receive RPC1063/ozanimod HCl 1 mg (equivalent to ozanimod 0.92 mg) capsule orally 
starting with a 7-day dose escalation regimen of RPC1063/ozanimod HCl 0.25 mg (equivalent to ozanimod 
0.23 mg) daily on Days 1 through 4 and RPC1063/ozanimod HCl 0.5 mg (equivalent to ozanimod 0.46 mg) 
daily (administered as two RPC1063/ozanimod HCl 0.25 mg [equivalent to ozanimod 0.23 mg] capsules) on 
Days 5 through 7, continuing with RPC1063/ozanimod HCl 1 mg (equivalent to ozanimod 0.92 mg) daily 
through Week 12. 


Sponsor: Celgene International II Sàrl 
 
 
Protocol No. RPC01-2201 
Efficacy and Safety of RPC1063 in CD 
 
24 May 2019, Version 5.0 
 
Confidential 
9 
Extension Period: 
All patients will receive RPC1063/ozanimod HCl 1 mg (equivalent to ozanimod 0.92 mg) capsule orally 
once daily through Week 160. 
Reference therapy, dosage and mode of administration: Not applicable 
Duration of treatment:  
Induction Period: 12 weeks  
Extension Period: 148 weeks 
Endpoints: 
Definitions  
Endoscopic 
Response: SES-CD decrease from baseline of ≥ 50% 
Remission: SES-CD ≤ 4 points and a SES-CD decrease ≥ 2 points with no SES-CD sub-score > 1 point  
CDAI 
Clinical Response: CDAI reduction from baseline of ≥ 100 points 
Clinical Remission: CDAI score of < 150 
PRO2  
Clinical Response:  PRO2 decrease ≥ 50% 
Clinical Remission:  Average daily stool score ≤ 3 points AND average daily abdominal pain score ≤ 1 point 
Mucosal Healing   
Endoscopic remission plus histologic improvement 
Induction Period 
Primary Efficacy Endpoint:  
 
Change in SES-CD from baseline at Week 12 
Other Efficacy Endpoints: 
 
Change in CDAI score from baseline at Week 12 
 
Proportion of patients with clinical remission based on CDAI at Week 12  
 
Proportion of patients with clinical response based on CDAI at Week 12 
 
Proportion of patients with clinical remission based on PRO2 definitions at Week 12 
 
Proportion of patients with clinical response based on PRO2 definitions at Week 12 
 
Proportion of patients with endoscopic remission based on SES-CD definitions at Week 12 
 
Proportion of patients with endoscopic response based on SES-CD definitions at Week 12 
 
Change in intestinal mucosa histopathologic features and disease activity 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Improvement in perianal and enterocutaneous fistulas at Week 12 in those patients with fistulas at 
baseline 


Sponsor: Celgene International II Sàrl 
 
 
Protocol No. RPC01-2201 
Efficacy and Safety of RPC1063 in CD 
 
24 May 2019, Version 5.0 
 
Confidential 
10 
Extension Period 
Efficacy Endpoints: 
 
Proportion of patients in endoscopic remission based on SES-CD definitions at Week 52 
 
Proportion of patients in endoscopic response based on SES-CD definitions at Week 52 
 
Proportion of patients in clinical remission based on CDAI at Week 52  
 
Proportion of patients in clinical response based on CDAI at Week 52  
 
Proportion of patients in clinical remission based on PRO2 definitions at Week 52 
 
Proportion of patients in clinical response based on PRO2 definitions at Week 52 
 
Proportion of patients in clinical remission at Week 52 based on CDAI and PRO2 definitions who 
are off corticosteroids of those on corticosteroids at baseline  
 
Proportion of patients in clinical remission based on CDAI over time  
 
Proportion of patients in clinical response based on CDAI over time  
 
Proportion of patients in clinical remission based on PRO2 definitions over time 
 
Proportion of patients in clinical response based on PRO2 definitions over time  
 
Change in intestinal mucosa histopathologic features, histologic disease activity, and biomarkers 
over time 
 
Change in fecal calprotectin and serum C-reactive protein (CRP) levels over time 
 
Improvement in perianal and enterocutaneous fistulas in those patients with fistulas at baseline over 
time 
Pharmacokinetic and Pharmacodynamic Endpoints 
 
Plasma concentration of RPC1063 and active metabolites at scheduled assessments during the 
treatment period  
 
Absolute lymphocyte count (ALC) derived from hematology laboratory results 
 
Peripheral immune cell phenotype determined by Flow cytometry  
Safety:  
The incidence, severity, relationship and type of treatment-emergent adverse events (TEAEs), serious AEs 
(SAEs), AEs leading to discontinuation of investigational drug, and AEs of special interest, and clinically 
meaningful changes from baseline on clinical laboratory measures, vital signs, ECG, and physical 
examinations will be assessed. 
The safety of patients will be monitored by collection of treatment-emergent AEs, serious adverse events 
(SAEs), physical examinations, vital sign measurements, ECG results, optical coherence tomography (OCT), 
pulmonary function tests (PFTs), and clinical laboratory tests.  Patients who discontinue from treatment due 
to lack of response, AEs, or other reasons, even if alternative treatment is given, will complete an Early 
Termination Visit and will be followed for 90 days for collection of safety data and for the assessment of 
their disease status. 
Statistical Methods: 
Induction and Extension Period Efficacy 
This is an open-label, single-arm trial.  As such, there are no hypothesis tests on the data collected in this 
trial.  In general, descriptive summaries will be presented for the efficacy and safety variables collected.  
Continuous variables will be summarized using number of patients (n), mean, standard deviation (SD), 
median, minimum, and maximum.  Categorical variables will be summarized using frequency counts and 
percentages. 
Safety  
All treatment-emergent AEs will be coded and tabulated by system organ class and preferred term.  Adverse 
events will be monitored during the trial and the data analyzed with respect to incidence as well as severity 
and potential relationship of the AEs to investigational drug.  The incidence of AEs, SAEs, AEs of special 


Sponsor: Celgene International II Sàrl 
 
 
Protocol No. RPC01-2201 
Efficacy and Safety of RPC1063 in CD 
 
24 May 2019, Version 5.0 
 
Confidential 
11 
interest, and AEs leading to discontinuation will be summarized and presented in descending order of 
frequency.  Associated laboratory parameters such as hepatic enzymes, renal function, and hematology 
values will be grouped and presented together.  Individual patient values will be listed and values outside of 
the standard reference range will be flagged.  Shift tables and analyses of changes from baseline will be 
produced.  The change from baseline for each of the vital signs and ECG parameters will be summarized.  
The incidence of abnormal vital signs parameters and outlier ECG results will be tabulated. 
Sample Size Justification 
The sample size of 60 patients has been chosen to enable estimates of response and remission rates with 
reasonable precision.  Assuming a remission rate of 15% and a response rate of 30%, it is estimated that the 
confidence interval (half-widths of the 95% CI) around the proportion of patients in response and remission 
will be 12.8% and 16.4% for 30 patients and 9.0% and 11.6% for 60 patients. 
Version and Date:  5.0 dated 24 May 2019 


Sponsor: Celgene International II Sàrl 
 
 
Protocol No. RPC01-2201 
Efficacy and Safety of RPC1063 in CD 
 
24 May 2019, Version 5.0 
 
Confidential 
12 
3. 
TABLE OF CONTENTS 
1. 
CLINICAL TRIAL PROTOCOL .................................................................................1 
SIGNATURES .................................................................................................................................2 
 
 
3. 
TABLE OF CONTENTS ...........................................................................................12 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................17 
5. 
INTRODUCTION ......................................................................................................20 
5.1. 
Crohn’s Disease ..........................................................................................................20 
5.2. 
RPC1063 .....................................................................................................................20 
 
 
 
 
6. 
TRIAL OBJECTIVES AND ENDPOINTS ...............................................................23 
6.1. 
Trial Objectives ..........................................................................................................23 
6.1.1. 
Induction Period Primary Objective ...........................................................................23 
6.1.2. 
Induction Period Secondary Objectives ......................................................................23 
6.1.3. 
Extension Period Primary Objective ..........................................................................23 
6.1.4. 
Extension Period Secondary Objectives .....................................................................23 
6.2. 
Endpoints ....................................................................................................................23 
6.2.1. 
Induction Period Endpoints ........................................................................................23 
6.2.2. 
Extension Period Efficacy Endpoints .........................................................................24 
6.2.3. 
Safety Endpoints .........................................................................................................25 
6.2.4. 
Pharmacokinetic and Pharmacodynamic Endpoints ...................................................25 
7. 
INVESTIGATIONAL PLAN .....................................................................................26 
7.1. 
Overall Trial Design ...................................................................................................26 
7.1.1. 
Induction Period ..........................................................................................................26 
7.1.2. 
Extension Period .........................................................................................................26 
7.2. 
Criteria for Trial Termination .....................................................................................27 
7.3. 
Schedule of Events .....................................................................................................27 
8. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................35 
8.1. 
Patient Inclusion Criteria ............................................................................................35 
8.2. 
Patient Exclusion Criteria ...........................................................................................37 
8.3. 
Trial Discontinuation ..................................................................................................39 


Sponsor: Celgene International II Sàrl 
 
 
Protocol No. RPC01-2201 
Efficacy and Safety of RPC1063 in CD 
 
24 May 2019, Version 5.0 
 
Confidential 
13 
9. 
TRIAL TREATMENTS .............................................................................................42 
9.1. 
Treatments Administered ............................................................................................42 
9.1.1. 
Instructions for Missed Dose(s) of RPC1063 Capsules .............................................42 
9.1.2. 
Induction Period ..........................................................................................................42 
9.1.3. 
Extension Period .........................................................................................................42 
9.2. 
Selection of Dose in the Trial .....................................................................................42 
9.3. 
Method of Assigning Patients to Treatment Groups ..................................................43 
9.4. 
Selection and Timing of Dose for Each Patient ..........................................................43 
9.5. 
Prior and Concomitant Treatments .............................................................................43 
9.5.1. 
Steroid Taper ..............................................................................................................43 
9.5.2. 
Allowed Medications ..................................................................................................44 
9.5.3. 
Concomitant Medications Prohibited Through the 30-Day Safety Follow-up 
Visit .............................................................................................................................44 
9.5.4. 
Concomitant Medications Between the 30-Day Safety Follow-up Visit and 
the 90-Day Safety Follow-up Visit .............................................................................45 
9.6. 
Medical Care of Patients after End of Trial ................................................................45 
9.7. 
Treatment Compliance ................................................................................................45 
9.8. 
Blinding ......................................................................................................................46 
10. 
INVESTIGATIONAL DRUG MATERIALS AND MANAGEMENT ....................47 
10.1. 
Investigational Drug ...................................................................................................47 
10.2. 
Packaging and Labeling ..............................................................................................47 
10.3. 
Investigational Drug Accountability ...........................................................................47 
11. 
ASSESSMENT OF EFFICACY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS ........................................................................................48 
11.1. 
Efficacy Assessments .................................................................................................48 
11.1.1. 
Primary Efficacy Assessments ...................................................................................48 
11.1.2. 
SES-CD.......................................................................................................................48 
11.1.3. 
Crohn’s Disease Activity Index ..................................................................................48 
11.1.4. 
PRO2...........................................................................................................................50 
11.1.5. 
Un-weighted Stool Frequency and Abdominal Pain ..................................................50 
11.1.6. 
Other Efficacy Measures ............................................................................................50 
11.1.6.1. 
Enterocutaneous and Perianal Fistula Drainage Assessment .....................................50 
11.1.7. 
Efficacy Definitions ....................................................................................................50 


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11.2. 
Pharmacokinetics and Pharmacodynamics .................................................................51 
11.2.1. 
Pharmacokinetics and Pharmacodynamics .................................................................51 
11.2.2. 
Flow Cytometry ..........................................................................................................51 
12. 
ASSESSMENT OF SAFETY .....................................................................................52 
12.1. 
Safety Parameters .......................................................................................................52 
12.1.1. 
Physical Examination .................................................................................................52 
12.1.2. 
Vital Signs ..................................................................................................................52 
12.1.3. 
Electrocardiogram .......................................................................................................52 
12.1.4. 
Ophthalmological Examination ..................................................................................53 
12.1.5. 
Pulmonary Function Tests ..........................................................................................53 
12.1.6. 
Height and Weight ......................................................................................................53 
12.1.7. 
Monitoring of Adverse Events and Serious Adverse Events ......................................53 
12.1.8. 
Monitoring of Concomitant Therapy ..........................................................................53 
12.1.9. 
Guidelines for Monitoring Patients Taking Their First Dose of RPC1063 ................53 
12.1.10. 
Clinical Laboratory Evaluations .................................................................................54 
12.2. 
Adverse and Serious Adverse Events .........................................................................56 
12.2.1. 
Definition of Adverse Events .....................................................................................56 
12.2.2. 
Definition of Serious Adverse Events ........................................................................56 
12.2.3. 
Assessment of Adverse Event Severity ......................................................................57 
12.2.4. 
Assessment of Adverse Event Relationship to Investigational Drug .........................57 
12.2.5. 
Reporting of Serious Adverse Events .........................................................................58 
12.2.6. 
Reporting of Serious Adverse Events to Regulatory Authorities and 
Investigators ................................................................................................................59 
12.2.7. 
Adverse Events of Special Interest .............................................................................59 
12.2.8. 
Monitoring of Patients with Adverse Events, Serious Adverse Events, and 
Adverse Events of Special Interest .............................................................................62 
12.2.9. 
Data Safety Monitoring Board ....................................................................................62 
12.2.10. 
Treatment of Overdose of Investigational Drug .........................................................62 
12.2.11. 
Procedures in Case of Pregnancy ...............................................................................62 
 
 
13. 
PLANNED STATISTICAL METHODS ...................................................................64 
13.1. 
Determination of Sample Size ....................................................................................64 
13.2. 
Statistical Methods ......................................................................................................64 


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13.2.1. 
General Considerations ...............................................................................................64 
13.2.2. 
Analysis Populations ..................................................................................................64 
13.3. 
Disposition, Demographics and Baseline Characteristics ..........................................64 
13.4. 
Induction and Extension Efficacy ...............................................................................65 
13.5. 
Safety Analyses ..........................................................................................................65 
13.6. 
Pharmacokinetic Analyses ..........................................................................................65 
13.7. 
Interim Analyses .........................................................................................................65 
14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................66 
14.1. 
Monitoring ..................................................................................................................66 
14.2. 
Data Management/Coding ..........................................................................................66 
14.3. 
Quality Assurance and Inspections .............................................................................67 
15. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................68 
15.1. 
Study Monitor and Source Data Verification .............................................................68 
15.2. 
Product Quality Complaint .........................................................................................68 
16. 
ETHICS ......................................................................................................................70 
16.1. 
Institutional Review Board or Independent Ethics Committee ..................................70 
16.2. 
Ethical Conduct of the Trial .......................................................................................70 
16.3. 
Patient Information and Consent ................................................................................70 
16.4. 
Patient Data Protection ...............................................................................................71 
16.5. 
Investigator Obligations ..............................................................................................71 
16.6. 
Protocol Signatures .....................................................................................................71 
17. 
DATA HANDLING AND RECORD KEEPING ......................................................72 
17.1. 
Inspection of Records .................................................................................................72 
17.2. 
Retention of Records ..................................................................................................72 
18. 
PUBLICATION POLICY, FINANCING, AND INSURANCE ................................73 
 
 
20. 
APPENDIX: INVESTIGATOR SIGNATURE .........................................................75 
 


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LIST OF TABLES 
Table 1: 
Abbreviations ..............................................................................................................17 
Table 2: 
Schedule of Events for Induction Period ....................................................................28 
Table 3: 
Schedule of Events for Extension Period ...................................................................31 
Table 4: 
Examples of Prohibited Cardiac Medications (Systemic Use) ...................................45 
Table 5: 
Definitions of Simple Endoscopic Score for Crohn's Disease ...................................48 
Table 6: 
CDAI Assessment .......................................................................................................49 
Table 7: 
Crohn's Disease Severity Definitions .........................................................................50 
Table 8: 
PRO 2 Assessment ......................................................................................................50 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this protocol. 
Table 1: 
Abbreviations 
Abbreviation or Specialist Term 
Definition 
5-ASA 
5-Aminosalicylic acid 
6-MP 
6-Mercaptopurine 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALC 
Absolute lymphocyte count 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
Anti-TNF 
Anti-tumor necrosis factor 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
AZA 
Azathioprine 
BCRP 
Breast Cancer Resistance Protein 
CD 
Crohn’s disease 
CDAI 
Crohn’s Disease Activity Index 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
DDI 
Drug drug interaction 
DLCO 
Diffusion capacity of the lung for carbon 
monoxide 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
Early Term 
Early termination 
FEV1 
Forced expiratory volume at 1 second 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 


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Abbreviation or Specialist Term 
Definition 
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 
Interferon 
IHC 
Immunohistochemistry 
IL 
Interleukin 
IRB 
Institutional Review Board 
ITT 
Intent to treat 
IUD 
Intrauterine device 
IUS 
Intrauterine-hormone releasing system 
IV 
Intravenous 
IVIg 
Intravenous immune globulin 
LAM 
Lactational amenorrhea method 
LFT 
Liver function test 
MMF 
Mycophenolate mofetil 
NASH 
Nonalcoholic steatohepatitis 
NSAID 
Nonsteroidal anti-inflammatory drug 
OCT 
Optical coherence tomography 
PD 
Pharmacodynamic 
PE 
Physical examination 
PFT 
Pulmonary function test (FEV1, FVC, and DLCO) 
PK 
Pharmacokinetic 
PQC 
Product Quality Complaint 
RT-PCR 
Reverse transcription polymerase chain reaction 
S1P1 
Sphingosine 1-phosphate 1 receptor 
SAE 
Serious adverse event 


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Abbreviation or Specialist Term 
Definition 
SD 
Standard deviation 
SES-CD 
Simple Endoscopic Score for Crohn’s Disease 
TB 
Tuberculosis 
TGFβ 
Transforming growth factor beta 
TNFα 
Tumor necrosis factor alpha 
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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6. 
TRIAL OBJECTIVES AND ENDPOINTS 
6.1. 
Trial Objectives 
6.1.1. 
Induction Period Primary Objective 
To assess endoscopic improvement following treatment with RPC1063 
6.1.2. 
Induction Period Secondary Objectives 
 To characterize clinical improvement, response, and remission following treatment 
with RPC1063  
 To assess changes in intestinal and blood biomarkers following treatment with 
RPC1063 by characterizing the following: 
 Intestinal mucosa histopathologic disease activity  
 Select cellular, protein, and molecular biomarkers in the intestinal mucosa and 
blood 
 To assess the pharmacokinetics (PK) and pharmacodynamics (PD) of RPC1063  
 To assess the safety of RPC1063  
6.1.3. 
Extension Period Primary Objective 
To characterize the longer term safety of continued dosing of RPC1063  
6.1.4. 
Extension Period Secondary Objectives 
 To characterize endoscopic improvement at Week 52 
 To characterize the histopathological changes of the intestinal mucosa at Week 52 
 To characterize the effect of RPC1063 in maintaining clinical improvement over time 
6.2. 
Endpoints 
6.2.1. 
Induction Period Endpoints 
Patients in the Induction Period will be assessed for the following efficacy endpoints: 
Primary Efficacy Endpoint 
 Change in SES-CD score from baseline at Week 12. 
Other Efficacy Endpoints 
 Change in CDAI score from baseline at Week 12 
 Proportion of patients with clinical remission based on CDAI at Week 12 
 Proportion of patients with clinical response based on CDAI at Week 12 
 Proportion of patients with clinical remission based on PRO2 definitions at Week 12 


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 Proportion of patients with clinical response based on PRO2 definitions at Week 12 
 Proportion of patients with endoscopic remission based on SES-CD definitions at 
Week 12 
 Proportion of patients with endoscopic response based on SES-CD definitions at 
Week 12 
 Change in intestinal mucosa histopathologic features and disease activity 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 Improvement in perianal and enterocutaneous fistulas at Week 12 in those patients 
with fistulas at baseline 
6.2.2. 
Extension Period Efficacy Endpoints 
Patients in the Extension Period will be examined for the following efficacy endpoints: 
 Proportion of patients in endoscopic remission based on SES-CD definitions at Week 
52 
 Proportion of patients in endoscopic response based on SES-CD definitions at 
Week 52 
 Proportion of patients in clinical remission based on CDAI at Week 52 
 Proportion of patients in clinical response based on CDAI at Week 52 
 Proportion of patients in clinical remission based on PRO2 definitions at Week 52 
 Proportion of patients in clinical response based on PRO2 definitions at Week 52 
 Proportion of patients in clinical remission at Week 52 based on CDAI and PRO2 
definitions who are off corticosteroids of those on corticosteroids at baseline  
 Proportion of patients in clinical remission based on CDAI over time 
 Proportion of patients in clinical response based on CDAI over time 
 Proportion of patients in clinical remission based on PRO2 definitions over time 
 Proportion of patients in clinical response based on PRO2 definitions over time 


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 Change in intestinal mucosa histopathologic features, histologic disease activity, and 
biomarkers over time 
 Change in fecal calprotectin and serum C-reactive Protein levels over time 
 Improvement in perianal and enterocutaneous fistulas in those patients with fistulas at 
baseline over time 
6.2.3. 
Safety Endpoints 
The incidence, severity, relationship and type of TEAEs, SAEs, AEs leading to discontinuation 
of investigational drug, and AEs of special interest, and clinically meaningful changes from 
baseline on clinical laboratory measures, vital signs, electrocardiograms (ECGs), and physical 
examination will be assessed. 
Safety assessments will include the following: 
 Collection of AEs 
 Physical examinations 
 Vital sign measurements 
 ECG results 
 Optical coherence tomography 
 Pulmonary function tests (PFTs) (FEV1, FVC, and diffusion capacity of the lung for 
carbon monoxide [DLCO], where available) 
 Clinical laboratory tests 
6.2.4. 
Pharmacokinetic and Pharmacodynamic Endpoints 
Pharmacokinetic and PD endpoints will include the following: 
 
 
 
 
 
 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Trial Design 
This Phase 2, multi-center, open-label trial, to be conducted in North America and Europe, is 
designed to assess the endoscopic improvement, clinical response/remission, and changes in 
intestinal and blood biomarkers in patients with moderately to severely active Crohn’s disease 
receiving RPC1063 as induction therapy.  The trial comprises 2 periods: Induction (12 weeks) 
and Extension (148 weeks).  Patients will be entered into the trial through the Induction Period.  
A central reader will calculate the SES-CD for eligibility and assessment of the primary endpoint 
to ensure objectivity. 
The safety of patients will be monitored by collection of treatment-emergent AEs, serious 
adverse events (SAEs), physical examinations, vital sign measurements, ECG results, optical 
coherence tomography (OCT), pulmonary function tests (PFTs), and clinical laboratory tests. 
Patients who discontinue from treatment due to lack of response, AEs, or other reasons, even if 
alternative treatment is given, will complete an Early Termination Visit and will be followed for 
90 days for collection of safety data and for the assessment of their disease status. 
7.1.1. 
Induction Period 
The trial will enroll approximately 60 patients with moderately to severely active Crohn’s 
disease.  Patient eligibility will be determined during a 5-week Screening Period.  All patients 
who meet eligibility criteria and enter into the trial will complete a 7-day dose escalation 
regimen consisting of 4 days of treatment with RPC1063/ozanimod HCl 0.25 mg (equivalent to 
ozanimod 0.23 mg) daily followed by 3 days treatment with RPC1063/ozanimod HCl 0.5 mg 
(equivalent to ozanimod 0.46 mg) daily (administered as two 0.25 mg capsules), with the final 
dose level of RPC1063/ozanimod HCl 1 mg (equivalent to ozanimod 0.92 mg) daily dose to be 
reached on Day 8.  Patients will then continue on RPC1063 1 mg daily during the Induction 
Period for 11 weeks. At Week 12 patients will be evaluated for endoscopic and clinical 
response/remission.   
Patients who complete the Induction Period will have the opportunity to receive continued 
treatment with RPC1063 in the Extension Period.  Investigators should assess patient’s clinical 
status at the end of the Induction Period and, using clinical judgment, determine if the patient 
should continue into the Extension Period or withdraw from the trial and receive alternative 
therapy. 
Induction Period visit schedule and procedures, including early termination and safety follow-up, 
are provided in Table 2.   
7.1.2. 
Extension Period 
All patients will receive RPC1063 1 mg daily dose in the Extension Period and may receive 
treatment through Week 160.   During the Extension Period, the investigator should continue to 
assess the patients clinical status and based on clinical judgment determine if the patient should 
continue or withdraw from the trial and receive alternative therapy.  Extension Period visit 
schedule and procedures, including early termination and safety follow-up, are provided in 
Table 3. 


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Patients who complete the Week 160 visit may have the option to immediately enter (without 
completing the 30-day or 90-day Safety Follow-up Visits) the open-label extension Phase 3 CD 
Study 
. 
7.2. 
Criteria for Trial Termination 
The Sponsor has the right to terminate the trial prematurely for safety reasons.  In addition, the 
Sponsor may terminate the trial prematurely for administrative reasons.  In all cases, all 
necessary measures must be taken to guarantee appropriate safety follow-up of all patients 
already included in the trial. 
The IEC or IRB and the Regulatory Authorities will be informed in writing about any premature 
termination of the trial. 
7.3. 
Schedule of Events 
The visit schedule and procedures for the Induction Period and Extension Period are provided in 
Table 2 and Table 3, respectively. 
 


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Table 2: 
Schedule of Events for Induction Period 
 
 
Trial Procedures 
Screening 
Induction Period 
 
Early Term 
Visit 
Safety Follow-up 
Dose Escalation 
1 mg Dose 
Visit I1 
Visit I2 
Visit I3 
Visit I4 
Day 1a,b 
Week 4b 
Week 8b 
Week 12b,c 
Day-35 
to 0 
Day 1 
Day 28±3 
Day 56±3 
Day 84±3 
Last Dose 
+30 ±3 days 
Last Dose 
+90 
±10 daysr 
 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical historyd,e 
X 
X 
 
 
 
 
 
 
Viral serologyf 
X 
 
 
 
 
 
 
 
Stool cultureg 
X 
 
 
 
 
 
 
 
Dispense investigational 
drug 
 
X 
X 
X 
X 
 
 
 
Administer 
investigational drug at 
clinic 
 
X 
X 
X 
X 
 
 
 
Review drug compliance 
 
 
X 
X 
X 
X 
 
 
Prior and concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
Medical procedures 
(non-trial) 
 
X 
X 
X 
X 
X 
X 
 
Efficacy 
Assessments 
CDAI patient diary 
Xh 
X 
X 
X 
X 
X 
 
 
CDAI clinical score  
Xh 
X 
X 
X 
X 
X 
 
 
Colonoscopy  
Xh 
 
 
 
Xi 
Xj 
 
 
SES-CD 
Xh 
 
 
 
X 
X 
 
 
Colonic biopsy 
X 
 
 
 
X 
Xj 
 
 


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Trial Procedures 
Screening 
Induction Period 
 
Early Term 
Visit 
Safety Follow-up 
Dose Escalation 
1 mg Dose 
Visit I1 
Visit I2 
Visit I3 
Visit I4 
Day 1a,b 
Week 4b 
Week 8b 
Week 12b,c 
Day-35 
to 0 
Day 1 
Day 28±3 
Day 56±3 
Day 84±3 
Last Dose 
+30 ±3 days 
Last Dose 
+90 
±10 daysr 
 
 
X 
 
 
X 
X 
X 
 
 
Enterocutaneous and 
perianal fistula drainagek 
X 
 
 
 
X 
X 
 
 
PK and PD 
Assessments 
 
 
 
X 
X 
X 
X 
 
 
 
PK blood samplingl  
 
X 
X 
X 
X 
X 
X 
X 
Flow cytometry 
 
X 
 
 
Xm 
X 
 
 
Safety  
Assessments 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
Xn 
 
 
X 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
 
Hematologys 
X 
X 
X 
X 
X 
X 
X 
 
Blood chemistry 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy test  
(WOCBP only)o 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation panel 
X 
 
 
 
 
X 
 
 
Urinalysis 
X 
 
X 
 
X 
X 
 
 
Physical examinationp 
X 
X 
X 
X 
X 
X 
X 
 
Pulmonary function 
testsq 
X 
 
 
 
X 
X 
 
 
Optical coherence 
tomography 
X 
 
X 
 
X 
X 
 
 


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a  The duration of Day 1 Visit will be approximately 7 hours.   
b  Trial visits should be scheduled in the morning, where possible, and on trial visit days patients should be instructed to withhold the dose until the trial visit .  The dose should be 
administered during the visit. 
c  Patients should continue taking investigational drug while it is being determined if they qualify for the Extension Period.  Those who do not qualify should return for their Early 
Term Visit as soon as is practical but no later than 4 weeks after their Week 12 visit. 
d  Medical history will include smoking and Crohn’s disease history.  Day 1 medical history can be abbreviated, noting events that occurred between Screening and Day 1. 
e  Active TB must be ruled out according to local medical practices.   
f  Serology testing will be performed at Screening to determine the patient's immune status with respect to the following viruses: Human immunodeficiency virus (HIV) antibodies, 
anti-hepatitis A virus IgM, hepatitis B surface antigen (HBsAg) and anti-hepatitis B core antigen (HBcAg) IgM, anti-hepatitis C virus (HCV) IgG or IgM.  In addition, patients 
must have documentation of positive Varicella Zoster Virus (VZV) IgG antibody status or complete VZV vaccination at least 30 days prior to first dose of investigational drug. 
g  At Screening the stool sample will be used to rule out serious infection and should include evaluation for C. difficile toxin as well as ova and parasitic examination. 
h   During Screening the CDAI clinical score, SES-CD and colonoscopy must be completed within 14 days of Day 1.  Patients should also begin completing the CDAI patient diary 
during this time. At Screening, patients will be issued a CDAI diary and will be trained in the completion of the diary. 
i  Week 12 colonoscopy should be performed either on day of visit or no more than 7 days prior to the visit date. 
j  Colonoscopy does not need to be performed at the Early Term visit if one was completed within 8 weeks of the Early Term visit. 
k  Enterocutaneous and perianal fistula drainage assessment will only be performed on patients with fistulas at baseline. 
l  Blood samples for PK evaluation are to be taken up to 15-30 minutes prior to investigational drug administration (pre-dose) and just prior to discharge from the clinic (6-8 hours 
post-dose) on Day 1.  Blood samples at subsequent visits will be trough level, taken just prior to investigational drug administration. The actual time of investigational drug 
administration for all visits with PK evaluation will be recorded.  The blood sample at the 30-day and 90-day Safety Follow-Up Visit can be collected at any point during the 
visit.  An additional PK sample will be obtained for patients with any AE resulting in discontinuation or SAE. 
m  Week 12 flow cytometry analysis will only be performed for patients with a baseline sample (Day 1). 
n  Prior to first dose of investigational drug, a 12-lead ECG will be performed. After the dose, patients will have hourly vital signs recorded at 1, 2, 3, 4, 5, and 6 hours post-dose.  
A second 12-lead ECG will be performed at the end of the observation period. 
o  For females of childbearing potential only, serum beta hCG is required at screening and a urine beta hCG is required at each visit.  Between scheduled visits up until the 90-day 
Safety Follow-up Visit, monthly 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. Counseling about pregnancy precautions and the potential risks of fetal exposure must be conducted for female subjects of 
childbearing potential. The Investigator will educate all FCBP about the different options of contraceptive methods or abstinence as appropriate. The subject will be re-educated 
every time her contraceptive measures/methods or ability to become pregnant changes. The female subject’s chosen form of contraception must be effective by the time the 
female subject is randomized into the study (for example, hormonal contraception should be initiated at least 28 days before randomization). 
p  The screening physical examination (PE) includes height and weight, other visits include weight.  A complete PE will be performed at Screening and end of trial visit (Week 12 
or Early Term).  The complete PE 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).  
An interim PE may be performed at all other visits.  The interim PE will include areas with previously-noted abnormalities and those 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). 
q  DLCO, if locally available, will be done at Screening and Early Term. 
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 AEs to 
RPC1063. 
s  If ALC is confirmed < 200 cells/μL, the Investigator will temporarily discontinue investigational drug. 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.  
Abbreviations: AE = adverse event; ALC = absolute lymphocyte count; CDAI = Crohn’s Disease Activity Index; DLCO = diffusion capacity of the lung for carbon monoxide; 
Early Term = Early Termination; ECG = electrocardiogram; PD = pharmacodynamic; PK = pharmacokinetic; SES-CD = Simple Endoscopic Score for Crohn’s disease; TB = 
tuberculosis; WOCBP = women of child-bearing potential 


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Table 3: 
Schedule of Events for Extension Period 
 
Trial 
Procedures 
Extension Period 
 
 
Treatment 
 
Safety Follow-
up 
 
E1a,b 
E2b 
E3b 
E4b 
E5b 
E6b 
E7b 
E8b 
E9b 
E10 
E11 
E12 
E13 
E14b 
Early 
Term 
 
W12 
W 
24 
W 
36 
W 
48 
W 52 
W 
64 
W 
76 
W 88 
W 
100 
W 
112 
W 
124 
W 
136 
W 148 
W 
160 
 
Day 84 
±3 
Day 
168 
±7 
Day 
252 
±7 
Day 
336 
±3 
Day 
364 
±3 
Day 
448 
±7 
Day 
532 
±7 
Day 
616 
±7 
Day 
700 
±7 
Day 
784 
±7 
Day 
868 
±7 
Day 
952 
±7 
Day 
1036 
±7 
Day 
1120
±7 
Day of 
Early 
Term 
Last 
dose 
+30 
±3 
days  
Last 
dose 
+90 
±10 
daysj 
 
Dispense 
investigational 
drug 
See Week 12 of the Induction Period 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xk 
 
 
 
 
Administer 
investigational 
drug at clinic 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Review drug 
compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Efficacy Assessments 
CDAI patient 
diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CDAI clinical 
score 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Colonoscopy 
 
 
 
Xc 
 
 
 
 
 
 
 
 
 
Xd 
 
 
SES-CD score 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Xd 
 
 
Colonic biopsy 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Xd 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 


Sponsor: Celgene International II Sàrl 
 
 
Protocol No. RPC01-2201 
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24 May 2019, Version 5.0 
 
Confidential 
32 
 
Trial 
Procedures 
Extension Period 
 
 
Treatment 
 
Safety Follow-
up 
 
E1a,b 
E2b 
E3b 
E4b 
E5b 
E6b 
E7b 
E8b 
E9b 
E10 
E11 
E12 
E13 
E14b 
Early 
Term 
 
W12 
W 
24 
W 
36 
W 
48 
W 52 
W 
64 
W 
76 
W 88 
W 
100 
W 
112 
W 
124 
W 
136 
W 148 
W 
160 
 
Day 84 
±3 
Day 
168 
±7 
Day 
252 
±7 
Day 
336 
±3 
Day 
364 
±3 
Day 
448 
±7 
Day 
532 
±7 
Day 
616 
±7 
Day 
700 
±7 
Day 
784 
±7 
Day 
868 
±7 
Day 
952 
±7 
Day 
1036 
±7 
Day 
1120
±7 
Day of 
Early 
Term 
Last 
dose 
+30 
±3 
days  
Last 
dose 
+90 
±10 
daysj 
Enterocutaneous 
and perianal 
fistula drainagee 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
 
 
PK and PD 
Assessments 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
 
PK blood 
samplingf 
X 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Safety Assessments 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematologyl 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Blood chemistry 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
Urine pregnancy 
testg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Physical 
Examinationh 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pulmonary 
function testi 
 
X 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 


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Protocol No. RPC01-2201 
Efficacy and Safety of RPC1063 in CD 
 
24 May 2019, Version 5.0 
 
Confidential 
33 
 
Trial 
Procedures 
Extension Period 
 
 
Treatment 
 
Safety Follow-
up 
 
E1a,b 
E2b 
E3b 
E4b 
E5b 
E6b 
E7b 
E8b 
E9b 
E10 
E11 
E12 
E13 
E14b 
Early 
Term 
 
W12 
W 
24 
W 
36 
W 
48 
W 52 
W 
64 
W 
76 
W 88 
W 
100 
W 
112 
W 
124 
W 
136 
W 148 
W 
160 
 
Day 84 
±3 
Day 
168 
±7 
Day 
252 
±7 
Day 
336 
±3 
Day 
364 
±3 
Day 
448 
±7 
Day 
532 
±7 
Day 
616 
±7 
Day 
700 
±7 
Day 
784 
±7 
Day 
868 
±7 
Day 
952 
±7 
Day 
1036 
±7 
Day 
1120
±7 
Day of 
Early 
Term 
Last 
dose 
+30 
±3 
days  
Last 
dose 
+90 
±10 
daysj 
Optical 
coherence 
tomography 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
a  The duration of Visit E1 will be approximately 3 hours.   
b  Trial visits should be scheduled in the morning, when possible.  At trial Visits Week 24, 52 and at Week 160, patients should be instructed to withhold the dose until the trial 
visit and the dose should be administered during the visit. 
c  At Week 52, a colonoscopy should be performed either on the day of visit or no more than 7 days prior to the visit date. 
d  Colonoscopy, biopsy, and SES-CD score do not need to be performed at the Early Term visit if the Early Term Visit occurs within 8 weeks of the Week 12 colonoscopy or after 
the Week 52 colonoscopy assessment. 
e  Enterocutaneous and perianal fistula drainage assessment will only be performed on patients with fistulas at baseline. 
f  Blood samples at each visit will be trough level, taken just prior to investigational drug administration.  The actual time of investigational drug administration for all visits with 
PK evaluation will be recorded.  The blood sample at the Follow-up visit can be collected at any point during the visit.  An additional PK sample will be obtained for patients 
with any AE resulting in discontinuation or SAE. 
g  For females of childbearing potential only, serum beta hCG is required at screening and a urine beta hCG is required at each visit.  Between scheduled visits up until the 90-day 
Safety Follow-up Visit, monthly 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. Counseling about pregnancy precautions and the potential risks of fetal exposure must be conducted for female subjects of 
childbearing potential. The Investigator will educate all FCBP about the different options of contraceptive methods or abstinence as appropriate. The subject will be re-educated 
every time her contraceptive measures/methods or ability to become pregnant changes. The female subject’s chosen form of contraception must be effective by the time the 
female subject is randomized into the study (for example, hormonal contraception should be initiated at least 28 days before randomization). 
h  A complete PE will be performed at Week 160 or Early Term, whichever is applicable.  The complete PE 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).  An interim physical examination may be performed at all other visits; weight will be recorded at all visits.  
The interim PE will include areas with previously-noted abnormalities and those 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 locally available, will be done at Week 52 and Early Term. 
j  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 AEs to 
RPC1063. 


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k  For eligible patients who are entering the Phase 3 open-label extension CD Study RPC01-3204 at a future date (not on visit Week 160), investigational drug will be dispensed in 
this study. For eligible patients who are immediately entering the Phase 3 open label extension CD Study RPC01-3204 on the same day as visit Week 160, investigational drug 
will be dispensed in Study RPC01-3204. 
l  If ALC is confirmed < 200 cells/μL, the Investigator will temporarily discontinue investigational drug. 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.  
Abbreviations:  AE = adverse event; ALC = absolute lymphocyte count; CD = Crohn’s disease; CDAI = Crohn’s Disease Activity Index; DLCO = diffusion capacity of the lung 
for carbon monoxide; Early Term = Early Termination; ECG = electrocardiogram; PK = pharmacokinetic; PD = pharmacodynamic; SES-CD = Simple Endoscopic Score for 
Crohn’s disease 
 


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8. 
SELECTION AND WITHDRAWAL OF PATIENTS 
8.1. 
Patient Inclusion Criteria 
To be eligible to participate in this trial, candidates must meet the following inclusion criteria: 
1. Male or female patients aged 18 to 75 years, inclusive  
2. Diagnosis of Crohn’s disease for at least 2 months (prior to Screening) by clinical 
endoscopic evidence and corroborated by a histology report (Note:  histopathology may 
be performed during Screening if no prior report is readily available). 
3. Crohn’s disease Activity Index score of 220 to 450 inclusive with an SES-CD score of 
≥ 6.  (If disease isolated to ileum, the requirement will be a SES-CD score ≥ 4.) 
4. Average daily stool score ≥ 4 points and/or an average daily abdominal pain score of 
≥ 2 points. 
5. Patients must meet one of the following criteria: 
 Have an inadequate response or loss of response to at least one of the following 
Crohn’s disease treatments : 
 Aminosalicylates, oral aminosalicylates ≥2.4 g/day or ≥3 g/day sulfasalazine for 
at least 4 weeks 
 Corticosteroids, oral prednisone ≥30 mg or budesonide ≥9 mg for at least 2 weeks 
or an equivalent (to oral prednisone) of intravenous corticosteroid for 1 week 
 Immunomodulators, oral azathioprine ≥ 1.5 mg/kg or 6-mercaptopurine 
0.75 mg/kg (documentation of therapeutic level of 6-thioguanine is also 
acceptable) or methotrexate ≥ 12.5 mg/week for at least 8 weeks 
 Biologic therapy (TNF antagonist or vedolizumab only) at an approved labeled 
dose used for induction therapy for at least 4 weeks or recurrence of disease 
activity despite scheduled maintenance therapy.  (Biologic therapy exposed 
patients will be capped at 50% of total enrolled patients) 
 And/or have been intolerant to any of the above mentioned therapies (e.g., unable to 
achieve doses, dose levels, or treatment durations because of treatment related side 
effects and/or laboratory abnormalities) 
6. The following background therapies for Crohn’s disease will be permitted on a stable 
dose: 
 Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, balsalazide) at a 
stable dose for at least 3 weeks prior to Screening endoscopy  
 Prednisone (doses ≤ 20 mg per day) or equivalent at a stable dose (dose ≤ 9 mg per 
day) for at least 2 weeks prior to Screening endoscopy 
 Budesonide therapy at a stable dose for at least 2 weeks prior to Screening endoscopy 


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 Antibiotics used for the treatment of Crohn’s disease (i.e., ciprofloxacin, 
metronidazole) at a stable dose for at least 2 weeks prior to Screening endoscopy 
7. 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 
endoscopy score 
8. 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 
 complete sexual abstinence  
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and lactational amenorrhoea method are not 
acceptable methods of contraception. Female condom and male condom should not be 
used together.  
Counseling about pregnancy precautions and the potential risks of fetal exposure must be 
conducted for female subjects of childbearing potential. The Investigator will educate all 
FCBP about the different options of contraceptive methods or abstinence as appropriate. 
The subject will be re-educated every time her contraceptive measures/methods or ability 
to become pregnant changes. The female subject’s chosen form of contraception must be 
effective by the time the female subject is randomized into the study (for example, 
hormonal contraception should be initiated at least 28 days before randomization). 
9. Ability to provide written informed consent and to be compliant with the schedule of 
protocol assessments 
10. Must have documentation of positive Varicella zoster virus (VZV) immunoglobulin G 
(IgG) antibody status or complete VZV vaccination at least 30 days prior to first dose of 
investigational drug 
11. For patients at high risk (i.e., family history, disease duration) for colonic malignancy, 
documented evidence of having had a surveillance colonoscopy within the last 2 years or 
according to local medical guidelines to evaluate for polyps, dysplasia, or malignancy.  


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If no recent history of surveillance colonoscopy, this can be done as part of colonoscopy 
performed during Screening 
8.2. 
Patient Exclusion Criteria 
Candidates will be excluded from entering the trial if any of the following exclusion criteria exist 
at time of enrollment or at the time point specified in the individual criterion listed: 
Exclusions Related to General Health: 
1. Diagnosis of ulcerative colitis or indeterminate colitis 
2. Crohn’s disease isolated to the stomach, duodenum, jejunum, or peri-anal region, without 
colonic or ileal involvement 
3. Known strictures or stenosis leading to symptoms of obstruction 
4. Current stoma or need for ileostomy or colostomy 
5. Extensive small bowel resection (>100 cm) or known diagnosis of short bowel syndrome 
6. Suspected or diagnosed intra-abdominal or perianal abscess that has not been 
appropriately treated 
7. Currently require or are anticipated to require surgical intervention for Crohn’s disease 
during the Induction Period 
8. Currently receiving total parenteral nutrition 
9. Positive stool culture for pathogens (ova and parasites, bacteria) or positive test for 
Clostridium difficile (C. difficile) at Screening.  Patients may be treated and retested but 
must have negative stool culture for pathogens (ova and parasites, bacteria) within 
30 days prior to first dose of investigational drug and 60 days prior to first dose of 
investigational drug for C. difficile 
10. Pregnancy, lactation, or a positive serum beta human chorionic gonadotropin (hCG) 
measured during Screening 
11. Clinically relevant hepatic, neurological, pulmonary, ophthalmological, endocrine, 
psychiatric or other major systemic disease making implementation of the protocol or 
interpretation of the trial difficult or that would put the patient at risk by participating in 
the trial 
12. Clinically relevant cardiovascular conditions, including history or presence of: 
 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 
 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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 Resting HR less than 55 beats per minute (bpm) when taking vitals as part of a 
physical examination at Screening 
 Mobitz type 2nd degree or 3rd degree AV block 
13. History of diabetes mellitus type 1, or uncontrolled diabetes mellitus type 2 with 
hemoglobin A1c > 9%, or diabetic patients with significant co-morbid conditions such as 
retinopathy or nephropathy 
14. History of uveitis or known macular edema 
15. Known active bacterial, viral, fungal, mycobacterial infection, or other infection 
(including tuberculosis [TB] or atypical mycobacterial disease [but excluding fungal 
infection of nail beds, minor upper respiratory tract infections and minor skin infections]) 
or any major episode of infection that required hospitalization or treatment with 
intravenous antibiotics within 30 days of Screening or oral antibiotics within 14 days of 
Screening.   
16. History or known presence of recurrent or chronic infection (eg, hepatitis A, B, or C, 
human immunodeficiency virus (HIV); recurrent urinary tract infections are permitted. 
17. 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) 
18. Past or current evidence of colonic dysplasia 
19. History of alcohol or drug abuse within 1 year prior to first dose of investigational drug 
20. History of or currently active primary or secondary immunodeficiency 
Exclusions Related to Medications: 
21. History of treatment with a biologic agent within 5 elimination half-lives of that agent 
prior to first dose of investigational drug 
22. History of treatment with an investigational agent within 5 elimination half-lives of that 
agent prior to first dose of investigational drug 
23. History of treatment with topical rectal 5-ASA or steroids within 2 weeks of Screening 
24. History of primary non-response to two approved biologic therapies used for the 
treatment of Crohn’s disease  
25. Receipt of a live vaccine within 4 weeks prior to Screening 
26. Previous treatment with lymphocyte-depleting therapies (e.g., Campath, anti-CD4, 
cladribine, rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, total body 
irradiation, bone marrow transplantation, alemtuzumab, daclizumab) 
27. Treatment with cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil within 
16 weeks of Screening 
28. Previous treatment with D-penicillamine, leflunomide, or thalidomide 
29. Previous treatment with natalizumab or fingolimod 


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30. History of treatment with intravenous immune globulin (IVIg), plasmapheresis, within 
3 months prior to first dose of investigational drug 
31. Planned concurrent treatment with immunosuppressive agents (e.g., azathioprine, 6-MP, 
or methotrexate) after enrollment.  Patients receiving azathioprine, 6-MP or methotrexate 
at Screening must discontinue treatment with these agents prior to first dose of 
investigational drug. 
32. Chronic non-steroidal anti-inflammatory drug (NSAID) use (Note: occasional use of 
NSAIDs and acetaminophen [eg, headache, arthritis, myalgias, or menstrual cramps] and 
aspirin up to 325 mg/day is permitted) 
33. Treatment with Class Ia or Class III anti-arrhythmic drugs) or treatment with two or more 
agents in combination known to prolong PR interval 
34. Treatment with any of the following drugs or interventions within the corresponding 
timeframe: 
 At Day 1   
 CYP2C8 inhibitors (eg, gemfibrozil or clopidogrel) or inducers (eg, rifampicin) 
 Two weeks prior to Day 1 
 Monoamine oxidase inhibitors (eg, selegiline, phenelzine)  
Exclusions Related to Laboratory Results: 
35. Serum creatinine  1.4 mg/dL for women or  1.6 mg/dL for men 
36. 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 
37. Platelet count  100,000/μL 
38. Hgb  8.5 g/dL 
39. Neutrophils < 1500/μL 
40. Absolute WBC count < 3500/μL 
41. Absolute lymphocyte count < 800/μL 
42. Electrocardiogram showing any clinically significant abnormality (e.g., acute ischemia, 
any significant heart conduction abnormality [e.g., left bundle branch block]) 
43. Forced expiratory volume at 1 second (FEV1) or forced vital capacity (FVC) < 70% of 
predicted values at Screening 
8.3. 
Trial Discontinuation 
Patients will be encouraged to complete the trial; 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 eCRF page describing the reason for discontinuation. 


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The criteria for enrollment are to be followed explicitly.  If a patient who does not meet 
enrollment criteria is inadvertently enrolled, the Medical Monitor must be contacted, and that 
patient will be withdrawn from the trial if continuation is determined to be a safety risk. 
Reasons for discontinuation include, but are not limited, to the following: 
 Physician decision:  The Investigator must discontinue investigational drug if it is 
determined that it is not safe or in the patient’s best interest to receive further 
treatment.  The Medical Monitor should be promptly notified of the decision 
 Non-compliance with investigational drug:  After consultation between the 
Investigator, the Medical Monitor, or Clinical Monitor, and the Sponsor when 
appropriate, a patient may be discontinued from the trial for failure to comply with 
dosing regimen as specified by the protocol 
 Non-compliance with protocol/protocol deviation:  A patient fails to follow protocol 
procedures, or other event or decision that stands in contrast to the guidelines set in 
the protocol 
 Adverse event:  A patient must be discontinued from investigational drug if, in the 
judgment of the Investigator or if specified in the protocol, the patient develops an 
AE such as an intercurrent illness or complication that justifies discontinuation of 
investigational drug 
 Lack of efficacy: Decision by the patient and/or the Investigator to discontinue 
treatment due to a lack of expected or desired effect related to a therapy 
 Withdrawal by Patient:  The patient may choose to discontinue investigational drug at 
any time.  Every effort should be made within the bounds of safety and patient choice 
to have each patient complete the Early Termination Visit and 30-day and 90-day 
Safety Follow-up Visits.  If a patient withdraws consent, the only additional trial data 
to be collected will be the follow-up of SAEs as mandated by the protocol 
 Pregnancy: If the patient becomes pregnant investigational drug must be discontinued 
(see Section 12.2.11 ) 
 Trial termination by Sponsor 
 Other 
All patients who discontinue the trial should complete an Early Termination Visit (see Table 2 
and Table 3).  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.  With the exception of patients who withdraw consent or are lost to follow-up, patients 
should complete the 30-day and 90-day Safety Follow-up Visits for the collection of safety data 
and to assess their disease status.  Alternative treatment for CD can be started, if needed, after the 
Early Termination Visit. 
The reason for discontinuation of investigational drug will be recorded in the clinical records and 
the patient’s eCRF.  For those patients whose status is unclear because they fail to appear for trial 
visits without stating an intention to discontinue trial participation, the Investigator should 


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Protocol No. RPC01-2201 
Efficacy and Safety of RPC1063 in CD 
 
24 May 2019, Version 5.0 
 
Confidential 
41 
document in the source documents the steps taken to contact the patient (e.g., dates of telephone 
calls, registered letters) prior to withdrawing the patient from the trial. 
Patients who withdraw from the trial will not be replaced. 


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Protocol No. RPC01-2201 
Efficacy and Safety of RPC1063 in CD 
 
24 May 2019, Version 5.0 
 
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42 
9. 
TRIAL TREATMENTS 
The Investigator must ensure that the investigational drug will be used only in accordance with 
the protocol.  Investigational drug should not be used for purposes other than as defined in this 
protocol. 
9.1. 
Treatments Administered 
 
 
 
 
 
 
 
9.1.1. 
Instructions for Missed Dose(s) of RPC1063 Capsules 
 
 
 
 
 
 
 
 
 
 
9.1.2. 
Induction Period 
Patients will receive RPC1063 1 mg oral capsule daily for 11 weeks after the 7-day dose 
escalation (12 weeks total duration). 
9.1.3. 
Extension Period 
All patients will receive RPC1063 1 mg capsule orally once daily for 148 weeks. 
9.2. 
Selection of Dose in the Trial 
The selected dose of 1 mg/day of RPC1063 is primarily based on the results from the Phase 2 
dose finding induction trial in UC (RPC01-202).  The 1 mg/day dose demonstrated better 
efficacy than the 0.5 mg/day dose across various clinical and endoscopic endpoints.   
Furthermore, the expected magnitude of pharmacodynamics effect on peripheral lymphocyte 
reduction and an acceptable safety profile was observed.  
A dose escalation over the first 7 days (0.25 mg/day on Days 1 to 4 and 0.5 mg/day 
[administered as two 0.25 mg capsules] on Days 5 to 7) will be implemented, as results from 
RPCS 001 and preliminary results from RPC01-202 indicate that use of a dose escalation 


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Protocol No. RPC01-2201 
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24 May 2019, Version 5.0 
 
Confidential 
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regimen mitigates the magnitude of reduction in HR.  Preliminary evidence from these trials 
suggest that patients who increase their dose progressively over the first week are less likely to 
have a clinically meaningful decrease in HR or blood pressure; therefore, a dose escalation 
starting with 0.25 mg RPC1063 for the first 4 days of dosing followed by 0.5 mg (administered 
as two 0.25 mg capsules) on Days 5 through 7 before progressing to the 1 mg/day dose will be 
used. 
9.3. 
Method of Assigning Patients to Treatment Groups 
Not applicable. 
9.4. 
Selection and Timing of Dose for Each Patient 
Patients will self-administer RPC1063 orally once-daily.  Investigational drug should be taken at 
approximately the same time each day with or without food. 
9.5. 
Prior and Concomitant Treatments 
All treatments, other than RPC1063, being taken by the patients on entry into the trial or at any 
time during the trial including through the 90-day Safety Follow-up Visit, are regarded as 
concomitant medications and must be documented on the appropriate section of the eCRF.  A 
history of all prior medications needs to be documented to at least 4 weeks prior to trial 
participation.  A history of previous treatments for CD needs to be documented. 
Patients who are receiving oral 5-ASA, oral corticosteroids, or purified medicinal probiotics at 
screening must keep their prescribed dosage steady through Week 8 and can only be 
discontinued or reduced in dose if Investigator judgment requires it because of toxicity or 
medical necessity.  After Week 8 these medications can be discontinued or reduced as medically 
indicated.  Oral 5-ASA, oral corticosteroids, or purified medicinal probiotics should not be 
started during the first 12 weeks of the study in patients who were not receiving them during 
screening.  Ideally, patients receiving 5-ASA or purified medicinal probiotics should maintain a 
stable dose throughout the trial. Patients not receiving oral 5-ASA, oral corticosteroids, or 
purified medicinal probiotics at screening can only begin dosing with these medications if 
Investigator judgment requires it because of medical necessity.  
9.5.1. 
Steroid Taper 
During the Induction Phase, patients are to maintain their stable baseline corticosteroid dose, if 
applicable. 
Corticosteroids may be tapered starting from Week 12 for patients entering the Extension Period.  
Patients receiving prednisone at a dose of > 10 mg/day (or equivalent) may have their dose 
reduced at a rate of 5 mg per week until a 10 mg/day dose is achieved.  Patients receiving 
prednisone at doses of ≤ 10 mg/day (or equivalent), or once a 10 mg/day dose (or equivalent) is 
achieved by tapering, may have their dose reduced at a rate of 2.5 mg/week until discontinuation.  
Beginning at Week 12, patients receiving budesonide may taper their dose at a rate of 3 mg every 
3 weeks.  For patients who do not tolerate a corticosteroid taper without recurrence of clinical 
symptoms of either CD or steroid withdrawal, the corticosteroid dose may be increased (up to the 
dose at trial entry if required), but tapering may be tried again. 


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9.5.2. 
Allowed Medications 
All prior medications (including over-the-counter medications) administered 30 days prior to the 
first dose of investigational drug and any concomitant therapy administered to the patient during 
the course of the trial (starting at the date of informed consent) until 90 days after the final dose 
of investigational drug will be recorded.  Additionally, all diagnostic, therapeutic, or surgical 
procedures and/or past biologic exposure relating to CD should be recorded.  Any medication 
that is considered necessary for the patient’s health and that is not expected to interfere with the 
evaluation of or interact with investigational drug may be continued during the trial 
(see Table 4). 
Administration of concomitant medications must be reported in the appropriate section of the 
eCRF along with dosage information, dates of administration, and reasons for use.  For 
medications with a single active ingredient, generic names for concomitant medication should be 
used if possible.  For combination products, brand names should be used.  The total daily dose 
should be filled in whenever possible. 
9.5.3. 
Concomitant Medications Prohibited Through the 30-Day Safety Follow-up Visit 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
  
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
  


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Table 4: 
Examples of Prohibited Cardiac Medications (Systemic Use) 
Pharmaceutical Class 
Example Medications 
Anti-arrhythmic drugs 
Amiodarone, bepridil hydrochloride, disopyramide, dofetilide, dronedarone, 
flecainide, ibutilide, sotalol, lidocaine, procainamide, propafenone, quinidine, 
tocainide 
9.5.4. 
Concomitant Medications Between the 30-Day Safety Follow-up Visit and the 
90-Day Safety Follow-up Visit 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
9.6. 
Medical Care of Patients after End of Trial 
Patients who leave the trial and complete their end of trial assessments, including the 30-day and 
90-day Safety Follow-up Visits, do not require any additional care provided by the sponsor; they 
will return to the care of their personal physician(s). 
9.7. 
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 
the trial.  Drug accountability will be noted by the Clinical Monitor during site visits and at the 
completion of the trial.  Patients will be asked to return all unused medication at the end of the 


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trial.  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 as described in Section 10.3.  
Overall trial 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, or by a qualified individual under the Investigator’s supervision, and compliance 
assessed.  Patients exhibiting poor compliance as assessed by medication counts (i.e., 2 or more 
missed medication days in 1 week) and their response to a medication compliance question at 
each visit should be counseled on the importance of good compliance to the trial 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 trial. 
9.8. 
Blinding 
This is an open-label trial without randomization. 


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10. 
INVESTIGATIONAL DRUG MATERIALS AND MANAGEMENT 
10.1. 
Investigational Drug 
 
   
 
 
 
 
 
 
 
 
10.2. 
Packaging and Labeling 
RPC1063 capsules will be packaged in 30 cc white high-density polyethylene bottles 
(35 capsules per bottle, apart from the dose escalation kits), closed with a 28 mm child resistant 
screw-cap that is induction sealed.  The labeling of investigational drug will be in accordance 
with GCP and any other local regulatory requirements. 
10.3. 
Investigational Drug Accountability 
Investigational drug should not be used for purposes other than as defined in this protocol. 
All supplies of investigational drug 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 of the disposition of all investigational drug supplies received 
during the trial.  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 the 
Clinical Monitor immediately.  Each Investigator will provide copies of the investigational drug 
accountability records for inclusion in the Trial Master File after database lock.  The Clinical 
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 the investigational drug only to the identified patients of this trial, 
according to the procedures described in this trial protocol.  After the end of the trial, the Clinical 
Monitor will perform final accountability, package, seal, and prepare for shipment.  
Investigational drug and all medication containers will be returned to the clinical supply 
distribution vendor and documentation will be returned to the CRO.  The CRO will verify that a 
final report of investigational drug accountability is prepared and maintained in the Investigator’s 
Trial Center File. 


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11. 
ASSESSMENT OF EFFICACY, PHARMACOKINETICS, AND 
PHARMACODYNAMICS 
11.1. 
Efficacy Assessments 
11.1.1. 
Primary Efficacy Assessments 
The SES-CD will be used to evaluate the primary efficacy endpoint. 
11.1.2. 
SES-CD 
The simple endoscopy score (SES-CD) assesses the degree of inflammation.  The SES-CD 
assesses the following 4 components: size of ulcers, ulcerated surface, affected surface, and 
presence of narrowing.  Each of these components are scored on a scale of 0 to 3 as outlined in 
Table 5. 
In the SES-CD, each of these 4 components are assessed in the five segments of the ileum and 
colon:  ileum, right, transverse, left (descending and sigmoid), and rectum.  The SES-CD is the 
sum of the individual scores of each of the components across the five segments.  Mild CD is 
defined as an SES-CD ≥3 but less than 7 points.  Moderate to severely active CD is defined as 
an SES-CD of ≥7 points.  
To ensure quality data and standardization, the same endoscopist should be used throughout the 
trial wherever possible.  Colonoscopies will be read at a centralized reading facility.  Each 
patient who enters into the trial will have colonic biopsies obtained during colonoscopy (see 
Table 2 and Table 3).  Details regarding the biopsies are provided in the biopsy manual. 
Table 5: 
Definitions of Simple Endoscopic Score for Crohn's Disease 
 
SES-CD Values 
Variable 
0 
1 
2 
3 
Size of ulcers 
None 
Aphthous ulcers  
(< 0.5 cm) 
Large ulcers  
(0.5 to 2 cm) 
Very large ulcers 
(>2 cm) 
Ulcerated surface 
None 
<10% 
10-30% 
>30% 
Affected surface 
Unaffected 
segment 
<50% 
50-75% 
>75% 
Presence of 
narrowings 
None 
Single, can be 
passed 
Multiple, can be 
passed 
Cannot be passed 
11.1.3. 
Crohn’s Disease Activity Index 
The Crohn’s Disease Activity Index (CDAI) is a composite score that is used to measure the 
clinical activity of Crohn’s disease.  The CDAI uses a questionnaire with responses scored 
numerically and weighted.  Scores range from 0 to approximately 600, with higher scores 
indicating greater disease activity.  The 8 components used to assess the CDAI and their 
weighting factors are noted in Table 6.  The definitions of mild, moderate, and severe Crohn’s 
disease are provided in Table 7. 


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Patient-reported outcomes (stool frequency and abdominal pain components of the CDAI Score 
and general well-being), and the other CDAI components will be collected in an electronic diary.  
Patients will complete the stool frequency, abdominal pain and general well-being components 
of the CDAI from the patient’s first screening visit and will continue throughout the trial. 
Patients will be instructed on the use and completion of questions on the electronic diary. 
The diary entries will be reviewed by site personnel during screening (prior to dosing, if 
applicable) and during all trial visits.  The stool frequency and abdominal pain diary entries 
preceding each trial visit will be used to calculate the CDAI score and will be calculated using 
the stool frequency and the abdominal pain data from the most recent 7 day period, or at least 
3 days within that 7 day period, prior to the visit, excluding the following: 
 One day prior to the start of a procedure or preparation for a procedure that would 
affect stool frequency  
 The day(s) of a procedure or preparation for a procedure that would affect stool  
frequency  
Because the colonoscopy preparations can interfere with the assessment of other clinical 
parameters, diary entries used to calculate the CDAI score will not correspond to day(s) of 
bowel preparation or endoscopy. 
Table 6: 
CDAI Assessment 
Clinical or Laboratory Variable 
Weighting Factor, × 
Number of liquid or soft stools each day for 7 days 
2 
Abdominal pain (graded from 0-3 on severity) each 
day for 7 days 
5 
General well-being, assessed from 0 (well) to 4 
(terrible) daily for 7 days 
7 
Presence of complications* 
20 
Taking diphenoxylate/atropine, loperamide, or 
opiates for diarrhea 
30 
Presence of an abdominal mass (0 as none, 2 as 
questionable, 5 as definite) 
10 
Hematocrit 47-HCT in men and 42-HCT in women 
6 
Percentage deviation from standard weight 
1 
Total Score 
 
*One point each is added for each set of complications: arthritis or arthralgia; iritis or uveitis; erythema nodosum, 
pyoderma gangrenosum, aphthous stomatitis; anal fissure, fistula or perirectal abscess; other bowel-related fistula; 
febrile (fever) episode over 100 degrees during the past week 


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Table 7: 
Crohn's Disease Severity Definitions 
Severity 
CDAI Score 
Mild 
150-220 
Moderate 
220-450 
Severe 
>450 
11.1.4. 
PRO2 
The PRO2 is a composite score based on 2 components of the CDAI, the number of liquid or 
soft stools/day for 7 days and the abdominal pain (rated on a scale of 0-3) assessed for 7 days 
(Khanna 2015).  The components of the score and their relative weightings are included 
in Table 8. 
Table 8: 
PRO 2 Assessment 
Component 
Weighting, x 
Number of liquid or soft stools/day for 7 days 
2 
Abdominal pain (0-3) for 7 days 
5 
The PRO2 assessment will utilize the two components of the CDAI: number of liquid or soft 
stools and abdominal pain. 
11.1.5. 
Un-weighted Stool Frequency and Abdominal Pain 
Stool Frequency as described in Table 8 will be obtained and calculated without a weighting 
factor for use as part of the inclusion criteria (4). Abdominal pain will also be obtained and 
calculated without a weighting factor for use as part of the inclusion criteria (4).  These 
un-weighted patient reported assessments will also be used as efficacy endpoints 
(Section 11.1.7). 
11.1.6. 
Other Efficacy Measures 
11.1.6.1. Enterocutaneous and Perianal Fistula Drainage Assessment 
Fistulas will be characterized as actively draining and open or closed.  Based on physical 
examination, a fistula will be considered open if an investigator can express purulent material 
from the fistula with application of gentle pressure (Present 1999). 
11.1.7. 
Efficacy Definitions 
Endoscopic 
Response: SES-CD decrease from baseline of ≥ 50% 
Remission: SES-CD ≤ 4 points and a SES-CD decrease ≥ 2 points with no SES-CD sub-score 
> 1 point 


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CDAI 
Clinical Response: CDAI reduction from baseline of ≥ 100 points 
Clinical Remission: CDAI score of < 150 
PRO2 
Clinical Response:  PRO2 decrease ≥50% 
Clinical Remission:  Average daily stool score ≤ 3 points AND average daily abdominal pain 
score ≤ 1 point 
Mucosal Healing:  Endoscopic remission plus histologic improvement 
11.2. 
Pharmacokinetics and Pharmacodynamics 
11.2.1. 
Pharmacokinetics and Pharmacodynamics 
Pharmacokinetic samples will be shipped to the central laboratory.  Details of the procedures 
to be followed for sample collection, storage, and shipment will be documented in a separate 
laboratory manual.  The actual time of investigational drug administration for all visits with PK 
evaluation will be recorded on the dosing log. 
The following PK and PD assessments will be performed on the visit days specified in Table 2 
and Table 3 to determine the safety profile of RPC1063: 
 Standard PK sampling: Samples on trial will be collected prior to dose administration 
(trough samples) and 6 to 8 hours after dose administration, as indicated in the 
Schedule of Assessments footnotes. 
 Intestinal mucosa: immunohistochemistry and/or in situ hybridization (IHC/ISH) for 
example CD20, CD4, CD8, Foxp3, 47, CCR7, IFN, IL17 
 Intestinal mucosa: transcript profiling (mRNA) for example IFN signature, T cell 
exhaustion signature, outcome signature, S1PR pathway  
 
 
 
 
 
 
11.2.2. 
Flow Cytometry 
Flow cytometry samples will be collected as specified in Table 2. 


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12. 
ASSESSMENT OF SAFETY 
12.1. 
Safety Parameters 
Safety will be evaluated by the incidence, severity, relationship and type of AEs, SAEs, AEs 
leading to discontinuation of investigational drug, and AEs of special interest; and clinically 
meaningful changes from baseline in clinical laboratory test results, vital signs, ECGs, and 
physical examinations. 
12.1.1. 
Physical Examination 
A complete physical examination will include evaluation of heart, lung, head and neck, 
abdomen, skin, and extremities.  All significant findings that are present at baseline must be 
reported on the relevant medical history/current medical conditions eCRF.  Significant findings 
made after enrollment that meet the definition of an AE must be recorded on the AEs eCRF. 
12.1.2. 
Vital Signs 
Systolic and diastolic blood pressure and pulse will be assessed in a sitting position.  An 
automated validated device may be used, if available. In case the cuff sizes available are not 
large enough for the patient's arm circumference, a sphygmomanometer with an appropriately 
sized cuff may be used. 
Patients will be carefully monitored after the first dose of investigational drug with a 6-hour 
post-dose monitoring period of hourly recording of pulse and blood pressure as described in 
Section 12.1.9. 
12.1.3. 
Electrocardiogram 
The 12-lead digital ECG devices will be provided to each clinical site by the central ECG 
laboratory for the duration of the trial.  Detailed instructions describing the process for recording 
and transmission of the digital ECGs will be outlined in the trial-specific manual and provided to 
the site before the start of the trial.  Paper versions of ECG tracings recorded at the times 
specified in the schedule of assessments (Section 7.3, Table 2, and Table 3) will be printed and 
photocopied to preserve the ink if necessary, and kept at the site as source documentation. 
ECG will be performed after the patient has been resting quietly in a supine position.  The 
screening ECG report from the central reader must be available to confirm patient eligibility 
before enrollment.  Electrocardiograms will be performed on Day 1 for all patients while in the 
clinic before the first dose of investigational drug administration and after the 6-hour post-dose 
vital signs assessment.  The 6-hour post-dose ECG will be evaluated by the treating physician, 
with input if needed from a local cardiologist or a central reader to confirm if extended 
monitoring is required.  Additional ECG monitoring will be performed on Days 5 and 8 if 
cardiac issues are identified on the prior day of dose escalation, as described in Section 12.1.9. 
Only clinically significant abnormalities should be reported in the medical history/current 
medical conditions or adverse event CRF.  Clinically significant findings must be discussed with 
the Medical Monitor before enrolling the patient in the trial. 


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12.1.4. 
Ophthalmological Examination 
An OCT will be performed as scheduled in Table 2 and Table 3.  If there is a suspicion of new 
onset or worsening macular edema, then general retinal examinations, including eye history, 
visual acuity, and dilated ophthalmoscopy will be obtained.  A general ophthalmologist can do 
the examination, although a retinal specialist would be preferred to do the examinations 
wherever possible. 
12.1.5. 
Pulmonary Function Tests 
Pulmonary function tests including forced expiratory volume in one second (FEV1) and forced 
vital capacity (FVC) will be performed as scheduled in Table 2 and Table 3.  In addition, 
diffusion capacity of carbon monoxide (DLCO) measurements will be performed where locally 
available.  DLCO will not be required at sites where there is no local testing facility.  These tests 
will be performed at a qualified pulmonary function laboratory or respiratory department.  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). 
12.1.6. 
Height and Weight 
Height will be measured at Screening only; weight will be measured at each visit. 
12.1.7. 
Monitoring of Adverse Events and Serious Adverse Events 
Throughout the course of the trial, every effort must be made to remain alert to possible AEs or 
SAEs.  Refer to Section 12.2 for definitions of AEs/SAEs, monitoring and reporting.  Refer to 
Section 12.2.7 for AEs of special interest.  
12.1.8. 
Monitoring of Concomitant Therapy 
The use of concomitant medication and procedures will be monitored throughout the trial.  
Refer to Section 9.5.3  for prohibited concomitant therapies. 
12.1.9. 
Guidelines for Monitoring Patients Taking Their First Dose of RPC1063 
On Day 1 of treatment for Induction, careful cardiac monitoring of the patients is required.  
The Investigator is responsible for monitoring the patient following the first intake of the 
investigational drug, as well as managing bradycardia symptoms should they occur.  The 
Investigator must review the baseline pre-dose ECG, pulse, and blood pressure during the 6-hour 
monitoring period, post-dose ECG, and assess discharge status at the time specified in Table 2.  
Baseline pre-dose ECG should be provided by the site and be available for comparison to the 
post-dose ECG in order to determine if criteria requiring extended monitoring are met.  
Resting pulse and blood pressure in the sitting position will be measured at the times specified in 
Table 2 (by the Investigator, an assisting nurse, or other medically qualified staff member).  
When obtaining the pulse and blood pressure before the first dose, the patient should be allowed 
to rest in a seated position at least 10 minutes before taking measurements.  The pulse and sitting 
blood pressure measurements should be repeated 2 additional times (before the first dose of 
investigational drug only).  The lowest pre-dose value of sitting pulse and blood pressure (based 
on systolic blood pressure) will be recorded in the case report form and serve as baseline for 


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comparison to post-dose values.  The repeat measurements will be made at approximately 
2-minute intervals.  For the hourly measurements after investigational drug administration, pulse 
and sitting blood pressure will be measured once and recorded in the eCRF. 
Patients should receive the first dose of investigational drug with or without food before 
12:00 pm (noon) in the clinic, if possible.  The first dose of investigational drug must be 
administered in a setting in which resources to appropriately manage symptomatic bradycardia 
are available.  A member of the Investigator team should be available to monitor the patient for 
the 6-hour monitoring period and will need to report any abnormalities to the Investigator.  
Atropine and epinephrine or isoproterenol need to be readily available to the site personnel. 
If any of the following criteria are met, additional extended monitoring (described below) should 
be instituted until the finding has resolved.  Baseline and hourly vital signs measurements 
(Hours 1 through 6) should be used to assess pulse (criteria 1 and 2 below) and ECG should be 
used to assess for AV block and QTcF interval (criteria 3 and 4 below). 
1. The pulse 6 hours post-dose is < 45 bpm  
2. The pulse 6 hours post-dose is at the lowest value post-dose (suggesting that the 
maximum PD effect on the heart may not yet have occurred) 
3. The ECG 6 hours post-dose shows new onset second degree or higher AV block 
4. The ECG 6 hours post-dose shows a prolonged QTcF interval (> 450 msec for males, 
> 470 msec for females) 
Should post-dose symptomatic bradycardia occur, the treating physician should be notified and 
he or she should initiate appropriate management, begin continuous ECG monitoring, and 
continue observation until the symptoms have resolved.  
Should a patient require pharmacologic intervention for symptomatic bradycardia, continuous 
overnight ECG monitoring in a medical facility should be instituted, and the first dose 
monitoring strategy should be repeated the following day (Day 2).  The first dose monitoring 
strategy should also be repeated at the times specified in Table 2 at Day 5 or Day 8 if any cardiac 
safety issues were observed on the previous Day of dose escalation (see Table 2). 
Patients should have written instruction on when to return to the clinic and a 24-hour contact 
phone number to call in the event of any new or warranted symptoms (eg, chest pain, dizziness, 
palpitations, syncope, nausea, vomiting).  Patients should be instructed not to drive on the same 
day after the first dose of investigational drug administration. 
12.1.10. 
Clinical Laboratory Evaluations 
The central laboratory will analyze the samples.  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.  


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 Hematology - RBC count, total and differential WBC count (basophils, eosinophils, 
lymphocytes, monocytes, and neutrophils), platelet count, mean platelet volume, 
hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin, 
and mean corpuscular hemoglobin concentration.  Total WBC and all differential 
WBC counts will be provided to the site in this open-label trial.  
During the treatment period, WBC differential results will be available to the 
Investigator.  Reductions in ALC levels is a known pharmacodynamic effect of 
RPC1063. If any of the following results are observed, the Investigator will be asked 
to repeat the laboratory tests within approximately 7 days: 
 Absolute neutrophil count [ANC] < 1000 cells/µL 
 Absolute lymphocyte count [ALC] < 200 cells/µL 
If the ANC is confirmed below the acceptable limits, the Investigator will be 
requested to closely monitor for risk of serious infection and institute appropriate 
follow-up, at the discretion of the Investigator. 
If the ALC is confirmed below the 200 cells/µL, 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, treatment may be reinitated at 
Investigator’s discretion (Section 9.1.1 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. 
 Chemistry   
 Full chemistry panel at Screening: sodium, potassium, chloride, calcium, 
magnesium, phosphate, blood urea nitrogen, glucose, albumin, alkaline 
phosphatase, creatinine, SGPT/ALT, SGOT/AST, GGT, amylase, total bilirubin, 
conjugated bilirubin, total cholesterol, triglycerides, HDL and LDL, C-reactive 
protein.  
 All other visits - blood urea nitrogen, albumin, alkaline phosphatase, creatinine, 
ALT, AST, GGT, amylase, total bilirubin, conjugated bilirubin, C-reactive protein 
 Urinalysis - leukocytes, specific gravity, bilirubin, blood, glucose, ketones, pH, 
protein, urobilinogen, urine color and appearance, and nitrate and leukocyte esterase 
 The central laboratory will analyze routine blood samples.  Details regarding 
collection of samples, shipment of samples, reporting of results, laboratory reference 
ranges, and alerting abnormal values will be supplied to the site before site initiation 
in a trial laboratory manual.  The results of the analysis will be made available to each 
site by the central laboratory. 
 Investigators will be asked to comment on those abnormalities on the respective 
laboratory result page, including a notation of the clinical significance of each 


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abnormal finding in the patient’s source documents.  The laboratory sheets will be 
filed with the patient’s source documents.   
 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. 
12.2. 
Adverse and Serious Adverse Events 
12.2.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product, which that does not necessarily have a causal 
relationship with the investigational treatment.  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 (ICH E2A, II.A.1). 
AEs will be monitored throughout the entire trial 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 trial 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. 
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself. 
An Adverse Drug Reaction (ADR) is defined as all noxious and unintended responses to a 
medicinal product related to any dose (ICH E2A, II.A.2).   
An Unexpected ADR is defined as an adverse reaction, the nature of which is not consistent with 
the applicable product information (ICH E2A, II.A.3). 
Each AE is to be evaluated for duration, severity, seriousness and causal relationship to the 
investigational drug.  The action taken and the outcome must also be recorded. 
12.2.2. 
Definition of Serious Adverse Events 
Definition of Serious Adverse Event (SAE):  An SAE (experience) or reaction is any untoward 
medical occurrence that at any dose (ICH E2A, II.B): 
 Results in death  
 Is life-threatening  


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NOTE:  The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization  
 Results in persistent or significant disability/incapacity, or 
 Is a congenital abnormality/birth defect 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but jeopardize the patient or may require 
intervention to prevent one of the other outcomes listed in the definition above.  These should 
also usually be considered serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
In case of a fatality, the cause of death is considered as the SAE, and the death is considered as 
its OUTCOME. 
12.2.3. 
Assessment of Adverse Event Severity 
The severity of the AE will be characterized as “mild, moderate, or severe” according to the 
following definitions: 
 Mild events are usually transient and do not interfere with the patient’s daily 
activities. 
 Moderate events introduce a low level of inconvenience or concern to the patient and 
may interfere with daily activities. 
 Severe events are incapacitating and interrupt the patient’s usual daily activity. 
12.2.4. 
Assessment of Adverse Event Relationship to Investigational Drug 
The causal relationship between the investigational drug and the AE has to be characterized as 
unrelated, unlikely, possible, probable, or related.  This medical assessment should be made as 
soon as feasible when reporting an SAE. 
The Investigator is requested to assess the relationship of any AEs to treatment using the 
following definitions: 
Unrelated:  those AEs which are clearly and incontrovertibly due to extraneous causes 
(concurrent drugs, environment, etc) and do not meet the criteria for drug relationship listed 
under Unlikely, Possible, Probable, or Related. 
Unlikely:  An AE may be considered unlikely if it includes at least the first two features: 
 It does not follow a reasonable temporal sequence from administration of the drug  
 It could readily have been produced by the patient’s clinical state, environmental or 
toxic factors, or other modes of therapy administered to the patient  


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 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 (eg, bone marrow 
depression, fixed drug eruptions, tardive dyskinesia, etc) 
 It follows a known pattern of response to the suspected drug 
Related: An AE may be considered related if it includes all of the following features: 
 It follows a reasonable temporal sequence from administration of the drug 
 It could not be reasonably explained by the known characteristics of the patient’s 
clinical state, environmental or toxic factors or other modes of therapy administered 
to the patient 
 It disappears or decreased on cessation or reduction in dose.  There are exceptions 
when an AE does not disappear upon discontinuation of the drug (eg, bone marrow 
depression, fixed drug eruptions, tardive dyskinesia, etc.) 
 It follows a known pattern of response to the suspected drug 
 It reappears or worsens if the drug is re-administered 
All efforts should be made to classify the AE according to the above categories. 
After initiation of investigational drug, all AEs, regardless of relationship to investigational drug, 
will be recorded until the patient completes his or her last trial visit. 
12.2.5. 
Reporting of Serious Adverse Events 
Reporting requirements for SAEs will be managed on behalf of the Sponsor by the CRO.  Full 
details of the procedures to be adopted will be documented in a safety management plan 
approved by responsible parties, in brief: 
The Investigator will report any SAE that occurs to any patient from the time written informed 
consent is signed through the last visit.  All SAEs that occur within 90 days of the last dose of 
treatment with the investigational drug, whether or not considered related to the investigational 


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product, must also be reported.  Any SAE that is ongoing when the patient completes the trial or 
discontinues from the trial will be followed by the Investigator until the event has resolved, 
stabilized, or returned to Baseline status. 
Any AE considered serious by the Investigator or Sub-investigator or that meets serious criteria 
should be reported to the CRO’s Pharmacovigilance group using the designated SAE reporting 
forms and procedures within 24 hours from the time the trial site personnel first learned of the 
event.  
The SAE hotline numbers are as follows: 
 
 
 
The initial report should be promptly followed by detailed, written reports, which will include 
copies of hospital case records, discharge summaries, autopsy reports and other documents when 
requested and applicable.  For unrelated cases, a full detailed case description may negate the 
need for additional hospital case records, discharge summaries etc. 
12.2.6. 
Reporting of Serious Adverse Events to Regulatory Authorities and 
Investigators 
Investigators will be notified by the CRO of all SAEs that require prompt submission to their 
IRB or IEC.  Investigators should provide written documentation of IRB/IEC notification for 
each report to the CRO.  The CRO will ensure that all SAEs are reported to the appropriate 
regulatory authorities.  Reporting of SAEs must comply with ICH E6, 4.11.1. 
12.2.7. 
Adverse Events of Special Interest 
Adverse events (AEs) of special interest include bradycardia, heart conduction abnormalities 
(2nd degree and higher AV block), macular edema, malignancy, serious or opportunistic 
infection, pulmonary effects, and hepatic effects. 
Special considerations regarding monitoring for these events are as follows: 
 Bradycardia and heart conduction abnormalities (eg, symptomatic bradycardia, 
2nd degree AV block, QT prolongation): 
- Patients will be closely monitored in the clinic after their first dose of the initial 
dose escalation regimen for a period of 6 hours after treatment.  
Electrocardiograms will occur pre-dose and at Hour 6 following dosing, with 
more frequent assessments if clinically indicated.  Resting pulse and blood 
pressure in the sitting position will be assessed pre-dose and then hourly for 6 
hours following dosing.  See the monitoring guidelines in Section 12.1.9 for 
further details.  
- Investigators should be particularly mindful of patients who have a pulse rate 
< 55 bpm prior to administration of the investigational drug.  Dose should be 
withheld for patients who have a pulse rate of <55 bpm prior to administration of 
investigational drug.  Atropine IV is recommended as the first line treatment of 


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bradycardia, up to a maximum daily dose of 3 mg.  In general, the common 
guidelines for treatment of bradycardia (eg, Advanced Cardiac Life Support 
guidelines) should be followed as appropriate. 
- Patients should be discontinued from participation in the trial if any of the below 
are present: 
o Mobitz type II 2nd degree AV block or  
o 3rd degree AV block or  
o Symptomatic bradycardia that is non-responsive to intervention (e.g., 
atropine or isoproterenol) and lasting ≥ 24 hours (i.e., across the entire 
dosing interval) 
 Pulmonary effects 
 Any condition that might affect the outcome of pulmonary function testing 
including infection, respiratory symptoms, occupational exposures (including 
asbestos) and cigarette smoking needs to be collected before PFT testing and 
transcribed to the pulmonary function tests eCRF page. If patients have decline 
in PFT values (FEV1 and/or FVC) below 50% of the predicted values, treatment 
should be discontinued.  If a patient discontinues due to respiratory AE, the 
Investigator should ensure that the patient has adequate evaluations as clinically 
indicated by a pulmonologist (consider PFTs, chest X-ray or high resolution 
computed tomography, based on findings of the other exams) at the time of the 
AE.  For patients with pulmonary nodules, lung biopsy should be considered 
(Cryptococcus pneumonia and pulmonary TB have been reported with 
fingolimod).  Further evaluations will be conducted until such time as resolution 
is confirmed or no further improvement is expected by the Investigator (based on 
a follow-up period of not less than 3 months). 
 Hepatic effects  
 If patients have elevations in the LFTs (ALT or/and AST) ≥3x 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 frequent testing.   The Investigator 
should establish causality.   
 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 
: 
o ALT or AST > 8x ULN or 
o ALT or AST > 5x ULN with confirmation, within 2 weeks or 
o ALT or AST > 3x ULN and (total bilirubin > 2x ULN or INR > 1.5) or 


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o ALT or AST > 3x ULN with the appearance of fatigue, nausea, vomiting, 
or right upper quadrant pain or tenderness, fever, rash and/or eosinophilia 
(>5%) 
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. 
 Evaluation of alternative causes for the liver test abnormalities could include any 
of the following: 
o Acute viral hepatitis 
o Alcoholic or autoimmune hepatitis 
o Hepatobiliary disorders 
o NASH 
o Cardiovascular causes 
o Concomitant treatments 
 Macular edema 
 For patients with abnormal OCT findings or with visual signs or symptoms of 
new onset or worsening macular edema that develop following initiation of 
treatment, a general ophthalmologic examination including eye history, visual 
acuity, and dilated ophthalmoscopy will also be performed 
 Investigational drug must be discontinued in any patient who has a confirmed 
diagnosis of clinically significant macular edema that is of new onset or worsened 
since baseline 
 Patients with a diagnosis of macular edema must be followed up monthly and 
more frequently if needed based on the ophthalmologist's judgment 
 Malignancies  
 Because RPC1063 is an immunomodulator, patients should be carefully 
monitored for infections and malignancies (including dermatologic malignancy) 
 The treating Investigator will complete a dermatological examination for 
monitoring of the potential development of new cutaneous malignancies during 
the trial.  Patients with any suspicious finding noted during the examination will 
be referred to an appropriately qualified dermatologist for evaluation and 
treatment, if warranted 
 Serious or opportunistic infections  
- TB, serious bacterial infections, systemic fungal infections, viral infections such 
as herpes infections (including herpes zoster and disseminated herpes simplex) 
and protozoan infections should be reported as AEs  


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- During the treatment period if a serious infection or a serious opportunistic 
infection is identified, investigational drug should be suspended until the patient 
has received appropriate treatment and has had resolution of the infection.  
Investigational drug can be restarted at the Investigator’s discretion after 
assessment of the patient’s clinical status (See Section 9.1.1 for instructions on 
resuming treatment after missing doses)  
- Patients withdrawn from the trial as a result of the above will be followed until 
lymphocyte levels return to the patient’s pre-treatment baseline or to the central 
laboratory’s Lower Limit of Normal, whichever is lower 
12.2.8. 
Monitoring of Patients with Adverse Events, Serious Adverse Events, and 
Adverse Events of Special Interest 
Investigators must carefully monitor each patient for AEs.  This includes clinical laboratory 
variables.  Assessments must be made of the seriousness, severity, and relationship to the 
administration of the investigational drug.  After the initial AE/SAE report, the Investigator is 
required to follow up proactively with each patient and provide further information to the CRO 
on the patient’s condition.  During the trial, all AE/SAEs should be followed up to resolution 
unless the event is considered by the Investigator to be unlikely to resolve due to the patient’s 
underlying disease, or the patient is lost to follow-up.  Safety reporting must comply with 
ICH E6, 4.11. 
12.2.9. 
Data Safety Monitoring Board 
An independent Data Safety Monitoring Board (DSMB) for the trial will at a minimum perform 
quarterly safety reviews starting after the first patient is dosed. 
12.2.10. 
Treatment of Overdose of Investigational Drug 
An overdose is any dose of investigational drug given to a patient or taken by a patient that 
exceeds the dose described in the protocol.  There is no information regarding overdose with 
RPC1063.  Any overdose, with or without associated AEs, must be promptly reported to the 
CRO’s Medical Monitor or other designated Drug Safety Center.  Overdoses do not need to be 
recorded as AEs in the eCRF; only in the case of any AEs associated with the overdose should 
these be reported on relevant AE/SAE sections in the eCRF.  
12.2.11. 
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 trial. 


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Male patients should also be instructed to notify the Investigator in the event that their female 
partner becomes pregnant.  Attempts should be made to follow female partners of trial patients, 
if they should become pregnant.  The Investigator must obtain informed consent from the 
pregnant partner of a trial patient prior to collecting data on her pregnancy and its outcome. 
All reports of congenital abnormalities/birth defects are SAEs.  Spontaneous miscarriages should 
also be reported and handled as SAEs.  Elective abortions without complications should not be 
handled as AEs.  All outcomes of pregnancy must be reported to 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. 
PLANNED STATISTICAL METHODS 
13.1. 
Determination of Sample Size 
Induction: 
The sample size of 60 patients has been chosen to enable estimates of response and remission 
rates with reasonable precision.  Assuming a remission rate of 15% and a response rate of 30%, 
it is estimated that the confidence interval (half-widths of the 95% CI) around the proportion of 
patients in response and remission will be 12.8% and 16.4% for 30 patients and 9.0% and 11.6% 
for 60 patients. 
13.2. 
Statistical Methods 
13.2.1. 
General Considerations 
All efficacy and safety data will be listed by patient and summarized.  Baseline is defined as the 
last observed measurement prior to the Induction Period Day 1 receipt of investigational drug. 
In general, descriptive summaries will be presented for the efficacy and safety variables 
collected.  Continuous variables will be summarized using number of patients (n), mean, 
standard deviation (SD), median, minimum, and maximum.  Categorical variables will be 
summarized using frequency counts and percentages. 
There will be no imputation for missing efficacy or safety observations 
13.2.2. 
Analysis Populations 
All patient populations will be defined and documented prior to database lock.  Due to the 
open-label, non-randomized nature of the trial design, the intent-to-treat (ITT) and safety 
populations will be the same: all enrolled patients who receive at least one dose of RPC1063.  
These populations will be used as the primary populations for all efficacy and safety parameters. 
13.3. 
Disposition, Demographics and Baseline Characteristics 
The number and percentage of patients in each population will be summarized.  Patient 
disposition, including the number of patients enrolled, dosed, completing the Induction Period, 
and not completing the Induction Period by reason for dropout, entering the Extension Period, 
completing the Extension Period, and not completing the Extension Period by reason for dropout 
will be summarized.  Patient demographics will be summarized and will include age, sex, race, 
ethnicity, height, weight, and body mass index. 
Baseline characteristics will be summarized for and will include age at CD symptom onset, age 
at CD diagnosis, years since CD symptom onset, years since CD diagnosis, baseline CDAI score, 
baseline SES-CD score, baseline PRO2 score, prior anti-TNF use, and prior corticosteroid use. 
Compliance with investigational drug will be summarized and will include the number of 
patients estimated to be < 80% compliant, 80 to 100% compliant, and > 100% compliant.  The 
total dose and average daily dose will also be summarized. 
 


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13.4. 
Induction and Extension Efficacy 
As there are no hypothesis tests on the data collected in this trial, all efficacy endpoints will be 
reported using descriptive statistics.  Proportions of patients in response and proportions of 
patients in remission will include 95% confidence intervals. 
13.5. 
Safety Analyses 
Adverse events will be monitored during the trial and the data analyzed with respect to incidence 
as well as severity and potential relationship of the AEs to investigational drug.  Adverse events 
with onset on, or after the first dose of investigational drug or with onset prior to the first dose of 
investigational drug that increase in severity on, or after the first dose of investigational drug will 
be considered treatment-emergent.  All treatment-emergent AEs will be coded and tabulated by 
system organ class and preferred term.  Incidence of AEs, SAEs, AEs of special interest, and 
AEs leading to discontinuation will be summarized and presented in descending order of 
frequency.  
Associated laboratory parameters such as hepatic enzymes, renal function, and hematology 
values will be grouped and presented together.  Individual patient values will be listed and values 
outside of the standard reference range will be flagged.  Shift tables and analyses of changes 
from baseline will be produced.  The change from baseline for each of the vital signs and ECG 
parameters will be summarized.  Incidence of abnormal vital signs parameters and outlier ECG 
results will be tabulated. 
13.6. 
Pharmacokinetic Analyses 
 
 
 
13.7. 
Interim Analyses 
No formal interim analysis is planned. 


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14. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
14.1. 
Monitoring 
The Sponsor has engaged the services of a CRO to perform all monitoring functions within this 
clinical trial.  CRO Clinical Monitors will work in accordance with CRO SOPs and have the 
same rights and responsibilities as monitors from the Sponsor organization.  Clinical Monitors 
will establish and maintain regular contact with the Investigator. 
Monitoring visits will be conducted according to all applicable regulatory requirements and 
standards.  Regular monitoring visits will be made to each center while patients are enrolled 
in the trial.   
14.2. 
Data Management/Coding 
Electronic Data Capture (EDC) will be used for this trial, meaning that all eCRF data will be 
entered in electronic forms at the site.  All EDC systems used in the trial will have access-
controlled security and an audit history available to document any changes made to the data 
throughout the course of the trial.  Data collection recorded in site source documents will be 
entered into the eCRF by authorized site staff designated by the Investigator.  Patients will record 
daily diary information directly into an electronic diary, and this will be considered a source 
document.  Appropriate training and security measures will be completed with the Investigator, 
all authorized site staff, and patients prior to the trial being initiated and any data being entered 
into the system for and/or by any trial patients. 
All data entered by the site staff must be entered in English.  The eCRFs should be completed 
contemporaneous to the patient’s visit.  The Investigator may delegate data entry, but is 
responsible for verifying that all data entries in the eCRFs are accurate and correct at the 
conclusion of the trial.   
Source documents are all documents used by the Investigator or hospital that relate to the 
patient’s medical history, that verify the existence of the patient, the inclusion and exclusion 
criteria, and all records covering the patient’s participation in the trial.  They include laboratory 
notes, ECG results, memoranda, pharmacy dispensing records, patient files, etc. 
Source documents will be made available for inspection by the Clinical Monitor at each 
monitoring visit.  The Investigator must complete eCRFs for each patient who receives 
investigational drug.  Any copy of source document(s) that are provided to the Sponsor or its 
representatives for any purpose (eg, in support of an SAE report) must be redacted such that all 
patient-identifying information is removed, and clearly labeled with the trial and patient number. 
All AEs and medical histories recorded in the eCRF will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA).  Concomitant medications will be coded using the World 
Health Organization (WHO) drug dictionary.  Versions of dictionaries to be used will be 
specified in the data management plan for the trial. 


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


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15. 
QUALITY CONTROL AND QUALITY ASSURANCE 
15.1. 
Study Monitor and Source Data Verification 
According to the Guidelines of Good Clinical Practice (CPMP/ICH/135/95), the Sponsor is 
responsible for implementing and maintaining quality assurance and quality control systems with 
written Standard Operating Procedures (SOPs).   
Quality control will be applied to each stage of data handling.   
The following steps will be taken to ensure the accuracy, consistency, completeness, and 
reliability of the data: 
 Investigator meeting(s)  
 Central laboratories for clinical laboratory parameters and ECGs  
 Center Initiation visit  
 Early center visits post-enrollment  
 Routine center monitoring  
 Ongoing center communication and training  
 Data management quality control checks  
 Continuous data acquisition and cleaning  
 Internal review of data 
 Quality control check of the final clinical study report 
In addition, Sponsor and/or CRO Clinical Quality Assurance Department may conduct periodic 
audits of the trial processes, including, but not limited to trial center, center visits, central 
laboratories, vendors, clinical database, and final clinical study report.  When audits are 
conducted, access must be authorized for all trial-related documents including medical history 
and concomitant medication documentation to authorized Sponsor’s representatives and 
regulatory authorities. 
15.2. 
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 
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 


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emailing customercomplaints@celgene.com or by contacting the Celgene Customer Care Center 
(1-888-423-5436). 


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16. 
ETHICS 
16.1. 
Institutional Review Board or Independent Ethics Committee 
An Independent Ethics Committee should approve the final protocol, including the final version 
of the ICF and any other written information and/or materials to be provided to the patients.  The 
Investigator will provide the Sponsor or CRO with documentation of IRB/IEC approval of the 
protocol and informed consent before the trial may begin at the trial center(s).  The Investigator 
should submit the written approval to the Sponsor or representative before enrollment of any 
patient into the trial. 
The Sponsor or representative should approve any modifications to the ICF that are needed to 
meet local requirements. 
The Investigator will supply documentation to the Sponsor or CRO of required IRB/IEC’s 
annual renewal of the protocol, and any approvals of revisions to the informed consent document 
or amendments to the protocol. 
The Investigator will report promptly to the IRB/IEC, any new information that may adversely 
affect the safety of patients or the conduct of the trial.  Similarly, the Investigator will submit 
written summaries of the trial status to the IRB/IEC annually, or more frequently if requested by 
the IRB/IEC.  Upon completion of the trial, the Investigator will provide the Ethics Committee 
with a brief report of the outcome of the trial, if required. 
16.2. 
Ethical Conduct of the Trial 
This trial will be conducted and the informed consent will be obtained according to the ethical 
principles stated in the Declaration of Helsinki (48th General Assembly, Somerset West, 
Republic of South Africa, October 2008 [or current version]), the applicable guidelines for Good 
Clinical Practice (GCP; CPMP/ICH/135/95), or the applicable drug and data protection laws and 
regulations of the countries where the trial will be conducted. 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording and reporting trials that involve the participation of human patients.  The 
trial will be conducted in compliance with GCP and the applicable national regulations so as to 
assure that the rights, safety and well-being of the participating trial patients are protected 
consistent with the ethical principles that have their origin in the Declaration of Helsinki. 
16.3. 
Patient Information and Consent 
The Investigator will explain the benefits and risks of participation in the trial to each patient, the 
impartial witness and obtain written informed consent.  Written informed consent must be 
obtained prior to the patient entering the trial and before initiation of any trial related procedure.  
The final, version dated form must be agreed to by the IRB/IEC and must be provided in 
language readily understood by the patient.  In case the patient is unable to read or write, an 
impartial witness should be present during the entire informed consent discussion.  After the 
patient has orally consented to participation in the trial, the witness’ signature on the form will 
attest that the information in the consent form was accurately explained and understood.  The 
Investigator will retain an original consent form for each patient, signed and dated by the patient 
or witness, and by the person who conducted the informed consent discussion.  The Investigator 


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


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


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


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20. 
APPENDIX: INVESTIGATOR SIGNATURE 
PROTOCOL TITLE: 
A Phase 2, Multi-Center, Open-Label Induction Trial with 
Extension Period to Assess Endoscopic Improvement and Changes in Intestinal and Serum 
Biomarkers in Patients with Moderately to Severely Active Crohn's Disease Receiving Oral 
RPC1063 as Induction Therapy 
PROTOCOL NO: 
RPC01-2201 
This protocol is a confidential communication of Celgene International II Sàrl.  I confirm that I 
have read this protocol, I understand it, and I will work according to this protocol.  I will also 
work consistently with the ethical principles that have their origin in the Declaration of Helsinki 
and that are consistent with good clinical practices and the applicable laws and regulations.  
Acceptance of this document constitutes my agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval from Celgene 
International II Sàrl. 
Instructions to the Investigator:  Please SIGN and DATE this signature page.  PRINT your name, 
title, and the name of the site in which the study will be conducted.   
 
I have read this protocol in its entirety and agree to conduct the study accordingly: 
 
Signature of Investigator: 
______________________________ 
Date: ________ 
Printed Name:  
 
______________________________ 
Investigator Title:  
 
______________________________ 
 
Name/Address of Site: 
______________________________ 
 
 
 
 
______________________________ 
 
 
 
 
______________________________ 
 
 
 
 
 
 
 
 
 
 


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This document summarizes the changes to Protocol RPC01-2201 from Version 4.0 (dated 29 
May 2018) to Version 5.0 (dated 24 May 2019).  
21. 
OVERVIEW OF KEY CHANGES 
The following bulleted list identifies the key changes to the protocol and provides the rationale 
for each change: 
 New contact information 
 Change to safety follow up from 75 days to 90-day (±10 days) Safety Follow-up Visit 
to ensure adequate collection of adverse events that could be associated with 
investigational drug.  The timing of the visit is based on the estimated time needed to 
clear the major active metabolites of RPC1063 in the vast majority of patients (ie, 5 
half-lives of CC112273 and CC1084037 and accounting for variation of half-life 
duration in a human population). 
 Extended requirements for contraception in females after treatment discontinuation 
from the 75-day Safety Follow-up Visit to the 90-day Safety Follow-up Visit. 
 Updated description of RPC1063 to include major active metabolite 
CC1084037compound background 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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22. 
DETAILS OF CHANGES FROM THE PRIOR PROTOCOL 
VERSION 
For each change to the protocol text, Table 9 provides the location of the change, the original 
text, the revised text, and the rationale for the change. Minor editorial changes are not identified. 
Table 9: 
Specific Changes to Protocol RPC01-2201 from Version 4.0 (29 May 2018) to 
Version 5.0 (24 May 2019) 
Protocol 
Section(s) 
Original Text 
Revised Text or New Text 
Rationale 
Protocol 
Synopsis, 
Section 7, 
Table 2, 
Section 8, 
Section 9, 
Section 12,  
75-day Safety Follow-up Visit 
90-day Safety Follow-up Visit 
Title Page  
 
 
  
 
 
 
 
  
 
 
 
Signature 
Page 
 
 
  
 
 
 
 


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Protocol 
Section(s) 
Original Text 
Revised Text or New Text 
Rationale 
Section 5.2 
RPC1063 
RPC1063 is a small molecule 
compound that selectively and 
potently activates the sphingosine 1-
phosphate 1 receptor (S1P1) and S1P5 
receptor (S1P5), although it is more 
selective towards S1P1 over S1P5.  In 
vitro, RPC1063 has little activity on 
the other S1P receptors, showing half 
maximal effective concentration 
(EC50) > 10,000 nM for S1P2, > 5000 
nM for S1P3, and > 2000 nM for S1P4.  
RPC1063 is extensively metabolized 
in humans with up to 13 metabolites 
identified in plasma, urine, and feces, 
including 1 major active metabolite 
(CC112273) in plasma. The RPC1063 
metabolites, CC112273, RP101988, 
RP101075, and RP101442, show a 
similar potency and selectivity profile 
to RPC1063. 
RPC1063( ozanimod) is a sphingosine 
1-phosphate receptor modulator, 
which binds with high affinity 
selectively to sphingosine 1-phosphate 
receptor subtypes 1 and 5. RPC1063 
causes lymphocyte retention in 
lymphoid tissues. The mechanism by 
which RPC1063 exerts therapeutic 
effects in CD (Crohn’s disease) is 
unknown but may involve the 
reduction of lymphocyte migration 
into the central nervous system. 
 
RPC1063 is 10-fold more selective for 
S1P1 relative to S1P5 and has little 
activity on other S1P receptors (S1P2, 
S1P3, and S1P4). RPC1063 is 
extensively metabolized in humans to 
form a number of circulating active 
metabolites. In vitro, RPC1063 and its 
active metabolites demonstrated 
similar activity and selectivity for 
S1P1 and S1P5. In humans, 
approximately 94% of circulating total 
active drug exposure is represented by 
RPC1063 (6%), CC112273 (73%), 
and CC1084037 (15%). 
 
 
 
 
 
 
 
Protocol 
Synopsis, 
Table 2, 
Section 8.1 
 
Counseling about pregnancy 
precautions and the potential risks of 
fetal exposure must be conducted for 
female subjects of childbearing 
potential. The Investigator will 
educate all FCBP about the different 
options of contraceptive methods or 
abstinence as appropriate. The subject 
will be re-educated every time her 
contraceptive measures/methods or 
ability to become pregnant changes. 
The female subject’s chosen form of 
contraception must be effective by the 
time the female subject is randomized 
into the study (for example, hormonal 
contraception should be initiated at 
least 28 days before randomization). 
 
 
 
 
 


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Protocol 
Section(s) 
Original Text 
Revised Text or New Text 
Rationale 
Protocol 
Synopsis, 
Section 8.1 
Male patients: 
Must agree to use a latex condom 
during sexual contact with women of 
childbearing potential while 
participating in the study until 
completion of the 75-day Safety 
Follow-up Visit. 
Removed text 
 
 
 
  
Protocol 
Synopsis, 
Section 8.1 
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 
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 
•complete sexual abstinence 
 
 
 

SAP_001.pdf: 
RPC01-2201 
 
A PHASE 2, MULTI-CENTER, OPEN-LABEL INDUCTION TRIAL WITH 
EXTENSION PERIOD TO ASSESS ENDOSCOPIC IMPROVEMENT AND 
CHANGES IN INTESTINAL AND SERUM BIOMARKERS IN PATIENTS WITH 
MODERATELY TO SEVERELY ACTIVE CROHN'S DISEASE RECEIVING ORAL 
RPC1063 AS INDUCTION THERAPY 
 
 
January 16, 2020 
 
Statistical Analysis Plan 
 
Version 1.5 
 
Prepared by: 
 
 
Celgene International II Sàrl 
Rue du Pré-Jorat 14 
2108 Couvet Switzerland 
 
 
 
  
 
 
 
 
 
 
 
 






 




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TABLE OF CONTENTS 
TABLE OF TABLES .......................................................................................................................... 9 
LIST OF ABBREVIATIONS .......................................................................................................... 10 
1. 
ADMINISTRATIVE STRUCTURE ........................................................................................ 12 
1.1. 
SPONSOR AND OVERSIGHT ................................................................................................ 12 
1.2. 
DATA QUALITY ASSURANCE ............................................................................................ 12 
2. 
INTRODUCTION ..................................................................................................................... 12 
3. 
OBJECTIVES ............................................................................................................................ 13 
3.1. 
INDUCTION PERIOD PRIMARY OBJECTIVE ......................................................................... 13 
3.2. 
EXTENSION PERIOD PRIMARY OBJECTIVE ........................................................................ 13 
4. 
INVESTIGATIONAL PLAN ................................................................................................... 13 
4.1. 
OVERALL TRIAL DESIGN AND PLAN ................................................................................. 13 
4.2. 
ENDPOINTS AND ENDPOINT DEFINITIONS ......................................................................... 13 
4.2.1. 
Definitions .................................................................................................. 14 
4.2.2. 
Efficacy Endpoints for Induction Period ................................................... 15 
4.2.3. 
Efficacy Endpoints for Extension Period ................................................... 17 
4.2.4. 
Safety Endpoints ......................................................................................... 18 
 
 
5. 
GENERAL STATISTICAL CONSIDERATIONS ................................................................ 18 
5.1. 
SAMPLE SIZE .................................................................................................................... 19 
5.2. 
RANDOMIZATION, STRATIFICATION, AND BLINDING ........................................................ 19 
5.3. 
STATISTICAL HYPOTHESES AND MULTIPLE ENDPOINT HANDLING ................................... 20 
5.4. 
ANALYSIS POPULATIONS .................................................................................................. 20 
5.5. 
OTHER IMPORTANT CONSIDERATIONS .............................................................................. 20 
5.5.1. 
Definition of Baseline ................................................................................. 20 
5.5.2. 
Study Day Calculation for Reporting Purposes ......................................... 20 
5.5.3. 
Visit Windows ............................................................................................. 20 
5.5.4. 
Handling of Missing and Partial Data ...................................................... 22 
5.5.5. 
Handling of Missing Segmental Scores for SES-CD, GHAS, and RHI ...... 23 
6. 
PATIENT DISPOSITION ........................................................................................................ 23 
7. 
DEMOGRAPHICS, BASELINE CHARACTERISTICS, AND MEDICAL HISTORY ... 24 
7.1. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ......................................................... 24 
7.2. 
MEDICAL HISTORY ........................................................................................................... 24 
7.2.1. 
General Medical History ........................................................................... 24 
7.2.2. 
Crohn’s Disease History ............................................................................ 24 
7.2.3. 
Anti-TNF/Biologic Treatment History ....................................................... 25 
7.3. 
PROTOCOL DEVIATIONS .................................................................................................... 26 
8. 
TREATMENTS, MEDICATIONS AND NON-TRIAL MEDICAL PROCEDURES ........ 26 
8.1.1. 
Prior and Concomitant Medications .......................................................... 26 


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8.1.2. 
Non-Trial Medical Procedures .................................................................. 26 
8.2. 
INVESTIGATIONAL DRUG ................................................................................................... 27 
8.2.1. 
Extent of Exposure ..................................................................................... 27 
8.2.2. 
Investigational Drug Compliance .............................................................. 27 
9. 
EFFICACY ANALYSIS ........................................................................................................... 27 
9.1. 
TREATMENT FAILURE RULES ............................................................................................ 28 
9.2. 
HANDLING ENDOSCOPY DATA.......................................................................................... 28 
9.2.1. 
SES-CD, GHAS, and RHI Related Endpoints ............................................ 28 
9.2.2. 
GHAS and RHI Related Endpoints (exploratory efficacy endpoints) ........ 29 
9.3. 
CONTINUOUS EFFICACY ENDPOINTS ................................................................................. 29 
9.4. 
PROPORTION-BASED EFFICACY ENDPOINTS ...................................................................... 29 
 
 
 
 
 
 
10. SAFETY ANALYSIS ................................................................................................................ 31 
10.1. ADVERSE EVENTS ............................................................................................................. 31 
10.1.1. Incidence of Treatment Emergent Adverse Events .................................... 32 
10.1.2. Relationship of Adverse Events to Investigational drug ............................ 32 
10.1.3. Severity of Adverse Event ........................................................................... 33 
10.1.4. Serious Adverse Events .............................................................................. 33 
10.1.5. Adverse Events Leading to Treatment Discontinuation ............................. 33 
10.1.6. Death .......................................................................................................... 33 
10.1.7. Adverse Events of Special Interest ............................................................. 33 
10.2. CLINICAL LABORATORY EVALUATIONS ........................................................................... 34 
10.2.1. Hematology ................................................................................................ 34 
10.2.2. Blood Chemistry ......................................................................................... 35 
10.2.3. Coagulation-related parameters ................................................................ 35 
10.2.4. Urinalysis ................................................................................................... 35 
10.2.5. Pregnancy Testing and Serology Testing ................................................... 36 
10.3. VITAL SIGN MEASUREMENTS ........................................................................................... 36 
10.4. ELECTROCARDIOGRAM ..................................................................................................... 38 
10.5. PULMONARY FUNCTION TESTING ..................................................................................... 38 
10.6. PHYSICAL EXAMINATION .................................................................................................. 39 
10.7. OTHER ASSESSMENTS ....................................................................................................... 39 
11. INTERIM ANALYSIS .............................................................................................................. 39 
11.1. INTERIM ANALYSIS ........................................................................................................... 39 
11.2. DATA SAFETY MONITORING BOARD ................................................................................ 39 
12. CLARIFICATIONS/CHANGES TO THE PROTOCOL PLANNED ANALYSES........... 40 
13. REFERENCES .......................................................................................................................... 41 
APPENDIX 1. 
IMPUTATION OF PARTIAL AND MISSING DATES .............................. 43 
APPENDIX 2. 
SIMPLE ENDOSCOPIC SCORE FOR CROHN’S DISEASE (SES-CD) .. 45 
APPENDIX 3. 
CDAI SCORE CALCULATIONS .................................................................. 46 


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APPENDIX 4. 
GEBOES HISTOLOGY ACTIVITY INDEX AND ROBARTS 
HISTOPATHOLOGY INDEX ................................................................................................. 50 
APPENDIX 5. 
DOCUMENT REVISION HISTORY............................................................. 54 
 
 
 


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TABLE OF TABLES 
Table 1. Abbreviations ...................................................................................................................10 
Table 2. Key Terms........................................................................................................................14 
Table 3. Key Endpoints..................................................................................................................15 
Table 4. Analytic Visit Windows...................................................................................................21 
Table 5. Continuous Endpoints and Imputation Methods .............................................................29 
Table 6. Categorical Endpoints and Imputation Methods .............................................................30 
Table 7. Vital Sign Abnormality Cutoffs .......................................................................................37 
Table 8. Adverse Event Date Imputation Rules .............................................................................43 
Table 9. Definitions of Simple Endoscopic Score for Crohn's Disease .........................................45 
Table 10. Score calculations, weights, and rules associated with  CDAI, its components, and 
associated endpoints ...................................................................................................46 
Table 11. GHAS Grading System ..................................................................................................51 
Table 12.  Per-CD Segment GHAS Scores Allowed for Histologic Remission ............................52 
Table 13. Robarts Histopathology Index (RHI) Grading System ..................................................52 
Table 14. Per-CD Segment RHI Scores Allowed for Histologic Remission .................................53 
 
 
 


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LIST OF ABBREVIATIONS 
Table 1. Abbreviations 
Abbreviation or 
Specialist Term 
Definition 
5-ASA 
5-Aminosalicylic acid 
6-MP 
6-Mercaptopurine 
AE 
Adverse event 
AESI 
Adverse event(s) of special interest 
ALC 
Absolute lymphocyte count 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
Anti-TNF 
Anti-tumor necrosis factor 
AP 
Abdominal Pain 
AST 
Aspartate aminotransferase 
AV 
Atrioventricular 
CD 
Crohn’s disease 
CDAI 
Crohn’s Disease Activity Index 
CI 
Confidence interval 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
DLCO 
Diffusion capacity of the lung for carbon monoxide 
DM 
Data management 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FEV1 
Forced expiratory volume at 1 second 
FVC 
Forced vital capacity 
GHAS 
Geboes Histology Activity Score 
HBsAg 
Hepatitis B surface antigen 
hCG 
human chorionic gonadotropin 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
ITT 
Intent to treat 
LFT 
Liver function test 
MedDRA 
Medical Dictionary for Regulatory Activities 
ms 
Milliseconds 
NRI 
Non-responder imputation 
OC 
Observed cases 
OCT 
Optical coherence tomography 
PFT 
Pulmonary function test (FEV1, FVC, and DLCO) 
PK 
Pharmacokinetic 
PT 
Preferred term 
PYE 
patient-years of exposure 
RHI 
Robarts Histopathology Index 
SAE 
Serious adverse event 
SD 
Standard deviation 
SES-CD 
Simple Endoscopic Score for Crohn’s Disease 
SF 
Stool Frequency 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 


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SDTM 
Study Data Tabulation Model 
SDTMIG 
Study Data Tabulation Model Implementation Guide 
SE 
Standard error 
SI 
Standard international 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
USA 
United States of America 
VZV 
varicella-zoster virus 
WBC 
white blood cell 
WHODrug 
World Health Organization Drug classification dictionary 


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1. 
ADMINISTRATIVE STRUCTURE 
1.1. 
Sponsor and Oversight 
This trial is being conducted under the sponsorship of Celgene.  The clinical monitoring and data 
management (DM) are being performed under contract with IQVIA, and statistical analyses are 
being performed under contract with PPD, LLC, with oversight from Celgene. 
1.2. 
Data Quality Assurance 
The Clinical Operations, DM, and Biostatistics departments at the contract research organizations 
(CRO) will collaborate internally and with the sponsor to ensure that the data collected and analyzed 
for this trial are of the highest quality possible and meet the data standards set for the trial.  This will 
be accomplished in part through programmed edit checks which will be reviewed by the statisticians, 
programmers and other team members on an ongoing basis to evaluate whether any checks need to 
be added or any existing checks need to be modified.  In addition, periodic reviews of listings of 
accumulating data, assessment of data query trends and resulting retraining of trial site personnel 
will be performed to further ensure data quality.  
2. 
INTRODUCTION  
 
 
  
 
 
 
   
 
 
 
 
 
 
 
  
 
   
                                                 
 
 


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3. 
OBJECTIVES 
3.1. 
Induction Period Primary Objective 
To assess endoscopic improvement following treatment with RPC1063.  
3.2. 
Extension Period Primary Objective 
To characterize the long term safety of continued dosing of RPC1063.  
4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Trial Design and Plan 
Approximately 60 patients with moderately to severely active Crohn’s disease will be enrolled into 
this trial. Patients who complete the Induction Period will have the opportunity to receive continued 
treatment with RPC1063 in the Extension Period, provided that the investigator determined using 
clinical judgement, that the patient should continue into the Extension Period. All patients in the 
Extension Period will continue to receive RPC1063 1.0 mg daily and may continue treatment 
through Week 160. During the Extension Period, the investigator should continue to assess the 
patient’s clinical status and based on clinical judgment determine if the patient should continue or 
withdraw from the trial and receive alternative therapy.   
The safety of patients will be monitored by collection of treatment-emergent AEs, AEs of special 
interest (AESI), serious adverse events (SAEs), AEs leading to discontinuation of investigational 
drug, physical examinations, vital signs measurements, ECG results, optical coherence tomography 
(OCT) examinations, pulmonary function tests (PFTs), and clinical laboratory tests. 
Patients who discontinue from treatment due to lack of response, AEs, or other reasons, even if 
alternative treatment is given, will complete an early termination visit and will be followed for 
90days for collection of safety data, including lymphocyte recovery, and for the assessment of their 
disease status. 
4.2. 
Endpoints and Endpoint Definitions 
The Simple Endoscopic Score for Crohn’s Disease (SES-CD) assesses the degree of inflammation 
and will be used to evaluate the primary efficacy endpoint. The SES-CD reflects the assessment of 
mucosal lesions in CD, and grades lesions by location (rectum, left colon, transverse colon, right 
colon and ileum) using ulcer size, extent of ulcerated surface, extent of affected surface, and 
presence/type of narrowing. Additional details and scoring algorithms can be found in Appendix 2. 
The Crohn’s Disease Activity Index (CDAI) is a composite score that is used to measure the clinical 
activity of Crohn’s disease. The CDAI uses a questionnaire with responses scored numerically and 
weighted.  Scores typically range from 0 to approximately 600, with higher scores indicating greater 
disease activity.  The 8 components used to assess the CDAI and their weighting factors along with 


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the data handling details for deriving the average daily scores (including the sub-scores) over the 7 
day period are noted in Appendix 3. 
The severity of Crohn’s disease is defined based on CDAI score as follows: mild with CDAI score 
of ≥150 to <220, moderate with CDAI score of ≥220 to ≤450 and severe with a CDAI score of >450. 
4.2.1. 
Definitions 
Table 2. Key Terms 
Term 
Definition 
SES-CD 
The sum of the scores for the 5 segments composed of the sum of 4 
separate components that include: Size of ulcers, Extent of ulcerated 
surface, Extent of affected surface and the presence and type of 
narrowing. The 4 components are evaluated for each of the accessible 
segments and are scored as 0 to 3. The segments include: rectum, 
sigmoid & left colon, transverse colon, right colon and the ileum. The 
range of SES-CD scores is 0 – 12 for each segment, and 0 – 56 for the 
overall SES-CD score, with larger scores indicating greater severity of 
disease. 
 
CDAI 
The weighted sum of the 8 components: Number of liquid or soft stools 
for 7 days, Abdominal pain for 7 days, general well-being for 7 days, 
presence of complications, taking diarrhea medication, abdominal mass, 
hematocrit and percentage deviation from standard weight. The typical 
range of CDAI score is 0 to > 600.  
 
PRO2  
 
The weighted sum of two items that separately contribute to the 
derivation of two CDAI sub-scores: PRO2 = SF*7*2 + AP*7*5.  See 
Table 10, Appendix 3 for details. 
 
SF/AP  
 
The unweighted sum of two items that separately contribute to the 
derivation of two CDAI sub-scores: SF/AP = SF + AP.  See Table 10, 
Appendix 3 for details.  NOTE: This definition is included for reference 
only; in some clinical trials for Crohn’s disease, this has been used for 
various endpoints. 
 
SF&AP 
SF & AP Remission, defined as Average daily stool score ≤ 3 points 
AND average daily abdominal pain score ≤ 1 point 
 
GHAS 
Geboes Histology Activity Score 
 
RHI 
Robarts Histopathology Index 
 


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Table 3. Key Endpoints 
Category or 
Shorthand 
Label 
Definition 
Endoscopy 
Endoscopic Change 
SES-CD change from baseline 
Endoscopic Response-25 
SES-CD decrease from baseline of ≥ 25% 
Endoscopic Response-50 
SES-CD decrease from baseline of ≥ 50% 
Endoscopic Remission 
SES-CD ≤ 4 points and a SES-CD decrease from 
baseline ≥ 2 points with no SES-CD sub-score 
> 1 point 
CDAI 
CDAI Change 
CDAI change from baseline 
SF Change 
SF Change from baseline 
AP Change 
SF Change from baseline 
CDAI Clinical Response 
CDAI decrease from baseline of ≥ 100 points 
CDAI Clinical Remission 
CDAI score of <150 
PRO2 
PRO2 Clinical Response 
PRO2 CD decrease ≥ 50% 
SF&AP 
SF & AP Remission 
Average daily stool score ≤ 3 points AND average 
daily abdominal pain score ≤ 1 point 
Histology 
GHAS Change 
GHAS change from baseline 
GHAS Remission 
No active inflammation in any measured segment; see 
Appendix 4 for details 
RHI Change 
RHI change from baseline 
RHI Response - by 
Segment 
RHI segment score decrease ≥ 50% 
 
 
RHI Remission- by 
Segment 
No active inflammation in a measured segment 
RHI Remission 
No active inflammation in any measured segment; see 
Appendix 4 for details 
Global RHI Score 
A weighted sum of the worst of each of the four 
disease components across the four colonic segments; 
see Appendix 4 for details 
 
Mucosal Healing 
RHI Mucosal Healing 
Endoscopic Remission combined with RHI Remission 
Biomarkers 
CRP Change 
C-reactive protein change from baseline 
CRP Response-10 
C-reactive protein < 10 mg/L 
FCP Change 
Fecal calprotectin change from baseline 
FCP Response-250 
Fecal calprotectin < 250 mcg/g 
4.2.2. 
Efficacy Endpoints for Induction Period 
Primary Efficacy Endpoint 
 Endoscopic Change  
 
Other Efficacy Endpoints 
 Category: Endoscopy 


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 Proportion of patients with Endoscopic Response-25   
 Proportion of patients with Endoscopic Response-50  
 Proportion of patients with Endoscopic Remission   
 Category: CDAI 
 CDAI Change  
 SF Change  
 AP Change 
 Proportion of patients with CDAI Clinical Response  
 Proportion of patients with CDAI Clinical Remission  
 Category: PRO2  
 Proportion of patients with PRO2 Clinical Response   
 Category: SF&AP  
 Proportion of patients with SF&AP Remission     
 Category: Histology 
 GHAS Change  
 Proportion of patients with GHAS Remission  
 RHI Change  
 Global RHI Score Change  
 Proportion of patients with RHI Response - by segment among non-RHI remitters at 
Baseline 
 Proportion of patients with RHI Remission  
 Proportion of patients with RHI Remission - by segment 
 Proportion of patients with RHI Remission - by segment among non-RHI remitters at 
Baseline 
 Category: Mucosal Healing 
- Proportion of patients with RHI Mucosal Healing      
 
 
 
  
 
 
 
 
 
 
  


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 
 
 
4.2.3. 
Efficacy Endpoints for Extension Period 
The efficacy endpoints for the induction period listed above in section 4.2.2 will be evaluated for all 
extension visits. 
In addition, proportion of patients achieving remission and remaining corticosteroid-free in the prior 
12 weeks will be evaluated at each time point of Week 36, Week 48, and Week 52, among the 
patients who received corticosteroids for CD at baseline. This analysis will be performed for CDAI 
Remission and SF&AP Remission. 
Clinical Remission (Based on CDAI) at both Week 12 and Week 52 will also be summarized.  
Following efficacy graphs will be presented. 
 CDAI change from Baseline (Observed) showing mean and 95% CI at each scheduled visit 
up to Week 52, overall and by Biologic Exposed vs. Biologic Naïve 
 CDAI (Observed) showing mean and 95% CI at each scheduled visit up to Week 160, overall 
and by Biologic Exposed vs. Biologic Naïve 
 Bar graph of CDAI Clinical Response (NRI) at Week 12 and Week 52, overall and by 
Biologic Exposed vs. Biologic Naïve 
 Bar graph of CDAI Clinical Response (Observed) at Week 12 and Week 52, overall and by 
Biologic Exposed vs. Biologic Naïve 
 Bar graph of CDAI Clinical Remission (NRI) at Week 12 and Week 52, overall and by 
Biologic Exposed vs. Biologic Naïve 
 Bar graph of CDAI Clinical Remission (Observed) at Week 12 and Week 52, overall and by 
Biologic Exposed vs. Biologic Naïve 
 Bar graph of Endoscopic Response-50 (Paired Segments, NRI) at Week 12 and Week 52, 
overall and by Biologic Exposed vs. Biologic Naïve 
 Bar graph of Endoscopic Response-50 (Paired Segments, Observed) at Week 12 and Week 
52, overall and by Biologic Exposed vs. Biologic Naïve 
 Stool frequency change from Baseline (Observed) showing mean and 95% CI at each 
scheduled visit up to Week 52, overall and by Biologic Exposed vs. Biologic Naïve 
 Stool frequency (Observed) showing mean and 95% CI at each scheduled visit up to Week 
160, overall and by Biologic Exposed vs. Biologic Naïve 


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 Abdominal Pain change from Baseline (Observed) showing mean and 95% CI at each 
scheduled visit up to Week 52, overall and by Biologic Exposed vs. Biologic Naïve 
 Abdominal Pain (Observed) showing mean and 95% CI at each scheduled visit up to Week 
160, overall and by Biologic Exposed vs. Biologic Naïve 
4.2.4. 
Safety Endpoints 
The incidence, severity, relationship and type of TEAEs, SAEs, AEs leading to discontinuation of 
investigational drug, and AEs of special interest; clinically meaningful changes from baseline for 
clinical laboratory measures, vital signs, electrocardiograms (ECGs), and physical examination will 
be assessed. 
Safety assessments will include the following: 
 Collection of AEs 
 Physical examinations 
 Vital sign measurements 
 ECG results 
 Optical coherence tomography 
 Pulmonary function tests (PFTs) (FEV1, FVC, and diffusion capacity of the lung for carbon 
monoxide [DLCO], where available) 
 Clinical laboratory tests 
 
 
 
 
 
 
 
 
 
 
 
5. 
GENERAL STATISTICAL CONSIDERATIONS 
All efficacy and safety data will be listed by patient.  Listings will be sorted by patient number and 
visit/study day.   


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Continuous data will be summarized using descriptive statistics: number of patients (n), mean, 
standard deviation (SD), standard error (SE), median, minimum and maximum.   
Categorical data will be summarized using the number and percent of patients.  When count or 
frequency data are presented, the percent will be suppressed when the count is zero in order to draw 
attention to the non-zero counts.  A row denoted “Missing” will be included in count tabulations 
where necessary to account for dropouts and missing values.  The denominator for percentages will 
be the number of patients within the population of interest, unless otherwise stated.  Denominator for 
percentages in demographic and baseline categories will use the number of non-missing values.  
Non-zero percentages will be rounded to one decimal place, except 100% will be displayed without 
any decimal places.   
Additional rounding rules are as follows: 
 If the original value has 0 decimal places: mean, median, and CIs will have one decimal place 
and SD will have 2 decimal places; 
 
 If the original value has 1 decimal place: mean, median, and CIs will have 2 decimal places 
and SD will have 3 decimal places; and 
 
 If the original value has 2 or more decimal places: mean, median, CIs, and SD will all have 3 
decimal places. 
Minimum and maximum will always have the same decimal places as the original measure, up to a 
maximum of 3 decimal places. 
Unless otherwise indicated, values that are collected with “<” sign and a numerical bound will be 
analyzed as half the numerical bound, without the sign in tables and figures.  Values that are 
collected with “>” sign and a numerical bound will be analyzed as the numerical bound, without the 
sign.  In listings, these data will be reported as collected, with the sign. 
 
5.1. 
Sample Size 
The sample size of approximately 60 patients for the Induction Period has been chosen to enable 
estimates of response and remission rates with reasonable precision.  To give this some context, if 
we assume a remission rate of 15% and a response rate of 30%, it is estimated that half-width of the 
95% CI around the proportion of patients in response and remission, respectively, would be 12.8% 
and 16.4% for a 30 patient study.  For a 60 patient study, on the other hand, the same half-widths 
would be 9.0% and 11.6%. 
5.2. 
Randomization, Stratification, and Blinding 
This is a non-randomized, unstratified, unblinded, single-arm, open-label trial. 


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5.3. 
Statistical Hypotheses and Multiple Endpoint Handling 
No statistical hypothesis testing will be performed in this trial.  
5.4. 
Analysis Populations 
All patients who are enrolled in the Induction Period and receive at least one dose of investigational 
drug will comprise both the Intent-to-Treat (ITT) population and the Safety population. Because this 
is a single arm open label study, these two analysis populations are indistinguishable. This 
population will be used to summarize all efficacy and safety data for both Induction and Extension 
Periods.  
5.5. 
Other Important Considerations 
5.5.1. 
Definition of Baseline 
Unless otherwise specified, baseline is defined as the last observation collected on or before the 
receipt of first dose of Investigational Product (IP). Calculation of Change and Percent Change from 
Baseline are done according to the following: 
 Change from Baseline to any trial Week t (Ct) is calculated as follows: 
o Ct = Mt – MB, where: 
 Mt is the measurement of interest at Week t 
 MB is the measurement of interest at Baseline 
 Percent change from Baseline to any trial Week t (Pt) is calculated as follows: 
o Pt = 100*(Ct/MB) 
NOTE: If MB =0 or missing then percent change from Baseline will not be determined.  
5.5.2. 
Study Day Calculation for Reporting Purposes 
The following conventions will be used to calculate study day for reporting purposes: 
 Study Day = date of measurement – first dose date +1, if date of measurement is on or after 
the first dose date.  
 Study Day = date of measurement – first dose date, if date of measurement is prior to the first 
dose date.  
 Study Day 1 is the first dose date of the Induction Period, and no Study Day 0 is defined. 
5.5.3. 
Visit Windows 
The analysis time point assignment for the post-baseline visits  will be assigned based on the 
analysis windows described in Table 4 below for the following items: 


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 Efficacy (please see Protocol Table 2 for a description of what study elements are considered 
to belong to the Efficacy category; it is also noted that not all Efficacy elements are 
considered in this SAP, please see the endpoints in Sections 4.2.2, 4.2.3, and 12) 
 12-lead ECG 
 Vital signs 
 Hematology 
 Blood chemistry 
 Pregnancy test 
 Urinalysis 
 Physical examination 
 Pulmonary function test 
 Optical coherence tomography 
 
Adverse events and coagulation panel data will not be windowed.   
If multiple assessments are available within a range, then the one closest to the target day will be 
used for that analysis time point. If multiple assessments are same distance, but on different sides of 
the target day, then the latter one will be used. If multiple assessments are available on the same day, 
then the average of these assessments will be used, except for the lab and ECG data for which the 
assessment at a later time of the same day will be used.    
Table 4. Analytic Visit Windows 
Visit 
Ideal Analysis Daya 
Visit Window 
Baseline 
1 
 <= 1 
Week 4 
29 
2 – 42 
Week 8 
57 
43 – 70 
Week 12 
85 
71 – 98 
Week 24 
169 
99 -– 210 
Week 36 
253 
211 – 294 
Week 48 
337 
295 - 350 
Week 52 
365 
351 - 392 
Week 64 
449 
393 - 490 
Week 76 
533 
491 - 574 
Week 88 
617 
575 - 658 


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Week 100 
701 
659 - 742 
Week 112 
785 
743 - 826 
Week 124 
869 
827 - 910 
Week 136 
953 
911 - 994 
Week 148 
1037 
995 - 1078 
Week 160 
1121 
>= 1079 
Safety Follow-up Day 30 
30 
≤ 60 
Safety Follow-up Day 75 and Day 90 
90 
≥ 61 
aExcept for the visits recorded as safety follow-up visits, the reference date will be the date of the first dose of IP in the 
study, and the relative day is calculated date of assessment/collection – date of the first dose of IP + 1 if the date of 
assessment/collection is on or after the date of the first dose of IP, or date of assessment/collection – date of the first dose 
of IP if the date of assessment/collection is before the date of the first dose of IP. The reference date for the visits 
recorded as safety follow-up visits will be the date of the last dose of IP in the study, and the relative day is calculated 
date of assessment/collection – date of the last dose of IP. 
Applying above visit window rules will be done after distinguishing treatment visits and follow-up 
visits by CRF visit labels. 
For all study elements to which the above table applies, the last available assessment will be derived 
as the last value on treatment, whether scheduled or unscheduled. 
5.5.4. 
Handling of Missing and Partial Data 
For all proportion-based efficacy endpoints, patients with missing efficacy data and the responses 
after treatment failure will be considered non-responders (NRI) in the primary analyses.  
Treatment failures at Week 12 and Week 52 will be determined based on the rules listed in Section 
9.1. In all analyses where NRI is used, responses of the patients who are treatment failures at Week 
12 will be imputed as non-responder at Week 12 and onwards. In addition, responses of the patients 
who are treatment failures at Week 52 will be imputed as non-responder at Week 52 and onwards. 
Continuous efficacy endpoints will not be imputed. 
Sensitivity analyses on missing data on selected endpoints are detailed in the efficacy analyses 
sections 9.1 and 9.2.  
With the exception of partial dates, missing demographic, disposition, baseline characteristics, 
medical history, and safety data will be analyzed using observed data only, without imputation.  For 


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partial dates, the algorithms for imputation will vary depending upon the parameter; the details can 
be found in Appendix 1.  
5.5.5. 
Handling of Missing Segmental Scores for SES-CD, GHAS, and RHI 
The analyses of change from baseline and the defined responder analyses for SES-CD, GHAS, and 
RHI, as applicable, will exclude the segments non-evaluable or missing at baseline, regardless of 
whether or not they become evaluable post-baseline. In addition, any missing segment scores (in the 
presence of at least 1 non-missing segmental SES-CD score) of SES-CD will be imputed by non-
missing score used in the previous visit. This methodology is the primary analysis and will also be 
referred to as “complete cases” or “paired segments” as only segments scored at both baseline and 
the repeat endoscopy will be assessed.  Exploratory analyses of the SES-CD scores based on 
available data without any adjustments or imputation will also be performed. 
6. 
PATIENT DISPOSITION 
A summary of disposition of all screened patients will be generated and will include the following 
information:  
 Number and percentage of enrolled patients in the Safety Population 
 Number and percentage of enrolled patients in the ITT Population 
 Number and percentage of enrolled patients dosed and not dosed 
 Number and percentage of enrolled patients discontinuing during Induction, with reasons 
 Number and percentage of enrolled patients discontinuing after Induction but prior to 
Extension, with reasons 
 Number and percentage of enrolled patients who completed Week 12 and continued into 
Extension 
 Number and percentage of enrolled patients discontinuing during Extension up to and 
including Week 52, with reasons  
 Number and percentage of enrolled patients discontinuing during Extension after Week 52, 
with reasons  
 Number and percentage of enrolled patients who completed Week 52 
 Number and percentage of enrolled patients ongoing and completing the Protocol (Week 
160) 
Only the primary reason for discontinuation will be tabulated. 
The reasons for Screen Failure will be separately tabulated according to the relevant Inclusion / 
Exclusion criteria.  The number and percentage of ITT patients by Region, Country, and Site will be 
tabulated. 


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7. 
DEMOGRAPHICS, BASELINE CHARACTERISTICS, AND 
MEDICAL HISTORY 
7.1. 
Demographics and Baseline Characteristics 
The demographics and baseline characteristics will be presented using descriptive statistics for the 
ITT population.   
Tabulated demographic characteristics will consist of  
 Sex 
 Age 
 Age Category  
 Ethnicity 
 Race 
 Weight (kg) 
 Height (cm) 
 Body Mass Index (BMI, kg/m2)   
A patient’s age in years is calculated using the integer part of the difference in number of days 
between the date of informed consent and date of birth divided by 365.25 or is recorded directly on 
the eCRF.  The number and percentage of patients in the following age categories will be presented: 
18-29, 30-39, 40-49, 50-59, 60-69, 70-75, < 65, ≥ 65, < median, and ≥ median.  
Tabulated demographic characteristics will consist separately of region (North America, Europe), 
country (Canada, Hungary, Poland, USA, Ukraine) and history of tobacco/nicotine use (current, 
former, never).  
7.2. 
Medical History 
7.2.1. 
General Medical History 
Medical history other than Crohn’s disease (CD) will be summarized for the ITT population and will 
display the number and percentage of patients with a significant history for each body system.   
7.2.2. 
Crohn’s Disease History 
The following CD history parameters will be summarized for the ITT population using descriptive 
statistics:  
 Age at CD symptom onset (yr) 
 Age at CD diagnosis (yr) 
 Years since CD symptom onset 
 Years since CD diagnosis 
 Years since CD diagnosis category (0 - <2, 2 - <5, 5 - <10, 10 - <15, and ≥15) 
 CDAI score at baseline  
 CDAI score at baseline category (<330 and ≥330) 


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 Baseline Stool Frequency (daily average)  
 Baseline Abdominal Pain (daily average) 
 Category of days available for stool frequency and abdominal pain calculations (< 3, 3-6, >=7) 
 SES-CD at baseline 
 SES-CD at baseline category (< 12 and ≥ 12; ≥ median, < median) 
 Baseline PRO2 
 Baseline SF&AP 
 Prior Corticosteroid use (Y/N) 
 Prior Immunomodulator use (Y/N) 
 Prior Biologics use (Y/N) 
 Prior 5-ASA use (Y/N) 
 Prior CD surgery History (Y/N) 
 Baseline Fecal Calprotectin (microgram/g) 
 Baseline Fecal Calprotectin (microgram/g) category (<250 and ≥250) 
 Baseline CRP (mg/L) 
 Baseline CRP (mg/L) category (<10 and ≥ 10) 
 Baseline Enterocutaneous and/or Perianal Fistulas (Y/N) 
 Draining Fistulas (Y/N) 
 Non-Draining Fistulas (Y/N) 
 Closed Fistulas (Y/N) 
 Biological Response (Biologic Primary Non-responder vs All Others) 
 Disease Location (Ileum only; Colon only; Ileocolonic (Ileum and Colon)) 
 Prior CD Surgery (Y/N) 
 
Incomplete diagnosis dates will be imputed as detailed Appendix 1. 
7.2.3. 
Anti-TNF/Biologic Treatment History 
The following Anti-TNF/Biologic treatment history parameters will be summarized for the ITT 
population using descriptive statistics:  
 Number and percentage of patients with any Prior Anti-TNF or other Biologic Medications for 
the treatment of Crohn’s Disease 
 Previously Treated patients that took Medications Prior to Study Entry, with the number and 
percentage of patients having type of response (Primary Non-Responder, Secondary Non-
Responder, Intolerant) and Length of time (<=1 year; >1 year and <=2 years; > 2 years) 
separately tabulated 
o Infliximab 
o Adalimumab 
o Certolizumab Pegol 
o Vedolizumab 
o Other 


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7.3. 
Protocol Deviations 
Deviations from the protocol will be recorded appropriately and tabulated at the end of the study.  
Protocol deviations may be classified into, but not necessarily limited to, the following categories: 
 Inclusion/exclusion criteria deviation 
 Patients deemed to have needed to be withdrawn but were not withdrawn 
 Incorrect treatment or dose 
 Prohibited medication use 
 Treatment non-compliance 
 Procedure non-compliance 
 
Tabulation and listing of deviations will be done according to ICH E3 2.  Classification of deviations 
as important protocol violations (which may alternatively be described as “major deviations”) will 
be done according to Section 10.2 of ICH E3 and will be decided on a case-by-case basis by the 
Sponsor.   
8. 
TREATMENTS, MEDICATIONS AND NON-TRIAL MEDICAL 
PROCEDURES 
8.1.1. 
Prior and Concomitant Medications 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
8.1.2. 
Non-Trial Medical Procedures 
Non-Trial medical procedures will only be listed. 
                                                 
2 http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_Guideline.pdf 


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8.2. 
Investigational drug 
All patients entering the Induction Period will initiate a 7-day dose titration regimen.  This regimen 
will consist of RPC1063 0.25 mg starting on Study Day 1 for 4 days (1 capsule per day), then 
RPC1063 0.5 mg starting on Study Day 5 for 3 days (2 capsules per day), followed by RPC1063 1.0 
mg beginning on Study Day 8 (1 capsule per day). Patients entering the Extension Period will 
continue with RPC1063 1.0 mg (1 capsule per day). 
8.2.1. 
Extent of Exposure 
Extent of exposure will be summarized for the Safety Population and will include the following: 
 Duration of Exposure (Person-Years) 
 Number of capsules administered 
 
These outcomes are derived using data as collected in the EDC system.  Duration of Exposure in 
person-years is calculated per-patient as ((Date of Last Dose – Date of First Dose) + 1)/365.25.  The 
number of capsules administered per-patient is directly obtained from the EDC system. 
8.2.2. 
Investigational Drug Compliance 
Drug Compliance will be summarized for the Safety Population and will include the following: 
 Number of capsules expected 
 RPC1063 Compliance Rate 
 
These outcomes are derived using data as collected in the EDC system.  Number of capsules 
expected is directly determined per-patient based on the number of capsules and bottles dispensed to 
the patient.  The RPC1063 compliance rate is calculated per-patient as (number of capsules 
taken)/(number of capsules expected) x 100.  The number of capsules taken is computed as the 
difference between the number of capsules dispensed at the previous visit and the number of 
capsules returned to the site at the following visit. 
9. 
EFFICACY ANALYSIS 
Unless otherwise stated, the ITT analysis population will be used for efficacy analyses.  Due to the 
open-label nature of the trial and the lack of a control group, efficacy data at all scheduled visits will 
be summarized and no formal statistical hypothesis testing will be performed. 
Certain related endpoints relying on the same fundamental measurement may result in analyses that 
are continuous in one case and categorical in another case.  For example, CDAI scores are the 
fundamental measurement for the CDAI Change from Baseline endpoint that is described in Section 
9.3, and CDAI Change from Baseline is a continuous analysis.  On the other hand, CDAI scores are 
the fundamental measurement for the CDAI Clinical Remission endpoint described in Section 9.4, 
and the proportion of remitters at a given visit is a categorical analysis. 


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All efficacy endpoints will be tabulated by scheduled visit.   
9.1. 
Treatment Failure Rules 
Final Treatment Failure status will be determined by internal clinical review using the following 
rules: 
1. Any protocol-prohibited change in CD medications including the following: 
a. Post-baseline initiation of, or increase in, corticosteroids to treat worsening CD to a 
dose greater than the maximum daily dose taken between the Screening and Baseline 
visits  
b. Prolonged course of systemic corticosteroids > 14 days for treatment of disease other 
than CD 
c. Initiation of an immune-suppressing therapy including 6-mercaptopurine (6-MP), 
azathioprine, anti-TNF agents, or vedolizumab 
d. Post-baseline initiation of antibiotics to treat worsening of CD/disease flare 
 
2. Surgical resection of small intestine or colon during the study as a treatment of CD-related 
symptoms 
3. Endoscopic dilation treatment for CD-associated stricture(s) during the study 
Treatment failures at Week 12 and Week 52 will be determined by using the above rules. Treatment 
failure status will be used as a criterion in NRI. Patients identified as Treatment Failures will be 
listed.  
 
9.2. 
Handling Endoscopy Data 
9.2.1. 
SES-CD, GHAS, and RHI Related Endpoints 
For the primary analysis of SES-CD score along with the sub-scores, only segments evaluated or 
imputed at both baseline and post-baseline will be summarized as described in section 5.5.5 
Handling of Missing Segmental Scores for SES-CD, GHAS, and RHI. This will be referred to as 
either “Complete Case” or “Paired Segment” analysis. For example, if the rectum and left colon 
were evaluated at baseline and segments for the rectum, left colon, transverse colon and right colon 
were evaluated or imputed at Week 12, only the rectum and left colon at baseline and the rectum and 
left colon at Week 12 would be used to derive SES-CD and the change from baseline to Week 12 in 
this table.  
SES-CD score will also be determined based on all available segments at a given visit without 
adjusting for the segments available at Baseline. These scores will be referred to as “Robarts 
Observed Scores”. 


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9.2.2. 
GHAS and RHI Related Endpoints (exploratory efficacy endpoints) 
The sub-scores and total scores for GHAS and RHI will follow the same approach as the SES-CD 
related endpoints except the imputation of missing segments as they are based on the same concept 
of evaluating 5 segments as described above. 
9.3. 
Continuous Efficacy Endpoints 
For continuous efficacy endpoints, the number of patients (n), mean, standard deviation (SD), 
standard error (SE), median, minimum and maximum will be presented for the actual values and 
change from baseline at all scheduled visits.  It is noted that percent change from baseline may be 
displayed for certain endpoint variations, based on the TFL shell specifications. 95% CI presented in 
efficacy graphs will be computed using the t distribution. 
All continuous efficacy endpoints will be tabulated by scheduled visit.  This includes (see Table 3) 
Endoscopic Change, CDAI Change, GHAS Change, RHI Change, CRP Change, and FCP Change.  
Per Section 5.5.3, efficacy data will be associated with Visits according to analytic visit windows. 
In all cases, the primary analysis will be based on observed cases.  
The list of continuous efficacy endpoints is shown in Table 5 below:  
Table 5. Continuous Endpoints and Imputation Methods 
Continuous Efficacy Endpoints 
Method(s) 
Endoscopic Change (Paired Segments, Total Score) 
OC  
CDAI Change 
OC  
SF Change 
OC  
AP Change 
OC  
GHAS Change from Baseline (Paired Segments, Total Score) 
OC 
RHI Change from Baseline (Paired Segments, Total Score) 
OC 
C-RP Change from Baseline 
OC 
FCP Change from Baseline 
OC 
Global RHI Score 
OC 
  
9.4. 
Proportion-based Efficacy Endpoints 
For binary categorical efficacy endpoints, the number and percentage of patients achieving the 
endpoint will be presented, along with a 95% Clopper-Pearson exact confidence interval.  This will 
be done for Weeks 12 and 52 only.   
The primary analysis for a given endpoint will be based on non-responder imputation (NRI).  
Sensitivity analyses around missing data will be observed case analysis.  
All proportion-based efficacy endpoints will be tabulated by scheduled visit.  The list of proportion-
based efficacy endpoints and methods are shown in Table 6 below:  


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Table 6. Categorical Endpoints and Imputation Methods 
Categorical Efficacy Endpoints   
Method 
Endoscopic Response-25 (Paired Segments) 
NRI, OC 
Endoscopic Response-25 (Robarts Observed) 
NRI,OC 
Endoscopic Response-50 (Paired Segments) 
NRI, OC 
Endoscopic Response-50 (Robarts Observed) 
NRI, OC 
Endoscopic Remission (Paired Segments) 
NRI, OC 
Endoscopic Remission (Robarts Observed) 
NRI, OC 
CDAI Clinical Response 
NRI, OC 
CDAI Clinical Remission 
NRI, OC 
PRO2 Clinical Response 
NRI  
SF&AP Clinical Remission 
NRI, OC 
GHAS Remission 
NRI, OC 
RHI Remission 
NRI, OC 
RHI Mucosal Healing 
NRI, OC 
RHI Response - by Segment 
NRI, OC 
RHI Remission by Segment 
NRI, OC 
C-RP Response-10 
NRI, OC 
FCP Response-250 
NRI, OC 
*Note: Endoscopic responses will be determined using both complete cases (paired segments) and 
Robarts observed scores (all segments) of the SES-CD assessment at Weeks 12 and 52.  
For the primary analysis of the endoscopic response and endoscopic remission scores using SES-CD 
from complete cases, only the sub-scores from segments evaluated or imputed at both baseline and 
post-baseline (i.e., Paired Segments) will be used to sum the SES-CD for deriving the response as 
described above in Section 5.5.5. For example, if the segments for the rectum and left colon were 
evaluated at baseline and segments for the rectum, left colon, transverse colon and right colon were 
evaluated or imputed at Week 12, only the rectum and left colon sub-scores at Week 12 would be 
used to derive endoscopic response at Week 12 in this table. 
Exploratory subgroup analyses on the select endpoints listed in Section 9.5 will be conducted.  
 
 
 
 
 
  
 
 
 
  
 
 
 
 


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10. 
SAFETY ANALYSIS  
All analyses of safety data will be conducted using the Safety population.  Statistical hypothesis 
testing will not be performed on any safety results.  No imputation of missing safety data will be 
performed except in the case of missing AE onset dates (Appendix 1). 
10.1. 
Adverse Events 
A TEAE is any reaction, side effect, or other untoward event, regardless of relationship to 
investigational drug, which occurs any time during or after the first dose of investigational drug, 
until 90 days following the last dose of investigational drug.   
For an event to be a TEAE, it must meet one of the following conditions: 
 Begins on Study Day 1, during or after ingestion of the first dose of investigational drug; 
 Begins after Study Day 1; or 


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 Begins before Study Day 1 and worsens in severity during or after the Study Day 1 ingestion 
of investigational drug. 
AEs with unknown onset dates or unknown end dates will be counted as having occurred during the 
investigational drug period (i.e., as TEAEs) unless the event resolves before Study Day 1.   
Only TEAEs will be presented in AE tables, according to the Medical Dictionary for Regulatory 
Activities (MedDRA®) version 18.1, system organ class (SOC), and PT.  Any AEs that occur prior 
to Study Day 1 without worsening in severity on or after Study Day 1 should be recorded on the 
medical history eCRF and will be summarized as part of medical history. 
Summaries of incidence of TEAEs will include only one occurrence of a PT per patient, i.e., 
multiple occurrences of the same PT will be counted only once.  As with the PT, multiple 
occurrences of TEAEs within the same SOC will be counted only once for that SOC.   
10.1.1. 
Incidence of Treatment Emergent Adverse Events 
In the tables showing incidence by SOC and PT, SOCs will be sorted by the alphabetical order and 
PTs will be sorted within SOC in descending order of incidence.  For tables showing incidence by 
PT only, the PTs will be sorted in descending order of incidence.   
An overall summary of TEAEs will show the number and percentage of the patients experiencing 
TEAEs in following categories 
 At least one TEAE   
 At least one Moderate or Severe TEAE   
 At least one Severe TEAE   
 At least one Possible, Probable or Related TEAE   
 At least one Related TEAE   
 At least one Serious TEAE   
 At least one Possible, Probable or Related Serious TEAE   
 At least one Related Serious TEAE   
 At least one TEAE Leading to Discontinuation of Study Drug   
 At least one TEAE Leading to Study Withdrawal   
 Death   
 Death - Possible, Probable or Related to Study Drug   
The incidence of all TEAEs along with number of events will be presented by SOC and PT and, 
separately by PT only and sorted in descending order of number of patients experiencing the TEAE.   
10.1.2. 
Relationship of Adverse Events to Investigational drug 
A summary of TEAEs by relationship to investigational drug will be presented in a table by 
incidence of occurrence.  The potential relationships are “Unrelated”, “Unlikely”, “Possible”, 
“Probable”, and “Related”.  A treatment-related TEAE is a TEAE with any relation to 
investigational drug other than “Unrelated” or “Unlikely”.  In the TEAE by relationship table, if a 


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patient reports multiple occurrences of the same TEAE, only the most related occurrence will be 
presented.  TEAEs that are missing relationship will be presented in the summary table as 
“Probable” but will be presented in the data listing with a missing relationship.  A summary of 
treatment-related TEAEs by SOC and PT will also be presented.   
10.1.3. 
Severity of Adverse Event 
A summary of TEAEs by severity will be presented in a table.  The potential severity levels are 
“Mild”, “Moderate”, and “Severe”.  TEAEs will be classified by severity.  In the TEAE severity 
table, if a patient reported multiple occurrences of the same TEAE, only the most severe occurrence 
will be presented.  TEAEs that are missing severity will be presented in summary tables as “Severe” 
but will be presented in the data listing with a missing severity.  A summary of severe TEAEs by 
SOC and PT will also be presented. 
10.1.4. 
Serious Adverse Events 
Criteria for determining SAEs are defined in the protocol.  
A summary of treatment-emergent SAEs will be presented by SOC and PT, and also by SOC and PT 
and relationship to study drug.  SAEs will also be listed separately. 
10.1.5. 
Adverse Events Leading to Treatment Discontinuation 
All TEAEs reported with an investigational drug action taken as “Permanently discontinued” will be 
summarized in a table by PT, and a listing excluding deaths will be presented. 
10.1.6. 
Death 
All patient deaths during this trial will be collected and presented in a listing.  The information that 
is presented will include, at minimum, the date of first dose, date of last dose, date of last visit, date 
of death, cause of death, and relationship to study drug. 
10.1.7. 
Adverse Events of Special Interest 
Target treatment emergent adverse events of special interest (AESIs) will be closely monitored in the 
trial.  AESIs include bradycardia and heart conduction abnormalities (e.g., symptomatic bradycardia, 
2nd degree AV block, QT prolongation), pulmonary effects (significant decline in forced expiratory 
volume in 1 second [FEV1], forced vital capacity [FVC], and diffusing capacity of the lung for 
carbon monoxide [DLCO] measurements), hepatic effects (confirmed liver function test (LFT) 
elevations > 3x ULN), macular edema based on abnormal OCT findings or visual signs/symptoms of 
new onset or worsening macular edema, serious or opportunistic infections and malignancies.   
AESIs will be summarized by SOC and PT and presented in a listing.  


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10.2. 
Clinical Laboratory Evaluations 
Laboratory assessments will be performed by a central laboratory.  All summaries will be based on 
the standard international (SI) units provided by the central lab.  Associated laboratory parameters 
such as hepatic profile, renal function, and hematology values will be grouped and presented 
together. 
Summary tables for hematology, chemistry, and urinalysis including actual values and change and 
percent change values from Baseline will be presented for clinical laboratory tests collected as 
numeric values.  These summaries will be provided for each visit, highest value, lowest value, and 
last value. 
Hematology and blood chemistry values will be flagged as “low”, “normal”, or “high” relative to the 
normal ranges of the central laboratory.  Categorical urinalysis values will be flagged as “normal” or 
“abnormal”.  Categorical laboratory data will be summarized using shift tables where appropriate. 
Laboratory data collected at unscheduled visits will be included in listings and will contribute to 
tables showing changes from Baseline to highest value, lowest value, and last value.  The results 
from safety follow-up visit will not be included in the calculations of highest, lowest, and last values.   
10.2.1. 
Hematology 
The following laboratory tests will be included in hematology summary tables:  
 Absolute Lymphocyte Count 
 Basophils 
 Basophils/Leukocytes 
 Eosinophils 
 Eosinophils/Leukocytes 
 Ery. Mean Corpuscular HGB Concentration 
 Ery. Mean Corpuscular Hemoglobin 
 Ery. Mean Corpuscular Volume 
 Erythrocytes 
 Hematocrit 
 Hemoglobin 
 Leukocytes 
 Lymphocytes 
 Lymphocytes/Leukocytes 
 Mean Platelet Volume 
 Monocytes 
 Monocytes/Leukocytes 
 Neutrophils 
 Neutrophils/Leukocytes 
 Platelets 
 


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Actual values, change from baseline, and percent change from baseline will be summarized by visit.  
Shift tables from baseline, by visit, will be presented.  The proportion of patients with abnormalities 
in Absolute Lymphocyte Count (ALC; ALC < 200 cells/uL; ALC < 500 cells/uL), Absolute 
Neutrophil Count (ANC; ANC < 1000 cells/uL), and Total WBC (WBC > 20,000 cells/uL) will be 
presented overall and by visit. 
10.2.2. 
Blood Chemistry 
The following laboratory tests will be included in the blood chemistry summary tables:  
 Alanine Aminotransferase  
 Albumin   
 Alkaline Phosphatase  
 Amylase 
 Aspartate Aminotransferase  
 blood Urea Nitrogen 
 C-Reactive Protein  
 Conjugated Bilirubin  
 Creatinine  
 Gamma Glutamyl Transferase  
 Glucose 
 Total Bilirubin 
 
Actual values, change from baseline, and percent change from baseline will be summarized by visit.  
Shift tables from baseline, by visit, will be presented.  The proportion of patients with abnormalities 
in Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) will be presented overall 
and by visit.  Abnormalities in both ALT and AST will be presented for the following categories: 
 > 1 x ULN;  
 ≥ 2 x ULN; 
 ≥ 3 x ULN; 
 ≥ 4 x ULN; 
 ≥ 5 x ULN;   
 ≥ 8 x ULN; and 
 ≥ 10 x ULN 
A listing will present abnormal chemistry values for all patients. 
10.2.3. 
Coagulation-related parameters 
Coagulation panel results (central laboratory) will be summarized continuously for the Screening 
and Early Termination visits.  A listing of abnormal coagulation-related parameters will be provided.  
10.2.4. 
Urinalysis 
The following laboratory tests will be included in the urinalysis:  


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 Specific Gravity 
 pH 
 Bilirubin 
 Glucose 
 Ketones 
 Leukocytes 
 Blood 
 Protein 
 Urobilinogen 
 Urine Color and Appearance 
 Nitrate 
 Leukocyte Esterase 
 
Actual values, change from baseline, and percent change from baseline will be summarized by visit 
for pH and Specific Gravity.  Shift tables from baseline, by visit, will be presented for Bilirubin, 
Glucose, Ketones, Leukocytes, Occult Blood, Protein, Specific Gravity, Urobilinogen, and pH.   
A listing of urinalysis values will be presented. 
10.2.5. 
Pregnancy Testing and Serology Testing 
Serum β-human chorionic gonadotropin (i.e., serum beta hCG) will be collected at Screening for 
females of childbearing potential.  Between scheduled visits, monthly urine pregnancy tests (i.e., 
urine beta hCG) should be conducted by females of childbearing potential, and if the urine test is 
positive at the scheduled visit, it should be confirmed with a serum beta hCG test.  
Serology testing will be collected at Screening for all patients and will include immunoglobulin G 
(IgG) antibodies to varicella-zoster virus (VZV), human immunodeficiency virus (HIV), 
immunoglobulin M (IgM) antibodies to hepatitis A virus (HAV), surface antigen of the hepatitis B 
virus (HBsAG), anti-hepatitis B core total antibodies (anti-HBc total), hepatitis B virus 
deoxyribonucleic acid (HBV DNA), and anti-hepatitis C virus (HCV) IgG/IgM.   
Serum pregnancy, urine pregnancy, and serology results will be listed only. 
10.3. 
Vital Sign Measurements 
The following vital signs measurements will be collected for Day 1 (Baseline, Hour 1, Hour 2, Hour 
3, Hour 4, Hour 5, and Hour 6, Week 4, Week 8, Week 12, Week 24, Week 36, Week 48, Week 52, 
and all visits subsequent to Week 52 according to the Protocol-defined schedule of vital signs 
assessments: 
 Heart Rate (sitting; ‘HR’) 
 Systolic Blood Pressure (sitting; ‘SBP’) 
 Diastolic Blood Pressure (sitting; ‘DBP’) 
 


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The baseline value for a given patient in any tabulation or listing will be the lowest pre-dose value 
observed on Day 1. 
Two separate continuous tabulations will be generated: for Study Day 1, actual values and change 
from baseline will be summarized continuously for Baseline, Hour 1, Hour 2, Hour 3, Hour 4, Hour 
5, Hour 6, and Hour 7.  Separately, for the post-baseline visits, the actual values and change from 
baseline will be summarized continuously for Week 4, Week 8, Week 12, Week 24, Week 36, Week 
48, Week 52, and all visits subsequent to Week 52 according to the Protocol-defined schedule of 
vital signs assessments. 
For Study Day 1, Heart Rate will be summarized categorically for the following categories for Day 1 
for Hours 1, 2, 3, 4, 5, 6, and Minimum Overall: 
 >= 65 
 60-64 
 55-59 
 50-54 
 45-49 
 40-44 
 35-39 
 < 35 
 
The proportion of patients requiring extended cardiac monitoring beyond Day 1, Hour 6, based on 
the criteria in Section 12.1.9. Guidelines for Monitoring Patients Taking Their First Dose of 
RPC1063 in the protocol , will be summarized categorically and will also be presented in a listing 
showing the criteria triggering a subject to be included in the listing.  A listing of vital signs for the 
subjects who required extended cardiac monitoring per protocol criteria will be presented. 
The number and percentage of patients who meet the criteria for clinically relevant abnormalities for 
HR, SBP, and DBP will be summarized by visit.  The criteria for clinically relevant abnormalities 
are shown in the following table.  All increases and decreases are relative to pre-dose on Day 1.  
Table 7. Vital Sign Abnormality Cutoffs 
Vital Sign 
Criteria for Abnormalities 
HR 
 120 bpm  
< 45 bpm   
SBP 
> 180 mmHg  
< 90 mmHg 
DBP 
> 105 mmHg 
< 50 mmHg 
 


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10.4. 
Electrocardiogram 
The following ECG values will be included for summarization:  
 QTcB – Bazett’s Correction 
 QTcF – Fridericia’s Correction 
 PR Duration 
 QRS Duration 
 QT Duration 
 RR Duration 
 Ventricular Rate 
 
QTcF is the primary measure of corrected QT, with Bazett’s correction serving as a supportive 
measure.  For all ECG measurements, actual values and change from baseline will be summarized 
continuously by visit.   
The proportion of patients with ECG outliers will be presented overall and by visit.  For this 
analysis, the categories defined below will be used: 
 QT > 480 milliseconds (ms), QT > 500 ms, Female: QTcF > 470 ms, and Male: QTcF > 450 
ms    
 PR < 120 ms, PR > 200 ms    
The interpretation of ECG results will be presented by visit (‘Normal’, ‘Abnormal, not clinically 
significant’, ‘Abnormal, clinically significant’). 
ECG abnormalities upon first dose of study drug will be summarized categorically, with the types of 
abnormalities sorted alphabetically within each time point. 
10.5. 
Pulmonary Function Testing 
The following pulmonary function test outcomes will be summarized continuously:  
 Largest forced expiratory volume in 1 second (i.e., FEV1) 
 Percent of predicted FEV1 
 Largest forced vital capacity (i.e., FVC) 
 Percent of predicted FVC 
 DLCO corrected for hemoglobin 
 
The actual value, change, and percent change will be summarized by visit.  It is noted that the 
percent predicted value for a given outcome is the ratio of the original value relative to the predicted 
value, reported as a percentage.   


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DLCO is collected at the local lab for each site where available, 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 
An abnormality is defined as percent predicted FEV1 < 70% and <80% of baseline or percent 
predicted FVC < 70% and <80% of baseline. Abnormalities will be summarized by number and 
percent by visit and shift tables. 
A listing of pulmonary abnormalities will be provided. 
10.6. 
Physical Examination 
Physical examination results will be listed only. 
10.7. 
Other Assessments 
A summary table of number and percent of patients with dermatological abnormalities by visit will 
be presented. This table will further include summary of last available value, and an overall 
summary.  Listings of dermatological abnormalities and abnormalities found during optical 
coherence tomography (OCT) will be provided. 
Listings of abnormalities in visual acuity and dilated ophthalmoscopy will be provided. 
11. 
INTERIM ANALYSIS 
11.1. 
Interim Analysis 
Due to the open-label nature of this study, there is no formal interim analysis of efficacy for this trial 
(i.e., no p-values will be produced and no adjustment for Type I error rates is needed).     
However, accumulating efficacy and safety results may be summarized and presented at various 
Congresses, Proceedings, Conferences, or in scholarly journals in an ongoing manner. Also, data 
may be periodically extracted and summarized for inclusion in regulatory filings, annual safety 
reports, or abbreviated safety CSRs.  
11.2. 
Data Safety Monitoring Board 
An overall summary that may include disposition, safety, and efficacy data from the trial may be 
presented to an independent DSMB as needed.  


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12. 
CLARIFICATIONS/CHANGES TO THE PROTOCOL PLANNED 
ANALYSES 
The primary purpose of this section is to modify and/or clarify items specified in the Protocol [A 
Phase 2, Multi-Center, Open-Label Induction Trial with Extension Period to Assess Endoscopic 
Improvement and Changes in Intestinal and Serum Biomarkers in Patients with Moderately to 
Severely Active Crohn's Disease Receiving Oral RPC1063 as Induction Therapy, Version 5.0, dated 
May 29, 2019], as follows: 
 GHAS and RHI and related endpoints are added to Section 4.2.1 
 Protocol Section 6.2. Endpoints 
A treatment failure criteria is defined Section 9.1.  Patients identified as Treatment Failures 
will be listed and a sensitivity analysis of the endoscopic endpoints undertaken. 
 Protocol Section 6.2.1 Induction Endpoints (i.e., Week 12) 
o 
 
 
 
 
 
 
 
 
 
o The intestinal mucosa histopathologic features and disease activity endpoints have been 
revised to reflect two specific measures: the Geboes Histology Activity Score (GHAS) 
and the Robarts Histopathology Index (RHI) 
 Protocol Section 6.2.2 Extension Endpoints (i.e., Week 52) 
o Per Section 4.2.3, all Induction Period endpoints will be replicated for the Extension 
Period 
o Section 4.2.3 describes additional endpoints for the Extension Period not applicable to the 
Induction period 
o The endpoints and analyses in Section 9.5 are not discussed in the Protocol 
 
 
 
 
 
 


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 Protocol Section 13.2 Statistical Methods 
o 13.2.1 General Considerations 
- Imputation for missing efficacy data will be performed as follows: 
- NRI will be used to impute missing binary endpoints and the responses after 
treatment failure as non-responder. Sensitivity analyses will include observed 
cases only for select endpoints.    
- Continuous efficacy endpoints will not be imputed.  
- Missing segmental scores for SES-CD, GHAS, and RHI are described in detail in 
section 5.5.5. 
- There will be no imputation for the safety observations. 
 Protocol Section 13.3 Disposition, Demographics, and Baseline Characteristics 
o Treatment compliance will be summarized continuously with respect to the number of 
capsules taken versus the number of capsules expected. Total dose will not be 
summarized and categories of compliance will not be considered. 
o Extent of exposure will be summarized with respect to duration of exposure and number 
of capsules administered 
 Protocol Section 13.5 Safety Analysis 
o The overall summary of TEAE’s will be repeated by study period (Day 1 through Day 
85; Day 86 through Day 365; ≥ Day 366) to show the timing of adverse event onset 
 Protocol Section 13.6 Pharmacokinetic Analyses 
o Pharmacokinetic analyses will be governed by a supplemental analysis plan.  Inclusion of 
the results of these analyses in the CSR is discretionary. 
 
 
 
 
 
 
 
 
 


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APPENDIX 1. 
IMPUTATION OF PARTIAL AND MISSING 
DATES 
Incomplete Dates of CD Symptom and CD Diagnosis 
If day is missing, day will be set to 15th of the month. 
If month is missing, month and day will be set to July 1st. 
If either imputation above results in a date < informed consent, then impute it as the date of informed 
consent -1. 
Adverse Event  
All AE onset dates must be entered on the eCRF as complete dates.  In the rare case that all or part 
of an AE onset date is missing but an AE resolution date is present and after first dose date then the 
AE onset date will be imputed as follows: 
Table 8. Adverse Event Date Imputation Rules 
Year of onset 
Month of onset 
Day of onset 
Onset date to be imputed as 
Missing 
Missing 
Missing 
Date of first dose 
year = year of first dose 
Missing 
Non-missing 
Set month to month of first dose 
year = year of first dose 
Missing 
Missing 
Set month and day to those of first dose 
year < year of first dose 
Missing 
Non-missing 
set month to December 
year < year of first dose 
Missing 
Missing 
set month and day to December 31 
year > year of first dose 
Missing 
Non-missing 
set month to January 
year > year of first dose 
Missing 
Missing 
set month and day to January 1 
year = year of first dose 
Month = month of first 
dose 
Missing 
Set day as day of 1st dose 
year = year of first dose 
Month < month of first 
dose 
Missing 
Set day as last day of onset month 
year = year of first dose 
Month > month of first 
dose 
Missing 
Set day as first day of onset month 
year < year of first dose 
Non-missing 
Missing 
Set day as last day of onset month 
year > year of first dose 
Non-missing 
Missing 
Set day as first day of onset month 
 
If AE resolution date is present and prior to first dose date, no need to impute incomplete AE start 
date, as the AE is not treatment emergent and the event should be in the medical history. 
Prior and Concomitant Medications 
 If year and month are present and day is missing then set day to first day of month for start 
date, and set day to last day of month for end date 


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 If year and day are present and month is missing then set month to January for start date, and 
set month to December for end date 
 If year is present and month and day are missing then set month and day to January 1 for start 
date, and set month and day to December 31 for end date 
 Completely missing dates will not be imputed 
If start date is completely missing and end date is not prior to the first dose, then the medication will 
be classified as concomitant; if the end date is missing, then the medication will be classified as 
concomitant.  Medications for which the start and end dates are completely missing will be classified 
as concomitant. 
 


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APPENDIX 2. 
SIMPLE ENDOSCOPIC SCORE FOR CROHN’S 
DISEASE (SES-CD) 
The simple endoscopy score (SES-CD) assesses the degree of inflammation.  The SES-CD assesses 
the following 4 components: size of ulcers, ulcerated surface, affected surface, and presence of 
narrowings.  Each of these components are scored on a scale of 0 to 3 as outlined below: 
Table 9. Definitions of Simple Endoscopic Score for Crohn's Disease 
 
SES-CD Values 
Variable 
0 
1 
2 
3 
Size of ulcers 
None 
Aphthous ulcers  
(< 0.5 cm) 
Large ulcers  
(0.5 to 2 cm) 
Very large ulcers 
(>2 cm) 
Ulcerated surface 
None 
<10% 
10-30% 
>30% 
Affected surface 
Unaffected 
segment 
<50% 
50-75% 
>75% 
Presence of 
narrowings 
None 
Single, can be 
passed 
Multiple, can be 
passed 
Cannot be passed 
 
In the SES-CD, each of these 4 components are assessed in the five segments of the ileum and colon:  
ileum, right, transverse, left (descending and sigmoid), and rectum. The SES-CD is the sum of the 
individual scores of each of the components across the five segments.  Sub-scores for each segment 
will be derived and used to create SES-CD. 
SES-CD sub-scores 
 SES-CD rectum 
 SES-CD left colon 
 SES-CD transverse colon 
 SES-CD right colon 
 SES-CD ileum 


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APPENDIX 3. 
CDAI SCORE CALCULATIONS 
The Crohn’s Disease Activity Index (CDAI) is a composite score that is used to measure the clinical 
activity of Crohn’s disease.  The CDAI uses a questionnaire with responses scored numerically and 
weighted.  Scores typically range from 0 to approximately 600, with higher scores indicating greater 
disease activity.  The 8 components used to assess the CDAI, their weighting factors and calculation 
rules are noted in the table below. The number of stools, abdominal pain and general well-being are 
patient-reported outcomes which will be entered daily into an e-diary by patients. The Hematocrit 
component will be coming from the lab data and the other 4 components will be entered by the site 
at each visit. 
Table 10. Score calculations, weights, and rules associated with  
CDAI, its components, and associated endpoints 
Item 
Weight 
Algorithm 
Number of liquid or 
soft stools 
(CDAI sub-score) 
2 
 Use the most recent 7 days prior to the visit date in 
Rave EDC database; excluding the day prior and the 
day of the endoscopy, as applicable. 
 
 Define: SF = average daily stool score = average of 
the number of liquid/soft stools for the available days 
in the 7-day window 
 
 If there are less than 3 days with non-missing values, 
then set SF to missing 
 
 If there are 7 days of data available, then the CDAI 
sub-score is equal to the sum of the 7 days*2; 
otherwise, the CDAI sub-score is equal to the average 
daily stool score*7*2; as a formula, this is written as 
 
CDAI sub-score = SF*7*2 
 
in both cases 
 
Abdominal pain 
(CDAI sub-score) 
5 
 Use the most recent 7 days prior to the visit date in 
Rave EDC database; excluding the day prior and the 
day of the endoscopy, as applicable. 
 
 Define: AP = average daily abdominal pain score = 
average of the abdominal pain level for the available 
days in the 7-day window 
 
 If there are less than 3 days with non-missing values, 
then set AP to missing 
 


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 If there are 7 days of data available, then the CDAI 
sub-score is equal to the sum of the 7 days*5; 
otherwise, the CDAI sub-score is equal to the average 
daily abdominal pain score*7*5; as a formula, this is 
written as  
 
CDAI sub-score = AP*7*5 
 
in both cases 
 
General well-being 
(CDAI sub-score) 
7 
 Use the most recent 7 days prior to the visit date in 
Rave EDC database; excluding the day prior and the 
day of the endoscopy, as applicable. 
 
 Define: GW = average daily general well-being score 
= average of the general well-being level for the 
available days in the 7-day window 
 
 If there are less than 3 days with non-missing values, 
then set GW to missing 
 
 If there are 7 days of data available, then the CDAI 
sub-score is equal to the sum of the 7days*7; 
otherwise, the CDAI sub-score is equal to the average 
daily general well-being score *7*7; as a formula, this 
is written as 
 
CDAI sub-score = GW*7*7 
 
in both cases 
 
Presence of 
complications* 
(CDAI sub-score) 
20 
 Sum=Total of the number of checked complications 
 CDAI sub-score = Sum * 20.  
 
Taking diarrhea 
meds* 
(CDAI sub-score) 
30 
 Variable: Yes=1; No=0 
 CDAI sub-score = Variable * 30 
 
Abdominal mass* 
(CDAI sub-score) 
10 
 Variable: No=0; Questionable=2; Definite=5 
 CDAI sub-score = Variable * 10 
 
Hematocrit 
(CDAI sub-score) 
6 
 Hematocrit (HCT) is obtained from the Hematology 
lab panel and can be found in the SDTM LB domain 


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 If HCT is missing, use the last non-missing value 
immediately preceding the time point; if the 
immediately preceding time point value is missing too, 
then set to missing 
      Men: CDAI sub-score = (47 - HCT) * 6 
 Women: CDAI sub-score = (42 - HCT) * 6 
 If CDAI sub-score is < 0, it will be recorded as 0 
 
 
Percentage deviation 
from standard weight 
(CDAI sub-score) 
1 
 The standard weight table was provided by Celgene to 
ERT for integration into the SitePro tablet algorithms 
(height in cm and weight in kg); ERT created four 
conversion tables which will be used in statistical 
analysis so that the %deviation from standard weight 
is automatically calculated by the ERT system, which 
allows ERT to calculate estimated CDAI scores 
embedded in their monthly SitePro.sas7bdat datasets.  
It is noted that these are CDAI estimates only and not 
for use in production TFLs. 
 If weight is missing, use the last non-missing 
%deviation from standard weight value immediately 
preceding the time point; if the immediately preceding 
time point value is missing too, then set %deviation 
from standard weight to missing   
 CDAI sub-score = %deviation from standard weight; it 
should be >=-10 (i.e., -10, -9; if calculated value is <-
10, it will be recorded as -10) in all cases 
 
 
CDAI  
(CDAI endpoint) 
n/a 
 
 CDAI endpoint = sum of the above 8 CDAI sub-
scores. If any of the 8 sub-scores are missing, then the 
CDAI endpoint score is missing. 
 
PRO2 
(CDAI associated 
endpoint) 
n/a 
 
 PRO2 = weighted sum of SF and AP = SF*7*2 + 
AP*7*5. If either SF or AP are missing, then PRO2 is 
missing.  
 
SF/AP  
(CDAI associated 
endpoint – included 
only for reference) 
n/a 
 
 SF/AP = unweighted sum of SF and AP = SF + AP.  If 
either SF or AP are missing, then SF+AP is missing.  
 
*: The visit date that is used to calculate the relative study day will be taken from Rave, instead of the 
system generated date in Sitepro.  


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In computing number of liquid or soft stools, abdominal pain, and general well-being, the date 
corresponding to Day 1 will be used as the baseline date. Dates for post-baseline visits will be 
obtained from the dates when CDAI components of extra-intestinal manifestations, opiate for 
diarrhea, abdominal mass findings, and weight were assessed at the site. 
For computing the CDAI total, following steps are followed for combining the individual 
components: 
 For Baseline visit, the components excluding hematocrit will be merged by patient, visit, and 
analysis date.  For post-Baseline visits, components excluding hematocrit will be merged by 
patient, visit, analysis visit, analysis date, and imputation.  Then the seven components are 
summed. 
 Merge with hematocrit values by patient for the analysis visit at Baseline, and patient, visit, 
analysis visit, analysis date, and imputation, for post-Baseline visits.  
 Add hematocrit value to the sum of the seven components from previous steps. 


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APPENDIX 4. 
GEBOES HISTOLOGY ACTIVITY INDEX AND 
ROBARTS HISTOPATHOLOGY INDEX 
The following tables give details of the scoring for the Global Histologic Disease Activity Score 
(GHAS)3,4 and a newly developed scoring system entitled the Robarts Histopathology Index (RHI)5.  
Higher numbers correspond to more inflammation and mucosal damage.  For each CD segment, the 
GHAS score can be treated as a continuous measure on a 16 point scale.  For each CD segment, the 
RHI score can be treated as a continuous measure on a 33 point scale.  Scoring for both indices will 
be performed for each segment (i.e., ileum, right, transverse, left (descending and sigmoid), and 
rectum) that is visualized and for which biopsy samples are available.  Similar to the SES-CD, sub-
scores for each segment will be derived. 
The eight components used to assess the per-CD segment GHAS score are noted in the table below.  
The maximum per-CD segment total score is 16. 
 
 
                                                 
 
 
 


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Table 11. GHAS Grading System 
GHAS Descriptors and Levels 
Epithelial damage 
0: Normal 
1: Focal Pathology  
2: Extensive Pathology 
Architectural changes 
0: Normal 
1: Moderately disturbed (<50%)  
2: Severely disturbed (>50%) 
Infiltration of mononuclear cells in the lamina 
propria 
0: Normal 
1: Moderately increase  
2: Severe increase 
Infiltration of polypmorphonuclear cells in the 
lamina propria 
0: Normal 
1: Moderately increase  
2: Severe increase 
Polypmorphonuclear cells in epithelium 
0: Normal 
1: In surface epithelium 
2: Cryptitis 
3: Crypt abscess 
Presence of erosion and/or ulcers 
0: No 
1: Yes 
Presence of granuloma 
0: No 
1: Yes 
Number of biopsy specimens affected 
0: None (0 of 6) 
1: ≤3% (1 or 2 of 6) 
2: 33-66% (3 or 4 of 6) 
3:>66% (5 or 6 of 6) 
1 
 
 
 
 
 
  
 
 
 
Exploratory GHAS Histologic Remission (no active inflammation in a measured segment) is defined 
in the following table, where the max overall GHAS score in a given segment must be less than or 
equal to 8, and each segment meets this standard: 
 
 


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Table 12.  Per-CD Segment GHAS Scores Allowed for Histologic Remission  
Epithelial damage 
0 
Architectural changes 
0-2 
Infiltration of mononuclear cells in the lamina 
propria 
0-2 
Infiltration of polypmorphonuclear cells in the 
lamina propria 
0 
Polypmorphonuclear cells in epithelium 
0 
Presence of erosion and/or ulcers 
0 
Presence of granuloma 
0-1 
Number of biopsy specimens affected 
0-3 
 
The four components used to assess the per-CD segment RHI score are noted in the table below.  
The maximum per-CD segment total score is 33. 
Table 13. Robarts Histopathology Index (RHI) Grading System 
Subcomponent 
Descriptors 
Scores 
Weighting 
factor 
Chronic 
inflammatory 
infiltrate 
0=No increase 
1=Mild but unequivocal increase 
2=Moderate increase 
3=Marked increase 
1 
Lamina propria 
neutrophils 
0= None 
1= Mild but unequivocal increase 
2=Moderate increase 
3=Marked increase 
2 
Neutrophils in 
epithelium 
0=None 
1 = <5% crypts involved 
2= <50% crypts involved 
3= >50% crypts involved 
3 
Erosion or 
ulceration 
0=No erosion, ulceration or granulation tissue 
1=Recovering epithelium + adjacent 
inflammation OR probable erosion-focally 
stripped 
2=Unequivocal erosion 
3=Ulcer or granulation tissue 
5 
 
An exploratory RHI Histologic Remission (no active inflammation in a measured segment) is 
defined in the following table. The maximum per-CD segment RHI score allowable for a segment to 
qualify for RHI Histologic Remission is 3. A patient not meeting at least one of the criteria 2, 3, or 4, 
below in a segment is defined as a non-RHI remitter for that segment. Note that criteria 1 is always 
met.  


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Table 14. Per-CD Segment RHI Scores Allowed for Histologic Remission 
Subcomponent Descriptors 
Scores 
Weighting 
factor 
Chronic inflammatory infiltrate 
0-3 
1 
Lamina propria neutrophils 
0 
2 
Neutrophils in epithelium 
0 
3 
Erosion or ulceration 
0 
5 
 
Global RHI Score 
Global RHI Score is a weighted sum of the worst, i.e., the highest, of each of the four disease 
component scores across the four colonic segments, rectum, left colon, transverse colon, and right 
colon. Same weighting factors used in computing the RHI Score is used. 
 
Global RHI Score =1x highest Chronic inflammatory infiltrate score + 2x highest Lamina propria 
neutrophils score + 3x highest Neutrophils in epithelium score + 5x highest Erosion or ulceration 
score. 
 
 
  
 
 
 
 


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APPENDIX 5. 
DOCUMENT REVISION HISTORY 
Version Date 
Notes/Revisions 
1.0 
March 03 2016 
Initial version. 
1.1 
November 23 2016 
Updated with details and additional analyses.   
1.2 
January 26 2017 
Updated with details on missing data and other details.   
1.3 
June 1, 2018 
Updated to reflect the Week 12 and Week 52 summary 
tables generated for topline analyses, definition of 
treatment failure, as well as to reflect endpoint 
alterations and additional details regarding CDAI, SES-
CD, GHAS, and RHI algorithms. Analysis of 
compliance rate categories has been excluded. 
 
Following endpoints have been removed from the SAP 
 PRO CD SF+AP response-25 
 PRO CD SF+AP response-50 
 PRO CD SF+AP response-30 + 2P 
 PRO2 CD response-25 
 SF&AP clinical response-2 
 SF&AP clinical response-1 
 Endoscopic remission-2 
 Histologic improvement 
 Histologic response 
 
Following endpoints have been added to the SAP 
 CRP-response-10 
 FCP response-250 
 Fistula Response  
 GHAS Improvement 
 GHAS Remission 
 RHI Improvement 
 RHI Response  
 RHI Remission 
 Global RHI Score 
 RHI Mucosal Healing 
 
1.4 
August 28, 2019 
LOCF removed. 
Treatment Failure rule is used in NRI  
Efficacy graphs added 
 
1.5 
January 06, 2020 
Changes from data review meeting 
 PFT abnormality has been revised 
 Missing segment imputation of SES-CD has 
been added 


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 Lower bound of 0 for Hematocrit sub-score of 
CDAI has been added 
 Treatment failure criteria has been revised 
 RHI response analysis on all patients has been 
removed 
 RHI remission by segment for subset of segment 
score > 3 is replaced by RHI remission by 
segment for non-RHI remitters 
 CRP Change among patients having CRP ≥ 10 
mg/L at Baseline has been added 
 Analysis window has been added to Safety 
follow-up visits 
 Unscheduled and early termination visits are 
included in all analysis windows 
 Patients requiring cardiac monitoring is 
determined programmatically  
 Listing of non-trial procedures added 
 Section on PK analysis is removed and 
combined with Section on PD  
 Description of SDTM data in Section 5 is 
removed